THE EFFECTS OF DRUG ABUSE ON THE HUMAN NERVOUS SYSTEM Edited by BERTHA MADRAS AND MICHAEL KUHAR Amsterdam • Boston • Heidelberg • London New York • Oxford • Paris • San Diego San Francisco • Sydney • Tokyo Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA First edition 2014 © 2014 Elsevier Inc. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/ permissions, and selecting Obtaining permission to use Elsevier material. Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, indepen- dent verification of diagnoses and drug dosages should be made. Library of Congress Cataloging-in-Publication Data The effects of drug abuse on the human nervous system / edited by Bertha Madras, Michael Kuhar. -- First edition. p. ; cm. Includes bibliographical references. ISBN 978-0-12-418679-8 I. Madras, Bertha, editor of compilation. II. Kuhar, Michael J., editor of compilation. [DNLM: 1. Substance-Related Disorders--physiopathology. 2. Nervous System--drug effects. 3. Risk Factors. 4. Substance-Related Disorders--epidemiology. WM 270] RC564 362.29--dc23 2013039438 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-418679-8 The charcoal drawing on the cover is by Vivian Felsen and is from the collection of Bertha Madras. For information on all Academic Press publications visit our web site at store.elsevier.com Printed and bound in USA 14 15 16 17 18 10 9 8 7 6 5 4 3 2 1 LIST OF CONTRIBUTORS Peter H. Addy Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT Scott Bowen Department of Psychology, Wayne State University, Detroit, MI, USA Kathleen T. Brady Mental Health Service, Ralph H. Johnson VA Medical Center, Charleston, SC, USA; Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA James Robert Brašić Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Johns Hopkins Outpatient Center, Baltimore, MD, USA Andreas Büttner Institute of Forensic Medicine, University of Rostock, Rostock, Germany Ryan HA. Chan Addiction and Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, CA, USA Domenic A. Ciraulo Department of Psychiatry, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA Wilson M. Compton Division of Epidemiology, Services and Prevention Research, National Institute on Drug Abuse, Bethesda, MD, USA Caryne P. Craige Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA Silvia L. Cruz Departamento de Farmacobiología, Cinvestav, Sede Sur, Mexico, Federal District, Mexico Tomas Drgon Molecular Neurobiology Branch, NIH-IRP (NIDA), Baltimore, MD, USA Deepak Cyril D’Souza Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT; Department of Psychiatry, Yale University School of Medicine, New Haven, CT Nicole M. Enman Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA xi xii List of Contributors A. Eden Evins Department of Psychiatry, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA William E. Fantegrossi Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Larry Gentilello Department of Surgery, University of Texas, Dallas, TX, USA Aryeh I. Herman Department of Psychiatry and VA Connecticut Healthcare System, School of Medicine, Yale University, West Haven, CT, USA Harold Kalant Department of Pharmacology & Toxicology, University of Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada Jongho Kim Department of Diagnostic Radiology and Nuclear Medicine University of Maryland Medical Center, Baltimore, MD, USA Stephen J. Kish Human Brain Laboratory, Centre for Addiction and Mental Health, Departments of Psychiatry and Pharmacology, University of Toronto, Toronto ON, Canada Marsha Lopez Division of Epidemiology, Services and Prevention Research, National Institute on Drug Abuse, Bethesda, MD, USA Bertha Madras Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, New England Primate Research Center, Southborough, MA, USA Diana Martinez Department of Biological Sciences, Rutgers University, Newark, NJ, USA Una D. McCann Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA John E. Mendelson Addiction and Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, CA, USA David E. Nichols Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA Mark Oldham Department of Psychiatry, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA Zev Schuman-Olivier Department of Psychiatry, Cambridge Hospital, Cambridge, MA; Cambridge Health Alliance, Somerville, MA; Harvard Medical School, Boston, MA List of Contributors xiii Rajiv Radhakrishnan Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT; Department of Psychiatry, Yale University School of Medicine, New Haven, CT Mohini Ranganathan Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT; Department of Psychiatry, Yale University School of Medicine, New Haven, CT George A. Ricaurte Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Cendrine Robinson Department of Medical and Clinical Psychology, Uniformed Services University of the Health Science, Bethesda, MD, USA R. Andrew Sewell Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT; Department of Psychiatry, Yale University