Addiction Neuroethics: The Promises and Perils of Neuroscience Research on Addiction (International Research Monographs in the Addictions)

ADDICTION NEUROETHICS The Promises and Perils of Neuroscience Research on Addiction

international research monographs in the addictions (irma) Series Editor Professor Griffith Edwards National Addiction Centre Institute of Pyschiatry, London Volumes in this series present important research from major centres around the world on the basic sciences, both biological and behavioural, that have a bearing on the addictions. They also address the clinical and public health applications of such research. The series will cover alcohol, illicit drugs, psychotropics and tobacco. It is an important resource for clinicians, researchers and policy makers. Also in this series: The Life of the Heroin User: Typical Beginnings, Trajectories and Outcomes Shane Darke ISBN 9781107000636 Mortality amongst Illicit Drug Users: Epidemiology, Causes and Intervention Shane Darke, Louisa Degenhardt and Richard Mattick ISBN 9780521855068 Treatment Matching in Alcoholism Edited by Thomas F. Babor and Frances K. Del Boca ISBN 9780521177269 Cannabis Dependence: Its Nature, Consequences and Treatment Edited by Roger Roffman and Robert S. Stephens, Foreword by G. Alan Marlatt ISBN 9780521891363 Gambling as an Addictive Behaviour: Impaired Control, Harm Minimisation, Treatment and Prevention Mark Dickerson and John O’Connor ISBN 9780521847018 Circles of Recovery: Self-Help Organizations for Addictions Keith Humphreys ISBN 9780521176378 A Community Reinforcement Approach to Addiction Treatment Edited by Robert J. Meyers and William R. Miller ISBN 9780521026345 Cannabis and Cognitive Functioning Nadia Solowij ISBN 9780521024808 Alcohol and the Community: A Systems Approach to Prevention Harold D. Holder ISBN 9780521035040

ADDICTION NEUROETHICS The Promises and Perils of Neuroscience Research on Addiction

ADRIAN CARTER AND WAYNE HALL

cambridge university press Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, Sa˜o Paulo, Delhi, Tokyo, Mexico City Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9781107003248 # Adrian Carter and Wayne Hall 2012 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 2012 Printed in the United Kingdom at the University Press, Cambridge A catalogue record for this publication is available from the British Library Library of Congress Cataloging-in-Publication Data Carter, Adrian. Addiction neuroethics: the promises and perils of neuroscience research on addiction / Adrian Carter and Wayne Hall. p. cm. – (International research monographs in the addictions) ISBN 978-1-107-00324-8 (Hardback) 1. Drug addiction. 2. Neurosciences–Moral and ethical aspects. I. Hall, Wayne. II. Title. III. Series. HV5801.C34 2012 174.20 8–dc23 2011026105 ISBN 978-1-107-00324-8 Hardback Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

To Donna and Pat

Contents

Preface Acknowledgements List of abbreviations

page xv xix xxi

Chapter 1. Introduction 1.1. Introduction 1.1.1. Neuroethics: the promises and perils of neuroscience research 1.2. Addiction enters the neuroscientific era 1.3. Aims and overview Part 1. The Science of Addiction Chapter 2. What is addiction? 2.1. Introduction 2.2. The phenomenology of addiction 2.2.1. Folk understanding of addiction 2.2.2. Clinical understanding of addictive behaviour 2.3. The social and economic costs of drug use and addiction 2.3.1. Prevalence of drug use and addiction in Australia 2.3.2. Drug use related harm 2.3.3. Burden of disease due to alcohol and drug use 2.4. Social response to drug abuse and addiction 2.5. Governing models of addiction 2.5.1. Moral vs. medical models of addiction 2.5.2. Neurobiological models of addiction 2.5.3. Potential consequences of neurobiological explanations of addiction 2.6. Conclusion

1 1 4 7 10

19 19 20 21 21 23 23 24 25 26 28 28 31 32 34 vii

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Contents

Chapter 3. The neurobiology of addiction 3.1. Introduction 3.2. The neuroanatomy of addiction 3.2.1. Reward and reinforcement: the ‘dopamine hypothesis’ 3.2.2. The endogenous opioid system 3.3. Memory, learning and habits 3.4. Compulsion, craving and inhibitory control 3.5. Executive control and cognitive impairment 3.6. Representing bodily urges 3.7. Stress and drug use 3.8. Molecular and cellular changes in addiction 3.8.1. Synaptic plasticity in addiction 3.8.2. Epigenetic changes in addiction 3.9. Vulnerability to addiction: genetic and neuropsychological factors 3.9.1. Genetic susceptibility to addiction 3.9.2. Vulnerabilities to addiction: a confluence of the genetic and the social 3.10. Conclusion

35 35 36

Chapter 4. Neurobiological treatment of addiction 4.1. Introduction 4.2. Pharmacological treatments that block drug binding 4.2.1. Agonists 4.2.2. Antagonists 4.2.3. Partial agonists 4.2.4. Duration of pharmacological treatment of addiction 4.3. Pharmacological treatments of withdrawal 4.4. Pharmacological treatments of craving and relapse 4.4.1. Dopaminergic mesolimbic reward pathway 4.5. Pharmacological interventions in systems related to the reward pathway 4.5.1. Opioids 4.5.2. The amino acid neurotransmitters: glutamate and GABA 4.5.3. Cannabinoids

61 61

38 45 46 47 47 50 50 51 52 53 55 55 57 59

62 62 66 67 68 69 70 70 72 72 73 74

Contents

ix

4.6. 4.7.

4.8. 4.9.

4.5.4. Corticotropin-releasing factor and the stress response 4.5.5. Memory manipulators and cognitive enhancers Pharmacogenetic treatment of addiction Novel approaches to drug treatment 4.7.1. Immunotherapies 4.7.2. Long-acting or sustained-release medications 4.7.3. Neurosurgery and deep brain stimulation 4.7.4. Transcranial magnetic stimulation 4.7.5. Applications of neuroimaging and neurocognitive screening in addiction treatment Psychosocial treatment of addiction Conclusion

Part 2. The Ethical and Philosophical Implications of Neuroscientific Knowledge of Addiction Chapter 5. Autonomy, addiction and the public good 5.1. Introduction 5.2. Approaches to ethical analysis 5.2.1. Introduction to ethics 5.2.2. Principlism 5.2.3. Human rights 5.2.4. A pragmatic approach to neuroethics 5.3. Ethical principles in the treatment of addiction 5.3.1. Autonomy and addiction 5.3.2. Addiction and the public good 5.4. The minimum conditions for the ethical treatment of addiction 5.5. Conclusion Chapter 6. Autonomy and the capacity to consent to addiction treatment 6.1. Introduction 6.2. The role of informed consent in addiction treatment 6.3. Can ‘addicts’ say ‘no’ to drugs? 6.3.1. Sceptical views of impaired autonomy in addicted individuals 6.3.2. Capacity to consent to abstinence-oriented treatment

74 75 75 76 76 77 78 79 79 81 81

85 85 87 87 90 94 95 97 99 101 102 103

105 105 106 108 113 114

x

Contents 6.4. Implications for obtaining informed consent to enter addiction treatment 6.5. Guidelines when admitting individuals into addiction treatment 6.6. Conclusion

Chapter 7. The rights of individuals treated for addiction 7.1. Introduction 7.2. Addiction, drug policy and human rights 7.2.1. Basic human rights for addicted individuals 7.3. The right to access to effective treatment of addiction 7.3.1. The case for medical treatment of addiction 7.3.2. Effective treatment of addiction 7.3.3. The right to access harm reduction measures 7.3.4. The right to effective medical treatment 7.4. The use of unevaluated and risky treatments of addiction 7.5. Respecting human rights when treating under legal coercion 7.6. Human rights in the treatment of addicted prisoners 7.7. Human rights in the treatment of addicted pregnant women 7.8. Future challenges for human rights practitioners 7.9. Conclusions

115 117 119 121 121 122 123 124 124 125 126 127 128 129 130 131 132 133

Chapter 8. Coerced treatment of addiction 134 8.1. Introduction 134 8.2. Approaches to coerced treatment 135 8.3. The case for legally coerced treatment 136 8.4. When is coerced treatment ethical? 138 8.5. Ethical issues in providing coerced addiction treatment 142 8.6. Is compulsory addiction treatment ethically acceptable? 142 8.7. Conclusion 144 Chapter 9. Ethics of addiction research 9.1. Introduction 9.2. Informed consent to participate in addiction research 9.3. Paying addicted subjects

146 146 148 150

Contents

xi 9.4. Privacy, confidentiality and anonymity 9.5. Administering addictive drugs in research studies 9.5.1. Why do neuroscientists give drugs to ‘addicts’? 9.5.2. The risks of giving ‘addicts’ drugs in research settings 9.5.3. Research participation by treated vs. untreated ‘addicts’ 9.5.4. Recruiting subjects and obtaining consent 9.6. Conclusion

Part 3. The Ethical and Public Policy Implications of Novel Technologies for the Treatment of Addiction Chapter 10. New developments in the treatment of addiction 10.1. Introduction 10.2. Novel pharmacological treatments of addiction 10.2.1. Ethical and policy issues in pharmacological R&D in addiction 10.2.2. Anti-craving drugs 10.3. Novel relapse prevention treatments 10.3.1. Drug vaccines as a prophylaxis against relapse 10.3.2. Sustained-release treatments: depot medications and drug implants 10.3.3. The Australian naltrexone implant experience 10.3.4. Coerced use of depot naltrexone to ‘restore autonomy’? 10.4. Conclusion Chapter 11. The search for a neurological ‘cure’ of addiction? 11.1. Introduction 11.2. A brief history of addiction ‘cures’ 11.2.1. Quacks and nostrums: 1830–1900 11.2.2. Early medical treatments of drug withdrawal: 1900–1970 11.3. The modern era: neurobiologically inspired addiction ‘cures’ 11.3.1. Ibogaine therapy 11.3.2. Ultra-rapid opioid detoxification

152 153 154 156 157 158 160

165 165 167 168 169 170 170 173 176 176 179 180 180 181 181 183 185 186 187

Contents

xii 11.3.3. Neurosurgical ‘treatment’ of addiction 11.4. Deep brain stimulation for intractable addiction? 11.5. Avoiding future therapeutic enthusiasms

Chapter 12. Preventive medicine and personalised treatment of addiction 12.1. Introduction 12.2. Bioprediction of addiction liability 12.2.1. Predictive genetic testing of addiction liability 12.2.2. Using genetic information to increase abstinence from drug use 12.2.3. Genetic discrimination and third party uses of genetic information 12.2.4. Premature commercialisation of genetic testing 12.2.5. Preventive interventions: ‘vaccinating’ against addiction 12.2.6. Predictive uses of neuroimaging technologies 12.3. Personalised treatment of addiction 12.3.1. Pharmacogenetic treatment of addiction 12.3.2. Neuroimaging and cognitive tests in the clinic 12.4. Conclusion Chapter 13. Feeling better than well 13.1. Introduction 13.2. Memory modifiers, cognitive enhancers and mood modulators 13.3. What’s wrong with neuroenhancement? 13.3.1. Concerns about safety and efficacy 13.3.2. Coerced neuroenhancement: a psychopharmacological ‘arms race’ 13.3.3. Equity of access to neuroenhancement technologies 13.3.4 Naturalistic objections to enhancement: morality and personhood 13.4. Lessons from recreational drug use and drug policy 13.5. The future of drug regulation 13.6. Conclusion

187 190 195

197 197 197 198 200 202 204 206 207 208 209 211 213 214 214 214 216 217 218 219 220 221 223 225

Contents Part 4. The Future of Addiction Research and Policy Chapter 14. The social and policy implications of addiction neurobiology 14.1. Introduction 14.2. Implications for public health policies towards drug addiction 14.3. Medicalisation of addiction 14.4. Neuroscience, addiction treatment and public health policy 14.4.1. Competing population health strategies 14.4.2. Subversive uses of neuroscience research on addiction 14.5. Drug policy and double standards 14.6. The prospects of novel pharmacological harm reduction: engineering ‘safer’ recreational drugs? 14.7. Conclusions

xiii

229 229 229 230 232 233 234 237 240 242

Chapter 15. Concluding remarks and summary 15.1. Introduction 15.2. Summary and conclusion 15.2.1. Key findings 15.2.2. Specific implications for the treatment of addiction 15.3. Neuroscience and the media: the role and responsibility of neuroscientists 15.4. The tasks ahead for ethicists and policy makers 15.5. Future directions for addiction neuroethics 15.5.1. Private and public understanding of addiction neuroscience 15.5.2. Capacity to consent in a research or treatment setting 15.5.3. Epidemiological modelling of addiction policy 15.5.4. Using incentives to reduce drug use and achieve better health outcomes 15.6. Conclusion

244 244 244 247

Glossary Bibliography Index

264 275 331

250 254 256 258 259 260 261 262 262

Preface

This book aims to provide a systematic analysis of the social and ethical implications of neuroscience research on addiction that will be of interest to a wide range of audiences. This includes those interested in, or working within, the fields of addiction and mental health, such as clinicians and health care professionals treating addiction and mental disorders, addiction researchers from neuroscience, psychology and the social sciences, lawyers, policy makers and public health educators. It should also be of interest to bioethicists, neuroethicists and others working in applied philosophy, who want to understand how neuroscience may affect society and public policy. Addiction Neuroethics is designed to be accessible to advanced undergraduate and post-graduate students in philosophy and ethics, medicine and psychiatry, psychology, social work, nursing and law, and educated general readers who want to learn more about the impact that drug use might have on the brain and on our ability to control our behaviour. In 1997, the then director of the National Institute on Drug Abuse, Alan Leshner, famously proclaimed that ‘addiction is a brain disease, and it matters’. Neuroscience research, Leshner promised, would revolutionise our ability to treat addiction and lead to greater acceptance by society of addiction as a psychiatric disorder, increasing access to medical treatment and decreasing societal discrimination and stigma affecting those suffering from addiction. Neuroscience research would put to an end claims that addiction was simply an excuse for engaging in immoral or weak-willed behaviour, and produce more humane and therapeutic approaches to addiction. Unfortunately, these optimistic predictions have yet to be realised. Most addicted individuals do not receive adequate medical or therapeutic assistance, even in developed countries. There is some evidence that negative attitudes toward ‘addicts’ have hardened with increasing acceptance of neurobiological models of psychiatric disorders. Some commentators have also begun to point out some potentially adverse consequences of the view that addiction is a brain disease. For example, an unqualified acceptance of the brain disease model of addiction carries substantial social policy risks: xv

xvi

Preface

• It focuses on addiction to the exclusion of other adverse effects of drug use (e.g. drug-related accidents, violence or drug-induced mental illness). • It may unwittingly promote a policy preference for biological treatment of addicted individuals over effective social policies to minimise drug use and addiction (e.g. taxation, barriers to access). • It may be seen as warranting experimentation with neurosurgical interventions in brain function to ‘cure’ addiction, as has happened in the case of neurosurgery and deep brain stimulation. • It may also increase the use of coercive forms of treatment for addicted persons whose capacity to make free and informed choices is said to be seriously impaired by their ‘brain disease’. These outcomes are already providing challenges to health care workers, scientists and policy makers working in the field of addiction. They have the potential to cause unanticipated harm to those who suffer from an addiction and lead to misguided social policies that may paradoxically increase drug-related harm. Such misuses of neuroscience research may also lead to community scepticism or mistrust of neuroscience and neuroscientists, impeding the timely translation of research into beneficial treatments and policy. According to many neuroscientists, addiction is a condition where repeated use of addictive drugs produces changes in the brain that undermine an addicted individual’s ability to control their drug use. According to prominent psychiatrists Charles Dackis and O’Brien, the brains of addicted individuals have been ‘hijacked’ by the drug. ‘Addicts’, they argue, are neurochemically driven to repeatedly consume drugs, despite the harm that their use causes to themselves and those around them. Such views question philosophical concepts such as free will, agency and responsibility. The ethical, social and public policy implications of addiction neuroscience will also provide instructive case studies for examining the broader neuroethical implications of neuroscience for society. A detailed consideration of the ethical, social and policy challenges raised by neuroscience research is essential if we are to realise some of Leshner’s promises about addiction neuroscience, with minimal delay and without causing harm. Our aim is to provide an accessible analysis of these challenges raised by developments in neuroscience, and, when possible, to offer guidelines and recommendations to those treating addicted individuals, conducting addiction research, seeking policy solutions, or simply affected by their own or a family member’s addictive drug use.

Preface

xvii

We have four major objectives that are reflected in the four parts of this book. First, we critically review neuroscience research on addiction, from genes and molecular and cellular biology through to neuropsychology and cognitive neuroscience. We examine the impact that addictive drug use has on decision-making and control over behaviour. We also include evidence from the social and historical sciences to provide a social context to our analysis of the neuroscience. This is both a synthetic and an analytical project: it aims to bring together information and research from a range of disciplines in order to better understand the potential social impacts of neuroscience research on addiction. Second, based on this review, we provide clear practical recommendations for treating addiction and dealing with addicted individuals, such as: • Entering addicted individuals into treatment • Providing treatments, including harm reduction programs, in a fair and equitable manner • The use of coercion in treating addiction • Conducting neuroscience research with addicted individuals Third, we examine the latest developments in neurobiological treatments of addiction to identify the ethical, social and policy issues that their potential future use may raise. These include: • • • • •

Novel psychopharmacological treatments Sustained-release medications (e.g. drug implants and depot injections) Drug vaccines to prevent relapse Neurosurgical treatments (e.g. deep brain stimulation) Genetic screening and neuroimaging to identify those vulnerable to developing addiction

Based on this analysis, we provide ethical guidelines for conducting research on these interventions and for their clinical use, should they prove safe and effective. Finally, we consider some unwelcome consequences of the misuse of neuroscience research for social and public health policy. These include: a focus on medical responses to addiction targeted at vulnerable individuals at the expense of more broadly effective population approaches; and the potential misuse of neuroscience research by the alcohol, tobacco and gambling industries to influence public policy in directions favourable to their interests. This book is only a beginning; we raise many questions that will require much more research and analysis. We therefore conclude the book with some suggestions for future research in the field of Addiction Neuroethics.

Acknowledgements

This book is an expanded and updated version of Adrian Carter’s Doctoral Dissertation submitted to the Queensland Brain Institute, The University of Queensland in 2009. It builds on Wayne Hall’s long-standing interests in the ethical, social and policy issues raised by research on addiction, initially as the Director of the National Drug and Alcohol Research Centre, University of New South Wales, and more recently as NHMRC Australia Fellow and Director of the Addiction Neuroethics Unit, The University of Queensland Centre for Clinical Research. There are many researchers and colleagues who we are indebted to for their kind support and insight during the research and preparation of this book. We would like to sincerely thank Judy Illes and Eric Racine for their ongoing support and encouragement for this project. They have been invaluable in highlighting the importance of Addiction Neuroethics as well as providing important reflections on our arguments. We would also like to offer our appreciation to the following for comments and insights on earlier drafts of the material in this book: Perry Bartlett, Director of the Queensland Brain Institute for funding Adrian Carter’s post-graduate research and his support throughout his thesis; Benjamin Capps, David Nutt and Richard Ashcroft who we collaborated with on a project for EMCDDA and who made important contributions on many parts of this research; Robert Hester, Craig Fry and Murat Yucel at The University of Melbourne; Dan Lubman at Turning Point, Melbourne; Mark Daglish of The University of Queensland; and Peter Miller at Deakin University. We would like to thank the two anonymous reviewers for their thoughtful comments on the proposal for this book, as well as the staff at Cambridge University Press (particularly Joanna Chamberlin). We would also like to thank colleagues at the Addiction Neuroethics Unit, UQ Centre for Clinical Research for their ongoing support and editorial advice: Jayne Lucke, Coral Gartner, Brad Partridge, Sarah Yeates, Rebecca Mathews and Stephanie Bell. We would also like to thank both our friends and families. Last but not least, we would offer our most sincere appreciation to Donna and Pat, without whose unflinching support, this book would not be possible. Any errors or omissions that remain, however, are solely the responsibility of the authors. xix

xx

Acknowledgements

Portions of Chapters 3 and 4 previously appeared in Carter, A., Capps, B., Nutt, D., ter Muelen, R., Ashcroft, R. and Hall, W. (2009) Addiction neurobiology: ethical and social implications, European Monitoring Centre for Drugs and Drug Addiction, Lisbon. Portions of Chapters 5 and 8 previously appeared in Carter, A. and Hall, W. (2007) The ethical use of psychosocially assisted pharmacological treatment of opioid dependence, World Health Organization, Geneva. Portions of Chapters 6 and 9 previously appeared in Carter, A. and Hall, W. (2008) The issue of consent to research that administers drugs of addiction to addicted persons, Accountability in Research, 15, 209–225 and Carter, A. and Hall, W. (2008) Informed consent to opioid agonist maintenance treatment: recommended ethical guidelines, International Journal of Drug Policy, 19, 79–89. Chapter 8 originally appeared in Mental health and human rights (Eds, Dudley, D., Silvoe, D. and Gale, F.) Oxford University Press, London, (2012). Portions of Chapter 10 previously appeared in Hall, W., Capps, B. and Carter, A. (2008) The use of depot naltrexone under legal coercion: the case for caution, Addiction, 103, 1922–1924. Portions of Chapter 11 previously appeared in Carter, A. and Hall, W. (2011). Proposals to trial deep brain stimulation to treat addiction are premature, Addiction, 106, 235–237 and Carter, A., Bell, E., Racine, E., and Hall, W. (2010) Ethical issues raised by proposals to treat addiction using deep brain stimulation, Neuroethics, 1–14. Portions of Chapter 12 previously appeared in Hall, W., Gartner, C. and Carter, A. (2008) The genetics of nicotine addictions liability: ethical and social policy implications, Addiction, 103, 350–359.

Abbreviations

aCG ADH ADHD AIDS ALDH AU$ BBV BOD CB1 CB2 COMT CRF D1, D2, D3, D4 DA DALYs DAT DBS DDS DNA DSM-III-R DSM-IV-TR DSM-V EAP ECT EEG EMCDDA

Anterior cingulate gyrus Alcohol dehydrogenase Attention deficit hyperactivity disorder Acquired immune deficiency syndrome Aldehyde dehydrogenase Australian dollars Blood-borne virus Burden of disease Cannabinoid receptor 1 Cannabinoid receptor 2 Catechol-O-methyl transferase Corticotropin-releasing factor Dopamine receptors 1, 2, 3 and 4 Dopamine Disability adjusted life years Dopamine transporter Deep brain stimulation Dopamine dependence syndrome Deoxyribonucleic acid Diagnostic and Statistical Manual for Mental Disorders, 3rd Edition, Revised Diagnostic and Statistical Manual for Mental Disorders, 4th Edition, Text Revised Diagnostic and Statistical Manual for Mental Disorders, 5th Edition Employment assistance programs Electroconvulsive therapy Electroencephalograph European Monitoring Centre for Drugs and Drug Addiction

xxi

xxii FDA fMRI GABA GHB HIV HCV HPA Axis HRT ICD ICD-10 IDU LSD LTD LTP MDMA MEG MOR MMT NAC NAcc NIAAA NIDA NMDA NRT OCD OFC PCP PD PET PFC PTSD RNA SPECT SSRI TMS UDHR UK UN UNAIDS

List of abbreviations US Food and Drug Administration Functional magnetic resonance imaging Gamma-aminobutyric acid Gamma-hydroxybutyric acid Human immunodeficiency virus Hepatitis C virus Hypothalamic–pituitary–adrenal axis Hormone replacement therapy Impulse control disorder International Classification of Disease, 10th Edition Injecting drug user Lysergic acid diethylamide Long-term depression Long-term potentiation 3,4-Methylenedioxy-N-methylamphetamine Magnetoencephalograph Mu-opioid receptor Methadone maintenance treatment N-acetylcystein Nucleus accumbens National Institute on Alcoholism and Alcohol Abuse National Institute on Drug Abuse N-methyl-D-aspartic acid Nicotine replacement therapy Obsessive compulsive disorder Orbitofrontal cortex Phencyclidine Parkinson’s disease Positron emission tomography Prefrontal cortex Post-traumatic stress disorder Ribonucleic acid Single photon emission computed tomography Serotonin selective reuptake inhibitors Transcranial magnetic stimulation Universal Declaration of Human Rights United Kingdom United Nations United Nations Joint Program on HIV/AIDS

List of abbreviations UNODC UROD US VTA WHO

United Nations Office on Drugs and Crime Ultra-rapid opioid detoxification United States Ventral tegmental area World Health Organisation

xxiii

1 Introduction

1.1.

Introduction

The brain is often seen as critical to our identity, the organ of individuality and mind that gives us our unique thoughts, personality and behaviour (Kagan, 2006). Understanding the mind in biological terms has become a principal concern for biological science in the 21st century (Kandel, 2006). Scientists have uncovered many of the changes in the brain that are associated with thought, cognition and behaviour in healthy individuals and in those suffering from psychiatric and neurological disorders. From this new understanding, novel neurological technologies are emerging with the potential to manipulate brain function in the hope of ameliorating, curing or preventing neurological and psychiatric disorders. Despite these epistemological and technological advances, there are important questions that remain unanswered: • Does our brain explain everything about us, or about our mind? • What are the implications of neuroscience research for our self-hood and agency? • How do neurobiological explanations affect a mentally ill individual’s self-understanding of their disease, their responsibility for their behaviour or their ability to overcome it? • How do neurobiological explanations affect our beliefs about the origins or causes of mental illness? • How should societies respond to mental illness in light of neurobiological explanations of mental illness? For some, neuroscience raises doubts about some of our most fundamental assumptions about freedom of the will and agency. Do we act wilfully, or is this simply an illusion, an epiphenomenon of brain events outside our

1

2

Addiction Neuroethics

consciousness? Are we simply neurobiological automatons at the mercy of the state of our neural circuits? This issue is particularly pertinent in the case of psychiatric disorders, such as addiction, where control over behaviour is seen by some as having been compromised by a ‘disease of the brain’ (Leshner, 1997). In everyday life, most people act on an implicit folk psychology in which they assume that they control their own behaviour. Our social institutions (e.g. family, marriage, government, criminal justice and legal systems) are premised on the understanding that we generally control our own behaviour, and hence are responsible for it. Some philosophers and scientists, however, take a rigorously reductive or neuroessentialist approach to mind and brain, in which the mind is brain and the brain is both necessary and sufficient for explaining the mind (Churchland, 1986; Crick, 1995). They argue that our thoughts and actions will ultimately be explained as a series of neurochemical events, and that mental illnesses will be shown to be the result of disturbed brain processes. The neuroessentialist view that a disorder is described solely by changes in the brain is more plausible in the case of neurological disorders where there is a direct relationship between changes in the brain and changes in behaviour. For example, the relationship between a trauma-induced lesion to the frontal parts of the brain and disinhibition in behaviour is simple and direct, notwithstanding the psychosocial factors that may make some people more likely to suffer a traumatic brain injury of this type, such as a propensity to take risks. In such cases we understand how the injury led to the observed changes in behaviour or cognition (e.g. loss of ability to form new memories following hippocampal lesions, or the inability to form successful social relationships following a lesion to the ventromedial frontal cortex). The relationship between brain and behaviour is neither as clear nor direct in most psychiatric disorders, such as addiction. The changes in brain function observed in patients suffering from mental illnesses are, in comparison, extremely complex, subtle and variable. They often arise as a result of minor shifts in ‘normal’ brain activity. Even the concept ‘normal’ brain function may be misleading because there is great variability in brain structure and function between healthy individuals. Psychological and social factors also play a much greater role in the development and manifestation of psychiatric disorders than in the neurological cases described above. Despite decades of increasing research into the neurobiological origins of consciousness, thought and behaviour, the fundamental questions of the relationship between brain and mind, self and society remain. Human beings

Introduction

3

are highly complex, biological and psychological beings who are embedded within a web of dense social interactions that occur in a variety of overlapping spheres, such as family, government, the criminal justice system, the public health system, commerce and industry (e.g. the pharmaceutical, tobacco and alcohol industries). Within this context, understanding and applying neuroscience can be complicated by a number of competing interests. Psychiatric disorders such as addiction are not just medical conditions that require treatment from health care professionals; they may also involve violations of social norms and laws, involving the criminal justice system. The behaviour of those affected can often cause significant social harm to others as well as themselves (e.g. adversely affecting communities and families). These disorders disproportionately affect certain subpopulations within society (e.g. socioeconomically disadvantaged and ethnic minority groups). In the case of alcohol and tobacco, there are commercial and other vested interests that profit from the sale and consumption of these addictive products who often seek to use addiction science to protect their interests. Psychiatric disorders, such as addiction, also provoke strong moral responses from others that can influence how neuroscience is understood and applied (Pescosolido, et al., 2010; Read and Law, 1999; Rose, 2003; Sartorius, 2010). Mental illnesses are highly complex disorders that are difficult to understand, generating significant fear and opprobrium that can lead to discrimination against, and stigmatisation of, those that suffer from them. For all these reasons, addicted and mentally ill individuals are vulnerable, socially, economically and cognitively. They may be mistreated for reasons of social expediency in order to reduce harm to others. These social circumstances can influence the way in which neurobiological research and technologies are understood or applied, sometimes with unacceptable or negative consequences. Neuroscience is a complex multidisciplinary field of research that crosses a number of interrelated, but methodologically diverse fields, from molecular and cellular biology to neuroimaging and cognitive and social neuroscience. Its findings also have a number of methodological limitations that can be difficult for the non-specialist to appreciate in popular media accounts of research findings. There is therefore significant potential for this research to be misused or misrepresented, or prematurely applied in ways that may cause serious harm to addicted persons. When we interfere with a person’s brain function, we have the potential to change his or her life not only for the better; we may change brain function in

4

Addiction Neuroethics

profound ways that we may not be able to fully appreciate or predict. The advent of powerful new technologies that can image or interfere with brain activity has the potential to manipulate behaviour, cognition and mood in new ways. With the potential to do significant good comes the risk of significant harm. Consideration of positive outcomes needs to be balanced by consideration of less welcome consequences that may limit the translation of addiction neuroscience into effective and appropriate treatments for addiction, and hamper the prevention of harmful forms of drug use. Failure to anticipate and prevent such potentially adverse outcomes may delay the translation of this research into successful clinical treatments. This book examines the social, ethical and public policy issues raised by neuroscience research and its potential applications in the treatment and prevention of addiction and the formulation of social policies towards drug use. If neuroscience research on addiction is to be translated into effective public health policies it is critical that we understand the ethical, philosophical and social contexts within which neuroscience research is conducted, understood and applied. 1.1.1.

Neuroethics: the promises and perils of neuroscience research

Mental illnesses, such as addiction, impose an enormous personal burden upon sufferers and their families, and a substantial economic burden on society. In developed countries, such as the United States (US), Canada and Australia, disorders of the brain and mind account for over a quarter of the total burden of disease, that is years lost from premature death and years of life lived with disability (Begg, et al., 2007; Ezzati, et al., 2004; Murray and Lopez, 1996). The treatment and rehabilitation of those affected by brain and mind disorders already commands a significant proportion of health care expenditure. In Australia, for example, this accounts for approximately 18% of the total health care budget, or around AU$8.5 billion (US$9 billion) per annum (Begg, et al., 2007). A similar situation confronts most developed nations, such as the United Kingdom and other European countries and the US (EMCDDA, 2006; Ezzati, et al., 2004; McKeganey, et al., 2007). It is clear that the effects of poor mental health and the costs of treating it present a major public health challenge. Increased funding of neuroscience research is often advocated because of the promise that its findings will reduce the incidence of mental illness and addiction and alleviate some of this burden. Neuroscientists have begun to uncover the neurobiological bases of human behaviour, including the genetic, neurochemical and electrophysiological

Introduction

5

mechanisms of major mental and neurological disorders.1 More generally, this research promises to revolutionise our understanding of the origins of all human behaviour, the experiences of consciousness and mental illness, and immensely increase our ability to treat, and possibly ‘cure’ or prevent, psychiatric disorders. The emergence of sophisticated neurotechnologies such as neuroimaging, psychopharmacology, electromagnetic brain stimulation and genetic screening offers the promise of new and effective methods for diagnosing, treating and preventing mental illness. Neuroscience research may also profoundly affect the way that citizens of developed societies think about and respond to people with addictive or other psychiatric disorders. Many scientists, clinicians and policy makers hope that neurobiological explanations of psychiatric disorders will reduce the stigma associated with mental illness, leading to better treatments, increased treatment seeking, greater investment in research and reduced social discrimination experienced by many mentally ill individuals. This view is summarised in the phrase: mental illness is ‘a disease like any other’ (Pescosolido, et al., 2010). Unfortunately, research suggests that these hopes remain to be realised (Angermeyer and Matschinger, 2005; Pescosolido, et al., 2010; Sartorius, 2010). Neuroscience is also beginning to uncover many of the neural mechanisms and structures that are involved in normal behaviour and cognition. In doing so, neuroscience has the potential to undermine or overturn beliefs that are central to common-sense ideas about free will, autonomy, responsibility and justice that form the basis of criminal law. If mental illness, addiction and abnormal behaviour are the result of aberrant neurophysiology, how does this affect the way we attribute responsibility or blame for the actions of the mentally ill? Conversely, if individuals use psychopharmacology to enhance performance, can they take credit for their achievement? This research also has important consequences for how society responds to people who are mentally ill or addicted. Sophisticated neuroimaging techniques may provide access to personal information that has not previously been available. Such information may

1

We take neurobiology to include studies of the genetic bases of behaviour that can predispose some individuals to developing certain addictive behaviours. This reflects the view that genetic influences on neuropsychiatric conditions are ultimately expressed neurochemically within the brain (see Caspi and Moffitt, 2006; Gallinat, 2008). There has also been an increase in studies that integrate both neuroscientific and genetic approaches, or neurogenetics (Akil et al., 2010; Li and Burmeister, 2009).

6

Addiction Neuroethics

be used by interested third parties, such as employers, educators, insurers and the courts, to discriminate against certain individuals (e.g. information about genetic risk of disease). The question of who should have access to this information and how it is used is of great public concern. In 2008, the US introduced the Genetic Information Non-discrimination Act to prevent the harmful misuse of genetic information. Very few countries, however, offer the same protections, and none have considered how to regulate the similar potential social uses of neuroscientific information about individuals. Neurotechnologies may also be used for non-therapeutic reasons, such as cognitive enhancement. The prospect of the future use of cognitively enhancing pharmaceutical drugs raises concerns about equity of access and unintended side-effects of their use, the ethical and social acceptability of pharmacologically assisted performance, and fears about the development of a psychotropic ‘arms race’ (see Chapter 13) (Hall, 2004). Some commentators have argued that there is already a growing use of psychotropic drugs, such as the stimulants, methylphenidate and modafinil, to enhance cognition or performance; they see this use as evidence of a strong demand for better forms of cognitive enhancement (Chatterjee, 2006; Chatterjee, 2007; Greely, et al., 2008; Maher, 2008; Sahakian and Morein-Zamir, 2007). The anticipation of the major ethical, social, legal and philosophical issues raised by neuroscience research on neuropsychiatric disorders has been given the name neuroethics (Illes, 2006). The influential American journalist, author and speechwriter for President Nixon, William Safire, defined neuroethics as ‘the field of philosophy that discusses the rights and wrongs of the treatment or enhancement of the human brain’ (Safire, 2002).2 While similar ethical issues have been addressed in genetic and stem cell technology, an ethical and philosophical analysis of the impact of neuroscience research is essential (Racine, et al., 2005). A small but dedicated community of researchers have begun to consider this task (Farah, 2010; Glannon, 2006a; Illes, 2006; Levy, 2007; Racine, 2010). The analysis of the ethical, social and philosophical implications of neuroscience research on addiction – which we will call Addiction Neuroethics – has received less attention (see Ashcroft, 2007; Carter, et al., 2009; WHO, 2004b for exceptions). Given the significant harm caused by drug addiction and abuse, there is an urgent need to investigate these issues in more detail to ensure that 2

The term neuroethics was used by Pontius (1973), but it was Safire’s definition that is associated with the formation of neuroethics as a field, the inauguration of a Neuroethics Society, and the publication of dedicated neuroethics journals.

Introduction

7

advances in the treatment of addiction are translated into clinical practice in ways that minimise harms and maximise benefits. Unlike other psychiatric disorders, addiction is, at least to some extent, the result of an individual’s choices: a person has to try drugs before they can become addicted to them. Illicit drug use (e.g. cannabis, cocaine and heroin) and addiction is highly stigmatised. More so than many other psychiatric disorders, addiction occupies the complex intersection of medical, social and legal responses to abnormal and socially disapproved behaviour. Experiences with addictive drugs also have the potential to inform the regulation and promotion of an ever-growing market for psychotropic medications. For all these reasons, Addiction Neuroethics provides an important area of study informing the ethical, social and public policy issues raised by neuroscience research more generally. 1.2.

Addiction enters the neuroscientific era

Drug addiction is a significant problem facing most societies. It is associated with increased violence, crime and mental illness, and is one of the leading causes of preventable mortality and disability in most developed societies (see Chapter 2). Significant costs are incurred in attempting to limit or regulate the use of both licit and illicit drugs, and in dealing with the physical, psychological and social costs of drug abuse and addiction. Despite over 150 years of scientific research into the nature of drug addiction and its treatment, a successful political or medical solution remains elusive. Significantly, there remains strong disagreement and debate over the nature and even the existence of addiction (Dalrymple, 2006; Szasz, 1975). Since the 1950s, animal, and more recently human, research has increasingly suggested that human addictive behaviours have a genetic and neurobiological basis (Koob and Le Moal, 2006; Nutt, et al., 2007b). Twin studies have identified a substantial genetic contribution to liability to develop addiction to tobacco, alcohol and illicit drugs. Molecular genetic studies have begun to identify individual genes that may increase the risk of addiction (Ball, 2007; 2008). Neuroscience studies in humans and animals have also shown how the chronic abuse of addictive drugs can disrupt key neural circuits involved in motivation and reward, memory and learning, and executive control, such as the ability to inhibit impulses or judge consequences (Goldstein, et al., 2009). This research has led to the brain disease model of addiction: the belief that the chronic use of addictive drugs ‘hijacks’ the brains of those addicted and drives them to continue to use

8

Addiction Neuroethics

drugs despite the harm that their use causes, and wishing that they could stop (Dackis and O’Brien, 2005; Leshner, 1997; Volkow and Li, 2005). Many addiction neuroscience researchers argue that their work will lead to increased funding for more effective treatments for addiction (Dackis and O’Brien, 2005; McLellan, et al., 2000). These include: targeted new drugs or treatments that prevent the development of drug addiction (e.g. drug vaccines), reduce cravings or the strong desire for drugs, prevent relapse to drug use, or reverse drug-induced cognitive impairments (e.g. improve cognitive control or unlearn the habit of drug taking); new diagnostic tools to identify people vulnerable to developing addiction and prevent it (e.g. neuroimaging and genetic screening), or the use of these diagnostic tools to personalise treatments to match the individual, such as pharmacogenetics (see Chapter 12) (Insel, 2009). There is also a growing belief that neurobiological research will provide causal explanations of addictive phenomena. Proponents of the brain disease model of addiction hope that an increased understanding of the neurobiological basis of addiction will lead to social policies that recognise addiction as a real neuropsychiatric condition that should be treated therapeutically (Dackis and O’Brien, 2005; McLellan, et al., 2000). This medical view of addiction contrasts with the more punitive approaches that have dominated policies towards illicit drug use and addiction for most of the last century, namely, the prosecution, detention or imprisonment of drug users and ‘addicts’, as well as sellers and suppliers of these drugs. Underlying the more traditional or moral approach is the view that compulsive drug use is simply freely chosen immoral behaviour best dealt with by using the criminal justice system to punish those who use illicit drugs and deter others from doing so (National Research Council, 2001). The impact that addiction has upon the capacity for addicted individuals to choose not to use drugs is at the centre of these neuroethical debates, and will be a major focus of this book. Neuroscience is often used in these debates to argue that addicted individuals lack the capacity to choose not to use drugs, and it is therefore important to carefully and critically examine the evidence for and against these claims. While the potential benefits of neurobiological research point towards socially desirable goals that most would share, the aspirations of advocates of this research need to be tempered by critical consideration of less welcome potential uses of neuroscience, especially those that may result from an overly simplistic interpretation of what neurobiological research reveals about addiction. For example, an unqualified acceptance of the brain disease model of addiction may be seen to warrant increased use of coerced or forced treatment

Introduction

9

of addiction because sufferers are seen as suffering from a disease that prevents them from choosing not to use drugs. Neurobiological explanations may also justify the use of risky and overly invasive medical interventions, such as neurosurgery, as has recently happened in Russia and China (Hall, 2006b), and deep brain stimulation (Carter, et al., 2010; Carter and Hall, 2011). It may also lead to an over-reliance on speculative or controversial policies to reduce addiction, such as the vaccination of genetically vulnerable adolescents, at the expense of alternative, less morally contentious social measures that aim to restrict availability or increase the price of legal drugs (see Chapter 14). The use of novel technologies from addiction neuroscience also raises a number of ethical concerns. For example, new targeted drugs may have unexpected impacts upon cognition, mood and behaviour. Addiction is a highly stigmatised condition, and information gained from neuroimaging and genetic screening may be used by third parties, such as employers, educators, insurance companies and the courts, to discriminate against those with, or suspected of having, a drug addiction. There are also competing public and social interests that can influence the way in which treatments are provided. Most advocates of the neurobiological model of addiction insist that emerging technologies will be used for the explicit purpose of treating an illness, or reducing the harm that addicted individuals cause to themselves. However, there are other competing social interests that may influence how these treatments are administered or provided. For example, a major justification for public and governmental support for some treatments of addiction is the reduced harm and social costs they offer, such as methadone maintenance treatment and other harm reduction programs. New treatments might be used with an aim of reducing social harm rather than treating the individual, and at the expense of their rights and freedoms. More ethically contentious uses of neurobiological treatments may reduce the very large prison costs associated with the incarceration of individuals convicted of a crime to which their addiction contributed (e.g. drug dealing, theft to fund an expensive drug habit), or as a form of extrajudicial punishment. Such uses of medical treatments are considered by many to be ethically unacceptable and could cause significant harm to socially vulnerable individuals. High-profile misuses of neurobiological technologies could also lead to significant mistrust of neuroscience, and prevent more ethically acceptable uses of these technologies to the detriment of society generally, as well as those directly affected by addiction.

Addiction Neuroethics

10

These are significant ethical and social challenges that need to be considered and balanced in the application of neuroscientific knowledge and technologies. They cannot be answered by scientific research alone, but need to be based on a thoughtful and transparent analysis of the ethical and public policy issues that neuroscience raises. It is critical that we consider the unintended negative consequences of neuroscience research of addiction if we are to realise its promise of reducing the burden and incidence of drug use, and in translating new advances into clinically meaningful treatments with minimal harm. 1.3.

Aims and overview

The aim of this book is to provide a critical review of the scientific, ethical and public policy issues that may arise in applying findings from leading genetic and neuroscience research to the treatment and prevention of addiction research. A central issue in Addiction Neuroethics is the question of the impact that chronic drug use and addiction have upon an individual’s ability to control their drug use. A major aim of the book is to examine how neuroscience research may affect our understanding of autonomy, selfcontrol and agency in addiction. Are addicted individuals able to consent to research that involves a choice about whether to use their drug of addiction? Can they consent to drug substitution treatments that involve administering a drug with similar effects to their drug of addiction? Are medical interventions that intervene directly in brain functioning (such as neurosurgery and deep brain stimulation) justified for addiction? Can, or more controversially should, society coerce addicted individuals into accepting and complying with treatments that may involve implanting long-acting drugs? This book is organised into four parts. Part 1: The Science of Addiction documents what is currently known about addiction. Part 2: The Ethical and Philosophical Implications of Neuroscientific Knowledge of Addiction examines how neuroscientific knowledge may impact upon the way in which we understand and treat those that suffer from an addiction. Part 3: The Ethical and Public Policy Implications of Novel Technologies for the Treatment of Addiction examines the practical ethical and public policy implications raised by the use of emerging treatment technologies to treat, prevent and possibly cure addiction. Finally, Part 4: The Future of Addiction Research and Policy considers the future implications of neuroscience for addiction research and public health policy.

Introduction

11

Part 1: The Science of Addiction Chapter 2: What is addiction? discusses the nature and the prevalence of addiction, providing an historical account of ideas about drug addiction, and the impact that addiction has had upon society. This includes: a phenomenological description of addiction as revealed through clinical observations and diagnostic studies; a brief review of how addiction has been understood and treated over the last century and a half; the prevalence and burden of licit and illicit drug use in developed nations, such as Australia, Europe and the US; and a brief history of major theories or models of addiction, including psychological, social, public health and economic perspectives on addiction. Chapter 2 concludes with an examination of how neuroscience may change our understanding of addiction. Chapter 3: The neurobiology of addiction provides an in-depth critical analysis of neurobiological research on addiction, including research in genetics, the molecular and cellular effects of drug use (e.g. synaptic plasticity and epigenetics), functional neuroanatomical changes produced by drug use, and their impact upon cognition and decision-making. The chapter also reviews factors that make some individuals more vulnerable to developing an addiction, including psychology, stressful environments and genetics. Chapter 4: Neurobiological treatments of addiction describes the neurotechnologies that have been developed, or are likely to emerge, from neurobiological research on addiction. These include: pharmacological treatments of addiction, immunological blockades (or drug vaccines) and sustained-release pharmacological preparations; diagnostic technologies such as genetic screening and brain imaging to identify vulnerability to addiction and guide clinical decisions in treatment selection; and neurological technologies, such as neurosurgery and deep brain stimulation. Part 2: The Ethical and Philosophical Implications of Neuroscientific Knowledge of Addiction begins with a discussion of the social and moral forces that influence the way in which society responds to addiction and drug abuse. It concludes with a discussion of the potential practical implications of neuroscientific knowledge in the treatment of addiction. Chapter 5: Autonomy, addiction and the public good introduces the ethical and philosophical themes that are central to the treatment and research of addiction: (1) autonomy and the impact that addiction may have upon an individual’s ability to make free choices, or be held responsible for their actions; and (2) under what circumstances, if any, a society may justifiably override an addicted individual’s autonomy. The chapter begins with a brief introduction to different approaches to ethics, including deontology, consequentialism,

12

Addiction Neuroethics

principlism and human rights. The central ethical principles of respect for autonomy and the public good are introduced, and their relevance to addiction and its treatment are discussed. We conclude with the specification of some minimal conditions for the ethical treatment of addiction. Chapter 6: Autonomy and the capacity to consent to addiction treatment examines the impact of neuroscience and neurobiological explanations of addiction on autonomy. This includes a discussion of the epistemology of neuroscience, that is how and what neuroscience can tell us, and significantly, the limits of this knowledge. The chapter pays particular attention to the implications of the ‘brain disease model of addiction’, as promoted by the influential US National Institute on Drug Addiction (NIDA), for autonomy. This analysis forms the foundation for considering the ethical acceptability of various aspects of the treatment of addiction in subsequent chapters. We conclude this chapter by considering the related issue of whether addicted individuals have the cognitive and volitional capacity to provide informed consent to enter some forms of addiction treatments, both medical (e.g. psychopharmacological) and psychosocial. Chapter 7: The rights of individuals treated for drug, alcohol and tobacco addiction uses a human rights approach to expand upon what the ethical treatment of addiction requires. We consider the relevance of human rights to addiction treatment and the rights and responsibilities of those suffering from an addiction. We examine when society may, or must, override an addicted individual’s autonomy in the interests of the public good or the interests of the addicted individual. Chapter 7 concludes with a discussion of the rights of vulnerable persons suffering from addiction or drug dependence, such as prisoners and pregnant women, areas in which a human rights approach has been successfully applied in other health areas. Chapter 8: Coerced treatment of addiction investigates whether, or under what circumstances, society may ethically force addicted individuals to undergo treatment, and if so, how coerced treatment should be administered. This chapter includes: a discussion of the types of coercion now often used in the treatment of addiction (e.g. drug courts, compulsory treatment); the relevance of various ethical justifications for coerced treatment (e.g. paternalism, the public good, utilitarianism); and concludes with some suggested guidelines for the provision of ethically acceptable forms of coerced treatment. Chapter 9: Ethics of addiction research analyses the ethical issues raised in conducting addiction research on human subjects. These include the ethics of

Introduction

13

research that involves: giving addicted participants their drug of addiction; paying drug using and addicted subjects for their research participation; and the potential risks to privacy and discrimination arising from the use of information gained from studies by third parties such as employers and insurers (e.g. brain scans, genetic tests). Part 3: The Ethical and Public Policy Implications of Novel Technologies for Treating Addiction builds upon the conclusions of Part 2 in order to better understand the moral and ethical context that may shape the way in which technologies are used, and the motivations for particular uses of them. This includes a discussion of the scientific validity of each of the technologies discussed. Chapter 10: New developments in the treatment of addiction analyses the likely use of novel treatments of addiction and their potential consequences, both negative and positive. These novel treatments include: powerful new psychopharmacological approaches, long-acting pharmacological preparations, such as drug implants, and drug vaccines. Chapter 11: In search of a neurobiological ‘cure’ of addiction briefly examines the history of the use of heroic, but potentially dangerous, technologies to ‘cure’ addiction. We review two recent events in addiction treatment: ultra-rapid opioid detoxification and the neurosurgical treatment of heroin addiction. These provide cautionary tales against current enthusiasms for neurological cures for addiction, such as deep brain stimulation. Chapter 12: Preventive medicine and personalised treatment of addiction reviews the use of a range of diagnostic technologies to identify those vulnerable to developing an addiction and novel interventions to prevent it. These include the possibility of genetic screening, neuroimaging or cognitive testing combined with drug vaccines or targeted psychosocial interventions. This chapter also examines the ethical, social and clinical feasibility of using these same technologies to match available treatments to particular individuals (e.g. pharmacogenetics). Chapter 13: Feeling ‘better than well’ examines the future use of emerging psychopharmacologies to enhance cognition, mood and arousal. There has been significant discussion in recent years about the ethical acceptability of the use of psychopharmacological enhancement, or cosmetic psychopharmacology; whether it should be permitted, and if so, how it may be regulated. This chapter examines the history of addictive or recreational drug use, and compares this with the use of powerful new psychopharmacologies to enhance cognition. This analysis will be used to develop recommendations for future regulation of emerging psychopharmacologies.

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Addiction Neuroethics

Part 4: The Future of Addiction Research and Policy considers the future implications of neuroscience for addiction research and public health policy. Chapter 14: The social and policy implications of addiction neurobiology discusses the wider social implications of neurobiological and genetic research of addiction on public policy. Among the questions addressed are: What are the implications of addiction neuroscience for the policy distinction between licit and illicit drugs? How will addiction neuroscience affect public health policies towards alcohol, tobacco and other drugs? How may neuroscience research be used by legal industries that promote the use of addictive commodities (e.g. alcohol and tobacco) or opportunities to engage in addictive behaviours (e.g. gambling, prostitution; internet games etc.)? Should we allow the development and marketing of pharmaceuticals that produce the desirable pharmacological effects of alcohol without its toxic effects? If so, how can we effectively regulate such forms of neurobiological harm reduction? Chapter 15: Concluding remarks and summary brings together some of the key arguments and issues discussed throughout the book. It also identifies important issues deserving of further empirical research and ethical and policy analysis. The purpose of this book is to provide a map of the neuroethical issues raised by the neuroscience of addiction, to guide clinicians, scientists and ethicists alike. As a highly interdisciplinary project, its findings will be relevant to a variety of audiences including: researchers in addiction, neuroscientists, psychologists and psychiatrists, philosophers and bioethicists, clinicians and those caring for addicted individuals, policy makers and social scientists. The potential benefits of this research are: 1 Identification of the most promising new approaches to the treatment and prevention of addiction 2 An analysis of the ethical and public policy issues raised by the utilisation of these technologies 3 A framework to consider the relevant ethical and scientific issues raised by research and treatment of addiction that can inform future thinking about these issues as the science and technology progresses 4 Identification of future directions for neuroethical research on addiction, and in particular, areas where research is most immediately needed 5 Guidance for other professionals working in the treatment and research of addiction, such as: a Carers or clinicians on the ethical and effective treatment of addiction

Introduction

15

b Ethicists and other commentators seeking an understanding of the state of neuroscience research of addiction, as well as an appreciation of the challenges and limitations in interpreting and applying neuroscience research c Neuroscientists and other researchers of addiction about some of the ethical issues involved in conducting research on addicted subjects d Policy makers involved in formulating public policies related to the treatment, prevention and research on addiction 6 Provide guidance to researchers and clinicians in the research and development, and use of emerging technologies to treat addiction 7 Stimulate public debate and awareness of neuroscience research on addiction and the ethical issues that it and its potential applications raise We begin by reviewing the current state of the science of addiction (Part 1).

Part 1

The Science of Addiction

2 What is addiction?

2.1.

Introduction

At the heart of debates in addiction neuroethics is the question, ‘What is addiction?’ Answers to this question have been hotly debated for more than two centuries (White, 1998). How we understand addiction has significant implications for the way we respond to people who continue to use drugs despite the harm that their drug use causes to themselves and others. Addiction has been most often seen as a form of criminal and immoral behaviour that is best dealt with by the criminal justice system. More recently, addiction has been understood as a disease of the will and, more recently, brain, that requires medical treatment. Drug addiction elicits strong moral responses because addicted persons can cause significant social harm to others, engage in criminal acts, and often display socially deviant and ‘compulsive’ behaviour. The central question is whether ‘addicts’ are able to control their drug use. Does addiction impair an individual’s ability to control drug use and drugseeking behaviour, and if so, in what way and to what extent? Neuroscience research promises to resolve this debate by providing a neurobiologically based causal account of how drugs of addiction change brain function and cognition in ways that explain one of the most prominent phenomena of addiction, namely ‘loss of control’ over drug use. In this chapter we examine how addiction has been understood in modern society, and discuss how neuroscience may affect this understanding. We begin with a brief review of common or folk understandings of addiction, and the clinical accounts of addictive behaviour that have informed these common-sense views. We then examine the impact that drug use and addiction has upon society and the way in which societies have typically responded to it. We conclude by analysing the two dominant models that have been used

19

Addiction Neuroethics

20

to explain addiction, the medical and moral, and discuss the relevance of neuroscience research to these models. 2.2.

The phenomenology of addiction

Addiction is a complex and highly heterogeneous condition that encompasses an array of problematic behaviours that evolve over time in different individuals in different ways. This can make defining addiction difficult. It is reflected in the terminology used to describe addictive patterns of drug use, namely, ‘addiction’, ‘dependence’ or ‘substance use disorder’. Addiction is often contrasted with dependence. An individual may be physically or psychologically dependent on a drug or both. People can become physically dependent on a substance without being addicted. Physical dependence involves the compensatory physiological changes that result from the repeated use of a drug, with the result that rebound aversive symptoms often occur when drug use is abruptly stopped. This is often called a withdrawal syndrome. Some drugs may also produce a discontinuation syndrome that occurs upon abrupt cessation of use, such as the selective serotonin reuptake inhibitors (SSRIs), without producing the drug-seeking behaviour that is characteristic of addiction (Nutt, 2003). Psychological dependence encompasses the variety of psychological changes that drive drug use or makes one feel that they need to use drugs. It is sometimes seen as synonymous with addiction. As a result, the term ‘addiction’ was dropped from most diagnostic criteria and the term dependence used in its stead (e.g. Diagnostic and Statistical Manual for Mental Disorders, 3rd edition, revised (DSM-III-R)). This decision has recently been contested by some addiction researchers who propose that ‘addiction’ be reintroduced into the Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-V) (O’Brien, et al., 2006). Addiction is also used to refer to the use of drugs in a way that repeatedly causes significant harms to the individual independently of symptoms of physical or psychological dependence. Therefore, some clinical diagnostic classifications refer instead to substance use disorder (American Psychiatric Association, 2000). Addiction is therefore a broad term used to describe a continuous disorder with varying degrees of severity and length of drug habit, patterns of drug use, degree of control over drug use, and amount of harm caused to self and others. We follow Courtwright (1982) in using ‘addiction’ to refer to a heterogeneous collection of patterns of problematic drug use that may or may not involve physical dependence and may cause varying levels of harm to the user and others.

What is addiction? 2.2.1.

21

Folk understanding of addiction

Folk or common-sense understanding of addiction can be surprisingly complex and may vary considerably according to the context in which it is understood and the type of persons involved. For example, an unsympathetic view is often held towards addicted persons from a lower socio-economic background whose addiction causes significant harm to others, particularly their children or dependents. Addiction is understood by widely used diagnostic criteria as a disorder in which an individual’s control over their drug use is impaired. It involves the habitual use of a substance despite the harms caused, at least in part because of difficulty in controlling use, as indicated by failed attempts to stop or limit drug use. This pattern of behaviour includes: drugs being used typically daily, or near-daily, in large amounts, and for substantial periods of time; using increasing doses of the drug to achieve the desired effects; experiencing withdrawal symptoms if drug use is stopped abruptly; using drugs to relieve these withdrawal symptoms; and continuing to use the drug despite problems caused by its use, such as, personal health and psychological problems, or adverse effects of drug use on partners, children, or workmates, and legal problems arising from drug use (e.g. drink or drug driving, violence and assaults while intoxicated, being arrested for drug and property offences committed to fund drug use). 2.2.2.

Clinical understanding of addictive behaviour

Folk understanding of addiction has been largely informed by clinical observations, and is codified in the major clinical diagnostic criteria for substance dependence or addiction (e.g. Diagnostic and Statistical Manual of Mental Illness, 4th ed. Text Revised (DSM-IV-TR) and the International Classification of Diseases, 10th ed. (ICD-10)). Addiction is defined in these classifications by the harm that it causes and the patterns of behaviour it involves. They describe addiction as a ‘loss of control’ over drug use, where drug taking becomes ‘compulsive’ and consumes a great deal of an individual’s time and resources to the detriment of performance in other important social roles, such as working or caring for children (American Psychiatric Association, 2000; WHO, 1993). The clinical study of addiction has suggested that addiction to most drugs of abuse shares a number of clinical features: 1 Drug use generally begins in adolescence or early adulthood when drugs are initially taken for the positive changes in emotion, cognition or behaviour that they elicit. This is referred to as positive reinforcement.

Addiction Neuroethics

22

Criteria for Substance Dependence (DSM-IV) Preoccupation w/obtaining Persistent physical or psychological problem Withdrawal Negative Affect

Preoccupation Anticipation

Persis tent desire

Taken in larger amounts than infected Binge Intoxication

Tolerance withdrawal Social, oc al cupational or recreation d e s i m o activities compr Spiralling Distress

Addiction

Figure 2.1. The cycle of addiction. (Reproduced with permission from Koob and Le Moal, 2006.)

2 Dependent drug use follows a chronic course of initiation of use, dependence, abstinence and relapse – commonly referred to as the cycle of addiction (see Figure 2.1). 3 With repeated use, individuals develop tolerance to drug effects so that greater quantities of the drug are required to achieve the original rewarding effects. 4 For most drugs of addiction, individuals experience severe withdrawal symptoms when drug use is abruptly stopped. These symptoms are relieved by drug use, providing a strong motivator to continue drug use. This is referred to as negative reinforcement. 5 Addicted individuals continue to use the drug despite the significant physical, psychological and personal harm that its use causes. 6 Chronic drug use leads to a preoccupation with consuming the drug, subjective experiences of intense drug cravings, and a sense of a loss of control over drug use. 7 Generally, the condition progressively worsens over time, with increases in the harm caused and in subjective craving and loss of control over use. 8 Addiction is a chronic condition where most addicted users relapse to harmful drug use following a period of abstinence or controlled drug use. Many ‘addicts’ report finding it very difficult to stop using drugs and present for help after a series of failed attempts to quit. If they succeed in quitting, they are very likely to relapse to drug use within the period of a year in the absence of additional psychosocial and pharmacological support to remain abstinent.

What is addiction?

23

This process of addiction appears to be shared by all kinds of addiction, including the putative ‘behavioural’ addictions, such as pathological gambling (Potenza, 2006). There is increasing support for the existence of other behavioural addictions such as sex and shopping addiction, and pathological eating and bulimia nervosa, although there is considerable debate as to whether these should be considered as ‘true’ addictions (Devlin, 2007; Holden, 2001; Petry, 2006; Potenza, 2006; Volkow and O’Brien, 2007). Neuroscience research is beginning to uncover a neurobiological pathway common to each of these addictions (see Chapter 3). People with an addiction are more likely than non-addicted persons to suffer from other forms of addiction, or have a family member affected by some type of addiction (Goodman, 2008). The focus of our discussion, however, is on addiction to psychoactive substances, both licit and illicit. There are a number of social and physiological differences between substance use and other addictive behaviours, over and above the unique legal and regulatory situation of most psychoactive substances. It is also not yet clear whether all forms of addictive behaviour should be grouped with drug-based addictions. For further discussion of the neuroscience of behavioural addictions, see Orford (2011), Grant et al. (2006), Potenza (2008) and Volkow and Wise (2005).

2.3. 2.3.1.

The social and economic costs of drug use and addiction Prevalence of drug use and addiction in Australia

Drug use and addiction has an enormous adverse impact on society, with most people in developed countries like Australia, Europe and the US using at least one licit drug, and often one or more illicit drug during their lifetime. Alcohol is unsurprisingly the most prevalently used addictive drug with over 90% of citizens in these countries having tried alcohol. Tobacco is the next most widely used addictive drug, with around 20% of the populations having smoked in the last 12 months. Almost 40% of Australians have tried an illicit drug (most often cannabis) and approximately 14% have done so in the last 12 months (AIHW, 2008). A small but significant minority of those who try any drug will develop an addiction to it. In developed countries like Australia, for example, a significant proportion of the population develop an addiction to illicit drugs (range 4–6%) or alcohol (range 8–15%), or both (AIHW, 2008) and around 17% are dependent on nicotine. Similar results have been found in most developed countries, such as the UK (McKeganey, et al., 2007), other European countries (EMCDDA, 2006), and the US (Kessler, et al., 2005; SAMSHA, 2006).

Addiction Neuroethics

24 2.3.2.

Drug use related harm

Drug abuse and addiction lead to increased rates of death from suicide, overdose and drug-impaired driving. There are also increased health costs from treating the toxic and psychopathological effects of chronic drug use (e.g. liver cirrhosis from alcohol abuse, cancers, drug-induced psychoses, cognitive impairment, and drug-related accidents and injuries). The complications of injecting drug use can include thromboses, septicaemia and the transmission of human immunodeficiency virus (HIV) and other blood-borne diseases. It is estimated that there are between 6500 and 9000 acute drugrelated deaths (e.g. overdose) in Europe every year (approximately 4% of all deaths in European adults aged 15–39 years) (EMCDDA, 2006). In 2004/05, 872 deaths were recorded in Australia due to the adverse effects of illicit drug use (see Begg, et al., 2007). Illicit opioids, such as heroin and morphine, are used by a very small minority of the population, with approximately 1–2% of the population in developed countries reporting heroin use at some point during their lives (AIHW, 2008; EMCDDA, 2006; SAMSHA, 2006). Opioid abuse is nonetheless a significant contributor to mortality and morbidity (Hall, et al., 2006). Opioids cause significant harm to those who use them: around one in four of those who report using heroin become dependent on it (Anthony, 1994), and in developed countries, dependent heroin users have a mortality rate that is 13 times higher than the rest of the population (Degenhardt, 2011; Hulse, et al., 1999). Within some European cities, 10–20% of the overall mortality among young adults can be attributed directly or indirectly to opioid use (EMCDDA, 2006). The increased risk of premature death arises from drug overdoses (Darke and Zador, 1996), violence and suicide (Darke and Ross, 2002; Goldstein and Herrera, 1995; Vlahov, et al., 2004) and acquired immune deficiency syndrome (AIDS) (Darke and Zador, 1996; Degenhardt, et al., 2011). Addicted illicit drug users also often engage in crime and violence to finance their drug use. This leads to substantial judicial and prison costs. Illicit drug abuse is associated with increased criminality, with 65–80% of arrestees in the UK having used illicit drugs in the 12 months prior to being arrested (McKeganey, et al., 2007). Chronic use of some substances (e.g. cocaine, methamphetamine, cannabis and alcohol) can also produce neuropsychological changes associated with impulsive violence (e.g. psychoses, impaired impulse inhibition). Drug abuse leads to lost employment and increased social welfare, and broader adverse impacts on families and relationships (EMCDDA, 2006; Hall, et al., 2006).

What is addiction?

25

Table 2.1 Contribution (% of total Disability Adjusted Life Years (DALYS)) of tobacco, alcohol and illicit drugs to burden of disease in Australia in 2003 (Begg, et al., 2007). Drug

Males

Females

Average

Tobacco Alcohol (net) Illicit drugs

9.6 3.8 2.6

5.8 0.7 1.2

7.7 2.3 2.0

Table 2.2 Total social costs of drug abuse, 2004/05 Illicit drugs ($b)

Alcohol ($b)

Tobacco ($b)

Alcohol and illicit drugs ($b)

Tangible Intangible Total

10.83 4.49 15.32

12.03 19.46 31.49

6.92 1.27 8.19

1.06

Proportion of unadjusted total

27.3%

56.2%

14.6%

1.9%

1.06

All drugs ($b) 30.83 25.22 56.05 100%

Tangible costs include events such as the treatment of addiction and related disease, lost productivity in the workplace, crime and road accidents. Intangible costs, in contrast, are those that result from factors such as pain and psychological suffering. $b ¼ billion AU$. Adapted from Collins and Lapsley (2008).

2.3.3.

Burden of disease due to alcohol and drug use

The use of addictive drugs is a significant contributor to the global burden of disease (BOD). In Australia in 2003, approximately 12% of the total BOD was due to different types of drug use (Begg, et al., 2007). See Table 2.1. Tobacco smoking made the largest contribution (7.7%), followed by alcohol (2.3%) and illicit drug use (2.0%) (Begg, et al., 2007). Collins and Lapsley (2008) have estimated the total social cost of drug use in Australia in 2004/05 as over AU$55 billion (US$58 billion). The costs associated with the use of each addictive drug are summarised in Table 2.2. The social and economic costs of drug abuse and addiction in European nations is also substantial (Andlin-Sobocki and Rehm, 2005; EMCDDA, 2006), with 10% of the overall burden of disease in Europe attributed to substance use disorders and addiction (Rehm, et al., 2005). In the UK, the

Addiction Neuroethics

26

estimated current economic burden of illicit drug use is £13 (€19) billion/ year, predominately due to costs incurred in dealing with drug-related crime. Alcohol contributes a further £20 (€29) billion/year (Nutt, 2007c). In the United States alone, illicit drug abuse and addiction costs society US$180.9 billion per year (ONDCP, 2004); in addition, alcoholism costs US$180 billion (NIAAA, 2000) and tobacco addiction around US$167 billion (Adhikari, et al., 2008). Studies also suggest that the burden of drug use is rising with increases in the number of people abusing drugs and the quantity and strength of drugs that they are using (EMCDDA, 2006; McKeganey, et al., 2007). Given the enormous health, economic and social burdens arising from alcohol and other drug abuse and addiction, there is strong public interest in preventing drug use and addiction, and in helping those who become addicted to stop using drugs or reduce the harm that they cause themselves and others. Despite this, only a minority of those with addiction receive treatment, and often this treatment is only modestly effective (McKeganey, et al., 2007). Of those Europeans who received treatment in 2005, 61% were treated primarily for opioid use (principally heroin); they were increasingly given access to effective treatments, such as methadone and buprenorphine maintenance (EMCDDA, 2006). However, the majority of addicted individuals do not receive treatment for their condition in the US (Demyttenaere, et al., 2004) or the UK (McKeganey, et al., 2007). 2.4.

Social response to drug abuse and addiction

The social harms caused by drug abuse and addictive drug use have prompted a number of responses to minimise drug use and the harm that it causes. Historically, most attempts to reduce or eliminate addictive drug use have involved the use of social policies, such as taxation of legal drugs like alcohol and tobacco and legal proscriptions on the use of illicit drugs for any except medical and scientific purposes (e.g. prohibitions and imprisonment). Taxation policies aim to reduce the affordability of legal drugs while penal sanctions aim to restrict access to illicit drugs (National Research Council, 2001). The modern era of drug control began in the US with the 1906 Food and Drugs Act and the 1914 Harrison Narcotics Act, which effectively removed the treatment of opioid addiction from the medical profession (Ling and Compton, 2005). Globally, opioid addiction came to be seen as a social evil that was best remedied by criminal prosecution of users and suppliers in an effort to reduce heroin availability, increase its price, punish those caught using the drug, and strengthen social disapproval of heroin use (Ling and Compton,

What is addiction?

