US DEPARTMENT OF HEALTH EDUCATION AND WELFARE • Public Health Service • Alcohol Drug Abuse and Mental Health Administration Behavioral Tolerance: Research and Treatment Implications Editor: Norman A. Krasnegor, Ph.D. NIDA Research Monograph 18 January 1978 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National lnstitute on Drug Abuse Division of Research 5600 Fishers Lane RockviIle. Maryland 20657 For sale by tho Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 (Paper Cover) Stock No. 017-024-00699-8 The NIDA Research Monogroph series iS prepared by the Division of Research of the National Institute on Drug Abuse Its primary objective is to provide critical re- views of research problem areas and techniques. the content of state-of-the-art conferences, integrative research reviews and significant original research its dual publication emphasis iS rapid and targeted dissemination to the scientific and professional community Editorial Advisory Board Avram Goldstein, M.D Addiction Research Foundation Polo Alto California Jerome Jaffe, M.D College Of Physicians and Surgeons Columbia University New York Reese T Jones, M.D Langley Porter Neuropsychitnc Institute University of California San Francisco California William McGlothlin, Ph D Department of Psychology UCLA Los Angeles California Jack Mendelson. M D Alcohol and Drug Abuse Research Center Harvard Medical School McLeon Hospital Belmont Massachusetts Helen Nowlis. Ph.D Office of Drug Education DHEW Washington DC Lee Robins, Ph.D Washington University School of Medicine St Louis Missouri NIDA Research Monograph series Robert DuPont, M.D. DIRECTOR, NIDA William Pollin, M.D. DIRECTOR, DIVISION OF RESEARCH, NIDA Robert C. Petersen, Ph.D. EDITOR-IN-CHIEF Eunice L Corfman, M.A. EDITOR Eleanor W. Waldrop MANAGING EDITOR Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Behavioral Tolerance: Research and Treatment Implications ACKNOWLEDGMENTS The technical review upon which this monograph is based was capably planned, conducted, and reported by staff of Macro Systems, Inc., Silver Spring, Maryland, under NIDA Contract No. 271-75-1139. The review took place at Rockville, Maryland, on June 23 and 24, 1977. Library of Congress catalog card number 77-93034 DHEW publication number (AIM) 78-551 Printed 1977 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of BioSciences Information Service, Chemical Abstracts, Psychological Abstracts, and Psychopharmacology Abstracts. Foreword Tolerance to the effects of abused substances has long been implicated as a causal factor in addiction. Such tolerance is not based entirely on pharmacologic processes; recently the role played by nonpharmacol- ogic factors has become an area of increasing research interest and potential clinical importance. An understanding of the mechanisms of tolerance is a key element in our eventually understanding the larger question of human dependence upon such substances, and ultimately will be useful for developing improved strategies for prevention and treatment. Aspects of tolerance are being investigated across a broad range of drugs, in humans as well as a variety of animal species. At present, no agreement exists on the mechanisms underlying behavioral tolerance, but as data continue to be added to the base of empirical knowledge, a theoretical synthesis may be approached. The technical review at which the papers in this monograph were pre- sented was held at the National Institute on Drug Abuse on June 23-24, 1977. At that meeting, past and present research findings on behavioral tolerance in substance abuse were presented; theoretical and experimental approaches to investigation in this field were com- pared and contrasted; an attempt was made to develop a working defi- nition of behavioral tolerance as it applies to substance abuse; and possible new initiatives for investigating the concept within clinical research and experimental treatment research settings were discussed, The central purpose of this monograph is to share what was communicated at the technical review, so as to stimulate further interest among the scientific and medical communities in the part played by nonpharmacol- ogic factors in drug tolerance and dependencies, and thus to further the accumulation of new knowledge. William Pollin, M.D. Director Division of Research National Institute on Drug Abuse v Technical Review Participants Jack D. Blaine, M.D. Eugene Le Blanc, Ph.D. Research Psychiatrist Director, Strategic Planning Clinical-Behavioral Branch and Research Branch Division of Research, NIDA Addiction Research Foundation 5600 Fishers Lane 15 Overlea Boulevard Rockville, Maryland 20857 Toronto, Ontario, Canada M4A1A9 Howard