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INTRODUCTION The Institute of Medicine (IOM) of the National Academy of Sciences has undertaken this review and analysis of the health-related effects of marijuana* at the request of the Secretary of the Department of Health and Human Services (DHHS) and the Director of the National Institutes of Health (NIH). Scientific controversy and public confusion about marijuana continue unabated and perhaps even are expanding, notwithstanding numerous reports on the topic from authoritative agencies and organizations (Fifth, Sixth, Seventh, and Eighth Annual Reports from the Secretary of Health, Education and Welfare to the Congress on Marijuana and Health; Fehr, et al., Cannabis: Adverse Effects on Health, l980a; Tinklenberg, Marijuana and Health Hazards and Marijuana in the '80s, a report of the Council on Scientific Affairs, the American Medical Association, l980). Increasing use of this substance and growing concern about its possible long- and short-term consequences for human health have added some urgency to the need for reassessment of the available data. Interest has been further heightened by recent suggestions that marijuana may also have some medical therapeutic value, which only intensifies the debate about what our public policy towards marijuana ought to be. With this as background, the Secretary of Health, Education, and Welfare, Joseph A. Califano, Jr., in a press statement on April l8, l979, announced the intention of his department to undertake a review that would "... assess the information and scientific work now available on the effects of marijuana." He followed that with a memorandum on May l6, l979, to Donald S. Fredrickson, Director of NIH in which he further stated: This review must be undertaken by an independent scientific body that has not staked out a position in this highly controversial field. This review should be conducted by a *The terms marijuana and cannabis will be used interchangeably in this report. Strictly speaking, they are not synonymous; cannabis is the more general term. (See Glossary, page 9.)
group of distinguished biomedical and clinical scientists and should involve thorough, systematic review and analysis of the research literature. . . . The report should identify the most urgently needed and promising lines of inquiry to build a firmer base for decision-making in years to come. The information should be available in a clear and incisive form for the general public. While the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA) and its National Institute on Drug Abuse (NIDA) have provided leadership in research related to biological and health effects of marijuana, it is most impor- tant that we have a review by an independent nongovernmental body, such as the Institute of Medicine. In order to avoid even the appearance of a conflict of interest, inasmuch as this review will cover part of the research plan of ADAMHA-NIDA, I believe it is important that the National Institutes of Health serve as the responsible DHHS agency for seeing that such a review is conducted. Following Mr. Califano's resignation, subsequent secretaries have confirmed to the Director of the NIH their desire to see this review carried forward. Accordingly, a contract between the NIH and the IOM was executed to provide for a study to commence September 30, l980, and be completed by December 29, l98l. THE COMMITTEE'S TASK Under this contract, the IOM agreed to appoint a committee to: l. analyze existing scientific evidence bearing on the possible hazards to the health and safety of users of marijuana; 2. analyze data concerning the possible therapeutic value and health benefits of marijuana; 3. assess federal research programs in this area; 4. identify promising new research directions, and make suggestions to improve the quality and usefulness of future research; 5. draw conclusions from this review that would accurately assess the limits of present knowledge and thereby provide a factual, scientific basis for the development of future government policy. Such an assessment also should be helpful to private citizens who want to make their own informed decisions about this subject. The committee's charge specifically excluded the analysis or formulation of public policy. PROCEDURE FOR THE STUDY Primary responsibility for the conduct of the study was vested in a steering committee of 22 biologists, behavioral scientists, and