27

2005). Over the years, a number of addictive recreational drugs have been added to the list of banned substances. The non-therapeutic use of opiates (e.g. heroin or morphine) and psychostimulants (e.g. cocaine or methamphetamine) is prohibited in all European countries. Cannabis is illegal in most European countries, although laws on possession and use are often not rigorously enforced. The distribution of these drugs is illegal, except for restricted medical purposes, and individuals may be charged with an offence and possibly imprisoned if they are caught selling them. While these measures have reduced opioid and other illicit drug use by comparison with that of alcohol and tobacco, they have increased harm in the minority of the population who use these drugs by encouraging: the use of injection to maximise drug effects, unsafe injecting practices (sharing needles and poor injecting technique), and the use of impure forms of drugs of uncertain strength. They have also increased incarceration of addicted users for crimes committed to fund their use of expensive illicit drugs (Hall, et al., 2006). Most societies also employ a range of social control measures to limit or reduce the use of licit drugs, such as alcohol and nicotine. These include: high rates of taxation, regulation of when and where drugs may be consumed, and how they may be sold (e.g. bans on advertising, limits on strength). Such social measures have significantly reduced the use of these drugs and the harm caused, and the burden upon society (Collins and Lapsley, 2007). These policies have been more rigorously pursued with tobacco in recent decades than with alcohol where policies in many developed countries have become progressively less restrictive over the same time period (Babor, et al., 2003). In the last few decades, there has been a gradual shift in our understanding of drug addiction. An increase in opioid addiction after the Second World War in many developed countries, and the failure of tough laws to reduce opioid dependence, have led to the re-emergence of a disease model of drug addiction analogous to that advocated for alcoholism by Benjamin Rush in the 1830s and Alcoholics Anonymous in the late 1930s (Joint Committee of the American Bar Association and the American Medical Association on Narcotic Drugs, 1961). The credibility of a disease model of opioid dependence was enhanced by the development of more effective pharmacotherapies for various drug addictions in the 1960s (e.g. opioids), and more recently in the 1980s and 1990s for alcohol and nicotine (Nutt, 1996). Neuroscience research on addiction has provided a rationale for many of these treatments (Hall, et al., 2004a). The modern era of pharmacotherapy for opioid dependence began in the mid1960s with the development of methadone maintenance (Dole and Nyswander,

Addiction Neuroethics

28

1965). Since then, advances in genetics and neuroscience have greatly improved our understanding of the biological basis of opioid dependence, in particular, and addiction in general (Volkow and Li, 2004). Research into opioid addiction has identified some of the biological and social factors that make some individuals more vulnerable to opioid dependence than others, including: psychological and genetic vulnerabilities and social factors, such as family history, socioeconomic background, and opportunities to use heroin (Volkow and Li, 2004). Recent research on the neurobiology of addiction has supported the suggestion that drug addiction is a neurobiological entity that often requires some form of pharmacological treatment (see Chapter 3). There has also been increased research into new and more effective pharmacotherapies for drug addiction (see Chapter 4). The increased choice of pharmacotherapies for addiction promises to broaden the acceptance of pharmacological approaches to its treatment by physicians and patients. While this research may soften punitive social attitudes towards drug-dependent individuals, suspicion and mistrust of ‘drug addicts’, particularly those addicted to illicit drugs, is still widespread within the health care system and society more broadly (Ballon and Skinner, 2008; Dietrich, et al., 2006; Rassool, 2007; Room, 2006). The way in which societies respond to drug addiction and drug abuse is determined by how addiction is understood. In the next section we discuss the competition between two dominant models – the moral and the medical – that have driven drug addiction treatment and policy. It has been argued that neuroscience research may resolve these debates in favour of the medical view. However, as we will see, addiction elicits strong moral responses that can influence how neuroscience research on addiction is understood and applied in treating or preventing addiction. 2.5.

Governing models of addiction

This section describes two competing models of addiction: the medical and moral (or sceptical) models. These two perspectives are presented as dichotomous views (see Figure 2.2). However, most views on addiction lie somewhere along a continuum between the moral and medical views of addiction representing an uneasy attempt to combine the most plausible elements of each. 2.5.1.

Moral vs. medical models of addiction

The dominant moral view is sceptical about the idea of ‘addiction’. It sees ‘addicts’ as drug users who knowingly and willingly choose to use drugs

What is addiction? CRIMINAL

MEDICAL

LIBERTARIAN

Incapacitation

Deferrence

Rehabilitation

Psychotherapy

Stabilisation (metabolic)

Compensation (neurasthenic)

Regulation

Taxation

Laissez-faire

Less restrictive ideas

29 More restrictive ideas

1850 Government role limited to taxation Increase of municipal and state regulation: growing medical interest in addiction 1890

1909

Criminal idea challenges medical approach as drugtaking population changes

1923 The classic era of narcotics control; increased minority involvement with drugs

1965

1990

The rise of modern treatment modalities Major expansion of the criminal justice system

Figure 2.2. Governing ideas about drug use. This is a schematic diagram depicting the development of dominant attitudes towards drug use during the 20th century. The trajectory of the line was determined from an expert committee’s judgements about the ‘ideological ‘centre of gravity’’ in the US, based on canonical historic texts. (Reproduced with permission from Gerstein and Harwood, 1990.)

30

Addiction Neuroethics

without regard for the adverse consequences that their actions bring upon themselves and others. On this view, ‘addiction’ is an excuse for continuing to use drugs while avoiding responsibility for the consequences of doing so (Dalrymple, 2006; Szasz, 1975). The moral view makes sense of one of the key features of ‘addictive behaviour’ (as described in Section 2.2): that drug use is initially a voluntary choice that develops into an addictive pattern of use in a minority of drug users, including those who use what are reputedly the ‘most addictive’ drugs; heroin, nicotine, cocaine and alcohol. These facts make it difficult to draw a clear distinction between voluntary drug use and addictive drug use (Anthony, et al., 1994). Moreover, supporters of the moral view observe that many, and perhaps most, ‘addicted’ users succeed in stopping their drug use by themselves (Granfield and Cloud, 1996; Heyman, 2009; Klingemann and Bergmark, 2006; Peele, 2004; Sobell, 2007). This view is also supported by the everyday experiences of the majority of people who are able to stop or regulate their drug use with a minimum of difficulty. Sceptical views of addiction, however, are less consistent with a number of reliable empirical observations about drug use and addictive behaviour: 1 It is a significant minority of people who use drugs who become addicted to that drug (see Section 2.3). 2 The size of that minority varies with how the drug is used and its pharmacological actions, such as its rapidity of onset and duration of effect. Shortacting drugs that are smoked (nicotine or crack cocaine), or injected (amphetamine, heroin or cocaine), are much more likely to produce addictive behaviour than longer acting drugs that are ingested (e.g. codeine, ecstasy, benzodiazepine) (Anthony, et al., 1994). 3 There is an identifiable subset of individuals who are more likely to develop an addiction. This includes people who: have more contact with drugs and peers who use drugs; use drugs at an earlier age; are from socially disadvantaged backgrounds; perform poorly in school; have a family history of addictive behaviour, and suffer from a mental disorder (Hawkins, et al., 1992). 4 Although many addicted individuals stop their drug use without assistance, others do not. Only a minority seek professional help, and most of those who do so return to drug use in the year after seeking it. Over time, repeated attempts to stop do result in a substantial proportion of persons with an addiction successfully quitting, but most who do seek treatment still find it difficult to stop (Teesson, et al., 2002). The use of drugs in the

What is addiction?

31

face of often serious negative health and social consequences, and often in the absence of any pleasure derived from their use, suggests that addiction is more than mere wilful bad behaviour. 5 The development of addiction and the expression of addictive behaviours follow a predictable course in the majority of those that become addicted. This includes: euphoria upon initial use; the development of tolerance to the drug with repeated use and the onset of withdrawal upon cessation; and the emergence of intense drug cravings that can lead to relapse, even months after abstinence has been achieved. This is referred to as the cycle of addiction. See Figure 2.1. 6 The moral view of addiction has not been successful in reducing drug use. The worldwide dominance of the moral view has led to the use of punitive laws to discourage drug use, and a lack of investment in medical research into addiction or the development of interventions to treat it (McLellan, et al., 2000). These efforts have largely proven ineffective in reducing drug use and addiction, and have often contributed to the social costs of addiction by imprisoning drug users who typically return to drug use and re-offend upon release (Gerstein and Harwood, 1990; National Research Council, 2001). These policies have also led to discrimination and inappropriate restriction or derogation of the rights of those who are addicted (see Chapter 7). The lack of success of these policies suggests that alternative explanations and policies are required that take account of the effect that repeated drug use has on an individual’s ability to refrain from using that drug. These observations have led to a medical or disease model of addiction, according to which regular drug use over long periods of time can produce physiological and psychological changes in the individual that progressively undermine the degree of choice they are able to exercise over their drug use. Such explanations increasingly appeal to neurobiological theories of addiction, which lend support more readily to medical-centred policies. Although such policies still allow punitive measures for addicted offenders, they place a greater emphasis on medical treatment and social support to assist addicted persons and problem drug users to become abstinent. 2.5.2.

Neurobiological models of addiction

Neuroscience research of addiction challenges traditional ideas of addiction as a purely voluntary choice. Animal and human studies suggest that chronic

32

Addiction Neuroethics

drug use can produce long-lasting changes in brain function that make drug use a central preoccupation and undermine the capacity of individuals to refrain from using drugs. A theory gaining widespread attention, particularly in the US, is that addiction is a ‘chronic, relapsing brain disease’, which we refer to as the brain disease model of addiction (Leshner, 1997). According to NIDA, addiction is a brain disease that is caused by the chronic selfadministration of drugs that produce enduring changes in brain neurotransmitter systems leaving addicted individuals vulnerable to relapse after abstinence has been achieved (Leshner, 1997; Volkow and Li, 2005). The chronic disease model of addiction holds that addiction is the result of abnormal neural tissue in the same way that cardiovascular disease is a result of abnormal heart tissue (Volkow and Li, 2004). Neurobiological theories of addiction attempt to identify the molecular and cellular mechanisms by which drugs act on the brain in ways that impair control over drug use. Neuroimaging studies since the 1990s have identified changes in brain regions involved in the cognitive processes of salience, motivation, memory and conditioned learning, and inhibitory control. These neuroadaptations can persist for months after abstinence (Volkow and Li, 2004). Behavioural genetic research also suggests that there is a substantial genetic contribution to addiction vulnerability (Ball, 2008; Ball, et al., 2007), with genetic factors estimated to explain between 40 and 60% of the variation in addiction liability (Li and Burmeister, 2009; Uhl and Grow, 2004). These results support a neurophysiological account of addiction in which addictive drugs alter the brain’s endogenous reward circuits that are essential to survival in ways that make drugs appealing to the exclusion of all other activities (see Chapter 3). It also offers an explanation of why those addicted to drugs continue to use drugs despite developing tolerance to their pleasurable effects and in the face of suffering serious aversive consequences. The brain disease model of addiction argues that the chronic use of addictive drugs ‘hijacks’ normal neural reward circuits (Dackis and O’Brien, 2005). 2.5.3.

Potential consequences of neurobiological explanations of addiction

The major hope of addiction neuroscience researchers is that it will provide more effective pharmacological strategies to treat and even prevent addiction. Proponents of neurobiological theories of addiction also believe that their work will reduce community scepticism about the ‘reality’ of addiction

What is addiction?

33

(Dackis and O’Brien, 2005; Leshner, 1997; McLellan, et al., 2000). Acceptance of the neurobiological model of addiction as a ‘chronic, relapsing brain disease’ (Leshner, 1997, p. 45), they hope, will supplant the ‘commonsense’ or moral view of drug use. As a result, punitive social policies towards addiction will be replaced by more humane ones, reducing stigmatisation and providing better access to more effective forms of addiction treatment. More sceptical social scientists point to a number of potentially less welcome social uses of the brain disease model of addiction. The ‘chronic brain disease’ view may be seen as warranting heroic interventions in the brain’s function, such as ultra-rapid opiate detoxification for heroin dependence (Hall, 2000) or the neurosurgical treatment of addiction (Carter, et al., 2010b; Hall, 2006b) (see Chapter 11). Moreover, a brain disease model of addiction might be used to justify coerced treatment if ‘addicts’ are seen to be at the mercy of their neurotransmitters (Caplan, 2008; Marlowe, 2006; Sullivan, et al., 2008), incapable of acting in their own best interests (see Chapter 8). Medical models of addiction may also erode support for social policies that reduce drug-related harm. By focusing on addiction as a categorical brain disease, and disregarding the dimensional nature of drug use and dependence, we may overlook the detrimental effects of drug use that can occur in the absence of addiction. For example, identifying those who are genetically vulnerable to alcohol dependence may give some the impression that the majority of non-vulnerable drinkers can use alcohol with impunity, ignoring the very serious health risks that can arise from alcohol abuse in the absence of dependence (Hall and Sannibale, 1996; Midanik, 2006). More speculatively, it could possibly lead individuals with an addiction to abdicate responsibility for their behaviour (Nelkin and Lindee, 1996; Satel, 1999; Valenstein, 1998). We discuss the possible implications of neuroscience research for drug and addiction policy in greater detail in Chapter 14. A deterministic account of addiction is not unique to genetics and neuroscience; similarly deterministic roles could be attributed to social factors that lead to drug use or make some more vulnerable to addiction, such as socioeconomic background, or early adolescent exposure to parental addiction. Neurobiological theories, and the neuroimaging evidence that supports them, arguably make the scientific case for a causal account more compelling and persuasive than allegorical appeals to social pressures (McCabe and Castel, 2008; Racine, et al., 2005; Weisberg, et al., 2008). Appeals to ‘faulty genes’ and ‘chemical imbalances’ also provide a more mechanistic or proximal, and thereby more plausible, account of addiction.

What is addiction?

34 2.6.

Conclusion

The potential applications of neuroscience and genetic research on addiction raise major ethical and social issues (Ashcroft, et al., 2007; Carter, et al., 2009; Hall, et al., 2004a). These can be considered under two broad headings: (1) the social and ethical implications of the new understanding of addiction offered by neuroscience and genetic research, and its impact on public understanding of, and policies towards, addiction (Part 2); and (2) the specific ethical issues that arise from the potential use of technologies that have already been developed, or may be developed in future, from neuroscience and genetic research (Part 3). Before discussing these major ethical and social issues, we review recent findings of neurobiological research on addiction (Chapter 3) and describe the new treatments that this research is yielding (Chapter 4).

3 The neurobiology of addiction

3.1.

Introduction

Neuroscience is beginning to reveal the neurochemical changes in the brain that may be responsible for the behavioural manifestations of addiction. In doing so, neuroscience is helping us understand that those who are addicted to drugs may suffer from neurocognitive and motivational impairments that require treatment. Our cognitive abilities enable us to quickly discern which activities are worth pursuing in our environment. Activities that serve important survival needs such as obtaining food, shelter or forming relationships are generally experienced as pleasurable and rewarding, thereby motivating behaviour. We quickly learn which activities are rewarding and what environmental cues are associated with receiving these rewards. These cues acquire an incentive or motivating quality that makes us more likely to pursue the goals that they signal in the future. Highly motivating goals or events become deeply engrained in our thinking, allowing us to respond to these rewards quickly and effortlessly, habitually and often without thinking. This learning increases the efficiency and power of thought by focusing our attention and energy on what is most relevant in our environment, making it more likely that we will achieve our goals with minimum effort. Not all forms of learned and rewarding activities are desirable, however. Drug use can become over-learned in the case of addiction. Repeated drug use over-activates the central reward systems in the brain, enabling drug use to take precedence over other goal-directed activities that are essential to survival. This ability for addictive drugs to strongly activate the reward pathway is commonly referred to as their reinforcing effect. Chronic use of addictive drugs can also dampen the central reward pathway’s responsiveness to the rewarding effects

35

Addiction Neuroethics

36

of everyday activities that motivate us and give life meaning, such as relationships, work and education. These changes are also believed to explain why the pursuit of drugs can come to dominate the lives of many individuals with an addiction, often at the expense of most other interests. Addiction can also impair a number of other cognitive processes that perpetuate drug use. Many symptoms of these impairments are described in the diagnostic criteria for drug dependence or addiction (American Psychiatric Association, 2000; WHO, 1993), including: • • • •

a feeling of compulsion to use drugs; an impaired ability to avoid using drugs when opportunities arise; an impaired understanding of the consequences of continued drug taking; and the ability for cues associated with drug use (e.g. location, time of day, or activities) or stress to produce a relapse to continued drug use in an abstinent individual, months and possibly years after stopping.

Neuroscience is beginning to uncover how chronic use of addictive drugs can also disrupt important neural pathways in the brain that produce these cognitive deficits. This section briefly reviews the neuroanatomical and neurochemical changes that may underpin these cognitive behaviours and describes how they develop and maintain the cycle of addiction. It concludes with a brief review of individual differences in genetic and neuropsychological make-up that can make some persons more vulnerable than others to developing an addiction. The impact that social events can have on how these vulnerabilities are expressed is also briefly discussed. 3.2.

The neuroanatomy of addiction

Addiction is a quintessentially complex behavioural disorder that has effects at the biological, psychological and social levels. This complexity is reflected in the number of neurocognitive systems that are affected by drug addiction. These systems have often been studied in isolation, leading to competing partial theories that purport to explain addiction. A more complete picture of the neuroanatomy of addiction is beginning to emerge from the integration of these different approaches to understanding addiction (Feltenstein and See, 2008; Goodman, 2008; Koob and Le Moal, 2006; West, 2006). Neuroimaging, using technologies such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), has provided critical insights into the way in which drug-induced changes in the brain can produce the type of cognitive deficits seen in drug-addicted people. The ability to

The neurobiology of addiction

37

Figure 3.1. Projections from the midbrain to the NAcc and forebrain. Dopaminergic neurons from the ventral tegmental area (VTA) and substantia nigra project to the central reward area, the nucleus accumbens (NAcc), and to the cortical areas primarily responsible for making decisions, such as whether to use drugs (e.g. the prefrontal cortex (PFC), and the anterior cingulate gyrus (aCG)). (Reproduced with permission from Hyman, et al., 2006.)

visualise the brain of addicted individuals has identified changes in multiple brain systems that may explain the apparent ‘loss of control’ and ‘compulsive’ drug taking in humans, confirming many findings of brain changes occurring in animal models of addiction. These changes may also explain why abstinence is difficult to achieve and why relapse often occurs after long periods of abstinence. The neurocognitive systems that are affected by addictive drugs include: • reward and reinforcement – in the nucleus accumbens (NAcc) • memory, learning and habits – in the amygdala, hippocampus and striatum • compulsion, craving and inhibitory control – in the orbitofrontal cortex (OFC) and anterior cingulate gyrus (aCG) • executive control and cognitive impairment – in the prefrontal cortex (PFC) • representation of bodily urges – in the insula cortex • stress – in the hypothalamic–pituitary–adrenal (HPA) axis. Changes to the reward pathway, with its dense connections to the forebrain and the higher cognitive centres of the frontal cortex, are central to the development of addictive behaviours (see Figure 3.1). However, this is unlikely to be the

Addiction Neuroethics

38

Table 3.1 The neurochemical sites at which drugs of addiction act (Reproduced with permission from Nutt and Lingford-Hughes, 2008) Drug

Target

Opioids Cocaine Amphetamines

Agonist at mu, delta and kappa opioid peptide receptors Inhibits dopamine transporter Stimulates dopamine release. May also stimulate noradrenaline and serotonin release depending on the precise amphetamine analogue being used Facilitates GABA-A and inhibits NMDA glutamate receptor function Agonist at nicotinic acetylcholine receptors Agonist at cannabinoid CB1 and CB2 receptors Facilitates GABA-A function

Ethanol Nicotine Cannabinoids Benzodiazepines

complete picture. This research is still in its infancy and there is considerable uncertainty about the degree to which certain neural regions are involved in addiction. It is also unclear how activities in various brain regions differ between individuals. In particular, there is debate within the field as to whether addiction results from: (a) abnormally strong urges, drives or motivations, which overcome our normal ability to inhibit behaviour or exercise executive control; or (b) cognitive impairment that reduces the ability to inhibit everyday impulses; or (c) some combination of the two. 3.2.1.

Reward and reinforcement: the ‘dopamine hypothesis’

In 2007, neuroscientists celebrated the 50th anniversary of the discovery of the key neurotransmitter, dopamine, by Arvid Carlsson (winner of the 2000 Nobel Prize for Medicine) (Bjorklund and Dunnett, 2007). Dopamine (DA) is arguably the most widely studied neurochemical in biological psychiatry and psychopharmacology (Iversen and Iversen, 2007). Dopamine is a key neurotransmitter that serves a variety of functions, including: fine-tuning motor control and cognitive function; modulating the salience of events and attention, learning and memory; bonding and attachment in relationships; and the planning and motivation of behaviour. Many of the most widely used medications in psychiatry act upon the dopaminergic system. There is a growing consensus that dopamine also plays an important role in addiction to most drugs of abuse (Volkow and Li, 2004), although the nature of its role remains a subject of debate (Berridge, 2007; Tassin, 2008). Despite the highly diverse neurochemical effect of drugs of addiction (see Table 3.1), nearly

The neurobiology of addiction

39

all drugs of addiction appear to activate the reward pathway by either directly or indirectly stimulating the release of dopamine (DA): a fact that was believed to be critically important in the development of addiction (Volkow and Li, 2004; Wise, 1996).1 There is, however, increasing controversy in the literature whether this is true of all drugs of addiction (e.g. Daglish, et al., 2008), and about what these increases in DA actually signify.2 The majority of neuroscience research on addiction (estimated to be 85%) is funded by the NIDA. NIDA’s leaders (e.g. Leshner and Volkow) have promoted one view of this work: the view of addiction as a ‘chronic relapsing brain disease’ driven primarily by changes in the dopaminergic reward pathway. Many neuroscience researchers have argued for a broader view and caution against prematurely accepting the, albeit highly plausible, dopamine hypothesis until these studies have been replicated in larger and more diverse populations addicted to a broader range of drugs. For example, dopamine does not explain all facets of addiction, especially opioid addiction (Daglish, et al., 2001). Other neurotransmitter systems are involved in the learning and reinstating of addictive behaviour and the euphoric effects of addictive drugs. Research is beginning to show that addiction also involves changes in other neurochemicals and neurotransmitter systems, including the endogenous opioids, glutamate and gamma-aminobutyric acid (GABA), noradrenaline, serotonin, the orexins, and corticotropin-releasing factor (CRF) (Goodman, 2008), some of which are discussed below. While changes in these systems are indeed important in a variety of addictions, they nearly all appear to exert their influence, directly or indirectly, through the dopaminergic reward system (Goodman, 2008). A complete discussion of all the neurochemicals involved in addiction is beyond the scope of this book. Those interested in the neurochemical activity of other molecules in addiction, in particular the important roles of noradrenaline, serotonin, GABA and glutamate, should refer to the comprehensive review by Goodman (2008).3 1

2

3

Neither benzodiazepines nor solvents (e.g. toluene) have been shown to increase DA in the nucleus accumbens (NAcc). In recent years, some researchers have questioned this received wisdom arguing that dopamine (with the possible exception of psychostimulant abuse) is not required for the initiation of addiction, that is the rewarding properties of addictive drugs, and is more important in the learning of reward, that is, the association of drug-induced reward with specific events or cues. Since 2005, pharmacological and genetic studies have highlighted an important role for noradrenaline and serotonin in the development and maintenance of addictive behaviours (Salomon, et al., 2006) that may occur independently of dopamine (Lanteri, et al., 2008).

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Addiction Neuroethics

Amphetamines, cocaine, alcohol, nicotine and cannabis, directly or indirectly, act on a forebrain structure known as the nucleus accumbens (NAcc) producing large and rapid releases of dopamine (Di Chiara, 1998; Robbins, et al., 2007). This increase in dopamine appears to be central to the development of addiction. The signal produced by addictive drugs originates in the neurons of the midbrain ventral tegmental area (VTA), which release dopamine into synapses in the NAcc (Di Chiara, 1998; Koob and Bloom, 1988; Wise and Bozarth, 1987), as shown in Figure 3.1. Cocaine, amphetamines and ecstasy increase the amount of dopamine available for post-synaptic signalling, either by increasing dopamine release or by reducing dopamine reuptake from the synapse (Hutcheson, et al., 2001) (see Figure 3.2). Alcohol, cannabis and nicotine increase dopamine activity indirectly, by stimulating neurons that influence dopaminergic neurons (Koob and Le Moal, 1997; Nisell, et al., 1994). For example, alcohol binds to GABA receptors that reduce the inhibitory influence of GABAergic neurons on dopamine-firing cells (see Figure 3.3).

Dopamine, reward and learning The NAcc is a critical part of the neural system involved in learning, reward and motivation. Everyday rewarding activities, or natural reinforcers, such as food, relationships and sex, produce much smaller increases in accumbal dopamine than drugs of addiction, some of which produce 10 times more dopamine in the NAcc than natural reinforcers. The increased dopamine response to these drugs also lasts much longer than natural rewards (Kelley and Berridge, 2002). It is this excess release of dopamine by addictive drugs that is thought to make drug use so much more appealing than everyday rewarding activities that some users repeatedly use drugs despite serious negative consequences (Hyman, 2005) (see Figure 3.4). The increase in dopamine signalling in the NAcc was believed to give drugs their rewarding or euphoric affects. Neuroimaging studies of intoxication show that increases in accumbal dopamine correlate with subjective reports of euphoria (Volkow, et al., 2004a). This is clearest for stimulant drugs (Drevets, et al., 2001; Laruelle, et al., 1995), although it has not always Such research appears to contradict studies that block dopamine during the self-administration of addictive drugs in animals (Koob and Le Moal, 2006). There is considerable debate in this area and more research is required. Interested readers are directed to a recent article in Biochemical Pharmacology by Tassin (2008).

Figure 3.2. Psychostimulant increase of dopamine activity at the accumbens. Stimulants such as cocaine and amphetamine increase synaptic dopamine at the nucleus accumbens by: (a) blocking the dopamine agonist transporter (DAT) (cocaine), which removes dopamine from the synapse, thus increasing the amount of dopamine active in the synapse and thereby increasing dopamine signalling; or (b) entering the dopamine neurons via DAT (amphetamine) and causing an increase in dopamine released by the neuron. (Reproduced with permission from Hyman, et al., 2006.)

Addiction Neuroethics

42 Nicotine, alcohol Opiates

Opioid peptides

–

Glutamate inputs (e.g. from cortex)

µ GABA

VTA interneuron Alcohol

+

?

Glutamate inputs (e.g. from amygdala)

+

?

– Stimulants

DA NAChR

PCP

– µ NMDAR

+ Nicotine

Alcohol

Opiates

DA

D1R or D2R

Cannabinoids

+

VTA

NAcc

Figure 3.3. Actions of a variety of drugs on accumbal dopamine activity. Nearly all drugs of addiction act by increasing the release of dopamine in the nucleus accumbens (NAcc; bottom right). This increase may be direct, such as with stimulants, which increases the release of dopamine by neurons of the ventral tegmental area (VTA; bottom left). Other drugs of addiction (e.g. alcohol, opioids, cannabis and nicotine) increase dopamine activity indirectly, by influencing neurons which then change the amount of dopamine released into the NAcc. This may be the result of an inhibition of a disinhibiting response, such as occurs with the opiates, as well as an excitatory response (e.g. nicotine). Note: ‘þ’ refers to an excitatory response, ‘’ denotes inhibition. NMDAR: N-methyl-D-aspartic acid receptor; NAChR: nicotinic acetylcholine receptor; PCP: phencyclidine; D1R: dopamine receptor 1; D2R: dopamine receptor 2. (Reproduced with permission from Hyman, et al., 2006.)

been found. There are many studies that show a poor correlation between subjective states of pleasure and drug taking (Robinson and Berridge, 2000). As tolerance develops, the consumption of larger amounts of drugs does not increase the amount of pleasure experienced. In fact in most cases, rewarding effects decrease with increasing use. Moreover, nicotine, a highly addictive drug, increases dopamine release in the NAcc in the absence of significant euphoric effects (Balfour, 2004; Koob and Le Moal, 2006; Nisell, et al., 1994). Research by Robinson et al. (2005) suggests that the hedonic effects of drug use are mediated by the opioid system rather than dopamine (see below). Recent research suggests that dopaminergic release within the NAcc may reflect the significance of stimuli, rather than their euphoria-inducing capacity. Chronic drug use produces changes in the motivation or reward pathway that

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Cocaine

Dopamine transporters

Dopamine Dopamine receptors FOOD

COCAINE

Figure 3.4. Rewarding activities increase dopamine signalling. Drugs of addiction act on the brain’s reward pathway to cause enormous increases in dopamine activity in the nucleus accumbens. Everyday activities also increase dopamine activity in this reward pathway, but to a much smaller extent. The exaggerated release of dopamine due to drugs such as cocaine produces changes in other parts of the nervous system that focus attention on drug use. (Source: adapted from the NIDA website: http:// www.nida.nih.gov/scienceofaddiction/images/014_big.gif)

sensitise the reward system to addictive drugs and drug stimuli. These systems do not mediate the pleasurable or euphoric aspect of drug taking so much as a ‘subcomponent of reward’ described as salience (Robinson and Berridge, 2000, p. s94). By associating large increases in dopamine with drug taking and drug stimuli, users learn to take drugs independently of any pleasure that their use may bring. Thus events may be perceived as salient not just because of their rewarding effects, but because they are novel or grab attention. This property may explain why aversive or unpleasant stimuli are also able to motivate behaviour (Robinson and Berridge, 2000), why drug use persists long after its immediate effects cease to be rewarding, and why nicotine increases dopamine release without producing euphoria (Robbins, et al., 2007). Research suggests that dopamine functions as a signal for learning about experiences; DA signals when a rewarding experience is new, better than expected or unanticipated (Schultz, 2006; Schultz, et al., 1997). This dopamine signal has been referred to as the prediction error signal (McClure, et al., 2003; Schultz, 2010). It is important in identifying and remembering which activities or experiences are worth repeating (Berridge and Robinson, 1998). Hence, when the dopamine system becomes over-aroused by drug use, the pursuit of the repetition of these effects can dominate other important goal-directed activities, leading to repeated use of a drug. While research suggests that drug use initially increases dopamine release, it is believed that chronic use of some drugs (e.g. cocaine, methamphetamine, nicotine and cannabis) dramatically decreases dopamine signalling

Addiction Neuroethics

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Healthy control

Drug abuser

Figure 3.5. Decreased dopamine receptors due to drug abuse. While drug use initially produces large increases in dopamine activity, chronic drug use eventually leads to a significant reduction in dopamine activity. Abuse of the stimulant, methamphetamine, produces significant decreases in the density of dopamine receptors in the striatum. Such persistent changes in dopamine signalling are thought to explain why individuals with an addiction become so motivated to consume these drugs. (Source: NIDA website, adapted from Volkow, et al., 2001.)

(Fehr, et al., 2008; Heinz, et al., 2005; Sevy, et al., 2008; Volkow and Fowler, 2000). Repetitive dopamine release in the reward pathway is believed to lead to a ‘down-regulation’ of dopamine signalling, and a dampening of activity in the reward pathway. This appears to largely result from a decrease in the availability of post-synaptic dopamine receptors in the striatum and NAcc (Cosgrove, 2010; Volkow, et al., 2009) (see Figure 3.5). Chronic drug use therefore significantly reduces activity in the dopaminergic reward system and appears to reset the threshold for activating the reward system, thereby making the NAcc less sensitive to the rewarding effects of everyday activities. However, increased doses of addictive drugs can still produce large dopamine releases that are able to activate the reward centres. As repeated drug use gains enhanced salience over everyday reinforcing activities, the conditioned association between the drug’s effects and external cues is strengthened. It is not yet clear whether the changes described are the result of chronic drug use, as Volkow and others suggest, or a pre-existing state that drives vulnerable individuals to use drugs (Garavan, et al., 2007). Large prospective studies that are now underway in Australia, the US and Europe (e.g. IMAGEN) may provide answers to these questions (Schumann, 2007).

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Dopamine and withdrawal The changes in the dopaminergic reward system produced by chronic drug use may also explain the process of drug withdrawal (Hyman, et al., 2006). Abrupt cessation of chronic drug use leads to a decrease in dopamine release and an elevated reward threshold that is experienced as aversive. These effects can lead to drug-seeking in order to relieve the aversive state of withdrawal. Relief of withdrawal symptoms can become a motivational state like thirst or hunger that motivates drug-seeking (Hutcheson, et al., 2001; Koob and Le Moal, 1997). The dopamine theory of addiction is a hedonic model of addiction. It assumes that individuals use addictive drugs to experience their pleasurable effects and avoid withdrawal symptoms (sometimes referred to as an aversive model of addiction). While withdrawal partially explains the desire of ‘addicts’ to take drugs, it does not explain the compulsion or loss of control over use in addiction, particularly once an addicted individual becomes abstinent (O’Brien, et al., 1998; Tiffany, 1990). In seeking to explain these phenomena, recent neurobiological research has focused on the effects that chronic drug use has on regions of the brain involved in behavioural control, memory, cognition and decision-making, and on other neurotransmitter systems, including the opioid system.

3.2.2.

The endogenous opioid system

The brain’s endogenous opioid system plays a significant role in addiction. It comprises a number of different peptides (e.g. endorphins, encephalin and dynorphin) that interact with one of the three opioid receptors – mu, delta and kappa. Mu receptors mediate the pleasurable effects of opioid drugs, such as heroin and morphine, and endogenous opioids, such as the endorphins.4 The identification of the mu-opioid receptor (MOR) as the site of action for heroin and other opioids led to the development of antagonists (drugs like naloxone and naltrexone) that prevent the rewarding effects of heroin by binding to the same receptors. Changes in brain opioid receptors may also play a part in addiction to other drugs, such as cocaine (Zubieta, et al., 1996) and alcohol (Heinz, et al., 2005). This may explain why opioid antagonists, such as naltrexone, appear to have some efficacy in the treatment of alcohol 4

Mice that do not possess mu-opioid receptors do not self-administer opioids (Becker, et al., 2000).

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(Pettinati, et al., 2006) and other addictions (Jayaram-Lindstrom, et al., 2008), including the so-called ‘behavioural addictions’, such as pathological gambling (Lahti, et al., 2010) and obesity (Greenway, et al., 2010) (see Section 4.5.1). Changes in dopamine and opioids in response to drug use appear to be necessary for the development of addiction.5 However, large increases in dopamine activity in the limbic regions are not sufficient because they can occur in both addicted and non-addicted individuals. Dopamine release explains why drugs of addiction are rewarding or reinforcing, but it does not explain why some users stop using drugs while others continue to do so when they are no longer rewarding, and in the face of negative social and physical consequences of use. Addiction may reflect the effects of a number of plastic changes, or neuroadaptations, in brain regions that are responsible for cognitive performance (see Section 3.8).

3.3.

Memory, learning and habits

Addiction involves learning new habits and associations. Drug-related cues can elicit craving in abstinent drug users and trigger relapse (O’Brien, et al., 1998). Stress and exposure to small amounts of a drug of addiction can also cause abstinent drug users to relapse to regular, harmful drug use. Animal studies show that a single exposure to a conditioned stimulus can reinstate addictive behaviours in animals that have been abstinent for long periods of time (Gold and Koob, 1989). It is not surprising, then, that changes in the neural pathways that underpin the learning of habitual behaviours (or conditioned responses) are involved in the development of addiction (Everitt and Robbins, 2005). Areas of the limbic system, primarily the hippocampus and the amygdala, are critical in the acquisition, consolidation and expression of drug-stimulus learning that seem to drive relapse to drug-seeking behaviours (See, 2005; Weiss, et al., 2000). Changes in the caudate and putamen are responsible for habit learning. Research suggests that the formation of habits can give special salience to cues and contexts in which drugs are used. These learned drug associations can stimulate drug craving that leads to relapse.6 5

6

Dopamine antagonists which block the release of dopamine prevent the reinforcing effects of drug use in animals. Rats treated with dopamine antagonists fail to associate the effects of drug use with the context in which the drugs were given (Hyman, 2005). More details of the different processes operating in each of these neural regions can be found in Everitt and Robbins (2005), Robbins and Everitt (2002), White (1996) and Wise (2004).

The neurobiology of addiction 3.4.

47

Compulsion, craving and inhibitory control

Neuroimaging researchers have studied changes in the frontal cortex of addicted individuals, particularly the orbitofrontal cortex (OFC) and the anterior cingulate gyrus (aCG). These regions are hypothesised to be involved in craving and compulsive drug taking and loss of control over drug use, respectively (Feil, et al., 2010; Jentsch and Taylor, 1999; Yucel and Lubman, 2007). The OFC provides internal representations of the salience of events and assigns values to them, allowing individuals to compare the likely consequences of pursuing different goals (Schoenbaum, et al., 2006). The aCG is involved in the inhibition of impulses to act (Yucel and Lubman, 2007) and in the control of attention (Bush, et al., 1998). Imaging studies have shown that reduced dopamine activity in the NAcc correlates with changes in activity in the OFC and the aCG (Goldstein and Volkow, 2002; Volkow and Fowler, 2000; Volkow and Li, 2004). Exposure to drugs and drug-related cues also dramatically increases activity in the OFC and aCG of addicted individuals (Daglish, et al., 2001) (see Figure 3.6). The increased metabolic activity in the OFC and aCG of active drug users in response to dopamine is thought to partly explain craving. Addicted individuals show increased activation in the OFC when presented with drug cues, memories of past drug experiences or their drug of addiction. The level of activity in the OFC and aCG is correlated with subjective drug craving (Daglish, et al., 2001; Risinger, et al., 2005; Volkow and Fowler, 2000). Changes in dopamine activity in the OFC also accompany the process of withdrawal (Volkow, et al., 1991). As an addicted drug user undergoes detoxification, metabolic activity within the OFC decreases from extremely high to extremely low. Exposing addicted individuals during withdrawal to either their drug of choice or drug-related cues produces hyperactivity within the OFC that is correlated with self-reported drug craving. These changes within the OFC can persist into abstinence, explaining why many abstinent drug users report continued urges to use drugs and relapse in response to drug-related cues. 3.5.

Executive control and cognitive impairment

It would appear self-evident that addicted persons have impaired executive control: an impaired ability to reason and rationalise decisions and actions. It is only recently, however, that changes in the neural centres of executive control and cognitive decision-making have been observed in addiction (Bechara, 2005; Garavan and Stout, 2005; Goldstein, et al., 2007; Goldstein, et al., 2009).

Addiction Neuroethics

48 (a) PFC ACG HIP

OFC NAcc

VP

Amyg

(b)

NON-ADDICTED BRAIN

ADDICTED BRAIN

PFC ACG

PFC ACG

GO

NO GO NAcc VP

OFC HIP Amyg

NAcc VP

OFC

HIP Amyg

Figure 3.6. This is a schematic diagram of the neuroanatomy of addiction, which depicts the plastic changes that result from chronic drug abuse and produce addiction. (a) The sagittal (side-on) view of a brain depicting four circuits that are postulated to have key roles in addiction: (1) the prediction of reward and pleasure involve the nucleus accumbens (NAcc) and ventral pallidum (VP); (2) memory and learning occur in the amygdala (Amyg) and hippocampus (HIP); (3) motivation, drive and salience evaluation occur in the orbitofrontal cortex (OFC); and (4) cognitive control, in charge of restraining cravings, is located in the prefrontal cortex (PFC) and anterior cingulate gyrus (ACG). (b) A hypothetical model of addiction. Chronic drug use increases the salience value of a drug and its associated cues in addiction (right) when compared to the non-addicted brain (left), whereas the strength of inhibitory control is weakened, setting up the stage for an unrestrained motivation. This results in the repeated use of drugs despite the attempts to stop. (Reproduced with permission from Baler and Volkow, 2006.)

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Hyman (Hyman, 2005, Hyman, et al., 2006) has suggested that the ability to update information within the PFC, select new goals and avoid the compulsive repetition of a particular behaviour is controlled by dopamine release. He hypothesises that changes in dopamine signalling affect our ability to select new goals or choose different behaviours. This appears to be confirmed by computational studies of firing in dopaminergic neurons (Schultz, 2006, 2007; Schultz, et al., 1997). Addictive drugs are believed to provide a potent signal that disrupts normal dopaminerelated learning in the PFC. Natural rewards, by contrast, produce relatively low levels of dopamine signalling, and so may fail to open the ‘PFC gate’. This may bias the behaviour of addicted individuals towards drug use and away from normal everyday activities. This hypothesis is supported by neuroimaging studies, which show that drug-related cues acquire an exaggerated incentive salience because they produce dopamine release in the nucleus accumbens and prefrontal cortex. As a result, drug-seeking behaviour is strengthened by dopamine effects in the prefrontal cortex (Berke, 2003; Berke and Hyman, 2000; Robbins and Everitt, 1999). In addition to increased motivation to use drugs, addicted individuals often have cognitive impairments that prevent them from recognising the consequences of their drug use or inhibiting their impulses to use drugs. Imaging research has found changes in the dorsolateral PFC and the aCG that seem to prevent addicted individuals from considering options other than drug use or inhibiting impulses to use drugs (Feil, et al., 2010; Garavan, et al., 2007). Neuroimaging studies are supported by neurocognitive tests that have found impaired attention and reduced executive control in addicted individuals (Bechara, 2001; Fillmore, 2003; Hester and Garavan, 2004). There is also evidence that drug users have impairments in the OFC region that are involved in attributing emotional value to outcomes. Drug users perform worse than healthy controls but better than patients with OFC damage on gambling tests, cognitive tasks which assess the ability of individuals to refuse large, immediate rewards with even larger losses, in favour of smaller, but long-term benefits (Bechara, 2005; Garavan and Stout, 2005; Goldstein, et al., 2007; Rogers, et al., 1999). These studies indicate that drug users are less able to activate the OFC while undertaking the gambling task (Ersche, et al., 2005). It is not possible within the scope of this book to fully review this vast area of research. Interested readers are directed to reviews by Yucel and Lubman (2007) and Feil et al. (2010).

Addiction Neuroethics

50 3.6.

Representing bodily urges

Several commentators have argued that in addition to the cognitive processes of analysing and balancing different action options, decision-making also includes affective and visceral processes (Paulus, 2007). There is an increasing emphasis on the role that interoception – the awareness or sensation of the body – plays in choosing certain actions (Craig, 2002; Damasio, et al., 2000). Interoception is important for an organism to maintain homeostasis: the process that keeps the body functioning in a stable, generally productive condition (Damasio, 1999). It is important in helping to decide what is required to meet the body’s needs (Paulus, 2007). The insular cortex – a region at the intersection of the frontal, temporal and parietal lobes – has been implicated in the representation of bodily sensation. The insula receives inputs from the cortex and the thalamus, which conveys information about the emotional and homeostatic state of the body. The insula also has projections to the sensory and association cortices, the OFC and aCG, and the brainstem and limbic system, including the amygdala, hypothalamus, NAcc and striatum. These dense connections enable the insula to integrate information from the body, emotional centres and conscious thoughts from cortical regions, and facilitate the conscious perception of the physiological state of the body. It sends this information to prefrontal cortical regions where it may influence decisions on what to do (Everitt and Robbins, 2005). Given the role that these functions play in addiction, it is not surprising that the insula is involved in addiction, and in particular, the perception of craving (Contreras, Ceric and Torrealba, 2007). Animal studies suggest that the insula may represent internal body states, such as craving, withdrawal, or the desire to take drugs, that are triggered by drug-associated cues (Bonson, et al., 2002; Kilts, et al., 2001). The insula is active during cue-induced craving in addicted subjects and its level of activation is correlated with subjective drug craving (Contreras, et al., 2007). Inactivation of the insula also prevents drug-seeking in rats (Contreras, et al., 2007). Individuals who suffered lesions to the insular cortex were able to quit smoking easily and without cravings (Naqvi, et al., 2007). 3.7.

Stress and drug use

Observational studies in addicted humans show that stress is a potent trigger for relapse to drug use (Koob, 1999). Stressful events, particularly when they occur repeatedly, make abstinent drug-addicted individuals more likely to relapse by increasing negative affect. Chronic drug use also produces neuroadaptive changes in what has been termed the ‘anti-reward’ pathway:

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51

the hypothalamic–pituitary–adrenal (HPA) axis and associated neuropeptides (Koob and Le Moal, 2005). Individuals in acute drug withdrawal show increased activity of CRF in the HPA and regions of the limbic system, and increased release of noradrenaline and dynorphin, both of which are associated with relapse to drug use. Stress and stress hormones can directly affect the reward pathway making individuals more vulnerable to developing drug addiction. While both acute and chronic stress affect the dopaminergic reward pathway, their effects on drug use differ. Acute stress triggers the release of dopamine (Marinelli and Piazza, 2002). The rapid increase of dopamine in the mesolimbic reward pathway can motivate drug-seeking in dependent individuals and lead to relapse in abstinent individuals (Marinelli and Piazza, 2002). While acute stress releases hormones that trigger the release of dopamine into the NAcc (Stamford, et al., 1991), repeated release of stress hormones, and consequently dopamine, sensitises the reward system over a long period of time (Marinelli and Piazza, 2002). Chronic stress results in neuroadaptations within the reward pathway that dampen dopaminergic activity and reduce sensitivity to normal rewards. These neuroadaptations to chronic stress are thought to reflect a reduction in the number of dopamine receptors that leads to the development of anhedonia; an inability to experience pleasure.7 This sensitisation makes former addicted individuals more responsive to addictive drugs and can persist well after the stress has abated. Genetically heightened sensitivity to stress or anxiety can also make individuals more sensitive to the effects of stress, and hence more vulnerable to developing addiction (Marinelli and Piazza, 2002). See Section 3.9.

3.8.

Molecular and cellular changes in addiction

There is increasing evidence that chronic drug use, and the changes in dopamine signalling outlined above, produce neuroadaptations at the molecular and cellular level in the neurocircuitry that maintains addiction; that is, in the mesolimbic and mesocortical systems. Chronic drug use leads to plastic changes at synapses in key neural circuits that are believed to be responsible for the characteristic addictive phenomena of craving, relapse and impaired decision-making and control over drug use (see Figure 3.7). 7

This sensitisation of the reward system due to chronic stress, the down-regulation of the dopamine receptors and the development of anhedonia is thought to be involved in some cases of depression, and suggests why dopamine agonists that aim to ameliorate this effect are effective in the treatment of depression. For further information see Willner (1997) and Willner et al. (2005).

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Figure 3.7. Schematic diagram of molecular changes in neural cells in response to drug use. Addictive drug use can produce downstream changes in intracellular (or second messenger) pathways that are believed to mediate changes in behaviour. It may also affect the regulation of gene expression, that is, produce epigenetic effects. These second messenger pathways also influence other cellular processes, such as cell-to-cell signalling at the synapse. This is referred to collectively as synaptic plasticity. (Reproduced with permission from, Nestler, 2004.)

3.8.1.

Synaptic plasticity in addiction

There has been significant research since the early 1970s to identify the molecular and cellular processes that can strengthen or weaken the connectivity between neurons. This process, which is referred to as synaptic plasticity, describes the molecular and cellular events by which information, experience or learned responses are represented in the brain. Synaptic plasticity allows synaptic connections to be strengthened, via long-term potentiation (LTP), or weakened, via long-term depression (LTD). LTP and LTD explain how learning is encoded via molecular and cellular changes in neural connectivity. The process underlying LTP is captured in the phrase: ‘neurons that fire together, wire together’.

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53

The association between synaptic changes and learning and memory was first described in hippocampal neurons, a region important in remembering the details or facts of events. It has been argued that addiction is a pathological form of learning and memory (Hyman, 2005; Hyman, et al., 2006; Kelley, 2004). Synaptic plasticity involves basic molecular processes that occur at most synapses throughout the brain, including the mesolimbic reward pathway and cortical regions, which are involved in strengthening or weakening synapses associated with a variety of cognitive functions. There is increasing evidence that synaptic plasticity is involved in the development and maintenance of addiction (Kauer and Malenka, 2007). Many of the molecules implicated in LTP and LTD have been shown to be involved in the synaptic plasticity arising from drug abuse (Kauer and Malenka, 2007; Kelley, 2004). Blocking some of these molecules, for example, prevents synaptic changes in animal models of addiction and the development of addictive behaviour (Kauer and Malenka, 2007). Many of the signalling molecules mentioned earlier are able to induce plastic changes at the synapse that underpin long-term neuroadaptations (for example, see Featherby, et al., 2008). The development of more deeply ingrained addictive behaviours in response to chronic drug use over longer periods of time are the result of plastic changes in the NAcc and other limbic regions. Synaptic plasticity within these regions results in the formation of strong, long-lasting associations between the reinforcing aspects of drug use and the various cues, both external and internal, connected with drug use (Calabresi, et al., 2007). It is these long-lasting changes that may underpin the experience of drug craving, the motivation to use drugs, and relapse on re-exposure to cues associated with drug use or when placed under stress. The study of the synaptic plasticity of addiction is a relatively new field of research (Kauer and Malenka, 2007; Pollock and Ramaswami, 2009). Identification of the molecular and cellular changes that maintain addiction may enable the development of novel pharmacological drugs that reverse or reduce some of these changes and thereby increase our ability to treat addiction (Calabresi, et al., 2007). The difficulty will be in finding drugs that can undo the pathological changes involved in addiction without impairing normal processes of learning and neuronal adaptation. 3.8.2.

Epigenetic changes in addiction

In recent years, there has been increasing interest in how environmental factors, such as stress, aggression and drug abuse, can regulate the

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expression of genetic information (Renthal and Nestler, 2008). The study of non-genetic factors that alter the expression of genes is referred to as epigenetics (Tsankova, et al., 2007). Research shows that environmental events or epigenetic factors, such as drug abuse, can interfere with gene expression by physically altering the ability of transcription factors8 to bind to the DNA (deoxyribonucleic acid) and transcribe a given gene (Maze and Nestler, 2011). These changes alter gene expression, without affecting the genetic code in the cellular central DNA. They do so in ways that influence other cellular processes (e.g. synaptic connectivity) that underpin the neurocognitive changes in addiction (Renthal and Nestler, 2008). In the cell nucleus, chromosomal DNA is tightly coiled around structures called histones that can prevent or inhibit the transcription of a given gene. Epigenetic events can cause chemicals to bind to the chromosome – a process called chromatin remodelling – that can interfere with gene expression in two ways. It can produce methylation (add methyl groups to DNA) that inhibits gene expression, or it can produce acetylation (add acetyl groups to the histones that loosen DNA folding) that facilitates gene expression. Research is beginning to identify epigenetic changes produced by drug abuse that may affect plasticity at the synapse. The chronic use of addictive drugs appears to produce a number of changes in neurons. It can increase dendritic branching and the formation of dendritic spines (Maze and Nestler, 2011; Robinson and Kolb, 2004). These are the specialised regions on the dendrites that enable the formation of strong synapses that facilitates faster synaptic signalling. These changes can play an important part in LTP and synaptic plasticity described above. Chronic administration of cocaine to rats, for example, increases dendritic branching and causes epigenetic modifications that increase synaptic plasticity (Nestler, 2004). Researchers have elucidated a number of the molecular mechanisms that are involved in epigenetic processes (see Renthal and Nestler, 2008) that could explain how drug use produces neuroadaptations that make addiction such a persistent problem. These molecules provide another potential target for pharmacological interventions to reduce and possibly reverse the effects of drug use.

8

Transcription factors are proteins that regulate the formation of RNA (ribonucleic acid) from DNA.

The neurobiology of addiction 3.9.

55

Vulnerability to addiction: genetic and neuropsychological factors

This section briefly summarises research on two related topics: (1) studies of twins and genetic association studies which indicate that genetic factors, such as individual differences in drug metabolism and neurotransmitter responses to drug effects, contribute to individual differences in vulnerability to addiction; and (2) neuropsychological and neuroimaging studies which suggest that genetic differences in addiction vulnerability may also underlie individual differences in cognitive performance that influence vulnerability to addiction. 3.9.1.

Genetic susceptibility to addiction

Familial studies have consistently shown that addiction ‘runs in families’ (Merikangas, et al., 1998), suggesting that there is a substantial genetic contribution to addiction vulnerability (Ball, 2008; Ball, et al., 2007). Twin studies indicate that addiction is among the most heritable of the complex psychiatric disorders (Goldman, et al., 2005) despite the fact that an individual must engage in drug use for the genetic predisposition to be expressed, and that decisions to use drugs can be influenced by personal choices and social policies. Evidence from twin and adoption studies suggests that 40–60% of the risk of developing substance abuse disorders is due to genetic factors (Li and Burmeister, 2009; Uhl, et al., 2004). Some studies suggest that the genetic contribution to addiction to some substances, such as cocaine, may be as high as 70% (Goldman, et al., 2005). An individual’s inherited genetic make-up can influence addiction risk in a number of ways. Genes may affect: the way in which individuals respond to particular substances (e.g. drug metabolism, absorption and excretion, and activity or sensitivity to drugs); behavioural traits that influence an individual’s willingness to try drugs (e.g. risk-taking behaviour, impulsivity, novelty-seeking); or the likelihood of developing problem use or dependence if a person uses drugs (e.g. how rewarding they find the effects of drugs) (Rhee, et al., 2003). This suggests two broad types of genetic predispositions to addiction: (1) genetic profiles that make some individuals more likely to find the acute effects of drugs rewarding; and (2) genetic profiles that make individuals more or less susceptible to developing addiction if they use drugs. Despite the strong evidence of genetic contributions to addiction vulnerability, attempts to reliably identify specific addiction susceptibility genes have been disappointing to date. Large-scale linkage and association studies

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have identified numerous promising candidate genes that confer vulnerability to addiction (Ball and Collier, 2002; Tyndale, 2003) but until recently, few of these alleles have been consistently replicated, and many of the associations that have predict only a modest increase in the risk of addiction (Ball, et al., 2007; Li and Burmeister, 2009). Most of the candidate genes identified so far are associated with the activity of dopamine and the dopaminergic system, dopamine receptors and transporters (e.g. catechol-O-methyl transferase (COMT) and dopamine receptor 2 (D2)), or proteins that influence the pharmacological activity or metabolism of addictive drugs. The strongest evidence for vulnerability or resilience to addiction concerns the gene, aldehyde dehydrogenase 2 (ALDH2), which encodes a variant of the enzyme involved in the metabolism of ethanol (Chen, et al., 1999; Thomasson, et al., 1991). The ALDH2 gene encodes for a less active variant of the metabolic enzyme. Individuals who are homozygous for the ALDH2 allele (i.e. have two copies) are more likely to experience facial flushing, nausea and headaches if they drink alcohol. A high prevalence of these alleles is thought to explain the lower incidence of alcoholism in some East Asian populations (Nestler, 2000). As addiction is a complex disorder, there are likely to be many genes associated with addiction risk, most of which make a small individual contribution to risk (Ball, 2008; Hall, et al., 2004b; Khoury, et al., 2003; 2004). The most plausible hypothesis is that there are a substantial number of genes that are involved in the initiation, adoption, persistence and cessation of drug abuse, each of which carries a small relative risk (Lerman and Berrettini, 2003). The effects of these types of genetic profiles will depend on environmental cues and triggers, such as stress, opportunity to use different drugs, peer and parental drug use. Improved understanding of genetic contributions to the development of addictive disorders raises the possibility that we can prevent the onset of drug use and addiction in high-risk individuals. It may be possible, for example, to prevent addiction by vaccinating individuals who are genetically vulnerable to addiction against the rewarding effects of drugs of abuse. Psychopharmacotherapies could also be tailored to an individual’s genomic vulnerabilities (referred to as pharmacogenomics or pharmacogenetics) to allow more effective and efficient treatment of addiction. By identifying genes and genetic products implicated in the development of addiction, such as initiation, problem drug use, tolerance, withdrawal, dependence, craving and relapse, it may also be possible to develop treatments tailored to an individual’s genetic and neuropsychological vulnerabilities. We discuss the plausibility and ethical issues raised by such proposals in Chapter 12.

The neurobiology of addiction 3.9.2.

57

Vulnerabilities to addiction: a confluence of the genetic and the social

There are also social factors that make some individuals more likely to develop an addiction than others. These include socio-economic background, exposure to parental drug use, peer drug use and early exposure to drugs, physical or sexual abuse, poor performance at school, and mental disorders, such as conduct disorder, anxiety and depressive disorders that develop during adolescence (Hawkins, et al., 1992). Both genetic and environmental susceptibilities to developing addiction are mediated by neuropsychological changes in the brains of drug users. Genes implicated in addiction are thought to produce changes in the structure or function of specific neural circuits during development that affect an individual’s responsiveness to the effects of drugs. The fact that the addiction liability of different drugs (i.e. their neuropharmacological properties) correlates with the genetic risk of addiction suggests that genetic vulnerabilities to addiction are mediated by neurobiology (Goldman, et al., 2005; Goldstein and Kalant, 1990). Environmental stressors and early exposure to drug use, particularly during adolescence and early development, can also have significant neuropsychological effects that leave individuals vulnerable to substance abuse or addiction (Volkow and Li, 2005). These events may also induce epigenetic changes (Maze and Nestler, 2011) (see Section 3.8.2). Brain imaging studies also suggest that addiction vulnerability may be increased by: a decreased sensitivity to natural reinforcers; disrupted activity in control circuits; sensitivity to conditioned drug stimuli; responses of motivation/drive circuits to drugs; and neurobiological factors involved in the modulation of these circuits (Volkow and Li, 2004). As already discussed, differences in dopamine circuits are thought to underlie individual differences in responsiveness to drug effects that, in turn, influence vulnerability and resilience. This variation in responsiveness to drugs is heavily influenced by genetic make-up. Dopamine activity is also affected by environmental events; for example, stress can increase dopamine release in the NAcc (Koob, 1999) and levels of the dopamine receptors (Papp, et al., 1994). In primate studies, for example, dopamine activity was shown to be affected by an individual’s position within the social hierarchy (Morgan, et al., 2002). Dopamine function also influences predispositions to self-administer drugs in animals, and genetic manipulation of the dopamine receptor, D2, markedly affects drug self-administration. Low D2 levels might predispose an individual

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to use drugs to compensate for decreased activation of the reward circuit, whereas high D2 levels might be protective. Genetic up-regulation of D2 receptors in rats reduces alcohol consumption, suggesting a new target for drug treatment or an environmental manipulation that increases D2 expression. The fact that many non-addicted individuals have low D2 levels suggests that low D2 only predisposes to addiction. More research is required to resolve this question. Other behavioural traits or cognitive capacities unrelated to the dopaminergic reward pathway may also influence vulnerability to addiction. Functional MRI of impulsive individuals reveals differences in the corticolimbic behavioural arousal and control circuits that are affected by addiction (Brown, et al., 2006). Cognitive control is another relatively stable trait that is an important predictor of life success and one that may play an important role in the development of addiction (Eigsti, et al., 2006). Individuals with disorders of impulsivity, such as attention deficit hyperactivity disorder (ADHD), or cognitive impairment are more likely to develop substance abuse disorders (Lynskey and Hall, 2001). There is also a high incidence of substance abuse among individuals with anxiety or depressive disorders in whom addiction may be the result of a failed attempt to self-medicate dysphoric (or unpleasant) mood states (Khantzian, 1985, 1997). Chronic drug use can also produce anxiety and depressive disorders, suggesting that the causal relationship between addictive and affective disorders can probably occur in both directions, and to varying degrees in different individuals. Epidemiological and neuropsychological research suggests that the brains of adolescents and young adults may be more vulnerable to addiction and substance abuse (Lubman, et al., 2007b; Volkow and Li, 2005). Mesocortical tracts that are involved in cognitive processing, executive control and motivation are not fully developed in the adolescent brain (Sowell et al., 2004).9 The neuroanatomical connections between the amygdala and PFC – the circuit responsible for cognitive control over emotions – are not fully developed until adult life (Cunningham, et al., 2002; Gogtay, et al., 2004). Neuroscientific evidence to support this hypothesis is still modest, but the hypothesis is supported by robust epidemiological evidence on the risks of adolescent alcohol and other drug consumption.

9

Myelination of the mesocortical tracts, a cellular process that enables neurons to signal quickly and efficiently, is not complete in the adolescent brain.

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These hypotheses suggest two predictions. First, as the regions of the brain responsible for impulse inhibition and reasoning about consequences are not fully developed, adolescents are more likely to engage in risky behaviours such as drug use. They will also find it more difficult to inhibit impulses, engage in more novelty-seeking, and suffer from a temporal myopia that prevents a full appreciation of the future consequences of their behaviour (Volkow and Li, 2005). Second, the developmental immaturity of the adolescent brain means that adolescents may be particularly vulnerable to the neurobiological changes that occur as the result of chronic drug use (Lubman, et al., 2007a). Neuropsychological changes at such a developmentally sensitive period can reduce an individual’s cognitive capacities in overcoming addiction. These hypotheses, which remain to be tested, could explain why epidemiological studies show that people who engage in substance abuse in early adolescence are more likely to develop addiction and less likely to recover than those who delay drug use until early adulthood. 3.10.

Conclusion

Neuroscience research suggests that addiction is, to some extent in some individuals, a pathological behaviour. Addictive drugs co-opt normal learning and motivating pathways in the brain that allow drug taking to dominate all other goal-directed activities. Such a view has the potential to provide an array of new and powerful treatments of addiction that target or ameliorate changes in brain function. It also has the potential to change how we think about and treat those who develop an addiction. Given the central importance of the brain, and the strong moral disapproval that many people feel towards those who abuse or are addicted to drugs, the impact of these changes in understanding of addiction also need to be considered. Such an analysis requires a critical examination of the emerging neuroscience understanding of addiction. This research also has implications for the types of social policies we use to reduce addiction and harmful drug use. The social and ethical implications of neuroscience research on addiction are explored in Parts 2 and 3 of this book. It is clear that neuroscience has highlighted significant changes in the brains of those addicted due to the chronic use of addictive drugs, particularly within the endogenous reward pathway and frontal cortical centres that are involved in decision-making and executive control. These changes also appear to be associated with many of the addictive behaviours that were described in Chapter 2: a decreased ability to control urges to use drugs,

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intense desires to use drugs triggered by drug-related cues, months after abstinence is achieved, and frequent relapse to chronic drug use. Together, this research makes a compelling case for the increased treatment of addiction and a greater emphasis on therapeutic approaches to it. However, this research on its own does not demonstrate that addiction is a simple brain disease in which addicts’ brains are ‘hijacked’ by the drug or that they are neurobiologically driven to use drugs, as has sometimes been suggested (Dackis and O’Brien, 2005). In fact there is compelling evidence that this simplistic interpretation is false (see Chapter 6). Understanding and interpreting the results of neuroscience research is a complex process. Part of this difficulty is due to the perennial mind–body problem: the philosophical problem of understanding how changes in the brain relate to the actions and choices that individuals make. Attempting to find a largely agreed-upon or workable solution to this deep philosophical question is beyond the scope of this book. In the absence of definitive answers, ethicists, neuroscientists and other researchers need to bring as much information as possible to bear on the topic. This includes not just a range of neuroscientific approaches, from the molecular to the psychological and social, but also approaches from other behavioural sciences, epidemiology and population studies, and the social sciences. An integrated approach is critical when assessing ethical or public policy conclusions drawn from neuroscience approaches. It is essential in avoiding drawing misleading ethical conclusions from isolated pieces of neuroscientific evidence while ignoring its epistemic limitations and underlying assumptions. In Chapter 6, we use such an integrated approach to examine a central question of the book: How does addiction affect the ability of addicted individuals to make autonomous decisions about whether or not to use their drug of addiction? Before doing so, we conclude Part 1 by reviewing new treatments that are emerging from neurobiological research.

4 Neurobiological treatment of addiction

4.1.

Introduction

Advances in genomic and molecular biology have significantly increased our ability to develop innovative drug treatments for addiction that target sites of action for many drugs of abuse in the brain (see Table 3.1). For most of these drugs, the molecular sites of action are neurotransmitter receptors and transporters that regulate neurotransmitter activity at the synapse (Iverson, et al., 2007). Drugs of abuse work by mimicking the effect of endogenous neurochemical signalling. Heroin, for example, produces its effect by mimicking the action of endogenous opioids (e.g. endorphins and encephalins) (Nutt, 1996). These discoveries have enabled scientists to identify and specifically target relevant receptor or transporter sites with drugs that interfere with activity at this site. The use of genetic manipulation techniques in animal models has also greatly increased our understanding of the psychopharmacology of addiction. Genetic manipulation in a developing animal allows researchers to observe the effect of increasing (e.g. over-expression mutants) or blocking (e.g. transgenic knockouts or dominant-negative mutants) the activity of specific molecules. These techniques help to understand the role that specific neurochemicals play in addiction, and in affecting responses to drug use; information that directs researchers to discover potential new therapeutic agents. These studies raise the prospect of a more rational (and less serendipitous) approach to developing new addiction treatments that are based on more comprehensive theories of the brain mechanisms underlying addiction (Nutt, 1996; Nutt, et al., 2007a). This chapter reviews the current and emerging neurobiological treatments of addiction, their mode of action and rationale for their use, and how they are, or are proposed to be, used. It provides sufficient scientific evidence to

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judge the ethical, social and public policy implications of their use, which are explored in Part 3 of this book. Pharmacological treatments of addiction can be classified into those that: • Block the target drug from binding to its site of action • Ameliorate the symptoms of withdrawal • Reduce the impact of drug craving or relapse, either by interfering with the central dopaminergic response to addictive drugs, or with other neurotransmitter systems related to the reward pathway (e.g. opioids, cannabinoids, glutamate/GABA and the stress response) Each of these areas has a potential use in the treatment of addiction and will be discussed below. 4.2.

Pharmacological treatments that block drug binding

The traditional approach to pharmacological treatment of addiction has involved administering drugs that interfere with or block the sites at which the drugs of addiction act in the brain (e.g. the mu-opioid receptor for heroin). These medications were first developed to treat opioid addiction, and have generally been the most effective (e.g. methadone, buprenorphine and naltrexone). Nicotine replacement therapy (NRT) is the most widely used form of substitution treatment, but it has not been proven very effective in helping smokers quit, with relapse rates of around 90% (Moore, et al., 2009). To date, effective pharmacological treatments of psychostimulant addiction have proven elusive. All treatments that act by blocking the direct binding of the abused drug fall into one of three categories: (1) agonist; (2) antagonist; and (3) partial agonist. A more complete review of available and promising pharmacological treatments of addiction is found in the clinical guidelines of the British Association for Psychopharmacology (Lingford-Hughes, et al., 2004), and recent reviews by Nutt and Lingford-Hughes (2008), Iverson et al. (2007) and Jupp and Lawrence (2009). A brief description of each approach, their potential for effective treatment, as well as their limitations is provided below and summarised in Table 4.1. A summary of all the main treatments for drug addiction in use or development is given in Table 4.2. 4.2.1.

Agonists

Agonists are drugs that act in a similar way on the same receptors as the endogenous neurotransmitter and the target drug of abuse and produce similar

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Table 4.1 Molecular targets of drugs of addiction and pharmacological approaches (current and theoretical) (source: adapted from Lingford-Hughes and Nutt, 2003)

Drug

Primary target

Primary action

Substitution therapy (e.g. agonists and partial agonists)

Relapse prevention (e.g. antagonists, blockers)

Mu opiate receptors

Mimic brain endorphins, ↑ dopamine

Methadone Buprenorphine

Naltrexone Naloxone Nalmfenec

DAT

↑ dopamine

DAT blocker (GR12909)a

Amphetamine and methamphetamine

DAT

↑ dopamine

Nicotine

Nicotinic ACH receptor

↑ dopamine, Mimic ACH

Dexamphetamineb Bupropiona, D3 ligands (BP-897)a Dexamphetamineb Bupropiona D3 ligands (BP-897)a NRT Snus Varenicline

GABA/ glutamate

↑ GABA # glutamate

BDZs

GABA

↑ GABA

Acamprosated Naltrexoned Disulfiramd Flumazenil

Cannabis

CB1 ? dopamine receptor ? opiates Serotonin ↑ serotonin transporter

BDZsb BDZ partial agonistsa Longer half-life BDZs BDZ partial agonistsa None

Opioids

Stimulants Cocaine

Sedatives Alcohol

Ecstasy

D3 receptor blockersa D2 blockers (antipsychotics)e Mecamylaminea

Rimonabant

SSRIsa Serotonin drugsa

BDZs, benzodiazepines; CB1, cannabinoid 1; DAT, dopamine transporter; ACH, acetylcholine; GABA, gamma-aminobutyric acid; SSRIs, selective serotonin reuptake inhibitors. a Theoretically effective but no clinical trial data. b Controversial, risk of dependency. c Not generally available. d Used to maintain abstinence. e Theoretically effective, but not in clinical trials.