D. Cappell, Ph.D. Charles P. O’Brien, M.D., Ph.D. Head, Psychology Director, Drug Dependence Treat- Addiction Research Foundation ment and Research Center 33 Russell Street c/o Veterans Admin. Hospital Toronto, Ontario, Canada M5S2Sl University and Woodland Avenues Philadelphia, Pennsylvania 19104 Stuart M. Deikel, M.A. Department of Psychology Constantine X. Poulos. Ph.D. McGill Universitv Scientist, Clinical Psychology Montreal, Quebec; Canada H3C3Gl Addiction Research Foundation representing Toronto, Ontario, Canada M5S2Sl Brooks Carder, Ph.D. Scientist Pierre F. Renault, M.D. Synanon Research Institute Chief, Clinical-Behavioral Branch P.O. Box 786 Division of Research, NIDA Marshall, California 94940 5600 Fishers Lane Rockville, Maryland 20857 Peter B. Dews, M.D., Ph.D. Head, Laboratory of Psychobiology Charles R. Schuster, Ph.D. Department of Psychiatry Professor of Psychiatry Harvard Medical School University of Chicago 25 Shattuck Street 950 East 59th Street Boston, Massachusetts 02115 Chicago, Illinois 60637 John L. Falk, Ph.D. Shepard Siegel, Ph.D. Professor of Psychology Professor of Psychology Rutgers University McMaster University Busch Campus Hamilton, Ontario, Canada L8S4Kl New Brunswick, New Jersey 08903 James H. Woods, Ph.D. Douglas P. Ferraro, Ph.D. Associate Professor of Pharma- Professor of Psychology cology University of New Mexico University of Michigan Albuquerque, New Mexico 87131 Ann Arbor, Michigan 48104 Reese T. Jones, M.D. Technical Review Moderator Associate Professor in Residence Norman A. Krasnegor. Ph.D. Department of Psychiatry Deputy Chief, Cl&&al-Behavioral University of California Branch 401 Parmassus Avenue Division of Research, NIDA San Francisco, California 94143 5600 Fishers Lane Rockville, Maryland 20857 vi Contents FOREWORD William Pollin . v TECHNICAL REVIEW PARTICIPANTS . vi INTRODUCTION Norman A. Krasnegor . 1 I. CONCEPTUALIZATION Theoretical Basis of Behavioral Tolerance: Implications of the Phenomenon for Problems of Drug Abuse Charles R. Schuster. 4 Behavioral Tolerance P. B. Dews. 18 II. NARCOTICS A Pavlovian Conditioning Analysis of Morphine Shepard Siegel. 27 Narcotic Tolerance and Operant Behavior James H. Woods and John Carney. 54 Conditioning Effects of Narcotics in Humans Charles P. O'Brien, Thomas Testa, Joseph Ternes, and Robert Greenstein. 67 III. ETHANOL Tolerance as a Behavioral Phenomenon: Evidence From Two Experimental Paradigms A. E. Le Blanc, C. X. Poulos, and H. D. Cappell. 72 IV. MARIHUANA Environmental Influences-on Marihuana Tolerance Brooks Carder. 90 Behavioral Tolerance to Marihuana Douglas P. Ferraro. 103 Behavioral Tolerance: Lessons Learned From Cannabis Research Reese T. Jones. 118 vii V. STIMULANTS Behavioral Tolerance to Cocaine William R. Woolverton and Charles R. Schuster. 127 VI. DEPRESSANTS Behavioral and pharmacological Components of Phenobarbital Tolerance Maisy Tang and John L. Falk. 142 LIST OF MONOGRAPHS. 149 viii Introduction Norman A. Krasnegor, Ph.D. Tolerance to a substance can be demonstrated by the observation that repeated administrations of a fixed dose lead to a diminu- tion of effect. Alternatively, one can demonstrate tolerance by showing that a substance’s original effect, diminished in magni- tude after sequential exposures to a fixed dose, can be reinstated by an increase in that dose. An understanding of how tolerance influences the dependence processes associated with chronic habit- ual drug and alcohol use is essential for those who work in the field of substance abuse research because of its reported necessary role in the maintenance of drug addiction and alcoholism. Accord- ing to this view, drug and alcohol addicts become physically dependent, in part, because the initial effects of a substance diminish with repeated use. In order to attain the original effect that a substance produces in a user, therefore, larger or more frequent doses are consumed. The problem is further com- pounded for addicts because the diminished response to a fixed dose of an abused substance may lead to the onset of withdrawal symptoms. Thus, the development of tolerance to a substance can contribute to the dependence process by escalating the need for more of that substance to attain a desired effect or to postpone or eliminate abstinence symptoms. Pharmacologists generally divide the study of tolerance into two broad categories: dispositional and functional. The former sub- sumes all studies on a substance’s effect when changes occur which limit the amount of a substance that bathes its target cells. Such investigations encompass research on altered absorption, distribu- tion, inactivation and/or excretion of a substance from the body. Also included under this