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36 APPENDIX: SUMMARY OF MARIJUANA AND HEALTH The Institute of Medicine (ION) of the National Academy of Sciencen has conducted a 15-month study of the health-related effects of marijuana, at the request of the Secretary of Health and Human Services and the Director of the National Institutes of Health. The IOM appointed a 22-member committee to: analyze existing scientific evidence bearing on the possible hazards to the health and safety of . . . users o : marijuana; analyze data concerning the possible therapeutic value and health benefits of marijuana; . ~. . . . assess federal research programs In marijuana; zoentzzy promising new research directions, and make sugggestions to improve the quality and usefulness of future research; and 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. This assessment of knowledge of the health-related effects of marijuana is important and timely because marijuana is now the most widely used of all the illicit drugs available in the United States. In 1979, more than 50 million persons had tried it at least once. mere has been a steep rise in its use during the past decade, particularly among adolescents and young adults. although there has been a leveling-off in its overall use among high school seniors in the pas t 2 or 3 years and a Small decline in the Percentage of seniors who use . it frequently. Although substantially more high school students have used alcohol than have ever used marijuana, more high school seniors use marijuana on a daily or near-daily basis (9 percent) than alcohol (6 percent). Much of the heavy use of marijuana, unlike alcohol, takes place in school, where effects on behavior, cognition, and psychomotor performance can be particularly disturbing. Unlike alcohol, which is rapidly metabolized and eliminated from the body, the psychoactive components of marijuana persist in the body for a long time. Similar to alcohol, continued use of marijuana may cause tolerance and dependence. For all these reasons, it is imperative that we have reliable ant detailed information about the effects of marijuana use on health, both in the long and short term.

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37 What, then, did we learn from our review of the published scientific literature? Numerous acute effects have been described in animals, in isolated cells and tissues, and in studies of human volunteers; clinical and epidemiological observations also have been reported. This information is briefly summarized in the following paragraphs. EFFECTS ON THE NERVOUS SYSTEM AND ON BEHAVIOR We can say with confidence that marijuana produces acute effects on the brain, including chemical and electrophysiological changes. its most clearly established acute effects are on mental functions and behavior. With a severity directly relates to dose, marijuana impairs motor coordination and affects tracking ability and sensory and perceptual functions important for safe driving and the operation of other machines; it also impairs short-term memory and Blown learning. Other acute effects include feelings of euphoria and other mood changes, but there also are disturbing mental phenomena, such as brief periods of anxiety, confusion, or psychosis. There is not yet any conclusive evidence as to whether prolonged use of marijuana causes permanent changes in the nervous system or sustained impairment of brain function and behavior in human beings. In a few unconfirmed studies in experimental animals, impairment of learning and changes in electrical brain-wave recordings have been observed several months after the cessation of chronic administration of marijuana. In the judgment of the committee, widely cited studies purporting to demonstrate that marijuana affects the gross and microscopic structure of the Herman or monkey brain are not convincing; Mach more work is needed to settle this important point. Chronic relatively heavy use of marijuana is associated with behavioral dysfunction and mental disorders in human beings, but available evidence does not establish if marijuana use under these circumstances is a cause or a result of the mental condition. There are similar problems in interpreting the evidence linking the use of marijuana to subsequent use of other illicit drugs, such as heroin or cocaine. Association does not prove a causal relation, and the use of marijuana may merely be symptomatic of an underlying .

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38 disposition to use psychoactive drugs rather than a "stepping stone" to involvement with more dangerous substances. It is also difficult to sort out the relationship between use of marijuana and the complex symptoms known as the amotivational syndrome. Self-selection and effects of the drug are probably both contributing to the motivational problems seen in some chronic users of marijuana. Thus, the long-tenm effects of marijuana on the human brain and on human behavior remain to be defined. Although we have no convincing evidence thus far of any effects persisting in human beings after cessation of drug use, there may well be subtle but important physical and psychological consequences that have not been recognized. EFFECTS ON THE CARDIOVASCULAR AND RESPIRATORY SYSTEMS There is good evidence that the smoking of marijuana usually causes acute changes in the heart and circulation that are characteristic of stress, but there is no evidence to indicate that a permanently deleterious effect on the normal cardiovascular system occurs. There is good evidence to show that marijuana increases the work of the heart, usually by raising heart rate and, in some persons, by raising blood pressure. This rise in workload poses a threat to patients with hypertension, cerebrovascular disease, and coronary atherosclerosis. Acute exposure to marijuana smoke generally elicits broncho-dilation; chronic heavy smoking of marijuana causes inflammation and pre-neoplastic changes in the airways, similar to those produced by Smoking of tobacco. Marijuana smoke is a complex mixture that not only has many chemical components (including carbon monoxide and "tar") and biological effects similar to those of tobacco smoke. but also some unioue ingredients. , . This sugges es the strong possibility that prolonged heavy smoking of marijuana, like tobacco, will lead to cancer of the respiratory tract and to serious impairment of lung function. Although there is evidence of impaired lung function in chronic smokers, no direct confirmation of the likelihood of cancer has yet been provided, possibly because marijuana has been widely smoked in this country for only about 20 years, and data have not been collected systematically in other coun- tries with a much longer history of heavy marijuana use.