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Table 4.2 A summary of current or developing pharmacological treatments of addiction (Reproduced with permission from Baler and Volkow, 2006)

Proposed targets

Medication

Interfere with the reinforcing effects of a drug: Substitution treatments Methadone Buprenorphine LAAM Nicotine replacement Trigger aversion Disulfiram # dopamine release Topiramate (antiepileptics) (Gabapentin) (Gamma-vinyl-GABA) Non-dopamine targets mu-opiate receptors Naltrexone cannabinoid receptors Rimonabant GABA receptors Interfere with drug delivery to the brain Interfere with drug metabolism

(Baclofen) Vaccines Methoxsalen Disulfiram

Compensate for long-term effects of drugs: Interfere with conditioned Antiepileptics (above) responses Glutamate Acamprosatec (Modafinil)c Strengthen saliency of natural reinforcers Bupropion (i.e. enhance DA function) (deprenyl þ nicotine) Interfere with stress (CRF antagonist) responses Interfere with withdrawal Clonidine Benzodiazepines Antiepileptics Propranolol a

Clinical effectiveness for: Opioids Opioids Opioids Nicotine Alcohol (cocaine)b Alcohol (cocaine) (Cocaine) (Cocaine) Alcohol and opioids (being tested for weight loss, nicotine and others) (Alcohol and cocaine) Nicotine and cocaine (heroin in development) Nicotine Alcohol Alcohol (cocaine) Alcohol (cocaine)

Nicotine (Nicotine) Not tested Heroin Heroin, Alcohol Alcohol

Medications for which there is only preliminary clinical data are identified in brackets to differentiate them from those for which there is proven efficacy. b The effects in cocaine addiction are not understood but do not seem to be mediated by triggering aversive responses. c Mechanisms of action are not properly understood.

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effects. Agonists used in addiction treatment often have a stronger affinity for the receptor site, so that the substitute drug (e.g. methadone) is not as readily shifted from the receptor as the abused drug (e.g. heroin). They also typically have a longer action and slower onset of effect to reduce their abuse potential. Agonist treatment was pioneered by the development of methadone treatment for opioid addiction in the 1960s (Dole and Nyswander, 1965). The aim of agonist treatment in opioid dependence is to replace the unsupervised use of an illicit opioid (e.g. heroin) of unknown strength and purity, with a safer, pharmaceutical drug (e.g. methadone) in a regulated dose that allows for support and education. Agonist treatments also reduce the incidence of acute adverse effects of drug use, such as overdose and the spread of blood-borne viruses (BBV). Agonists prevent or minimise the symptoms of withdrawal, reduce craving for the drug of addiction, and hence reduce the use of street drugs, and increase retention in, and compliance with, treatment. Agonists have a number of social benefits as well, in that they reduce the incidence of drug-related social harm, such as crime, theft and violence. Agonists are often used in substitution treatment programs (see Section 4.2.4) in which the aim of treatment is long-term maintenance. The most well known is methadone maintenance therapy (MMT). Agonists may also be prescribed for shorter periods to help individuals with an addiction become abstinent by managing withdrawal symptoms. Patients are provided with a tapered dose of the drug that is steadily reduced over a number of days until abstinence is achieved. The disadvantage of agonists is that they can cause similar harm as the abused drug if they are used in large doses, injected or diverted to the black market where they are used by drug-naı¨ve individuals who lack the tolerance of chronic users. Agonist treatments are therefore usually provided under strict controls and restrictions which can make treatment difficult and unattractive to potential patients (e.g. requiring daily supervised dosing). Because agonists produce a similar reinforcing effect to the target drug, they are also addictive (e.g. methadone and buprenorphine for heroin dependence) and may be difficult to withdraw from if users want to become abstinent. Substitution treatment using dopamine agonists has not been successful in the treatment of addiction to cocaine and amphetamines, except for comorbid treatment of ADHD (Lingford-Hughes and Nutt, 2003).1 Drugs that increase

1

Substitution treatment does not imply any particular mechanism of action (i.e. agonist or antagonist). Instead it refers to a medication given to mimic some or all of the effects of the abused drug. As the drugs of abuse can have very different mechanisms of action, a

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dopamine can cause additional health problems, particularly relating to the heart, and they can be abused. Drugs that act as a direct agonist at the dopamine receptor (e.g. bromocriptine, pramipexole) may theoretically be able to substitute for stimulants, but they also cause nausea, and can cause psychotic symptoms and movement disorders. Dopamine agonists have also been shown to induce impulse control disorders (ICDs) and other compulsive behaviours in patients with Parkinson’s and other diseases, particularly those with a history of drug use (Ambermoon, et al., 2011; Carter, et al., 2010). 4.2.2.

Antagonists

Antagonists work by blocking the receptor sites at which the drug of addiction acts (e.g. naltrexone blocks mu-opioid receptors for treating heroin dependence), thereby reducing their rewarding effect. Antagonists must also be: safe; remain bound in the brain for long periods, reducing the dose frequency; and possess a strong affinity for the receptor site so that they cannot be easily shifted by the drug of addiction. Antagonists are most often used to prevent relapse because they block the reinforcing effect of addictive drugs so long as they are taken. This use is referred to as relapse prevention (see Section 4.2.4). The advantage of antagonists is that they are generally: safer than agonists when used as intended, do not have reinforcing effects, and can reduce the acute adverse effects of the abused drug (e.g. overdoses). Their safer profile means that they can be provided with less oversight and regulation than agonist treatments. One problem with antagonists is that they can precipitate withdrawal symptoms because they block the activity of the drug of addiction. Initiating their use therefore requires that addicted persons complete withdrawal and be drug free. A second issue arises from their lack of a rewarding effect: patients often stop taking them and quickly relapse to drug use. In the case of opioids, this can increase the risk of a drug overdose because users have lost their opioid tolerance. New slow-release formulations of these drugs (e.g. naltrexone implants that reportedly last between 1 and 6 months) have been developed in order to overcome the poor compliance with oral forms of these drugs (see Section 10.3.2).

substitute could be an agonist (e.g. methadone) or a re-uptake blocker (e.g. bupropion). Therefore we will not use the terms agonist or antagonist when discussing substitution and relapse prevention for stimulant abuse.

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Naltrexone has been the antagonist most often used to treat opioid dependence. It also appears to be effective in reducing alcohol consumption, possibly by blocking alcohol-induced increase in opioid activity (Srisurapanont and Jarusuraisin, 2005). Flumazenil is an extremely potent benzodiazepine antagonist, but is only effective if given intravenously or subcutaneously. It is also short acting and can cause convulsions. Rimonabant is a cannabinoid receptor (CB1) antagonist initially developed to aid weight loss. While it showed potential in the treatment of cannabis dependence, as well as other addictions (e.g. obesity, smoking), it was removed from the market because of an increase in psychiatric symptoms and suicide (Christensen, et al., 2007). There are no effective antagonist treatments for psychostimulant dependence. Older ‘typical’ antipsychotics are potent dopamine antagonists that block the effects of stimulants. But they also cause such marked dysphoria that users often stop taking them. Two drugs being investigated have shown potential in preclinical trials. Studies in rats show that dopamine receptor 3 (D3) antagonism can reduce drug-seeking, while a dopamine receptor 1 (D1) antagonist may also reduce psychostimulant consumption (Vorel, et al., 2002).

4.2.3.

Partial agonists

Partial agonists are drugs that bind to the site of action, but produce a smaller effect than full agonists (e.g. buprenorphine for opioid dependence, varenicline for nicotine dependence). Like their pharmacological cousins, partial agonists should ideally have a long half-life and a strong affinity for the binding site in order to block the effects of the addictive drug. They are attractive because they potentially combine some of the advantages of both agonists and antagonists. Partial agonists produce some reinforcing effects and are more likely to retain people in treatment than antagonists. As their agonistic effects are reduced, they are much less likely to cause acute adverse effects such as overdose, although overdose is possible (e.g. buprenorphine). Their safer profile means that they can be provided with less supervision and more take-away doses.2 Because 2

There have been increasing problems from injected buprenorphine, particularly when the buprenorphine tablet has been spat out due to poor observation of consumption, thus causing greater risk of injection related harm. There is generally more willingness to allow takeaways of Suboxone: a combination drug that contains both buprenorphine and naloxone.

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partial agonists such as buprenorphine have a lower risk of overdose, much higher doses can be given ensuring full occupancy of the opioid receptors and effectively blocking the effects of any street heroin use. Partial agonists induce less receptor adaptation, which reduces the aversive symptoms of withdrawal compared to full agonists. Despite these positive features, partial agonists do pose a number of risks. As they produce a small agonist effect, they can still cause adverse events similar to the addictive drug and can be addictive, albeit to a lesser extent than full agonists. Partial agonists may not be as effective as full agonists in reducing drug cravings because of their attenuated rewarding effects (Lingford-Hughes, et al., 2004). Trials of partial agonists for other drugs of addiction have had mixed results. Varenicline, a partial nicotinic agonist, has been effective in the treatment of nicotine dependence, and is possibly more effective than bupropion and NRT (Rollema, et al., 2007). It may also be effective in treating alcohol dependence (Steensland, et al., 2007), suggesting a role for the nicotinic pathway in addiction more generally (Glick, et al., 2002). Reports that varenicline can lead to agitation, depressed mood and suicidal ideation prompted the US FDA (US Food and Drug Administration) to issue a public health warning (Kuehn, 2009). A benzodiazepine partial agonist that produced sedation and reduced the risk of addiction in preclinical trials failed to have the same effects in human trials (Nutt and Lingford-Hughes, 2008). Researchers were optimistic that partial dopamine agonists (e.g. aripiprazole) would be successful in the treatment of psychostimulant addiction, but this optimism failed to be realised (Karila, et al., 2010). 4.2.4.

Duration of pharmacological treatment of addiction

Pharmacological treatments of addiction may be provided for varying lengths of time, depending on whether the treatment goal is maintenance treatment or abstinence. Agonists or partial agonists may be used in tapered withdrawal: gradually declining doses over a number of days in order to ease the symptoms of withdrawal from the addicted drug to achieve abstinence. Agonists or partial agonists may also be used for longer periods in order to encourage less harmful forms of drug use in the short to medium term. The treatment drug is provided as a substitute for the use of the abused drug, and is therefore commonly referred to as substitution or replacement treatment. When this is seen as a long-term treatment, it is referred to as maintenance therapy.

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Antagonists may also be used for short periods of time to speed up detoxification (e.g. rapid opioid detoxification). These treatments have not been particularly effective in the long term, and can sometimes be dangerous if done under general anaesthesia (Mattick and Hall, 1996) (see Section 11.3.2). When antagonists are used as a prophylactic against relapse to drug use in the medium to long term this is called relapse prevention. The intended duration of treatment is often not as clear as this simplified analysis suggests, particularly at the beginning of treatment. The initial aim of treatment may be to stabilise a patient, to provide support and counselling, and to engage them in considering longer term solutions. Only as treatment progresses are more substantive treatment aims established (see Chapter 6 for a more detailed discussion of the ethical provision of addiction treatment). 4.3.

Pharmacological treatments of withdrawal

The pharmacological treatment of withdrawal is often referred to as symptomatic support. While distressing and intolerable, withdrawal symptoms are rarely life threatening, with the exception of severe alcohol withdrawal. Alleviation of withdrawal symptoms is nonetheless a clinical priority because they prompt a return to drug use. The treatment of withdrawal may be used to supplement pharmacological treatments such as those discussed above, or as the sole form of treatment, particularly where adequate treatment is lacking or where pharmacological treatments, such as agonist maintenance, are not available. Benzodiazepines are often prescribed in treating alcohol withdrawal to prevent seizures and delirium tremens, by increasing activity in the brain’s inhibitory system (via GABA) and dampening glutamate activity. Increased glutamate activity is neurotoxic and it is hypothesised to explain cognitive impairments found in alcohol abuse. Future treatments of alcohol withdrawal may prevent neuronal loss by decreasing glutamatergic activity. Acamprosate, a drug used to treat alcohol dependence, appears to reduce glutamate overactivity in animals, and could be trialled for this purpose in humans (Boeijinga, et al., 2004). The symptoms of opioid withdrawal can be significant (e.g. tachycardia, severe sweating) and require symptomatic relief. Cessation of opioids in dependent individuals causes a significant increase in noradrenergic activity that can be reduced by using the adrenergic agonists, lofexidine or clonidine (Maldonado, 1997). These drugs have no effect, however, on other

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symptoms of withdrawal such as nausea, diarrhoea and insomnia. There has been far less research on the development of pharmacological treatments for withdrawal symptoms for other drugs of addiction (Nutt and LingfordHughes, 2008). 4.4.

Pharmacological treatments of craving and relapse

Craving is a major issue in the long-term treatment of addiction. Withdrawing from drugs of addiction is a manageable process but cravings can persist, and trigger relapse, long after abstinence has been achieved. There has been increased interest in anti-craving drugs recently (O’Brien, 2005). As we described in Chapter 3, there are several neural circuits and neurochemicals that can produce cravings. 4.4.1.

Dopaminergic mesolimbic reward pathway

Many researchers hoped that drugs that target the dopaminergic system could provide effective treatment for addiction, but an effective dopaminergic treatment of addiction remains elusive. This may be partially explained by the complex interplay between the four dopamine receptors that have different impacts upon addictive behaviour, and the multiple receptors on which many drugs of abuse act. One exception is bupropion – a dopamine transporter inhibitor – that has proven effective in helping some smokers to stop. The interesting question is why bupropion does not appear to work for other addictions. It may be that the drugs used so far have targeted the wrong dopamine receptor (e.g. D2). New treatments may need to consider changes in other neurotransmitter systems. The fact that dopamine plays a central role in cognition makes the development of an effective dopaminergic treatment of addiction without serious adverse side-effects difficult. Pharmacological treatments to reduce drug reinforcement Another approach to treating addiction has been to block the rewarding effects of addictive drugs by blocking dopamine receptors to prevent users experiencing a ‘high’. Several antipsychotic drugs, which are dopamine (DA) antagonists, have been trialled for this purpose without success. Their effectiveness in reducing craving and the reinforcing effects of drugs in the laboratory has not translated into successful clinical trials. Antipsychotics are also not well-tolerated by addicted individuals who are particularly

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sensitive to the extrapyramidal effects of D2 blockers (i.e. disorders of movement and motor control such as those seen in Parkinson’s disease) (Hyman, 2005). The poor results of DA antagonists may be related to the fact that people who are dependent on alcohol and stimulants have fewer D2 receptors in the NAcc. Given dopamine’s role in everyday motivation, blocking D2 receptors may also decrease sensitivity to natural reinforcers. One drug that affects dopamine activity and that has proven effective in the treatment of nicotine addiction is bupropion (Jorenby, et al., 1999). Its exact mechanism of action is still uncertain although it appears to inhibit the re-uptake of dopamine and noradrenaline (Ascher, et al., 1995). Bupropion is also a nicotine receptor antagonist. Clinical trials are underway to investigate the use of bupropion in the treatment of methamphetamine addiction (Karila, et al., 2010). DA partial agonists could theoretically reduce the symptoms of anhedonia, but these drugs have not proven clinically effective. Aripiprazole, a D2/D3 partial agonist with some promise in treating addiction, has yet to prove effective (Karila, et al., 2010; Vergne and Anton, 2010). Researchers are currently investigating a D1 partial agonist that also possesses D3 antagonist activity (Iverson, et al., 2007). Disulfiram, an older drug that has been used in the treatment of alcohol consumption, has shown promise in the treatment of psychostimulant addiction. Disulfiram (commonly known as Antabuse) blocks the hepatic enzyme, aldehyde dehydrogenase (ALDH), which breaks down acetaldehyde. Accumulation of acetaldehyde causes the flushing, headache, nausea and vomiting that discourage drinking. Because disulfiram also blocks dopamine beta-hydroxylase (DBH), a neural enzyme that converts dopamine to noradrenaline and can increase dopamine levels, it may be useful in the treatment of psychostimulant addiction (Preti, 2007), but has yet to prove so (Pani, et al., 2010). Pharmacological treatments to reduce cue-conditioned craving Events or stimuli associated with drug use can elicit intense cravings that lead to relapse. These conditioned cues trigger an expectation of drug reward that can lead to an aversive state if the expected drug reward does not occur. Decreasing DA activity seems to be responsible for cue-induced craving. Drugs which prevent this may ameliorate craving. Neuroscientists hoped that DA partial agonists could provide some reinforcing effects by slightly increasing DA activity, without much of an addiction

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risk. These drugs could theoretically be useful for treating other DA-deficient consequences of drug abuse, such as withdrawal, while blocking the reinforcing effects of psychostimulant use. The D3 receptor partial agonist (BP897) which is effective in blocking cue-induced cocaine-seeking behaviour in animals was unfortunately found to be toxic in humans (Pilla, et al., 1999). Drugs with similar pharmacokinetic properties are being investigated (Nutt and Lingford-Hughes, 2008). Pharmacological agents targeted at the other dopamine receptors appear more promising (Baler and Volkow, 2006).

4.5.

Pharmacological interventions in systems related to the reward pathway

An overemphasis on the role of DA in addiction has possibly impeded the development of other more effective pharmacological treatments. The preclinical promise of dopaminergic drugs to treat addiction has not lived up to expectations. Clinical investigation of drugs that target other neurotransmitter systems that modulate the DA reward pathway may have greater success (Lingford-Hughes and Nutt, 2003). These related circuits indirectly affect the reward pathway by: regulating either dopamine cell firing or the release of dopamine in the NAcc (e.g. opioids, and the amino acids, glutamate and GABA); or interfering with the post-synaptic response to dopamine stimulation (e.g. cannabinoids) (Iverson, et al., 2007). Better data is required on their clinical safety and efficacy.

4.5.1.

Opioids

Changes in the opioid system play an important role in all forms of addiction. There are three receptor subtypes that mediate the effects of endogenous opiates. Neuroimaging studies suggest that changes in mu-opioid receptor (MOR) levels may be fundamental in addiction (Zubieta, et al., 2000). Stimulation of kappa receptors reduces dopamine release in the NAcc which may be responsible for feelings of dysphoria. Delta antagonists reduce selfadministration of alcohol in rats, and may therefore play an important role in reinforcement (Lingford-Hughes and Nutt, 2003). Mu-opioid receptors on GABAergic neurons in the VTA attenuate DA activity in the reward pathway. Abstinent drug-addicted individuals (e.g. alcohol, cocaine and heroin) have higher mu-opioid receptor levels, and these levels are correlated with craving (Heinz, et al., 2005; Williams, et al., 2007;

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Zubieta, et al., 1996). The mu-opioid antagonist, naltrexone, reduces relapse in alcohol dependence (Pettinati, et al., 2006; Volpicelli, et al., 1995), probably because it blocks the actions of endogenous endorphins that are released by alcohol (Herz, 1997). Opioid antagonists have also shown some efficacy in the treatment of obesity (Volkow and Wise, 2005) and pathological gambling (Grant, et al., 2010; Lahti, et al., 2010), suggesting that the opioid system may play a role in other forms of addiction, although apparently not in nicotine or cocaine addiction (Vocci and Ling, 2005). 4.5.2.

The amino acid neurotransmitters: glutamate and GABA

Many of the neuroadaptations that occur in addiction involve changes in the prefrontal cortex, an area that has numerous connections with the dopaminergic reward pathway. Activity in these cortical circuits is mediated by the amino acid neurotransmitters, glutamate and GABA, promising new drug targets. Studies have begun to investigate whether drugs that target these neurotransmitter systems reduce drug self-administration in animals (Kalivas and Volkow, 2005). Glutamate is the principal excitatory neurotransmitter in the brain. The glutamatergic system is well placed to influence dopamine signalling because its neurons in the prefrontal cortex and amygdala make reciprocal connections with the dopaminergic mesolimbic reward pathway. The glutamate receptor subtype, N-methyl-D-aspartic acid (NMDA), plays an important role in nicotine, cannabis, alcohol and benzodiazepine addiction (Lingford-Hughes and Nutt, 2003; Wolf, 1998). For example, antagonists of the NMDA receptor inhibit sensitisation to stimulants and the development of opioid dependence (Lingford-Hughes and Nutt, 2003; Trujillo and Akil, 1995). Co-treatment with the NMDA blocker, dizocilpine, also attenuates tolerance to opioids (Trujillo and Akil, 1991). There appears to be a compensatory increase in the numbers of glutamate receptors in alcohol addiction that may explain the hyper-excitability seen in alcohol withdrawal. Acamprosate, a drug that is effective in promoting alcohol abstinence, decreases glutamate release (O’Brien, 2005). N-acetylcysteine (NAC), an activator of the cystine-glutamate exchange, is currently in phase 1 clinical trials for cocaine dependence (LaRowe, et al., 2006; Mardikian, et al., 2007; Moussawi, et al., 2009). Not all NMDA receptor antagonists are clinically useful because some produce hallucinations and psychotic symptoms. Dopaminergic activity in the reward system is under inhibitory control of the GABA-B receptor subtype (Cousins, et al., 2002). GABA agonists reduce

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the reinforcing effects of a number of drugs, presumably by decreasing dopaminergic activity. For example, baclofen, a muscle relaxant that stimulates the GABA-B receptor, reduces the reinforcing effects of a number of addictive drugs, including heroin, psychostimulants and alcohol in animal studies (Brebner, et al., 2005; Cousins, et al., 2002). A recent clinical trial of baclofen found that it was effective in reducing alcohol consumption in alcoholic patients with severe liver cirrhosis (Addolorato, et al., 2007). GABA-enhancing drugs may maintain abstinence by preventing cue- and drug-induced increases in dopamine. Several anticonvulsants or antiepileptics have shown promise in the treatment of addiction, although their mechanism of action is not fully understood. Valproate, tiagabine and topiramate have shown some efficacy in alcohol, opioid and cocaine dependence (Kampman, et al., 2004; Myrick and Anton, 2004; Zullino, et al., 2005). Another antiepileptic, gammavinyl-GABA (vigabatrin) might also be effective (Brodie, et al., 2005; Johnson, et al., 2007; Sofuoglu and Kosten, 2006). Glutamate is also involved in the neuroadaptations that underpin the learning of addictive behaviours as a result of chronic drug use. Future research will investigate whether glutamatergic drugs can be used to ‘unlearn’ these behaviours by reversing changes in synaptic plasticity (Nutt and LingfordHughes, 2008) (see Section 3.8). The molecules that sustain these processes may prove to be effective targets for the treatment of addiction (Calabresi, et al., 2007). A great deal of research is required before this hope may be realised, but it holds significant promise, particularly in addictions that do not yet have effective pharmacological treatments. 4.5.3.

Cannabinoids

The cannabinoid receptor system is believed to be involved in the neural processes underlying reward, learning and memory. The CB1 cannabinoid receptor modulates dopamine cells and post-synaptic responses from dopamine stimulation, and can therefore influence the reinforcing effects of drugs. The CB1 antagonist, rimonabant, was recently shown to attenuate the reinforcing effects of various drugs of abuse, but in light of significant side-effects (e.g. suicide risk) it has been withdrawn from the market (Stapleton, 2009). 4.5.4.

Corticotropin-releasing factor and the stress response

Since stress is a potent trigger for relapse (see Section 3.7), dampening the stress response could reduce relapse to drug use (Bruijnzeel and Gold, 2005).

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The stress response is mediated by CRF in the HPA axis and amygdala. CRF antagonists, which can interfere with the stress response, may prevent relapse. They have been shown in animals to prevent the initiation of drug use and stress-induced reinstatement of drug-seeking behaviour for a variety of drugs (Koob and Kreek, 2007; Koob and Le Moal, 2008). Dynorphin is another molecule in the stress pathway that is being targeted. Given the significant role stress plays in triggering relapse, identification of agents that can dampen stress responses is highly desirable (Koob, 2008). 4.5.5.

Memory manipulators and cognitive enhancers

Pharmacological treatments that either enhance or dampen memories associated with drug use have also been investigated as addiction treatments. The adrenergic beta-blocker, propranolol, interferes with the formation and recall of emotionally salient memories, and may be useful in treating post-traumatic stress disorder (PTSD) (Pitman, et al., 2002). Propranolol may also be useful in reducing conditioned responses to drugs such as cocaine (Kampman, et al., 2001; Milekic, et al., 2006). Memory enhancers have also been suggested as a potential adjunct to psychotherapy because of the effectiveness of a similar approach in treating phobias. Drugs that improve alertness and attention, such as modafinil which is used to treat narcolepsy, are being tested in the treatment for cocaine addiction (Dackis, et al., 2004).3 The development of effective treatments for Parkinson’s and Alzheimer’s diseases, which increase memory and attention, may also provide innovative approaches to the treatment of stimulant addiction (e.g. ampakines) (Nutt and Lingford-Hughes, 2008). It is hoped that the increase in cognition and attention may aid those addicted to make decisions not to use drugs and inhibit impulses to use them, and ameliorate the deficits in executive control due to chronic drug use. Significant research is required to assess this possibility. 4.6.

Pharmacogenetic treatment of addiction

Pharmacogenetics has been suggested as one way to improve the modest efficacy of drug treatments of addiction. Genetic information (e.g. about drug 3

Modafinil has abuse liability. It is already reportedly being abused by long-distance drivers to drive for longer and by athletes in competition. It is not yet clear what the harm of long-term modafinil use may be.

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metabolism or dopaminergic response to drugs) could be used to match addicted individuals to the treatment that is most likely to enable them to quit. A pharmacogenetic test for nicotine dependence, the NicoTest (http:// www.nicotest.com/), was marketed in the UK via direct-to-consumer advertising for this purpose, although it has since been withdrawn. The test used polymorphisms of the D2 allele to advise smokers to use bupropion or NRT. A number of clinical trials have been conducted to test the value of using this genetic information to tailor cessation treatment to smokers. Similar proposals have been made in matching individuals with other addictions to particular pharmacological treatments. For example, a recent study has found that naltrexone treatment of alcohol dependence appears to be more effective in individuals with a particular variant of the OPRM1 gene, the mu-opioid receptor gene (Anton, et al., 2008). Similar results have been seen in the treatment of opioid addiction (Lawford, et al., 2000), as well as addiction to other drugs (Hejazi, 2007; O’Brien, 2008). Genetic screening to predict those vulnerable to developing addiction has also been proposed. The ethical and public policy implications of such proposals are discussed in Part 3 of this book.

4.7.

Novel approaches to drug treatment

Developments in medical technologies are opening up novel alternatives to pharmacological treatment of addiction. These treatments represent potentially significant advances in the treatment of addiction that expand the variety of approaches available to clinicians and addicted individuals. These technologies can be invasive or have significant side-effects, increasing the need for caution and rigorous evaluation. We discuss the ethical impact of these technologies in Part 3.

4.7.1.

Immunotherapies

Immunotherapies represent an innovative strategy in the treatment of addiction (Nutt and Lingford-Hughes, 2004). These include vaccines against the effects of nicotine, cocaine and heroin that act by binding to the target drug in the bloodstream, preventing it from reaching the brain (Kosten and Owens, 2005). These vaccines have been successful in reducing drug self-administration in animal models of addiction. There have also been a number of phase II clinical trials for cocaine and nicotine vaccine reported (e.g. Cerny and Cerny, 2008;

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Maastricht University Medical Center, 2009; Martell, et al., 2009; National Institute on Drug Abuse, 2010). Drug vaccines are primarily intended to be used in relapse prevention. However, the term ‘vaccine’ may raise expectations about their potential use to prevent drug addiction when used as a prophylactic treatment (e.g. in combination with genetic screening of adolescents for addiction susceptibility) (Hall and Carter, 2004). The effectiveness of such an approach is uncertain, and even if successful, would raise a number of ethical concerns that are discussed in Section 12.2.5. 4.7.2.

Long-acting or sustained-release medications

Several research groups in the US, Australia, Denmark, China and Russia are working to develop long-acting or sustained-release formulations of effective drug treatments. To date, these developments have focused on treatments that interfere with the pharmacological action of the drug of abuse (i.e. agonists, partial agonists and antagonists). Sustained-release pharmacological treatments offer the significant advantage of overcoming the issue of poor treatment compliance and the difficulties in ensuring patients continue to take their medication. Compliance is a persistent problem in many areas of medicine, but is particularly salient in addiction treatment where an individual’s condition may reduce their ability or willingness to comply with treatment, where patients may not wish to be treated, find the side-effects intolerable or undesirable, or believe that the treatment is no longer required after becoming abstinent. The development of sustained-release treatments of addiction will make it possible to reduce dosing from a daily event to a monthly or even half-yearly occurrence. This removes the significant burden of daily, or near-daily, dosing that is common to many existing pharmacological treatments of addiction such as methadone, buprenorphine and naltrexone. The inconvenience of daily dosing can have a significant impact upon work and family, and ultimately lead to the discontinuation of treatment and relapse. Implantable agonists or partial agonists reduce the risk of their diversion to drug black markets, as can happen where take-away doses are given. Sustained-release medications also provide a relatively stable concentration of the drug that avoids the peaks and troughs that occur with daily dosing. There are two classes of sustained-release medications: depot injections and drug implants. Depot formulations are small oil suspensions of polymer microspheres that contain the target drug that are injected into the muscle

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(intramuscular). Drug implants are larger, polymer-based implants that are surgically inserted under the skin (subcutaneous). Depot injections are easier to insert than the larger implants. However, current implants have been shown to last up to 6 months (Hulse, et al., 2004; Hulse, et al., 2005), compared to around 1 month for the injectable form (Gastfriend, 2011). Unlike depot injections, drug implants can be removed. This is an advantage if a medical reason necessitates its removal, but may also present problems if a drugaddicted individual attempts to remove the implant themselves.

4.7.3.

Neurosurgery and deep brain stimulation

A radical, and so far rarely used treatment, is neurosurgical ablation of brain structures implicated in addiction. Neurosurgery involves the lesioning of a small region of brain tissue to ameliorate the abnormal functioning of a neural circuit. Neuroscientists in Russia and China have used neuroscience research on the effects of chronic drug use on the nucleus accumbens and the cingulate gyrus to justify the stereotactic ablation of these regions (Gao, et al., 2003; Medvedev, et al., 2003). Neurosurgery is the most invasive and permanent form of treatment used, and is often only considered appropriate in a few severe conditions where there are few options, all of which have been tried unsuccessfully. It is generally considered a treatment of ‘last resort’, requiring careful ethical and clinical consideration (Hall, 2006b; Valenstein, 1973; 1986). The ethical and social issues raised by the use of these treatments are discussed in Section 11.3.3. Deep brain stimulation (DBS) is another form of neurosurgery that has been proposed as a treatment of addiction in the media (BBC News, 2007) and by clinicians (Krack, et al., 2010; Lu, et al., 2009; Stelten, et al., 2008). It involves the insertion of electrical stimulating electrodes deep into the brain regions involved in addiction, allowing activity in these areas to be manipulated. DBS is most often used in the late-stage treatment of Parkinson’s disease although it is also being trialled in several intractable psychiatric conditions, such as Tourette’s syndrome (Servello, et al., 2008; Visser-Vandewalle, et al., 2006), obsessive compulsive disorder (Greenberg, et al., 2006; Lipsman, et al., 2007) and depression (Mayberg, et al., 2005; Schlaepfer, et al., 2008). There have been several case reports of the effects of DBS on addiction (see Carter and Hall, 2011). While this treatment is not as damaging as ablative neurosurgery, it does present considerable risks and can result in permanent neurological damage. The side-effects of this novel treatment are also unknown. For example,

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some patients with Parkinson’s disease who have been treated with DBS have developed impulsive behaviours that appear similar to addictive disorders (Frank, et al., 2007; Smeding, et al., 2007). The ethical implications of the use of DBS to treat addiction are particularly pertinent given the growing enthusiasm for its use (Lu, et al., 2009; Stelten, et al., 2008), and are discussed in Section 11.4. 4.7.4.

Transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a non-invasive treatment that involves placing a small magnetic coil against an individual’s skull in order to block or enhance neural activity in a particular cortical region (Machii, et al., 2006). The coil produces a strong magnetic field that can change neuronal electrical activity (Pascual-Leone, et al., 2002). By manipulating cortical activity, it is hoped that TMS might prove to be a useful treatment for a range of psychiatric disorders (Ridding and Rothwell, 2007), including addiction (Feil, et al., 2010). TMS raises fewer health and safety concerns than neurosurgery or DBS because it does not involve physical penetration of neural tissue (Anand and Hotson, 2002). A TMS device received FDA approval for the treatment of major depression; however, some have significant doubts about its clinical utility (Rosack, 2007). 4.7.5.

Applications of neuroimaging and neurocognitive screening in addiction treatment

Neuroimaging using functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetoencephalography (MEG), and electroencephalography (EEG) are non-invasive techniques that enable researchers to identify functional and structural abnormalities in the brains of addicted individuals. It has been suggested that these techniques might also be used to develop more effective and better-targeted treatments of addiction (Volkow and Li, 2005; Yucel and Lubman, 2007). Neuroimaging, for example, may help to identify neuropsychological deficits that are the primary source of an individual’s inability to stop using drugs (e.g. strong underlying urges for drugs, poor inability to resist impulses to use drugs, sensitivity to stress or strong habit) (Paulus, et al., 2005). This would allow clinicians to give specific pharmacological treatments to individuals that would increase their chances of success.

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Researchers have been able to identify patterns of activation within the brains of addicted individuals during decision-making that predict whether that individual is likely to relapse to drug use (Paulus, et al., 2005; Schutz, 2008). This may be significant in identifying which sort of psychotherapy an individual may find effective, as well as identifying those individuals who will require more intensive interventions (Yucel and Lubman, 2007). Research has also identified three triggers for relapse: cues associated with drug use (e.g. images of the addictive drug); stress; and drug priming (small amounts of a drug that lead to a relapse to chronic drug abuse). These triggers appear to be mediated by distinct neural pathways, although there is some degree of overlap. Preclinical studies have shown that some pharmacological medications are able to target each of these pathways, without affecting the other two (Shaham and Hope, 2005). If we can identify these patterns of neural activation in individuals, it may be possible to provide pharmacological treatments that remedy these deficits (Schutz, 2008). The costs associated with neuroimaging technology can be a significant impediment to its routine use in addiction treatment. Neurocognitive tests, such as tests of attentional bias towards drug use, impulsivity or the ability to resist immediate rewards, may be a more cost-effective way of making treatment decisions. These tests are much cheaper to administer, and have been shown to be accurate in identifying those likely to relapse to drug use. For example, cognitive tests found that measures of an addicted individual’s response time to certain tasks reflect attentional bias towards drugs (Cox, et al., 2002), or impairments in executive control (Goudriaan, et al., 2008a). Tasks measuring impairments in decision-making capacity (e.g. Cambridge Gambling Task, Iowa Gambling Task) in an opioid-dependent population significantly predicted those who remained abstinent from opioids 3 months after treatment (Passetti, et al., 2008). Neuroimaging studies may also play an important role in developing more effective psychological treatments of addiction that target particular neurocognitive changes associated with addiction. Neuropsychological deficits, for example, may be used to develop drugs that increase executive control. This may be done by increasing dopaminergic activity in the PFC, particularly during withdrawal and early abstinence, when there is often a drop in executive control at a time when executive control is required to resist urges to use drugs. Many psychotherapies aim to develop awareness of the costs and benefits of continued drug use, thereby improving response selection (i.e. improving PFC function). Some also develop drug refusal skills and better ways of

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coping with craving by improving inhibitory control (e.g. improving aCG functioning) (Yucel and Lubman, 2007). Neuropsychological studies could strengthen the rationale for psychotherapies that aim to remedy deficits in decision-making and executive control or develop new skills. They may help researchers and clinicians to understand the involvement of comorbid psychiatric conditions or behavioural problems that can interfere with treatment. Neuropsychological studies also provide a stronger justification for public health funding of research and treatments that aim to ameliorate disruptions in psychological functioning. The ethical and public policy concerns raised by the use of neuroimaging and cognitive testing are discussed in Chapter 12. 4.8.

Psychosocial treatment of addiction

Psychosocial interventions, such as cognitive behavioural therapy, motivational interviewing, drug counselling and 12-step support groups (based on the Alcoholics Anonymous (AA) model) provide an important adjunct to pharmacological addiction treatment in maintaining abstinence. While psychosocial treatments are not the focus of the book, there is a need for greater investment in the combined use of pharmacological and psychosocial treatment of addiction. The demonstration of cognitive deficits in impulse inhibition and a pathological focus on drug use in addiction highlight the importance of psychosocial therapies that can ameliorate cognitive deficits (Volkow and Li, 2005). Neuroscience may also help in designing therapies which are more effective for addicted individuals with particular kinds of cognitive deficits. It is likely that new pharmacological treatments, such as those that reverse the learned habits of addiction or ameliorate the cognitive deficits, will be provided in combination with effective psychotherapeutic approaches. This is similar to the combined pharmacological/psychotherapeutic approach used in overcoming learning disabilities or brain trauma (Volkow and Li, 2005). It will be important that developments in neurobiological treatment of addiction are not seen to replace the need for intensive psychosocial interventions. We discuss this concern in more detail in Chapter 14. 4.9.

Conclusion

Neurobiological research has the potential to deliver more effective treatments of addiction that are designed to meet individual needs and treat specific cognitive deficits. However, addiction is a condition that is highly

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stigmatised and causes strong moral responses that can motivate how we as a society respond to it. The problem remains of how to provide these treatments in ways that are fair and cause no unnecessary harm. In Part 2, we examine how neuroscientific research on addiction may affect the way in which we respond to those who are addicted, before examining the ethical and public policy questions of how best to provide treatment in Part 3.

Part 2

The Ethical and Philosophical Implications of Neuroscientific Knowledge of Addiction

5 Autonomy, addiction and the public good

5.1.

Introduction

Ethics is the domain of enquiry whose task it is to formulate, interpret and apply the most appropriate principles to guide human conduct. Philosophical and applied ethical enquiries, when related to neuroscience, have been termed neuroethics, although the methods of analysis and theoretical frameworks used in these enquiries are not unique to this field. Neuroethics emerged as a distinct field in 2002, following a number of conferences held by organisations such as the Royal Institute of London, the American Association for the Advancement of Science, and the Dana Foundation. In the same year, the journal Neuron devoted a special issue to neuroethical concerns, and the seminal text, Neuroethics: Mapping the Field was published, based on papers presented at a conference held by the Dana Foundation earlier that year (Marcus, 2002). Neuroethics integrates perspectives from a wide range of disciplines that includes ethics, neuroscience, psychology, neurology, the social sciences, philosophy of mind, and the philosophy of science. It applies to neuroscience approaches from traditional ethical and bioethical fields, including research ethics, clinical ethics, public health ethics and human rights. Neuroethics is seen by most practitioners as a sub-discipline of bioethics that has a particularly pragmatic approach to ethical analysis with a focus on achieving practical outcomes, clinical guidelines and social consensus (Illes, 2007; Racine, 2008; 2010). This approach is driven largely by some of the founding members of the Neuroethics Society. There are those, however, who emphasise the philosophical and social scientific questions raised by neuroscience research (Gillett, 2008; Giordano and Gordijn, 2010; Levy, 2007). While neuroethics has been dominated by a pragmatic bioethics approach common in North America, it would be wrong to assume that

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this is something inherent about the field, rather than a consequence of its most dominant figures. As the field has grown and expanded, it has attracted researchers with different and divergent approaches to neuroethics, including a greater emphasis of the philosophical (e.g. Grant Gillet, Neil Levy) and sociological (e.g. Nik Rose) aspects of neuroscience research and its applications. There has been significant disagreement among bioethicists about whether neuroethics constitutes a new and distinct discipline of bioethics, with an issue of the American Journal of Bioethics in 2005 devoted to this question (Racine, 2010). Similar doubts were raised about bioethics in the 1970s. While neuroethics is heavily informed by antecedent bioethical discussions, particularly those involving the ethical implications of genetics (Roskies, 2007), neuroethics is unique in its specific investigation of ethical issues related to brain science. The unique relationship between brain and cognitive capacities such as reasoning, desire, will and moral decision-making is something that is not at the centre of other bioethical disciplines in the same way that it is in neuroethics (Roskies, 2007). Neuroethics is unique in that it attempts to understand the thing with which it is being understood (Leshner, 2005). The brain is both the object and subject of study. The scientific implications and the therapeutic and other practical applications of neuroscience and genetic research raise major ethical and social issues (Farah, 2010; Glannon, 2006a; Illes, 2006; Levy, 2007; Levy and Clarke, 2008; Racine, 2010). In the context of addiction, these can be considered under two broad headings: (1) ethical issues that arise from neuroscience and genetic knowledge of addiction (e.g. autonomous decisionmaking capacity, nature of morality); and (2) the broader social and ethical implications of potential technological applications of neuroscience (e.g. for therapeutic, preventive and enhancement purposes). Part 2 of this book is concerned with the first of these areas. Questions arising from the application of technologies derived from neuroscience research are discussed in Part 3. Various ethical approaches have been used to identify and analyse the ethical issues in neuroscience research, and to frame and justify various policy responses to address them. Two ethical principles are particularly important in evaluating the ethical implications of applying neuroscientific knowledge of addiction to improve the lives of addicted persons: respect for autonomy, or the respect for persons, and what we will refer to as the public good. These two principles can come into conflict because addiction and its treatment often involve two competing aims: (1) the treatment of an

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individual suffering from a putative neuropsychiatric condition, and (2) the protection of society from the harmful behaviour of some of its addicted citizens. These ethical values may be framed within a broad conception of human rights, or the respect for persons. By balancing such individual rights with the public interests or public good, a framework may be developed that can shape our responses to addiction and the findings emerging from current neuroscience research. In this chapter, we provide a brief introduction to the approach to ethical analysis that will be used throughout the book. We then discuss the ethical principles that are most pertinent to the treatment of addiction, namely, respect for autonomy and the public good, and examine what each of these principles entails. We conclude with a suggested list of the minimum ethical requirements for the treatment of addiction that may be used as a guide in making ethical decisions about enrolling individuals in treatment. These include deciding when and how to use medical treatments, particularly in situations involving the criminal justice system, and protecting society from harmful behaviour that addicted individuals may, on occasion, engage in. These minimum ethical requirements will inform the ethical analysis in subsequent chapters.

5.2. 5.2.1.

Approaches to ethical analysis Introduction to ethics

There is a bewildering diversity of approaches to evaluating the good and making normative judgements. This has resulted in a variety of ethical theories that purport to provide rationales for common moral rules and allow us to decide what conduct is right or good or which course of action ought to be pursued (MacIntyre, 1998; Rachels, 1999). Ethical approaches may be: (1) duty- or action-based, providing guidance and justification for which course of actions are right or wrong, or what action a person is obligated to take in certain situations, or (2) agent-based, placing greater emphasis on the qualities or virtues of the individual making a moral judgement or performing a moral act, rather than the action itself. Duty-based ethics is most often understood by the twin pillars of moral reasoning: the action-based approaches of deontology and consequentialism (Rachels, 1999).1 Deontology is the notion that there exists a universal way to 1

Consequentialism and deontology could be further classified as ‘act-based’ and ‘outcomebased’ respectively.

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behave that is governed by natural or universal rules or principles: an intrinsic moral ‘oughtness’ that Immanuel Kant opaquely refers to as the categorical imperative (Kant, 1996). Deontology is a rights or duty-based system that requires a moral individual to behave in accordance with these universal moral principles. A deontologically minded individual can be confronted with situations where two or more moral principles or rules come into conflict. The deontological position can also lead to cases where principled courses of action might allow harm that could otherwise have been avoidable. For example, a deontological approach might prevent the use of life-saving research or treatment if it violates a pre-established universal moral law, such as always treating persons as ends rather than means. Consequentialism is a form of moral calculus in which the rightfulness or wrongfulness of competing courses of action (or in some formulations, moral rules) are determined solely by weighing up the costs and benefits to determine which action (or moral rule) will produce the greatest good for the greatest number (Singer, 1993). The most well-known form of consequentialism is utilitarianism, made famous by Jeremy Bentham (1988) and John Stuart Mill (2001). Utilitarianism is the ethical principle that the moral worth of an action is determined solely by its contribution to overall utility. Utility has been defined by various commentators as the greatest pleasure or happiness for the greatest number.2 A common criticism of consequentialism is that it can be seen to justify actions that are considered immoral by many persons, such as the torture or killing of a single person in order to benefit the larger majority. Agent-based ethical approaches have focused on the role of community (e.g. communitarian ethics) or relationships between different agents (e.g. feminist ethics or ethics of care) in moral decision-making. These ethical approaches are heavily influenced by the virtue ethics approach of Aristotle, and more recently Alasdair MacIntyre (1985). They often object to ethical theories that give priority to individual liberty, such as libertarianism. Communitarian ethics attempts to make moral choices that benefit the common good or the public interests. They developed in part as a reaction to a perceived overemphasis on the principle of respect for autonomy (Callahan, 2003). Utilitarian calculations typical of consequentialist accounts are often down-played, and are replaced by an emphasis to act with other community

2

In modern times, utility has been redefined in various different ways, such as Peter Singer’s preference utility, or the satisfaction of preferences (Singer, 1993).

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members in mind. Communitarianism ‘is meant to characterise a way of thinking about ethical problems, not to provide any formulas or rigid criteria for dealing with them’ (Callahan, 2003, p. 288) A challenge for communitarianism is achieving consensus on what the common good is, or even which community or communities’ views need to be considered (Keane, 2005). Similar to communitarian ethics, feminist ethics or ethics of care emphasise the relationship or interaction between agents in a moral dilemma (Beauchamp and Childress, 2001; Noddings, 1984; Nussbaum, 1990). Relationshipbased ethics developed in response to criticisms that contemporary ethical approaches that relied solely on ethical theory or key ethical principles failed to consider the importance of moral relationships, and the role of emotion and subjectivity in moral reasoning. Relationship-based ethical approaches are less interested in the application of moral principles than the interaction between the moral agents involved in a particular situation, emphasising the moral impulse and the subjective experience of ethics, as well as personal traits such as sympathy, compassion, fidelity, discernment and love (Noddings, 1984; Nussbaum, 1990). Ethics of care requires a moral individual to act on behalf of persons with whom one has a significant relationship, including those caring for addicted individuals.3 While we will not be discussing these ethical approaches explicitly, they represent important approaches to ethics that can inform or influence the moral decision-making process. They help to identify who the important actors are in a specific moral dilemma and remind those making moral judgements of their interdependence with other moral agents. The pluralistic use of a number of ethical methods that we will use is consistent with the pragmatic approach to moral decision-making developed by Dewey (1990), and is discussed further below. Neither deontology nor consequentialism appears sufficient to address the ethics of neuroscience research or the treatment of addiction. For example, a strict utilitarian approach may approve the coercive use of risky or invasive medical treatments to manipulate the behaviour of an addicted individual to stop them using drugs, irrespective of the damaging effects that the treatment may have on the addicted individual. In contrast, deontological approaches 3

Feminist ethics specifically requires the moral agent to act on behalf of, or consider seriously, the impact or role of women in moral situations. While ethics of care was largely initiated by feminist writers, it has been criticised by recent feminists who argue that it fixes women’s role as the givers of care and self-sacrifice (Beauchamp and Childress, 2001).

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may fail to make the most of neuroscience research on addiction. A dogmatic adherence to ‘universal’ moral principles might prevent the application of neuroscience research to addiction because it violates some moral principle (e.g. respect for autonomy), despite the benefit it may bring to both society, and the addicted individual. Holding the deontological view that all drug use is immoral would prohibit the use of substitution treatments, such as methadone, that have been found to be effective in reducing the harms associated with intravenous heroin use for both the individual and society. In recent years, more pragmatic approaches to ethics have been developed in order to eschew these limitations. Two of these are discussed below.

5.2.2.

Principlism

Principlism emerged in the US in the 1970s and has become a widely recognised and used approach in Anglo-American bioethics, particularly in the fields of research, medical and psychiatric ethics (Brody, 1998; Jonsen, 1998). Principlism was developed by Tom Beauchamp and James Childress in their influential bioethics text, Principles of Biomedical Ethics (Beauchamp and Childress, 2001). It is based on four fundamental ethical principles: respect for autonomy,4 beneficence, non-maleficence and justice that were identified in the 1972 Belmont Report on the ethics of medical research. It has been argued that autonomy and justice reflect deontological principles, whereas beneficence and non-maleficence are consequentialist (Brody, 2003). Respect for autonomy is the principle by which we ought to respect the choices and actions of other rational or competent persons by not interfering with these choices or actions, and allowing persons to decide upon a course of action without influence, coercion or force (Beauchamp and Childress, 2001). 4

The publication of the first edition of the Principles of Biomedical Ethics in 1979 by Beauchamp and Childress began a shift from the use of ‘respect for persons’ as described in The Belmont Report to ‘respect for autonomy’. Some have argued that this shift meant that individuals with compromised autonomy were no longer protected under the principle of respect (Lysaught, 2004). However this argument, we believe, employs too narrow a definition of respect for autonomy, and one not intended by Beauchamp and Childress. As they argue in later editions (e.g. Beauchamp and Childress, 2001, 4th ed.), respect for autonomy requires both negative (maintaining or facilitating autonomy) and positive (freedom to act as one chooses) obligations, consistent with the Belmont Report (Beauchamp and Childress, 2001). It is beyond the scope of this book to resolve such detailed debates and we will be using the terms ‘respect for persons’ and ‘respect for autonomy’ interchangeably.

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Respect for autonomy is based on the notion of equality and dignity for all persons (Ashcroft, 2005). It is not something that is given to someone, but something that an individual possesses by virtue of being a person (Kant, 1996). Respect for autonomy is also an important principle in human rights: we possess a variety of rights by virtue of being an autonomous person (see Section 5.2.3 and Chapter 7).5 Autonomy is the term used to describe the abilities and conditions necessary for an individual to act of their own accord. There are two features that are considered by most to be essential to autonomy: liberty or freedom (independence from controlling influences), and agency (the capacity for intentional action, or competence) (Beauchamp and Childress, 2001). Competence is a major feature required for autonomy and reflects a certain cognitive capacity to make wilful and ‘authentic’ decisions. Competence, or the capacity for agency, is particularly pertinent to analyses of neurobiological explanations of addiction, where the decision-making capacity of addicted individuals is in question (see Chapter 6). The ability to make autonomous choices is based on self-deliberation, self-determination and self-governance, which some moral theories regard as a requirement of being a person (i.e. ‘personhood’). Individuals who lack the rational or volitional capacity to make such choices are not considered to be autonomous, and therefore may not be entitled to the same rights and protections. This aspect of respect for autonomy is derived from Kant’s narrower conception of respect, which prevents us from interfering in an individual’s life for our own interests and enjoins us to treat someone as a means rather than end (Kant, 1996). Mill argued for a broader understanding of respect for autonomy that obliged us to not only accept Kant’s negative understanding of respect as non-interference, but also a positive obligation to strengthen or facilitate autonomy wherever possible (Mill, 2001). According to Mill, a loss of autonomy due to mental illness, coma, or some social constraint, obliges the state to restore autonomy where possible, and oversee the welfare of affected individuals when autonomy cannot be restored.6 It will be this broader

5

6

The relationship between autonomy and rights is not quite as straightforward as this suggests. Individual’s lacking autonomous decision-making capacity still possess rights. What respecting these rights in a non-autonomous individual requires will differ. It is important to distinguish between autonomy and the respect for autonomy. Autonomy is a descriptive term that includes certain traits, attributes or opportunities of an individual. We can have more or less autonomy depending on the situations we find ourselves in. Our level of autonomy can also change over time (e.g. infancy, adulthood and

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understanding of respect for autonomy that will be used throughout this book. Respect for autonomy is an important consideration in the ethics of addiction where the volitional capacity of addicted individuals is in question (Carter and Hall, 2008b; Cohen, 2002). In medical ethics, the respect for autonomy is usually seen as entailing a number of obligations. These include: the acquisition of free and fully informed consent from individuals to enter treatment or participate in research; the right not to be adversely affected (e.g. by research or treatment) without one’s informed consent; the maintenance of privacy and confidentiality; and the freedom to choose or refuse treatment or to participate in research, referred to as voluntariness (Beauchamp and Childress, 2001). We discuss these implications for addiction in Chapters 6 and 9. Beneficence is the principle that we ought to choose actions that benefit others, or to ‘do good’. The principle of beneficence requires that an action’s benefits should outweigh the harms. The converse of beneficence is the principle of non-maleficence, or ‘do no harm’ (Beauchamp and Childress, 2001). Non-maleficence requires us to refrain from causing harm or injury, or from placing others at risk of harm or injury. In biomedical research, this requires researchers to minimise the risks of research participation (Brody, 1998). Together these principles require that the benefits of participation in research or treatment to society should outweigh the risks to participants and that the benefits exceed the risks for individual participants. An important question in the treatment of addiction and other psychiatric disorders is deciding who ought to receive the benefits and burdens of treatment. This is a question of justice: what is fair and deserved. Justice is the principle of providing an equitable distribution of the risks and benefits of research or treatment participation (Beauchamp and Childress, 2001). However, what this entails, that is what is deserved and fair, is not easily discerned.

dementia). In contrast, respect for autonomy is an ethical principle or obligation that individuals are afforded by virtue of being a person. In situations where autonomy is absent (e.g. coma), our beneficent obligation requires that we, or other responsible sections of society (e.g. health care professionals), undertake measures to restore or facilitate autonomy (e.g. to offer medical assistance to those who are unconscious and in immediate danger, such as individuals suffering a stroke or heart attack). This balancing of autonomy and beneficence is referred to as paternalism. See Chapter 8 for a more detailed discussion of paternalistic justifications in the treatment of addiction (e.g. treatment under coercion).

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Justice is arguably the most complex of the four principles. Some argue that justice requires that we all be treated equally. Given that inequity is inherent in society (e.g. social, psychological and biological), treating people equally is not the same as ensuring that all have an equal distribution of resources. Most ethicists agree that there are a number of characteristics or factors that may be used for distributing burden and benefit, such as achievement, training, merit, experience, contribution, need and effort (Beauchamp and Childress, 2001). There are therefore a number of slightly different conceptions of justice; that is, formulations of how burdens and benefits should be distributed, with each formulation specifying some characteristic or property that is used for guiding fair distribution of burden and benefit. Beauchamp and Childress (2001) specifically refer to this description as the principle of distributive justice. Distributive justice arises as an issue in bioethical debates about: the allocation of health resources; ameliorating inequity in health outcomes, including both the incidence of disorders and access to treatments; and the distribution of risk, burden and benefit in research into, or the treatment of, medical disorders such as addiction. Distributive justice is sometimes distinguished from more specific forms of social justice, such as retributive or criminal justice (infliction of punishment for harm caused, usually through criminal law) and rectificatory justice (just compensation for transactional problems such as breach of contract, usually through civil law) (Beauchamp and Childress, 2001). No one conception of justice will be sufficient for balancing all concerns and interests, particularly in the case of addiction and addictive drug use, which can be complex and multifactorial. Therefore, we employ a broad definition of distributive justice to include the distribution of all rights and responsibilities in society. We will follow Beauchamp and Childress in considering justice to be synonymous with distributive justice. Relationships between the principles Respect for autonomy has been regarded by a number of leading commentators as the ascendant moral principle of the four (Callahan, 2003). This is not surprising given the importance paid to respect for persons in 20th century Western democracies where principlism emerged. Respect for autonomy is particularly prominent in medical, research and clinical ethics, which aim to protect the rights of those who are being treated or who are participating in research. Respect for autonomy gained prominence during the Nuremberg trials of Nazi medical staff for experimentation on prison inmates after World

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War II in which respect for research participants was widely disregarded. Respect for autonomy is also central to ethical debates that involve persons where an individual’s capacity to make authentic and uncoerced, competent decisions is in question. This is a central ethical concern in addiction neuroethics and will be discussed in more detail below (see Section 5.3.1). The four principles form a useful framework for ethical analyses of neuroscience and genetic research on addiction, and they will be a starting point for the ethical analyses that follow. They are, however, rarely decisive. A major problem with principlism is the difficulty in resolving conflicts between the four principles, as well as conflicts between the principles and strongly felt moral intuitions in specific cases. We will discuss these criticisms in Section 5.2.4. Before doing so, we briefly examine human rights. This is an approach to ethics that has been important in enacting policy changes in nation states, and one that accords priority to human dignity and a respect for personhood. 5.2.3.

Human rights

The four ethical principles discussed above form the basis of important statements of human rights, such as the Universal Declaration of Human Rights (UDHR) (Brody, 1998). The UDHR sets out an international set of human rights to be honoured by all signatory nations (United Nations General Assembly, 1948). The UDHR recognised that all people have rights by virtue of being human. It aims to treat all people as equal, irrespective of who they are or where they come from, and to promote and protect the right to life, liberty and security of person (International Federation of Red Cross and Red Crescent Societies and Francois-Xavier Bagnoud Center for Health and Human Rights, 1999; Mann, 1999). The UDHR also includes ‘negative rights’ such as: the rights not to be enslaved or kept in servitude; not to be tortured or subject to cruel, inhuman and degrading treatment or punishment; and not to be denied basic medical treatment. It also obliges signatory states to afford people equal treatment before the law and the equal protection of the law, without discrimination by requiring that everyone charged with a penal offence should be presumed innocent until proved guilty according to law in a public trial with access to ‘all the guarantees necessary for his (sic) defense’ (United Nations General Assembly, 1948). An often neglected aspect of human rights is the derogation of the rights of individuals whose behaviour adversely affects the rights of other members of society. Rights entail certain obligations, such as refraining from behaviour

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that harms others. Human rights therefore also impose certain obligations on the state to protect the rights of others in society through policies or actions such as the derogation of liberty of those who violate the rights of others (e.g. incarceration of persons who commit criminal offences). Some rights cannot be derogated under any circumstances, such as the right to health and life. Ethical principles provide guidance to individuals, such as physicians, carers, researchers and patients on ethically sound ways of providing a treatment or conducting research (Mann, 1997). In contrast, acceptance of the principles of human rights obliges governments and the state to promote, respect and protect the rights of their citizens.7 Human rights are most relevant to the way in which treatments and interventions are used to treat and prevent addiction. Respect for human rights should inform how the state and society as a whole responds to individuals with a drug addiction, for example, by introducing policies and laws to deal with people who are addicted to drugs. Treatment of addiction often applies the coercive powers of the state and other forms of denial of liberty and autonomy (see Chapter 8). Treatment of addiction therefore requires careful justification, and the balancing of treatment and policy decisions (Gostin and Mann, 1999). Given the important and unique role of human rights in influencing governmental policy and treatment of their own citizens, in Chapter 7 we discuss the human rights implications of treating individuals with a drug or alcohol addiction. 5.2.4.

A pragmatic approach to neuroethics

The approach to ethical analysis used in this book is pluralistic in the sense described by Baruch Brody (2003) and more recently Eric Racine (2010). This is not simply a descriptive pluralism in which we acknowledge that in a liberal democratic society, people hold different moral values. The pluralism that we adopt is normative: ‘it is the claim that several independent moral appeals (appeals to the properties of an action) are relevant in determining the rightness or wrongness of actions’ (Brody, 2003, p. 2). This may include many of the moral approaches described above. It may involve an analysis of the consequences of certain actions or it may involve an appeal to: the dignity and autonomy of an individual; certain rights for this individual; certain virtues in an individual; justice and fairness; the consideration of the social 7

The effect of human rights law is far less emphatic than this simplified description suggests. While the majority of nation states are signatories to legally binding conventions, such as the United Nations Bill of Rights, their application is often less than ideal.

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and communitarian relevance of an action; relationships between the individual when making a moral judgement and the person(s) that it affects; and, significantly, an appeal to respecting a deontological moral constraint (Brody, 2003). The general aim is to bring as much information and perspective to bear as possible on an analysis of the ethical acceptability of particular cases or issues. Our approach to moral decision-making has much in common with Eric Racine’s pragmatic neuroethics (Racine, 2010). We follow Racine in employing a particularly Deweyian or pragmatic view of ethics as a method of enquiry (Dewey, 1990). According to pragmatism, ethical enquiry is not simply the detached or disinterested adherence to inflexible ethical theories or the abstract balancing of a priori principles. Rather, pragmatic ethics involves an engagement with the context in which an ethical decision is to be made. Pragmatic ethics is judged not only by what it argues, but also by what it achieves: ‘[e]nquiry is always aimed at judgement, tied to decision, and accompanied by action’ (McGee, 1999, p. 24). Pragmatism also connects ethics to empirical research. A persistent obstacle to empiricism in ethics has been the naturalist fallacy as described by David Hume in 1739 (Hume, 1978). The naturalistic fallacy holds that moral principles cannot be derived from empirical observations (a posteriori); ethics predicates are irreducible to natural properties and are true independently of the natural world (a priori). On this view, we are unable to learn anything about making ethical choices from scientific research. For many, a major aim of bioethics (and naturalism) was to establish links between the humanities and the sciences, so that science and empiricism may be able to enlighten or better inform moral reasoning either in specific instances (moderate naturalism) or in general (strong naturalism) (Moreno, 1999; Potter, 1970). Proponents of the naturalistic fallacy reacted against a strong understanding of naturalism that reduced moral decision-making to science, thus eliminating ethics as an independent form of inquiry. These are complex meta-ethical arguments. We will follow bioethicists such as Jonathan Moreno and Eric Racine in applying a pragmatic or moderate naturalistic approach to bioethics that builds upon an interaction between theory and empiricism, reason and experience (Moreno, 1999; Racine, 2010). As Racine says, pragmatic neuroethics is ‘an approach to bioethics that emphasises the value of pluralism and the need to develop frameworks allowing for the integration of both theoretical and practical research to improve patient care’ (Racine, 2010, p. 73). An approach that has received much attention within biomedical ethics is one that aims to reconcile general or universal ethical principles with more

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specific moral intuitions about a particular situation. Rawls has described this approach as the search for ‘reflective equilibrium’ (Rawls, 1971). This approach was later adopted and expanded on by Beauchamp and Childress in their influential ‘four principles’ approach (Beauchamp and Childress, 2001). This is a pluralist approach in which a set of prima facie ethical principles are tested against our moral intuitions about a particular situation. Any discrepancy between the two is addressed by an iterative, dialectical process that brings our moral intuitions, our gut instincts, into line with our rational ethical principles. Each of the principles and moral intuitions are adjusted until a situation is reached in which there is an agreement between the two. The understanding of the ethics of addiction and drug treatment and policy used in this book is derived from empirical research, combined with general ethical principles (such as the ‘four principles’) as applied to specific situations in order to specify the conditions for ethically sound treatment of drug addiction. It is important to note that empirical evidence is not being used to validate or prove a prima facie ethical perspective.8 Rather, the ethical principles have been derived from ethical theories such as those discussed above. The empirical evidence will be used to determine the best way of achieving these ethical goals. This is akin to the distinction between instrumental and final reasoning (Casebeer, 2003). The ethical principles outlined above were derived from final reasoning: what sorts of goals is it desirable to set in order to achieve ethical ends? The empirical approach is used as part of an instrumental reasoning: what are the best means of attaining the final goals, in this case ethical treatment of persons with drug addiction and the use of neuroscience research of addiction to help addicted persons change their behaviour for the better.

5.3.

Ethical principles in the treatment of addiction

The ethical analysis used in this book will make use of the four main principles of medical treatment: respect for autonomy, non-maleficence, beneficence and distributive justice (Beauchamp and Childress, 2001). While most would argue that these principles are ethically significant, there is much disagreement about what respecting these principles might entail, or how it

8

This is not an attempt to naturalise moral decision-making in the sense of strong naturalism described by Racine (2010) and advocated by others (Hauser, 2006).

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would be achieved. Most reasonable people would agree that individuals should be respected and treated fairly, but consensus often proves elusive in the case of the treatment of addiction because of disagreements about: whether addiction exists and if so what sort of entity it is; what ethical treatment is; what these ethical principles require us to do; and where the balance of effort and responsibility rests? These disagreements are often largely driven by different answers to the following questions: • What is the nature of addiction? How does addiction affect those who suffer with it? • What sort of person is a drug-dependent individual? What are they capable of, and responsible, for? • How does the behaviour of addicted individuals affect society? • What are the respective rights and responsibilities of society and drugdependent individuals? The ethical tension in the treatment of addiction arises from the debate as to whether addiction is a psychiatric condition that requires medical treatment (according to the medical model), or whether drug use is a freely chosen behaviour that (when prohibited by law) requires punitive responses that may include the deprivation of liberty (according to the moral model) (see Section 2.5). Neither explanation is fully satisfactory. As we will see in coming chapters, drug addiction and drug abuse can share attributes of both choice and disorder. The dilemma remains: how do we ethically deal with persons with disorders that may require treatment, and who engage in behaviours that are harmful to themselves and others? There are competing ethical principles that need to be balanced and reconciled: respect for autonomy (the impact that addiction has upon the autonomous decision-making capacity of addicted individuals), and the circumstances under which society can override autonomy in that person’s own interest, called paternalism, or deprive an individual of their liberty in order to protect the public good. This is, in part, an empirical question, one that we will examine in the next chapter. The impact that addiction has upon the addicted individual is one that many hope neuroscience may help us to answer. The ethical principles of non-maleficence and beneficence are less controversial in examining the impact that neuroscience research has on the way in which we treat addiction. Most reasonable people would agree that we should aim to benefit and avoid doing harm to those who seek treatment for addiction. There is nonetheless disagreement about the harms and benefits of different treatment approaches, the evidence for which is discussed in Part 3.

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Based on the ethical approach developed above, there are two major ethical concerns that are central to the treatment of persons with addiction: (1) how does addiction affect the autonomy of the addicted individual, that is, their ability to make free choices about their drug use; and (2) should, and if so under what circumstances, should society override this autonomy in order to protect the welfare of the individual (i.e. paternalism) or society (i.e. public good)?9

5.3.1.

Autonomy and addiction

How much autonomy do drug-dependent persons have? To what extent are they able to make decisions about their drug use, consent to enter addiction treatment, choose not to use drugs, be involved in decisions about their treatment, and take responsibility for their actions? Answers to these questions depend upon what sort of condition addiction is. Whether we believe it is a brain disease or simply wilful bad behaviour influences the degree to which the societal response is medical, or judicial, or some combination of the two. It also affects how responsible we hold those who use drugs to be for their actions, and how much of the burden of treating the condition we think should be borne by the individual and how much by society. As defined in psychiatric classifications, addiction is a disorder in which an individual’s control over their drug use is impaired. People with an addiction continue to use drugs in the face of enormous negative consequences, and despite often expressing a wish that they could stop. This perspective is codified in the diagnostic criteria for addiction, in which a loss of control over drug use is central and becomes compulsive – something engaged in at the expense of all other goal-directed activities, such as work, relationships and caring for children (American Psychiatric Association, 2000; WHO, 1993).

9

Throughout this book, we use the phrase ‘the public good’ to refer to the general welfare of society. In the case of drug use and addiction, this primarily focuses on the fundamental needs of society such as safety, health, economic and social prosperity. However, the public good also includes less tangible, but similarly important pursuits such as the pursuit of collective projects and shared values. These are important components of the ‘good life’. Our discussion, however, has focused primarily on the more fundamental elements of the public welfare as it is these that are most critically threatened by addiction and drug use, and without which the pursuit of virtue, collective projects and shared values would not be possible.

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This definition of addiction is contested by commentators who are sceptical about the existence of addiction. They argue instead that drug use is a decision that users freely and knowingly make (e.g. Dalrymple, 2006; Davies, 1997; Foddy and Savulescu, 2006; Satel and Lilenfeld, 2007; Szasz, 1975). The effect of drug use and addiction on autonomy is of fundamental importance to this debate and is also central to the expression of one’s rights. Respect for autonomy is becoming increasingly important in research on addiction (Levy, 2006b) and other psychiatric conditions (Glannon, 2006a; Levy, 2007). For much of the 20th century, drug-dependent persons were seen as autonomous, self-governing individuals who wilfully, knowingly and voluntarily engaged in criminal and immoral behaviour (Gerstein and Harwood, 1990; Heyman, 2009; Peele, 1998; White, 1998). The presumed autonomy and responsibility of such individuals has been called into question by recent genetic and neuroscientific research on addiction (Leshner, 1997; Volkow and Li, 2004). It is increasingly argued, most notably by the directors of NIDA and the National Institute on Alcoholism and Alcohol Abuse (NIAAA), who conduct over 85% of global research on drug abuse and addiction,10 that addiction is a ‘chronic, relapsing brain disease’ (Leshner, 1997, p. 45). The brain disease model of addiction challenges the traditional belief that drug use is always a voluntary choice. It argues that prolonged drug use results in long-lasting changes in brain structure and function (neuroadaptations) that undermine voluntary control (see Chapter 3) (Leshner, 1997; Volkow and Li, 2004). These neuroadaptations that can persist for months, and possibly years, after users become abstinent, explain why many abstinent drug-addicted individuals relapse to drug use (Volkow and Li, 2004). Neurocognitive studies have also shown that addicted individuals display cognitive deficits in decision-making tasks that limit their capacity to make free decisions about their drug use (Bechara, 2005; Bechara, et al., 2001; Fillmore, 2003; Grant, et al., 2000; Hester and Garavan, 2004; Jentsch and Taylor, 1999; Rogers and Robbins, 2001; Yucel and Lubman, 2007). See Section 3.5 for a more detailed discussion of this research. These results are used to support a neurobiological account in which addictive drugs subvert endogenous reward circuits that are essential to survival, thereby giving drug use an overriding motivational salience that works to the detriment of all other goal-directed activities (Dackis and O’Brien, 2005). According to proponents of the brain disease model, these brain changes also

10

Reported in Vrecko (2010).