School of Medicine, New Haven, CT Patrick D. Skosnik Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT; Department of Psychiatry, Yale University School of Medicine, New Haven, CT Mehmet Sofuoglu Department of Psychiatry and VA Connecticut Healthcare System, School of Medicine, Yale University, West Haven, CT, USA Luke E. Stoeckel Department of Psychiatry, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA Pierre Trifilieff School of Public Health, Columbia University, New York, NY, USA George R. Uhl Molecular Neurobiology Branch, NIH-IRP (NIDA), Baltimore, MD, USA Ellen M. Unterwald Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA Donna Walther Molecular Neurobiology Branch, NIH-IRP (NIDA), Baltimore, MD, USA Andrew J. Waters Department of Medical and Clinical Psychology, Uniformed Services University of the Health Science, Bethesda, MD, USA Naimah Weinberg Division of Epidemiology, Services and Prevention Research, National Institute on Drug Abuse, Bethesda, MD, USA Erika Weisz Department of Psychiatry, Massachusetts General Hospital, Boston, MA CHAPTER ONE Drug Use and Its Consequences Bertha Madras Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, New England Primate Research Center, Southborough, MA, USA 1. INTRODUCTION Humans are explorers of territory, new ideas, social contacts, mates, and sources of food. Successful exploration produced rewards, reinforced behaviors, and enhanced survival. Over millennia, our ancestors explored plants as food sources and seren- dipitously discovered that certain plants engendered unique rewarding stimuli. Some ingested phytochemicals were mildly arousing (e.g. nicotine, caffeine), others enhanced mood or altered perception, reduced dysphoria and pain, or intoxicated with mild or intense euphoria (alcohol, marijuana, hallucinogens, opiates, cocaine). Over the past two centuries, consumption of these substances expanded exponentially. Isolation from source materials, purification, chemical modification, delivery by chemical mechanisms or devices for maximum effect, and global marketing contributed to this expansion. Modern chemistry, production, and marketing methods produced an array of consumed drugs capable of generating hedonic signals that usurped motivational and volitional control of behaviors essential for survival. Drug use (tobacco, alcohol, other drugs) now accounts for nearly 25% of deaths annually in the United States. Death is not the sole peril. We have witnessed an unprecedented level of adverse biological, behavioral, medical, and social consequences. 1.1. Early Origins The use of psychoactive drugs for religious, ritualistic, and medical purposes is an ancient practice, documented in texts, evidenced in artifacts (e.g. seeds, pipes), in trace chemi- cal signatures, and artistic and sculptural images. References to excessive alcohol con- sumption are found in ancient, historical documents and literary prose (e.g. the historian Josephus, and William Shakespeare). Opiates are implicated in this quote from Homer (ninth century B.C.): “presently she cast a drug into the wine of which they drank to lull all pain and anger and bring forgetfulness of every sorrow…” Opiates were used for medicinal or psychoactive purposes, as they migrated from Sumeria to India, China and Western Europe (Brownstein, 1993). By the sixteenth century, manuscripts describing opi- oid drug abuse and tolerance were published in various countries, a consequence greatly The Effects of Drug Abuse on the Human Nervous System © 2014 Elsevier Inc. http://dx.doi.org/10.1016/B978-0-12-418679-8.00001-0 All rights reserved. 1 2 Bertha Madras accelerated by the isolation of morphine from the opium poppy in 1803 (Brownstein, 1993). Marijuana is another ancient drug, used by Eastern cultures for medical and psy- choactive purposes. Physical evidence of its use was found in ashes beside a skeleton of a 14-year-old girl, apparently in the midst of a failed breech birth (Zias et al., 1993). Cryptic mentions of mystifying drug effects in ancient texts (Dannaway et al., 2006; Dannaway, 2010), or religious prohibitions are scattered in various sources, but there is scant evidence that ancient drug use was as extensive or propagated the same public health, welfare, safety concerns, and consequences or responses, as in modern times. 