Biological Vulnerability to Drug Abuse DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration Biological Vulnerability to Drug Abuse Editors: Roy W. Pickens, Ph.D. Division of Clinical Research National Institute on Drug Abuse Dace S. Svikis, B.A. The Johns Hopkins University School of Medicine Baltimore, Maryland NIDA Research Monograph 89 1988 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, Maryland 20857 NIDA Research Monographs are prepared by the research divisions of the National Institute on Drug Abuse and published by its Office of Science. The primary objective of the series is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisors MARTIN W. ADLER, Ph.D. MARY L. JACOBSON Temple University School of Medicine National Federation of Parents for Philadelphia, Pennsylvania Drug-Free Youth Omaha, Nebraska SYDNEY ARCHER, Ph.D. Rensselaer Polytechnic lnstitute Troy, New York REESE T. JONES, M.D. Langley Porter Neuropsychiatric lnstitute RICHARD E. BELLEVILLE, Ph.D. San Francisco, California NB Associates,Health Sciences Rockville, Maryland DENISE KANDEL, Ph.D. KARST J. BESTEMAN College of Physicians and Surgeons of Alcohol and Drug Problems Association Columbia University of North America New York, New York Washington, D. C. GILBERT J. BOTVIN, Ph.D. Cornell University Medical Collage HERBERT KLEBER, M.D. New York, New York Yale University School of Medicine New Haven, Connecticut JOSEPH V. BRADY, Ph.D. The Johns Hopkins University School of Medicine RICHARD RUSSO Baltimore, Maryland New Jersey State Department of Health Trenton, New Jersey THEODORE J CICERO, Ph.D. Washington University School of Medicine St. Louis, Missouri NIDA Research Monograph Series CHARLES R. SCHUSTER, Ph.D. Director, NIDA THEODORE M. PINKERT, M.D.. J.D. Acting Associate Director for Science, NIDA Parklawn Building, 5600 Fishers Lane, RockviIle, Maryland 20857 Biological Vulnerability to Drug Abuse ACKNOWLEDGMENT This monograph is based on papers and discussions from a technical review on biological vulnerability to drug abuse held on June 2 and 3, 1986, at Rockville, Maryland. The review meeting was sponsored by the Office of Science and the Division of Clinical Research, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder's permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U. S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. DHHS Publication No. (ADM)90-1590 Alcohol, Drug Abuse, and Mental Health Administration Printed 1988, Reprinted 1990 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index Biosciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. iv Preface Surveys have shown a heterogeneous pattern of illicit drug use by the American public. Fortunately, many people never experiment with illicit drugs and, therefore, avoid the personal tragedy that drug abuse can bring. Others may be enticed into experimenting with drugs but, having done so, refrain from any further drug use. Still others, however, who begin with experimentation, eventually develop a regular pattern of drug use that is difficult to termi- nate although it may produce severe personal, social, and medical complications. The factors that account for these individual differences in outcome to drug use are largely unknown. They un- doubtedly will include a wide range of behavioral, biological, psychosocial, and cultural influences. In addition, the combina- tion of factors that account for drug experimentation may be dif- ferent from the combination of factors that account for chronic drug abuse/dependence. It is important to understand the factors involved in the etiology of drug abuse for several reasons. Not only will this knowledge expand our scientific knowledge base, but it will hopefully lead to improved strategies for the treatment and prevention of drug abuse as well. Research findings suggest that genetic factors are involved in the etiology of alcoholism. It is expected that genetic factors may also be involved in the etiology of drug abuse. In an attempt to understand the role of genetic factors in drug abuse, a technical review on "Biological Vulnerability to Drug Abuse" was held on June 2-3, 1986, in Rockville, MD. Researchers from the fields of alcoholism and drug abuse were invited to review the present state of knowledge in the area and to discuss future research directions. This research monograph is based in large part on the proceedings of that review. Included are discussions of strategies for identi- fying genetic factors in drug abuse, assumptions and methodological issues that underlie each strategy, results of recent investiga- tions in the area, and implications of the findings for treatment and prevention of drug abuse. The technical review and resulting research monograph are intended to stimulate research interest in v the genetics of drug abuse, as well as in other factors that may be involved in the etiology of drug abuse. Charles R. Schuster, Ph.D. Director National Institute on Drug Abuse vi Contents Page Genetic Vulnerability to Drug Abuse Roy W. Pickens and Dace S. Svikis. 1 Influence of Genetic Factors on Drug-Reinforced Behavior in Animals Richard A. Meisch and Frank R. George. 9 Family Pedigree Studies of Biological Vulnerability to Drug Dependence James R. Stabenau. , . 25 The Twin Method in the Study of Vulnerability to Drug Abuse Roy W. Pickens and Dace S. Svikis. 41 Etiologic Factors in Substance Abuse: An Adoption Study Perspective C. Robert Cloninger. 52 The High-Risk Paradigm in Alcohol and Drug Abuse Research Ralph E. Tarter. 73 Personality Factors in Drug Addiction James N. Butcher . 87 Individual Differences in Drug Response James R. Wilson. 93 The Role of Psychopathology in the Familial Transmission of Drug Abuse Bruce J. Rounsaville . 108 vii Page Methodological Issues in Family, Adoption, and Twin Research Dace S. Svikis and Roy W. Pickens. 120 Analytical Approaches to Twin and Family Data Matt McGue . 134 Exploring Drug Abuse With Genetic Strategies: Cautionary Tales Irving I. Gottesman. 150 Biological Vulnerability: Treatment Implications/Applications George E. Bigelow, Robert K. Brooner, Mary E. McCaul, and Dace S. Svikis . 165 The Applications of Biological Vulnerability Research to Drug Abuse Prevention Edward Kaufman . 174 List of NIDA Research Monographs . 181 viii Genetic Vulnerability to Drug Abuse Roy W. Pickens and Dace S. Svikis INTRODUCTION The purpose of this review is to assess the current status of our knowledge regarding genetic factors in drug abuse. That genetic factors may be involved in drug abuse is suggested by several decades of research in the field of alcoholism, where research has strongly implicated a role for genetic factors in the etiology of the disorder. For example, animals can be selectively bred to show alcohol-accepting characteristics (Deitrich and Spuhler 1984). Human family studies have shown that first-degree relatives of alcoholics are more likely to be alcoholic than first-degree rela- tives of nonalcoholics (Cotton 1979). Adoption studies have found that adopted-away children of alcoholic parents are more likely to develop alcoholism than adopted-away children of nonalcoholic parents (Goodwin et al. 1973). Twin studies have found that monozygotic twins are more likely to be concordant for alcoholism than dizygotic twins (Kaij 1960). Finally, high-risk studies have shown that children of alcoholics differ from children of non- alcoholics in response to alcohol (Schuckit 1985). In contrast to alcoholism, little is known about genetic factors that contribute to other types of drug abuse (e.g., heroin addic- tion and cocaine abuse). In terms of etiology, most attention in the drug abuse field has been focused on psychosocial factors that contribute to drug experimentation by adolescents (Jones and Battjes 1985). Only limited attention has been paid to the role of genetic and environmental factors in drug abuse, particularly as it relates to the development of compulsive patterns of drug abuse and/or drug dependence. Evidence suggests that the pattern of inheritance for drug abuse