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explain why ‘addicts’ continue to use drugs despite tolerance to their pleasurable effects and in the face of serious adverse consequences. It also explains why ‘addicts’ have difficulty in understanding or considering the long-term consequences of drug use and have diminished control over their drug use. If taken literally, the brain disease model may be used to argue that those with an addiction lack the autonomy to make informed choices about drug use, as some ethicists and clinicians have indeed argued (Charland, 2002; Cohen, 2002; Elliott, 2002). This would include the choice to enter treatment or to participate in research, referred to as informed consent (see Chapters 6 and 9). For example, this model could also potentially be used to justify coerced treatment of addiction (see Chapter 8), the use of treatments whose proponents are overly optimistic about their ability to ‘cure’ addiction, or the use of highly invasive treatments, such as neurosurgery (see Chapter 11). It may also encourage a reliance on medical or biological approaches to treatment at the expense of more broadly effective social policies for preventing drug use and harm (see Chapter 14). Brain disease explanations of addiction could also potentially impact upon addicted individuals’ beliefs about their ability to refrain from drug use or overcome addiction. This could result from giving them the impression that their behaviour is controlled by their neurotransmitters and therefore outside their own control (sometimes referred to as fatalism) (Satel and Lilenfeld, 2007). It could, in contrast, empower them to make better choices and seek professional help. Future research in this area may help to clarify these uncertainties (see Chapter 15). Neurobiological research on addiction can make significant contributions to the understanding of whether addicted individuals are autonomous or not, and therefore responsible for their actions. The debatable status of addicted persons before the law has produced an ambivalent societal response to their criminal acts such as consuming an illicit drug and engaging in criminal behaviour while intoxicated or in order to fund illicit drug use (e.g. drug dealing or stealing). A large part of this debate concerns an addicted individual’s capacities, such as the capacity to consent, or to take responsibility for their actions. We examine the impact that neuroscience has in this regard in greater detail in Chapter 6. 5.3.2.

Addiction and the public good

The behaviour of addicted persons can cause significant harm to the rest of society. As discussed in Chapter 2, drug addiction and drug abuse can lead

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to increased violence and physical assault, property damage and theft, family neglect and abuse, as well as both physical and psychological damage. Addiction can produce more indirect harms, such as loss of employment and increasing dependence on social welfare and increased public health care costs (e.g. for treatment of infections with blood-borne viruses). Consequently, there is an ethical warrant or obligation for society to prevent these harms, or to ensure the public good. In the language of human rights, liberty is the condition in which an individual has the ability to act according to his or her own will within a coercive – but stabilising – framework of law. Liberty is premised on the notion that each individual may have a different conception about what is good for them, and they should have the freedom to act on these choices, provided that they do not infringe the autonomy of others. Their choices are restrained by the state, which upholds individual rights and equality of opportunity. State coercion is justified because different conceptions of the good may come into conflict, and social stability calls for rules to govern each others’ private lives in the public sphere (Capps, 2007). Liberty therefore refers to the freedom to engage in some activity without hindrance from others, so long as the expression of one’s liberty is not to the detriment to the autonomous choices of others. Thus, in systems of rights, individual ‘choices’ are often qualified by the public interest or the public good,11 which includes the justification of interference. When we break legally enforceable rules, we should expect that we will be dealt with fairly before the law, through a system of adjudication that may, in the event of conviction for wrong-doing, deprive us of our liberty. Thus, human rights frameworks recognise the value to individuals of their personal liberty and their ability to exercise their autonomy, and hence they recognise the need for an appropriate justification for any interference in the enjoyment of these.

5.4.

The minimum conditions for the ethical treatment of addiction

The treatment of drug addiction should observe the minimum requirements for ethical acceptability of any form of medical or psychosocial treatment: 11

The ‘public good’ and ‘public interest’ are sometimes treated as synonymous in the philosophical literature. The latter tends to be predominantly found in legal terminology, the former in ethical discussions. For simplicity, we refer to the ‘public good’ throughout this report (Capps, et al., 2008).

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respecting the autonomy of persons who are treated, avoiding harm (nonmaleficence) and doing good (beneficence), and providing a fair distribution of costs and benefits of treatment and policy (distributive justice). Based on the preceding analysis, these ethical principles could be taken to imply the following requirements: 1 There should be rigorous evidence of the safety and effectiveness of the treatment that is provided. 2 Effective treatment should be provided safely in well-structured, wellresourced and well-managed treatment programs. 3 Treatment staff should observe the ethical principles of: respecting patients’ autonomy by ensuring that they give free and informed consent to participate in treatment, protecting their privacy and the confidentiality of information provided to treatment personnel, and delivering treatment in a way that maximises its effectiveness for each individual by matching patients to the treatment that meets their individual needs and situation. 4 Where an addicted individual’s behaviour causes harm to others in society, or impinges on the full expression of their rights, the rights of the addicted individual may be restricted in order to protect the public welfare. 5 Restricting individual rights in the public interest must only be done for compelling reasons based on empirical, clinical and scientific evidence, and the restriction must be relevant to the harm caused, or potentially caused, to others, and must be proportional to the harm. 6 Treatment programs should ensure that addicted persons have equitable access to treatment and that they do not bear a disproportionate social burden in accepting treatment. 7 It is important that neurobiological treatment is not used to compensate for poor social policies that lead some to drug use and addiction, or inappropriate drug policies that may be involved in the negative impact of drug use.

5.5.

Conclusion

While autonomy is a guiding premise in respecting the rights of individuals, individuals do not have rights to simply do as they please; their actions must be guided by responsibility towards others. Thus, in some situations, where individuals are incapable of controlling their actions, or acting in a way that may harm themselves or others, punitive or restrictive measures may be justified. However, the state should recognise the complexity of drug

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addiction and use the best evidence in deciding how to tackle the problem. This calls for a balanced or considered use of the brain disease model of addiction. At the start of this book we emphasised that the ‘medical’ and ‘moral’ models play a large role in the development of appropriate responses to addiction. It is clear from the neuroscience of addiction that decision-making may be impaired by addiction. However, as we will see in the next chapter, it is generally not so impaired that addicted persons lack autonomy, or forfeit their ability to express their liberty by virtue of the fact that they are addicted. The sections that follow explore how these ethical principles are affected by the key role of choice in drug use, and the possible ways in which the environment and genes affect an addicted individual’s neuropsychological capacity for decision-making, as understood by addiction neuroscience.

6 Autonomy and the capacity to consent to addiction treatment

6.1.

Introduction

The process of consenting to treatment of addiction raises a number of ethical issues. Most of these centre around the fact that the treatment of addiction often involves the management of behaviour that is defined as criminal, that creates adverse consequences for both the individual and the rest of society, and that is increasingly understood to be neurobiologically driven, to at least some degree. When addicted individuals seek treatment, they are often in desperate social, financial and health circumstances: they may be neurocognitively impaired and may have a comorbid psychiatric disorder such as depression or anxiety. They are often under some degree of external coercion to enter treatment from family members, employers or the courts. There may be conflict between the interests of the addicted person seeking treatment, the community who funds treatment programs and those who decide how they are run. These tensions may influence what people are required to consent to when they enter treatment, and the circumstances under which their consent is obtained. This chapter analyses the issues involved in obtaining informed consent to enter addiction treatment, and the role that it plays in producing positive treatment outcomes. We begin by reviewing recent research on the neurobiological changes that underlie addictive behaviours (e.g. compulsion and craving), and the impact that this has had on some bioethicists’ thinking about the capacity of addicted individuals to give free or internally uncoerced consent to participate in certain types of treatment, such as agonist maintenance therapies for opioid dependence that involve long-term administration of opioid drugs. We conclude with some practical ethical guidelines for how informed consent to enter such addiction treatment should be obtained.

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We focus specifically on the agonist maintenance treatment of opioid addiction because this is the condition in which the capacity to consent is most often questioned. Similar ethical issues arise in the treatment of addiction to other substances, different treatment strategies and philosophies (e.g. abstinence, antagonist maintenance or relapse prevention), and in different treatment contexts (e.g. privately funded, state coerced). We illustrate this by providing a brief analysis of the implications of the ethical analysis of consent to abstinence-oriented treatment for opioid dependence. 6.2.

The role of informed consent in addiction treatment

Informed consent is the process by which individuals agree to enter treatment in the knowledge of its possible risks and benefits, and in the absence of duress or coercion. Informed consent is commonly taken to require that the individual: (1) has the capacity to understand the treatment and communicate their wishes, or cognitive capacity; (2) is free to make decisions (i.e. internally or externally uncoerced) or volitional capacity; and (3) is informed of the risks and benefits of treatment, as well as those of other treatment options (Faden, et al., 1986; Roberts, 2002b; Walker, et al., 2005). We would suggest including a fourth requirement that is neglected in traditional characterisations of informed consent: (4) that patients have equal access to all effective forms of treatment, where treatment is appropriately operated and resourced (see Table 6.1). This is particularly relevant in the provision of drug dependence treatment where there are competing social and political forces that determine what treatment options are made available, and the manner in which these treatments are provided. An ongoing challenge in treating addiction is providing good treatment in the face of shrinking budgets and increasing demand, particularly in many developing countries. In some countries, treatments such as agonist maintenance are prohibited by law (Krupitsky, et al., 2010). Such constraints limit the extent to which those who provide addiction treatment may be able to meet these standards for obtaining informed consent. From the perspective of those providing treatment (e.g. care givers), individuals should have access to all effective forms of treatment that are possible within the political and economic context in which treatment is governed. Access to treatment should not be determined by the moral attitudes towards addiction of those operating the treatment program. There has been little research into the process of informed consent in the treatment of mental health, and in particular, substance abuse and addiction

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Table 6.1 The four requirements necessary for informed consent to agonist maintenance treatment of opioid dependence (Carter and Hall, 2008a). Informed consent requirement Capacity

Freedom

Information

Options/access

Description The decision-making and cognitive capacities to understand a treatment, and to communicate an intention or preference (e.g. cognition, decision-making, comprehension) The ability to make a choice without being coerced, internally (e.g. due to a psychiatric or neurological deficit) or externally (e.g. by the state). Some argue that there are two types of freedom: positive freedom (the potential for self-determination or self-realisation) and negative freedom (the absence of obstacles or interference from others) (Feinberg, 1980) To have all available information regarding the risks and benefits of treatment, and those of other alternatives, as well as rules and requirements of treatment Equal access to all forms of effective treatment, where treatments are appropriately operated and resourced

(Sugarman, et al., 1999; Walker, et al., 2005). A systematic review in 1999 found only two studies of consent in substance abuse treatment settings (Sugarman, et al., 1999). An updated review found that very little had changed. One study found that injecting drug users (IDUs) had the capacity and comprehension to consent to a clinical trial of an HIV vaccine (Harrison, et al., 1995). Another study demonstrated that capacity to consent in these individuals could be enhanced by the use of audiovisual aids (Fureman, et al., 1997), while a recent study found that the use of corrected feedback enhanced the recall of informed consent information of substance-abusing offenders entering a research study (Festinger, et al., 2010). While such studies suggest that addicted drug users have the cognitive capacities to comprehend and communicate during the process of consent, they do not shed light on the ability of addicted individuals to provide free and internally uncoerced consent to participate in research, clinical trials or treatments that involve the consumption of their drug of addiction or an agonist that has similar effects (e.g. methadone). There has been very little research on volitional capacity, partly due to the difficulty in measuring subjective phenomena such as desire, craving or

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compulsion (Roberts, 2002b). Some studies have attempted to measure the decision-making capacity of dependent drug users (Cairns, et al., 2005; Hazelton, et al., 2003; Hotopf, 2005; Kiluk, et al., 2010; Smith, et al., 2006). Kiluk and colleagues (2010) found that addicted individuals entering treatment generally had poor recall of the consent process, and that their performance in treatment was associated with neurocognitive indicators, such as intelligence and attention. The development and use of such neurocognitive tests might help in ensuring that consent is free and informed; it may also assist in providing more effective treatments that are tailored to an individual’s specific needs and abilities (Jeste and Saks, 2006). The highly regulated and institutionalised nature of informed consent has seen the process reduced to a medico-legal event, epitomised by signing a consent form. This approach to consent is more valid in medical research and surgical procedures, where the concept of informed consent was initially developed. It is less applicable in the treatment of mental disorders and addiction. There is great variability in the degree of addiction, and the social and cognitive capacities of individuals presenting for addiction treatment (Roberts, 2002b), as well as differences in their willingness to change (Walker, et al., 2005). The narrow and rigid structure of the informed consent form can gloss over the complex nature of consent, particularly in the case of substance abuse where it is more difficult to ascertain whether consent is free and informed, and where the capacity to consent may change dramatically over time. As we will show, adopting a view of the consent process that is too narrow can also lead to poorer treatment outcomes. 6.3.

Can ‘addicts’ say ‘no’ to drugs?

There are clearly situations in which addicted drug users lack the capacity to consent. An individual suffering from severe alcohol-induced dementia, an acute amphetamine-induced psychotic episode, or a comorbid psychiatric condition (such as major depression with suicidal impulses), for example, is unable to meet the criteria for informed consent. However, this is true of any individual suffering from a similar brain injury or severe psychiatric disorder. Are addicted individuals incompetent by virtue of their being addicted, in the absence of other impairments? It has been argued that ‘addicts’ are unable to refuse their drug of addiction and are therefore unable to provide free and internally uncoerced consent to any addiction treatment or research (see Section 9.5) that involves the provision of their drug of addiction or its agonist, such as methadone or buprenorphine

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maintenance treatment (Charland, 2002; Cohen, 2002; Elliott, 2002; Roberts, 2002a). This argument, if accepted, could affect the way in which treatment is provided, the strength of the carer–patient relationship, the degree of involvement individuals have in decisions regarding their treatment, and therefore the likelihood of treatment success. It may also have significant implications for how addicted individuals are regarded in society and the social policies that we adopt to treat addiction and drug use (Carter, et al., 2009; Carter and Hall, 2007a). For much of the 20th century, drug-dependent persons were seen as autonomous, self-governing individuals who wilfully, knowingly and voluntarily engaged in criminal and immoral behaviour (Dalrymple, 2006; Davies, 1997; Heyman, 2009; Szasz, 1975). The presumed autonomy and responsibility of such individuals has been called into question by recent genetic and neuroscientific research on addiction conducted primarily at NIDA and NIAAA in the US (Leshner, 1997; Volkow and Li, 2004). The directors of these Institutes have argued that addiction is a ‘chronic, relapsing brain disease’ (Leshner, 1997, p. 45) caused by chronic self-administration of drugs that produces enduring changes in brain neurotransmitter systems that leave individuals with an addiction vulnerable to relapse after abstinence has been achieved (Volkow and Li, 2005). See Chapter 3. The brain disease model of addiction challenges the traditional belief that drug use is always a voluntary choice by arguing that prolonged drug use results in long-lasting changes in brain structure and function that undermine voluntary control (Leshner, 1997; Volkow and Li, 2004). Neuroimaging studies have shown that chronic drug use produces a significant decrease in dopaminergic activity that is involved in the disruption of limbic and prefrontal regions (Volkow and Li, 2005). Adaptations in limbic regions emphasise the rewarding effects of drugs and make addicted individuals less sensitive to the rewarding effects of natural reinforcers (everyday stimuli such as food, work and relationships). Disruption of functioning in the prefrontal regions focuses addicted individuals’ attention on drug use and impairs their ability to control impulses to use drugs (Volkow and Fowler, 2000; Volkow, et al., 2003). These neuroadaptations can persist for months, and possibly years, after abstinence has been achieved (Volkow and Li, 2004). Neurocognitive studies have also shown that addicted individuals display cognitive deficits in decision-making tasks (Bechara, 2005; Bechara, et al., 2001; Fillmore, 2003; Grant, Contoreggi and London, 2000; Hester and Garavan, 2004; Jentsch and Taylor, 1999; Rogers and Robbins, 2001; Yucel and Lubman, 2007).

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These types of findings are used to support a neurophysiological picture of how addictive drugs ‘subvert’ or ‘hijack’ endogenous reward circuits in the brain that are essential to survival, thereby giving drug use an overriding motivational salience that works to the detriment of other important goaldirected activities (Dackis and O’Brien, 2005). According to proponents of the brain disease model, these neuropharmacological changes in the brain explain: why addicted persons continue to use drugs despite tolerance to their pleasurable effects and in the face of serious adverse consequences; and why they have difficulty in understanding or considering the long-term consequences of drug use and a diminished ability to control their drug use. When taken literally, the model of addiction arising from this research has been used to argue that persons with an addiction fail the first two tests of informed consent: (1) the capacity to understand; and (2) the ability to make free and autonomous choices. Recently, some bioethicists and clinicians have been prompted by the emerging neurobiological conception of addiction to question the capacity of opioid-dependent individuals to consent to some forms of treatment for their dependence (Charland, 2002; Cohen, 2002; Elliott, 2002; Roberts, 2002a). ‘Heroin addicts’, they argue, are by definition unable to make rational decisions about whether to accept an offer of heroin either in the setting of a research study (Cohen, 2002), or in a clinical trial of heroin maintenance treatment (Charland, 2002). In the case of heroin maintenance, if a treatment can only be offered to patients after its safety and efficacy have been demonstrated in a randomised controlled trial, then the acceptance of Charland’s argument would preclude the trial, and hence clinical use, of heroin maintenance. Moreover, if these arguments were accepted, they would raise similar doubts about the capacity of opioid ‘addicts’ to freely consent to any treatment that involved being maintained on an agonist, such as methadone, or a partial agonist like buprenorphine, arguably two of the most effective pharmacological treatments of opioid addiction (Gowing, et al., 2009; Mattick, et al., 2009; Mattick, et al., 2008). Charland (2002) argues that heroin ‘addicts’ are incapable of saying ‘no’ to the offer of free heroin. The warrant for this argument is the testimony of one former heroin ‘addict’ and statements by neuroscience researchers that the brains of opioid-dependent individuals are so altered by opioids that they are unable to consider the risks of using these drugs. In using heroin, Charland argues, ‘[t]heir decision is not truly theirs’ (Charland, 2002, p. 43). According to Charland, opioid-addicted individuals are therefore unable to consent to participate in trials of injectable heroin.

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Charland’s claim that heroin users are unable to say ‘no’ to an offer of heroin is empirically false. For example, the Swiss Heroin Trials were not inundated with untreated ‘heroin addicts’ seeking ‘free heroin’. This was clearest in a randomised controlled trial of immediate versus delayed entry to heroin maintenance (with the delayed entry group given access to usual treatment: methadone maintenance or abstinence) (Perneger, et al., 1998). The researchers intended to recruit 40 patients in each group but were only able to recruit 24 and 27 patients, respectively. Moreover, when those who were allocated to delayed entry to heroin treatment were offered the choice at the end of 6 months, two thirds of the group decided against receiving heroin (Perneger, et al., 1998). Severely dependent, treatment refractory heroin ‘addicts’ were thus capable of saying ‘no’ to both an initial and a delayed offer of prescribed heroin. Similar patterns were seen in the recruitment of subjects to prescribed heroin trials in other countries (Scherbaum and Rist, 2010). Further evidence that heroin-dependent individuals are able to rationally consider whether to participate in heroin trials comes from a recent study that interviewed a large cohort of heroin-dependent individuals (Scherbaum and Rist, 2010). Almost half of the heroin-dependent individuals interviewed (44%) would not participate in a trial of prescribed heroin if given the chance (reflecting the recruitment experience in heroin trials). Significantly, this choice was independent of the severity of their addiction, suggesting that such choices were not determined by an irresistible urge for heroin. What was particularly interesting is that their assessment of the pros and cons of participating in a trial of heroin prescription were consistent with their preference for prescribed heroin, suggesting that these decisions were based on deliberation and not simply the result of irrational and irresistible urges to take heroin as Charland suggests. Their choices were considered and consistent with their rational assessments; a common requirement of autonomous decisionmaking (Levy, 2006b) and informed consent (Carter and Hall, 2008b). Charland and Cohen interpret the DSM-IV criteria that describe loss of control and compulsive behaviour in absolute terms. They assume that addicted individuals lack any capacity to control their drug use rather than showing varying degrees of impaired control over drug use in varying situations. The DSM-IV criteria that they rely on are simply descriptive terms, and in themselves do not constitute evidence. Contrary to Charland’s views, there is other evidence that addicted individuals are able to exert some control over their drug use. They may, and often do, stop using drugs without assistance for varying periods, either to reduce their tolerance (in order to get a bigger ‘hit’) or to take time out from the

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rigours of their lifestyle (Granfield and Cloud, 1996; Heyman, 2009). In fact, many opioid-addicted individuals stop using drugs in response to major life events (e.g. the birth of a child, ultimatums from friends and family, or threats from employers) (Dalrymple, 2006; Heyman, 2009). This demonstrates that addictive behaviour is not solely the result of altered brain neurochemistry. Many also overcome addiction without treatment (Granfield and Cloud, 1996; Heyman, 2009). If addicted individuals were unable to choose not to use drugs, one wonders how such types of recovery would be possible. The experience of returning Viet Nam veterans who were able to quit opioid use without treatment once back in the US is further evidence that addiction is a more complex condition than simplistic brain disease models might seem to suggest (Gerstein and Harwood, 1990). In order for addiction to plausibly forestall autonomy in individuals with an addiction, the internal and external forces must be demonstrably irresistible and absolute (Levy, 2006b). It is clear from behavioural and observational studies that this is generally not the case. Also, the evidence some ethicists cite from the neuroscience literature is less compelling than they might realise. It is unclear that when neuroscientists refer to the brains of the addicted as being ‘hijacked’ by a drug, they mean it in the literal and absolute way intended by Charland, Cohen and Elliot. Qualitative research by our group has found that while scientists and clinicians use the terms ‘loss of control’ and ‘compulsive’ to describe addiction, they often acknowledge that addicted persons do in fact maintain some control over their drug use, and that they are not literally compelled to take drugs. As the highly regarded addiction neuroscientist and Harvard Provost, Steven Hyman, argued, ‘addicted individuals have substantial impairments in cognitive control of behaviour, but this ‘loss of control’ is not complete or simple’ (Hyman, 2007, p. 8). Evidence for compulsive drug use in neuroscientific research emerged from highly controlled laboratory animal models (Olds and Milner, 1954). These animal models have a limited application to the study of human compulsive behaviour, and the contexts in which humans typically use drugs (Ahmed, 2010; Cantin, et al., 2010; Epstein, et al., 2006; Foddy and Savulescu, 2006; Kalant, 2010). Getting animal models such as rodents ‘hooked’ on drugs is surprisingly difficult. Scientists often employ inbred lines of animals that more easily become addicted. Many of the observed addictive behaviours (e.g. self-administration, conditioned place preference) can also disappear by providing animals with a more naturalistic environment that researchers refer to as an ‘enriched environment’ (Ahmed, 2010; Alexander, et al., 1981; Alexander, et al., 1978; Xu, et al., 2007).

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Human neuroimaging and neurocognitive research on addiction are also less compelling than critics appear to realise. This research shows that on average addicted subjects as a group show more disruptions in brain function that are associated with a reduced ability to control drug use, and poorer performance on neurocognitive tests of decision-making than do non-addicted individuals. But these changes in brain function and neurocognitive deficits do not necessarily and absolutely undermine autonomous decision-making capacity. That is, these studies find a tendency for addicted individuals to have a diminished neurocognitive capacity and function compared to non-addicted individuals. Significantly, not all of those who are addicted display these deficits, while some non-addicted controls do (Bechara, 2005; Bechara, et al., 2001). It is also possible that differences between addicted and non-addicted populations precede drug use and possibly make some more likely to become addicted and are not necessarily a consequence of drug use (although there is evidence for both arguments (Levy, 2006b). The fact that social measures, such as higher prices and increased taxation, and contingency management programs1 are able to reduce addictive drug use (Elster and Skog, 1999; Fingarette, 1988; Higgins and Petry, 1999; Marteau, Ashcroft and Oliver, 2009; Neale, 2002; Stitzer, Iguchi, Kidorf et al., 1993) suggests that addiction is not simply the result of disordered neurotransmitters. For all these reasons, it would be a mistake to conclude that all ‘addicts’ are, by definition, incompetent to consent to treatment or research that involves the administration of drugs of addiction. 6.3.1.

Sceptical views of impaired autonomy in addicted individuals

Other bioethicists have argued that addiction has no impact on the ability of addicted persons to make autonomous decisions about drug use (Foddy and Savulescu, 2006). These authors argue that neuroscience research shows that the motivation to use addictive drugs is no different from other biological drives (e.g. the motivation to eat strawberries) (Foddy and Savulescu, 2006). While some individuals repeatedly choose to engage in an activity that is harmful and even life threatening, it does not mean that they could not have chosen otherwise. These sceptics ignore two critical pieces of evidence on the neuropharmacology of addictive drugs. First, the effects of addictive drugs on brain 1

Contingency management involves the use of positive reinforcement (e.g. monetary rewards) to encourage abstinence from addictive drug use, as indicated by clean urine samples.

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functioning are supraphysiologically greater than those of natural rewards like food (Volkow, et al., 2004b). Rewarding activities cause the release of dopamine in the ventral striatum that gradually reduces with each repeated experience of the rewarding activity. This attenuation does not appear to occur with drugs of addiction. These effects can confer a motivational salience on drug use that trumps everyday rewarding activities from activating brain reward pathways. Second, chronic drug use also produces changes in the higher cortical areas of the brain that impair addicted individuals’ capacity to inhibit the desire to use drugs (Bechara, 2005; Bechara, et al., 2001; Fillmore, 2003; Grant, et al., 2000; Hester and Garavan, 2004; Jentsch and Taylor, 1999; Rogers and Robbins, 2001; Yucel and Lubman, 2007). In summary, neuroscience research on addiction does not prove that addicted persons lack autonomy: while their autonomy is in some instances clearly impaired, particularly during acute withdrawal or intoxication (see Section 6.4), addicted individuals retain some degree of control over their drug use and some degree of autonomy (Carter and Hall, 2008b; Levy, 2006b). The aim of treatment should be to increase patient decision-making capacity and autonomy (Spriggs, 2003, 2005), rather than preventing addicted individuals from participating in research and treatment that may be of benefit to them. More research is required to understand to what degree, and in what circumstances, the autonomy of addicted individuals is impaired, and how we may best increase it. We discuss these future directions for addiction neuroethics research in Chapter 15. 6.3.2.

Capacity to consent to abstinence-oriented treatment

Bioethicists’ concerns about capacity to consent to addiction treatment have been selectively raised about pharmacological maintenance treatment. Cohen and Charland, for example, seem to implicitly assume that the only free and informed decision that an addicted person is capable of making is the decision to enter abstinence-oriented treatment. By the same type of reasoning, there are grounds for arguing that decisions in favour of this treatment type may not be truly free or informed. Many addicted individuals enter abstinenceoriented treatment under some form of coercion, such as the threat of criminal prosecution, or the loss of employment or a relationship. Heroin-addicted individuals who enter such treatment may overestimate their capacity to achieve abstinence, underestimate the difficulties of remaining abstinent, and may not appreciate the risks of such treatment (e.g. increased risk of a fatal overdose on relapse to heroin use in a condition of opioid naivete´

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(Mattick and Hall, 1996)). Abstinence-oriented treatment programs, no less than agonist maintenance treatment, must also meet ethical obligations to inform opioid-dependent patients of the low success rate of their treatment, the increased risk of fatal overdose that they assume in entering such treatment, and the availability of other approaches to treatment, including agonist maintenance treatment. 6.4.

Implications for obtaining informed consent to enter addiction treatment

Acute intoxication with most drugs of addiction, such as opioids, alcohol, benzodiazepines, ecstasy and amphetamines, can produce behavioural and cognitive changes that undermine both an understanding and appreciation of the consequence of participating in research or entering addiction treatment (Curran, 1991; Curran, et al., 2001; Finnigan and Hammerslay, 1992; Mintzer, et al., 2005; Mintzer and Stitzer, 2002). The ‘high’ produced by these drugs can also affect an individual’s interest in the consequences of entering treatment, thereby impairing their volitional capacity (i.e. their motivation to participate and consider the consequences of participating). Repeated use of most drugs of addiction can also lead to a withdrawal syndrome on cessation of drug use. The symptoms of withdrawal to some drugs, such as alcohol, nicotine and opioids, can also produce cognitive impairments (Lyvers and Yakimoff, 2003; Munro, et al., 2000; Rapeli, et al., 2006). Relief of withdrawal symptoms is often a potent motive for entering treatment or participating in research that involves drug consumption or subject payments that may be used to buy drugs. There is much variability in addicted individuals’ response to drugs and the degree of impairment they experience. Impairment may differ depending on the type of drug being abused (e.g. stimulants have been shown to improve cognition on some measures) (Mehta, et al., 2000), the route of administration, the severity of the addiction, the level of tolerance, and the amount of time since last drug use. A commonly held (and we believe reasonable) view is that drug-dependent people are able to give free and informed consent if they are not intoxicated or suffering acute withdrawal symptoms at the time when consent is requested (Adler, 1995; Gorelick, et al., 1999; Grisso and Applebaum, 1998). A non-abstinent drug-dependent individual can spend significant time between periods of acute intoxication and withdrawal in which they are not severely cognitively impaired. As yet, there is no way to measure or define the effect of these symptoms in a clinical setting in a

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clear-cut and objective fashion (Dunn and Jeste, 2001; Dunn et al., 2006). More research in this area is urgently required. Given that there are circumstances associated with drug abuse (e.g. comorbid psychiatric disorder, unemployment, poverty, violence, withdrawal and intoxication) that can impair an addicted individual’s ability to make far-reaching decisions about treatment, a client should only be asked to consider detailed treatment requirements once they have become stabilised in treatment. Patients should therefore not be asked to sign a detailed treatment contract on admission to treatment. Consent in this instance is provisional. The worst of drug withdrawal symptoms should be reduced by medication (or have abated in the case of unmedicated withdrawal) before they are required to make long-term decisions that are implied by signing a treatment contract. Addiction may therefore affect addicted individuals’ ability to consent to treatment in the short term and their capacity to choose a specific treatment from the types available, in some individuals and in some situations. This impairment is not absolute, and is not seen in all individuals in all circumstances at all times. It is unwise to assume that decision-making in addicted persons is so impaired as to eliminate autonomy. In the absence of evidence to the contrary, we should assume that addicted persons possess decisionmaking capacity and attempt to engage them as much as possible in making their own decisions rather than making decisions for them, or worse still, overriding their wishes by compelling them to enter treatment. The courts presume that addicted individuals are responsible for their actions (rather than exculpating them on the grounds of their addiction); it seems reasonable to make the same assumptions in the treatment setting when seeking their consent to be treated. The nature of addiction means that giving informed consent to treatment is considerably more complicated than signing a legally binding consent form. Treatment providers must engage with the individual and validate their experience, create trust, be flexible and aim to enhance their autonomy and increase their decision-making capacity. Such an approach can avert many of the problems that can emerge from an inadequate consent process, such as the therapeutic misconception2 in the case of clinical research, or a misunderstanding of the treatment aims or regulations (Fisher, et al., 2008). Successful addiction treatment depends upon the quality of the clinician–client

2

The mistaken belief that participation in a clinical trial will be of therapeutic value to participants.

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relationship (Bell, et al., 1995; Fisher, et al., 2008). Treatment that engages with the client and fosters control over drug use may be more effective than treatment that limits autonomy by using rigid treatment protocols. It would appear that an ethical approach that values the relationship with the addicted patient, such as an ethics of care or a virtue ethics approach (see Section 5.2), may not only be the kindest to sufferers of addiction, but also the most effective in treating addiction and reducing drug-related harm. In dealing with withdrawing drug-addicted persons in desperate physical and mental states, treatment services must acknowledge the very real neurobiological changes that affect their ability to control their drug use and to make decisions about themselves. These facts can be acknowledged while recognising that drug-dependent persons who are not in these states still possess some capacity to make decisions about their treatment. This capacity should be nurtured and developed, through medication, therapy and social support, so that addicted persons can play an active role in their treatment and recovery. Once they have stabilised, it is important that treatment services provide accurate information about the likely success, risks and benefits of the different treatment options, and the rules and obligations entailed in accepting these treatments. 6.5.

Guidelines when admitting individuals into addiction treatment

From the analysis presented above, a number of ethical guidelines for admitting individuals into addiction treatment become apparent. These guidelines were developed for the pharmacological treatment of addiction, but can be applied to all forms of addiction treatment, including abstinence-oriented treatment. These guidelines are summarised in Table 6.2. First, when drug-addicted individuals enter treatment, they are often in a desperate state. They may be willing to agree to almost anything in order to enter treatment (e.g. to end their withdrawal symptoms or avoid the negative social consequences of their addiction). For these reasons, individuals in this situation should not be asked to provide detailed consent to a treatment program, apart from indicating their acceptance of the immediate offer of assistance. A client can only begin to think about treatment after they have either been stabilised on a longer acting drug (e.g. methadone or buprenorphine), or they have completed supervised withdrawal. Second, when choosing what sort of treatment to enter, it is important that the client understands the likely effectiveness of the treatment, the benefits and risks of completing treatment, and the requirements of the program. The

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Table 6.2 The minimum requirements for acquiring free and fully informed consent to agonist maintenance treatment Minimum requirements for informed consent to addiction treatment include providing information to clients about: 1. 2. 3. 4. 5. 6. 7.

Clinical characteristics and diagnosis Treatment recommendations Risks and benefits of treatment Costs of treatment Program rules – rights and obligations Alternative services and interventions Freedom to choose and refuse treatment

While these guidelines were developed for harm reduction treatments, they broadly apply to the process of obtaining consent to all forms of addiction treatment. Source: adapted from Walker, et al., 2005.

treatment that is chosen should reflect the aims of the individual rather than those of the staff or the wider community. The staff member’s responsibility is to ensure that the client is well informed about the treatment options that are available, their goals, risks and benefits, and the expectations of them in entering the program. This will include discussions about the pros and cons of abstinence versus maintenance treatment goals, as well as an honest appraisal of the risks and the likelihood of benefiting from both types of treatment. Third, informed consent to a detailed treatment contract requires formal communication of the rules and regulations of treatment and an individual’s obligations. This may include: information on drug testing regimes, program responses to positive urine samples, the intended length of treatment, costs, where and how often drugs are to be dispensed, other treatment requirements, the involvement of the criminal justice system, and rights to privacy and confidentiality, including informing participants of the limits of confidentiality (e.g. that it is mandatory to report child abuse or homicide). These rules and obligations should be aimed at the treatment of the individual, while still protecting society from harm. A more detailed discussion of the sorts of rules and regulations that are applied in the case of pharmacological treatment of opioid addiction as well as a more detailed discussion of the social and moral forces that shape how treatment is provided can be found elsewhere (Carter and Hall, 2007a).

Autonomy and the capacity to consent to addiction treatment 6.6.

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Conclusion

In many developed countries it is generally a legal obligation in medical and psychiatric treatment to obtain a signed treatment ‘consent form’ during intake. The process of gaining consent is important not only to satisfy legal and ethical requirements; it plays a crucial role at the beginning of treatment. Unlike traditional consent procedures, such as those found in medical research, the effect that addiction has on an individual’s decision-making capacities means that informed consent is a critical part of successful treatment. Obtaining consent should be a process that engages the patient and creates a strong and trusting carer–patient relationship; one that validates the patient’s experiences and aims to maximise autonomy, encourage self-belief, and a willingness and capacity to change (Walker, et al., 2005). Thinking of informed consent as a single event of unilateral transfer of information from carer to patient can undermine a positive and productive treatment process. Little attention has been given to investigating what is required for informed consent to treatment of drug addiction or how this is best obtained. Studies suggest that participants in treatment or clinical trials often fail to understand or recall much of the information provided during the consent process, including the risks and benefits of the treatment (Festinger, et al., 2007). Successful strategies for improving consent have been investigated in other health areas, such as the use of improved and simplified consent forms (see Festinger (2010) for a review). In addiction, video aids (Fureman, et al., 1997) and ongoing corrected feedback or the multiple learning approach (Festinger, et al., 2010) have successfully improved consent comprehension, and therefore validity, in a research context. Approaches such as the corrected feedback procedure can transform the process of obtaining consent from a one-time event into an ongoing and engaging process that begins at the time of entering into treatment and continually evolves during treatment to create a dynamic clinical relationship. These sorts of approaches are also endorsed by many ethics review boards including the National Institute of Health. More research is needed on this topic, as are studies of attitudes and understanding of consent by physicians, carers and researchers (Forman, et al., 2002; McCrady and Bux, 1999). Better staff training is desirable, not just to meet legal requirements or provide the minimum of rights, but to facilitate better treatment. Research into the development of tools to better assess the capacity of drug-addicted individuals may aid in their treatment, not just to establish consent, but to identify the extent of any cognitive deficits (Cairns, et al., 2005; Hotopf, 2005; Kiluk, et al., 2010). While their usefulness in the clinical

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setting is uncertain, it is clear that ethical treatment of addiction should aim to improve an individual’s decision-making capacity and ability to make autonomous choices rather than override or undermine them. There is an enormous variability in the physical, social and psychological circumstances of addicted individuals who enter treatment and varying degrees of intention and capacity to change. This is a major challenge in the provision of addiction treatment that highlights the importance of an engaged consent process that addresses an individual’s needs. Obtaining a better understanding of the neurocognitive changes that underpin these differences, and tools to measure them, may prove useful in this task (Dunn and Jeste, 2001).

7 The rights of individuals treated for addiction

This chapter was originally included in ‘Mental Health and Human Rights’ edited by M. Dudley, D. Silove and F. Gale (Oxford University Press, 2012) and is reproduced by permission of Oxford University Press. 7.1.

Introduction

Individuals with a drug addiction are a uniquely vulnerable and stigmatised group among persons with mental disorders. Unlike other mental disorders, the status of addiction as a mental illness is hotly contested: by the public, politicians and policy makers. The activities that comprise some types of addictions are defined as criminal offences, such as the possession and distribution of proscribed substances (e.g. heroin, cocaine). Persons with a history of criminal convictions are also more likely to become dependent on alcohol and illicit drugs. Addiction also has an enormous negative impact upon the health and welfare of the rest of society. Consequently, those dependent on drugs are often discriminated against as a result of their status as ‘addicts’ and/or ‘criminals’. Policies towards those with an addiction are often motivated by a combination of strong moral disapproval of drug use and a need to protect society from the harmful behaviour of the minority who abuse drugs and engage in behaviour that harms others. The goal of treating a debilitating and chronic condition often receives a much lower priority. This can lead to discrimination and inappropriate restrictions on, or violation of, the rights of those with an addiction. It can also adversely affect the type and quality of treatment offered to individuals with a substance use disorder and the manner in which it is provided. Many countries have a rights-based or rights-influenced jurisprudential system, and most are signatories to at least one important international human 121

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rights convention or covenant (see Section 5.2.3). Despite this, very few, if any, developed societies treat addiction in a way that does not inappropriately derogate these rights. We examine the rights of individuals being treated for a drug addiction and discuss what might be entailed in upholding these rights. The advantage of a human rights approach to the treatment of addicted individuals is that it has the potential to encourage nation states to enact policies for the medical treatment of addiction, in contrast to ethical arguments that are easily contested. This approach goes beyond ethical injunctions as nation states are legally bound to protect human rights. While, in practice, abuses of the rights of addicted persons are unlikely to receive legal scrutiny (Gilmore, 1995), it is still valuable to highlight what a rights-based approach to addiction treatment would entail, and by which current practices may be judged publicly. 7.2.

Addiction, drug policy and human rights

In response to the harms caused by drug abuse and addiction, most nation states have criminalised some forms of drug use in order to deter non-users from using drugs, prevent addiction, protect society from drug-related harm, and punish those whose drug use harms others. These punitive policies include the prohibition of the possession, production and distribution of many addictive substances on pain of imprisonment (derogation of the right to liberty and freedom), forced addiction treatment with or without detention (derogation of the right to bodily integrity and consent), compulsory drug testing (derogation of the right to privacy) and child protection orders (derogation of the right to family). Addiction is also being increasingly recognised by some as a mental health disorder that requires treatment (Dackis and O’Brien, 2005). Most developed and developing countries employ a range of medical or therapeutic approaches to minimise the harm that addiction and drug abuse cause to those who abuse them (see Section 2.4). Social policies towards drug use and addiction are therefore ambivalently motivated by competing, but not necessarily conflicting, aims: a punitive or judicial approach that aims to protect society and punish ‘addicts’; and a therapeutic, often medical, approach that aims to treat and prevent addiction. Confusion about the aims and motivation of policies to deal with addictive behaviour – to treat a valid medical condition or to punish criminal behaviour – can lead to inappropriate or unjustified violation of the human rights of those who are addicted.

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Basic human rights for addicted individuals

Under human rights law, people with an addiction should be afforded the same rights as other members of society: they should be treated equally and with equity before the law, irrespective of their age, gender, ethnicity or other status (Barrett and Nowak, 2009; Gilmore, 1995; Wolfe, et al., 2010).1 Individuals suffering from an addiction should not have their rights denied simply by virtue of their being addicted. People with an addiction, who are also involved in criminal activities, should not be discriminated against by virtue of their status as criminals or as a result of their incarceration, other than the legal restrictions entailed in their punishment (United Nations General Assembly, 1948). All prisoners are entitled to equivalence in treatment, and should have access to the same medical health care that is available to the broader public. Any restrictions on the rights of those addicted must be in accordance with the law and proscribed by a court (which is argued to reflect the harm that their behaviour causes to others), and in line with restrictions imposed on someone else convicted of the same crime. Addicted individuals may have some rights derogated, such as: the right to freedom and liberty (e.g. when imprisoned after conviction and sentencing for a criminal offence), and some social and economic rights (e.g. removal of children into protective custody because of child abuse, or quarantining social welfare payments to ensure that the money is spent on children’s welfare rather than on the purchase of drugs). These derogations must be protected by due process. Importantly, individuals with an addiction maintain a right to health that cannot be derogated under any circumstances, including imprisonment for a serious crime (Gostin, 2001). To do so violates the most basic of human rights, and is an extreme form of extrajudicial punishment that is cruel and inhumane. A number of countries and multilateral agencies have produced charters and codes of ethics that explicitly outline what these human rights principles require of governments and their agencies (see ANCD, 2007; UNODC, 2010; WHO, 1995, 2005). 1

This is formally recognised in the Universal Declaration of Human Rights, and codified in legally binding instruments such as the International Covenant of Civil and Political Rights (ICCPR) and the International Covenant of Economic, Social and Cultural Rights (ICESCR). With the Universal Nations Charter, these four documents comprise the International Bill of Rights, and are the primary source of all human rights law. Human rights are also protected by regional declarations in Europe, the Americas, Africa, Asia and in Arab countries.

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The validity of the restrictions and derogations of the rights of addicted individuals often depends upon balancing: (1) the rights of the individual to liberty and freedom; (2) the obligation of the drug-dependent individual not to harm society; and (3) the state’s obligation to protect other individuals’ health, liberty and freedom from harm caused by addictive drug use. Whether we think that particular drug policies inappropriately violate an individual’s human rights will depend on whether we see addiction as a wilful and immoral act for which individuals with a substance use disorder should be made responsible, or as a mental illness requiring medical treatment. If we accept the latter, two further questions arise: What is an effective and appropriate form of treatment for a condition where control over behaviour is impaired? How should this treatment be provided? 7.3.

The right to access to effective treatment of addiction

Many politicians and policy makers, as well as libertarians, see addiction as a self-serving excuse for the abuse of recreational drugs (Davies, 1997; Szasz, 1975). Those who hold such views are often sceptical about whether addiction is a mental disorder. On this view, addiction and the choice to abuse drugs is a moral weakness: users choose to continue to use drugs despite the negative impact that consumption has on them or the rest of society. Addiction sceptics see punitive responses as the most appropriate way of deterring people from using illicit drugs and punishing those that break laws against using some drugs (if they accept the validity of such laws) or harming others. Such sceptical views about addiction are inconsistent with a number of observable facts: (1) addiction is more likely to occur in people from socially disadvantaged groups or with a family history of drug problems; (2) addiction risk varies in ways that depend on which drugs are used and how they are administered (i.e. more common for short-acting drugs that are injected); (3) it is responsive to pharmacological treatment; and (4) has a significant genetic basis (Ball, 2008). Punitive approaches to dealing with addiction have also been largely unsuccessful in reducing its incidence or the harm that it causes to drug-dependent persons and others (Gerstein and Harwood, 1990). 7.3.1.

The case for medical treatment of addiction

In recent years, scepticism about addiction has been partially replaced by the view that addiction is to some extent a mental (or brain) disorder requiring

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medical treatment. This shift has largely occurred because of scientific evidence that many addictive phenomena arise from the effects of chronic drug use on the brain (Volkow and Li, 2004). The evidence in support of this view has been outlined in detail in Chapter 3. This research has demonstrated that addiction is a real condition that involves significant impairments to decision-making that benefit from medical or therapeutic intervention. It is not, however, a condition that extinguishes autonomous decision-making capacity regarding drug use (Carter and Hall, 2008b; Levy, 2006b) (see Chapter 6). 7.3.2.

Effective treatment of addiction

The stigma attached to addiction has meant that sufferers in many developing and some developed countries have been denied access to effective treatment. People who hold moral or sceptical views of addiction often believe that abstinence from all drugs is the only appropriate goal of treatment and that this can be achieved by forcing drug users to become abstinent (see Chapter 8). Research suggests that this expectation is unrealistic because most people addicted to drugs will relapse to drug use without pharmacological and psychosocial support (Gerstein and Harwood, 1990). Addiction sceptics often oppose addiction treatments that involve replacing a drug of dependence with less harmful drugs that produce similar (although not identical) effects to the drug of dependence in controlled, supervised doses of known strength and purity (e.g. agonist or partial agonist treatment using methadone or buprenorphine for opioid dependence). These treatments are known as drug substitution, replacement or maintenance treatments of addiction (see Section 4.2). Their aim is to stabilise the behaviour of addicted individuals and reduce the harm that their drug use causes, while encouraging them to use psychological counselling and social support. These treatments also yield significant reductions in the social harm and public health costs associated with addiction (e.g. reduced crime and violence), a fact that is often used to garner public support for them. The most well-known form of maintenance therapy is methadone maintenance therapy or MMT (Ward, et al., 1998a). Despite good evidence of the effectiveness of MMT, some countries have denied addicted individuals access to this form of treatment by banning its use (e.g. Russia). Drugdependent individuals in many of these countries have minimal access to a limited range of less effective treatments, exposing them to greater harm from their continued use of illicit drugs. In the case of opiate addiction,

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those who relapse to opiate use following a period of abstinence (whether voluntary or enforced) are at significant risk of overdose if they use their usual dose of the drug (Darke and Hall, 2003). Failure to provide addicted individuals with more effective forms of medical treatment is arguably a denial of their right to health, and indeed of life, in the case of fatal overdose. When agonist substitution treatments are allowed, a punitive attitude by treatment staff can still mean that these treatments are operated in ways that impinge on addicted individuals’ right to health. Treatment centres in countries such as China, Viet Nam and the Lao People’s Democratic Republic (PDR) often resemble forced labour camps (sometimes called re-education through labour centres), where patients are treated under compulsory orders and made to work in order to pay for their ‘treatment’ (Cohen and Amon, 2008; UNODC, 2006a; WHO, 2009). Many countries also place arbitrary limits on the length of treatment that are unrelated to their health or medical needs, that drives many to return to illicit drug use when they are no longer able to receive pharmacological substitution. The size of the dose of methadone provided to individuals in MMT may be inadequate (Ward, et al., 1998a). The dose needs to be high enough to reduce the symptoms of withdrawal and cravings, but not so high that it harms the individual, or can be diverted to the black market. An inadequate dose will often cause many individuals to return to illicit drug use to alleviate the symptoms of withdrawal and craving. The result of a positive test of illicit drug use often results in a reduction in methadone dose to punish sufferers for non-compliance with program rules. This is often counterproductive in that it leads to expulsion from the program and a return to illicit drug use, increasing risk to the individual and society. Continued illicit drug use during MMT is more likely a signal that the dose is not high enough and needs to be increased (Bell, et al., 1995). See Carter and Hall (2007a) for a more detailed discussion of the practical issues involved in the provision of opioid substitution treatment. 7.3.3.

The right to access harm reduction measures

An addicted individual’s right to health also includes access to measures that enable them to reduce harms caused by their drug use (Elliott, et al., 2005). For example, needle exchange programs offer clean needles to injecting drug users to reduce sharing of contaminated equipment, and hence infection with blood-borne viruses, such as HIV and the hepatitis C virus (HCV).

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Opponents of needle exchange programs argue that these programs implicitly condone the injection of illicit drugs. However, epidemiological studies of these programs have shown that they have no effect on levels of injecting drug use (Elliott, et al., 2005). These arguments also ignore the fact that people with an addiction find it difficult to abstain from injecting drug use. Given that continued drug use is likely, failure to provide relatively cheap harm reduction programs such as needle exchange denies addicted drug users their right to health, and in the case of HIV, life. These programs have recently been supported by the United Nations and the World Health Organisation (UNODC, 2006b; UNODC and WHO, 2008; WHO, 2008). Access to these programs has gradually expanded to include countries with more punitive policies towards drug addiction (e.g. South-East Asia) although they are often only offered as small scale ‘pilot’ programs and rather punitively run (Cohen and Amon, 2008; Wolfe, Carrieri and Shepard, 2010). 7.3.4.

The right to effective medical treatment

The right of addicted individuals to equal access to effective medical treatment is most often advocated for the treatment of HIV/AIDS: that is, the right to equal access to antiretroviral drugs (ARVs). In many countries, such as in Asia and the former Soviet Union, injecting drug users (IDUs), who make up the majority of HIV-positive cases, are much less likely to receive ARVs (Cohen and Amon, 2008; Wolfe, 2007). While access to ARV for HIV-positive IDUs is increasing via The Global Fund (http://www.theglobalfund.org/en/) and similar initiatives (e.g. Viet Nam and China), access for HIV-infected drug users is still limited in many high need areas. A common reason used to justify the failure to treat HIV in IDU is that these individuals will not adhere to ARV treatments, allowing the development of viral resistance (WHO, 2006). However, research has consistently found no difference between IDU and non-IDU populations in compliance with ARV treatment, particularly when it is provided in conjunction with drug substitution treatment (Wolfe, 2007). HIV treatment programs often discourage IDUs from seeking or remaining in treatment by requiring them to pay for their medication or hospitalisation, have their name recorded in government registries that may be subsequently used to discriminate against them (e.g. denial of employment), or submit to drug tests with the threat of criminal prosecution for a positive test. Inequity in access may also result from structural inadequacies within the health system: many AIDS clinics will refuse to treat current IDUs, and few

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substance abuse clinics provide HIV treatment. This is a denial of the right to health and poor public health policy that increases HIV infection rates among the general population (WHO, 2006). 7.4.

The use of unevaluated and risky treatments of addiction

Neuroscience research on addiction has yielded a number of novel medical technologies that could be used to treat and, purportedly, cure addiction. Some of these are invasive, costly, and can cause significant harm to the patient. Ultra-rapid detoxification (UROD) was a radical treatment promoted to opioid-dependent individuals as a ‘cure’ for opioid addiction. UROD was based on the belief that opioid addiction was the result of the state of the addicted individual’s opioid receptors. It involved the use of an opioid antagonist (naltrexone) to flush out all exogenous opioids from the brain, while under general anaesthesia for 24–48 hours. It was expensive and required intubation of the patient who was treated in an intensive care unit. Several deaths were recorded during treatment, and when clinical trials were conducted, most patients relapsed to heroin use with an increased risk of fatal overdose when they did so. More recently, clinicians in China and Russia have used neurosurgery to ‘treat’ addiction (Hall, 2006b). These invasive and risky treatments were performed without proper evaluation of their safety or efficacy, or any systematic effort to identify any adverse side-effects of the treatment. A more thorough discussion of the use of risky and invasive neurological ‘cures’ of addiction is given in Chapter 11. The premature use of these technologies and interventions is often justified by appealing to neurobiological models of addiction. Proponents employ simplistic, yet plausible misrepresentations of the neurobiology of addiction to suggest that it is simply the result of a ‘diseased organ’ (in the case of neurosurgery) or a ‘neurochemical imbalance’ (in the case of UROD) that the treatment will correct. This gives patients and families a dangerously unrealistic expectation of the effectiveness of the treatment and their ability to remain abstinent, with potentially fatal consequences. Individuals with an addiction and their families are extremely vulnerable: they are often marginalised within society and desperate for a cure. The use and promotion of potentially dangerous and highly invasive neurological treatments without evidence of their safety and efficacy obtained from properly conducted clinical trials denies sufferers of addiction the right to safe and effective health care. Individuals with a substance use disorder have the

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right to treatments that have been assessed for their safety and efficacy as would be expected for any other disorder. 7.5.

Respecting human rights when treating under legal coercion

A persistent problem in the treatment of addiction is attracting sufferers into and retaining them in treatment. One response has been to use the coercive power of the state to force individuals with an addiction into treatment (e.g. by threatening them with imprisonment if they do not comply). Coerced treatment of addiction is most often justified on the grounds of protecting the public by reducing the harms caused by drug use. However, the brain disease model of addiction may also increase the use of treatment under coercion to prevent individuals from harming themselves. Forced treatment of addiction to prevent individuals from harming themselves would need to demonstrate that the individual in question is unable to choose not to use drugs, or in some other way cognitively impaired, so as to undermine their autonomy, either as a result of chronic drug use, or a comorbid psychiatric disorder. Neuroscientific research has shown how the chronic abuse of drugs can produce long-lasting neuroadaptations in the brain that can affect the ability to choose not to use drugs. This provides a stronger argument that addiction is, to some degree, a neuropsychiatric condition in need of treatment. As we argued in Chapter 6, however, this research does not show that addicted individuals lack any ability to refrain from using drugs. Both neuroscience and social science show that most addicted individuals retain some autonomous decision-making capacity in regards to drug use. A major aim of treatment should be to facilitate and fortify patient autonomy. Coerced treatment involves a derogation of a number of human rights, including the right to liberty and freedom and to bodily integrity (Gilmore, 1995). Given that addiction, as a rule, does not override autonomy, the state is not justified in detaining and forcing individuals into treatment simply by virtue of the fact that they are addicted (often referred to as compulsory treatment). Coerced treatment may be justified if offered in response to harm caused by the addicted individual to others (e.g. theft, child neglect), or when it is offered as an alternative to imprisonment or removal of child into custody, if the addicted person refuses or fails to comply with the treatment (referred to as legally coerced treatment). In the latter case, the addicted individual is able to refuse treatment, but would have to suffer the same punishment as anyone judged responsible for the offence for which they have been convicted. It is important that when coerced treatment is used,

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individuals are offered the choice of treatment from a range of effective treatments (Porter, et al., 1986). We provide a more detailed analysis of the ethical warrant for treatment under coercion in Chapter 8. 7.6.

Human rights in the treatment of addicted prisoners

The treatment of addiction and injecting drug use within prisons is an area in which the respect for the rights of addicted individuals has been grossly inadequate (Bruce and Schleifer, 2008). Few prisons in developed or developing nations provide effective treatment for addiction (Jurgens and Betteridge, 2005). When addicted individuals enter prison, they more often than not receive little or no treatment for their condition. Consequently, many are forced to undergo unsupervised withdrawal or ‘cold turkey’. This can produce severe withdrawal symptoms, including nausea and diarrhoea, convulsions, anxiety and dysphoria. It may also have serious medical consequences, particularly for pregnant women and their foetuses, immunocompromised individuals (common amongst intravenous drug users), and in the case of those with comorbid medical disorders (e.g. depression) may potentially increase the risk of suicide (Fiscella, et al., 2005). Very few prisons operate drug substitution programs. Consequently, many individuals stabilised on methadone or buprenorphine maintenance treatment prior to entering prison are forced to go through withdrawal. This amounts to a violation of the right not to be subjected to cruel and inhumane punishment and a derogation of the right to health. Forced detoxification would be unacceptable in the wider community, and should not be accepted as part of prisoners’ punishment. Given that the freedom and liberty of prisoners are restricted by the state, they are unable to take action themselves to prevent symptoms of withdrawal. This increases the burden upon the state to ensure that these symptoms are properly treated. The lack of adequate addiction treatment can lead to the use of drugs within prison, increasing the risks of drug overdose, and HIV and HCV infection. The human rights claims for this failure would be significant for someone on a legitimate and widely accepted treatment program prior to incarceration, such as methadone maintenance, who contracted HIV after injecting drugs in prison to relieve the symptoms of withdrawal. ‘[B]y entering prisons, prisoners are condemned to imprisonment for their crimes; they should not be condemned to HIV and AIDS’ (UNCHR, 1996). Forced detoxification can also lead to overdose if individuals with no opioid tolerance relapse to opioid use in prison or upon release, as many often do (Kariminia, et al., 2007).

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Few prisons provide access to sterile injecting equipment for IDUs. This is despite high rates of HIV (10–20%) and HCV (30–40%) infection occurring in prisons (Jurgens and Betteridge, 2005). Approximately one third of prisoners report injecting drugs while incarcerated and a high proportion share injecting equipment. These individuals are at a very high risk of contracting HIV or HCV. Failure to provide prisoners with the means to avoid these diseases, arguably denies them access to health measures available to the rest of society, violating the ‘principle of equivalence’ (the obligation to provide equivalent care to prisoners as available to the general population) and the right to health (UNAIDS, 2006). It is also a failure of ‘duty of care’. 7.7.

Human rights in the treatment of addicted pregnant women

Substance abuse during pregnancy is a significant problem. In the US, almost 5% of pregnant women under the age of 44 have abused illicit drugs in the last month, 10% have abused alcohol and up to 18% of pregnant women are smokers (SAMSHA, 2006). Substance abuse during pregnancy can have adverse effects on both the mother and the developing foetus, and may increase the risk of medical complications during birth (Campbell and Fleischman, 1992). Individuals born to substance-using mothers often suffer from significant structural brain abnormalities (e.g. significant neuronal loss and smaller brains) and lifelong cognitive and behavioural deficits for the abuse of drugs such as alcohol (e.g. foetal alcohol syndrome), cocaine and methamphetamine (Campbell and Fleischman, 1992). Exposure to addictive drugs in utero also increases the cost of neonatal care (e.g. due to low birth weight and extended stays in hospital) and ongoing health costs to treat health issues that may persist throughout the child’s life (Mathieu, 1995). The treatment of substance abuse or addiction during pregnancy raises some of the most challenging ethical issues in medical ethics: that of balancing the interests of the foetus and the freedom of the mother (Roberts and Dunn, 2003). Society often imposes limits on the autonomy of individuals when their behaviour impacts on the rights of others, such as overriding a competent patient’s refusal of treatment to prevent the spread of an infectious disease. Some have advocated the use of civil commitment of drug-abusing pregnant women to treatment programs (e.g. Mathieu, 1995). However, the case for overriding the autonomy of drug-abusing pregnant mothers to protect the foetus from harm is complicated by the uniquely interdependent relationship between the mother and foetus, and the uncertain legal status of the foetus (Chervenak and McCullough, 1997).

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There are two arguments against state-sanctioned coercive treatment and detention of pregnant mothers: (1) the stress and anxiety associated with forced detention or medical intervention, or the experience of intense withdrawal symptoms, can have serious adverse effects on the mother and foetus; and (2) the threat of compulsory treatment programs may deter women from presenting themselves early for prenatal care and pre-term health checks in order to avoid compulsory detention or intervention (Ridgely, et al., 2004). Both of these outcomes would adversely affect the health and welfare of the child and mother in ways that may offset any benefits of coerced treatment (Chavkin, 1996; Madden, 1996). Increasing access to addiction treatment for consenting addicted mothers is a preferable option (Roberts and Dunn, 2003). Given the potential harms from enforced addiction treatment for pregnant women, treatment programs should rely on less restrictive and coercive forms of treatment that do not override the mother’s autonomy. This may involve improving engagement with clinicians and education (Merrick, 1996), reinforcing abstinence using vouchers and other forms of contingency management, offers of free prophylactic support to prevent relapse, less punitive responses to positive drug tests, and offers of effective and safe substitution treatments (Madden, 1996; Roberts and Dunn, 2003; Ward, et al., 1998b). There also needs to be investment in programs that attempt to remove the social and environmental factors that can drive women to abuse drugs, such as homelessness, domestic violence and sexual abuse, lack of education, trauma and social isolation, and provide education and psychosocial support (Madden, 1996). 7.8.

Future challenges for human rights practitioners

A contentious issue in drug policy is whether a respect for human rights entails the decriminalisation of currently illicit drugs for adult use. Some have produced cogent arguments for doing so (Barrett and Nowak, 2009; Cohen and Csete, 2006; Husak, 1992). The major problem is that international covenants on human rights conflict with international drug control treaties that most states have also signed (Barrett and Nowak, 2009). These prohibit the legalisation of the production, sale and use of proscribed drugs such as amphetamines, cannabis, cocaine and heroin. These treaties have strong support from the international community and from public opinion in most developed countries. Any country that decided to establish legal markets for these drugs would need to renounce or ignore these international treaties and bear the strong international disapproval that would follow either action.

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There are significant social factors that contribute to addiction. These include: coming from a lower socio-economic background; early exposure to drug use in the family and among peers; a family history of drug abuse; and lack of access to education. Social policies that address these issues can have a significant impact on the incidence and burden of drug use and addiction (Spooner, et al., 2001b). The role of comorbid psychiatric disorders, such as personality disorders, in the development of addiction is another area that requires greater attention (Chambers, 2008). Better diagnosis, treatment and early intervention are urgently required. Imprisonment of individuals for illicit drug use to deal with an inadequately treated psychiatric disorder could be argued to be an inappropriate derogation of the right to freedom and a denial of the right to health. There is significant debate in the human rights literature, however, as to how, if at all, human rights law can contribute to social policies that address social and structural disadvantage. This is an area that will need to be examined further by human rights experts. 7.9.

Conclusions

Rights in the treatment of addiction, particularly within criminal populations, have been largely ignored by most nation states, despite clear United Nations (UN) and WHO guidelines. Given that those with a substance use disorder are marginalised within society and suffering from a condition that affects their ability to access proper treatment, there is arguably a greater burden on society to ensure that those addicted are able to access effective medical treatment. The right to health requires that addicted individuals have access to the most effective forms of addiction treatment available, where treatment is motivated by an intention to treat a neuropsychiatric disorder, rather than a form of extrajudicial punishment. When the behaviour of addicted individuals causes harm to society, they should be treated the same as other individuals who commit such acts. Those incarcerated should be given access to effective addiction treatments, such as MMT, as well as other harm reduction measures (e.g. needle exchange programs). Where coercion is used, it must be done in a way that does not unduly deny the right to liberty and freedom. The right to effective health care should not be denied simply by virtue of their status as a ‘criminal’ or an ‘addict’. Human rights law would suggest that the treatment of addiction be recognised as a health issue, and not simply a criminal justice one.

8 Coerced treatment of addiction

8.1.

Introduction

There is good evidence that those who enter treatment for drug abuse will benefit from the treatment, and the longer they remain in treatment, the better off they will be (Gerstein and Harwood, 1990; Ward, et al., 1998a). A persistent problem in treating addiction is attracting addicted individuals into effective treatment and keeping them there long enough to benefit from the encounter. The reluctance of many drug-dependent persons to enter treatment has led to the use of various forms of coerced treatment. Proponents argue that coerced treatment of addiction is justified by the reduced harm caused to families and friends of addicted individuals, health care professionals and carers of addiction, and others in society, as well as increased public health and other governmental costs by individuals who have been coerced into treatment (Chandler, et al., 2009; Nace, et al., 2007; Sullivan, et al., 2008). Others have argued that individuals suffering from an addiction are so overwhelmed by their condition that society is in fact obliged to force them into treatment for their own good (Caplan, 2008). Can legal coercion be used ethically and effectively in the treatment of drug addiction? If so, under what conditions is it ethical to do so? The aim of this chapter is to examine the ethical validity of coercing addicted individuals into treatment. We begin by briefly reviewing the various ways in which coercion may be used, and examine the ethical arguments offered in favour of the use of coerced treatment. We examine the plausibility of brain disease models of addiction that have been used to justify the use of forced or mandated addiction treatment, and describe a number of guidelines for the ethical use of coercion in the treatment of addiction. We conclude with a brief analysis of the practical issues that can emerge in providing addiction

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treatment under coercion when treatment is administered by different professional groups and may serve the mixed social goals, medical care and criminal justice. 8.2.

Approaches to coerced treatment

Coerced addiction treatment may vary in the amount of force used, and therefore, the degree to which they contravene an individual’s liberty, freedom and autonomy. Mild informal coercion includes social pressure from friends and family to enter treatment (Maddux, 1988). More formal coercion (not involving the criminal justice system) may come from employers and government agencies who make it a condition of continued employment that an addicted employee undergoes treatment (e.g. deregistration if addicted doctors refuse to enter treatment) (Weisner, 1990). Legally sanctioned forms of coercion involve the use of the criminal justice system to enforce entry to treatment on pain of imprisonment (Klag, et al., 2005). For comprehensive reviews of the various approaches to coerced treatment, see Pritchard et al. (2007) and Hall and Lucke (2010b). Social coercion is an effective motivation for addicted individuals to enter and complete treatment (Hasin, 1994; Room, et al., 1991; Wild, et al., 1998). Addiction puts an enormous emotional and financial burden on families and friends. It is not surprising that family and friends may pressure addicted persons to seek treatment by highlighting the destructive impact of their drug use or threatening to end a relationship if they continue to use alcohol and drugs. Addicted individuals often do not fully appreciate the impact that their drug use has on themselves or others. Pressure from family and friends to cease their drug use often provides an external indication that their drug use is problematic. Unfortunately, for some long-term drug abusers, such important social ties have lost either influence or significance in their lives, so more coercive forms of intervention may be required to encourage treatment entry. Formal non-criminal coercion by employers and other non-governmental agencies, such as Employment Assistance Programs (EAP) in the US, are negotiated between agencies or employers and the individual. The ethical guidelines for how these programs operate are codified in the appropriate laws (e.g. industrial relations, professional codes of conduct). Physicians can often be forced to undergo addiction treatment in order to retain their license to practice (McLellan, et al., 2008).

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While informal social coercion and formal non-criminal coercion represent very important drivers for entering treatment, they arguably raise fewer ethical issues in the treatment of dependence than legally coerced treatment. In both cases, the dependent person is relatively free to agree to treatment or suffer the threatened consequences, such as the loss of employment or relationship. The coercive pressure in these situations arguably does not deprive them of their liberty or override their autonomy. The form of coercion that raises more ethical concerns is legal coercion, in which the threat of imprisonment or other legal action is used to motivate entry into, or compliance with, addiction treatment. It is this form of coercion that we will turn our attention to for the remainder of this chapter. 8.3.