1.2. Modern Era The past two centuries have witnessed an exponential rise in drug use and a corre- sponding increase in associated consequences. The increase has been fueled by mod- ernization: (1) the discovery and cross-cultural propagation of psychoactive drugs by explorers of new continents; (2) the advent of organic chemistry, which enabled isola- tion of pure, potent drugs from plants (e.g. cocaine, morphine) and de novo synthesis of new drugs (e.g. oxycodone, methamphetamine, amphetamine, cannabicyclohex- anol) guided by structures of isolated phytochemicals (morphine, ephedrine, THC or Δ-9-tetrahydrocannbinol); (3) the development of modern drug delivery systems, the needle/syringe, the cigarette-rolling machine, and synthetic salt forms of drugs that enable efficient drug delivery systems; (4) the advent of sophisticated agricul- tural and purification methods increased drug concentrations in plants and improved crop yields; (5) modern capitalism increased prosperity and expendable income across classes. Expansion of user markets raised the profitability for manufacturing and sales of drugs; (6) sophisticated global marketing exploited modern, efficient communica- tion and transportation systems; (7) cultural shifts eroded parental/family oversight at earlier stages of development; (8) drug use was normalized by cultural icons, media, and internet sites; (9) drug use was promoted by wealthy individuals for cryptic rea- sons, by underwriting state ballot and legislative initiatives to promote drug normal- ization, and by profit-seeking industries using advertising targeted to youth. The net effect was to make highly potent drugs widely available. A new enterprise, distribution of simple chemicals isolated and purified from plants, was born (Figure 1). The nine- teenth century came to a close, with a cocaine and morphine epidemic in the United States, and a severe opium epidemic, especially in Asia. The twentieth century closed with global marketing and consumption of an array of phytochemicals and synthetic, “designer” drugs. The trajectory of the twenty-first century will be driven by national and international laws, regulations, shaped by biomedical science and informed public opinion. In the late nineteenth century, drugs were advertised, freely available, unregulated in patent medicines, sold freely in drugstores, dissolved in popular drinks (colas and wines), as tonics, elixirs, and remedies. The major drugs at that time, heroin, morphine, cocaine, Drug Use and Its Consequences 3 Figure 1 The biology of addiction. A simple ingested chemical, isolated from a plant and of molecu- lar weight less than 1000, can profoundly affect the brain and body. On top right is a photo of “skin popping”, a method of injection of cocaine under the skin that leaves lesions. The bottom right is a photo of a person with respiratory depression, resulting from a heroin overdose. and marijuana, were marketed without restraint and had vocal or covert supporters, including high-profile physicians, Sigmund Freud and William Halsted, who succumbed to severe addiction (Musto, 1968, 2002; White, 1998; Musto et al., 2002; Gay et al., 1975; Cohen, 1975). Problems with cocaine were evident from the beginning. By the turn of the twentieth century, 200,000 people are estimated to have been addicted to drugs in the United States alone. Increased availability, rapid rates of brain entry, distribution of multiple drugs, and initiation by younger populations more susceptible to addiction created an unfettered market for drugs. 1.3. Advent of Regulations and Laws The adverse consequences aroused attention and legislative responses from physicians, national governments, and international organizations. As the medical historian David Musto stated “from repeated observation of the damage to acquaintances and society”, awakened national and international governments to counteract these trends with regu- latory, taxation and laws. In 1875 opium dens were outlawed in San Francisco. In 1906, the federal government passed the Pure Food and Drugs Act, a law a quarter-century 4 Bertha Madras in the making, that prohibited interstate commerce in adulterated and misbranded food and drugs and required accurate labeling of patent medicines containing opium and other drugs. The modern regulatory functions of the Food and Drug Administration (FDA) began with the passage of the 1906 Pure Food and Drugs Act, which provided basic elements of protection that consumers had not known before that time. Despite rapid metamorphic changes in our medical, cultural, economic, and political institutions over the past century, the core public health mission of the FDA retains a protective bar- rier against unsound claims and unsafe, ineffective drugs. The 1906 legislation was extended by passage of the Harrison Act in 1914 forbid- ding the sale of narcotics or cocaine, except by licensed physicians. Regulatory mecha- nisms marched in tandem with newly emerging drugs, restricting harm to individuals by restricting access to drugs. Prior to the 1960s, Americans did not see drug use as an acceptable behavior, or an inevitable fact of life. Tolerance of drug use led to a dramatic rise in crime between 1960s and early 1990s, and the landscape of America was altered forever, (DEA). Consequently, the Drug Enforcement Administration (DEA) was created in 1973 by Executive Order to establish a single unified command over legal control of drugs and address America’s growing drug problem. Congress passed the Controlled Substances Act to consolidate and replace, by then, more than 50 pieces of drug legisla- tion. It established