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39 EFFECTS ON THE REPRODUCTIVE SYSTEM AND ON CHROMOSOMES Although studies in animals beve shown that delta-9-THC (the major psychoactive constituent of marijuana) lowers the concentration in blood serum of pituitary hormones (gonadotropins) that control reproductive functions , it is not known if there is a direct effect on reproductive tissues. Delta-9-THC appears to have a modest reversible suppressive effect on sperm production in men, but there is no proof that it has a deleterious effect on male fertility. Effects on human female hormonal function have been reported, but the evidence is not convincing. However, there is convincing evidence that marijuana interferes with ovulation in female monkeys. No satisfactory studies of the relation between use of marijuana and female fertility and child-bearing have been carried out. Although delta-9-THC is known to cross the placenta readily and to cause birth defects when administered in large doses to experimental animals, no adequate clinical studies have been carried out to determine if marijuana use can harm the human fetus. There is no conclusive evidence of teratogenicity in human offspring, but a slowly developing or low-level effect might be undetected by the studies done so far. The effects of marijuana on reproductive function and on the fetus are unclear; they may prove to be negligible, but further research to establish or rule out such effects would be of great importance. Extracts from marijuana smoke particulates ("tar") have been found to produce dose-related mutations in bacteria; however, delta-9-THC, by itself, is not mutagenic. Marijuana and delta-9-THC do not appear to break chromosomes, but marijuana may affect chromosome segregation during cell division, resulting in an abnormal number of chromosomes in daughter cells. Although these results are of concern, their clinical significance is unknown. THE IMMUNE SYSTEM Similar limitations exist in our understanding of the effects of marijuana on other body systems. For example, some studies of the immune system demonstrate a mild, immunosuppressant effect on human beings, but other studies show no effect.

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40 THERAPEUTIC POTENTIAL The committee also has examined the evidence on the therapeutic effects of marijuana in a variety of medical disorders. Preliminary studies suggest that marijuana and its derivatives or analogues might be useful in the treatment of the raised intraocular pressure of glaucoma, in the control of the severe nausea and vomiting caused by cancer chemotherapy, and in the treatment of asthma. mere also is some preliminary evidence that a marijuana constituent (cannabidiol) might be helpful in the treatment of certain types of epileptic seizures, as well as for spastic disorders and other nervous system diseases. But, in these and all other conditions, much more work is needed. Because marijuana and delta-9-THC often produce troublesome psychotropic or cardiovascular side-effects that limit their therapeutic usefulness, particularly in older patients, the greatest therapeutic potential probably lies in the use of synthetic analogues of marijuana derivatives with higher ratios of therapeutic to undesirable effects. The NEED FOR MORE RESEARCH ON MARIJUANA The explanation for all of these unanswered questions is insufficient research. We need to know much more about the metabolism of the various marijuana chemical compounds and their biologic effects. This will require many more studies in animals, with particular emphasis on subhuman primates. Basic pharmacologic information obtained in animal experiments will ultimately have to be tested in clinical studies on human beings. Until 10 or 15 years ago, there was virtually no systematic, rigorously controlled research on the human health-related effects of marijuana and its major constituents. Even now, when standardized marijuana and pure synthetic cannabinoids are available for experimental studies, and good qualitative methods exist for the measurement of delta-9-THO and its metabolites in body fluids, well-designed studies on human beings are relatively few. mere are difficulties in studying the clinical effects of marijuana in human beings, particularly the effects of long-term use. And yet, without such studies the debate about the safety or hazard of marijuana will remain unresolved. Prospective as,

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41 cohort studies, as well as retrospective case-control studies, would be useful in identifying long-term behavioral and biological consequences of marijuana use. The federal investment in research on the health-related effects of marijuana has been small, both in relation to the expenditure on other illicit drugs and in absolute teems. The committee considers the research particularly inadequate when viewed in light of the extent of marijuana use in this country, especially by young people. We believe there should be a greater investment in research on marijuana, and that investigator-initiated research grants should be the primary vehicle of support. The committee considers all of the areas of research on marijuana that are supported by the National Institute on Drug Abuse to be important, but we did not judge the appropriateness of the allocation of resources among those areas, other than to conclude that there should be increased emphasis on studies in human beings and other primates. Recommendations for future research are presented at the end of Chapters 1-7 of this report. CONCLUSIONS The scientific evidence published to date indicates that marijuana has a broad range of psychological and biological effects, some of which, at least under certain conditions, are harmful to human health. Unfortunately, the available information does not tell us how serious this risk may be. The major conclusion is that what little we know for certain about the effects of marijuana on human health--and all that we have reason to suspect--justifies serious national concern. Of no less concern is the extent of our ignorance about many of the most basic and important questions about the drug. Our major recommendation is that there be a greatly intensified and more comprehensive program of research into the effects of marijuana on the health of the American people.