The case for legally coerced treatment

One of the major justifications for the use of legally coerced treatment is criminal justice: that treating offenders’ drug dependence will reduce the likelihood of their reoffending (Chandler et al., 2009). Studies from both the US and Australia have shown quite convincingly that treatment of heroin addiction significantly reduces criminal behaviour while addicted participants remain in treatment (Bell, et al., 1992; Gerstein and Harwood, 1990; Hubbard, et al., 1988; Ward, et al., 1992). The use of drug-treatment programs as an alternative to incarceration has also been motivated by the failure of prison terms to reduce drug use and drug-related crime, and the over-representation of drug-dependent people in prisons (Hall, 1997b; Pedic, 1990; Stathis, 1991; Stathis, et al., 1991). Medical models of addiction highlight the causal role that addiction plays in the criminal acts (such as theft or drug dealing) that lead to imprisonment and in the high rates of recidivism after release when offenders relapse to drug use (Gerstein and Harwood, 1990). The advent of HIV/AIDS has provided an additional argument for treating drug abuse (Dolan, et al., 1996). By keeping injecting drug users out of prison, there is likely to be a reduction in the transmission of infectious diseases such as HIV and HCV. Injecting drug users in prison are at a significantly increased risk of contracting blood-borne viruses – and potentially spreading the viruses to the wider population upon release – because of a lack of access to sterile injecting equipment in most prisons (Dolan, et al., 1996; Small, et al., 2005; Wood, et al., 2005) (see Section 7.6). The incidence of HIV and HCV is also significantly higher in prison populations than the wider public (Dolan, 1999; Dolan, et al., 2006). The ethical, correctional and public health arguments for drug treatment under coercion are reinforced by the

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economic argument that it is less costly to treat offenders who are drug dependent in the community than it is to imprison them (Gerstein and Harwood, 1990). Legal coercion covers a wide range of strategies for getting individuals into treatment programs. The most coercive is compulsory treatment. In these programs, such as civil commitment programs in the US and Sweden, individuals were sentenced by the court to addiction treatment in a secure facility for a specified period of time (Farabee and Leukefeld, 2001; Weisner, 1990). The offender was given no choice about whether to enter treatment, and usually no choice about the type of treatment they received. Such treatment strategies were used frequently in the past but are now much less popular. This is probably due, in part, to the difficulty in ethically justifying deprivation of liberty, and evidence suggesting that less coercive forms of treatment (e.g. diversion courts) are more effective (Wild, 1999).1 The form of legal coercion that has become increasingly popular within the criminal justice system is the use of diversionary programs that offer drug addicted persons addiction treatment as an alternative to imprisonment. This can occur at various stages in the criminal justice process. In the first instance, treatment may be offered as an alternative to being prosecuted before being charged by police. This is not an ideal method of coercion because it falls outside judicial oversight. It is possible that relying on the discretion of police may open the way for individuals being coerced into treatment for reasons other than criminal behaviour, such as odd or unconventional behaviour or being a member of an ethnic or social minority (Hall, 1997b). Legally coerced treatment is most often advocated for persons charged with, or convicted of, an offence to which their drug dependence has contributed. It is generally offered as an alternative to imprisonment in order to have legal sanctions deferred, reduced or lifted, or as a condition of parole (Klag, et al., 2005; Rotgers, 1992). Suspension of legal sanctions is usually made conditional upon successful completion of a treatment program, with the threat of imprisonment if the person fails to comply (Hall, 1997b; Spooner, et al., 2001a). Each of these forms of legally coerced treatment have different legal and social consequences for the offenders subjected to them, and require varying degrees of deprivation of liberty, restraint and hardship. The ethical validity of the use of these forms of coercion will be outlined below. 1

While civil commitment statutes were created throughout the 1960s in the US, no state is currently committing significant numbers for drug treatment (Gostin, 1993). Similar laws are still available in the Australian states of Victoria and New South Wales (the Inebriates Act, 1912), but are not currently used (Hall, 1997b).

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When is coerced treatment ethical?

Careful consideration of ethical issues is critical when the state uses the threat of imprisonment to encourage drug-dependent persons to seek treatment. Coerced treatment of addiction must operate within a constitutional and legal framework that protects the civil liberties of the people being coerced (Klag, et al., 2005). It is important that treatment does not override an individual’s basic human or civil rights in order to achieve broader social goals (Anderer, 1992; Bersoff, 1992; Kleinig, 2004; Wexler, 1993). Under what circumstances, if any, is society justified in restricting the liberty of addicted persons? Coerced treatment for addiction may be justified by appealing to either of two ethical notions: paternalism or the public good. Addiction negatively affects an individual’s health and social welfare, with a significantly increased risk of premature mortality and serious morbidity. Coerced treatment of addiction could therefore be justified for paternalistic reasons: that is, on the grounds that it is in the best interests of the individual. This would involve coerced treatment for the addicted individual’s ‘own good’. Paternalism arises as a result of the conflict of the principles of beneficence and respect for autonomy. In the past, it was seen that a physician’s responsibility was to help patients based on their assessment of the patient’s needs, and not necessarily their wishes. However, since the rise to prominence of the principle of respect for autonomy, the issue of when it is appropriate to override an individual’s wishes, that is paternalism, has become more critical. Two forms of paternalism can be distinguished on the basis of the degree of coercion involved (Feinberg, 1971). Treatment that is provided against an individual’s wishes (on the grounds of beneficence), where the individual is deemed competent to make relevant decisions, is referred to as hard paternalism. When an individual is deemed incapable of making a competent decision, treatment is imposed because it is argued that their condition prevents them from making informed decisions on their own behalf. Treatment is provided on beneficent grounds, in order to prevent substantially nonvoluntary or non-autonomous harm. This form of coerced treatment is referred to as soft paternalism.2 It is soft paternalism that is most often used 2

It has been argued that soft paternalism is not actually a form of paternalism (Feinberg, 1971). Interventions that prevent harm caused by an involuntary behaviour cannot be paternalistic as they cannot override autonomy if it is not present. This discussion is beyond the scope of the book. Interested readers should refer to Beauchamp and Childress (2001) and Feinberg (1971).

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to justify coerced treatment in the case of addiction, on the assumption that addicted individuals are unable to make informed decisions. In many countries, people with serious mental illnesses can be compelled to accept psychiatric treatment under certain circumstances, usually after some form of judicial or quasi-judicial review. Health care professionals are not required, however, to treat people suffering from other medical conditions against their will, unless the individual lacks the capacity to give free and informed consent to treatment, as is true of minimally conscious patients, for example. While there is a strong beneficent justification for providing treatment in these circumstances, respect for an individual’s liberty to make their own decisions about treatment generally overrides the beneficent drive to intervene (Childress, et al., 2002; Dworkin, 1972). This would preclude the use of coerced treatment of addiction under hard paternalism. The use of paternalistically coerced treatment could be justified if addicted individuals were seen to suffer from a brain disease that robbed them of their autonomy and impaired their capacity to consent to treatment, as has been argued by some bioethicists (Caplan, 2006; Caplan, 2008; Charland, 2002; Cohen, 2002). However, as we argued in Chapter 6, this soft paternalist rationale for coerced addiction treatment is not supported by a critical review of the neuroscience of addiction. While addicted individuals’ decisionmaking is impaired, they, in general, retain some degree of control over their drug use – assuming the absence of some other cognitive impairment (e.g. acquired brain injury, acute psychotic episode) – undermining the soft paternalistic justification of coerced treatment. The second principle that can be used to justify coerced treatment of drug abuse and addiction is to protect the social welfare or the public good. The public good rationale for the use of coerced treatment depends upon the negative impact that drug-dependent persons have on society (e.g. via drug dealing and other criminal activity to finance their drug use). Coerced addiction treatment is ethically justified in order to protect the public good; any benefits derived by the addicted offender are secondary on this rationale. This has been the most commonly used justification for coerced treatment of addiction (Hall, 1997b). The question is: when or under what circumstances is coerced treatment justified in order to protect the public good? Some authors reject any form of treatment under coercion for drug dependence. Radical libertarians such as Thomas Szasz deny that drug dependence exists and argue that drug use is always voluntary (Szasz, 1975). According to Szasz, the law should not prohibit adults from using any drug, and any drug user who commits a criminal offence should be punished. The

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punitive policy consequences of Szasz’s libertarianism enjoy more public support in developed countries, such as the US, than the other implication of his views, that we should legalise the use by adults of all currently illegal drugs. Others, such as Robert Newman, accept that drug dependence exists but oppose compulsory drug treatment on the grounds that it does not work (Gostin, 1993; Newman, 1974; Wild, 1999). If treatment under coercion were ineffective (as Newman claims), then there would be no ethical justification for providing it. Of course, even if treatment under coercion is effective, it does not necessarily follow that it should be provided. For example, the community might place a higher value on punishing than rehabilitating offenders (Hall, 1997b). Contrary to Newman and similar critics, there is some observational evidence that coerced addiction treatment can be effective, when compared with the status quo, which in the case of treatment as an alternative to imprisonment is often forced detoxification (Hall and Lucke, 2010b). There is suggestive evidence from quasi-experimental study designs that drug courts reduce recidivism in the short term of 1–3 years (Belenko, 2002; Turner, et al., 2002; Wilson, et al., 2006). But the effects on recidivism (assuming them to be causal) are modest, as one might expect given the recidivist offenders who are selected for drug courts (Aos, et al., 2006). A recent comparison of legally mandated and voluntary addiction treatment clients in five European countries found that clients who were coerced into treatment achieved similar reductions in substance use and reoffending as those who entered treatment voluntarily (Schaub, et al., 2010). Much of the uncertainty about the effectiveness of coerced addiction treatment is due to the preference for quasi-experimental designs with poorly constructed comparison groups. Coercion is also often poorly defined, making comparisons between studies difficult, and there can be a disjuncture between nominally coerced treatment and participants’ experience of coercion (Klag, et al., 2005; Wild, 2006). Evaluations of coerced addiction treatment have rarely assessed any unintended adverse effects. These may include: reduced access to voluntary treatment by those who want it and reduced quality of its provision; reduced quality of client–therapist relationships (Wild, 2006); possible net-widening effects that may increase the number of offenders within the embrace of the criminal justice system (Clancey and Howard, 2006); and a lack of attention in these programs to the views of participants and their families (Urbanoski, 2010; Wild, 2006). Clearly, more research is required to determine what

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forms of coerced treatment are effective and what the potential adverse consequences of such treatment might be. We support the consensus view on drug treatment under legal coercion prepared for the World Health Organisation (WHO) (Porter, et al., 1986). This argued that coerced treatment was legally and ethically justified if and only if: (1) the rights of the individuals were protected by ‘due process’ (in accordance with human rights principles); and (2) effective and humane treatment was provided. Due process would require some form of judicial oversight of the coerced treatment process. In the absence of such due process, coerced treatment could become de facto imprisonment without judicial oversight. In the absence of humane care and effectiveness, coerced ‘drug treatment’ would not meet the WHO ethico-legal standard, and would simply be a cost-cutting exercise (given that it is less expensive to coercively treat addiction than it is to imprison addicted persons convicted of an offence). The uncertain benefits of coerced treatment have led some proponents to argue that offenders should be allowed two ‘constrained choices’ (Fox, 1992).3 The first constrained choice would be whether they participate in drug treatment at all. If they decline to be treated, they would be dealt with by the criminal justice system in the same way as anyone else charged with the same offence. Those who agreed to be treated would be offered a second constrained choice: this would be a choice of the type of addiction treatment that they received. There is some empirical support for these recommendations: coerced treatment that requires some degree of ‘voluntary interest’ on the part of the offender is more effective (Gerstein and Harwood, 1990). The constrained choice condition has three implications. First, pharmacological treatment options, including agonist maintenance, should be included in the range of options offered to coerced individuals. There has been a tendency for coerced treatment programs, particularly in the US, to only offer ‘drug-free’ abstinence-oriented treatment, which prevents coerced opioid addicted individuals from accessing the forms of treatment that are most likely to benefit them, such as methadone or buprenorphine (Hall, 1997b; 3

There is somewhat of a contradiction in the notion of a ‘constrained’ choice. Is it really a choice if it is constrained? In reality most choices are constrained to some degree, yet we still refer to them as choices. It could be argued that the notion of a truly free and unconstrained choice is an unrealistic ideal that is not realised in the social and neurobiological world in which choices are taken.

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Hall and Lucke, 2010b). Second, there should be a range of drug-free treatment options available for those who do not wish to use pharmacological treatment. Third, the safety, effectiveness and cost-effectiveness of any form of treatment offered should be rigorously evaluated (National Research Council, 2001). 8.5.

Ethical issues in providing coerced addiction treatment

Ethical issues in coerced addiction treatment also arise from the interaction between the correctional and drug-treatment systems (Platt, et al., 1988; Reynolds, 1992; Rotgers, 1992; Sheldon, 1987; Skene, 1987). A major problem is the conflict between the expectations of correctional and treatment personnel about the effectiveness of drug treatment and their understanding of each other’s roles and responsibilities. Treatment staff see the drug offender as their client and, hence, as someone who should be involved in treatment decisions and the confidentiality of whose personal information should be respected. Treatment staff are not surprised if their clients relapse to drug use, something they are more inclined to deal with therapeutically, rather than punitively. Correctional and judicial personnel, by contrast, often expect treatment to produce enduring abstinence. They see treatment as under the control of the court, and regard any drug use as an offence that treatment staff are legally obliged to report to the court. When these expectations of treatment effectiveness are not met, and there is little communication between courts and treatment services, judges and magistrates may become sceptical about the value of coerced treatment and reduce their use of it (Baldwin, 1979; Skene, 1987). The effective and ethical use of coerced drug treatment requires a shared understanding of the likely benefits of treatment and a clear statement of the roles and responsibilities of correctional and treatment staff for monitoring and reporting upon an offender’s progress in drug treatment. Ideally, these issues should be addressed in written protocols that govern interactions between courts and treatment personnel. 8.6.

Is compulsory addiction treatment ethically acceptable?

Compulsory treatment – unconditional, mandated entry to addiction treatment – does not offer an addicted individual any choice. This type of coerced treatment involves an extreme violation of an individual’s autonomy and

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liberty.4 Mandatory treatment has generally involved the confinement of individuals in specialised drug-treatment facilities, or prison hospitals, usually with the goal of attaining abstinence from drugs (Farabee and Leukefeld, 2001; Gostin, 1993; Klag, et al., 2005; Weisner, 1990).5 Upon successful completion of an abstinence program, individuals may be released from the facility into some sort of intensely supervised outpatient facility. Failure to comply with any condition of the program usually results in being re-admitted to a secure inpatient facility (Gostin, 1993). Because compulsory treatment involves a maximal deprivation of liberty, it correspondingly requires a more stringent ethical and legal justification than less coerced forms of treatment. Arguably this includes stronger evidence that this form of treatment is safe and effective and that the consequences of not treating the person are serious and highly likely to occur (Aronowitz, 1967; Childress, et al., 2002). Given the evidence presented above, it is hard to justify the use of compulsory treatment regimes for either paternalistic or public good reasons (Leukefeld and Tims, 1988). Compulsory treatment programs abolish the autonomy of the individual, and arguably constitute a violation of civil liberties in a manner that contravenes the International Bill of Human Rights. A recent report by the United Nations Office on Drugs and Crime (UNODC) argued that compulsory treatment of drug addiction without consent was not only ineffective in treating problem drug use, but was a form of imprisonment that violated international human rights agreements (UNODC, 2010). Some have argued that health care professionals also have deontological obligations (e.g. only a beneficent duty to provide medical care) that would prevent them from being involved in the judicial activities such as the state-run detention of addicted persons (Szasz, 1975).6 Coercive diversion strategies, by contrast, are less restrictive, involving constrained choices that often occur

4

5

6

It could be argued that if addiction was a condition that completely eliminated an individual’s autonomy, then compulsory treatment would not be a violation at all. It would be the benevolent restoration of a disabled individual’s autonomy. However, as outlined in Chapter 6, addiction is generally not such a condition. Antagonist treatments, such as naltrexone detoxification or maintenance, are the favoured pharmacological treatment methods in such situations. The advent of sustained-release formulations of antagonists or drug vaccines may be particularly attractive to proponents of compulsory treatment regimes. The ethics of these forms of treatment are discussed in Section 10.3. The role of health care professionals in other state matters, such as criminal justice, is highly controversial. It is important to note that the Szaszian view is one that is not necessarily held by all health care professionals.

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before treatment entry. They are accordingly less ethically objectionable than compulsory treatment. A choice not to enter treatment would leave the person to face the judicial system, but with their human rights intact. Another concern with the use of compulsory treatment is its effect on the ability for those seeking treatment to find it. It makes little sense if the provision of treatment places for compulsory treatment reduces the availability of places for those voluntarily seeking it (Hall, 1997b; Leukefeld and Tims, 1988). Compulsory treatment programs can also increase the burden on programs that are effective, well funded and well resourced. It can also affect staff morale and have a negative impact on what might otherwise be successful treatment centres (Hall, 1997b). 8.7.

Conclusion

Coercing individuals into treatment can be an ethically acceptable and effective method of helping someone overcome addiction, as well as providing a number of economic and public welfare benefits for society. Such a view was recognised in a recent discussion paper by the UNODC which argued that coerced treatment of addiction may be an acceptable alternative to imprisonment that is consistent with several international drug control conventions (e.g. Single Convention on Narcotic Drugs from 1961) and is supported by evidence of effectiveness (UNODC, 2010). The use of coerced treatment should not be at the expense of an individual’s human and civil rights and not inappropriately deprive their liberty. The most ethically defensible form of coerced treatment is as an alternative to punishment for a convicted crime. Treatment may be offered as an alternative to incarceration with the threat of imprisonment should they fail to comply with the treatment program. Offenders should still have the choice of which form of treatment, with all forms of effective treatment being available. Not all individuals respond positively to the same treatment and offenders are likely to benefit from an approach in which they have a personal investment. This ‘choice’ fulfils both ethical and pragmatic obligations. Coerced treatment should also be seen as an opportunity to engage with addicted individuals who are often isolated and to create cohesion between health care systems and addicted persons (UNODC, 2010). Programs should aim to minimise the use of coercive measures and respect, and ideally maximise, the autonomy of addicted individuals. The perceived level of coercion by those entering addiction treatment does not necessarily depend on whether treatment was mandated or not, but is influenced by a range of

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factors that undermine personal autonomy (Wild, et al., 1998). When coercion is used it should be with the aim of treating a medical condition, by providing a choice of effective treatments, and not as a form of extrajudicial punishment. Not only are overly punitive, coercive policies unethical, they often produce more harm to society and the individual than more minimally coercive treatment approaches. The potential use of novel neuroscientific treatments of addiction undercoercion raises a number of additional ethical challenges. Long-acting sustained-release drug implants and drug vaccines that block the action of addictive drugs for 6 months or more have been advocated for the coerced treatment of addiction, particularly for opiate addiction (Caplan, 2006; Caplan, 2008; Marlowe, 2006; Sullivan, et al., 2008). We discuss the ethical issues this raises in Section 10.3.

9 Ethics of addiction research

9.1.

Introduction

Ethical review of human research is now standard practice in university and other medical research centres. It gained increasing importance following the notorious Nuremberg War Crimes Trial of World War II which found that German medical scientists had conducted hazardous research on unconsenting ‘participants’ who were harmed as a result. There have also been more recent high-profile abuses of research involving unconsenting minority participants in the US (e.g. Tuskegee Syphilis study (Reverby, 2009)) and in developing countries such as Guatemala (Minogue and Marshall, 2010). As a result of these abuses, a consensus has developed about the key ethical principles that should be respected in any research endeavour to protect human subjects from unnecessary harm or being used in research studies without their consent.1 There are a number of key concepts used in contemporary social and medical research approaches to protecting the rights of research participants (Economic and Social Research Council, 2005; National Bioethics Advisory Commission, 1999; National Health and Medical Research Council, 1999). All of these concepts are underpinned by a basic respect for persons, which entails a number of obligations:

1

The emergence of research ethics and ethical review is a lot more complex than this cursory review suggests, involving such historical events as the thalidomide episode during the 1950s and the infamous Tuskegee Syphilis study from 1932 to 1972, which led to the 1979 Belmont Report and the Declaration of Helsinki in 1964. There is insufficient space in the book to present a more detailed and rigorous history of the development of research ethics. Interested readers should refer to Brody (1998).

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1 Participation must be voluntary and informed consent must be obtained before entering someone into a research study. This can be especially relevant where researchers deal with ‘captive audiences’ for their subjects, that is, populations who are socially restricted or marginalised in some way (e.g. prison populations). 2 Researchers must respect the privacy of the prospective participant, and take every reasonable effort to ensure their confidentiality. 3 Researchers must attempt to avoid any foreseeable risk of harm to the participant (non-maleficence), and if possible, maximise benefit (beneficence). Ethical guidelines for research can conflict with the pressure for research to provide new insights into human illness, suffering and behaviour. Scientists need to find a balance between conducting research that provides rigorous answers to scientific questions and subjecting participants to unnecessary harm or violating their right to self-determination or autonomy. In some contentious areas of research, such as the trialling of experimental treatments in patients suffering from incurable diseases, a number of competing concerns may need to be balanced. These may include: the desire to further scientific knowledge and conduct experiments that provide robust answers to important scientific questions; the desire to develop new treatments that may benefit not only others in society, but the person participating in the study; the desire not to harm participants; and the desire to respect the rights of persons of sound mind to make informed choices to participate in ‘risky’ studies, particularly when inaction is highly likely to result in their death. In such cases, it may not be entirely clear what the right course of action is. The best one can do is to ensure that all research receives independent ethical review to protect research participants as best as possible.2 Similar issues are raised by proposals to use neurosurgical techniques to treat addiction (e.g. deep brain stimulation). These are discussed in Chapter 11. Researchers should also publicly debate contentious ethical matters in order to clarify what is at issue and identify solutions that are broadly socially acceptable and supported. 2

Despite the significant attention given to the conduct of human research in the last three decades or so, there is limited evidence to show that ethics review protects and informs subjects in the way that it claims. While ethics review may not reach the ideal ethical standard of human research that it aspires to, the institutional processes of review and transparency have, however, helped to prevent the worst of ethical abuses that have occurred as a result of human research and treatment in the preceding decades (e.g. the Tuskegee and Guatemalan Syphilis Studies).

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Ethical review is especially important when research is conducted on vulnerable groups who are marginalised within the community, such as illicit drug users. The possibility of increasing stigmatisation and social harm from research participation must be carefully considered. The intersection between personal choice and public health creates a number of very difficult ethical considerations for people conducting research into drug use and addictionrelated problems. In this chapter, we review some of the major ethical issues that emerge in performing research on addicted participants. A respect-for-persons approach to ethical analysis requires that subjects participate in research voluntarily. As with similar decisions to enter treatment (see Chapter 6), this requires that subjects provide informed consent to participate in research. Addicted individuals may also be vulnerable because they suffer from comorbid mental disorders (e.g. anxiety, depression or psychosis), and are socioeconomically disadvantaged. They may also be susceptible to the therapeutic misconception (Appelbaum, et al., 1987). Addicted individuals are therefore acutely vulnerable to any coercive aspects of their personal and social situation that may affect their ability to freely participate in research. We begin by briefly reviewing the issue of consent to research participation. We then examine some ethical issues that are specific to addiction research: the payment of subjects for research participation; the possible use of information about addicted subjects that may be used by third parties to discriminate against them (e.g. privacy and confidentiality); and the administration of addictive drugs to addicted individuals in clinical or laboratory research studies. 9.2.

Informed consent to participate in addiction research

In all major research ethics statements, the respect for persons requires that individuals provide meaningful, informed and voluntary consent (i.e. of their own free will) to participate in research (Faden, et al., 1986). Informed consent is the process whereby individuals agree to participate in research in full knowledge of its possible risks and benefits, and in the absence of any duress, coercion or undue inducement. Researchers need to ensure that participants: have the capacity to understand the risks and benefits of participating in research; understand what their participation will entail; appreciate the consequences of participating or not; understand that their participation or refusal to participate will not affect any treatment they may receive; are not under some form of external or internal pressure, real or

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perceived, to participate; and are fully informed of the risks and benefits of participating in the research study. There are a variety of factors that can affect the ability of addicted individuals to provide free and informed consent to participate in a research study. Many of the issues involved in the consent to enter addiction treatment discussed previously are also relevant to the consent to participate in addiction research (see Chapter 6 for a more comprehensive discussion of the issue of addiction and the capacity to consent). For example prospective participants should not be intoxicated or suffering from withdrawal symptoms when asked to consent to research (Carter and Hall, 2008b). There are standardised scales for assessing symptoms of drug intoxication and withdrawal, such as the Mini-Mental State Examination (MMSE) (Smith, et al., 2006), the Clinical Opiate Withdrawal Scale (COWS) (Wesson and Ling, 2003) and the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A) (Ebbets, 1994), that should be used to assess the capacity of addicted individuals to give consent. The chronic use of addictive drugs can also cause significant cognitive deficits (e.g. Wernicke-Korsakoff syndrome) or serious psychiatric symptoms (e.g. psychosis, anxiety and depression) that may impair an addicted person’s capacity to provide informed consent. Subjects with an addiction also experience a number of other social, economic and psychological conditions that can impair their ability to provide free and uncoerced consent. Individuals may have been convicted of a criminal offence and may be incarcerated. 3 Individuals involved with the justice system, correctional services or child protection agencies may believe that they may be punished by refusing to participate in a study. It is therefore especially important that addicted subjects in these settings be made aware that they are free to refuse to participate in a research study at any time without penalty. While addiction does not override an individual’s capacity to make autonomous decisions, it can impair autonomy in certain situations (see Chapter 6). Researchers need to minimise the impact of these impairments when attempting to recruit addicted individuals to participate in research. It may be necessary when recruiting participants for studies that put subjects at some risk (e.g. those that administer drugs) to use clinical diagnostic tests 3

Research with prison inmates is an important area of research in addiction. A large percentage of inmates use drugs or are addicted. At present, addiction treatment in many prisons is inadequate. More research is required to develop effective treatment programs within prison settings.

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(e.g. MMSE) to ensure that subjects have the capacity to consent to participate (Fry, et al., 2006; Smith, et al., 2006). There has been almost no research on the use of such diagnostic tests to ensure or improve addicted participants’ capacity to consent to a research study. Research in this area is urgently needed (Carter and Hall, 2008b). Addiction is a highly stigmatised condition. This can encourage negative stereotypes about the reasons why addicted persons participate in research, despite evidence suggesting that their motivations are similar to those of the general population (Fry and Dwyer, 2001). Presuppositions about ‘addicts’’ motivation for research participation can colour beliefs about their capacity to consent to research that involves administering their drug of addiction or offering payments for participation, for example. The limited bioethical discussion of this topic has been based, largely, on a priori reasoning and ‘fireside inductions’ in the absence of empirical evidence, as the following brief review will show. 9.3.

Paying addicted subjects

As individuals with an addiction often have low incomes, they could be argued to be particularly vulnerable to financial inducements to participate in research, such as payments for research participation. On the other hand, it can be argued that addicted participants should be compensated for their time and inconvenience in the same way as any other research subject. A balance needs to be achieved between adequately compensating subjects for their time and providing financial inducements that are large enough to render them unable to properly assess the consequences of participating in research (Hando and Darke, 1998). There are a large number of studies that have examined the use of monetary rewards as compensation for illicit drug users’ time (American Psychiatric Association, 2000). It has been argued that providing subject payments to addicted participants will lead to increased drug use and more social harm (i.e. the payment will be used to obtain drugs). Some have proposed that the use of vouchers provides a solution to this. Experience in the UK suggests that this method of remuneration can have undesired effects, both for the subject and the wider community. Some subjects may approach members of the public to exchange the vouchers for cash, usually at a reduced rate. This means that subjects receive less money while creating a public nuisance. This practice arguably violates both respect for autonomy and beneficence.

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Another alternative would be to reimburse subjects on the basis of bus tickets and taxi receipts. This approach is problematic for many addicted individuals who may not be organised enough to return receipts or cash cheques. Many have temporary or unstable accommodation and some will be homeless. For virtually all of these subjects, $5 to $10 is a significant amount of income that they can ill afford to lose via an inconvenient reimbursement process. The consequence may be that subjects are either disadvantaged financially by taking part in the research, or will choose not to take part because of this disincentive. Both choices will mean that they will be discriminated against by not having an equitable opportunity to participate in, and benefit from, research. There is no credible reason why addicted participants should not be compensated for their time in the same way as any other individual who participates in similar research. In fact, to deprive addicted participants of equivalent reimbursement, without an adequate reason, would violate the principles of respect for persons and the duty to treat all individuals equally. Research has shown that providing addicted participants with subject payments does not lead to increased harm to them or society, if done appropriately (Fry, et al., 2006). As we showed in Chapter 6, there is no neurobiological reason why addicted participants should not be provided with appropriate subject payments; they have the capacity to make autonomous decisions about how they choose to spend money received from research participation. Research in fact suggests that providing subject payments can actually increase participants’ comprehension of the consent process, including the risk and benefits of participating, study design and participant rights (Festinger, et al., 2009). One objection offered to paying drug-using research participants is the view that society should not exacerbate or assist drug use. However, there is no evidence to suggest that participating in research leads to any increase in drug use (Adler, 1995; Fry, et al., 2006; Wood and Sher, 2000). Withholding subject payments may actually be counterproductive if it were to lead to a decrease in addicted persons participating in research and a failure to improve treatments for addiction. Research participation also represents an opportunity for addicted individuals to be provided with important information about their condition, including the availability of treatment, and an opportunity to facilitate contact with treatment services, if they wish it. The issue of research participation as an opportunity for treatment is discussed in Section 9.5. Addiction and illicit drug use can elicit strong moral reactions that prejudice our perception of why addicted individuals agree to participate in studies.

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Fry and Dwyer (2001) have shown that addicted individuals’ motivation for participating in research is the same as the general population. Some may wish to obtain money, as do many non-addicted participants. Addicted participants are also motivated by more socially conscious aims, such as helping to advance our understanding of addiction and develop more effective treatments for it, and to learn more about their own condition. It is important that our moral presuppositions do not prevent us from fulfilling our ethical commitment in conducting addiction research and deprive addicted participants of their due. 9.4.

Privacy, confidentiality and anonymity

The issue of privacy and confidentiality is extremely important when dealing with research participants, such as injecting drug users, who engage in an illegal and harmful behaviour that marginalises them from the general community. Such marginalisation can lead to discrimination and stigmatisation. Stigmatisation is often seen as a barrier to the provision of effective drug treatment, and can be an impediment to treatment seeking (Pescosolido, et al., 2010; Sartorius, 2010). Drug addiction is also associated with other activities or situations that may be of interest to governmental agencies, such as child welfare and protection, and education departments. In the course of research participation, information relevant to these areas may be requested or disclosed in conversations or observations. The communication of this information to third parties, such as the police or government, may have significant adverse outcomes for the addicted participant, such as loss of child custody, social welfare or employment. Extreme care is required in protecting this information. Participants need to know who will have access to the information and under what circumstances. A standard procedure in conducting research, particularly with vulnerable or stigmatised groups, is to agree to keep any information private, and to not pass it on to third parties who may use it to discriminate against them. However, declaring an intention not to communicate personal information obtained during research does not guarantee that this information will not be accessed. For instance, it is impossible in Australia for researchers to guarantee that data collected on the criminal activities of drug users will not be subpoenaed by police, despite researchers’ best intentions (Fitzgerald and Hamilton, 1996; Scott and White, 2005). In this setting, the only way to ensure research subjects are not harmed via their research participation is to keep the data in an anonymised form. This

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can be done at either the data collection stage, by asking participants to select a pseudonym, or at the data entry stage, by randomly assigning names or unique code numbers to each individual’s responses. Anonymising subjects at the data collection stage has the advantage of protecting researchers from ever knowing the participant’s real name, preventing this information from being subpoenaed in court. It also has the scientific advantage of blinding the researcher. The major disadvantage is that it precludes subject follow-up, which can provide clinically significant information, particularly in longitudinal studies that are needed to evaluate the long-term effectiveness of a treatment or the natural history of drug use. This is an important clinical consideration in the case of addiction treatment where relapse or adverse outcomes may occur months and years after treatment (Scott and White, 2005). Longitudinal studies that require storage of personal information for follow-up need to be especially stringent in protecting the confidentiality of research information (WHO, 2004a). Anonymity will not always provide absolute protection against the violation of privacy. For example, many medical and health care professionals are legally obliged to report certain events to the police, such as child sexual and physical abuse. A balance needs to be found between an ethical duty to prevent harm to research participants from discrimination, and the ability of the study to obtain scientific and clinically important information. It is important that the participant be made aware of the efforts taken to protect privacy and the extent of that protection, including when and under what circumstances this privacy may be violated. 9.5.

Administering addictive drugs in research studies

The administration of addictive drugs to research participants can provide valuable scientific information about the effects that these drugs have on behaviour and cognition. Such research also raises ethical challenges. Administering addictive drugs to drug-naı¨ve participants could theoretically introduce individuals to the effects of an addictive drug that they would not otherwise use. This seems unlikely to produce addiction or other harms. Studies have consistently found that providing drug-naı¨ve participants with an appropriate dose of an addictive drug in a laboratory setting by a qualified health professional does not increase the risk of developing an addiction or its associated harmful behaviours (Adler, 1995; Kirulis and Zacny, 1998; Wood and Sher, 2000).

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A greater ethical challenge is raised by administering drugs of addiction to drug-dependent people. If addiction is a condition that impairs an individual’s ability to ‘say no’ to a drug, the question arises: can a drug-dependent person give free and uncoerced consent to participate in research that provides them with that drug? Some bioethicists have expressed strong doubts about the capacity of addicted individuals to provide completely free or internally uncoerced consent to participate in such studies (Charland, 2002; Cohen, 2002). If their arguments were accepted, they would significantly impair the ability of neuroscientists to conduct this type of research. As we argued in Chapter 6, the loss in autonomy in addiction is neither as simple nor absolute as some bioethicists’ analyses suggest. While the capacity to make autonomous decisions regarding drug use may be impaired in some addicted individuals in certain circumstances, the majority of drug-dependent individuals retain a degree of autonomous decision-making capacity. Rather than simply override the autonomy of addicted individuals, researchers need to recruit prospective addicted participants and obtain their consent in ways that facilitate or maximise their autonomy. This could be done by minimising situations that may elicit strong cravings for drugs that may impair addicted persons’ ability to make free decisions about participating in such research, and by ensuring that the benefits of participating outweigh any potential risks (e.g. by providing participants access to treatment services, health care professionals and medical advice) (Adler, 1995; Carter and Hall, 2008b; Fitzgerald and Hamilton, 1996). Denying addicted individuals the right to participate in research that may be of benefit to them would not only be a violation of the principle of distributive justice, but it may, from a utilitarian perspective, lead to poorer outcomes for addicted individuals and the community. 9.5.1.

Why do neuroscientists give drugs to ‘addicts’?

As outlined in Chapter 3, neuroscience research over the last 50 years has had a significant impact on our understanding of the nature and origins of addiction (Koob and Le Moal, 2006; Nutt, et al., 2007b; Volkow and Li, 2004). Changes in brain function may explain the apparent inability of some addicted individuals to refrain from drug use despite the negative consequences of continued use. Clinical neuroscience research has also increased our ability to treat addiction by increasing the range of treatments that are available to assist addicted persons to become and remain abstinent (Iverson, et al., 2007) (see Chapter 4). Human studies of the effect of drugs of addiction on brain structure and function, in particular the visualisation of these changes using neuroimaging

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(e.g. fMRI, PET and EEG), have been critical in improving our understanding of addiction. Research in animal models has identified the central reward pathways in the brain on which most drugs of addiction appear to act (Koob and Le Moal, 2006). While animal studies have elucidated the neuropharmacology of reward that appears to be common to all mammals, they cannot be straightforwardly applied to the complex cognitive and social behaviours in human drug addiction, such as subjective craving, impaired decision-making and impulse inhibition. Nor can animal studies determine whether promising drug treatments of addiction are safe and effective in addicted humans (Epstein, et al., 2006; Fisch, 2007; Geyer and Markou, 1995). There are significant evolutionary, cognitive and cultural differences between highly controlled laboratory animal models of addiction and the typical patterns of addictive drug use in humans. Human experimentation is essential to bridge this gap. The advent of non-invasive methods of visualising brain function has permitted many of the neurobiological theories of addiction derived from animal models to be tested, and in many cases, confirmed in addicted human individuals (Garavan, et al., 2007; Volkow, et al., 2007). Neuroimaging has also highlighted significant changes in the cortical centres of the human brain that underpin the impairments of the higher order cognition that are unique to addicted humans. The administration of addictive drugs, such as cocaine and amphetamines, is an important scientific tool for elucidating the changes in brain function that are involved in cognitive, emotional and behavioural processes affected by addiction. There is a clear utilitarian justification for this type of research; it has the potential to provide more effective pharmacological treatments of addiction that will reduce the harm it causes to the individual and society. The potential personal, social and scientific benefits of neuroscience research of addiction, however, are not sufficient to justify research if it exploits a vulnerable population. We need to show that those participating in such research are capable of consenting freely, that consent is obtained in ways that respects their autonomy, and that there is an acceptable balance of risk and benefit to addicted research participants. Neuroscience research on addiction does not prove that addicted subjects lack the ability to make autonomous decisions about drug use, but it does suggest that their autonomy may be impaired in some situations (i.e. during acute withdrawal or intoxication). This suggests that we need to move beyond simplistic either/or debates about whether addiction always prevents addicted individuals from making free and uncoerced decisions about drug use in experimental settings. The strong assertion that ‘addicts’ are by definition

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unable to make free and autonomous decisions about drug use is difficult to support. However, it would be wrong to suppose that there are no problems in obtaining consent from addicted individuals to participate in research that involves administering drugs of addiction. Researchers need to take these impaired capacities into account when designing experiments, recruiting addicted participants and obtaining their consent to participate. They must look for ways to increase the autonomous decision-making capacity of research participants, and therefore the validity of their free and informed consent to participate. We offer some suggestions for how this might be achieved. 9.5.2.

The risks of giving ‘addicts’ drugs in research settings

Addiction neuroscientists have a responsibility to ensure that research participation by addicted subjects carries minimal risk (i.e. the anticipated risk of harm or discomfort is no greater than that ordinarily experienced in daily life, or in the performance of routine physical or psychological examinations or tests). The degree of risk associated with research participation will depend on the amount of drug provided, the route of administration and the context in which it is given, the state of the participant (abstinent, detoxified or drug using), the length of the study, the extent of monitoring of the participant’s condition during the study, and the adequacy of follow-up procedures to detect adverse effects. Some have argued that the risks of participating in such research are much lower than those assumed by an addicted individual in their everyday drug use (Adler, 1995). Non-abstinent drug-addicted individuals often engage in the chronic use of illicit drugs of unknown strength and purity, using the most hazardous route of administration (e.g. intravenous injection in suboptimal conditions) and using poor injection technique. In a research setting, by contrast, addictive drugs are provided under medical supervision by an appropriately qualified professional, using pharmaceutical medications of known strength, and at lower doses than are typically used recreationally (Adler, 1995). In a research setting, there is also no risk in obtaining drugs, such as violence or criminal conviction for possession of an illicit substance, or theft to fund an expensive habit. The relative risk of participating in experiments that administer drugs of addiction is therefore much lower than the everyday risks run by a non-abstinent drug-addicted individual. An additional concern has been that participation in research studies may increase addicted individuals’ drug use. This concern has been most often expressed about addicted subjects who have completed or are entering addiction

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treatment. The evidence from follow-up studies suggests that research participation does not increase drug use or cause abstinent addicted subjects to relapse (Bigelow, et al., 1994; Faillace, et al., 1972; Kranzler, et al., 1990; Modell, et al., 1993). Indeed, most addicted subjects who participate in nontherapeutic research that administers addictive drugs appear to derive some benefit from their participation (Montoya and Haertzen, 1994). At a minimum they receive a medical examination by a health professional in a supportive environment. They also receive information about, and access to, treatment services and educational material about drug use and addiction. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) guidelines for research that administers alcohol to alcohol-dependent subjects recommends that ‘a serious and concerted effort should be made to link alcohol-dependent research subjects who are not in treatment with treatment services. This linkage should be active in bringing together the subject with alcoholism treatment personnel’ (National Advisory Council on Alcohol Abuse and Alcoholism, 1989). 9.5.3.

Research participation by treated vs. untreated ‘addicts’

In the absence of any validated method of accurately assessing addicted persons’ capacity to consent to research participation, some have suggested that the distinction between treated and untreated addicted subjects may serve as a useful surrogate of capacity to consent (Cohen, 2002; National Advisory Council on Drug Abuse, 2005). Very different conclusions have been drawn from this suggested distinction. The National Bioethics Advisory Commission (1999) concluded that only addicted individuals who were not currently in treatment should be allowed to participate in research that administered their drug of addiction. This view has been contested by Cohen (2002) who argued that only addicted individuals who have entered, or intend to enter, treatment, have the capacity to freely consent to participate in such research. Cohen argues that by entering treatment, addicted persons demonstrate that they are able to make autonomous and voluntary decisions about their drug use. He claims that because of the impact that addiction has upon affected individuals, those that continue to use drugs are ‘in denial’ about their condition, and therefore lack the insight to make autonomous decisions about research participation. Cohen provides no empirical evidence for this claim. There are several problems with Cohen’s argument: 1 It is unwise to assume that the only competent choice an addicted person can make is not to use drugs. We generally assume that people are

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competent, unless there are good reasons for believing otherwise, and hence assume that they are responsible for harmful choices, such as drunk driving or solo-sailing around the world. The choice to use a drug under the medical supervision provided in a research study could be construed as a more informed choice than the decision to use an illicit drug without medical supervision. 2 We should not assume that an individual who continues to abuse drugs despite serious negative consequences is in denial about their condition. Many addicted persons are aware of the impact that their drug use is having, but continue to use drugs because they prefer to sacrifice long-term harm for short-term gain; that is, they heavily discount future consequences in preference to the short-term gain of the drug’s effects (Ainslie, 2000, 2001; Elster and Skog, 1999). 3 The decision to enter treatment may be an indication that the individual is not beholden to strong drug cravings, and hence possesses the volitional capacity to choose whether or not to participate in research. But it does not guarantee that their choice is free. Many addicted individuals enter treatment as a result of some form of coercion, whether from courts, friends or families, or employers (Pritchard, et al., 2007; Wild, 2006). An addicted individual who agrees to participate in a research study in the absence of external coercion could arguably be making a more autonomous and internally uncoerced decision than someone entering treatment in a state of withdrawal or under legal duress. 4 It is more difficult than Cohen assumes to define an ‘addict’ who is being ‘treated’. Cohen implicitly assumes that an addicted person who enters treatment will, from that time forward, refrain from using drugs. In reality, most will relapse at some point. The neuropsychological changes that underpin relapse have been demonstrated in addicted subjects who have been abstinent for months (Childress, et al., 1999). Many addicted individuals in treatment continue to use their drug of addiction. A decision to enter treatment does not therefore ensure that an addict has the capacity to resist desires to use drugs or to consent to research offering them access to their drug of addiction. 9.5.4.

Recruiting subjects and obtaining consent

Anyone who conducts research with addicted participants should design their participant recruitment strategies to increase the autonomous decisionmaking capacity of prospective participants. This would involve minimising

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situations that may elicit strong, over-powering urges or cravings for drugs that may impair the ability of addicted subjects to make free decisions about participation in experiments that administer drugs of addiction. There are a number of ways that researchers could do so: 1 When advertising for participants researchers should minimise any expectation that potential participants will receive an addictive drug. This would reduce the number of participants whose major reason for research participation was to acquire drugs. For example, advertisements could avoid any mention of drug use. Study descriptions could emphasise that participants are not assured of receiving a drug by indicating that they may be assigned to a control group that does not receive the addictive drug. 2 Researchers should avoid administering drugs shortly after obtaining participants’ consent (Walker, 2008). A participant’s belief that a drug of addiction will be immediately made available may trigger strong cravings that overwhelm rational appraisal of the risks and benefits of participation for all the reasons outlined above. The possibility of drug administration at some later time (e.g. in 1 or 2 weeks) is less likely to overwhelm rational thought. Craving is a strong urge that begs immediate gratification and impairs rational thought about what to do in the immediate future (Elster and Skog, 1999). The strength and immediacy of the urge to take drugs may mean that individuals who are strongly affected by craving are less likely to persist with time-consuming consent procedures or delays in receiving their drug of choice. They are more likely to spend their time acquiring their drug by conventional means (e.g. illicit drug markets). Removing the arousal of immediate drug use would give time for craving to pass, and thereby allow for a more rational approach to consent (Walker, 2008). 3 Researchers should obtain participants’ consent in ways that minimise stress and cognitive load that can impair autonomous choices (Baumeister, 2003; Levy, 2006a). This could be accomplished by using audiovisual tools that can increase comprehension or ease stress, and thus maximise the capacity of addicted individuals to consent to research (Dunn and Jeste, 2001; Fureman, et al., 1997). More research is required on how best to do so: we have found few studies examining ways to improve consent to research in substance-abusing populations (Festinger, et al., 2010; Fureman, et al., 1997). An ongoing consent process that continued to engage subjects about their participation in the study (e.g. corrected feedback) increased

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addicted subjects’ understanding of the purpose and potential risks and benefits of research participation (Festinger, et al., 2010). 4 Researchers should also consider including simple tests of decision-making capacity in the consent process. Tests of cognitive capacity (e.g. Minimental state examination) have been shown to be effective in psychiatric and addicted populations (Cairns, et al., 2005; Hazelton, et al., 2003; Hotopf, 2005; Smith, et al., 2006). At present there are no validated measures of volitional capacity, although the MacArthur Competence Assessment Tools for Clinical Research (M-CAT) show some promise (Dunn, et al., 2006). Such tests would be useful in ensuring that an individual has the freedom to consent to research participation. 9.6.

Conclusion

Addicted individuals arguably have the same right to participate in, and benefit from, scientific research into their condition as anyone afflicted by any medical or behavioural disorder. The view that addicted individuals lack the capacity to give free and informed consent would, if accepted, significantly hinder research on addiction, and hence the development and evaluation of new treatments that may benefit addicted persons. This would not only be a violation of the principle of justice (equal distribution of the benefits of research) but it may, from a utilitarian point of view, lead to poorer outcomes for addicted individuals and society. We need to be mindful of putting in place well-intended, but overly paternalistic, research policies that deny addicted individuals the right to participate in research. We also need to acknowledge, however, that addiction can impair decisionmaking. This is clearest when addicted persons are intoxicated or in acute withdrawal. Apart from these acute states, we believe that while addiction can impair autonomy it does not, by definition, preclude addicted participants from making free and uncoerced choices about drug use in experimental settings. Researchers and policy makers still have a moral obligation to ensure that the rights of addicted individuals are protected and that their autonomy in making decisions about research participation is maximised. Researchers and ethicists need to avoid over simplified conclusions that encompass all addicted individuals (e.g. the opposing views that all ‘addicts’ are or are not incapable of giving free and informed consent). We need to develop more nuanced views that begin with the presumption that addicted persons possess some decision-making capacity and attempt to build on that capacity by recruiting addicted research participants and obtaining consent in

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ways that engage them as much as possible in making decisions about whether or not to participate in research studies, especially those that involve administering drugs of addiction. To achieve this end, we need more research on the impact that cognitive impairment and strong urges to use drugs have on the volitional capacity of addicted individuals in different stages of addiction, and in different research and clinical contexts.

Part 3

The Ethical and Public Policy Implications of Novel Technologies for the Treatment of Addiction

10 New developments in the treatment of addiction

10.1.

Introduction

The neurobiological treatments that are emerging from neuroscience research have the potential to reduce the harm caused by drug use in new ways. The treatments may be more targeted to specific neurobiological deficits, with fewer side-effects, while new brain imaging technologies and genetic screening may enable researchers and clinicians to better understand addiction at the individual level and personalise treatments to improve treatment efficacy. Neurobiological technologies have prompted some to suggest that a ‘cure’ for addiction may be in sight (see Chapter 11). With the potential to do good comes the potential to do harm. These novel technologies have the potential to impact upon brain and behaviour in ways that we do not fully comprehend. The brain is a complex organ, and our understanding of how subtle changes in brain function relate to our ability to think and make choices is still underdeveloped. The significant breakthroughs in our understanding of the neuroscience of mental illness and advances in our ability to ameliorate it may blind us to how little we truly understand about the relationship between brain and behaviour. We need to find a balance between the seduction of ‘technological fixes’ for complex social problems and technophobia – the unreasonable fear of technologies that intervene on the brain (Watkins, 2010). It is critical that we carefully consider the scientific basis for the use of novel and emerging technologies, the benefits and harms that they may cause, and the social and moral forces that may shape how these technologies are applied and understood. Such an analysis is a critical first step in examining the ethical use of emerging technologies for various purposes. In the previous chapters, we examined the impact that neuroscience research may have upon the way in which we understand addiction and think

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about and treat those that suffer from it. In the following chapters, we outline the ethical and social issues that may arise from the use of new technologies for the treatment of addiction. This represents an initial attempt to identify these problems. A solution will require more systematic and detailed analysis by neuroscience researchers, ethicists, policy makers and the broader community as the science and technologies progress. It is, however, important to begin to map out the issues that will arise as many of the proposed technologies progress from the scientist’s lab to the clinician’s bedside and policy-maker’s desk. These chapters highlight the challenges that clinicians, patients, policy makers and politicians are likely to encounter, and the ethical and social dilemmas that will need to be negotiated, analysed and resolved. In this chapter, we outline and discuss some of the practical ethical, social and public policy issues raised by the use of: novel psychopharmacological treatment technologies most likely to emerge from recent neurobiological research; drug vaccines that block the pharmacological action of addictive drugs; and long-acting or sustained-release formulations of drugs (e.g. naltrexone implants). In Chapter 11, we briefly examine the potential use of more invasive and potentially dangerous neurological interventions, such as neurosurgery and deep brain stimulation (DBS) in order to ‘cure’ addiction. These treatments are often heralded as ‘miracle cures’ of addiction to a vulnerable and desperate population. In Chapter 12, we examine the use of sophisticated diagnostic technologies to identify those vulnerable to developing addiction, and hence a candidate for interventions to prevent the development of addictive disorders in the young (Insel, 2009). This is an attractive option, and one, that if successful, would be highly desirable. There are, however, a number of ethical, scientific and public policy issues that proponents of preventive strategies tend to overlook, and that may impede their translation into policy or lead to unintended harm. In the final chapter of Part 3, we explore the use of potential psychopharmacological treatments of addiction by those who are not addicted or ill; that is the use of drugs to become better than well. This has been variably referred to as cognitive enhancement and cosmetic psychopharmacology. The use of drugs for enhancement purposes in healthy individuals raises some interesting issues regarding the regulation and provision of new medicines and what we consider to be legitimate uses of neurotechnologies. Our focus in these chapters is inevitably on some of the more speculative uses of improved understandings of addiction neurobiology to treat and prevent addiction. This reflects, in large part, the media’s fascination with

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possibilities that are unlikely to be fulfilled (e.g. universal vaccination of adolescents against addictive drugs, surgical ‘cures’ of addiction, and the discovery of ‘genes for’ addiction). These scenarios nonetheless need to be critically scrutinised because media discussions of them may affect public attitudes towards addiction neuroscience, for better or worse. 10.2.

Novel pharmacological treatments of addiction

Neuroscience research is uncovering many of the neurochemical changes that are responsible for the development and maintenance of addiction (see Chapter 3). These include the pharmacological actions of addictive drugs that make them enjoyable and reinforce their use, and the neurochemical changes in the brain that may explain the disrupted decision-making, craving, relapse and affective modulation. Neuroscience has discovered the molecular mechanisms that underpin these changes at all levels of neural behaviour, including cell signalling, molecular trafficking, genetic regulation and cellular modification (e.g. synaptic remodelling). Each of these molecular events represents a potential pharmacological target for treating or reducing addiction, many of which we describe in Chapter 4. These include drugs that: • Improve executive control (e.g. modafinil (ProVigil), methylphenidate (Ritalin)) • Dampen memories that can trigger craving and relapse (e.g. propranolol) • Reduce or eliminate craving (e.g. acamprosate, bupropion, disulfiram, naltrexone) • Mitigate aversive or negative affect that leads to relapse to addiction (e.g. corticotropin-releasing factor receptor antagonists) • Reverse synaptic or epigenetic changes that may underpin many of the neurocognitive changes caused by chronic drug use Researchers are also attempting to develop drugs that mimic the pleasant or desired effects of currently abused drugs, without their deleterious and harmful qualities (Nutt, 2006). We discuss this proposal in Section 14.6. It is not possible to evaluate the ethical use of the numerous drugs (currently more than 80) that are under investigation (Nutt and Lingford-Hughes, 2008). Many of these drugs are still in preclinical or early clinical trials. Interested readers should see Koob et al. (2009), Goodman (2008) or Jupp and Lawrence (2009) for a more detailed analysis of potential new drugs. Instead, we discuss some of the general ethical issues that arise in the research and

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development of pharmacological treatments of addiction, before examining specific ethical issues raised by anti-craving drugs. 10.2.1.

Ethical and policy issues in pharmacological R&D in addiction

The safety and efficacy of new drugs for the treatment of addiction needs to be evaluated in the same way as any other psychiatric drugs. The strong social desire to reduce the harm that addiction causes can produce pressure to expedite the approval of new drugs before their effectiveness in treating addiction has been established. The result can be the use of new treatments in the absence of the rigorous scrutiny routinely required of medications in other disorders. For example, the naltrexone implant was provided to thousands of opioiddependent Australians before its use had been approved by the Australian regulator (the Therapeutic Goods Administration) (see Section 10.3.3). The assessment of new drugs for addiction can also be influenced by the conflicting aims of addiction treatment: (a) to protect society from the harmful behaviour of addicted individuals and (b) to treat the addicted person. It is important that when we assess the safety and efficacy of new drugs that we do so primarily from the point of view of treating an individual suffering from a disorder rather than from the point of view of its effectiveness as a psychopharmacological restraint preventing addicted persons from harming others (Carter and Hall, 2007a). A major R&D hurdle is to encourage pharmaceutical companies to invest in drug development for addiction. Many pharmaceutical companies are reticent about being involved in addiction research, given the stigma associated with its clientele, and doubts about whether pharmacotherapies for addiction will be profitable given that addicted individuals have a limited capacity to pay for their treatment. Koob et al. (2009) argues that recent success with acamprosate and varenicline might change this view, although it remains to be seen if pharmaceutical companies will be as enthusiastic to develop treatments for illicit drugs whose use is illegal and stigmatised and where there are fewer dependent drug users with less capacity to pay for treatment. Given the enormous social cost of drug addiction, there is an economic incentive for governments to invest in developing pharmacological addiction treatments but with the exception of the US, few have done so. Partnerships between government and industry might stimulate research (Koob, et al., 2009). A survey of pharmaceutical executives, however, suggests that the industry is now more risk averse (Ragan, 2007). This has been partly in response to criticisms that industry has been ‘selling sickness’ to promote

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products such as the serotonin selective reuptake inhibitor (SSRI) antidepressants (Healy, 2004; Moynihan and Cassels, 2005). Industry may also not wish to develop treatments for addiction to illicit drugs if the drugs have other potentially more profitable uses (Koob, Lloyd and Mason, 2009). 10.2.2.

Anti-craving drugs

Given that cravings can be potent triggers of a relapse to drug use following periods of abstinence, there is growing interest in pharmacological treatments that can eliminate or reduce cravings (O’Brien, 2005). Drugs that are claimed to have ‘anti-craving’ properties include acamprosate, bupropion, disulfiram, modafinil and naltrexone. See O’Brien (2005) and Yahyavi-Firouz-Abadi and See (2009) for more detailed reviews of drugs currently being investigated for their ability to reduce cravings and prevent relapse. A potential problem with anti-craving drugs is that their long-term use may have subtle, but significant, adverse effects on motivation. It has already been suggested, for example, that naltrexone – described as the model anti-craving drug (O’Brien, 2005) – may produce dysphoria and other depressive symptoms in the long term (Dean, et al., 2006; Miotto, et al., 2002). Naltrexone can also reduce the rewarding or hedonic effects of everyday activities such as eating (Yeomans and Gray, 2002), sex (Murphy, et al., 1990) and physical exercise (Daniel, et al., 1992). Our desire for things is fundamental to our sense of self. It is our willing or striving for things that makes us who we are. Some bioethicists have accordingly been critical of using drugs that may interfere with or dampen our sense of self (Kass, 2002). While the use of drugs in healthy adults to significantly alter our sense of self may raise important ethical concerns (Levy, 2007), the situation is arguably different in the case of using these drugs to treat addiction. Addicted individuals are already suffering from a condition that adversely interferes with their self-hood by affecting their choices and the kind of life that is open to them. It also causes significant emotional, physical and psychological harm. A drug that ameliorated these losses could be more correctly seen as enabling than impairing self-hood. This criticism is not new to anti-craving drugs. Similar criticisms were levelled at the use of methadone maintenance in the 1970s and 80s, and more recently buprenorphine. These drugs have been referred to as ‘liquid handcuffs’ or ‘chemical straightjackets’ (Guichard, et al., 2007; Nelkin, 1973). Given that addiction is a condition that often severely limits the ability of addicted persons to lead a normal life or fulfil even minimal needs, a more

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reasonable approach to considering the ethical acceptability of the use of ‘anti-craving’ drugs is one that examines their ability to reduce harmful drug use and improve the quality of addicted persons’ lives. A more important ethical issue is raised by the moral view that only drug treatments that block the agonist action of addictive drugs (such as naltrexone) should be used to treat addiction. This view may lead to the premature development and use of anti-craving drugs at the expense of other, more effective methods that use agonist drugs, such as methadone and buprenorphine, which also reduce cravings for street opioids. It is important that medications are measured by their ability to treat a condition with minimal side-effects, and not because their psychopharmacological action is morally more attractive. 10.3.

Novel relapse prevention treatments

Relapse to drug use is one of the greatest impediments to successfully overcoming addiction. Once an individual relapses, they often return to chronic and harmful drug use; the cycle of addiction continues and may worsen. A significant amount of research has been invested in helping addicted individuals to reduce the length and severity of such relapses. One method has been to provide a pharmacological prophylaxis against relapse that blocks or attenuates the rewarding effects of addictive drugs. There are two technologies that have received significant attention recently: drug vaccines and sustained-release medications. 10.3.1.

Drug vaccines as a prophylaxis against relapse

Immunotherapies, such as a ‘nicotine vaccine’, block the psychoactive effects of a drug by either stimulating the immune system to produce antibodies (active immunisation) or through the introduction of synthetic monoclonal antibodies into the blood stream (passive immunisation) (Harwood and Myers, 2004). These antibodies bind to the target drug, preventing it from acting on receptors in the brain (Kosten and Owens, 2005; Nutt and LingfordHughes, 2004). The first demonstration of the feasibility of a drug vaccine was in 1974 when morphine antibodies reduced the self-administration of heroin in rhesus monkeys (Bonese, et al., 1974). Since then, vaccines have been developed against nicotine, cocaine, methamphetamine and phencyclidine (or PCP) (Kantak, 2003; Orson, et al., 2008). The majority of research has focused on nicotine (one of the most harmful addictive drugs) and cocaine (where there are no effective pharmacological treatments available).

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Animal studies have shown that drug vaccines reduce the amount of a drug that reaches the brain and dopamine released in the nucleus accumbens, the rate of clearance across the blood–brain barrier, the volume of drug distribution, and the self-administration of the target drug (Hall, 2002a; Kosten and Owens, 2005). Vaccines have a very clear advantage over traditional small molecule pharmacological approaches (e.g. agonists and antagonists). They are long-lasting and so overcome compliance issues that arise with daily dosing. They are also highly specific, and because they remain in the blood stream, produce no adverse effects on the central nervous system as may occur with traditional pharmacological approaches (e.g. varenicline can increase suicidal ideation in some individuals). These advantages suggest that immunotherapies may be effective in reducing relapse to drug use (Kosten and Owens, 2005). Active vaccination against nicotine, for example, could reduce relapse to smoking in abstinent smokers during the first few months after quitting when most smokers relapse (Vocci and Chiang, 2001). Ex-smokers would be given a series of vaccinations during the critical period after cessation when most are vulnerable. This would be combined with behavioural programs to reduce the chances that a ‘slip’ to drug use will lead to a return to regular cigarette use. While a nicotine vaccine could be circumvented by increasing the dose of nicotine, attenuating the rewarding effects of nicotine may be enough to reduce rates of return to daily smoking (Hall, 2002a; Vocci and Chiang, 2001). A number of phase II clinical trials for cocaine and nicotine vaccines have been reported (Maastricht University Medical Center, 2009; Martell, et al., 2009; National Institute on Drug Abuse, 2010). Most studies found that sufficient immunoprotection was achieved in only one third of participants. Two thirds of subjects did not develop sufficient immunoprotection against the drug in order to prevent a relapse to drug use. Those individuals that developed the highest level of antibodies as a result of the vaccine derived the most benefit from the intervention. Increasing the number and/or size of doses may increase immunogenicity and effectiveness, but may also increase any side-effects. New formulations of vaccines are currently in development that may provide greater immunoprotection against drug use (Moreno, et al., 2010). Should more broadly effective vaccines be developed, there are a number of ethical issues that ought to be considered before the routine use of vaccination to treat addiction. First, there are questions regarding the extent to which individuals would have to give consent to vaccination treatment. It is likely that immunotherapies for illicit drugs like cocaine may be used in

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situations that are inherently coercive, such as when treatment is the result of encounters with the justice system. For example, addicted women could be compelled to undergo ‘vaccination’ in order to protect the interests of the foetus during pregnancy (from the direct effects of the substance use). Vaccines could also be used to manage addicted parents involved in the child welfare system in order to protect the interests of children from poor or abusive parenting. The ethical obstacle is that such treatments transgress traditional bounds of autonomy. Without a ‘best interest’ defence, such measures would have to overcome this hurdle by appealing, for example, to the ethical principle of protecting the ‘interests’ of the public. The problem is that it is sometimes difficult to disentangle the effects of drugs from drug-related behaviour (caused by other social, environmental and psychological determinants), so that the focus on addiction may become disproportionate. If, according to the brain disease model of addiction, addicted individuals lack autonomy regarding decisions to use drugs, then individuals may be ‘treated’ in their ‘best interests’, in the absence of their consent. Some have argued that this approach may be used by the treating physician to restore the addicted person’s autonomy (Caplan, 2008). The argument is that this is an established practice in medical settings. However, if autonomy is only impaired temporarily and/or partially, an issue may arise in the use of vaccines which produce lasting effects that continue after autonomy is re-established (Hall, et al., 2008). In such situations, it would be more appropriate to use a short-acting drug, such as an agonist, to overcome withdrawal symptoms, or to wait for intoxication to pass before administering a drug vaccine. Given that there are significant doubts over the effectiveness and safety of drug vaccines, any use under coercion could only be warranted following considerable experience of its successful use in voluntarily treated patients (Hall, 2002a). Second, vaccines may also prove counterproductive if addicted individuals attempt to overcome the antagonistic action of the vaccine by increasing drug doses, and thereby increase the risk of harm from the peripheral drug effects (e.g. cardiac arrest from cocaine use). Those who ambivalently agree to vaccination might also switch to using other, possibly more dangerous drugs, different and more harmful routes of administration (e.g. intravenous injection), or much higher doses than usual (Murray, 2004). Vaccines could also paradoxically be seen as making experimentation with drugs less risky, and therefore unwittingly increase drug use. Third, vaccines do not ameliorate underlying problems that may be associated with compulsive drug use and addiction. They do not deal with the

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underlying addictive condition (such as craving, loss of control or withdrawal), events that may lead to relapse, or comorbid mental conditions (Ashcroft and Franey, 2004). Thus, while vaccines may find a place in the treatment of addiction, they should not be seen as ‘magic bullets’. Addiction is a chronic condition and vaccines, like traditional addiction medications, will presumably need to be used in conjunction with behavioural treatments and psychosocial support if lifelong abstinence is to be achieved (Nutt and Lingford-Hughes, 2004). Many addicted persons will be wary of a treatment that prevents them from using drugs to either relieve withdrawal symptoms or to attenuate the symptoms of an undiagnosed mental illness or other subclinical conditions involving distress. One does not have to uncritically accept self-medication as an explanation of addiction (Khantzian, 1997; Mueser, et al., 1998) to acknowledge that psychological and social factors may sustain drug use in ways that vaccination alone will not address. Finally, the use of a vaccine may also block the action of agonists or partial agonists (e.g. methadone and buprenorphine for opioid dependence) eliminating the use of maintenance therapies while immunological blockade persists. This would be undesirable if an effective and inexpensive treatment was developed that was blocked by the vaccine. Vaccines may also block the action of medications used in the treatment of other physiological conditions, such as opioid analgesics for pain relief (Ashcroft and Franey, 2004). None of these issues preclude the use of effective vaccines to treat addiction and reduce problematic drug use, should they prove safe and effective in clinical trials. It does mean, however, that care is needed in how these treatments are used. The ‘vaccine’ label may raise public expectations that immunotherapies could be used to prevent the development of addiction in children, particularly those with a family history of addiction. The additional scientific and ethical problems raised by the preventive use of drug vaccines are examined in Section 12.2.5. 10.3.2.

Sustained-release treatments: depot medications and drug implants

Depot injections (intramuscular injections of oil suspensions) and drug implants (larger magnesium stearate or polymer-based implants surgically inserted under the skin) are sustained-release forms of drugs currently used to treat addiction. These provide a slower, more sustained-release of medications to counteract the effects of drugs over longer periods. Because they only

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need to be taken every 1 to 6 months (depending on the specific formulation) sustained-release medications are an attractive option in preventing relapse. The most widely used drug in sustained-release technologies is naltrexone. There are several forms of intramuscular depot naltrexone injections in development, including: Vivitrol (manufactured by Alkermes, Cambridge, Massachusetts, US), Depotrex (manufactured by Biotech, Bethesda, Maryland, US) and Naltrel (manufactured by Drug Abuse Sciences, Hayward, California, US) (Comer, et al., 2006; Garbutt, et al., 2005; Kranzler, 1998; Krupitsky and Blokhina, 2010; Kunoe, et al., 2009). There are also several naltrexone implants in development in Australia (GoMedical Industries), Russia (Prodetoxone), the US and China. Currently, only the injectable sustained-release naltrexone manufactured by Alkermes Inc. (Vivitrol) has been approved by the FDA for the treatment of alcohol in 2006, and opioid dependence in 2010 (FDA, 2010). A depot and implant slow-release preparation of the opioid partial agonist, buprenorphine, are also being trialled for the treatment of opioid dependence (Ling, et al., 2010; Sigmon, et al., 2006; Sobel, et al., 2004; White, et al., 2009). Sustained-release formulations of lofexidine for the treatment of nicotine dependence (Rawson, et al., 2000) and a flumazenil implant for the treatment of benzodiazepine addiction are also being developed (Nutt and Lingford-Hughes, 2008). Sustained-release medications have several advantages over traditional oral treatment medications. First, they only need to be taken monthly, compared to daily for conventional medical treatments, allowing for better treatment compliance. Patients are less inconvenienced by the requirements of daily dosing, and can perhaps be aided in realising their long-term goal of abstinence by overcoming spontaneous urges to use drugs that overwhelm their longer term goals (Ainslie, 2001). Second, the steady release of the drug from implants and depot injections provides a more even level of drug that avoids the pulsatile response from daily dosing that may lead to more erratic decision-making (Gastfriend, 2011). Third, sustained-release drugs bypass the first-pass hepatic metabolism, significantly reducing the amount of drug used per day and providing a larger active amount of drug in the blood stream than oral administration (Gastfriend, 2011). Fourth, agonist or partial agonist sustained-release medications, such as buprenorphine (Ling, et al., 2010), can also prevent the diversion of drugs to the black market and the associated harm that they may cause. The ethical considerations for the use of sustained-release antagonists are similar to those for immunotherapy described above (Murray, 2004). As with immunotherapies, sustained-release medications for preventing relapse to

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illicit drug dependence may occur in situations where capacity to give consent is compromised – either as a consequence of addiction itself – or as a result of some form of external coercion (e.g. as part of a drug court order; see Chapter 8). We discuss such proposals in Section 10.3.4. Sustained-release antagonists (e.g. naltrexone) raise similar safety concerns regarding changes in patterns of drug use, including switching to other illicit drugs not blocked by the implant, new routes of consumption such as injection, and attempting to overcome their antagonist effects by using very high doses (Murray, 2004). This may paradoxically lead to greater drug harm and even overdose as individuals treated with sustained-release antagonists no longer possess the tolerance that they did while using drugs (Gibson, et al., 2007). The case of a 17-year-old girl who was able to overcome naltrexone blockade in the third week after receiving a depot injection using oxycodone (Fishman, 2008) suggests that these concerns are justified (Krupitsky and Blokhina, 2010). There is also a report of an individual that managed to overdose while treated with the Russian naltrexone implant (Kruptisky, et al., 2007). A review of Australian coronial records identified five patients treated with naltrexone implants who had overdosed (Gibson and Degenhardt, 2007). At least two, and possibly four, died while supposedly protected by naltrexone blockade. It is also possible for treated individuals to remove their implants themselves, potentially causing serious physical harm. This eventuality will need to be considered when debating the ethical and clinical merits of using drug implants under coercion, particularly naltrexone implants, where failure to comply with treatment may lead to overdose death should the individual return to opioid use, as most do. If these treatments are used with patients who give free and informed consent, their use arguably presents no special ethical issues. However, the use of sustained-release medications for preventing relapse is most likely to occur in situations where capacity to give consent is compromised. This may simply be the result of a loss of autonomy as a consequence of addictive drug use, a comorbid psychiatric disorder or adverse social circumstances. This is a feature of many pharmacological treatments of psychiatric disorders that can in principle be managed by appropriate consent procedures (see Chapter 6). There have, however, been growing calls for the use of sustained-release medications, such as naltrexone implants, under some form of legal coercion (e.g. court-ordered) (Caplan, 2008; Marlowe, 2006; Sullivan, et al., 2008). We discuss the ethical acceptability of such a proposal after describing a recent experience with naltrexone implants in Australia.