8 clinicians. Although they all were experts in relevant disciplines, only a few had previously been involved in the study of marijuana or had taken public positions on the subject. The committee was divided into six panels, each concerned with major scientific areas: cardiovascular and respiratory system effects; neurobiological effects; epidemiological, behavioral, and psychosocial effects; reproductive biology and effects on the fetus; pharmacology, cell biology, and immunology; and genetic and oncogenic effects. Each panel was chaired by a member of the committee and usually had one or more additional committee members and several expert consultants, whose names appear in the front of this report. The committee also consulted with many other experts in the course of its work and received valuable help from many persons and organizations. The full committee met five times to coordinate and assess its progress. In the intervals between these meetings, the panels held their own independent sessions and various ad hoc working groups met as necessary. The chairman and members of the committee staff were invited observers at the Conference on Adverse Health and Behavioral Consequences of Cannabis Use, which was sponsored by the Addiction Research Foundation (ARF) of Ontario and the World Health Organization (WHO) and held in Toronto, Canada, from March 30 to April 3, l98l. Other members of our committee served as working members of that conference. We were also fortunate in being able to work closely with members of the ARF/WHO conference staff and having access to all the documents prepared for the Canadian meeting as well as the revised draft of the summary report of the conference (l98l). The committee began by systematically reviewing all the literature published since l975 on marijuana and related subjects, which had been collected by our staff through a Medline computer search. Earlier literature was selectively examined, as were a variety of other documents, reviews, and monographs on the subject. Our objective was not merely to compile and summarize, but also to evaluate the evidence critically and, with the aid of our consultants, form some judgment of the quality and reliability of the work. Our report is an assessment of what is and is not known, based on our best interpretations of the scientific literature. We confined our attention to published scientific articles as the primary sources of information, relying heavily on experts in each field to select the relevant papers and help us interpret the data. To obtain additional information and opinions from the public and from professional groups on the health-related effects of marijuana, we solicited written responses in a notice in the Federal Register of February 24, l98l. Responses were received and incorporated into the records of the committee. (See Appendix A for a complete description.) The responses fell into three categories: l. The dangers of marijuana. Letters in this category came from mothers whose children were using or had used marijuana. These parents believed that drug use by their children led to a lack of motivation and loss of interest in school and other activities. Letters about the harmfulness of the use of marijuana were also received from physicians and scientists.
2. The therapeutic potential of marijuana. Half of the responses were from people who used marijuana illegally for various medical problems and who urged that it be made easily available to patients. Several letters submitted by legislators and doctors described problems in obtaining marijuana for therapeutic use (see Appendix B). A group interested in the legitimate medical use of cannabis emphasized the need for continuing investigation into the numerous constituents of the marijuana plant for therapeutic uses. 3. Support of general use and legalization of marijuana. Letters were received from individuals and groups favoring the use of marijuana and actively promoting its legalization. This report covers most of the concerns expressed by the public, except the question of legalization. The various statements included many opinions and much anecdotal evidence from laymen and scientists. The committee took note of this material, but has not cited any of it in this report unless it was supported by published data in the scientific literature. THE ORGANIZATION OF THE REPORT This report is divided into eight chapters and a summary. The summary includes the principal findings and conclusions of the study, together with suggestions for future research. The first chapter reviews what is known about the chemistry and pharmacology of marijuana. Chapter 2 deals with the epidemiology and demography of the use of marijuana in the United States. The next three chapters discuss the effects of marijuana on cells, tissues, organs, and biological systems. Chapter 6 deals with behavioral and psychosocial effects. Chapter 7 discusses the present status of marijuana as a therapeutic agent. Chapter 8 describes and analyzes the federal research program on marijuana. This report is intended to be intelligible to readers who are not expert on the subjects at hand. We have tried to use technical language only where accuracy would be compromised by less precise terms, and to keep the discussions as brief and as clearly stated as is consistent with our obligation to present a valid critique of the state of knowledge in this field. Although we have surveyed the literature as thoroughly as possible, our citations are selective rather than exhaustive, because they are intended to illustrate or document only the key points in the discussion. For comprehensive bibliographies, see Waller et al., l976; Abel, l979; and Kalant et al., l980. GLOSSARY OF TERMS FOR MARIJUANA-RELATED PRODUCTS CANNABIDIOL (CBD) and CANNABINOL (CBN) are major cannabinoids generally present in cannabis (see CANNABIS and CANNABINOIDS).
