National Institute on Research Findings on Smoking of Abused Substances U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration Research Findings on Smoking of Abused Substances Editor: C. Nora Chiang, Ph.D. Richard L. Hawks, Ph.D. Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 99 1990 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 20657 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 Research Findings on Smoking of Abused Substances ACKNOWLEDGMENT This monograph is based on the papers and discussion from a technical review on “Research Findings on Smoking of Abused Substances” held on November 10, 1988, in Rockville, MD. The review meeting was sponsored by the Office of Science and the Division of Preclinical 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 number (ADM)90-1690 Printed 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 Contents Page Introduction and Overview . 1 C. Nora Chiang Current Patterns of Drug Abuse That Involve Smoking . 5 Donald R. Wesson and Peter Washburn Clinical Pharmacology of Inhaled Drugs of Abuse: Implications in Understanding Nicotine Dependence . 12 Neal L. Benowitz The Pharmacology of Cocaine Smoking in Humans . 30 Reese T. Jones Marijuana Smoking: Factors That Influence the Bioavailability of Tetrahydrocannabinol . 42 Mario Perez-Reyes Effects of Habitual Use of Marijuana and/or Cocaine on the Lung . 63 Donald P. Tashkin, Suzanne Fligiel, Tzu-Chin Wu, Henry Gong, Jr., Richard G. Barbers, Anne H. Coulson, Michael S. Simmons, and Theodore F. Beals Marijuana Effects and Urinalysis After Passive Inhalation and Oral Ingestion . 88 Edward J. Cone v Pyrolytic Degradation of Heroin, Phencyclidine, and Cocaine: Identification of Products and Some Observations on Their Metabolism . 97 C. Edgar Cook and A. Robert Jeffcoat Chemical and Biological Analysis of Marijuana Smoke Condensate . , . 121 Charles M. Sparacino, Patricia A. Hyldburg, and Thomas J. Hughes Pyrolysis and Inhalation Studies With Phencyclidine and Cocaine . , . 141 Billy R. Martin and Joseph Boni Animal Models of Drug Self-Administration by Smoking . 159 Ronald W. Wood List of NIDA Research Monographs . 172 vi Introduction and Overview C. Nora Chiang and Richard L. Hawks For centuries, smoking has been a popular route for the self-administration of recreational drugs such as tobacco, marijuana, and opium. Recently, smoking has also gained popularity for the use of phencyclidine (PCP), co- caine, and methamphetamine. It is likely that smoking as a route of admin- istration is being more frequently chosen by drug abusers as a “safer” route because of the dangers of intravenous (IV) transmission of the human immunodeficiency virus. This route of administration is a major contribut- ing factor to the current epidemic of cocaine and methamphetamine abuse. The toxicity resulting from this route of administration is complex. Not only the drug itself but also the resulting degradation products contribute to the pharmacological and toxicological effects. In addition, there are unique pharmacokinetic and behavioral characteristics associated with smoking as a route of administration. To understand the particular toxicity associated with smoking, it is necessary to integrate research findings in several areas. These include chemistry, pharmacology and toxicology, pharmacokinetics, and behavioral and clinical observations. A technical review concerning research finding on smoking of abused substances was held by the National Institute on Drug Abuse on November 10, 1988. The first presentation by Dr. Donald Wesson on the pattern as well as the techniques for the self-administration of abused drugs revealed that cocaine and methamphetamine smoking is on the rise and that the methods for smoking abused drugs are quite variable. Often, combinations of drugs are smoked. This information is important for the interpretation of clinical observations and for the design of research experiments for the investigation of various aspects of smoking of abused drugs. Dr. Neal Benowitz discus& the unique pharmacokinetic and pharmaco- dynamic aspects of the smoked route of drug administration that may con- tribute to the abuse of tobacco cigarettes. Using nicotine as an example, Dr. Benowitz demonstrated that the inhalation route provides a very rapid delivery of the drug into the brain. The smoker is therefore able to titrate the level of the drug in the brain to achieve a desired mental state. This user control would be expected to enhance the reinforcing nature of the 1 drug and thus contribute to the preferred use of inhalation for abused substances. The pharmacokinetic and pharmacodynamic data on cocaine presented by Dr. Reese Jones showed rapid peak effects and peak plasma levels from smoked and IV doses as compared with those from intranasal and oral doses. He explained that the rapidly developed tolerance, which occurs even with the first dose of cocaine, is a contributing factor to the much less intense drug effects perceived from the oral and intranasal doses. As the intense peak effect is important to drug abusers, the differences between addictive potential and lethality of cocaine from different routes of adminis- tration undoubtedly could be partly due to the pharmacokinetic differences. The dynamics of smoking marijuana was presented by Dr. Mario Perez- Reyes. A great portion of tetrahydrocannabinol (THC) is either degraded during pyrolysis or lost in sidestream smoke. Therefore, the manner in which marijuana cigarettes are smoked plays an important role in determin- ing the amount of THC inhaled or the resultant plasma concentrations. Consequently, great variability in both plasma levels and observed effects has been reported for the smoked dose. The assumption that smokers have control over the rate of THC inhaled is also evidenced by the observation that the smoke volume inhaled per puff during smoking progressively decreases. Lungs are the principal organ exposed to the smoke and pyrolysis products of abused drugs. The long-term effects of such smoking on the lung were discussed by Dr. Donald Tashkin. Chronic smoking of only a few mari- juana cigarettes a day has been shown to have long-term adverse effects on the lung. A comparison of habitual smoking of marijuana and tobacco indi- cates that both cause functional alterations in the respiratory tract but on different sites. The adverse effects on the respiratory tract and the lung caused by marijuana plus tobacco are additive. Preliminary data from studies with free-base cocaine smokers revealed a high proportion of sub- jects with acute cardiopulmonary symptoms temporally related to cocaine smoking. Further research should be directed at the effect of cocaine smok- ing on lung function and structure. Health concerns about passive exposure to tobacco smoke have led to simi- lar concerns about marijuana smoke. Additionally, passively inhaled THC has been raised as an issue in urine testing. As summarized by Dr. Edward Cone, the duration of a positive test for urine for cannabinoids and the intensity of behavioral and pharmacological effects depend upon the amount of THC that actually gets into the body. Passive inhalation of great amounts of smoke could no doubt result in significant behavioral responses as well as positive urine analyses. However, exposures that occur in social situations are unlikely to result in levels that could produce noticeable pharmacological effects or positive results for cannabinoids in urinalysis. 2 On the other hand, oral ingestion of marijuana in a brownie containing the equivalent of one 2.8 percent cigarette was shown to result in measurable pharmacological effects and positive urines for about a week. It is con- ceivable that such ingestion could be inadvertent. Since all the pyrolysis products of abused substances in the mainstream smoke are inhaled and could contribute to the pharmacological effects and toxicities associated with smoking, the identification