176 10.3.3.

Addiction Neuroethics The Australian naltrexone implant experience

Consent can be compromised by failures in either the procedure of recruiting participants or the regulation of new clinical treatments. A proportion of the public and some elected officials in countries such as Australia and the US oppose on moral grounds the use of agonist drugs in maintenance forms of addiction treatment. Some have argued that treatment choice should be limited to antagonist medications, such as naltrexone (Thomas and Buckmaster, 2007), and that ‘addicts’ be coerced into using implantable naltrexone (Caplan, 2006). The recent experience of the use of naltrexone implants in Australia is a case in point. These implants were inserted in thousands of opioid-dependent individuals despite the fact that they have not been shown to be safe and effective in randomised clinical trials, as required for all other medications in Australia (Wodak, et al., 2008).1 As has also occurred with neurosurgery in Russia and China and with ultra-rapid opioid detoxification (or UROD: see Section 11.3) in Australia, neurobiological explanations of addiction have been used to provide a rationale for this treatment (Carter and Hall, 2007a). These failures to properly assess and regulate a treatment before its clinical use do not give prospective recipients a realistic impression of a treatment’s success, and provide an insufficient assessment of the risks that it may pose. This compromises the ability of addicted individuals to give free and fully informed consent to undergo the treatment. 10.3.4.

Coerced use of depot naltrexone to ‘restore autonomy’?

There have been increasing calls for the coerced or mandated use of naltrexone implants to treat opioid addiction (Caplan, 2008; Marlowe, 2006; Sullivan, et al., 2008). Advocates of this view, such as Caplan, argue that opioid addiction robs individuals of their autonomy, which naltrexone restores (Caplan, 2006; Caplan, 2008). Naltrexone, he argues, restores heroin-addicted individuals’ autonomy by removing their cravings for heroin and blocking the euphoric effects of heroin, if they succumb to temptation. This is a superficially attractive solution to the over-representation of illicit drug users in prisons and the high proportion of opioid use and incidence of HIV and

1

Clinical trials are now underway but have yet to show that they are safe and effective in the long term or in unselected patients or superior to the current gold standard (i.e. methadone).

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HCV in prisons (Marlowe, 2006). There are, however, several problems with this argument that need to be considered. First, as we argued in Chapter 6, the claim that heroin ‘addicts’ are incapable of making autonomous decisions about their drug use is not supported by behavioural, neuroscientific or social scientific evidence (Carter and Hall, 2008b; Foddy and Savulescu, 2006; Walker, 2008). Caplan’s claim that coercion may be used to enforce the use of naltrexone implants assumes that addicted individuals have some capacities of choice and, therefore, some degree of autonomy. In fact, Caplan argues that we should ignore addicted persons’ residual autonomy in the interests of ‘creating autonomy’, and that we should be permitted to do so for up to 6 months. If these judgements are made in the ‘best interests’ of addicted persons, then we should arguably minimise infringements of autonomy (once it is re-established) by allowing some choices, and, as argued below, provide treatment that has been shown to be safe and effective. Second, there is as yet no compelling evidence of the long-term efficacy or safety of sustained-release naltrexone in unselected patients, either coerced or uncoerced. The claim that sustained-release naltrexone is safe and effective appears to be based on the use of oral naltrexone which was approved for use in the US over 30 years ago. This is a very weak basis for the claim that coerced naltrexone implants will be safe and effective when used under legal coercion in unselected opioid-dependent individuals, in long-acting formulations. Oral naltrexone has in fact been rarely used to treat heroin addiction since its registration because, as meta-analyses of the best clinical trials show, its efficacy in unselected patients is no better than placebo in retaining patients in treatment, or reducing opioid drug use (Kirchmayer, et al., 2003). There are also doubts about the safety of oral naltrexone in treating unselected opioiddependent patients. Its acute toxicity may be low (O’Brien and Cornish, 2006), but the risk of fatal opioid overdose is doubled when patients stop taking naltrexone and return to opioid use, as most do (Digiusto, et al., 2004; Gibson and Degenhardt, 2007). A drug that is no better than placebo in unselected opioid-dependent patients and that doubles the risk of overdose when these patients stop using it is neither safe nor effective. It is a plausible hypothesis that implantable forms of naltrexone will improve its efficacy and safety by reducing the poor adherence with the oral form of the drug (O’Brien and Cornish, 2006). But the hypothesis needs to be properly tested in controlled clinical trials and to date there have been too few trials of sufficient size and duration to evaluate its efficacy compared to the

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current best treatments. Historical experience with implantable forms of disulfiram (Antabuse) in the treatment of alcohol dependence does not inspire confidence that the difference in efficacy between oral and implantable forms of naltrexone will be as large as proponents of the implants have assumed. Even if implantable forms of naltrexone prove effective in treating uncoerced opioid-dependent persons, we will still need studies of its efficacy and safety in treating legally coerced patients. A number of concerns have been raised about possible unintended adverse consequences of its legally coerced use (MacCoun, 2004). These include the possibilities that addicted subjects will attempt to override the naltrexone blockade by increasing the doses of opioid drugs or use other drugs not blocked by naltrexone, such as stimulants and benzodiazepines (MacCoun, 2004). Third, there are agonist medications, such as methadone and buprenorphine, that have been shown to be effective in numerous clinical trials and meta-analyses, and used successfully for decades in the case of methadone. Caplan claims that naltrexone is superior to agonist opioid drugs such as methadone and buprenorphine in restoring the autonomy of ‘addicts’. Methadone and buprenorphine, he asserts, merely substitute a less harmful opioid for the preferred drug, reducing the societal costs of addiction but producing little or no benefit for the patient. These claims are not well supported. Naltrexone is arguably not unique in restoring addicted individuals’ autonomy. Oral methadone and buprenorphine also eliminate withdrawal symptoms and relieve opioid craving, thereby enabling opioid-dependent persons to make more autonomous decisions about their drug use. While methadone and buprenorphine reduce societal costs of opioid addiction, the primary justification for using them is that their pharmacokinetic properties (namely, their long half-life, slow onset of action and strong opioid receptor binding) reduce the need to use illicit opioids and improve patient health and wellbeing (Amato, et al., 2005). Caplan does not distinguish between the court-mandated naltrexone implants and the inclusion of implants among a range of treatments from which addicted persons may choose as an alternative to imprisonment (Presenza, 2006). These options involve very different levels of coercion. Mandatory treatment does not allow the person any choice: the court orders that the person must receive a naltrexone implant as a condition of being paroled. In legally coerced treatment, by contrast, convicted persons would be given a series of ‘constrained’ choices, as we outlined in Chapter 8: (1) the choice of whether to accept treatment or to receive the standard court penalty for their offence (e.g. imprisonment); and for those who choose treatment (2) a choice of

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treatment type that could include naltrexone, but would also allow other options including agonist maintenance (Hall, 1997b; Porter, et al., 1986). If used under coercion, naltrexone implants would have to be offered as one of a range of treatment options that included agonist maintenance. Addicted individuals could select from these options after being given accurate and disinterested information on the benefits and risks of each. This approach would be much less objectionable than mandatory treatment in which a naltrexone implant was the only treatment option and the views of the addicted individual were ignored or overridden. The effective and safe use of naltrexone implants in legally coerced subjects would still have to be established before being widely adopted. 10.4.

Conclusion

Neuroscience has the potential to provide powerful new methods for reducing addictive behaviour and the harm that it causes. It is important that these treatments are developed and used in ways that take account of the social context in which addiction treatment is provided; that is, possible conflicts between the public’s desire to reduce societal harm and punish wrongdoers versus the need to treat a medical condition. Research will also have to consider the ambivalence of some addicted individuals in stopping drug use, especially when coerced into doing so. The history of addiction treatment is littered with therapeutic enthusiasms prematurely embraced and widely disseminated by uncritical proponents before the necessary evidence has been collected to evaluate their safety and efficacy. This has often left the field to belatedly discover that these new treatments are at best no better than placebos and, at worst, harm some of their supposed beneficiaries. If we are to capture the benefits of emerging new types of addiction treatment, these therapeutic mistakes need to be avoided by rigorous evaluation of the safety and effectiveness of these treatments and an appreciation of the ethical issues that can arise from their use. In the next chapter, we discuss some of the more dangerous uses of neuroscience to ‘cure’ addiction.

11 The search for a neurological ‘cure’ of addiction?

I know of no class of people who have been so victimized by the quack as the inebriate. Rogers (1913) cited in White (2003, p. 261)

11.1.

Introduction

History shows that the desperation for a ‘cure’ of addiction can lead to the use of risky medical procedures before they have been rigorously tested for safety or efficacy. Drug-addicted individuals are often desperate for an effective and relatively painless end to their addiction and hence susceptible to the promotion of ‘heroic’ addiction cures in the media, or directly to them and their families (e.g. Wark, 2009). Neurobiological rationales for these treatments often lend these interventions a spurious scientific credibility. Patients and their families may be willing to pay large sums of money for these treatments, and demand that these treatments be provided by government or health insurers (Diefenbach, et al., 1999; Racine, et al., 2006; 2007). Drug-addicted individuals and their families can in the process be exploited by unscrupulous practitioners for professional, moral or commercial gain. They can also be misled by enthusiastic proponents of new treatments whose zeal to do good makes them morally blind to the harm that they can cause. In this chapter, we briefly review the history of putative addiction ‘cures’ and discuss some recent examples of therapeutic enthusiasms that have appealed to a neurobiological rationale, such as ultra-rapid opioid detoxification and ablative neurosurgery. These lessons need to be understood by the scientists and clinicians that promote new treatments, by ethicists and the media that report on them, and by those who regulate them.

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181

A brief history of addiction ‘cures’ The history of the treatment of narcotic withdrawal is a long and mainly dishonorable one. Kleber and Riordan (1982, p. 30)

Medical interventions to treat drug and alcohol addiction emerged in the 1750s, although records of the treatment of addiction date back to the earliest recorded history (White, 2003). From around 1830, there was a proliferation of medical ‘cures’ of addiction. This trend increased in the 19th century with the emergence of a wide array of chemical, physical, psychological and social interventions that all promised to ‘cure’ addictions to alcohol, tobacco, cocaine and the opiates. Putative addiction ‘cures’ share many of the following features: a quick and self-contained intervention that cures addiction without the need for extensive follow-up or counselling; it requires little or no effort from the patient and causes minimal discomfort; it is often a proprietary intervention from which the inventors stand to make significant profit; and because they are proprietary, there is usually a lack of any independent assessment of its effectiveness and safety. We briefly describe the history of such ‘cures’, from the circa 1830 to the present day. 11.2.1.

Quacks and nostrums: 1830–1900

American medicine at this time was an immature and poorly regulated profession: ‘Doctor’ was a title that any practitioner could adopt, with or without medical training. A burgeoning patent medicine industry employed the authority of science but without the rigour and transparency that we now expect. In addition, the emerging mass print media widely advertised these ‘panaceas’ directly to the public (White, 2003). Medicines were dominated by cure-all ‘tonics’, ‘elixirs’ and other products that often contained addictive substances, such as heroin, alcohol and cocaine (e.g. Coca Kola, Mrs Winslow’s Soothing Baby Formula). These products provided rapid but temporary symptomatic relief for a range of ailments, while contributing to a growing problem of addiction to tonics sold as cures. Increasing problems with addiction and an empowered temperance movement advocating abstinence created a market for medicinal ‘cures’ of drug and alcohol addiction that promised to ‘destroy’ the appetite for drugs (White, 2003). These ‘cure alls’ were distributed by drug companies, private physicians and for-profit addiction cure institutes, such as the Keeley

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Institute (see below). The American Medical Association filed reports of hundreds of these products (Helfand, 1996). Many of these ‘cures’ contained significant doses of the drugs from which patients were trying to abstain (sometimes at doses significantly higher than their usual daily intake) (Helfand, 1996). Cocaine-containing products, such as Wine of Coca, Coca cigarettes and Dr Birney’s Catarrh Powder, were promoted as cures for ‘consumption’ (White, 2003). Many ‘medicines’ promoted as ‘temperance remedies’ contained up to 45% alcohol. In the late 1800s some physicians used injectable morphine as a cure for opium addiction before recognising that this form of administration posed a greater addiction problem than orally administered opium. Unfortunately, this lesson was soon forgotten when physicians introduced the use of a ‘non-addicting’ substance, heroin, to treat morphine addiction. Similarly, a large number of products were marketed as cures for nicotine dependence: Baco-Cure, Nicotol, Nix-O-Tine, Tobacco Redeemer and No-To-Bac. Many opiate cures (e.g. Antidote, Starnes’ Drug Habit Cure and Narcoti Cure) contained morphine. Their use became either a de facto tapered form of withdrawal or oral maintenance. These drugs were marketed through health-related books, magazines, newspapers, flyers, and billboards, often targeting family members. Some promoters claimed that an addicted family member could be secretly cured by spiking their food or drinks with their products. Physicians were also paid to provide lists of addicted patients who could be targeted for promotions or referred to treatment centres or institutes. Even at this early stage of addiction medicine, many such treatments were promoted as cures for what was regarded as a heritable disease (Helfand, 1996). The Keeley Cure One of the more controversial treatments for addiction in the latter quarter of the 19th century was the Keeley Cure. This was developed by Leslie E. Keeley, a former civil war surgeon, who claimed that ‘[d]runkeness is a disease and I can cure it’ (quoted in Barclay, 1964, p. 344). Popularity of the treatment grew after favourable articles appeared in the Chicago Tribune in 1891 (Helfand, 1996). The Keeley Cure was used to treat alcohol dependence from 1879 to 1965 via a network of Keeley Institutes with over 200 branches throughout the US and Europe. The Keeley Institutes were estimated to have treated over 400 000 patients by 1939 and claimed to have ‘cured’ some 17 000 (Helfand, 1996; Time, 1939), earning an estimated US$1 million.

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The Keeley Cure paved the way for subsequent addiction treatments in the 20th century. The Keeley Cure treated alcoholism as a disease, rather than as a vice or habit, thereby foreshadowing subsequent claims that alcoholism had a physiological basis (White, 2003). The Keeley Institute also treated addicted individuals in a more humane manner than had been the norm previously, providing a supportive environment with many of the features of later therapeutic communities. The Keeley Cure involved the injection of a ‘secret’ double chloride of gold, up to four times a day, and accompanied by a tonic every 2 hours. Because Keeley refused to divulge the contents of his ‘secret’ remedy, the medical establishment viewed him as a profit-based entrepreneur. Assays of the ‘double chloride of gold’ suggested that it contained a combination of strychnine, alcohol, apomorphine, willow bark, ammonia and atropine (Tracy, 2005). Regulation of addiction treatments It became apparent to the organised medical profession that many of the purported cures of addiction did not work or contained large doses of addictive drugs that did more harm than good. As early as 1827, the Medical Society of New York attempted to expose fraudulent practices of addiction cure entrepreneurs (Helfand, 1996). A report exposing fraudulent opium antidotes was published in the Journal of the American Medical Association in 1880. Little could be done to regulate these doubtful remedies in the absence of any regulatory system for medicines. These came in 1906 with the passage of the Food and Drug Act that followed Samuel Hopkins Adams’ expose´ in Collier’s magazine that many patent medicines contained dangerous amounts of alcohol, opiates or cocaine. Despite this many of these products were still promoted and sold in the 1940s and 50s (Helfand, 1996). 11.2.2.

Early medical treatments of drug withdrawal: 1900–1970

At the beginning of the 20th century, doctors and researchers began to more systematically study addiction and search for effective treatments (Campbell, 2007). For much of this period, the primary aim of treatment was seen as safely withdrawing individuals from their addictive drug (Kleber and Riordan, 1982). Despite strong evidence that most addicted individuals returned to drug use after periods of abstinence, many doctors believed that

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the greatest obstacle to abstinence was completion of withdrawal. It was not until the second half of the 20th century that scientists and health care professionals realised that withdrawal was the easiest part of treatment; the greatest obstacle was preventing relapse to drug use after completion of withdrawal. Belladonna treatment of drug withdrawal came to prominence in 1901 and dominated withdrawal treatment for the next 30 years. The most famous was the Towns-Lambert treatment. It involved hourly administration of alkaloids derived from plants from the nightshade family (e.g. scopolamine) for several days until scopolamine intoxication occurred. Drug withdrawal using scopolamine intoxication caused severe diarrhoea and distress (e.g. hallucinations, severe stupor) and could cause death (Kolb and Himmelsbach, 1938). Despite these harms, belladonna treatments remained standard practice for several decades. The ‘success’ of the treatment was probably due to its stupefying effects that prevented the patient from discontinuing withdrawal. It also reassured clinicians and patients that their ‘care’ was having a clinical effect (Kolb and Himmelsbach, 1938). Other medical treatments used during this period included: peptization and water balance treatments (e.g. sodium thiocyanate), which could make patients ‘wildly delirious and psychotic’ for months (Kolb and Himmelsbach, 1938); bromide sleep treatment; lipoid treatments; endocrine treatments (e.g. thyroid hormone, epinephrine, ovarian extracts and insulin); and immunity treatments that injected serum removed from blisters produced on the patient. These treatments were worthless at best, and life threatening at worst. Bromide sleep treatment (BST), for example, involved the induction of a coma via repeated administration of sodium bromide with revival using oxygen. Despite deaths, proponents advocated its use in ‘well selected patients’ (Kolb and Himmelsbach, 1938). A variety of convulsive or shock therapies used for other mental disorders were also promoted as addiction cures. Convulsions were induced using pentylenetetrazole (Avery and Campbell, 1941), 70% carbon dioxide inhalation (Avery and Campbell, 1941), insulin shock therapy (TILLIM, 1942), and electroconvulsive therapy (or ECT) (Kelman, 1964; Thigpen, et al., 1953). ECT was first reported as a treatment of withdrawal in 1946. There were few follow-up studies. Roper (1966) reported giving repeated daily sessions of ECT to a patient until he became incontinent ‘of urine and feces’ and was ‘disorientated in time, place and person’ (p. 1081). These effects were seen as evidence of the therapeutic effect of ‘depatterning’ (Shorter and Healy, 2007). The apparent ‘effectiveness’ of ECT was probably due to

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the severe confusion it induced that prevented patients from discontinuing withdrawal (Kleber and Riordan, 1982). The antipsychotic, chlorpromazine, was also used to manage withdrawal. According to the authors of the first trial, it relieved the symptoms of withdrawal and had a ‘lobotomy-like effect’ that left patients ‘indifferent, quiet and immobile’ (Kleber and Riordan, 1982). Patients were given large doses of the drug every 4 hours for 3 days during which they largely slept and so were unable to complain about withdrawal symptoms (Kleber and Riordan, 1982). Despite subsequent studies showing that antipsychotics were not effective treatments for drug withdrawal, hospitals continued to prescribe them rather than use tapered doses of the patients’ drug of dependence or a related drug with similar effects (Kleber and Riordan, 1982). These treatments shared a number of unfortunate characteristics. Most were claimed to be remarkably successful by their advocates, only later to be found to be of little use at best or quite harmful at worst. Apart from those that contained alcohol or opiates, few relieved withdrawal symptoms. Their apparent effectiveness was largely due to the creation of stupor, sedation or confusion that prevented patients from discontinuing treatment. Hibernation therapy where the patient was rendered unconscious for up to 72 hours is a perfect example of this (Newman and Berris, 1941), anticipating the introduction of ultra-rapid opioid detoxification in the 1990s (discussed below). Some patients who underwent these ‘treatments’ suffered serious adverse events and in some cases died. Most of those who completed these treatments relapsed to drug use in the next 12 to 24 months. 11.3.

The modern era: neurobiologically inspired addiction ‘cures’

The implementation of stricter regulations and the rise of evidence-based medicine have made it more difficult to promote ‘cures’ of addiction but they have not prevented new therapeutic enthusiasms for addiction treatments being embraced by desperate addicted persons and their families. Gaps in therapeutic regulations have been used by medical entrepreneurs and for-profit clinics to promote interventions of unknown and often doubtful worth. These include self-help books (e.g. Eskapa, 2008) and centres, nutraceuticals and complementary medicine, none of which is regulated as rigorously as pharmaceuticals. The World Wide Web has also been used to promote dubious remedies outside of the reach of national therapeutic regulations. Online communities (e.g. http://www.thesinclairmethod.net/community/) and

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blogs (e.g. http://junkieboyfromoz.blogspot.com/) provide information on how to source treatments, as well as support and advice for those undergoing them. In recent years, putative cures of addiction have been promoted via an increasingly global media that transcends national boundaries. Public interest in health and medical science, particularly stories about ‘advances’ that will ‘revolutionise’ medicine, has allowed new treatments to be promoted to consumers in overly optimistic and unbalanced ways. New treatments of modest effectiveness are often described as ‘silver bullets’ and ‘miracle cures’ in the print and web-based media, blogging and social media (Racine, et al., 2007). We describe several such neurobiologically inspired ‘cures’ of addiction. 11.3.1.

Ibogaine therapy

Ibogaine is an alkaloid derived from the bark of the root of the West African Tabernanthe iboga plant used in Gabonian initiation ceremonies because of its potent hallucinogenic and psychedelic effects. While its use is banned in the US, it is legally available in many Western countries, including Canada and Holland, where it is used in for-profit clinics to treat various types of addiction including opiate, cocaine and crack, methamphetamine and alcohol. Proponents claim that a single dose prevents withdrawal from addicted drugs, as well as subsequent cravings, with the active metabolite remaining in the body for up to 6 months. It is also claimed that Ibogaine induces a psychedelic experience that provides therapeutic insight into the bases of an individual’s addiction. The first report of its use as an ‘anti-addiction’ drug emerged in the 1980s. It has since been used to treat thousands of individuals in the absence of controlled clinical evaluations of its safety and efficacy (Vastag, 2005). Ibogaine can reduce the self-administration of morphine, heroin, cocaine, alcohol and nicotine in rodents (Parker and Siegel, 2001), but there is limited clinical evidence of its effectiveness in humans (Vastag, 2005). The Food and Drug Administration approved a clinical trial of Ibogaine in 1993 but the National Institute on Drug Abuse did not fund the study because of concerns about the drug’s safety (Vastag, 2005). Ibogaine has been largely promoted and provided via private clinics and networks of underground psychopharmacologists. A single treatment costs between US$3500 and $10 000. The Iboga Therapy House in Vancouver, for example, charges US$5500 for a 5-day treatment, but offers a discounted rate for spiritual and ‘therapeutic trips’. Clinics such as the Iboga Therapy House claim a 65% cure rate, but these claims have never been independently tested or confirmed. Side-effects include impaired muscle co-ordination and

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perception, vomiting, hallucinations and extraordinary perceptual experiences. A number of deaths have been reported from cardiac or liver failure and aspiration of vomit (Vastag, 2002). 11.3.2.

Ultra-rapid opioid detoxification

Ultra-rapid opioid detoxification (UROD) treatment for opioid dependence came to public prominence during the 1990s in Australia (Hall, 2000). It involved the use of the opioid antagonist, naltrexone, to accelerate opioid detoxification under general anaesthesia or heavy sedation (Gold, et al., 1999; Loimer, et al., 1990; Loimer, et al., 1988; O’Connor and Kosten, 1998; Scherbaum, et al., 1998). Withdrawal was accomplished within 24 hours, but at the expense of an intensive care bed, intubation and artificial ventilation, specialist nursing, and supervision by an anaesthetist (Gonzalez, et al., 2004; Hall, 2000). UROD was an extremely expensive procedure that involved a small risk of mortality from anaesthesia, with several deaths recorded (Badenoch, 2002; Gold, et al., 1999; Hamilton, et al., 2002; Mayor, 1997). This risk was difficult to justify given that untreated opioid withdrawal is generally not life threatening, and can be safely achieved in other ways with a minimum of discomfort (Gonzalez, et al., 2004). UROD also proved to be no more effective than accelerated detoxification under light sedation (Gowing, et al., 2006). UROD was heavily promoted to patients and their families as a neurobiological ‘cure’ for heroin addiction. Its proponents argued that heroin addiction was caused by disordered opioid receptors in the brain that UROD rapidly normalised. Individuals and their families paid large sums to undergo a procedure that proved to be ineffective and increased their risk of dying from a drug overdose when they relapsed to heroin use. The fact that the treatment was presented as a neurobiological ‘cure’ gave patients an unrealistic expectation of the long-term efficacy of the treatment. It also reduced their opioid tolerance and thereby increased their risk of overdosing when they returned to opioid use (Hall, 2000). This treatment exemplifies the ways in which neuroscience research can be misused to persuade addicts and their families to incur large debts to fund an ineffective and potentially dangerous ‘treatment’ (Hall and Mattick, 2000). 11.3.3.

Neurosurgical ‘treatment’ of addiction

Modern neurosurgical treatment of mental illness in humans begins with Egas Moniz in 1935 and the advent of leukotomy, or frontal lobotomy

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(Valenstein, 1986). Moniz believed that individuals with schizophrenia or depression suffered from ‘faulty wiring’ in their frontal lobes that could be treated by neurosurgery (Wind and Anderson, 2008). The behavioural effects of severing the frontal lobes in primates (Swayze, 1995) led Moniz to believe that a similar procedure could cure these mental disorders in humans. Similar assumptions about other psychiatric disorders led to the subsequent use of neurosurgical procedures for the treatment of a wide range of mood and anxiety disorders (Valenstein, 1986), including addiction. Neurosurgical treatment for addiction began in 1962 and continued throughout the 1970s when a number of small case series were reported of neurosurgical ‘cures’ for addiction. These procedures included cingulotomy (ablation of the anterior cingulate) (Balasubramaniam, et al., 1973; Foltz and White, 1962; Kanaka and Balasubramaniam, 1978; Sharma, 1974), hypothalamotomy (ablation of the ventromedial nucleus of the hypothalamus) (Dieckmann and Schneider, 1978; Muller, et al., 1973), and resection of the substantia innominata and the nucleus accumbens (Knight, 1969). Nearly all of these studies reported reasonable success in preventing drug use, with little or no cognitive side-effects. They were seen by their proponents as curing addiction. In fact, one group was so impressed with the results of cingulotomy that it advocated neurosurgery as a ‘first line treatment’ rather than a treatment of ‘last resort’ (Kanaka and Balasubramaniam, 1978). The group accordingly performed this procedure on individuals who had been addicted for as little as 6 months, and who may not have attempted any other type of treatment (Kanaka and Balasubramaniam, 1978). The absence of any reported cognitive side-effects is not surprising because attempts to identify cognitive and behavioural change in these patients were grossly inadequate, with limited follow-ups, as was true of many of these early psychosurgical procedures (Valenstein, 1986). The neurosurgical treatment of addiction fell out of favour during the 1970s when it became apparent that the procedures pioneered by Moniz, Walter Freeman and others were not as effective as first thought, and in fact caused significant cognitive deficits. The development of more effective psychopharmacological treatments for mental illness (such as chlorpromazine in 1954) also provided alternative treatments of psychiatric disorders. The use of neurosurgery to ‘cure’ addiction has recently been renewed and justified by appeals to current neurobiological research of addiction. Russian and Chinese surgeons used neurosurgical procedures to treat heroin addiction until 2002–03, when public criticism prompted both countries to stop the controversial treatment. Reportedly, 305 patients were operated on in Russia

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(Walsh, 2002) and over 500 in China (Xinhua News Agency, 2005). In China, stereotactic surgery had been used to destroy the nucleus accumbens (Gao, et al., 2003), the brain region that mediates the rewarding effects of opioids and other drugs (Robbins, et al., 2007). Gao et al. (2003) thought it plausible that ablating this area would reduce the rewarding effects of heroin, and thereby decrease the likelihood of relapse after achieving abstinence. In Russia, neurosurgeons lesioned an area called the cingulate gyrus (Medvedev, et al., 2003), a brain region that has previously been lesioned to treat obsessional disorders (Orellana, 2002). The aim of the surgery was to interrupt obsessional thoughts about drug use. Clinicians in China have recently recommenced neurosurgical treatment of opioid addiction as part of a clinical trial (Goff, 2005), and the procedure was recently trialled in alcohol-dependent patients (Wu, et al., 2010). These reports raise a number of major ethical concerns (Hall, 2006b). First, there is no compelling reason to use neurosurgery to treat heroin addiction. There are effective forms of treatment that substantially reduce illicit opioid use and stabilise the lives of individuals addicted to heroin (e.g. substitution or maintenance treatment on methadone or buprenorphine) (Amato, et al., 2005; Mattick, et al., 2009; Ward, et al., 1998a). Patients and practitioners who find opioid agonist maintenance morally objectionable, or who work in settings that prohibit its use, can use the antagonist naltrexone in oral or implantable form (Krupitsky, et al., 2010). Second, there are major concerns about the safety and efficacy of these procedures. Stereotaxic neurosurgery is an invasive procedure that involves drilling holes in the patient’s skull and inserting electrodes deep into the brain to destroy the target region. Advocates of these procedures argue that they are less invasive and destructive than older forms of psychosurgery, and report lower rates of complications (Gao, et al., 2003; Medvedev, et al., 2003). However, these were uncontrolled studies that did not properly evaluate the cognitive and behavioural effects of destroying such important neurological regions as the NAcc and aCG (Gao, et al., 2003; Medvedev, et al., 2003). Much less invasive forms of neurosurgery are now used sparingly in treatment refractory cases to produce smaller, better-targeted lesions, the location of which is verified by neuroimaging (Gabriels, et al., 2003; Lipsman, et al., 2007). None of the procedures performed in China or Russia meet these standards. Third, there are major concerns about the effects of producing irreversible lesions in neural centres that are implicated in the control of food intake, sexual behaviour and the formation of social bonds, among other pleasures.

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What effect will these procedures have on the person’s responsiveness to reward, their motivation, mood state, risks of depression and suicide, and capacity for planned action? What will happen if heroin-addicted patients attempt to compensate for the attenuated reward from heroin by increasing their use to doses that may be lethal? No attempt has been made to answer these questions. The published evaluations have been limited to showing minimal changes on crude cognitive and personality tests (Gao, et al., 2003; Medvedev, et al., 2003), providing, at best, very coarse assessments of adverse effects on personality and cognition. Fourth, the published evaluations of the procedures were only compared to patients’ prior experiences with detoxification (Gao, et al., 2003; Medvedev, et al., 2003). Relapse to opioid use is the norm after detoxification which is not a treatment in its own right (Mattick and Hall, 1996). A more informative comparison would have been with an effective treatment of opioid addiction, such as methadone or buprenorphine maintenance. However, MMT has only recently become available in China and access remains limited (Cohen, 2004). It is prohibited by law in Russia (Krupitsky, et al., 2004). There has not even been an attempt to compare the efficacy of surgery with oral naltrexone, which has been used in Russia, reportedly with better results than in Western countries because of supervised dosing (Krupitsky and Blokhina, 2010). Fifth, there are doubts about whether patients have given free and informed consent to participate in this surgery (Kleinig, 1985). Chinese and Russian policies towards opioid dependence are highly punitive, with imprisonment and compulsory detoxification as the first line, and indeed, primary forms of ‘treatment’. Under these conditions, there are doubts about how freely consent can be given to undergo neurosurgery. Nor can patients be said to have provided informed consent when they were offered only ineffective treatment options such as detoxification (see Chapter 6). In the absence of controlled outcome or preclinical studies of safety, it is unclear how wellinformed patients can be about the risks of the procedure to which they are asked to consent. 11.4.

Deep brain stimulation for intractable addiction?

Deep brain stimulation (DBS) is a less invasive and more targeted form of neurosurgery that has received considerable attention in the last decade. DBS involves the insertion of microelectrodes into particular regions of the brain in order to modulate neural activity via the passage of an external electrical

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current. DBS is hypothesised to create a functional lesion at the target region that resolves an electrical imbalance at the level of the cortico-basal gangliathalamocortical loop, thereby reducing psychiatric symptoms (Stelten, et al., 2008). DBS was first introduced for the treatment of movement disorders (Benabid, et al., 1993). More recently it has also been used to treat multiple sclerosis (Wishart, et al., 2003), and to a lesser extent, cluster headache (Franzini, et al., 2003) and the minimally conscious state (Schiff, et al., 2009; Yamamoto, et al., 2005). Researchers are also investigating the use of DBS in the treatment of intractable psychiatric disorders, such as Tourette’s syndrome (Servello, et al., 2008; Visser-Vandewalle, et al., 2006), obsessive compulsive disorder (FDA, 2009; Greenberg, et al., 2006; Lipsman, et al., 2007) and depression (Mayberg, et al., 2005; Schlaepfer, et al., 2008). The use of DBS for psychiatric disorders is still experimental, with most studies involving case reports and small-scale clinical trials. More research is required to determine if DBS will be successful for these psychiatric disorders, and if so, in which patients (Synofzik and Schlaepfer, 2008, 2011). Proponents have argued that it may also be possible to use DBS to treat obesity (Hamani, et al., 2008; Sani, et al., 2007) and impulsive and violent behaviour (Franzini et al., 2005). There is now interest in trialling DBS for the treatment of drug addiction (Bauer, et al., 2008; Krack, et al., 2010; Lu, et al., 2009; Stelten, et al., 2008). The use of DBS to ‘cure’ addiction received renewed interest after a study reported that smokers who had suffered an acute lesion to the insula cortex were able to easily stop smoking when they attempted to do so (Naqvi, et al., 2007). Significantly, these individuals reported no cravings for cigarettes. Based on this finding, some scientists advocated the use of DBS in regions such as the insula to ‘cure’ addiction: ‘[c]ould there be a surgical ‘cure’ for smoking?’ (BBC News, 2007). At the 2008 Society for Neuroscience meeting, the NIDA director declared that this research had given her ‘a renewed hope for a cure [of addiction]’ (Carter, personal report). Based on previous experiences with other putative ‘cures’ of addiction, we need to be more cautious if we are to avoid an expensive, uncertain, invasive and dangerous procedure being prematurely adopted. Evidence for the use of DBS in the treatment of drug addiction comes from studies in animal models of addiction, where stimulation or lesioning of the dopaminergic reward pathway reduces the self-administration of addictive drugs (Knapp, et al., 2009; Levy, et al., 2007; Liu, et al., 2008; Rouaud, et al., 2010; Vassoler, et al., 2008). The effect of DBS on addictive behaviour for

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patients treated for other conditions (e.g. PD, obsessive compulsive disease (OCD), Tourette’s syndrome) has been equivocal. For example, two PD patients were successfully treated with DBS for dopamine dysregulation syndrome (DDS)1 (Witjas, et al., 2005); an addictive use of their dopamine medication. However, a larger study reported that 12 of 17 such patients were unimproved or worse after DBS (Lim, et al., 2009). DBS has also been reported as successfully treating seven Parkinson’s’ disease patients who developed problem gambling or hypersexuality while receiving dopamine replacement therapy (DRT) (Ardouin, et al., 2006). However, DBS has also been reported to induce addictive behaviour when applied in brain regions suggested as targets for DBS in addiction (Frank, et al., 2007; Smeding, et al., 2007). Some advocates of trialling DBS to treat addiction appeal to the ‘positive’ results of neurosurgical treatment of addiction discussed above. As noted, while these procedures were reported to reduce drug use in some patients in the short term, the follow-up has been too short in most cases to evaluate their long-term safety and effectiveness (Hall, 2006b; Synofzik and Schlaepfer, 2011). In fact, of the 17 patients with the longest follow-up (12–25 months), only three remained completely abstinent (Gao, et al., 2003). There have been five reports of the use of DBS to treat addiction to nicotine, alcohol and heroin (Heinze, et al., 2009; Kuhn, et al., 2009; Kuhn, et al., 2007; Mantione, et al., 2010; Mu¨ller, et al., 2009). In the first, a woman who was unsuccessfully treated for agoraphobia using bilateral DBS of the NAcc incidentally reported that her comorbid alcohol dependence had improved (Kuhn, et al., 2007). The same group reported smoking cessation in three of 10 patients who underwent DBS of the NAcc for Tourette’s syndrome, OCD or anxiety (Kuhn, et al., 2009). A 47-year-old woman treated with DBS of the NAcc for treatment refractory OCD quit smoking and lost weight post-surgery (Mantione, et al., 2010). However, these changes emerged 10 months after her OCD symptoms disappeared, suggesting that this may have been an indirect effect of successful treatment of her OCD. There has only been one report of the effects of DBS used to specifically treat addiction. Craving for alcohol and alcohol consumption were greatly reduced in three long-term, treatment refractory alcohol-dependent 1

DDS is a condition in which PD patients become addicted to their dopamine medication. It is characterised by a loss of control over their medication intake, doctor shopping and the use of increasing doses that exceed those necessary for treatment of their PD symptoms.

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individuals who underwent DBS of the NAcc (Heinze, et al., 2009); two were abstinent after 1 year and a third had markedly reduced their drinking (Mu¨ller, et al., 2009). These were, however, small case-studies with short-term follow-up and no comparison group (Carter, et al., 2010b). The history of neurosurgical treatment in psychiatry cautions against uncritically accepting such putatively ‘positive results’ from uncontrolled and often selectively reported clinical case series (Valenstein, 1986). This is a poor evidence base to support trials of DBS in addiction (Synofzik and Schlaepfer, 2011). The use of DBS in debilitating conditions such as Parkinson’s disease is justified by the severity of the condition and the irreversible deterioration in motor function and increasing disability that faces Parkinson’s patients who no longer respond to dopamine replacement treatment. We also have a clearer understanding of the pathophysiology of PD, an organic disorder that arises from degeneration of dopaminergic neurons in the substantia nigra. PD more aptly fits with the hypothesis used to justify DBS: it is characterised by a disruption of function in a particular region of the brain that is not otherwise easily reversed or slowed. By contrast, while addiction almost certainly involves changes in brain structure and function, it is also influenced by a complex of psychological and social factors. Also, unlike PD, the trajectory of addiction is not towards irreversible deterioration and death. Addictive disorders vary widely in severity, duration and outcome. Addictive disorders are generally more amenable to pharmacological and psychotherapeutic treatment than PD. DBS does have a number of potential advantages over other treatments. It is more targeted than pharmacological approaches: it stimulates specific mood or reward circuits, whereas psychopharmacological treatments have widespread neurochemical effects throughout the brain that can produce significant side-effects leading to non-compliance. DBS may also be more effective in treating intractable cases than other treatments (Schlaepfer, et al., 2008; Synofzik and Schlaepfer, 2011). On the other hand, pharmacological side-effects are more manageable than those associated with DBS, more easily reversed by ceasing taking a drug, and generally less severe and expensive. DBS is also an invasive neurological intervention that carries with it significant risks. These include severe short- and long-term risks on both biological and psychosocial levels. For example, 1–2% of patients who undergo DBS suffer major negative surgical outcomes, such as intra-cerebral haemorrhages, that can lead to significant loss of cognition or motor function, and possibly death. The successful insertion of stimulating electrodes can

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lead to a number of cognitive, behavioural or emotional disturbances, that include dysarthria, worsening of apathy, depression, anxiety and severe panic (McNeely, et al., 2008), impulsivity (Frank, et al., 2007), cognitive impairments (e.g. in verbal fluency, colour naming, selective attention and verbal memory (Smeding, et al., 2006)), walking disturbances (Kenney, et al., 2007), and sudden symptom reoccurrence or exacerbation due to stimulation interruption (Greenberg, et al., 2006). Non-responsiveness to intractable psychiatric conditions can also lead to severe disappointment, worsening of symptomatology and suicide (Abelson, et al., 2005; Agid, et al., 2006; Gisquet, 2008; Schupbach, et al., 2006). This suggests that the very uncertain benefits of DBS in alleviating the symptoms of addiction do not outweigh the known harms associated with the procedure, or the harm of not providing DBS and relying upon currently available treatments provided to the highest standard (Carter and Hall, 2011). If we assume that DBS proves to be safe and effective, two additional ethical issues need to be addressed. First, it may be a challenge to obtain valid informed consent. Addicted individuals may enter treatment under some form of coercion (see Chapter 8). Managing patient expectations about the limited and uncertain benefit of the treatment is also an important challenge (Bell, et al., 2010; Synofzik and Schlaepfer, 2011). Addicted individuals are often desperate for a cure, and may have unreasonably high expectations based on uncritical media reports, as has happened with previous psychosurgical enthusiasms (Diefenbach, et al., 1999). Patients will need to understand that DBS is unlikely to cure their addiction; it will not eliminate comorbid psychiatric disorders or address poor social circumstances, and they will require ongoing psychosocial support (Carter, et al., 2010b). DBS is also an expensive procedure, costing over US$50 000 for the initial surgery, with ongoing costs of over US$10 000 every few years to monitor patient response and replace the battery (Baltuch and Stern, 2007). Unlike OCD, Tourette’s and PD, addiction is extremely common, affecting approximately 10% of the population; more if nicotine addiction is included. Should DBS stimulation live up to its proponents’ enthusiastic claims, a significant ethical challenge will be raised in allocating resources for this treatment in an equitable manner. Given the enormous shortfall in access to current forms of addiction treatment, DBS will be available only to those that can afford it. While this is not reason enough not to develop it – there are many other expensive, high-technology treatments for which this is the case – it will be important to ensure that resources for existing treatment programs for addictive or neurological disorders do not suffer as a result of the development and

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use of DBS by a wealthy minority. The opportunity costs of providing DBS, even if it proved to be safe and effective, make such trials a low priority for public funding. With further research, DBS may play a greater role in the treatment of intractable psychiatric disorders. If this proves true then some persons whose addiction has failed to respond to existing treatments may wish to trial DBS. The history of previous neurobiological ‘cures’ of addiction would suggest that extreme caution is required in how such individuals are recruited, how the intervention is evaluated, and how the results of the trials are interpreted and communicated, and how the treatment is applied. There is some hope that other forms of electromagnetic stimulation, such as transcranial magnetic stimulation (TMS), may provide a non-invasive method of neurological addiction treatment (Feil, et al., 2010). There are, however, serious doubts about the clinical utility of these technologies, which are discussed elsewhere (Rosack, 2007; Slotema, et al., 2010). 11.5.

Avoiding future therapeutic enthusiasms

This short history illustrates that medical ‘cures’ of addiction may be promoted and used outside of the mainstream medical regulatory process by a desperate and increasingly well-connected public via the media and Internet. Scientists and clinicians cannot take a hands-off approach in such circumstances. We should be wary of interventions whose advocates claim will provide a quick and simple method of overcoming addiction, or unrealistic ‘cure’ rates. Such caution is especially warranted when the promoter of the treatment stands to profit from its use and resists independent evaluation. We should also be wary of interventions that do not insist on the need for ongoing and long-term psychosocial care. Most addiction neuroscientists and researchers acknowledge that addiction is a complex biological, psychological and social condition for which there is unlikely to be a simple neurological ‘silver bullet’ that cures drug addiction in the way that a short course of penicillin eliminates bacterial infection. It is especially important that the public learn to avoid confusing successful completion of withdrawal with a cure for addiction. The success of a treatment of addiction must be measured in its long-term effects on the health and quality of life of the addicted individual. The evidence that many treatments ‘cure’ addiction is based on short-term assessments of their impact: namely, the ability to complete withdrawal and achieve short periods of abstinence. Completion of withdrawal is a relatively simple process; it is the long-term

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maintenance of abstinence and the prevention of relapse that are the sine qua non of successful addiction treatment. Successful addiction treatment requires efforts to create the psychological and social conditions necessary to foster a drug-free lifestyle by eliminating social isolation, reducing stress and fostering social inclusion (e.g. counselling, housing and education, employment). A treatment that does not attempt to facilitate the improvement of all of these factors is unlikely to be the panacea that many would hope. Many of the failures of addiction treatment are due to inadequate access to well run and optimally provided forms of existing treatments. It is critical that invasive and heroic treatments such as DBS and neurosurgery provided to the few who can pay do not prevent the provision of available treatments to the highest possible standard.

12 Preventive medicine and personalised treatment of addiction

12.1.

Introduction

A major policy aim of current research on mental illness is to prevent them from occurring (Insel, 2009). The prevention of mental health problems can not only reduce personal suffering, but is also an extremely costeffective health policy. The emergence of sensitive diagnostic tools, such as genetic screening, neuroimaging and cognitive tests to screen individuals for a vulnerability to develop an addiction has given hope to the realisation of this potential (Ho, et al., 2010; Hutchison, 2010; Singh and Rose, 2009). In this chapter we critically evaluate the likelihood of these types of ‘bioprediction’ (Singh and Rose, 2009) being realised and consider the ethical issues that will arise if this were to happen. Technologies that identify addiction vulnerability are only as good as the interventions available for preventing it. Therefore, we also consider the technologies most often promoted for the prevention of addiction: drug vaccines. We also examine a more plausible use of these diagnostic technologies, namely, better matching individuals to drug treatments of addiction (e.g. pharmacogenetics), with the aim of increasing the chances of a successful treatment outcome. This possibility has been referred to as ‘personalised medicine’. This technology, if successful, would substantially reduce the costs of treating addiction.

12.2.

Bioprediction of addiction liability

Genetic screening is the most commonly discussed approach to identifying addiction susceptibility. The feasibility of predictive genetic tests of disease risk – ‘bioprediction’ – has been evaluated in a variety of areas of medicine. 197

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We therefore focus on the use of genetic information in predicting an individual’s likelihood of developing an addiction. However, many of the same issues will also arise if biomarkers based on brain functioning are developed for predicting future addiction risk or treatment matching. There has been more limited research on this possibility to date (Singh and Rose, 2009), so we will only briefly examine brain imaging technologies and other neurocognitive tools that are beginning to receive some attention as possible predictors of addiction risk. 12.2.1.

Predictive genetic testing of addiction liability

In 1999, Francis Collins, (then) Director of the US Human Genome Institute, outlined an optimistic vision of ‘genomic medicine’ in which genomic testing would revolutionise health care over the next decade (Collins, 1999, 2003). Collins foresaw genomic screening being used preventively to: (1) identify healthy individuals who carry susceptibility alleles for diseases, such as cancers and heart disease; and (2) to intervene with those at higher genetic risk to either change their behaviour (e.g. increasing exercise or eating a healthier diet) or to use drugs (e.g. antihypertensives) that reduced their risk of developing these diseases. Collins imagined, for example, that smokers would be screened for genetic susceptibility to lung cancer and those at highest risk counselled to stop smoking. Similarly optimistic projections have been made for genomics in mental health (Insel, 2009) and addiction (Uhl and Grow, 2004). If susceptibility genes were identified for addiction risk then children and adolescents could be genetically tested and those at higher risk given preventive behavioural and pharmacological interventions to reduce their likelihood of using drugs (Collins, 1999). The potential benefits of such testing would be to inform individuals about their susceptibility to addiction, potentially increasing their motivation to refuse drugs, and allowing them to make better life choices by, for example, avoiding circumstances in which they may be offered drugs. A more advanced response, assuming that effective preventive technologies and behavioural interventions are developed, would be to identify individuals with genetic predispositions and to offer such assistance. It is also possible, although perhaps unlikely, that preventive measures could be imposed upon ‘high-risk’ individuals. The result of such testing may be that one might see fewer individuals ‘risking’ the criminal justice system, because they chose, or were compelled, to avoid the effects of addictive drugs. A second possibility is that individuals thought to be ‘at risk’ may be helped

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or even coerced into social programs (for example new housing or education schemes) that keep them away from drugs and environmental situations that may lead them to use drugs. There is an obvious objection to these proposals in that it is not good public health policy to inadvertently encourage people to use drugs, regardless of their genetic risk of dependence (Hall, 1996; Hall, et al., 2002). Chronic drug use can have severe physical or psychological health effects without resulting in addiction. A significant amount of harm caused by alcohol arises from acute intoxication in non-addicted individuals (e.g. motor vehicle and work place accidents, violence). But even if society places a high value on individual autonomy, there are a number of reasons why the use of predictive genetic testing, and especially genetic screening for addiction, is unlikely to be an effective policy (Hall, 2005b; Holtzman and Marteau, 2000). First, single alleles are poor predictors of addiction risk (Hall, et al., 2004; Khoury, et al., 2004). Testing for multiple genetic variants that were individually weak predictors could, in theory, improve prediction if the results of multiple genetic tests were combined (Khoury, et al., 2004). However as the number of genes involved in disease susceptibility increases, the less useful most individuals will find information about their genotype (Hall, et al., 2004; Khoury, et al., 2004). A small fraction of individuals will be at very high risk of developing an addiction, but the overwhelming majority of individuals will have an average genetic risk. Modelling of genetic data for nicotine dependence suggests that large populations would need to be screened to identify a small number of persons who will be at high risk because they carry multiple susceptibility alleles (Hall, 2007; Vineis, et al., 2001). Modelling also suggests that combining the best replicated alleles is unlikely to do any better than crude family history information (e.g. how many parents smoked cigarettes) even if 20 or more genes were tested (Gartner, et al., 2009). The efficiency of genomic screening could potentially be improved if screening was confined to the 10% or so of the population at high risk of addiction because of a history of early onset disease among first degree relatives (Khoury, et al., 2003). Triaging genetic screening on the basis of family history is a major retreat from the whole population screening envisaged by Collins. The predictive value of the alleles identified to date means that they are unlikely to be useful in screening for risk of alcohol dependence. The ALDH and alcohol dehydrogenase (ADH) variants are protective but genetic tests are not needed to establish their presence: nausea and facial flushing following the consumption of even a small amount of alcohol would inform individuals

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of their ALDH/ADH status. Most of the other risk alleles identified to date are only modestly predictive of an increased risk (e.g. a 1.3-fold increase in the risk of AD) (Munafo`, et al., 2007; Smith, et al., 2008). Second, predictive genetic testing could have unintended adverse effects. This would be the case if, for example, testing adolescents for susceptibility to addiction increased their preparedness to try drugs, that is if they were prompted to try drugs to test the accuracy of genetic predictions (Hall, et al., 2002). It would also be of concern if a particular genetic make-up led individuals to believe they were able to use drugs without risking addiction. Under these circumstances, a negative genetic test result could encourage drug use, risking the acute harmful effects of drug use and intoxication, while a positive result may encourage fatalistic attitudes to drug use; the belief that an individual is unable to prevent or overcome addiction regardless of their choices (see below). Third, screening is only ethically justifiable if there is an effective intervention to prevent the disorder in those who are identified as being at increased risk (Khoury, et al., 2003). No interventions currently exist to prevent addiction, although the prospect of preventive vaccination against drugs such as cocaine, opiates and nicotine, or long-acting antagonists may raise this possibility in the future (Hall and Carter, 2004; Hall, et al., 2004a). We discuss the use of vaccines for this purpose below. Others argue that it may allow individuals to better plan their future or to make more informed decisions about their lives. This argument has been used in the testing for Huntington’s chorea. However, the situation is different in Huntington’s disease because individuals not only plan their future, but avoid the transmission of the disease to children (who can be screened). Thus ‘treatment’ may be considered as avoidance of the inheritance of the disease. There are reasons to be sceptical of the effectiveness of genetic information in motivating individuals to abstain from drug use, which we discuss next. 12.2.2.

Using genetic information to increase abstinence from drug use

Francis Collins’ assumption that people would be more likely to comply with advice not to smoke if they have been told that they are at increased genetic risk of developing tobacco-related diseases has not been supported by research. Randomised trials of personalised feedback about genetic susceptibility to tobacco-related disease have failed to find improvements in long-term smoking cessation rates (Carpenter, et al., 2007; Ito, et al., 2006; Lerman, et al., 1997; McBride, et al., 2002). Smokers who were advised they had a positive

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test result for genetic susceptibility to lung cancer (CYP2D6 status) were no more likely to attempt to quit, nor were they more likely to succeed in quitting, than smokers who were not advised of their genetic risk (Audrain, et al., 1997; Lerman, et al., 1997). In one study, smokers who were told they had a greater genetic susceptibility to chronic obstructive pulmonary disease were more likely to attempt to quit and use cessation aids than those who tested negative (Carpenter, et al., 2007) and marginally more likely to be abstinent at 3 months (12% versus 4%). Another study, which provided nicotine replacement therapy and telephone counselling for all participants, did not find any difference in cessation rates between smokers advised of a positive or negative genetic test result (McBride, et al., 2002). An additional concern is that smokers who are told that they are at lower genetic risk of tobacco-related diseases may be less motivated to quit (Lerman and Berrettini, 2003; Marteau and Lerman, 2001; Wilfond, et al., 2002). There is limited evidence on this issue. Studies of the effects of hypothetical genetic feedback on smokers have found lower motivation to quit among those given a ‘low risk’ result (Hoff, et al., 2005). One randomised trial found that smokers who were told that they were at low risk of tobacco-related diseases had lower smoking cessation rates than those not given any genetic risk information (Ito, et al., 2006). A more recent randomised controlled trial, however, found some evidence of a beneficial effect of genetic counselling on adherence and no evidence of reduced motivation in those who failed to quit (Marteau, et al., 2010). Genetic testing of children and adolescents to discourage smoking initiation has also been proposed. Such testing poses additional ethical concerns. The potential impact of labelling a child or adolescent as being at increased risk of addiction is unknown, but could be damaging to self-image (Wilfond, et al., 2002). These issues require careful consideration because some providers of adolescent medicine have expressed an interest in genetic testing of their patients for nicotine addiction susceptibility (Tercyak, et al., 2007). Some have also asked adolescents about their interest in having such genetic tests (Tercyak, et al., 2006). Popular understandings of the role of genetics, at least as expressed in the media, are often deterministic, suggesting that if one has ‘the gene for X’ they are very likely to develop that disorder, and conversely that they will be at low risk of doing so if they do not (Khoury, et al., 2000). Popular media reporting of a commercially available pharmacogenetic test for choosing either NRT or bupropion for smoking cessation, the NicoTest™

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(http://www.nicotest.com), describes it as a test for ‘the smoker’s gene’ or the ‘addiction gene’ (BBC News, 2004; Doyle, 2004). These views reflect the media’s appreciation of Mendelian disorders like Huntington’s disease, cystic fibrosis and Tay-Sachs disease, where modes of genetic transmission are easier to understand (Khoury, et al., 2000). If these views are indeed widely held, the challenge for public education will be explaining the personal and public health implications of polygenic disorders in which individual alleles only weakly predict disease risk and are significantly influenced by a person’s environment. If done well, this type of public education may allay anxieties about the third party uses of genetic information. Public education will also need to avoid conveying any unintended message that public health drug control strategies can be replaced by high-risk genomic medicine strategies (Carlsten and Burke, 2006; Merikangas and Risch, 2003; Willett, 2002). The surest way for many individuals in developed societies to reduce their disease risk remains to stop drug use, reduce caloric intake and increase exercise (Merikangas and Risch, 2003; Peto, 2001; Rose, 1992; Vineis, et al., 2001). If society is to avoid blaming individuals for their risk status we also need to modify our physical and social environments in ways that facilitate desirable changes in risk behaviour. Population-based tobacco control strategies such as taxing cigarettes and reducing the opportunities to smoke have halved cigarette smoking rates in Australia (White, et al., 2003) and the US (Pierce, et al., 1998) over the past three decades. It makes more policy sense to reduce cigarette smoking by increasing taxes on tobacco products, banning cigarette advertising, and restricting opportunities to smoke than it does to spend resources on identifying those at higher genetic risk of becoming nicotinedependent or developing tobacco-related diseases, if they smoke tobacco (Hall, et al., 2002; Khoury, et al., 2004). We discuss the potential impact of genetic and neuroscientific research on such social policy in Chapter 14. If genetic screening was shown to be effective in identifying those susceptible to addiction and reducing drug use and harm, there are several additional ethical concerns that will need to be taken into account. We discuss some of these next. 12.2.3.

Genetic discrimination and third party uses of genetic information

Genetic information on addiction risk may potentially be used by third parties such as insurance companies, employers and educators, and the courts

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(Billings, et al., 1992; Taylor, 1998). A recent Australian study has confirmed anecdotal reports of genetic discrimination, with a small percentage of individuals being refused health and life insurance based on genetic tests (Taylor, et al., 2008). In some cases, individuals were even refused coverage for conditions that were not relevant to their genetic test. This experience illustrates how genetic and neuroscientific research may have adverse outcomes if applied without care. Given the nature of genetic transmission, genetic risk information may not only affect the individual being tested, but also their close relatives. Genes expressed in the central nervous system and associated with complex behavioural phenotypes are likely to influence multiple phenotypes (a phenomenon known as genetic pleiotropy). Genes associated with addiction may therefore carry information about the risk of developing other mental disorders. It is not clear how this collateral information would be handled following genetic testing. This raises a number of ethical issues about who should be able to access this information. What measures should be taken to protect privacy? Under what circumstances should this information be shared and with whom (Rothstein, 1998; Rothstein and Anderlik, 2001)? Bioethicists’ concerns about the ethical and policy implications of genetic testing have been strongly influenced by experiences with genetic testing for Mendelian disorders, the paradigm case being Huntington’s disease (Marteau and Richards, 1996). Because the mutations that cause this serious neurological disorder are strongly predictive of disease risk, genetic testing creates serious ethical dilemmas for affected individuals and family members (Marteau and Richards, 1996). Huntington’s disease, however, is a poor model of the situation that arises with genetic liability to addiction. Addictions are polygenic disorders involving multiple alleles of weak effect, as well as environmental interactions and epigenetic effects. The predictive validity of genetic testing may only modestly improve upon the crude, but inexpensive, prognostic tool of family history. If the pessimists are right, the ethical and policy issues identified by bioethicists will not arise because research will not identify alleles that are strongly predictive of addiction risk. Even on the most optimistic scenario, the predictive genomics of addition is unlikely to lead to genetic screening of whole populations for the reasons outlined above. Rather, predictive genetic testing is more likely to be offered to the minority of persons with a family history of early onset addictive disorders; approximately 10% of the population. Fear of genetic discrimination may nonetheless deter such people from having genetic tests that may benefit them. Similar fears may also deter individuals from participating in genetic research on addictive disorders,

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thereby impairing the acquisition of scientific knowledge about the prevention and treatment of these disorders. It remains to be seen whether community concerns about third party use of genetic information prove to be a major impediment to addiction genomic research and future medical applications. Further empirical studies, like those of Caron et al. (2005) and Condit et al. (2006), are required to assess if these concerns are warranted. Of course, it is possible to eliminate the risks of third party use of genetic information by banning all genetic tests. However, this policy would prevent us from realising any benefits that genetic testing may bring; it would also be an overly paternalistic and arguably unethical policy. A better approach would be to look for safeguards to prevent individuals’ privacy and confidentiality being unfairly compromised. The challenge will be to develop policies that allow for the use of genetic information to reduce the incidence of disease and improve the health and welfare of individuals and society, while minimising any negative consequences of stigmatisation and discrimination. The United States government has legislated to ban genetic information by enacting the Genetic Information Non-Discrimination Act in 2009 (AlonsoZaldivar, 2008). The Act protects persons with a genetic mutation, but who are not yet symptomatic, from being discriminated against by health insurers and employers. Under the Act, health insurers are not allowed to request genetic information from clients or to require them to undergo genetic testing (Appelbaum, 2010). They are also not permitted to use genetic information to decide whether they will insure clients or to set their insurance premiums. Employers are prohibited from using genetic information to make decisions about hiring, promoting or firing an employee, and from requiring genetic testing under any circumstances. The legislation has also yet to be tested in the courts, so it is not clear what level of protection the Act offers against genetic discrimination and what impact it will have on public anxieties about such discrimination (Rothstein, 2008; Van Hoyweghen and Horstman, 2008). The same is true of moratoria and legislative bans on genetic discrimination in life insurance that have been introduced in many European countries (Joly, et al., 2010). 12.2.4.

Premature commercialisation of genetic testing

Third party misuse of genetic information may also arise from the premature marketing of genetic tests that have not yet been clinically validated directly to consumers (DTC). Genetic tests for alcohol and nicotine dependence are

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not yet used in clinical practice but some companies are selling putative genetic tests for addiction susceptibility DTC. Five companies offer testing for nicotine dependence (23 and me, deCODE, Gene Planet, Biomarker Pharmaceuticals and Lumigenix), four for alcohol flush response (23 and me, deCODE, Gene Planet and Lumigenix) and three for alcohol dependence (23 and me, Biomarker Pharmaceuticals and Lumigenix). One company, 23 and me, also offers pharmacogenetic testing for naltrexone response. Consumers send the company a swab of cells from the inside wall of their cheeks, which are subsequently sent to the company’s laboratories for genetic testing, in some cases for as little as $200 (e.g. 23 and me). The US FDA has proposed that DTC genetic tests be regulated because of concerns about the questionable validity and clinical utility of the alleles tested. In the case of addiction liability testing, the genes tested are only weakly predictive of addiction risk, with the exception of the variant for alcohol flush reaction (for which a genetic test is redundant). For most of the other DTC genetic tests for addiction, consumers will typically be told that they are at average or slightly above average or below average risk. The pharmacogenetic test for naltrexone response does potentially provide actionable information, assuming the consumer can correctly interpret the test result. Most of these companies assert that their tests are intended purely for research and educational purposes and are not to be used diagnostically. Consequently, most provide genetic risk information in the absence of genetic counselling. Navigenics is one exception, although it does not offer testing for alcohol or nicotine dependence. Given the limited genetic literacy of the general public, consumers may incorrectly interpret their risk of disease. Mandatory pre- and post-test genetic counselling could be enforced through regulation of DTC genetic tests by the FDA. Developing standards to protect the privacy of consumers’ genetic information should be a priority for policy makers. DTC tests raise greater privacy concerns than laboratory-based tests given they are purchased over the internet, and genetic information can be shared with others (e.g. 23 and me). The potential for surreptitious testing via DTC tests (i.e. family members of individuals collecting a sample of DNA without their permission) is an emerging privacy concern, although it is not clear how common this is (Udesky, 2010). It is vital to develop measures to safeguard the privacy of genetic information derived through DTC genetic testing by preventing surreptitious testing (e.g. of minors in the case of disputed paternity).

206 12.2.5.

Addiction Neuroethics Preventive interventions: ‘vaccinating’ against addiction

The term ‘vaccine’ raises questions about its possible preventive use. Misconceptions that a vaccine will produce lifelong immunity against nicotine could prompt parents to ‘vaccinate’ their children against this and other drugs (Cohen, 1997). As minors, children would not be legally able to consent to vaccination. Since parents already make choices for their children about other vaccines, it could be argued that vaccination against nicotine and other drugs is simply another decision that parents should be able to make on behalf of their children (Cohen, 1997). Given that there is a fundamental difference in vaccinations to prevent infection and vaccines to control behaviour, this argument is likely to be contested by civil libertarians and others who place a high value on personal autonomy (Hasman and Holm, 2004). It may also be rejected by adolescents who disagree with their parents’ wishes. In addition to the ethical issues raised by the use of drug vaccines to treat addiction discussed in Section 10.3.1, there are also major ethical and practical obstacles to the preventive vaccination of children. First, the limited period of protection provided by existing vaccines would require booster injections, perhaps every 2 or 3 months throughout adolescence (Kosten, et al., 2002). Apart from the time and organisation that such programs would involve, some have argued that exposure to needles and desensitisation will compound the ‘drugs problem’ in adolescents, and may contribute to adolescents’ distrust of adults and drug education. Second, the fact that the vaccine could be circumvented by using higher doses of drugs means that vaccination could be counterproductive if adolescents were prompted to test its efficacy or attempted to override the immunoprotection. Furthermore, experimentation would not itself be deterred, particularly with drugs not covered by vaccination, and overdose – albeit at higher thresholds – would still be a risk. Third, it would be costly to universally vaccinate children with a vaccine of modest preventive efficacy (Hall, 2002a). Vaccination of ‘high-risk’ adolescents seems a more plausible and less expensive option. The feasibility of even this approach is doubtful given the low predictive validity of genetic screening, the doubtful preventive efficacy of current drug vaccines (Cornuz, et al., 2008), and the possible adverse effects of vaccination (as outlined above). In order to be ethical, use of preventive drug vaccination would need to demonstrate: (1) the long-term benefits of the vaccine (Ashcroft and Franey, 2004; Hall, 2002a; Harwood and Myers, 2004); and (2) that genetic tests accurately predict the risk of nicotine addiction. Given the limited predictive power of genes studied to date, and

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doubts about the long-term efficacy of preventive vaccination, it is unlikely that preventive vaccination would be an effective or an ethical intervention (Hall, 2005b). The ‘off label’ use of a drug vaccine by a physician acting at the request of a parent is the most likely way that a vaccine will be used preventively. It is difficult to see how this use could be prevented if a vaccine is approved for therapeutic use, other than by education of physicians and parents about the limitations of this approach (Hall, 2002a). 12.2.6.

Predictive uses of neuroimaging technologies

Neuroimaging could also be used to identify neuropsychological vulnerabilities that predispose individuals to develop addiction if they use drugs (e.g. poorly functioning inhibitory control circuits or specific responses to rewarding stimuli) (Paulus, et al., 2005; Schutz, 2008). Neuroimaging studies have shown how addictive drugs can produce cognitive changes that focus attention on drug use, and make strong urges to use drugs more difficult to resist. Characteristic patterns of brain activity in childhood and adolescence, for example, could potentially predict increased risks of addiction in adult life. This could include brain scans that identify poorly functioning inhibitory control circuits or highly responsive reward systems (Volkow and Li, 2005). These predictions should be treated with caution for a number of reasons. First, neuroimaging research is at risk of repeating the early experience in studies of disease genomics: promising results are reported in small study samples that may not be replicated in larger studies. A recent study of metaanalyses of structural changes in brain regions associated with psychiatric illness found that the majority of positive results were unlikely to be replicated (Ioannidis, 2011), suggesting that such concern is warranted. Second, it is not currently possible to determine whether changes in brain structure and function identified in this research precede chronic drug use, and are therefore predictive of future drug abuse, or whether they are a consequence of chronic drug use (Paulus, 2007). Untangling the origins of changes in brain function requires large prospective studies that involve studying subjects from a young age, prior to drug exposure, and re-examining them over a period of years to detect any differences in neuroimaging findings between those who have and have not used drugs and become addicted. There are several such studies currently underway in Australia, the US and in Europe (e.g. IMAGEN study (Schumann, 2007); http://www.imageneurope.com/) that may help to resolve these uncertainties.

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Third, given the costs of conducting neuroimaging research, it will be logistically difficult and expensive to do the large-scale studies required to establish the predictive utility of diagnostic neuroimaging. Studies of genetic association that predict addiction liability require the synthesis of results from thousands of individuals in order to determine that an association is valid. A similar analysis in neuroimaging studies necessary to exclude false positive results may make the costs of such research prohibitive. Should the technology prove effective, the potential use of predictive neuroimaging will raise the same ethical issues involved in testing for alleles that predict an increased risk of serious neurological disease, such as privacy and discrimination and the misuse of technology (Illes and Racine, 2005; Illes, et al., 2007). There are also subtler questions of human rights to consider, especially if imaging is conducted under any form of legal coercion. Furthermore, because the changes in the limbic regions that respond to drugrelated cues persist well into abstinence (Childress, et al., 1999), there is the possibility that an individual recovering from addiction will be discriminated against despite being drug-free. The increased use of these methods could also lead to the belief that a refusal to undergo brain scans on civil liberties grounds may be indicative of addiction. Even if these studies show that there are neuropsychological differences that predispose some individuals to develop an addiction, it is not certain that neuropsychological changes will more accurately identify those at higher risk than more accessible social measures, such as family history of drug use, socio-economic status, and age of initiating drug use. Neuroimaging can also be extremely expensive.1 Given the current under-funding of addiction treatment, a higher priority might be given to increasing treatment places, education and other social initiatives to reduce drug use and addiction.

12.3.

Personalised treatment of addiction

A more plausible predictive use of genetic and neuroimaging technologies is to better target existing addiction treatments to the specific neuropsychological or 1

A magnetic resonance scanner for fMRI can cost between US$1 million for a 1.5 tesla unit, and over US$2.4 million for a larger 3 tesla scanner. The cost of PET scans can vary widely depending on the class of machine, the experimental methodology used, the number of scans performed annually, and the type and availability of radiopharmaceuticals. A study in 2005 estimated that a typical scan could cost between US$2000 and 8000 depending on the number of scans performed annually (Chuck, et al., 2005).

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genetic needs of the addicted person (Insel, 2009). Research has shown that individuals may have genetic or neuropsychological differences that respond better to specific types of treatment. The ability to better target addiction treatments to meet individuals’ genetic or neuropsychological make-up has the potential to lead to improved clinical outcomes, as well as reduce public health costs. 12.3.1.