l0 CANNABINOIDS are a class of 2l-carbon compounds present in Cannabis sativa. The basic structure contains a six-membered hydroaromatic ring and a benzene ring joined by a pyran moiety (see Figure l-l in Chapter l). Derivatives include a number of carboxylic acids, their analogues, and transformation products. CANNABIS is a general term for any of the various preparations of the plant Cannabis sativa and the cannabinoids obtained from it. "Cannabinoid" is a generic term for a class of compounds. Cannabis sativa, also called hemp, is an herbaceous annual plant that readily grows in temperate climates. Depending on the geographic region, and other considerations, the various natural preparations of cannabis possess different physical characteristics and concentrations of cannabinoids. Cannabis preparations may contain over 420 different compounds; of these, 6l have been identified as cannabinoids, many of which possess some biological activity. Marijuana, hashish, and tetrahydrocannabinol are examples of different forms or components of cannabis. HASHISH is a resin, generally more potent than marijuana, which is obtained from Cannabis sativa by shaking, pressing, or scraping the leaves and flowers of the plant and usually contains some of the latter. MARIJUANA is a general term for crude preparations obtained from the plant Cannabis sativa and is a mixture of crushed leaves, twigs, seeds, and sometimes the flowers of this plant. In the united States, the term "marijuana" has often been used interchangeably with cannabis to refer to any part of the plant or extract therefrom or any of the synthetic cannabinoids that induce somatic and psychic changes in man. SINSEMILLA is a seedless variety of high-potency marijuana, originally grown in California. TETRAHYDROCANNABINOL (THC) is one of the major groups of cannabinoids. Delta-9-THC is the principal active constituent in natural cannabis preparations. Delta-9-THC is also known as A-l-THC, by a different system of nomenclature. (In the United States, the A-9-THC content of marijuana ranges from immeasurable amounts to about 6 percent.) Another active isomer, A-8-THC, is less often present in marijuana and typically occurs in minute amounts. Many derivatives of A-9-THC have been synthesized. REFERENCES Abel, E.L. A Comprehensive Guide to the Cannabis Literature Westport, Conn.: Greenwood Press, Inc., l979. American Medical Association. Marijuana in the '80s. Report of the Council on Scientific Affairs. Chicago 1ll.: American Medical Association, l980. Fehr, K.O., Kalant, O.J., Kalant, H., and Single, E.W. Cannabis: Adverse Effects on Health. A statement prepared by the scientists of the Addiction Research Foundation of Ontario. Toronto: Addiction Research Foundation, l980.
1l Kalant, O.J., Fehr, K.O., and Arras, D. Cannabis: Health Hazards: A Comprehensive Annotated Bibliography. Toronto: Addiction Research Foundation, l980. Report of Addiction Research Foundation/World Health Organization (ARF/WHO). Conference on Adverse Health and Behavioral Consequences of Cannabis Use. ARF/WHO, l98l. Tinklenberg, J.R. (ed.) Marijuana and Health Hazards: Methodological Issues in Current Research. New York: Academic Press, Inc., l975. U.S. Department of Health, Education, and Welfare, Public Health Service. Marihuana and Health. Fifth Annual Report to the Congress from the Secretary of Health, Education, and Welfare, l975. DREW Publication No. (ADM)76-3l4. Washington, D.C.: U.S. Government Printing Office, l976. U.S. Department of Health, Education, and Welfare, Public Health Service. Marihuana and Health. Sixth Annual Report to the Congress from the Secretary of Health, Education, and Welfare, l976. DHEW Publication No. (ADM)77-443. Washington, D.C.: U.S. Government Printing Office, l977. U.S. Department of Health, Education, and Welfare, Public Health Service. Marihuana and Health. Seventh Annual Report to the Congress from the Secretary of Health Education, and Welfare, l977. DHEW Publication No. (ADM) 79-700. Washington, D.C.: U.S. Government Printing Office, l979. U.S. Department of Health, Education, and Welfare, Public Health Service. Marijuana and Health. Eighth Annual Report to the Congress from the Secretary of Health, Education, and Welfare, l980. DHEW Publication No. (ADM) 80-945. Washington, D.C.: U.S. Government Printing Office, l980. Waller, C.W., Johnson, J.J., Buelke, J., and Turner, C.E. Marihuana: An Annotated Bibliography New York: Macmillan Information, l976.