Testing for Abuse Liability of Drugs in Humans U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration Testing for Abuse Liability of Drugs in Humans Editors: Marian W. Fischman, Ph.D. The Johns Hopkins University School of Medicine Baltimore, MD Nancy K. Mello, Ph.D. Harvard Medical School/McLean Hospital Belmont, MA NIDA RESEARCH MONOGRAPH No. 92 1989 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, MD 20857 i 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 Institute REESE T. JONES, M.D. Troy, New York Langley Porter Neuropsychiatric Institute RICHARD E. BELLEVILLE, Ph.D. San Francisco, California NB Associates, Health Sciences DENISE KANDEL, Ph.D. Rockville, Maryland College of Physicians and Surgeons of Columbia University KARST J. BESTEMAN New York, New York Alcohol and Drug Problems Association of North America HERBERT KLEBER, M.D. Washington, D.C. Yale University School of Medicine New Haven, Connecticut GILBERT J. BOTVIN, Ph.D. Cornell University Medical College RICHARD RUSSO New York, New York New Jersey State Department of Health JOSEPH V. BRADY, Ph.D. Trenton, New Jersey The Johns Hopkins University School of Medicine Baltimore, Maryland 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, Rockville, Maryland 20857 ii Testing for Abuse Liability of Drugs in Humans iii ACKNOWLEDGMENT This monograph is based upon papers and discussions from a conference on Testing for Abuse Liability of Drugs in Humans which took place on November 5-6, 1988, at ameetingof the committee on Problems of Drug Dependence, at the Scanticon Conference Center in Princeton, New Jersey. The conference was sponsored by the Committee on Problems of Drug Dependence, Inc., the National Institute on Drug Abuse, the Food and Drug Administration, and the Drug Enforcement Administration. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published figures and tables, as noted in the text. Some of these have been modified for use in this monograph. Further reproduction of the 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 maybe used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. The opinions expressed herein are the views of the author(s) and do not necessarily reflect the official position 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 commodity, service, or company). Trade or proprietary names (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 number (ADM) 89-1613 Alcohol, Drug Abuse, and Mental Health Administration Printed 1989 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 C ONTENTS Foreward ix Preface xiii I. I NTRODUCTION 1. Testing and Abuse Liability of Drugs in Humans Charles R. Schuster 1 2. The Necessity and Utility of Abuse Liability Evaluations in Human Subjects: The FDA Perspective Frank J. Vocci, Jr 7 3. The Role of Abuse Liability Testing in Drug Control Procedures Howard McClain, Jr. and Frank Sapienza 21 4. Historical Perspectives on the Use of Subjective Effects Measures in Assessing the Abuse Potential of Drugs Jerome H. Jaffe and Faith K. Jaffe . 43 II. DRUG IDENTIFICATION AND CLASSIFICATION 5. Human Abuse Liability Assessment by Measurement of Subjective and Physiological Effects Donald R. Jasinski and Jack E. Henningfield 73 6. Drug Discrimination: Methods for Drug Characterization and Classification George E. Bigelow and Kenzie L. Preston 101 v III. ASSESSMENT OF THE REINFORCING PROPERTIES OF DRUGS 7. Abuse Liability of Anxiolytics and Sedative/Hypnotics: Methods Assessing the Likelihood of Abuse John D. Roache and Roland R. Griffiths 123 8. Drug Self-Administration Procedures: Alcohol and Marijuana Nancy K. Mello 147 9. The Use of Choice Procedures for Assessing the Reinforcing Properties of Drugs in Humans Chris E. Johanson and Harriet de Wit 171 10. Relationship Between Self-Reported Drug Effects and Their Reinforcing Effects: Studies with Stimulant Drugs Marian W. Fischman 211 IV. EPIDEMIOLOGIC ASSESSMENT OF DRUG ABUSE 11. Case Reports and the Assessment of Drug Abuse Liability Edward C. Senay 231 12. United States Epidemiologic Data on Drug Use and Abuse: How are They Relevant to Testing Abuse Liability of Drugs? James C. Anthony and Alison M. Trinkoff 241 13. Current Approaches to Measurements of Drug Use and Abuse in Sweden Ulf Bergman and David Lee 267 vi V. EVALUATION OF THE ABUSE LIABILITY OF DRUGS IN HUMANS: ISSUES AND FUTURE DIRECTIONS 14. Pharmacokinetic and Phartnacodynamic Drug Interactions: Implications for Abuse Liability Testing Edward M. Sellers, Usanda Busto, and Howard L. Kaplan 287 15. Promising New Biologic and Behavioral Correlates of the Reinforcing Properties of Drugs Jack H. Mendelson, Nancy K. Mello, Scott E. Lukas, Bryan T. Woods, and Siew K. Teoh 307 16. Drug Abuse Liability Testing: Human Subject Issues Herbert D. Kleber 341 17. Issues in Human Drug Abuse Liability Testing: Overview and Prospects for the Future Joseph V. Brady 357 18. Conference Summary and Perspectives on Human Drug Abuse Liability Testing Mary Jeanne Kreek 371 Index 377 List of NIDA Research Monographs 393 vii F OREWARD Ladies and Gentlemen: I take great pleasure in welcoming you to this important conference on Testing for Abuse Liability of Drugs in Humans. I thank you all for coming and participating in the conference. This unique conference is sponsored by the Committee on Problems of Drug Dependence (CPDD), the Drug Enforcement Administration (DEA), the Food and Drug Administration (FDA) and the National Institute on Drug Abuse (NIDA). I encourage you to participate in the discussions. Speaking for CPDD, we are delighted to be co-sponsoring this conference with these governmental agencies. This partnership between the public and private sector is essential if we are going to solve the multiple problems associated with the abuse of chemical substances. There are a number of people to thank for organizing this excellent meeting. First and foremost, I thank Drs. Marian W. Fischman and Nancy K. Mello, who served as co-chairs of the committee who prepared the scientific program and other aspects of the meeting. They, and each member of the human testing committee of CPDD are to be congratulated for putting together such an excellent meeting. A debt of gratitude is also owed to Dr. Martin W. Adler, the executive officer of CPDD and his fine staff who handled all of the logistical aspects of the meeting. Finally, on behalf of CPDD, I thank the government agencies who are sponsoring this conference with CPDD for all aspects of their support. Their participation in the planning of the conference was essential. Let me hasten to add our thanks to those pharmaceutical companies who have supported CPDD financially this year. Your generous contributions have been used to support this conference and other work of CPDD. ix I want to spend just a few minutes talking about what CPDD is doing at the present time and why this conference is such a vital portion of that endeavor. The major tenet of the CPDD today is the same as it has been throughout its 60 years of existence. That is, the problems caused by drug dependence and drug abuse will be alleviated only by the appropriate use of knowledge generated from research. Clearly this includes all aspects of treatment, prevention, clinical, basic and many types of research. The three specific objectives of CPDD are: 1) the testing of the dependence liability of drugs, 2) holding the best and most comprehensive scientific meetings on this topic, and 3) serving in advisory and other cooperative capacities with governmental agencies who also are concerned with the abuse of chemical substances. This conference addresses each of these specific objectives. Testing for abuse potential and physical dependence liability CPDD initiated its activity in the testing of dependence liability of chemical substances about 50 years ago when it set up the monkey colony at the University of Michigan. When the number of compounds exceeded the facility at that institution, a second colony was established at the Medical College of Virginia of Virginia Commonwealth University. Initially, both of these colonies were supported only by the generous contributions of the pharmaceutical industry. In recent years, as research has become more expensive, additional funding from NIDA was necessary to continue these tests in monkeys and to expand the testing to include other species and other procedures.