Pharmacogenetic treatment of addiction

The use of genetic information to guide treatment decisions is referred to as pharmacogenetics (Ho, et al., 2010; Hutchison, 2010). For example, genetic information about nicotine metabolism or dopamine response to nicotine could be used to match smokers to the treatment most likely to produce abstinence (Munafo`, et al., 2005b). The two major issues in assessing addiction pharmacogenetics are: (1) will the genotypes identified predict differential responses to treatment?; and (2) if so, will the additional costs of genetic testing be justified by the improvements in outcome (Flowers and Veenstra, 2004)? Munafo` (2009) argues that to be useful, genes need to have a high prevalence and be highly predictive of differential treatment response. Screening for rare polymorphisms is not very useful unless they are very strong predictors of treatment outcome because a very large number of people will have to be tested to identify the small number who respond differentially to treatment. The predictive value of the polymorphisms for the outcome of interest (e.g. differential response to smoking cessation interventions) reflects the sensitivity and specificity of the genetic test for the polymorphisms and the penetrance of the gene, that is, the degree to which people with the polymorphism differ in their response to treatment from those who do not. A genetic test for a gene of low prevalence and penetrance is unlikely to be useful (Flowers and Veenstra, 2004). These are the characteristics of the alleles that have been evaluated to date in studies of nicotine pharmacogenetics (Lee and Tyndale, 2006). If we assume that genes are able to predict treatment response, how would we assess the cost-effectiveness of pharmacogenetics? We know that the costeffectiveness of pharmacogenetic tests is affected by the characteristics of the genes being tested, the condition being treated and the treatments that genetic tests are being used to select among (Flowers and Veenstra, 2004). The type of research required to assess the cost-effectiveness of the addiction pharmacogenetic test, NicoTest for example, demonstrates what is required to

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evaluate pharmacogenetic tests. NicoTest uses a genetic test for a polymorphism in the D2 allele to determine whether a smoker is more likely to quit smoking using NRT or bupropion (http://www.nicotest.com/). One could model the cost-effectiveness of NicoTest using empirical evidence on: the prevalence of the D2 polymorphism among smokers; its predictive value for success in quitting with NRT or bupropion; the cost charged for the test; epidemiological models of the tobacco-related mortality and morbidity that would occur among smokers who continue to smoke versus those who successfully quit using these methods; and estimates of the costs of treating tobacco-related disease that have been averted by successful quitting. A comparison is required to decide whether the improvement in cessation rate that is achieved by NicoTest is worth the additional costs incurred by the genetic testing and counselling that its use entails (Flowers and Veenstra, 2004; Munafo`, et al., 2005a). This requires studies that compare the costeffectiveness of NicoTest with simpler and cheaper methods of treatment selection, such as, offering all patients the most effective treatment (averaged across genotypes) (Hall, et al., 2002). Modelling suggests that a hypothetical genetic test to match smokers to treatment is unlikely to be cost-effective (Welton, et al., 2008). Evaluations of NicoTest would also need to consider the social and psychological consequences of giving smokers information about their genetic susceptibility to nicotine dependence. The implicit assumption that this information will motivate smokers to use the treatment provided cannot be simply assumed to be true (Marteau and Weinman, 2006). We need to investigate the ‘folk genetics’ of nicotine dependence: the everyday inferences that people in the community draw about the plasticity of smoking and its amenability to intervention if it is seen as being ‘genetic’. Specifically, we need to discover whether popular simplifications of smoking ‘genetics’ entail the belief that smoking is a fixed and immutable behaviour that can only be changed with great difficulty, if at all, by biological interventions (Nelkin, 1973). Two studies on smokers’ understanding of the implications of information about genetic risk for cessation suggest that smokers who accept the plausibility of a genetic contribution to cigarette smoking are less confident about their selfefficacy in quitting and more likely to see a biological intervention as required to become abstinent (Cappella, et al., 2005; Wright, et al., 2003). Researchers will also need to assess whether giving genetic risk information discourages future quit attempts in those who try and fail to quit. This would be undesirable because most smokers only achieve abstinence after a number of failed quit attempts (John, et al., 2004). More work is required on this issue.

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Neuroimaging and cognitive tests in the clinic

Neuroimaging may also prove useful for identifying individuals with different subtypes of addiction or comorbid mental health issues, or particular cognitive deficits that require specific types of treatment (Singh and Rose, 2009). The use of brain imaging to tailor addiction treatment does not present any special ethical issues in addition to those discussed above. Other uses of neuroimaging outside the clinic may do so. For example, neuroimaging studies are able to detect dramatic changes in limbic responses to drug-related cues that would identify an individual as drug-dependent (Childress, et al., 1999). This opens up the possibility of discrimination by interested third parties, such as employers, educators, insurance companies and the courts, and violations of privacy (Canli and Amin, 2002; Farah and Wolpe, 2004; Illes and Racine, 2005). Anecdotal evidence suggests that this has already occurred (Anon, 2005). It may also raise issues of consent, given that these neuroimaging tests could use drug cues that are presented without the subject’s awareness (Whalen, et al., 1998).2 Given the enormous costs associated with addiction, this use of the technology to screen individuals may be an attractive option to employers. Because the changes in the limbic regions that respond to drug-related cues persist well into abstinence, there is the possibility that an individual will be discriminated against even when they are drug-free. The fairness of such a discriminatory policy would need to be established. Unlike genetics, there is no legislation to protect against the misuse of information gleaned from imaging technologies. Advances in neuroimaging technologies raise the more speculative possibility of ‘reading people’s minds’ by using these methods to ascertain the truthfulness of what defendants or suspects say (Farah, 2002; Foster, et al., 2003; Illes, 2003; Ross, 2003). Neuroimaging is already being widely promoted on the internet by commercial interests purporting to have developed technologies that can identify truth-telling (e.g. NoLieMRI, http://www. noliemri.com/ and Cephos, http://www.cephoscorp.com). Neuroimaging of truthfulness has reportedly been used to influence court decisions in the US and India. This is more of an aspiration than reality at present, although some entrepreneurs claim that electrophysiological methods can be used to

2

It is possible to mask images by presenting them for intervals that are too short to be perceived consciously so that the viewer is not aware of having viewed the image. The masked images still produce changes in neural activity that can be detected by neuroimaging.

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determine if a person is being truthful (Foster et al., 2003). Future improvements in neuroimaging may, even if imperfectly, disclose facts about a person that they may prefer to keep private (Ross, 2003). Advances in neuroimaging technology are also making it possible to obtain personal information about an individual that may predict behaviour or identify aspects of personality (Abler, et al., 2005; Canli and Amin, 2002; Farah and Wolpe, 2004; Fischer, et al., 2001; Fischer, et al., 1997; Singer, et al., 2004). The claims of entrepreneurs promoting these technologies to the public (e.g. truth-telling, personality matching and as tests of marital fidelity) raise the need for consumer protection against the over-interpretation of equivocal test results and bogus claims (Caplan, 2002; Farah, 2002, 2005). Important ethical issues would be raised if persons are compelled to undergo these tests by third parties, such as employers. During the course of neuroimaging studies, up to 40% of brain scans of research participants show ‘suspicious’ brain anomalies, with between 0.5 and 8% of research brain scans uncovering clinically significant neuropathology (Illes, et al., 2006; Illes, et al., 2004a; Illes, et al., 2004b). The emergence of incidental findings from neuroimaging research can lead to discrimination, a possibility that can complicate the process of obtaining consent to participate in these studies (Anon, 2005; Illes, et al., 2006). Neuroimaging is extremely expensive and will not be available in many places, particularly under-resourced drug and alcohol treatment centres. A cheaper alternative is the use of neurocognitive tests (such as tests of attentional bias towards drug use, impulsivity, or the ability to resist immediate rewards) to guide treatment decisions, e.g. by identifying those most likely to relapse (Paulus, et al., 2005). These tests are cheap and easy to use, often involving cards or a computer screen, and have been shown in several small studies to be able to predict the likelihood of relapse to drug use (Cox, et al., 2002; Goudriaan, et al., 2008a, 2008b; Paulus, et al., 2005). Peripheral markers have also been suggested as potential predictors of effective treatment response. Ersche and colleagues (2011) measured changes in mRNA following a challenge with the dopamine agonist, pramipexole. Changes in mRNA were correlated with addiction severity and cognitive response to dopamine agonists, which they argued could be used to guide treatment decisions. This is a relatively new area of enquiry that will require significant research in larger and more varied samples of addicted individuals before the clinical and scientific validity of their use is established. If successful, cognitive tests may represent a significant step forward in personalising addiction treatment. This possibility raises similar ethical concerns regarding privacy

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and discrimination as for other diagnostic technologies. If the appropriate controls and regulations are in place, these concerns could be easily overcome. 12.4.

Conclusion

Substantial challenges remain before optimistic predictions about preventive genomic medicine and personalised treatment can be realised in the field of addiction. A major challenge is the lack of commonly occurring, genetic variants that strongly predict addiction risk. However, prediction is only half the problem. Should more accurate diagnostic technologies emerge that can predict addiction liability, effective preventive interventions will need to be developed. None currently exist. There is also doubt whether information about an individual’s addiction risk is likely to affect their behaviour more than advice to not smoke and avoid binge drinking; sensible advice irrespective of your genetic make-up. Population health strategies such as increased taxation and reduced opportunities to smoke or drink alcohol are likely to remain more efficient preventive strategies for reducing the harm of drug use. Further research is needed on how best to present genetic and neuropsychological information to motivate desired behavioural change and avoid undermining successful public health strategies for reducing addiction and disease risk (McBride, et al., 2010). Any future predictive use of genomic or neuroscientific information on addiction risk will also need to address concerns about privacy and the third party use of genetic information. There is also considerable doubt whether these technologies will be able to accurately identify those vulnerable to addiction in a cost-effective manner. Evaluations of the utility of genetic, pharmacogenetic and neuroimaging prediction in the field of addiction will require substantial investments in research and development and health services evaluation. The ethical and public policy analyses presented above provide a framework for considering the use of emerging neurotechnologies for the treatment and prevention of addiction. As the science progresses, and a clearer understanding of the effectiveness, accuracy and side-effects of the proposed technologies emerges, these analyses will need to be updated. These ethical frameworks will, however, provide a useful way of identifying the social and ethical issues that need to be taken into account when doing so.

13 Feeling better than well

13.1.

Introduction

People are said to be increasingly interested in using medical or other interventions not just to treat a diagnosed illness, but to enhance their everyday well-being, that is to be better than well (Elliott, 2003). Witness the growing ‘lifestyle medicine’ industry that includes improved sexual performance, cosmetic surgery and anti-ageing products, as well as a burgeoning complementary medicine and nutraceutical industry that claims to overcome the stresses of day-to-day life. Interest in such interventions is reflected in the media enthusiasm for medical or scientific stories that herald the introduction of new treatments to overcome everyday concerns about stress, boredom, ageing and worry. Some advocates of enhancement argue that neuroscience research has the potential to dramatically extend our ability to create new drugs that may improve our lives in ways that older technologies could not (Greely, et al., 2008). In this chapter, we examine some of the concerns raised by the proposed development of new neuroscience-based technologies for tackling addiction and other mental disorders that may also be used to make us better than well. Psychopharmacological enhancement is particularly pertinent to the addiction field since addiction can be viewed, in some cases, as a failed attempt at enhancing cognition or emotional well-being. 13.2.

Memory modifiers, cognitive enhancers and mood modulators

Several of the drugs that have been developed to treat symptoms of addiction also appear to improve cognition, behaviour and mood. For example, some researchers are developing drugs that can dampen memories, possibly making it easier for addictive behaviours to be unlearned (e.g. propranolol) (Kampman,

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et al., 2001; Milton, et al., 2008). Others are trialling drugs, such as modafinil, that improve cognition or executive control to assist addicted persons to choose not to use drugs (Dackis, et al., 2004; Heinzerling, et al., 2010; Vosburg, et al., 2010). Oxytocin, a drug that has been shown to influence neurobiological processes involved in addiction (e.g. sensitisation, tolerance and self-administration) (McGregor, et al., 2008; Sarnyai, 1998; Sarnyai and Kovacs, 1994), could also be used to enhance social cognition, such as increasing trust (Kosfeld, et al., 2005) and reducing fear of others (Domes, et al., 2007a). It could potentially be used to enhance empathy, improve our ability to ‘read’ others’ mental states (Domes, et al., 2007b) and facilitate social bonding and co-operation (Kosfeld, et al., 2005). Ritalin (methylphenidate), a drug used to treat ADHD, has also been shown to be an effective treatment of cocaine dependence in individuals with ADHD (Levin, et al., 2007). Ritalin (methylphenidate) and other similar stimulant drugs (e.g. Adderall or amphetamine) are reportedly already being used by healthy individuals to enhance cognition (Greely, et al., 2008; Sahakian and Morein-Zamir, 2007), although some have argued that these claims may be overstated (Lucke, et al., 2011b). All of these types of drug could potentially be used by healthy adults to enhance normal cognitive or psychological functioning, such as to improve memory and learning, increase wakefulness and alertness, facilitate social interaction, modulate mood and even enhance moral reasoning (Persson and Savulescu, 2011). The enhancement uses of pharmaceuticals is an issue that is not unique to drugs used to treat addiction; similar issues have arisen with drugs used to treat other psychiatric disorders (e.g. stimulant drugs used in ADHD, cognitive enhancers in dementia and antidepressant drugs). The history of addictive drugs may be informative about likely adverse effects of enhancement use of neuropharmaceuticals. Drug addiction could be seen as a consequence of using drugs like amphetamines, cocaine and opioids for cognitive or mood enhancement. All modern drugs of abuse were previously used as pharmacological treatments for illness that were later coopted by recreational users for other purposes that can broadly be considered as forms of enhancement (Ragan, 2007). In fact, the line between enhancement and recreational drug use is not distinct. The field of addiction may therefore provide some pertinent lessons for possible outcomes of widespread adoption of ‘cosmetic psychopharmacology’ (Lucke, et al., 2011a). The ethical debate over the use of drugs for enhancement purposes involves arguments about whether there is a clear distinction between ‘enhancement’

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and ‘therapy’. An in-depth discussion of this debate can be found elsewhere (see Academy of Medical Sciences, 2008; Parens, 2002). The general view is that there is, at best, an ambiguous distinction between technologies that raise the baseline of human capacities in impaired persons and interventions, such as viral vaccines and education, which may enhance normal human functioning. Some authors (e.g. Outram, 2010) argue that no clear distinction can be drawn between treatment and enhancement. Some critics have suggested that well-known psychiatric medications, such as methylphenidate (Ritalin) and modafinil (Provigil), are already being used to improve mood and attention in those who are not suffering from a mental illness (Fukuyama, 2002). There has been speculation that drugs that are being developed to treat Alzheimer’s disease (Porrino, et al., 2005) and post-traumatic stress disorder (PTSD) will be used by healthy individuals to enhance or modulate memory and cognition (Chatterjee, 2007; Glannon, 2006b; Hall, 2004). There is also anecdotal evidence that some individuals use Prozac and other SSRI antidepressants to reduce the neurotoxic effects of MDMA (3,4-methylenedioxy-N-methylamphetamine or ecstasy) or to moderate the ‘come down’ or negative after effects of an MDMA high. In light of the history of drug use, the enhancement use of novel drugs developed for the treatment of addiction and other psychiatric disorders is highly likely. The advent of cognitive enhancing drugs will force society to reflect on what forms of drug use are acceptable by adults, when such use should be prohibited, and when and how such prohibitions should be enforced? The moral opprobrium levelled at some forms of recreational drug use contrasts with the enthusiastic embrace of therapeutic or lifestyle drugs (Academy of Medical Sciences, 2008; Maher, 2008; Sahakian and Morein-Zamir, 2007). These seemingly inconsistent attitudes may well be reconciled by assimilating all enhancement use to recreational use and prohibiting it. We discuss some of the ethical concerns about enhancement below. 13.3.

What’s wrong with neuroenhancement?

A number of objections have been raised against the proposed use of pharmacological neuroenhancers. Utilitarian ethicists do not reject the idea of enhancement in principle and prefer instead to focus on the risks and benefits of using technologies that may affect the brain. Are they safe for individuals to use? What may be the social consequences of such use? Is it likely to increase the greater good? In many cases, utilitarian ethicists

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positively evaluate enhancement uses because of their potential capacity to increase the sum of human happiness. In principle objections to enhancement are more often expressed by deontological and virtue ethicists. They express concerns about the ability for individuals to give informed consent to enhancement when experiencing coercion to undergo it, and worry about the effects that use of these technologies may have on how we think about ourselves as persons and on our views of the human ethical virtues. The latter often ask the following questions: Is it fair to use pharmacological enhancement? Are enhanced actions valued in the same way as our unenhanced actions? These ‘in principle’ objections to neuroenhancement are often referred to as ‘naturalistic objections’. While these arguments are most often used in relation to pharmacological enhancement, similar concerns can be raised about neuroenhancement using neurological interventions (e.g. electrical and magnetic stimulation, electrical implants). As the enhancement use of these technologies is still speculative, we restrict our discussion to the more likely possibility of neuropharmacological enhancement. 13.3.1.

Concerns about safety and efficacy

There are good reasons to be concerned about the possible harms that may arise from the enhancement use of pharmaceuticals. The frequency of adverse reactions to many therapeutic drugs provides empirical evidence that using drugs that act on the CNS can harm users in unexpected and unanticipated ways. When these drugs are used to treat serious human diseases, such adverse reactions may be accepted as the price for achieving relief from the symptoms of serious illness and disability. The tradeoff between adverse sideeffects and benefits may be less clear when drugs are used for enhancement in healthy individuals (Chatterjee, 2004; Wolpe, 2002). In public debates, these concerns are often summarised in popular slogans, such as, there are ‘no free lunches’ and ‘no pain without gain’. It is not always clear to what extent these are meant to be empirical claims about the harms that will arise from enhancement use or a consequentialist gloss on more fundamental objections to enhancement. We discuss these in principal objections below. Some critics appeal to an evolutionary argument. They argue that all technologically achieved gains in human abilities necessarily involve tradeoffs with other capacities that were selected in our ancestral environment. They argue that if we optimize some abilities this is likely to be at a cost to overall performance (Farah, 2002). The homeostatic response of the human

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brain to regular use of neuropharmaceuticals (as indicated by the development of tolerance and the experience of withdrawal symptoms on abrupt cessation of use) lends credibility to such an argument. Those who defend enhancement concede that there may be adverse side-effects but argue that these can be identified and addressed by monitoring adverse effects and advising potential users of these risks (Caplan, 2002; Stock, 2002). The understandable focus on the safety of enhancement uses of pharmaceuticals has led some to underestimate the difficulty in assessing the efficacy of putative neuroenhancers. Placebo effects are likely to complicate the assessment of claims made for enhancement technologies and will make it important to assess longer term efficacy in addition to their safety. We will also need to see whether the human brain adapts to enhancement technologies in ways that undermine their effectiveness or cause harm, if users compensate by increasing their dose or use combinations of enhancing drugs (as can occur among heavy recreational drug users). The effect of prolonged use of many psychoactive drugs suggests that this is a possible consequence that warrants examination. We will also need to provide consumer protection against doubtful claims for the efficacy of enhancement technologies. Given the spurious claims already made for a range of medical interventions (e.g. to enhance sexual performance), exaggerated or dubious claims of efficacy for neuroenhancers are also to be expected. In principle, none of these are insurmountable problems. Safety and efficacy could be assessed by adapting the regulatory apparatus that has evolved to assess the safety and efficacy of therapeutic pharmaceuticals (Farah, et al., 2004; Greely, et al., 2008). Consumer protection laws and regulations could be invoked to regulate marketing of these technologies. If we choose this path, we can anticipate debates about whether or not to allow direct–toconsumer advertising of these technologies. It is difficult to see this not occurring given the widespread promotion of ‘natural’ ageing, menopausal, sexual performance and beauty enhancements technologies of doubtful efficacy in liberal societies. 13.3.2.

Coerced neuroenhancement: a psychopharmacological ‘arms race’

A common concern about enhancement technologies is that their widespread use will raise the standards for what counts as ‘normal’ (Farah, 2002; Parens, 2002). This would, these critics suggest, force an ‘arms race’ in which everyone would be coerced into using enhancement technologies as a way

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of ‘keeping up’ with peers who use them. This dilemma may also be felt acutely by parents in deciding whether to give their child ‘every opportunity’. Arguably this has happened in the sports arena with performance enhancing drugs (e.g. cycling); some claim that it has also driven the rising use of stimulant medication by school-aged children and university students (Fukuyama, 2002; Greely, et al., 2008). Such a trend could potentially increase discrimination against people with medical conditions who decline to be enhanced (Parens, 2002). The rejoinder of those who defend enhancement is that banning it would be an even more coercive approach than the coercive influence of any speculative bandwagon effects that may arise from its widespread use. These critics argue that those who do not want to be enhanced should not be permitted to use the law to prevent those who do wish to be enhanced from doing so (Caplan, 2002). Caplan (2002) argues that this is not accepted practice in other areas of social policy. We have not banned private school education, academic coaching or cosmetic surgery, for example. More overtly coerced enhancement may occur in schools where underperforming children could be coerced to undergo cognitive enhancement. Such a proposal is not without precedent. There are media claims that students have been expelled or threatened with expulsion if their parents refuse to medicate their child with the stimulant drug, Ritalin, for an ADHD diagnosis (Montreal Gazette, 2006). The same could occur in the workplace. If an effective drug emerged that increased the performance of those working in performance intensive professions, such as pilots, surgeons or truck drivers, would we allow, and even more strongly, mandate its use if it was shown to increase safety (Savulescu, 2005)? Employers may make preparedness to use enhancements a requirement of employment. Such an approach has been a common practice in the military (Rasmussen, 2008). Coerced enhancement may also conceivably occur in prisons where enhancement of cognitive performance may be seen as the remedy for high rates of poor cognitive performance. 13.3.3.

Equity of access to neuroenhancement technologies

An obvious concern about the societal implications of widespread use of enhancement technologies is that not everyone will have equal access to these technologies and that as a consequence, the advent of neuroenhancement will amplify existing social inequalities because their cost will prevent the poor from accessing them (Farah, 2002; Fukuyama, 2002; Parens, 2002). This argument prompts a number of responses from those who defend

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enhancement. First, is the response that this is a criticism of existing social hierarchies rather than a compelling objection to enhancement per se (Caplan, 2002; Levy, 2007). The same objection could be used, for example, to justify bans on private education, tutoring and private schools, cosmetic surgery and orthodontics, or infertility treatment. Caplan also persuasively argues that neuroenhancement may in fact reduce inequity by ameliorating neuropsychological deficits in the less well off to create a more even playing field (Caplan and Elliott, 2004). Others suggest ways in which these inequities in access can be addressed. One way would be to make all forms of enhancement freely available to everyone who wanted them at low cost, for example by publicly subsidising the use of cognitive enhancement technologies. This is what many developed societies have done with medical treatments, including some that are arguably forms of enhancement, such as in vitro fertilisation and contraception (Parens, 2002). Others argue that the free market will solve the problem of access. While new technologies may be expensive at first, uptake by the wealthy will drive down prices and increase access as patents expire, technology research and development costs are recouped, and there are improvements in the efficiency of the production and delivery of the technology (Stock, 2002). 13.3.4.

Naturalistic objections to enhancement: morality and personhood

There are a number of less well-formulated and articulated objections to neuroenhancement that underlie the intuitive unease that some critics feel about using new technologies to enhance normal human functioning. First, there are the implications that the widespread use of neuroenhancements may have for our sense of personhood and identity. Are people who undergo enhancement still ‘themselves’? Are they responsible for and hence able to take the credit for their neuroenhanced performance? Is it ‘natural’? Second, is it morally permissible to use pharmacological short cuts to achieve admirable, and perhaps profitable, social goals? Is enhancement, in fact, a form of ‘cheating’? Will neuroenhancement technologies devalue our sense of achievement? The latter concerns are often expressed in Calvinist terms that future generations will not appreciate the value of hard-earned success, and that enhancement will thereby undermine important social and moral values. The latter is the view most often taken towards the use of performance enhancing drugs in elite sport and the use of recreational drugs to enhance mood. It may also be translated into societal attitudes towards neuroenhancement of cognitive performance, memory and mood.

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These arguments question whether neuroenhancement is natural or authentic; they do not depend on the consequences of neuroenhancement. The problem with such criticisms is that there are a number of interventions that society has already adopted about which similar objections could be made (e.g. private education and tuition, oxygen replenishment to aid sports recovery, the use of vitamins and other supplements, computer-aided devices, binoculars and reading glasses). Advocates of in principle objections need to provide a convincing argument why interventions such as drugs or neural implants are morally different from other forms of enhancement that have been widely embraced by society. We believe that a convincing argument is yet to be made. Support for naturalistic objections is also weakened by evidence that current non-pharmacological enhancements also produce changes in neurochemical activity. Levy (2007) has provided a strong case for arguing that there is nothing inherently different about pharmacological neuroenhancement that would justify in principle objections to it. 13.4.

Lessons from recreational drug use and drug policy

The ethical issues raised by enhancement are often discussed as if they were novel. However, pharmacological neuroenhancement has arguably been practiced by human beings since our ancestors discovered the psychoactive effects of plant-based drugs like alcohol, nicotine, opium, cannabis, psilocybin and coffee. Writers and artists have long promoted the use of drugs such as wine and hashish (Baudelaire, 2002), opium (De Quincey, 1900) and psilocybin (Huxley, 1954) to enhance creative and perceptual experiences. In addition, most current pharmaceutical drugs of abuse were initially used for medical purposes (e.g. heroin, cocaine, amphetamines, cannabis and MDMA). Their medical use often provided occasions for users to experience improved mood and performance when they were not ill. Hence, morphine came to be used in the late 19th century demi-monde in the US for its euphoriant, relaxation and stimulant effects (Courtwright, 1982). The use of LSD (lysergic acid diethylamide) and cannabis was widely advocated in the 1970s as a form of ‘mind expansion’ by people who initially experimented with them in medical and scientific settings, such as Timothy Leary (Stevens, 1987). More recently, MDMA, a drug first used in the 1930s for psychiatric treatment, has been widely used by young adults as a social facilitator and dance party energizer (Cohen, 1998). What might we learn about neuroenhancement from our experiences with addictive drugs? First, we may learn something about the likely effects of

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such use on users and society in the short and medium term. Second, we could anticipate how these drugs might be used when they leave the clinical and research laboratory. Third, we might also have something useful to learn about options for regulating new drugs, particularly from the success or otherwise of attempts made over the past century to regulate the use of enhancing psychoactive substances via international treaties, legislation, regulation and criminal justice policies (Courtwright, 2001). The following are some broad generalizations derived from this history. The first generalization is that the use of all psychoactive drugs entails some risks when used in certain ways by some users. These risks include: the acute effects of drugs when used at recommended doses as well as in overdose; and the adverse effects of chronic use that it may take decades to discover. The frequency and severity of these adverse effects depend upon the way in which drugs are used (e.g. the typical quantity and frequency of use, the most common route of administration and the typical setting of use). Their prevalence of use will also be affected by the availability of these drugs, especially to young adults, the more adventurous of whom are likely to use drugs in non-approved and non-recommended ways, in multiples of therapeutic doses, in conjunction with other drugs, and in settings that may increase risk (e.g. before driving cars). Second, addiction is one harmful consequence of using many psychoactive drugs that improve mood, performance and a sense of personal well-being in the short term. It represents a pharmacological misappropriation of brain mechanisms that have been selected by evolution to reward behaviour that is required for individual and species survival, such as eating, drinking and copulating (Hall, 2002b; Hill and Newlin, 2002). Addiction is a risk that we should anticipate from the chronic use of enhancement technologies that acutely improve mood and cognitive performance. Given similar enthusiastic claims made in the past about the enhancing properties of cocaine, heroin and diazepam, we should be sceptical of any claims that new drugs are ‘nonaddictive’ until this has been demonstrated in long-term observation of their use in humans. Third, there are ‘long waves’ in the patterns of drug consumption. The use of new drugs often shows dramatic ‘epidemic’ enthusiasms that are terminated by increasing disillusionment among users as the adverse consequences of sustained and heavy use become apparent to peers and younger potential users (Kleiman, 1992). Positive experiences – the common outcome of initial experimentation – are reported to peers by satisfied users who unwittingly proselytise the benefits of using the drug to others. The emergence of websites

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and blogs dedicated to communicating information about psychoactive experimentation has greatly increased the reach of such messages beyond that of word of mouth and popular music in the peer groups of the 1960s and 1970s. Unless a drug’s acute effects are serious, it takes time for the casualties of new forms of drug use to emerge. Where adverse events are rare, they may only be detected after large numbers of people have used the drug, and there may be a delay before these effects are accepted as drug-related by the drug using community. The same patterns of drug use are apparent in therapeutic enthusiasms for new therapeutic drugs, most recently in the rapid expansion of amphetamine and antidepressants prescribing in many developed societies in the 1990s and an earlier enthusiasm for benzodiazepines (Healy, 2002, 2004; Rasmussen, 2008). Fourth, the moderate use of some drugs is not harmful to users and may indeed be beneficial. Alcohol used in small quantities, for example, may improve mental and physical health in middle aged adults whereas regular use to intoxication by young adults contributes to the major social harms that alcohol use causes. The regulatory challenge is to capture any benefits of such use while minimising the harms among heavier users and enabling users to develop social rules to regulate use in ways that achieve these ends. 13.5.

The future of drug regulation

The most draconian form of drug regulation is prohibition in which all but medical use is prohibited on pain of imprisonment. This policy has been advocated by Fukuyama (2002) who proposed that the state ban the use of all enhancement technologies. He also advocated national and international bans on some enhancement technologies (e.g. reproductive cloning and genetic engineering whose ‘enhancements’ will be transmitted to descendants) and very tight government regulation of the few biotechnologies that were not banned. It would seem that a well-known champion of liberal capitalism and the free market has seemingly become a reluctant advocate of state regulation. Stock (2002), by contrast, believes that a free market is the best way to solve any problems that may be caused by enhancement technologies. Bans and regulations, he argues, will not stop these technologies from being developed because they are natural consequences of cutting edge research. They will be developed in societies such as China (which has heavily invested in biotechnology) whose leaders do not share the ethical concerns of developed societies like the US, Europe and Australia. Bans and regulations, Stock argues, will also exacerbate the problems of access and safety. They

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will ensure unequal social access to these technologies because the rich will be most able to evade the bans by going off shore; they will prevent us from learning about the risks of the technologies in a timely way because any adverse effects will be hidden; and they will lead to poor quality control when drugs are illegally produced in underground markets or in countries that do not impose strict regulation of the production of medications, as has happened with online pharmaceutical websites. Stock accordingly advocates allowing the use of these biotechnologies so that any harm that they cause becomes apparent sooner than it would if they were developed secretly. Our experience with the regulation of addictive substances suggests that prohibition will reduce but not eliminate the use of enhancement technologies (Hall and Lucke, 2010a). Any such reduction in their use will come with social costs. Foremost among these will be the creation of a black market if there is unmet demand for the product and a substantial minority of the population rejects the ban. A ban is also a maximally coercive and paternalistic policy that requires strong justification, given the strong support for free markets in most other areas of commerce. Experience with alcohol shows that a regulated legal market can reduce use (Babor, et al., 2003). The imposition of government taxes on these commodities can discourage use and the revenue generated from taxation can be used to fund interventions that reduce harm (e.g. tobacco cessation) (Cook, 2007; MacCoun and Reuter, 2001). Restrictions on sales and access by minors reduce but do not eliminate use. So does minimising the ready availability of the product and reducing opportunities to use, as has happened with cigarettes in countries that have imposed significant restrictions on where they may be smoked. A regulated market like prescribed pharmaceuticals is a medical model of regulation. This would involve the use of the existing regulatory methods to assess safety and efficacy and provide consumer protection against doubtful claims (Farah, et al., 2004; Greely, et al., 2008). The medical profession would become the gatekeeper to accessing these technologies via prescriptions and the group that assessed their safety and efficacy. One challenge would be in ensuring that the independence and credibility of the medical profession was not impaired by financial ties to the emerging enhancement industry, as has arguably occurred in the case of pharmaceuticals for the treatment of depression (Healy, 2004). There also needs to be an ethical debate within the medical profession about whether they should be involved in prescribing pharmaceuticals for enhancement purposes, and if so, in what ways (Hotze, et al., 2011). Some

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medical professions have already begun to anticipate such developments, producing ethical guidelines for the prescription of psychopharmacological enhancers (Larriviere, et al., 2009). The explicit and widespread prescription of medications to those who are not ill would be seen by some as lying outside the traditional ethics of medical practice. Others would argue that such practices have already occurred in the history of the oral contraceptive and use of hormone replacement therapy to improve well-being (Lucke, et al., 2011a; Lucke, et al., 2009), and are already commonplace, such as the ready prescription of sleeping pills to overcome jetlag (Chatterjee, 2007). Given this, it is important that debate about the role of general practitioners is transparent and open to ensure that harm can be minimised (Hotze, et al., 2011). 13.6.

Conclusion

Neuroscience research has the potential to benefit people with mental disorders by improving our understanding of the causes of these disorders and improving their treatment. It may also create new drugs that enhance human cognitive performance and mood in people who do not have disorders. The prospect of neuroenhancement use of these drugs raises ethical concerns. These include: consequentialist concerns about the safety and efficacy of neuroenhancement; the possibly coercive use of these technologies; issues in ensuring equitable access to the technologies; and concerns about the implications of neuroenhancement for our understanding of ourselves as persons. The development of sensible regulatory and other policies towards neuroenhancement has much to learn from experiences with the regulation of psychoactive substances. The challenge will be in avoiding the issue being presented as a false forced policy choice between legal prohibition and a free market in neuroenhancement. We need to examine a broader range of options that may include adapting the existing regulatory apparatus for therapeutic drugs to the regulation of new forms of neuroenhancement that may emerge.

Part 4

The Future of Addiction Research and Policy

14 The social and policy implications of addiction neurobiology

14.1.

Introduction

Neuroscience research does not occur in a social or moral vacuum. There are a range of factors that drive how neuroscience research is undertaken, understood and applied. While most of the interest in neuroscience research has focused on its potential to improve addiction treatment, policy makers, scientists and health care professionals also need to consider the possibly wider social and public policy consequences of neuroscientific research. They will also need to anticipate and respond to the potential misuse of neuroscience research by the alcohol, tobacco and gambling industries whose primary goal is to promote the use of their products. These applications have the potential to significantly affect: the ways that drugs are regulated, restricted or provided to the community; the types of treatments for addiction that are provided and how they are accessed; the types of addiction research that are funded; the portrayal of addiction and drug use to the public via the popular media; and the ways in which the public and policy makers think about drug use and addiction. 14.2.

Implications for public health policies towards drug addiction

As described in Chapter 2, there has been a long running conflict between moral and medical models of addiction (Gerstein and Harwood, 1990). A moral model of drug use sees it as a largely voluntary behaviour in which people freely engage. Drug users who offend against the criminal code, on this view, are therefore to be prosecuted and imprisoned if found guilty (Heyman, 2009; Szasz, 1975). A medical model of addiction, by contrast, recognises that while many people can use drugs without losing control over their use, a minority do struggle to manage their drug use and develop a

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mental or physical disorder – an addiction – that may require treatment if the sufferer is to become and remain abstinent (e.g. Leshner, 1997; Volkow and Li, 2004). Neuroscience promises to resolve this debate by providing causal explanations of addictive behaviour in terms of changes in brain processes. If accepted, such causal accounts undermine the simple view that the use of addictive drugs is a matter of individual choice and hence that drug users are best dealt with by punishment and imprisonment. According to its proponents, the brain disease model will lead to changes in social and public health policies towards addiction that will have the dual benefits of providing more humane and ethical responses to addiction, as well as more effective treatment for addiction and drug-related harm (Dackis and O’Brien, 2005; Leshner, 1997; McLellan, et al., 2000; Volkow and Li, 2004). These benefits include: • • • • • •

Less reliance on expensive punitive policies More funding of addiction research and treatment services Greater access to treatment for those who are addicted Increased coverage of addiction treatment by insurance companies Greater investment in addiction treatment R&D Decreased stigmatisation of addicted persons that will decrease social isolation and encourage treatment seeking.

Despite over a decade of active promotion of the ‘addiction is a brain disease’ view by the Directors of NIDA, these benefits have yet to be realised. Addiction researchers, especially social scientists working within the addictions field, have also highlighted some potentially less welcome effects of neuroscience models of addiction on social and public health policy (Carter and Hall, 2007b; Midanik, 2006; Room, 2007). They argue that neuroscience research can overemphasise biomedical approaches to the treatment of addiction – that is medicalise addiction – at the expense of psychosocial policies that aim not only to treat addiction, but also to reduce drug use in society. These factors may affect the range of treatments that addicted individuals can choose from and their beliefs about how hard it is to cease using drugs, and how best to do so. We discuss these concerns below. 14.3.

Medicalisation of addiction

Medicalisation is the process whereby behavioural or social problems are explained as medical disorders that should be treated therapeutically. Some critics believe that a focus on the genetic and neurobiological basis of

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behaviour will lead to a ‘medicalisation’ of stigmatised forms of behaviour including addiction (Ashcroft, et al., 2007; Conrad, 1992; Midanik, 2006; Press, 2006; Verweij, 1999). These commentators argue that medicalisation leads to an overemphasis of the biological origins of behaviour at the expense of social and psychological explanations. They also believe that medicalisation will adversely affect people who engage in stigmatised forms of behaviour like smoking or other drug abuse (Caron, et al., 2005; Room, 2005). If addictions are seen as simply neurobiological disorders that reflect genetic predispositions, these critics argue that society may rely on medical interventions at the expense of broader social approaches to prevent or reduce drug use and addiction (e.g. high taxes, restrictions on sale and access to drugs) (Carlsten and Burke, 2006; Caron, et al., 2005; Merikangas and Risch, 2003). The use of medical interventions to address social problems has been pejoratively referred to as a ‘technological fix’ (Nelkin, 1973). The term was first used in its more literal sense by the scientist Alvin Weinberg in the 1960s to describe quick and inexpensive medical solutions to difficult social problems (Watkins, 2010). Similarly, some scholars use medicalisation in a more positive sense to describe the increased use of effective medical treatments by those who were previously denied access, either for social or scientific reasons. Critics of medicalisation argue that it may undermine addicted individuals’ preparedness to cease drug use if they believe that their addiction is the result of their neurobiological and genetic traits. This is often referred to as fatalism (Alper and Beckwith, 1993). More evidence is needed to evaluate the validity of such claims. It could be argued, for example, that addiction neuroscience encourages individuals to seek treatment or empowers them to make choices not to use drugs (Condit, et al., 2006). The existence of an authoritative scientific explanation of addicted individuals’ experiences might increase their willingness to engage in medical treatment (Hall, et al., 2008). In the interim, information about ‘addiction genes’ and ‘neurochemical imbalances’ should be carefully communicated to avoid undermining addicted individuals’ belief in their capacity to stop using drugs, or their willingness to try. The medicalisation of addiction also raises the question: should drug policies treat differently those who come from different socio-economic backgrounds or have greater genetic or neurobiological vulnerabilities to addiction? An inappropriate emphasis on genetic predispositions and social triggers could undermine health and social responsibility. Social policies need to appropriately acknowledge and balance the social, genetic and environmental causes of, and solutions to, addiction. Drug using and addictive

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lifestyles often (but not always) go hand-in-hand with poverty and low social status. Both the medical and moral models raise the possibility of targeting at-risk individuals or communities, rather than addressing the social environments that may increase the risk of addiction. As we discuss below, one concern is that ‘brain disease’ explanations of addiction are more likely to shift the focus away from social approaches. Critics also argue that the medicalisation of addiction could change the ways in which society thinks about and responds to drug use and addiction (Backlar, 1996; Caron, et al., 2005). Medicalisation could, for example, stigmatise those who are vulnerable to addiction, such as those that possess particular genetic alleles or mutations, are positive for genetic markers associated with drug abuse (Caron, et al., 2005) or display particular patterns of neural activation (Carter, et al., 2009). On this view, neuroscience and behaviour genetics could exacerbate institutionalised discrimination, particularly by courts, educators and employers, and health and life insurers. These forms of discrimination could also amplify more informal modes of stigmatisation (Anderlik and Rothstein, 2001; Billings, et al., 1992; Geppert and Roberts, 2005; Greely, 2001; Hall and Rich, 2000) that are recognised as primary barriers to the access of effective treatment of addiction and mental illness (Pescosolido, et al., 2010; Sartorius, 2010). It is not clear how realistic these fears may prove to be, but they deserve to be further investigated (Bennett and Smith, 2007; Caron, et al., 2005; Condit, et al., 2006). 14.4.

Neuroscience, addiction treatment and public health policy

There is a concern among some public health professionals that neurobiological explanations of addiction narrow the field’s focus to biomedical treatment of severely addicted persons at the expense of psychosocial support for addicted individuals to work their way out of their situation. While the neurobiological changes in the brain are an important factor in the maintenance of addictive behaviour, treatment of addiction requires a multifaceted ‘whole-of-life’ approach that combines neurobiological reduction of the symptoms of addiction and psychological tools and social support to improve addicted individuals’ capacity to make affirmative choices that improve their quality of life, and motivate them to choose a more socially adaptive lifestyle. Psychosocial approaches to overcoming addiction are less seductive to funding agencies, the media and the general public than technological fixes. It is also cheaper and more attractive for governments to fund research that promises to ‘cure’ a ‘disease of addiction’ than to address the social drivers of

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addiction, such as poverty, lack of education and social isolation (Kleiman, 1992). Psychosocial projects that aim to provide a ‘whole-of-life’ approach to addiction, such as ‘Parents under Pressure’ (http://www.pupprogram.net.au/), are more intensive and require long-term investment and commitment by participants. Many believe that it is these sorts of intensive psychosocial interventions that are required to overcome addiction, preferably with psychopharmacological or neurobiological support. It will be critical that policy makers avoid being seduced by the allure of high-tech approaches at the expense of psychosocial methods that create the necessary conditions for successful treatment. Neuroscience is likely to not only affect the clinical treatment of addiction, but also social policy and addiction research. We discuss these below. 14.4.1.

Competing population health strategies

Predictive genomic medicine and neurobiological ‘cures’ of addiction promise high-tech strategies that target interventions at individuals who have been identified as being at the highest risk of developing, or who have already developed, an addiction (Collins, 1999). Social scientists and public health professionals are concerned that premature adoption of such approaches (e.g. genetic screening and drug vaccination, deep brain stimulation) may be at the expense of more broadly effective population health policies (Haga, et al., 2003; Rose, 1992). Population health policies aim to reduce the use of drugs of addiction either by banning their use (in the case of controlled drugs like cannabis, heroin and cocaine) or by reducing access to legal drugs such as alcohol and tobacco by imposing high taxes on them and restricting who can use them (e.g. by imposing age limits) and where they can be used (e.g. banning use in many public places) (Room, 2007). These policies affect the whole community, not just those who are drug-dependent or at risk of becoming so. Population-based tobacco control strategies, such as taxing cigarettes, advertising bans and restricting the areas where people can smoke, have halved cigarette smoking rates in Australia (White, et al., 2003) and the US (Pierce, et al., 1998) over the past three decades. These population-based strategies are more efficient than high-risk strategies (Rose, 1992; Vos, et al., 2010), because fewer resources are needed to increase taxes on tobacco products, ban cigarette advertising and restrict opportunities to smoke than are needed to screen whole populations to identify and intervene with the minority who are at high genetic risk of becoming nicotine-dependent or developing tobacco-related

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diseases, if they smoke tobacco (Hall, et al., 2002). There are similar arguments for the greater efficiency of population-based strategies in reducing risky alcohol use (Doran, et al., 2010). These may include: increased taxes on beverages with a higher alcohol content, setting a floor price for alcohol beverages, reductions in the promotion of, and decreased availability of alcohol (Doran, et al., 2010). The concept of addiction as a brain disease could be used to promote the use of high-risk approaches, that is, those aimed at individuals at high risk of addiction. Such a model lends itself to a seductive simplification, often promoted by the alcohol and tobacco industries: we should attempt to identify the minority of drinkers and smokers who are genetically or neurobiologically vulnerable to developing an addiction so that the rest of the population can drink and smoke with impunity (Hall, 2002). This view ignores the adverse public health effects of alcohol intoxication and cigarette smoking, and it is at odds with the dimensional nature of drug use and the symptoms of dependence. It also misrepresents genetic and neuroscientific evidence. Multiple genes are implicated in addiction, each of which is weakly predictive of an increased susceptibility to develop alcohol and other types of dependence (Gartner, et al., 2009; Hall, et al., 2002). Also, the neuropsychological changes identified with addiction are not seen in all addicted individuals (see Chapter 6). As we discuss below, this view is popular with the alcohol and tobacco industries who oppose population level policies that may reduce alcohol and tobacco use. 14.4.2.

Subversive uses of neuroscience research on addiction

There is a risk that an overemphasis on the neurobiology of addiction could result in a drop in investment in psychosocial and population-based research to reduce drug use and harm. Midanik (2006) argues that the medicalisation of alcohol research in the US has shaped the funding priorities of the NIAAA in favour of neurobiological research on alcohol use for more than a decade (see Figure 14.1). It is not only governments that are investing heavily in neuroscience research. The Alcoholic Beverage Medical Research Foundation (ABMRF), an organisation funded by several large alcohol companies from the US, proudly boasts that it is ‘the largest, independent, non-profit foundation in North America devoted solely to supporting research on the effects of alcohol on health and behaviour and on the prevention of alcohol-related problems’ (http://www.abmrf.org/about_us.asp). The majority of its substantial investment is in neurobiological research. While potentially providing new

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160 000 000

140 000 000

Biomedical + Neuroscience Biometry and Epidemiology

120 000 000

Treatment Research Branch Prevention Research Branch

US dollars

100 000 000

80 000 000

Health Services Research Centers Program and Special Programs

60 000 000

40 000 000

20 000 000

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Figure 14.1. NIAAA Research grant awards by branch/division, 1990–2002. Dollars adjusted for inflation. (Reproduced with permission from Midanik, 2006, p. 108).

treatments, this focuses policy attention on the neurobiological causes of addiction, strengthening the view that addiction is a brain disease, and potentially reducing funding for population health approaches to reducing drug use and harm, and research into improving the under-resourced treatment and social support initiatives for alcohol problems. The alcohol, tobacco and gambling industries are predictably opposed to population-level approaches to reducing drug use. Reduced per capita consumption of their products means reduced industry profits. Public health professionals are concerned about the potential misuse of neuroscience research by industries that wish to promote and maintain the sale and consumption of harmful products. Such an approach is not without precedent. The history of tobacco policy indicates that companies that profit from the sale of addictive products will oppose or undermine public health policies that seek to reduce the use of their products (Brandt, 2007; Gundle, et al., 2010; Oreskes and Conway, 2010). Analyses of industry documents demonstrate that this is why the tobacco industry funded behavioural and molecular

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genetic research on smoking and tobacco-related disease in the 1970s and 1980s (Gundle, et al., 2010). They realised that by locating the risks of smoking in the genome of the individual smokers, tobacco would be seen as less of a cause of disease. Genetic and behavioural research helped the tobacco industry argue the case that the cause of addiction was not the addictive and harmful product, but the ‘diseased’ individuals who consumed them. The alcohol industry has also promoted the idea that alcohol-related problems are confined to a minority of genetically and neurobiologically vulnerable drinkers (Hall, 2005a). The policy implication drawn by the industry is that alcohol problems are better addressed by identifying and intervening with problem drinkers rather than adopting effective strategies for reducing population-level alcohol consumption, such as increased taxation and reduced availability of alcohol (Babor, et al., 2010). The gambling industry, facing similar environmental restrictions in some countries (e.g. mandatory precommitment and maximum betting), has begun to heavily fund research into the genetics and neurobiology of problem gambling (Vrecko, 2008), presumably for similar strategic reasons. Industry funding also has the potential to influence the scientific evidence base behind addiction. For example, Chapman and MacKenzie (2010) have argued that pharmaceutical industry funding of drug-assisted tobacco cessation has promoted the prevailing, and they believe erroneous, view that unassisted smoking cessation is difficult. The tobacco industry has already demonstrated its willingness to use and fund scientific research to raise doubts about tobacco-related harm in the eyes of politicians, policy makers, journalists and the public, where in fact there was largely a scientific consensus (Oreskes and Conway, 2010). These industries are adept at utilising public relation companies, contrarian scientists, and the media to manipulate debates, knowingly misusing scientific evidence and creating spurious ‘controversies’ about the harms caused by their products. Similar industry uses of neuroscience research should be anticipated and pre-empted. What can be done to minimise the effects of any undue influence by industry? We provide the following observations: • These experiences should provide a powerful disincentive for addiction neuroscientists to accept funding from the tobacco, alcohol and gambling industries. Neuroscientists need to understand that while industry may express the wish to reduce the harm caused by their products, they will strongly resist ways that do so by reducing population-level use of their products, and hence their profits.

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• In the event of such misuses of neuroscientific research for commercial and other non-scientific goals, neuroscientists should be prepared to speak out. • Neuroscientists should also support public health advocates in highlighting the need for governments to fund other types of addiction research that may be in greater need of funding. • Journalists and the public need to understand the motivation of the addictive industries and be mindful of previous tactics they have employed. Journalists are justified in being sceptical about industry-funded research and should avoid regurgitating industry press-releases. 14.5.

Drug policy and double standards

Neurobiological research on drugs and addiction also raises subversive questions for drug policy. There is no obvious neurobiological justification for the fact that alcohol and tobacco are legal while heroin, cocaine and cannabis are not. The legal status of these drugs is not correlated in any simple way with their effects on brain neurochemistry (Ashcroft, et al., 2007; Nutt, et al., 2007a). Nor does the legal status of these drugs reflect the relative harms caused by their current use, even after we take account of the much lower rates of problem use of illegal drugs that may be attributed in part to their prohibition (Hall, et al., 1999; Nutt, et al., 2007a). Neuroscientists with Millian liberal political views (e.g. Blakemore, 2002; Iversen, 2002) see their research as facilitating more consistent policies towards licit and illicit drugs that reflect their relative harmfulness. Yet policies towards different drugs are moving in very different directions and for reasons that have little to do with addiction neuroscience. Tobacco policies in many developed countries have become much more restrictive, but only after half a century of anti-smoking efforts, and despite the concerted opposition of the tobacco industry (Rabin and Sugarman, 2001). Alcohol policy, by contrast, has been deregulated in Britain, with increased trading hours, reduced alcohol price and heavy promotion to young adults (Room, 2007), with predictable increases in casualties among young adults and adverse effects on social amenity in many UK cities (Hall, 2005a). Liberal government policies have also expanded access to gambling with predictable effects on the prevalence of problem gambling (Orford, 2011; Productivity Commission, 2010). Experiences over the past century do not encourage optimism that addiction neuroscience research will produce radical changes in international policies towards illicit drugs. The most widely adopted form of liberalisation

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has been the decriminalisation of cannabis. Under this policy it remains illegal to produce or supply cannabis but fines or other non-criminal penalties are imposed for possession and/or use of quantities of cannabis up to a specified maximum amount. Persons possessing larger quantities of cannabis may still face criminal charges. The main argument in favour of decriminalisation is that it reduces some of the societal costs of cannabis prohibition while retaining most of its benefits (Hall and Pacula, 2003; Room, et al., 2010). Since the mid-1980s, several Australian states and territories have legislated to replace criminal penalties for cannabis use with fines (referred to as expiation). Studies have shown that cannabis use rates in Australian states that decriminalised its use did not differ from those that did not (AIHW, 2008; Ali, et al., 1999; Donnelly, et al., 1995; Williams, et al., 2001). The Australian experience largely replicates analyses of survey data in the US in the 1970s and 1980s, and Italy, Portugal and England in the 1990s and 2000s (Room, et al., 2010). The negligible impact of cannabis decriminalisation can probably be explained by two factors: (1) there is little difference between states that do and do not enforce criminal penalties; and (2) the risk of arrest for cannabis use is so low (typically only 2% of persons who used cannabis in the past year) that the criminal penalties provide little deterrent against use (Hall and Pacula, 2003). A legal cannabis market would allow the cultivation, production, distribution, wholesale and retail sale, promotion and advertising of cannabis to adults. There are no legal cannabis markets anywhere in the world because UN treaties preclude it (MacCoun and Reuter, 2001; Room, et al., 2010). However, a number of countries have experimented with policies that have allowed limited de facto retail cannabis markets. In the Netherlands since 1976, a written policy of non-enforcement has made it de facto legal to possess and sell up to 30 grams of cannabis while the country officially retains a prohibitionist policy against cannabis (Korf, 2002; Room, et al., 2010). Prosecutors and police refrain from enforcing the law when the quantity possessed or sold does not exceed 30 grams and when sales occur in licensed coffee shops (MacCoun and Reuter, 2001). In the 1990s, the government limited the number and location of coffee shops and in 1995 it reduced the quantity of cannabis that could be legally sold to 5 grams (Korf, 2002). Policy analysts have disagreed about whether the coffee shop system has affected rates of cannabis use in the Netherlands (Room, et al., 2010). MacCoun and Reuter (1997; 2001) compared survey data on cannabis use in the Netherlands, US, Denmark and Germany. They concluded that

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removing criminal penalties for use in the Netherlands had little effect on cannabis use until 1992. However, increased access to cannabis via coffee shops between 1992 and 1996 was associated with increased rates of cannabis use by young people. Korf (2002) challenged MacCoun and Reuter’s analysis, arguing that trends in cannabis use in the Netherlands, other European countries and the US were unrelated to changes in policy and simply mirrored similar changes in cannabis use that occurred among youth in all these countries. The major problem with Dutch cannabis policy is the ‘back door problem’, namely, that retail cannabis sales are legal out the front door of coffee shops, but the supply of cannabis through the back door remains illegal (Room, et al., 2010). The ‘obvious’ solution, according to critics of cannabis prohibition, is to legalise the cultivation and sale of cannabis, as advocated by those who want drug policy to be better attuned to the harms that different drugs cause (e.g. Kisely, 2008). There are a number of major social and political obstacles to a legal cannabis market in developed countries (Hall, 2008). First, international drug control treaties prohibit the legalisation of cannabis for recreational use. These treaties have strong support in the international community (particularly in the US) and are also supported by public opinion in most developed countries. Any country that legalised cannabis would have to renounce these international treaties and bear the strong international and public disapproval that would follow (Room, et al., 2010). Second, public support for cannabis law reform (which has generally been in the minority) has declined during the early 2000s, probably because of stronger evidence that cannabis use can harm some users (Matthew-Simmons, et al., 2008). In Australia (and many other developed countries) the cannabis policy debate has often been simplified by the media to a choice between two cognitive policy short hands: (1) we should legalise cannabis, or at the very least decriminalise its use, because its use is perceived as harmless; or (2) we should continue to prohibit its use because it harms some users (Hall, 1997a). Given this simplification, evidence that cannabis use can harm some users has been seen as strengthening the case for prohibition (Hall and Degenhardt, 2009; Hall and Pacula, 2003). This occurred in the UK when evidence on cannabis use and psychosis was used as the reason for reinstating criminal penalties for cannabis use in 2009 that had been removed in 2004. A different route to legalising cannabis sales has been followed in California. In 1996 a citizen-initiated referendum, Proposition 215, was passed by 56% to 44%. This allowed the ‘medical use of marijuana’ for a liberal set of ‘indications’ that included not only nausea, weight loss, pain and muscle

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spasm (for which there was some evidence of efficacy) but any ‘serious medical condition’ that a doctor believed could be relieved by marijuana (Gieringer, 2003). Proposition 215 (and similar referenda later passed in other US states) created a number of problems. First, these state laws conflicted with US Federal law that banned the use of cannabis for any purpose (Barnes, 2000). Second, is the problem of securing a legal supply of cannabis. This was solved in California by Cannabis Buyers’ Clubs that sold cannabis to patients who had a doctor’s ‘prescription’ (Pacula, et al., 2002). In the absence of a legal cannabis supply, these clubs obtained their cannabis from the illicit market. The US Supreme Court ruled in 2001 that persons who sold or supplied cannabis for medical use were not protected from Federal criminal prosecution by state laws. The Bush administration attempted to enforce Federal laws but the Obama administration decided not to do so in states that allowed the medical use of cannabis. There have been no formal evaluations of Californian policy. The age and sex of medical cannabis users suggests that they are unlikely to have had cancer or neurological diseases. In one study a substantial proportion of such users reported using cannabis as a substitute for alcohol and illicit drugs (O’Connell and Bou-Matar, 2007). Despite these policy experiments, there is good reason to doubt neuroscience will resolve drug policy debates in such a politically and morally saturated area. If anything, addiction neuroscience research is more likely to be used to justify a continuation of current policies. It could also conceivably be used to justify even more restrictive policies towards illicit drugs in the interests of preventing adolescents from acquiring a ‘chronic brain disease’ or significant cognitive impairments identified by neuroscience research. 14.6.

The prospects of novel pharmacological harm reduction: engineering ‘safer’ recreational drugs?

A less radical potential benefit from neuroscience research on addictive drugs is the development of new forms of recreational drugs that eliminate or significantly minimise the harmful effects of currently abused recreational drugs. The development of safer alternatives for alcohol was proposed by Professor David Nutt (2006). Nutt has asked two questions. Firstly, can we make alcohol safer? And secondly, can we use pharmacology and neuroscience to engineer a safer alternative to alcohol?

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The answer to the first question is clearly ‘yes’. We can make alcohol safer by encouraging drinkers to consume less alcohol per occasion. That goal can be accomplished by imposing lower taxes on lower alcohol beverages or a volumetric tax on alcoholic beverages (Babor, et al., 2003). There may also be pharmacological methods of reducing alcohol-related harm. One suggestion is to use drugs to prevent the memory loss associated with alcohol intoxication (Nutt, 2006). Acamprosate, which reduces glutamate activity, could also be given to chronic drinkers to reduce the glutamatergic neural toxicity associated with withdrawal each morning following a late night of drinking. Researchers have recently identified an antioxidant, Tempol, which can reduce the oxidative neural damage associated with chronic cocaine use (Numa, et al., 2008). As researchers identify the neuropharmacological basis for the harms of chronic drug use, there may be an increase in the demand for pharmacological harm reduction treatments that are not substitution based. On the second question, David Nutt persuasively argues that it would be technically possible to develop a water soluble GABA agonist that possessed most of the socially desirable properties of alcohol with less biological toxicity. This is not a new suggestion. Attempts have been made to introduce alcohol-like drugs in the recent past. During the 1930s, two products were promoted to the public as non-intoxicating alternatives to alcohol: prescription brand whiskey and RMS private formula. These products were quickly removed from the market and the company fined when it became apparent that they simply contained alcohol (Helfand, 1996). Thalidomide was also marketed in Britain by Distillers, an alcohol beverage manufacturer, because its directors thought that it might be an ‘ideal tranquillising agent to replace alcohol among those people who would prefer to ‘transform their minds’ by this alternative means’ (Knightly, 1979, p. 43). If we assume that the scientific hurdles for creating a non-toxic and less addictive form of alcohol were surmountable, the major obstacles to any such product being introduced and marketed are likely to be social, ideological and regulatory. This is true for any of the ways in which such a drug may be introduced into developed societies; whether being approved for use as a therapeutic drug, or being manufactured and distributed by freelance psychopharmacologists. There are major doubts about whether the pharmaceutical industry will invest the substantial funds needed to undertake preclinical and clinical R&D on such a drug, and sponsor the drug’s passage through pharmaceutical regulatory systems, such as the FDA (Ragan, 2007). The regulatory system is also likely to discourage any attempt to introduce such a drug as a harm

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reduction intervention in alcohol-dependent patients. Experience with substitute prescribing for nicotine dependence reveals a perverse regulatory double standard: the pharmaceutical regulatory system insists upon much tighter regulations for the least harmful nicotine products (e.g. low nitrosamine smoked tobacco, or snus) than are imposed on the far more dangerous smoked tobacco products (Stratton, et al., 2001). These regulations provide major disincentives to pharmaceutical harm reduction approaches. The prevailing regulatory philosophy seems to be that a patient’s health is less important than their being drug-dependent, even if this means being dependent on a much less hazardous drug or using a drug in a much less harmful way. Safer recreational drugs may emerge as a by-product of basic pharmacological research or they may be approved for therapeutic use for an unrelated indication, in which case their desirable properties may be discovered by amateur psychopharmacologists. If these drugs prove relatively easy to produce using widely available precursors, then recipes disseminated via the internet may be used for home production, as has happened with GHB (or gamma-hydroxybutyric acid) (Gahlinger, 2004). The experience with GHB suggests that if this were to happen the first regulatory impulse would be to ban the drug by making it a criminal offence to produce, sell or use it. This outcome would accord with the conservative regulatory climate in the US and other developed countries such as Australia, Canada and many European nations, which has ensured that no new recreational substance has been approved for unregulated use in well over a century (McAllister, 2000). These major social and regulatory challenges do not invalidate the merit of searching for a ‘safer tipple’ (Hall, 2006a). It is an idea well worth discussing. A wider public discussion of the possibility may be beneficial even if only for its educational value in reminding citizens in developed countries that: alcohol affects brain chemistry in the same way as many prohibited drugs; it is an extremely toxic substance when used to excess, as it so often is; and it is a major cause of violence, injury and social disorder, especially among young adults. 14.7.

Conclusions

The two major potential benefits to be gained from an improved understanding of the neuroscience bases of addiction are improved treatment and, possibly, the prevention of drug addiction. Neuroscience research on addiction, however, is unlikely to reduce the importance of public health drug control policies or the need for psychosocial initiatives. It is much simpler,

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cheaper and more efficient to discourage the whole population from smoking tobacco, for example, than it is to attempt to make smoking safer by identifying those at highest risk of nicotine addiction or smoking-related disease. The same is arguably true for alcohol and illicit drugs. The challenge for the addiction neuroscience community is to explain addiction in ways that give biology its due without depicting addicts as automatons under the control of receptors in their brains (Carter, et al., 2009; Hyman, 2007). This means seeing addiction as the result, in part, of choices that are made by individuals. It will also mean seeing loss of control over drug use as a matter of degree, with dependent drug users retaining the capacity to choose to become abstinent and to seek help to do so. It would be wise to encourage the community to see pharmacological drug treatments as prostheses for an impaired will, a kind of Ulyssean self-binding against temptation, rather than as the sine qua non of addiction treatment. Pharmacological treatment is only the beginning of the process of recovery and reintegration of the drug-dependent person into the community that will require attention to a broader range of social policies in seeking to prevent drug use by our youth (Room, 2007).

15 Concluding remarks and summary

15.1.

Introduction

This book represents a systematic attempt to map the ethical issues that are likely to be raised by neurobiological research on addiction, specifically, its implications for: how we understand and think about addiction; the ways in which we may undertake research on addiction; and the ways in which we use promising emerging neurotechnologies to treat and prevent addiction. We summarise some provisional conclusions from our survey and highlight areas in need of further investigation. 15.2.

Summary and conclusion

A major attraction of neuroscience explanations of addiction is their potential to reduce scepticism about the ‘reality’ of addiction. By highlighting the neurobiological changes that focus the attention of addicted persons on drug taking and make it more difficult not to use drugs, a neuroscience-based understanding of addiction may lead to more humane and effective treatment of those with an addiction. If addiction comes to be seen as a ‘chronic and relapsing brain disease’, then, some have argued, imprisonment may be replaced by greater access to more effective forms of medical treatment, including agonist replacement therapy, that are covered by medical insurance (Dackis and O’Brien, 2005). A more balanced appraisal of the implications of addiction neuroscience must also consider some less welcome potential uses of a neurobiological model of addiction. Failure to do so could lead to unnecessary harm, community scepticism about the validity or usefulness of neuroscience research, and delays in the translation of research into clinical practice. It is these less welcome uses that we have attempted to draw to the attention of ethicists, addiction

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neuroscientists and geneticists, clinicians and carers, policy makers, and the public more generally. It may seem at times that we are being overly critical of the benefits that neuroscience research on addiction offers. It is because of our belief in the potential benefits of addiction neuroscience that we seek to ensure that these benefits are realised with a minimum of adverse side-effects. There is no shortage of proponents of addiction neuroscience willing to argue its potential to transform addiction treatment and policy. What is needed is a more balanced and critical appraisal of the hurdles in translating the potential of neuroscience into achievable outcomes. Such an analysis is critical in the field of addiction where various political, commercial and ideological interests seek to use scientific research to influence policy. Statements that drug use ‘hijacks’ the brain, for example, have been used by some bioethicists to justify claims that individuals with an addiction lack the ability to make wilful and autonomous decisions about the consumption of their drug of addiction (Charland, 2002; Cohen, 2002); in Charland’s words, ‘[t]heir decision is not truly theirs’ (Charland, 2002, p. 43). While we believe that such simple interpretations of the neuroscience of addiction are misplaced (see Chapter 6), if they were accepted by ethical review boards, for example, they would prevent important addiction research from being conducted (Carter and Hall, 2008b). It could also be seen as giving warrant to policies that coerce addicted persons into receiving neurobiologically based forms of treatment (Hall, et al., 2004a; Hall and Lucke, 2010b). The history of the treatment of addiction has demonstrated that ‘drug addicts’ and their families can be exploited by unscrupulous practitioners for professional, moral or commercial purposes. Neurobiological rationales for treatment can lend a spurious scientific credibility to ineffective treatments. The promotion of UROD – opioid detoxification conducted under general anaesthesia – as a neurobiologically based ‘cure’ for heroin addiction, provides a poignant example of how addiction neuroscience can be used to exploit a vulnerable and desperate population (Hall, 2000). The fact that the treatment was presented as a ‘cure’ gave patients the unrealistic expectation of the long-term efficacy of the treatment, while also reducing their opioid tolerance and thereby increasing their risk of overdosing when they returned to opioid use, as the majority did. A more recent example of the questionable use of addiction neuroscience has been the neurosurgical treatment of heroin addiction in China and Russia (Hall, 2006b). Neuroscience research on the effects of chronic drug use on the nucleus accumbens has been used to justify the stereotactic ablation of this

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‘diseased organ’. This procedure has been implemented with little thought for unintended side-effects of the procedure, or for the capacity of patients to give free and informed consent in a society where ‘addicts’ are routinely imprisoned. The view of addiction as a ‘disease’ could also lead to some unwelcome uses of neurotechnologies to prevent addiction. Genetically and socially vulnerable adolescents may be vaccinated against the effects of drugs such as heroin, cocaine and nicotine (Hall and Carter, 2004). Genetic tests of purported vulnerability to addiction have already been marketed directly to the public, with little communication of the complexity of the genetic basis of addiction (Sherman, 2006). The same has been true for genetic tests, such as NicoTest, that purport to tailor cessation treatment to individuals. Not only are these strategies likely to be ineffective or ethically problematic approaches to preventing drug dependence, but their use is likely to be at the expense of more prudent, less costly and broadly effective social policies that address the problem of drug use by all members of society. The rhetoric of ‘disease’ may also lead to a focus on pharmacological strategies for ‘curing’ addiction rather than on broader social policy measures that reduce the harm of drug use across society, such as: educating the public about the consequences of drug use, irrespective of addiction; reducing drug availability and opportunities to use harmful drugs; increasing drug prices; encouraging peer disapproval to reduce drug use; and minimising the socioeconomic conditions that increase the likelihood of drug use. The idea of addiction as a ‘brain disease’ could also conceivably be used to justify increased use of treatment under legal coercion (Caplan, 2008; Hall, et al., 2004a). If people who use drugs are unwilling to participate or comply with existing treatments, then it may be argued that they need to be treated against their will, either in their own ‘best interests’, or more commonly, for the protection of the community. Simplistic descriptions of addiction as a neurobiological disease could be used to garner public support for the arguably unethical use of coerced pharmacological treatment. The advent of sustained-release formulations of drug treatments, such as depot naltrexone or drug implants, and drug vaccines, heightens the likelihood of this happening. While treatment of addiction as an alternative to imprisonment may be a useful option under appropriate forms of judicial oversight for those addicted persons who engage in criminal behaviour, the routine coerced treatment of addicted individuals is ethically more contentious. The use of legally coerced treatment of addiction needs to be applied carefully, using due process and with addicted individuals given a choice of treatments, including both

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pharmacological and psychosocial treatments (Hall, 1997b; Hall, et al., 2004). The safety and efficacy of coerced treatments also needs to be properly evaluated. These examples of actual and potential misuses of addiction neurobiology underline the need for more critical ethical reflection on the potential social impact of neurobiological models of addiction. 15.2.1.