a single system of control for both narcotic and psychotropic drugs for the first time in the U.S. history (DEA). Since the creation of the DEA, drug policy has been debated as choices between activists for free access to drugs and advocates for restrictive policies (Dupont et al., 2011). Activists view regulations as a restraint on their right to freely pursue “victimless” drug-induced pleasure, expansion of consciousness and of potential, self-medication, and profit. They are buoyed by narrow views that claim few people become addicted and that some addicts are productive. For example, Nikki Sixx documents in his book “The Heroin Diaries: a Year in the Life of a Shattered Rock Star”, his abil- ity, albeit limited, to perform during a severe addiction. Significantly, drug use is highest among 15–25 year olds, the “age of invulnerability”. Advocates of stringent policies view drug use issues through a prism of human health, welfare, social, and safety concerns. The resistance to drugs and a shift in perceptions takes years to penetrate the public opinion, when drug use becomes viewed as reducing natural potential, and the consequences of drugs in family members, schools, and the work- place begin to take a toll (Musto, 1995). The counterclaims to restrictive legal and social containment of drug commerce and consumption are based on drug-seeking and use as historical, normative, acceptable, inevitable, a rite of passage, an expres- sion of personal liberty, an extension of natural potential, and a victimless social activity. Some advocates acknowledge the evidence that drugs can produce adverse consequences to individual users (overdose and death, HIV-AIDS, dehydration), and focus on reducing “drug-associated harm”. Needle exchange programs (designated Drug Use and Its Consequences 5 syringe exchange program by advocates to substitute the pejorative delivery sys- tem “needle” with a container designation “syringe”), provision of water bottles at ecstasy-infused “rave” parties, and advocating for over-the-counter naloxone for opioid overdose crises, are practical solutions to “harm reduction”. Reducing supply or demand for drugs and prevention and intervention program are not emphasized in this movement. From my perspective, “harm reduction” is incompatible with strong evidence from addiction biology and medicine that drug use is associated with unacceptable, elevated risks in multiple domains: physical, mental, cognitive, behavioral, safety, education, and employment. Fundamental questions are rarely addressed in the case made for legaliza- tion: “will addiction rates rise and will people who initiate drug use intend to become addicted?”; “Do recovering addicts regret their recovery and desire the addicted state?” “Do addicted people benefit more, physically, personally, socially, emotionally and psy- chologically, from programs/services that accept and facilitate continued, uncontrollable drug use or from treatment programs and recovery services that emphasize abstention?”; “Is drug use a victimless activity?” Acceptance of the inevitability of use and mitigation of potential adverse consequences, without advocacy for prevention and treatment per se, is poor medical, public health, and national policy. 1.4. Current Legislative Initiatives The front lines of this debate reside in the status of marijuana. In a 1980 Gallup Poll, 53% of the population favored legalization. Within 6 years, the number fell to 27%, and by 2011, it rose to 50%. Currently, there is a concerted political and media campaign to erode or eliminate many of the federally driven legal constraints, implemented over the past century, with the goal of legalizing marijuana, initially as a medicine. At the federal level, the FDA reaffirmed in 2006, that “there are no sound scientific studies supporting the medical use of marijuana. Bills introduced to legalize marijuana and to restrict the reach of the FDA in states that approved marijuana as a medicine have not progressed through the legislative process. The DEA reaffirmed that it would not shift marijuana to Schedule II, the IRS issued a ruling that prohibits business-related tax deductions for businesses selling or cultivating marijuana. Most of the legislative actions are occur- ring at the state level. In 2011, no fewer than 130 pro-legalization legislative bills were introduced in states, more than double the rate in 2008 (SOS Annual Report, 2011). In the same year, 49 states introduced 299 pieces of antidrug legislation, and of these 77 were signed into law. Initiatives defeated introduction of medical marijuana in 16 states, legalization of taxation and regulation bills in five states, and decriminalization in six states. Some focused on the status of marijuana, others restricted the sale and posses- sion of a synthetic cannabinoid (K2), “spice and bath salts”, or promoted veteran’s drug treatment courts, enhanced prescription drug monitoring laws, and established Good Samaritan laws.