Key findings

Neuroscience research of addiction holds the promise of providing a number of novel treatment technologies that may significantly reduce the impact and prevalence of addiction and drug abuse. Addiction is a complex neurobiological, psychological and social disorder. The use of new technologies is complicated, not simply by the complexity of the disorder, but also by the tension between competing social goals: that of treating a neuropsychiatric condition and the goal of protecting society from the harmful behaviour of some drug users. This balance is further complicated by the social and moral attitudes held by many towards those who use and especially those who become addicted to illegal drugs. It is accordingly important to carefully consider the ethical motivation for intervention and the social context in which these technologies are used. Of central importance to this task is a consideration of how neuroscience research of addiction influences our understanding of addiction. Of particular concern is how neuroscience affects our understanding of the autonomous decision-making capacity of addicted individuals. This has important implications for how society attempts to engage or encourage addicted individuals into treatment, particularly those who may not want to be or are ambivalent about being treated. A review of the literature on the neuroscience of addiction reveals that chronic drug use can adversely affect the neurocognitive systems involved in making decisions and controlling behaviour. However, these effects do not abolish the ability of addicted individuals to choose not to use drugs, as the effectiveness of contingency management programs indicates (Higgins, 2006; Marteau, et al., 2009; Stitzer, et al., 1993). While neuroscience does provide a strong justification for medical treatment and intervention, it does not suggest that we should override the autonomous decision-making capacity of the individual, simply because he or she is addicted. The rights of individuals with an addiction should be respected in the same manner as other members of society. The choice of treatments available to addicted persons should be dictated by a need to treat their condition;

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treatment should not be a form of extrajudicial punishment. This is particularly relevant to policy decisions about the use of substitution or replacement therapies where their use may be limited, or provided in ways that are not motivated by a desire to treat addiction. The converse of this argument is that treatments should be provided under conditions and regulations that do not further harm society. Treatments often involve the use of drugs that can cause harm if misused. The implications of these findings are summarised below in ten key ethical themes that have emerged from the book: Theme 1 Neurobiological research on addiction is revealing complex interactions between drugs of addiction, biological responses to drugs and the social circumstances of drug users. As this understanding develops over the next decade, more research will be needed to systematically explore the social and ethical implications of addiction neurobiology, and its application to the treatment and prevention of addiction. Theme 2 Appropriate societal responses to drug use and addiction will need to find ways of giving due consideration to ‘disease’ models of addiction while still acknowledging the social conditions that lead to drug use and the choices that individuals with addictions can still make. Theme 3 Policies towards drug use and addiction need to address both its public health and criminal justice consequences. Addiction is not simply a criminal justice problem or a health care problem; it is both. That is why dealing with addiction is such a complex societal challenge. Responses to addiction may need to include both punitive measures and improved access to addiction treatment. Getting the balance right is the challenge; arguably in many societies the current balance is overly punitive. Theme 4 The autonomy of addicted individuals varies, so due care is required in using medical, paternalistic and criminal measures to control and treat addiction.

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When addicted persons’ autonomy is seriously impaired (e.g. by intoxication or severe withdrawal), it may be appropriate to take paternalistic measures to protect them from harming themselves or others. However, their autonomy is not often or consistently impaired in this way to sufficiently warrant routine use of strong paternalistic interventions that override their wishes. Treatment of addiction should aim to build on and support autonomy, and ensure that consent to treatment is as informed and free as possible. Theme 5 A major challenge for addiction policy and ethics will be finding ways to educate the public about the neurobiological basis of addiction in ways that recognise that drug use and addiction involve changes in brain function, but can still nonetheless be affected by individual and social choices, and the social environment. Theme 6 Strong public interest in neuroscience research on addiction, and the potential for its misuse and misunderstanding in such a politically and morally saturated area as addiction, requires addiction neuroscientists to disseminate their findings responsibly and accurately. This includes anticipating potential misinterpretations and proactively engaging with the media and politicians to minimise common misunderstandings. Theme 7 While many of the prospective developments in neuroscience will support measures of addiction treatment, prevention and monitoring, the potential limitations of a neuroscientific approach also need to be considered. Future policies should continue with those current policies that are successful in treating or preventing drug addiction, while integrating new methods that emerge from addiction neuroscience. Theme 8 All new treatments and preventive interventions for addiction should be rigorously evaluated for safety and efficacy before being introduced into routine practice. We should not allow an understandable fascination with

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neuroscience research findings to allow enthusiasts for new treatments and moral entrepreneurs to subvert or circumvent this requirement. Theme 9 There should be equitable access to treatment that does not disproportionately deny human rights, privacy, consent or liberty in order to satisfy public opinion that is focused on addressing crime committed by addicted individuals. Addicted individuals are already vulnerable, and often live in disadvantaged situations. Their disadvantage should not be compounded by unjustified discrimination and stigmatisation. Theme 10 Drug strategies in most developed nations have to focus on both reducing illicit drug trafficking and dealing with problem drug users. Future developments in addiction neuroscience may assist in reducing the prevalence of illegal drug use and levels of drug dependence while promoting public health and improving social conditions that are associated with drug use. Continuing analysis and debate is required on how novel developments in neuroscience affect current and future policies to ensure that the benefits from any developments in this area deliver maximum benefit, and that potential problems are anticipated and avoided. 15.2.2.

Specific implications for the treatment of addiction

These ethical principles have led to the following specific observations on the use of emerging technologies for the treatment of addiction. These are very much provisional conclusions that have emerged from analyses performed to date. They will need to be updated and revised in the light of subsequent science and policy debates and analyses. Informed consent (Chapter 6): 1 While addiction can impair decision-making capacity in some situations in some individuals, addicted persons maintain some level of autonomous decision-making that should be respected, and, as much as possible, enhanced. 2 Addicted persons should not be asked to consent to a detailed treatment contract or to participate in a research study while intoxicated or in withdrawal. Symptoms should have abated or the person stabilised on an agonist drug.

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3 Physicians and researchers should make every attempt to minimise the risks of participation, and maximise the benefits, of treatment and research. 4 Physicians and researchers should attempt to facilitate and increase patient autonomy. Coerced treatment (Chapter 8): 1 The use of some form of coercion or persuasion may be a legitimate ethical part of addiction treatment. If so, the state needs to fulfil its human rights obligations by offering the highest possible standard of health care, ensuring equity in access, and enabling addicted individuals to express their autonomy and liberty. It is also important in recognising that some crimes are committed by some addicted individuals to fund their drug use. 2 Any use of legal coercion should not override whatever autonomous decision-making capacity addicted individuals retain. It should also be motivated by a desire to treat the individual, and not be used as a form of costcutting or extrajudicial punishment. 3 Individuals who are legally coerced into treatment under judicial oversight should be offered a dual-constrained choice: first, a choice of whether to enter treatment or not, with refusal leaving them to face criminal proceedings for their crime like any other individual charged with the same offence; and second, a choice of treatment from a range of effective options that includes substitution or maintenance therapy. 4 While new prophylactic technologies that block drug effects are a potentially important treatment option, they should only be one type of treatment among a choice of many. In making a choice about treatment, addicted persons should be given accurate information about the advantages and disadvantages of each, including their likelihood of success. Neurobiological relapse prevention (Section 10.3): 1 Relapse to drug use is common in persons treated for addiction. Pharmacological treatments that help to reduce relapse, such as naltrexone implants and drug vaccines, may prove to be an important innovation if their safety and efficacy is established in properly evaluated and controlled clinical trials. 2 Clients should also be made aware of any potential side-effects, the likelihood of success, and in the case of opioid addiction, the risk of overdose should they cease treatment and return to opioid use, or try to override the blockade by increasing their drug dose.

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3 The offer of implants and drug vaccines under legal coercion should be evaluated in clinical trials, and if effective, include the choice of other treatment options. Preventive vaccination of vulnerable populations (Section 12.2.5): 1 Drug vaccines may potentially be used to prevent those who are identified as vulnerable to addiction (e.g. genetic or neuropsychological screening) from developing one, particularly during adolescence when many addictions begin. 2 The preventive use of genetics and vaccines in high-risk persons is limited by the low predictive power of screening technology to identify them. Widespread genetic screening for the entire population is not feasible on the basis of present data about alleles that predict increased risk of addiction. 3 Some parents may wish to vaccinate their children, particularly if there is a family history of drug addiction. Enthusiasm for these preventive technologies must be tempered by a clear acknowledgement of the limited protection that these vaccines may provide. Unlike normal vaccines, they are likely to be short-lived, requiring boosters, and can be overridden by using larger doses of the addictive drug or by using a different drug. If the latter occurred, preventive vaccination could prove to be counterproductive. Neuroscience and privacy (Section 12.2.3): 1 Neuroimaging has enabled researchers to gain insight into the neurobiological effects of acute and chronic drug use and their effects on behaviour, cognition and personality. It is important that the claims about these findings reflect the limitations of neuroimaging. Reports should acknowledge these important technological limitations and experimental caveats. Often neuroimaging studies only show trends or small average differences between groups of people that poorly discriminate between individuals. 2 All neuroimaging results should remain confidential as is the case for all other medical information. Treatment of addiction in prisons (Section 7.6): 1 The principle of equivalence of care means that addicted prisoners should have access to drug treatment and harm minimisation measures that can protect their health. The options available should generally mirror those available to the wider community. For opioid-dependent individuals, this

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would include some form of substitution treatment. Prisoners should also have access to voluntary HIV and HCV testing and counselling. 2 There are both ethical and medical objections to enforced, unsupervised and unmedicated opioid detoxification, as often occurs on admission to prisons. These objections are stronger for those who were stabilised on an agonist maintenance treatment before their incarceration. 3 A general principle, that has both ethical and medical justification, is that prisoners should enjoy similar privacy protections in health care as the rest of the population. Addiction treatment during pregnancy (Section 7.7): 1 Addicted pregnant women should be engaged and positively encouraged to enter treatment and receive early antenatal care. 2 There are ethical objections to the forcible treatment of addiction for pregnant women. Such measures can be counterproductive, causing greater harm to the mother and child by discouraging addicted pregnant women from seeking help early in their pregnancies. 3 There is a need in many countries for more investment in treatment programs that are tailored towards the special needs of drug-dependent women. Psychopharmacological harm reduction (Section 14.6): 1 Neuroscience holds out the possibility of developing safer forms of currently addictive drugs. Regulatory barriers are likely to be the greatest hurdle to the introduction of such drugs. We should consider each drug on its merits, and based on a cost/benefit analysis of the harms that each drug causes or alleviates. Medicalisation of addiction (Chapter 14): 1 Neuroscience research has made significant advances in our understanding of the nature of addiction, and the cognitive and behavioural changes that underpin it. This will potentially lead to more effective treatment, and more humane social policies, although its impact has arguably been limited to date. 2 This enthusiasm needs to be tempered by an acknowledgement of the role that social and psychological factors play in the initiation of drug use, the development and expression of addictive behaviours, the way that society responds to addiction, and the effectiveness of these responses. 3 Addiction neuroscience may help us to understand the biological and cognitive aspects of addiction, but it does not reduce the importance of

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the social and psychological aspects of the way in which society responds to addicted persons. Acknowledging this is important in preventing neuroscience research from being misused to promote dubious ‘cures’ of addiction (e.g. neurosurgery, UROD) that are marketed to vulnerable and desperate ‘addicts’, with little or no evidence of their safety or efficacy. 4 An uncritical acceptance of the ‘brain disease’ view of addiction may lead to policies that focus on medical and neurobiological treatment of ‘sick’ individuals, ignoring the often harmful effects of drug use in the population. Policy makers need to ensure that an emphasis on neuroscience research does not obviate the need for effective social policies that create environments that reduce drug use and harm across the population. 15.3.

Neuroscience and the media: the role and responsibility of neuroscientists

Public interest in scientific findings and the political imperative for scientists to justify public funding have increased pressure on scientists to report their research findings in the popular media (Resnik, 1998). Given public interest in neuroscience research, and the potential for misunderstandings to rebound to the detriment of the research, neuroscientists and geneticists arguably have a moral responsibility to be proactive in their dealings with the media (Blakemore, 2002). They specifically need to ensure that accurate information is released to the media and that their publications include prominent disclaimers that correct predictable misinterpretations of their findings (ANCD, 2005; Australian Press Council, 2001). The media has an important role in educating the public about drug use, and treatments and interventions for addiction. Neuroscientists, however, need to be aware of how their research is understood by individuals outside the scientific community. They particularly need to anticipate how their research will be read through the prism of a simplistic, or folk, understanding of genetics and neuroscience, which assumes that if one has a particular gene, neurochemical balance or brain scan, then one has, or is likely to develop, an addiction or other neuropsychiatric condition. There are at least three issues of importance here. First, neuroscientists need to make it clear that addiction is not a simple single-gene disorder. It is not the case that if you have ‘the gene’ then you will become addicted and that you won’t if you don’t. It is important to understand the limitation of

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deterministic ideas of genetics, and how misunderstanding may affect how ‘at risk’ individuals think about themselves or how they may be treated by others in the community. Second, given the seductive power of ‘colourful’ brain images, neuroscientists should clearly convey the limitations of neuroimaging as an experimental and diagnostic tool (Dumit, 2004). As for genetic research, scientists need to avoid overly reductive interpretations of neuroimaging studies that reduce addiction to changes in brain function. The claims of entrepreneurs promoting these technologies to the public (e.g. for the purposes of truth-telling, personality matching, testing marital fidelity or marketing purposes) raise the need for consumer protection against the misinterpretation of equivocal test results (Caplan, 2002; Farah, 2002, 2005; Racine, et al., 2007). The same is true of potential claims about the use of neuroimaging or cognitive tests to identify those who are more vulnerable to developing an addiction. Third, research is required to determine what the public think about drug use and possible neurobiological interventions and treatments. The Academy of Medical Sciences in the UK conducted an insightful consultation in this respect. For example, the public was critical of the media coverage of celebrity drug users, which portrays them as glamorous and far removed from the ‘reality of cocaine addiction’ (Academy of Medical Sciences, 2008, p. 110). More research of this type is required to understand public attitudes towards new research and technologies (see below). There is a tendency for neuroscientists with politically liberal proclivities to assume that their findings can only be used to promote more humane policies towards addiction. The Chinese and Russian use of neuroscience to rationalise neurosurgical interventions cautions against such an optimistic assumption. Neuroscientists need to be aware of the social and moral context in which their research will be understood and used. Addiction evokes strong moral responses that neuroscience can be used to justify. These views can often be resistant to contradictory evidence. Neuroscience can also be used by vested interests, such as the alcohol, tobacco and gambling industries, to influence policy to suit their goals. Neuroscientists and other researchers need to be mindful that some enthusiasts will seize upon statements about their research to promote dubious treatments or social policies that serve their interests but lead to increased societal harm. Neuroscientists and clinicians need to consider the challenges in delivering the treatments that may arise from their research that may not have been considered when conducting their studies, such as getting individuals into treatment, ensuring compliance with treatment, and the political

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unwillingness to allow or provide certain forms of addiction treatment. Neuroscientists need to be aware of the competing social forces that can determine how treatment is provided (e.g. the social imperative to punish harmful or illegal behaviour versus the intention to treat a medical condition). Scientists need to be realistic about the claims they make when reporting their research. A competitive research environment can motivate researchers to exaggerate the benefits of advances in their field. Scientists need to moderate their optimism and enthusiasm about new treatments by recognition of past failures, such as disulfiram, naltrexone, neurosurgery and UROD. Addiction neuroscientists cannot evade responsibility for the uses made of their research once it is in the public domain by remaining silent in the face of the ethically questionable uses made of it. We need more addiction neuroscientists who understand the limits of their research, and are therefore well placed to reduce inappropriate uses, by making clear what neuroscience cannot say, the limits of how it should be used, and where there is uncertainty and where we should proceed with caution (Hyman, 2007; Kalant, 2010). Above all we need neuroscientists who are prepared to speak out when their work is used to the detriment of those who are drug-addicted. If neuroscientists are seen as complicit in provoking unrealistic expectations, or they fail to speak out against misuses of their work, the public may become sceptical or antagonistic towards neuroscience research.

15.4.

The tasks ahead for ethicists and policy makers

Given the challenge in balancing neuroscience research with competing interests, it is important that ethicists and policy makers appreciate the complexity of neuroscience research, in particular the limits of neuroscientific knowledge (Hyman, 2007; Kalant, 2010). This appreciation is necessary to limit the potential misuse of neuroscience in the service of pre-existing moral attitudes towards addiction and those that suffer from it. Ethicists and policy makers therefore need to be aware of the assumptions and hypotheses inherent in various neuroscientific approaches to the study of addiction (e.g. animal, neurocognitive, human neuropathological and psychiatric genetic studies), that can limit the interpretation and application of the research. These can include the following: 1 The translation of experiments in animal models of addiction in highly controlled laboratory settings to the addictive use of drugs in humans living

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3

4

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within highly complex social environments is limited. These studies are often erroneously invoked to suggest that drug use is compulsive. However, even in animal models, manipulation of the environment can have an effect on the self-administration of drugs (Ahmed, 2010; Xu, et al., 2007). These findings need to be confirmed in human research. Even then, there will be questions whether animal models of addiction are measuring the same neurobiological processes as in humans. Small differences in cognition or decision-making behaviour between groups of addicted and non-addicted individuals represent trends between groups of individuals; they cannot necessarily be used to diagnose a disorder or to predict individuals’ future behaviour. Not all addicted persons display these deficits, while some non-addicted persons do. These studies should not be used to make strong claims about addiction such as all addicted persons: have a complete ‘loss of control’ over drug use; use drugs ‘compulsively’; or their brains have been ‘hijacked’ by the drug. The identification of changes in neural activity, using neuroimaging for example, does not necessarily mean that an individual is suffering from a brain disease that requires pharmacological treatment. These changes may be either a cause or a consequence of addictive drug use. Also, it is not clear that these changes are either necessary or sufficient for addiction. We should avoid overly reductionist interpretations of neuroscience research on addiction in the absence of very strong evidence that a behaviour can be reduced to changes in the brain. Identification of differences in activity using brain imaging, for example, should not be misconstrued as the root cause of addiction, or the best site for pharmacological or other interventions. Humans are deeply embedded biopsychosocial beings whose behaviour is influenced by a host of factors. In some cases, neuroscience evidence may provide justification for social or public policy interventions (e.g. prohibition on the sale of alcohol and tobacco to minors). Some neuroscientists mistakenly assume that identification of a neurobiological change caused by drug use necessitates a medical solution; this is to ignore the social context in which people use drugs, or the ameliorative impact of changes in the environment on neurobiology. Neuroscientists need to be careful to avoid the neuroessentialist approach (the belief that all of human experience and behaviour can be explained by the brain) if they are to understand psychiatric disorders, such as addiction (Racine, et al., 2005). There are major challenges in translating measurements at the cellular, molecular and neural level in highly controlled and artificial laboratory

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settings to the behaviour of groups of humans interacting in complex psychosocial environments. Scientists need to develop a more integrative approach to understanding addiction (such as the one proposed in this book), that utilises a range of approaches and different types of evidence – clinical, psychological, epidemiological and sociological – to bear on the complex issues raised by drug use and addiction. Ethicists should be clear when discussing the more speculative uses of emerging technologies, such as cognitive enhancement or experimental technologies such as deep brain stimulation, to distinguish between what is possible and likely, and what is highly speculative. An overemphasis on more speculative uses of novel neurotechnologies can give potential patients and the public an unrealistic impression of the imminence of their development and likely effectiveness. This may undermine a clear assessment of the risks and benefits of these technologies before they become widely used (Bell, et al., 2010; Carter, et al., 2010b). 15.5.

Future directions for addiction neuroethics

The analysis of the social and ethical implications of addiction neuroscience is a relatively recent development.1 This book represents a prospectus for further research and debate, rather than a set of definitive conclusions. As neuroscience research progresses, and the evidence of effectiveness and safety for emerging technologies evolves, the analyses presented will need to be revised and updated appropriately. It may be that as the science continues, some of the ethical issues identified in this review prove to be less serious than they now appear, as has proven to be the case, for example, with fears about human reproductive cloning in the early 2000s and the genetic prediction of disease risk after completion of the Human Genome Project (Evans, et al., 2011). It is also likely that new ethical issues will arise that we have not anticipated. In addition to the standard scientific questions about the safety and efficacy of new interventions, there remain important questions that are amenable to empirical research. Some promising potential future research programs are outlined below. 1

While analysis of the social and ethical issues involved in the treatment of addiction and the ethical methods used in these analyses may not be particularly new, the specific issues raised by current neuroscientific research of addiction, and the emergence of novel neural technologies to treat addiction are.

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Private and public understanding of addiction neuroscience

The potential impact that addiction neuroscience has on society will depend in large part on how it is received, understood and applied by the public, and by those suffering from addiction or directly affected by it (e.g. families, carers, friends). Public stigma and discrimination are seen as major impediments to treatment seeking in addiction (Pescosolido, et al., 2010). There is optimism that neuroscience research will reduce stigma and improve access to treatment by demonstrating that addiction is a brain disease (Pescosolido, et al., 2010; Sartorius, 2010). Despite more than a decade of neuroliteracy campaigns (e.g. National Alliance on Mental Illness Campaign to End Discrimination, US Congress ‘Decade of the Brain’), stigma and discrimination have not declined. In fact, there is evidence that increased acceptance of genetic and neurobiological explanations of addiction and other psychiatric disorders may harden attitudes and increase stigma (Angermeyer and Matschinger, 2005; Pescosolido, et al., 2010). Stigma and social disapproval are also potent tools for discouraging drug use. We need to ask what impact will any reduction in stigma have on young people’s propensity to experiment with addictive drugs. Some critics of the brain disease model are concerned about its impact on drug users’ self-understanding (Satel and Lilenfeld, 2007). Some have argued that neurobiological views of addiction exaggerate the difficulty in overcoming common forms of addiction, reduce drug users’ beliefs in their ability to achieve abstinence, and encourage the view that addiction can only be overcome by using pharmacological interventions (Chapman and MacKenzie, 2010; Hughes, 2009). Acceptance of these views might deter addicted individuals from taking steps to reduce their drug use or attempting to achieve abstinence. Very little is known at present about the public’s awareness of addiction neuroscience or its impact on their understanding of addiction. For example: • How do neurobiological explanations of addiction affect people’s attitudes towards drug use and people with an addiction? Are they accepted or discounted, or integrated into pre-established frameworks? • How does this research affect their ideas of personal responsibility and blame for drug use and criminal activity that may be engaged in to fund drug use? How, in turn, does addiction neuroscience affect people’s support for the types of policies advocated to deal with addiction (e.g. coerced treatment of addiction, preventive vaccination of individuals at high risk of developing addiction, invasive neurosurgery)?

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• How do neurobiological explanations affect addicted individual’s understanding of themselves and their condition? Do they undermine their capacity and willingness to stop using drugs? The type of research required to address these challenging questions will involve a combination of qualitative and quantitative social scientific techniques (e.g. questionnaires, interviews, focus groups). Within the field of neuroethics, this experimental approach is referred to as empirical neuroethics (Illes, 2007; Racine, 2010). Empirical neuroethics embraces a pragmatic approach to ethical and philosophical analysis (Racine, 2003). The process is a dynamic and iterative one that engages with those that are affected by the issues that it seeks to understand: scientists and scholars engaged with journalists and commentators, patients, families and caregivers, as well as clinicians and policy makers in order to achieve a ‘cycle of knowledge’ (Illes, 2007. p. s59). Interviews with addicted individuals could be used to assess the impact of neuroscience research on their beliefs about their capacity to abstain from drugs, the willingness of those addicted to seek and complete treatment, particularly during adolescence, and their perceptions of coercion in research and treatment recruitment. This research would have the added benefit of informing clinicians in how best to use neuroscientific research in the treatment of addicted individuals. A similar approach has been undertaken to understand the impact of genetic research on public understanding of nicotine addiction (Cappella, et al., 2005; Caron, et al., 2005; Condit, et al., 2006; Hughes, 2009; Leader, et al., 2010; Wright, et al., 2007). The Academy of Medical Sciences in the UK has begun such an analysis (Academy of Medical Sciences, 2008). These studies could also be complemented by analyses of media coverage of addiction neuroscience research to assess how researchers communicate their findings and discuss policy implications, and how the media portrays this research.

15.5.2.

Capacity to consent in a research or treatment setting

As discussed in Chapter 6, there has been considerable debate recently about whether addiction undermines the ability of those that suffer from it to make free and internally uncoerced decisions about using drugs. This issue has farreaching implications for the ability of addicted persons to consent to research, clinical trials or treatment that administers their drug of addiction

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(Carter and Hall, 2008a; Carter and Hall, 2008b). It is surprising then that few studies have assessed the capacity of addicted individuals to provide consent to research or treatment or sought to develop methods of facilitating consent (Festinger, et al., 2010). Further research is urgently required (Jeste and Saks, 2006). Can we better understand and measure the impact of addiction on the autonomous decision-making of those that suffer from it? Is it possible to develop diagnostic tools that may help us to establish if an addicted individual has the cognitive and volitional capacity to consent, for example, to participate in research?

15.5.3.

Epidemiological modelling of addiction policy

What are the likely public health costs and benefits of various public policies involving the use of emerging technologies to treat and prevent addiction? While researchers often address important clinical questions about the safety and efficacy of new treatments, there is often a paucity of research that attempts to identify what the economic costs and benefits of the translation of these technologies into broad public policies might be. The emergence of epidemiological modelling of the cost-effectiveness of drug treatments has made it possible to assess these aspects, before technologies are introduced into routine practice. For example, Gartner and colleagues have used such an approach to investigate the potential public health costs and benefits of allowing smokers to use oral tobacco products, such as snus (Gartner, et al., 2007) or the utility of predictive genetic screening for the risk of developing nicotine dependence (Gartner, et al., 2009). Similarly, Wallace (2004) prospectively assessed the likely epidemiological and economic impact of a nicotine vaccine by comparing its public health impact and cost with Zyban. The proposed use of a now withdrawn genetic test (the NicoTest) to determine whether a nicotine-dependent individual is more likely to derive benefit from NRT or Zyban has also been evaluated in this way (Morley, 2008). Epidemiological and economic modelling could be used to estimate the impact of various policy approaches on the population prevalence of addictive disorders and drug-related disease. It could also allow us to estimate the likely effectiveness and cost-effectiveness of emerging applications of addiction neurobiology. This could include proposals to: • screen whole populations for genetic susceptibility to addictive disorders • use drug vaccines, sustained-release medications and new pharmacotherapies to treat and potentially prevent addiction

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• use these new treatments under legal coercion • use neuroimaging to identify those with an addiction or a predisposition to develop one. 15.5.4.

Using incentives to reduce drug use and achieve better health outcomes

There has been renewed interest in the use of monetary and other incentives to promote people to make healthier lifestyle choices (Marteau, et al., 2009). Recent clinical trials have found incentives to be effective in treating drug and behavioural addiction and reducing drug-related harm (Higgins, 2006; Higgins, et al., 1991; Higgins and Petry, 1999). For example, a controversial program in Scotland offered pregnant smokers shopping vouchers if they stopped smoking (Ballard and Radley, 2009). Such proposals raise significant ethical and social challenges. First, is it ethically acceptable to use financial inducements to addicted individuals who accept interventions, if they primarily benefit the rest of society (e.g. sterilisation of addicted women) (Fenton, 2003; Horka-Ruiz, 2000), particularly when the financial inducements are quite large? The use of large financial inducements in a research setting is seen as unacceptable by many (Fry, et al., 2006). Second, there are doubts about public acceptance of tax-payer funded programs that pay ‘addicts’ for making choices (e.g. to desist from using drugs) that many members of the public believe they should already be making. Will society accept policies that are seen to reward individuals for what is considered by many to be immoral and sometimes illegal behaviour? As evidence of the effectiveness of such programs grows, these social and ethical challenges will need to be addressed. 15.6.

Conclusion

Neuroscience research of addiction promises to substantially reduce the incidence and severity of addiction in society. These will be welcome developments that will hopefully reduce the personal and public costs of drug abuse. However, addiction and drug use does not occur in a moral or social vacuum. Drug use and addiction are highly stigmatised forms of behaviour that elicit strong moral responses. Neuroscience research is usually conducted with the aim of reducing the incidence and harm caused by disorders of the brain. However, in the case of addiction, people’s responses to it are often motivated by desires other than a wish to treat an individual’s medical

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condition. There are a variety of social and moral forces that can drive how these advances are understood and employed, and therefore their effectiveness and the level of unintended harm they may cause. For all these reasons it is important that we also consider the potential harms that may arise from the use and misuse of neuroscience research on addiction. If we do not, we may fail to realise the full benefit that neuroscience research on addiction offers to affected individuals and the broader society.

Glossary

Abstinence The cessation of drug use after an extended period of use of an addictive drug. Abstinence in a dependent drug user may lead to the experience of withdrawal symptoms. Addiction The repetitive engagement in an activity, such as drug use, gambling or eating, despite the negative consequences that it causes. Addiction usually involves intense craving for the addictive activity and an impaired ability to control use. These aspects of addiction are sometimes referred to as psychological dependence. Addiction also often involves the development of tolerance towards the drug of abuse, and symptoms of withdrawal upon cessation of use. This is often referred to as physical dependence. Addiction vulnerability The genetic, psychological and social (or environmental) factors that increase the likelihood of developing a drug addiction. For example, genetic factors include genes involved in the metabolism and activity of addictive drugs in the brain, psychological factors include high impulsivity, whereas social factors include early exposure to peer or familial drug use. Agent A person who is the subject where there is action. The person who performs an action. Ethical conduct is usually taken to presuppose the possibility that individual human agents are capable of acting responsibly. Agonist A substance which binds to the same receptor as the target drug (in this case the drug of addiction) producing the same or similar pharmacological effects. Alleles A member of a pair or series of different forms of a gene that are often responsible for hereditary variation. Amygdala A small group of neurons in the limbic system of the brain that is involved in the processing of emotional information, learning and memory. Anhedonia The inability to experience pleasure. Antagonist A substance which binds to the same receptor as the target drug (in this case the drug of addiction) preventing it from having its usual effects.

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Anterior cingulate gyrus The front part of the cingulate cortex, a region along the medial surface between the two cerebral hemispheres, which is involved in decision-making and particularly the regulation of emotional impulses to act. Anti-reward pathway A pathway in the brain that is hypothesised to limit reward triggered by excessive activity in the reward system. It is most often associated with systems involved in affect regulation such as the corticotropin-releasing factor stress system. Associative learning A learning process in which a new response becomes associated with a particular stimulus. Autonomy (Greek ‘self’ and ‘law’) The capacity for self-government and self-realisation. Agents are autonomous if their actions are truly their own. Liberty and agency are essential features of autonomy. Beneficence The ethical principle that one should aim to do good to others. Buprenorphine A drug that is a partial agonist of opioid receptors. It is often used in the treatment of opioid dependence, either as a form of maintenance, or as an aid to withdrawal. It can also lead to dependence. Cerebrum The two uppermost lobes of the brain, that consists of a left and right hemisphere. An evolutionarily recent part of the brain that sits above the more primitive parts of the brain, such as the mid and hindbrain. Also often referred to as the forebrain. CNS depressants A class of drugs that slow CNS function, and can lead to fatal overdose in large doses from respiratory and cardiac failure. Coercion The use of force to encourage someone to enter treatment. The type of force used may vary depending on the amount of choice that an individual has. Mild forms include pressure from friends and family; the strongest forms involve detaining individuals in treatment against their wishes. Compulsion In addiction, compulsion refers to an experience of a strong, usually irresistible drive or desire to consume drugs that is often contrary to one’s will. Conditioned incentive-learning The association of reward with a previously neutral stimulus when paired with a naturally rewarding event (e.g. addictive drug use). Conditioned incentive-learning is an important addictive process that underpins behaviours such as conditioned place preference. Confidentiality The communication of private information from one person to another, where it is expected that the recipient of confidential information (e.g. a health care professional) will not disclose this

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information to third parties under normal circumstances. Confidentiality restricts the use of personal information about an individual so that it cannot be communicated to others without their consent. Cortex The outer mantle of the brain, specifically the cerebrum, which is involved in the highest cognitive functions, such as conscious sensation and movement, language and decision-making. Craving An intense and seemingly irresistible desire to experience the effects of drugs. Cues, or drug cues Events which have the ability to bring up memories that can often trigger emotional responses. Drug cues are those which recall memories associated with drug use that often trigger intense cravings for the drug. Delirium tremens An acute episode of delirium induced by severe alcohol withdrawal Dignity Respect, esteem or worthiness of action; the innate value of all human beings; or the empowerment of agents to make decisions and choices about their own lives. Dimensional disorder The view that addictive drug use lies along a continuum of increasing severity of problematic drug use and harm, where it is difficult to draw a sharp distinction between addictive and non-addictive drug use. The dimensional view of addiction is contrasted with a categorical view of addiction, where an individual either has or does not have an addiction. Distributive justice The ethical principle according to which all individuals should be treated fairly and there is a fair distribution of the risks and benefits of certain actions. Dopamine A chemical in the brain, or neurotransmitter, that is central to the development of addiction. It is found in the regions of the brain that are involved in the regulation of movement, motivation, emotion and reward. Down-regulation A process which causes a reduction in the expression of a given gene. Drug priming The use of a small amount of an addictive drug in abstinent addicted individuals that produces intense cravings for the drug that often leads to a relapse to chronic drug use. Dysphoria A feeling of being unwell, anxious, depressed and restless. Endogenous A chemical or substance produced within the body. Endophenotype Some measurable biological characteristic or biomarker of a person that is believed to have some genetic basis. To be an endophenotype, a biomarker must be: associated with an illness; heritable; visible

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irrespective of whether an illness is active or not; and co-segregate with the illness within families. Endorphins and encephalin Forms of endogenous opioids: naturally occurring substances in the human brain that bind to the same receptors as morphine. Epigenetics The study of non-genetic factors (e.g. environmental events such as chronic drug use) that alter the expression of genes in persistent ways. Equality The principle of equal treatment by the law and in medical care. Equivalence, the principle of The obligation to provide equivalent health care to prisoners as available to the general population. Ethics The study of the concepts involved in practical reasoning: good, right, duty, obligation, virtue, freedom, rationality, choice etc. (Sometimes referred to as the study or formalisation of morality.) In contrast, bioethics is a more practical approach that focuses on the outcomes of ethical debate. Euphoria A feeling of exuberance, elation and maximum well-being. Executive control The cognitive ability to control other important, but subordinate cognitive processes and behaviour. It is considered to be a central process in decision-making. Fatalism The belief that a set of pre-existing circumstances or events predetermined a particular outcome. It is often used in genetics and biology to suggest a belief that an agent could not avoid a particular outcome, and should not attempt to do otherwise. fMRI Functional magnetic resonance imaging (or fMRI) is a brain imaging technique that measures changes in blood flow in order to visualise brain activity during particular tasks. Forebrain The largest and most evolutionary recent division of the brain, including the cortex, limbic system and basal ganglia. It is the region of the brain involved in our most advanced cognitive functions. Freedom The belief that everyone is entitled to make choices. The corollary of this is that persons are to be held responsible for the consequences of their actions. Freedom is closely related to the notion of autonomy and is synonymous with liberty. Frontal cortex A region of the cerebrum that is involved in our most higher order cognitive functions, such as decision-making and social or moral judgement. Harm minimisation (or reduction) An approach to the treatment of addiction and drug abuse with the principle aim of reducing the harm caused by drug use to both the individual and society without necessarily eliminating drug use. Harm reduction is an evidence-based approach

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towards drug policy that its proponents claim takes no position on the rights and wrongs of using drugs. Needle exchange programs and methadone maintenance are two types of harm reduction programs. Heroin A synthetic opiate that is the most commonly abused and one of the most addictive illicit drugs. Heroin prescription trials Clinical trials of the prescription of injectable pharmaceutical heroin for treatment refractory heroin-addicted individuals in order to improve health and well-being by replacing the use of unsupervised illicit heroin use. Hippocampus An area of the brain involved in learning and memory, specifically memory for the facts or details of events, referred to as declarative memory. Homeostasis The ability of an organism to maintain internal stability, by adjusting its physiological processes. Homozygous A term used to describe when an individual carries two identical copies of a gene (one from each parent) at a particular locus on each of the two chromosomes. An individual who carries two different copies of a gene is said to be heterozygous for this gene. Human rights A set of norms that govern the treatment of individuals, or groups of individuals, by states and non-state actors based on ethical principles incorporated into national and international legal systems. Human rights are more commonly understood as the basic rights and freedoms to which all humans are entitled to, by virtue of being a person. ‘All human beings are born free and equal in dignity and rights’ (United Nations Declaration of Human Rights; see Rights). Hypothalamus A small, but important part of the brain that maintains many of the body’s internal functions, such as eating, drinking and the regulation of hormones, such as the stress hormones. Impulse inhibition The cognitive ability to resist strong urges or desires. Incentive sensitisation A theory of addiction that holds that addicted individuals become hypersensitive to drug effects and stimuli or events associated with drug use, that lead to a shift from drug ‘liking’ to drug ‘wanting’. The incentive sensitisation theory of addiction is believed to explain the apparently compulsive patterns of drug use. Incubation of craving The increase in craving in the weeks following abstinence of drug use. Informed consent A process whereby individuals are informed about a particular treatment or research study that they are to enter, and where individuals are free to participate or not.

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Insula cortex A region of cortex that lies at the intersection of the frontal, temporal and parietal lobes that is involved in the process of interoception, or the conscious experience of the body. Interoception The conscious experience, awareness or sensation of the body. Liberty A condition in which an individual has the ability to act according to his or her own will. Liberty consists of positive and negative components: the freedom of self-governance and self-realisation (positive liberty) and the freedom from obstacles or interference from others (negative liberty). Liberty is considered by many to be synonymous with Freedom. Limbic system A diverse array of densely connected brain regions that are involved in the regulation and generation of our emotions and desires. These regions are also involved in learning and memory. Long-term depression A molecular adaptation that occurs at the synapse between two neurons that leads to a weakening of the connection between these neurons. Long-term potentiation A molecular adaptation that occurs at the synapse between two neurons that leads to a strengthening of the connection between these neurons. Maintenance therapy The long-term replacement of an abused drug with its agonist in a regulated way to prevent relapse to more dangerous and illicit drug use. The most well-known type is methadone maintenance. Medicalisation The process whereby behavioural or social problems are understood as medical disorders that should be treated medically, often at the expense of social approaches. Mesolimbic pathway See Reward pathway. Minimal risk Where the anticipated risk of harm or discomfort is no greater than those ordinarily experienced in daily life, or the performance of routine physical or psychological examinations or tests. Motivation The promotion of an action in response to a particular kind of environmental event or object. Mu receptor The primary opioid receptor that mediates the pleasurable effects of both opiate drugs, such as heroin and morphine, as well as endogenous opioids, such as the endorphins. Naloxone A potent opioid antagonist that is used to treat opioid overdose, and is included in the drug, Suboxone, to discourage its injection. Naltrexone A potent opioid antagonist that binds to the target opioid receptors preventing heroin and other opioid agonists from having an effect.

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Naltrexone is often used as a form of relapse prevention. Naltrexone is also used to treat alcohol dependence and eating disorders. Natural reinforcers Everyday activities which are reinforcing or rewarding, such as food, sex and relationships. Natural reinforcers also activate the brain’s reward pathway, but to a much lesser extent than addictive drugs. Neurotransmitter A chemical produced within the neurons in the brain that carries signals to other neurons, usually by binding to receptors on adjacent neurons at the synapse. They are a type of signalling molecule that also includes other substances such as neural hormones. Non-maleficence The ethical principle that we should cause no harm to others. Nucleus accumbens A central part of the mesolimbic reward pathway that encodes information related to the rewarding or reinforcing properties of an event, or drug, and signals its salience. Nearly all drugs of abuse act upon the nucleus accumbens, thereby reinforcing their use. Opioid naivete´ The term given to a condition in which a former opioid addict who has withdrawn from opioid use, loses their tolerance to opioids. Opioid-naive users who return to opioid use are at a higher risk of overdose if they inject their usual dose of opioid. Orbitofrontal cortex A region of the prefrontal cortex involved in the attribution of salience to events, craving and the motivation to use drugs. Overdose An acute condition that results from taking too much of a drug. It can cause unconsciousness, brain damage and death. It is more commonly used in reference to the CNS Depressants, such as alcohol and heroin. Partial agonist Drugs that bind to the target receptor of a drug of addiction, partially blocking and partially activating the receptor. They can be used to treat drug dependence (e.g. buprenorphine for the treatment of opioid dependence). Paternalism The name given to the position that persons have a right to act in the interests of others without the consent of, or even against the will of, these others. (Sometimes substituted by parentalism.) PET Positron emission tomography (or PET) is a brain imaging technique that uses radioactively labelled molecules to visualise brain structure and function. Pharmacogenomics/pharmacogenetics The use of genetic or genomic information about an individual to select the pharmacological or psychosocial treatments that will maximise the chance of successful treatment for that person.

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Physical dependence A physiological state that is indicated by the occurrence of withdrawal symptoms when regular drug users abruptly stop taking the drug and accompanied by the development of tolerance, requiring higher doses to achieve the same drug effect. Preclinical trials The testing of new medical technologies, such as a drug treatment, in animal models in order to gather evidence for conducting human clinical trials. Prefrontal cortex The very anterior of the frontal cortex of the brain that includes the orbitofrontal cortex and the anterior cingulate cortex. It is considered the highest cortical area in the brain and underlies our most complex behaviours, including personality, social and moral behaviour, executive control and planning. Privacy An individual’s right to keep their personal information and affairs confidential, and out of public view, or to control who has access to this information and what they can do with it. Public good, the Refers to competing claims made by a public concerned with such values as equality, happiness, security or safety. There is a view that public good, also sometimes held to be equivalent to the ‘public interest’, is roughly synonymous with a definition of ‘general welfare’, and juxtaposed with autonomy and individual interests. Others take a broader or inclusive view of the public good to include more positive pursuits, such as the pursuit of collective projects and shared values. Receptor A large molecule on a cell’s surface that is a specific target for particular chemicals. In the brain, this is most often neurotransmitters, but it can also include hormones and other endogenous chemicals that bind to it and signal what is going on outside the cell (signal transduction). Reinforcement A neural process within the reward pathway that ensures that an activity or event is seen as salient and motivating. A stimulus that produces this effect within the reward pathway is said to be a reinforcer. Addictive drugs are potent reinforcers. Reinforcers Any event or stimulus that motivates an individual to repeat its use or occurrence. Reinstatement The resumption of addictive behaviours (e.g. selfadministration, conditioned place preference, behavioural sensitisation) following their extinction. Reinstatement is believed to be an animal model of relapse-like behaviour. Relapse The resumption of regular drug use after a period of abstinence, often in response to drug-related cues or stress. Relapse is common after addicted persons have achieved abstinence.

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Relapse prevention The use of a prophylaxis, usually pharmacological (e.g. naltrexone) or psychological support, to reduce the likelihood of returning to regular drug use. Most drugs used in relapse prevention work by preventing the drug of addiction from binding to its receptor. Drug vaccines have also been developed to reduce relapse to the use of some drugs of addiction (e.g. nicotine, cocaine). Respect for autonomy The principle by which we ought to respect the choices and actions of other rational or competent persons by not interfering with these choices or actions, and allowing persons to decide upon a course of action without influence, coercion or force. Reuptake The chemical process whereby signalling molecules or neurotransmitters are removed from the synapse by transporters on the cell surface. Reuptake is an important process that regulates the activity of signalling molecules. Reward The neural process that reinforces behaviour and signals that some experience, such as using drugs, is positive. It is usually associated with pleasure or euphoria. It is partly mediated by the release of dopamine into the nucleus accumbens. Reward pathway A central circuit in the brain that reinforces behaviour when activated. Most drugs which activate this reward pathway are addictive, and their effects are usually experienced as rewarding and pleasurable. The circuit includes neurons of the ventral tegmental area, nucleus accumbens, and part of the prefrontal cortex, referred to as the mesolimbic pathway, and the amygdala and hippocampus. Rights (moral) Entitlements to the protection of persons’ important interests. When these rights are effective, this protection is provided as something that is owed to persons for their own sakes. Salience The motivating quality of an event or experience. In contrast to reward, salient events need not be pleasurable. They are things that grab our attention, and motivate us to pursue them. Salient events are also reinforcing. Self-administration The most widely used animal model of addiction. Animals are trained to perform some behaviour (usually pressing a lever) in order to receive an addictive drug. Animals quickly learn to self-administer most drugs of abuse. Snus An oral form of tobacco that has been treated to remove the major carcinogens present in traditional chewed tobacco. Stimuli Events or experiences that trigger a cognitive or behavioural response. In neuroscience, stimuli narrowly refers to events that trigger a neurobiological (often neurochemical) response in the brain.

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Striatum A region deep within the brain that is involved in the planning and regulation of movement and executive control pathways. Suboxone A combination of drugs used in the treatment of opioid dependence. Its principal ingredient is buprenorphine but it also contains the opioid antagonist, naloxone, to discourage patients from dissolving and injecting the drug as injecting naloxone produces opioid withdrawal symptoms. Substitute Any drug that mimics the primary effects of a drug of addiction that is given to replace the abuse of the drug of addiction. Substitution treatment See Maintenance therapy. Swiss heroin trials A series of clinical trials of the prescription of injectable pharmaceutical heroin to long-term, treatment-refractory heroin-addicted individuals. See Heroin prescription trials. Synapse The specialised junction between two neurons across which neurotransmitter release allows signalling from one neuron (the presynaptic neuron) to the next (the post-synaptic neuron). Molecular and cellular specialisations at the synapse allow for quick and highly regulated communication between the two neurons. Synaptic plasticity Molecular and cellular changes between two cells that either strengthen or weaken their connection. Also see Long-term potentiation and Long-term depression. Tapered withdrawal The slowly decreasing administration of an addictive drug, or its agonist, over a period of days or weeks to assist addicted individuals to withdraw from their target drug and become abstinent. Thalamus The thalamus is the key relay station for all incoming sensory information. It is located deep within the brain, and is responsible for isolating important messages from the mass of sensory information entering the brain. Therapeutic misconception The mistaken belief that participation in a clinical trial will be of therapeutic value to participants. Tolerance A physiological state in which an individual is less responsive to the effect of a drug, leading to the use of higher doses. Tolerance is the result of neurochemical changes within the brain as a result of regular drug use. It often leads to physical dependence. Transporter A large molecule in the cell membrane that pumps signalling molecules such as neurotransmitters out of the synapse, thereby regulating their activity. Twins Twins may be dizygotic or monozygotic. Dizygotic twins are formed by the fertilisation and implantation of two separate eggs in a single

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uterus at the same time. They are commonly referred to as ‘fraternal’ or ‘non-identical’ twins. Monozygotic twins are formed from a single fertilised egg. Monozygotic twins therefore possess almost identical DNA and are commonly referred to as ‘identical twins’. Ultra-rapid opioid detoxification A form of opioid detoxification that reduces the withdrawal process to 24 hours by administering high doses of the antagonist, naltrexone, while the patient is under general anaesthesia. Utilitarianism A set of moral theories that decide what is ethically right by evaluating the consequences of an action or a rule. The simplest form is that of Jeremy Bentham (1748–1832) according to whom right actions were those that produce the greatest happiness for the greatest number of people. Ventral tegmental area (VTA) A group of dopaminergic neurons that make up a key part of the brain’s reward pathway. Neurons in the VTA synapse onto neurons in the nucleus accumbens and the prefrontal cortex. Withdrawal Symptoms that develop when an individual abruptly stops or abstains from chronic drug use. The symptoms of withdrawal can include nausea, headaches and seizures, depending on the drug of addiction. Some drugs have very mild or no withdrawal symptoms (e.g. cocaine), while others cause intense discomfort (e.g. alcohol, heroin).

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Index

abstinence, 264 capacity to choose abstinenceoriented treatment, 114–15 acamprosate, 63, 69, 73, 241 acetylation, 54 addiction, 7–10, 19–20, 264, see also dependence behavioural, 23, 46 clinical understanding of, 21–3 cycle of, 22, 31 definition, 20, 100 ethical principles in treatment, 97–102 autonomy, 99–101 minimum conditions for ethical treatment, 102–3 public good, 101–2 folk understanding of, 21 genetic basis. See genetic contribution to addiction medicalisation of, 230–2, 253–4 models of, 28–34 brain disease model, 8, 27–8, 31, 100–1, 244–7 hedonic models, 45 moral (sceptical) model, 28–31, 113–14 neurobiological models, 31–3 molecular targets of addictive drugs, 63 neuroanatomy of, 36–8 social factors, 133, see also vulnerability social response to, 26–8

addiction ‘cures’, 181–5, see also pharmacotherapy; treatments avoiding future errors, 195–6 early history, 181–2 Keeley Cure, 182–3 neurobiologically inspired cures, 185–90 ibogaine therapy, 186–7 neurosurgical treatments, 187–90 ultra-rapid opioid detoxification (UROD), 187 regulation, 183 withdrawal treatments, 183–5 addiction neuroethics, 7, see also neuroethics challenges, 256–8 future directions, 258–9 addiction research, 146–8, 160, 248, see also neuroscience drug administration, 153–60 reasons for, 154–6 risks of, 156–7 treated versus untreated addicts, 157–8 informed consent, 148–50 capacity to consent, 157–8, 160 obtaining consent, 159–60 motivations for participation, 150 payment of participants, 150–2 privacy and confidentiality issues, 152–3 recruitment of participants, 158–60 admission guidelines, 117–19

331

332 adolescents, 58–9 vaccination against addiction, 207 agent, 264 agonist treatments, 62–6 GABA agonists, 73–4 partial agonists, 67–8, 71 agonists, 65, 264 partial agonists, 67, 270 AIDS treatment, 127–8 alcohol burden of abuse, 25–6 engineering safer alternatives, 241 predictive testing for dependence, 200 prevalence of use, 23 social policies, 27 industry influence, 236 withdrawal treatment, 69 alcohol dehydrogenase (ADH), 71 aldehyde dehydrogenase 2 (ALDH2) gene, 56 alleles, 264 amygdala, 264 anhedonia, 264 animal models, 113, 256–7 anonymity, addiction research and, 152–3 Antabuse, 71 antagonist treatments, 46, 66–7, 70–1 antagonists, 66, 264 antiretroviral (ARV) therapy, 127–8 anterior cingulate gyrus (aCG), 47, 265 anticonvulsant therapies, 74 antipsychotic treatment, 185 anti-reward pathway, 50, 265 anxiety, 58 aripiprazole, 71 associative learning, 265 attention deficit hyperactivity disorder (ADHD), 58 Australia burden of disease related to drug use, 25 cannabis decriminalisation, 238

Index naltrexone implant experience, 176 prevalence of drug use and addiction, 23–4 autonomy, 91–2, 249, 265, see also informed consent addiction effects on, 99–101 overriding, 98 respect for, 86, 90–2, 94, 272 restoration of, 92 coerced treatment using drug implants, 176–9 aversive model, 45 baclofen, 74 behavioural addictions, 23, 46 belladonna treatment of withdrawal, 184 beneficence, 92, 265 addiction research, 147 bioprediction of addiction liability, 197–8 genetic tests, 198–200 commercialisation of, 204–6 genetic discrimination issue, 202–4 use of results to increase abstinence, 200–2 neuroimaging studies, 207–8 blame, 5 body awareness, 50 brain disease model, 8, 27–8, 31, 32, 244–7 autonomy implications, 100–1 implications for capacity to consent, 109–10 potential consequences of, 33, 244–7 bromide sleep treatment (BST), 184 buprenorphine, 67, 174, 265 bupropion, 70, 71 burden of disease (BOD) drug and alcohol use related, 25–6 psychiatric disorders, 4 California, cannabis policy, 239–40 candidate genes, 55

Index cannabinoids, 74 cannabis legalisation, 237–40 capacity to choose, 8, 32, 91, see also autonomy; self control addiction effects, 108–13, 261 abstinence-oriented treatment, 114–15 implications for consent to treatment, 115–17 sceptical view, 113–14 cognitive capacity, 106 volitional capacity, 106, 107, see also informed consent categorical imperative, 88 CB1 cannabinoid receptor, 74 cerebrum, 265 children, vaccination of, 206 chlorpromazine treatment, 185 choice, 28–30, see also capacity to choose constrained choices, 141–2, 251 chromatin remodelling, 54 cigarette smoking. See nicotine dependence; tobacco clonidine, 69 CNS depressants, 265 coerced treatment, 129–30, 134–5, 144, 246–7 approaches to, 135–6 constrained choices, 141–2 depot naltrexone use to restore autonomy, 176–9 effectiveness, 140–1 ethical issues, 142 compulsory treatment, 142–4 justifications for, 138–42 legal coercion, 136–8 neuroenhancement, 218–19 pregnant women, 132 vaccination, 171–2 coercion, 265 cognitive enhancement, 6, 75, 214–16, see also neuroenhancement

333 cognitive impairment, 47–50, 58 communitarian ethics, 88–9 comorbid conditions, 133 competence, 91, see also capacity to choose compulsion, 47, 265 compulsory treatment, 142–4, see also coerced treatment conditioned incentive-learning, 265 confidentiality, 147, 252, 265 addiction research and, 152–3 consequentialism, 88 constrained choices, 141–2, 251 convulsive therapy, 185 corrected feedback, 107, 119 cortex, 266 corticotropin-releasing factor (CRF), 75 craving, 47, 70, 266 incubation of, 268 perception of, 50 pharmacotherapy, 169–70 ethical issues, 169–70 reduction of cue-conditioned craving, 72 research participation and, 159 crime, 24 cycle of addiction, 22, 31 decriminalisation of illicit drugs, 132 cannabis, 237–40 deep brain stimulation (DBS), 78–9, 190–5 costs of, 195 risks of, 193–4 delirium tremens, 69, 266 dendritic spines, 54 deontology, 88 dependence, 20, see also addiction alcohol, predictive testing for, 200 heroin, 62–5 nicotine, 76, 200–2

334 dependence (cont.) genetic screening to increase abstinence, 200–2 pharmacogenetic treatment issues, 209–11 physical, 20, 264, 271 psychological, 20, 264 vulnerability to, 28 depot injections, 78, 174 depression, 51, 58 detoxification, 69 dignity, 91, 266 dimensional disorder, 266 direct to customer (DTC) genetic tests, 204–6 discontinuation syndrome, 20, see also withdrawal discrimination, 9, 259 genetic discrimination, 202–4 disease model. See brain disease model distributive justice, 93, 266 disulfiram, 63, 71 dizocilpine, 73 dopamine, 39, 46, 266 agonists, 65–6 antagonists, 46, 70–1 environmental interactions, 57–8 learning and, 40–3 partial agonists, 71, 72 reward system and, 40–4 stress effects, 51 withdrawal and, 130 dopaminergic treatment, 70 drug addiction. See addiction drug cues, 266 drug implants, 78, 174 coerced use to restore autonomy, 176–9 naltrexone, 175, 176 drug policy, 122, 237–40, 248 neuroenhancement drug regulation, 223–5 neuroscience implications, 250

Index drug priming, 266 drug use. See also drug addiction; opioid use alcohol, 23 Australia, 23–4 burden of, 25–6 social costs, 25 harm related to, 24–5 lessons for neuroenhancement, 221–3 reduction using incentives, 262 social response to, 26–8 tobacco, 23 dynorphin, 75 dysphoria, 266 electroconvulsive therapy (ECT), 185 empirical neuroethics, 260 encephalin, 267 endophenotype, 266 endorphins, 267 enhancement. See cognitive enhancement; neuroenhancement epigenetic changes, 53–5 epigenetics, 267 equality, 91, 93, 123, 267 access to neuroenhancement technologies, 219–20 equivalence, 267 ethics, 87–90, 267, see also neuroethics agent-based approaches, 88–9 challenges, 256–8 duty-based approaches, 87–8 ethical principles in addiction treatment, 97–102 autonomy, 99–101 minimum conditions for ethical treatment, 102–3 public good, 101–2 of care, 89 euphoria, 267 executive control, 47–50, 267

Index fatalism, 101, 267 feminist ethics, 89 flumazenil, 67 forebrain, 267 freedom, 267 frontal cortex, 267 functional magnetic resonance imaging (fMRI), 267 GABA agonists, 73–4 genetic contribution to addiction, 7 pharmacogenetic treatment, 75–6 vulnerability, 32, 55–7 interaction with environmental factors, 57–9 Genetic Information NonDiscrimination Act, USA, 6, 204 genetic information security, 6, 202–4 genetic pleiotropy, 203 genetic tests of addiction liability, 198–200 commercialisation of, 204–6 genetic discrimination issue, 202–4 use of results to increase abstinence, 200–2 GHB (gamma-hydroxybutyric acid), 242 glutamate, 73, 74 habits, 46–7 harm reduction, 267 approaches, 240–2 HCV infection coerced treatment and, 136–7 risk for prisoners, 130–1 hedonic models, 45 heroin, 268, see also opioid use pharmacotherapy for dependence, 62–5 prescription trials, 268 hibernation therapy, 185 hippocampus, 268

335 histones, 54 HIV infection, 127–8 coerced treatment and, 136–7 risk for prisoners, 130–1 homeostasis, 268 human rights, 94–5, 268, see also rights of addicted individuals addicted pregnant women, 131–2 addicted prisoners, 130–1 future challenges, 132–3 legal coercion and, 129–30 Huntington’s disease, 200 hypothalamus, 268 ibogaine therapy, 186–7 immunotherapies, 76–7, 170–3 impulse inhibition, 268 incentive sensitisation, 268 incentives to reduce drug use, 262 information security, 6, 252 informed consent, 105–6, 119–20, 268, see also autonomy; capacity to choose addiction impact on capacity, 108–13, 261 abstinence-oriented treatment, 114–15 implications, 115–17 sceptical view, 113–14 addiction research participation, 147, 148–50, 157–8, 160 obtaining consent, 159–60 brain disease model implications, 109–10 conclusions, 250–1 deep brain stimulation (DBS), 194 neurosurgical procedures, 190 requirements for, 107, 118 research on, 106–8 role in addiction treatment, 106–8 vaccination, 171–2

336 insula, 50, 269 interoception, 50, 269 justice, 92–3 distributive, 93, 266 Keeley Cure, 182–3 learning, 46–7 associative, 265 conditioned incentive, 265 dopamine and, 40–3 legal coercion, 136–8, see also coerced treatment legalisation of illicit drugs, 132 cannabis, 237–40 libertarianism, 140 liberty, 102, 269 limbic system, 269 lofexidine, 69 long-acting medications, 77–8 long-term depression (LTD), 52–3, 269 long-term potentiation (LTP), 52–3, 269 maintenance therapy, 68, 125–6, 269 media, 254–6 medicalisation of addiction, 230–2, 269 memory manipulators, 75 mental illnesses. See psychiatric disorders methadone, 65 maintenance therapy (MMT), 65, 125–6 methylation, 54 methylphenidate, 215, 216 minimal risk, 269 modafinil, 75, 215, 216 moral (sceptical) model, 28–31, 113–14 mortality, drug-related, 24 motivation, 35, 269, see also reward system anti-craving drug effects, 169–70 mu-opioid receptor (MOR), 45–6, 72, 269

Index N-acetylcysteine (NAC), 73 naloxone, 45, 269 naltrexone, 45, 67, 73, 76, 143, 168, 269 long-term effects on motivation, 169 sustained-release technologies, 174 coerced use to restore autonomy, 176–9 implants, 175, 176 naturalistic fallacy, 96 needle exchange programs, 126–7 negative reinforcement, 22 Netherlands, cannabis policy, 238–9 neuroanatomy of addiction, 36–8 neurobiological models, 31–2, see also brain disease model potential consequences of, 32–3 neurocognitive tests, 80, 211–13 neuroenhancement, 214–16 drug regulation, 223–5 lessons from recreational drug use, 221–3 problems with, 216–21 coercion, 218–19 equity of access, 219–20 naturalistic objections, 220–1 safety and efficacy concerns, 217–18 neuroessentialist approach, 2 neuroethics, 4–7, 85–7 challenges, 256–8 empirical, 260 future directions, 258–9 pragmatic approach, 95–7 neuroimaging, 79–80 biopredictive use, 207–8 costs, 208 use in personalised treatment, 211–13 neuropsychological studies, 80–1, 113 neuroscience, 1–4, 229, 244–7 challenges, 256–8 issues, 5–6 limitations, 244–7, 249 media and, 254–6

Index potential benefits, 4–5, 14–15 treatments, 8 public health policy implications, 229–30 research findings, 59–60, see also addiction research subversive use of, 234–7 neurosurgery, 78, 187–90, 246 neurotransmitter, 270 NicoTest, 76 evaluation, 209–10 nicotine dependence. See also tobacco genetic screening to increase abstinence, 200–2 pharmacogenetic test, 76 pharmacogenetic treatment issues, 209–11 vaccines, 200–2 nicotine replacement therapy (NRT), 62 N-methyl-D-aspartic acid (NMDA) receptor, 73 antagonists, 73 non-maleficence, 92, 270 addiction research, 147 noradrenaline, 39 nucleus accumbens (NAcc), 40, 270 deep brain stimulation (DBS), 192–3 reward system and, 40–4 surgical ablation, 189 opioid naivete´, 270 opioid system, 45–6 pharmacological blocking, 72–3 opioid use. See also drug use capacity to consent to treatment, 110–12 disease model of dependence, 27–8 harm related to, 24 pharmacotherapy, 28 agonist treatment, 62–5 ultra-rapid opioid detoxification (UROD), 128, 187, 245

337 vulnerability to dependence, 28 withdrawal, 69–70 orbitofrontal cortex (OFC), 47, 49, 270 overdose, 270 oxytocin, 215 Parkinson’s disease (PD), 192, 193 partial agonist treatments, 67–8, 71 cue-conditioned cravings, 72 partial agonists, 67, 270 paternalism, 92, 98, 270 hard paternalism, 138 justification for coerced treatment, 138–9 soft paternalism, 138, 139 payment for research participation, 150–2 personalised treatment, 208–13 neuroimaging applications, 211–13 pharmacogenetic, 209–11 pharmacogenetic treatment, 75–6, 209–11 pharmacogenetics, 270 pharmacotherapy, 28, 62, see also treatments approaches, 63 craving, 70–2, 169–70 ethical issues, 169–70 reduction of cue-conditioned craving, 72 reduction of drug reinforcement, 70–1 current treatments, 64 duration of treatment, 68–9 ibogaine therapy, 186–7 immunotherapies, 76–7, 170–3 investment in development, 168–9 long-acting or sustained-release medications, 77–8, 173–6 maintenance therapy, 68, 125–6, 269

338 pharmacotherapy (cont.) novel approaches, 76 relapse prevention, 170–9 research and development issues, 168–9 relapse treatment, 70–2 stress response, 75 substitution treatment, 65, 68, 125–6 treatments related to reward system, 72–5 amino acid neurotransmitters, 73–4 cannabinoids, 74 cognitive enhancers, 75 memory manipulators, 75 opioid system, 72–3 treatments that block drug binding, 62–9 agonists, 62–6 antagonists, 66–7 partial agonists, 67–8 withdrawal symptoms, 69–70 physical dependence, 20, 264, 271 pluralistic approach, 95–6 policy. See drug policy; public health policy positive reinforcement, 21 positron emission tomography (PET), 270 pragmatic approach, 95–7 preclinical trials, 271 prediction error signal, 43 prefrontal cortex (PFC), 49, 271 pregnant women, 131–2, 253 prevalence of drug use alcohol, 23 Australia, 23–4 tobacco, 23 preventive medicine, 197, see also vaccines principlism, 90–4 relationship between principles, 93–4 prison costs, 9, 24 prisoners, 130–1, 252–3

Index privacy, 147, 252, 271 addiction research and, 152–3 prohibition policies, 26–7 neuroenhancement technologies, 223, 224 propranolol, 75 psychiatric disorders, 2–4 burden of, 4 psychological dependence, 20, 264 psychosocial approaches, 81, 232–3 public good, 86, 99, 271 addiction and, 101–2 communitarianism, 88–9 justification for coerced treatment, 139 versus autonomy, 98 public health policy, 229–30, 232–7, 248, see also drug policy competing strategies, 233–4 epidemiological modelling, 261–2 industry influence, 234–7 public understanding, 249, 259–60 media role, 254–6 receptor, 271 regulation of neuroenhancement drugs, 223–5 reinforcement, 21, 271 dopamine effects, 40–3 natural reinforcers, 40, 270 negative, 22 pharmacological reduction of drug reinforcement, 70–1 reinforcers, 271 reinstatement, 271 relapse, 271 learning and, 46–7 prevention, 66, 69, 170–9, 272 drug vaccines, 170–3 stress effects, 50–1 treatment, 70–2 triggers, 80 relationship-based ethics, 89

Index research. See addiction research responsibility, 5 reuptake, 272 reward, 272 reward systems, 36, 37 dopamine and, 40–4 pharmacological blocking, 70–1, 72–5 amino acid neurotransmitters, 73–4 cannabinoids, 74 memory manipulators, 75 opioid system, 72–3 reward pathway, 272 stress effects, 51 rights, 272 rights of addicted individuals, 121–2, 123–4, 247–8, see also human rights access to treatment, 124–8 effective treatment, 125–6 harm reduction measures, 126–7 HIV treatment, 127–8 legal coercion and, 129–30 pregnant women, 131–2 prisoners, 130–1 unevaluated and risky treatments, 128–9 rimonabant, 67, 74 Ritalin, 215, 216 salience, 43, 272 sceptical view, 28–31, 113–14 scopolamine intoxication, 184 selective serotonin reuptake inhibitors (SSRIs), 20 self control, 2, 10, see also autonomy; capacity to choose loss of, 19 self-administration, 272 serotonin, 39 smoking. See nicotine dependence; tobacco snus, 261, 272 social coercion, 135

339 social harm reduction, 9 social policies. See public health policy social response to drug use, 26–8 stigma, 5, 259 stigmatisation, 152 stimuli, 272 stress, 50–1 neuroadaptations to, 51 pharmacotherapy, 75 striatum, 273 subject payments for research participation, 150–2 Suboxone, 67, 273 substance abuse disorder, 20 substitute, 273 substitution treatment, 65, 68, 125–6 sustained-release medications, 77–8, 173–6 advantages, 174 coerced use to restore autonomy, 176–9 ethical issues, 174–5 symptomatic support, 69 synapse, 273 synaptic plasticity, 52–3, 273 tapered withdrawal, 68, 273 taxation policies, 26 technological fix, 231 Tempol, 241 thalamus, 273 thalidomide, 241 therapeutic misconception, 116, 148, 273 tiagabine, 74 tobacco. See also nicotine dependence genetic screening to increase abstinence, 200–2 prevalence of use, 23 social policies, 27, 202 industry influence, 235–6 tolerance, 22, 264, 273

340 topiramate, 74 Towns–Lambert treatment, 184 transcranial magnetic stimulation (TMS), 79 transporter, 273 treatments, 8, see also pharmacotherapy abstinence-oriented, capacity to consent, 114–15 admission guidelines, 117–19 case for medical treatment, 124–5 compulsory treatment, 142–4, see also coerced treatment consent to. See informed consent deep brain stimulation (DBS), 78–9, 190–5 ethical principles in, 97–102 autonomy, 99–101 minimum conditions for ethical treatment, 102–3 public good, 101–2 history of addiction ‘cures’, 181–5 history of addiction ‘cures’ early history, 181–2 Keeley Cure, 182–3 regulation, 183 withdrawal treatment, 183–5 legal coercion. See coerced treatment neurosurgery, 78, 187–90, 246 new developments, 165–6 personalised treatment, 208–13 neuroimaging applications, 211–13 pharmacogenetic treatment, 209–11 psychosocial approaches, 81 rate of treatment, 26 right of access to, 124–8, 250 effective treatment, 125–6 harm reduction measures, 126–7 HIV treatment, 127–8 safety requirement, 250

Index transcranial magnetic stimulation (TMS), 79 unevaluated and risky treatments, 128–9 twins, 273 ultra-rapid opioid detoxification (UROD), 128, 187, 245, 274 Universal Declaration of Human Rights (UDHR), 94 utilitarianism, 88, 274 utility, 88 vaccines, 76–7, 170–3, 206–7 children, 206 ethical issues, 171–3 high risk adolescents, 207 nicotine, 200–2 preventive use, 252 valproate, 74 varenicline, 67, 68 ventral tegmental area (VTA), 40, 274 vigabatrin, 74 violent behaviour, 24 vulnerability, 55–9, 264 bioprediction, 197–8 genetic tests, 198–200 neuroimaging studies, 207–8 genetic basis, 32, 55–7 interaction with environmental factors, 57–9 opioid dependence, 28 withdrawal, 20, 22, 264, 274 capacity to consent and, 115 discontinuation syndrome, 20 dopamine and, 130 history of treatments, 183–5 orbitofrontal cortex changes, 47 pharmacotherapy of, 69–70 prisoners, 130 tapered, 68, 273