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3
FIRST, DO NO HARM: CONSEQUENCES OF MARIJUANA USE AND ABUSE

Primum non nocere. This is the physician's first rule: whatever treatment a physician prescribes to a patient—first, that treatment must not harm the patient.

The most contentious aspect of the medical marijuana debate is not whether marijuana can alleviate particular symptoms but rather the degree of harm associated with its use. This chapter explores the negative health consequences of marijuana use, first with respect to drug abuse, then from a psychological perspective, and finally from a physiological perspective.

The Marijuana "High"

The most commonly reported effects of smoked marijuana are a sense of well-being or euphoria and increased talkativeness and laughter alternating with periods of introspective dreaminess followed by lethargy and sleepiness (see reviews by Adams and Martin, 1996,1 Hall and Solowij,59 and Hall et al. 60). A characteristic feature of a marijuana "high" is a distortion in the sense of time associated with deficits in short-term memory and learning. A marijuana smoker typically has a sense of enhanced physical and emotional sensitivity, including a feeling of greater interpersonal closeness. The most obvious behavioral abnormality displayed by someone under the influence of marijuana is difficulty in carrying on an intelli-



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Page 83 3 FIRST, DO NO HARM: CONSEQUENCES OF MARIJUANA USE AND ABUSE Primum non nocere. This is the physician's first rule: whatever treatment a physician prescribes to a patient—first, that treatment must not harm the patient. The most contentious aspect of the medical marijuana debate is not whether marijuana can alleviate particular symptoms but rather the degree of harm associated with its use. This chapter explores the negative health consequences of marijuana use, first with respect to drug abuse, then from a psychological perspective, and finally from a physiological perspective. The Marijuana "High" The most commonly reported effects of smoked marijuana are a sense of well-being or euphoria and increased talkativeness and laughter alternating with periods of introspective dreaminess followed by lethargy and sleepiness (see reviews by Adams and Martin, 1996,1 Hall and Solowij,59 and Hall et al. 60). A characteristic feature of a marijuana "high" is a distortion in the sense of time associated with deficits in short-term memory and learning. A marijuana smoker typically has a sense of enhanced physical and emotional sensitivity, including a feeling of greater interpersonal closeness. The most obvious behavioral abnormality displayed by someone under the influence of marijuana is difficulty in carrying on an intelli-

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Page 84 gible conversation, perhaps because of an inability to remember what was just said even a few words earlier. The high associated with marijuana is not generally claimed to be integral to its therapeutic value. But mood enhancement, anxiety reduction, and mild sedation can be desirable qualities in medications—particularly for patients suffering pain and anxiety. Thus, although the psychological effects of marijuana are merely side effects in the treatment of some symptoms, they might contribute directly to relief of other symptoms. They also must be monitored in controlled clinical trials to discern which effect of cannabinoids is beneficial. These possibilities are discussed later under the discussions of specific symptoms in chapter 4. The effects of various doses and routes of delivery of THC are shown in Table 3.1. Adverse Mood Reactions Although euphoria is the more common reaction to smoking marijuana, adverse mood reactions can occur. Such reactions occur most frequently in inexperienced users after large doses of smoked or oral marijuana. They usually disappear within hours and respond well to reassurance and a supportive environment. Anxiety and paranoia are the most common acute adverse reactions;59 others include panic, depression, dysphoria, depersonalization, delusions, illusions, and hallucinations.1,40,66,69 Of regular marijuana smokers, 17% report that they have experienced at least one of the symptoms, usually early in their use of marijuana.145 Those observations are particularly relevant for the use of medical marijuana in people who have not previously used marijuana. Drug Dynamics There are many misunderstandings about drug abuse and dependence (see reviews by O'Brien14 and Goldstein54). The terms and concepts used in this report are as defined in the most recent Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ),3 the most influential system in the United States for diagnoses of mental disorders, including substance abuse (see Box 3.1). Tolerance, dependence, and withdrawal are often presumed to imply abuse or addiction, but this is not the case. Tolerance and dependence are normal physiological adaptations to repeated use of any drug. The correct use of prescribed medications for pain, anxiety, and even hypertension commonly produces tolerance and some measure of physiological dependence. Even a patient who takes a medicine for appropriate medical indications and at the correct dosage can develop tolerance, physical depen-

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Page 85 TABLE 3.1 Psychoactive Doses of THC in Humans Investigators THC Delivery System THC Dose Administered Resulting Plasma Concentrations of THC Subjects' Reactions Heishman and co-workers (1990)62a One 2.75% THC cigarette smoked 0.32 mg/kga 50-100 ng/ml At higher level, subjects felt 100% "high" and psychomotor performance was decreased; at 50 ng/ml, subjects felt about 50%, "high" Kelly and co-workers (1993)85 1-g marijuana cigarette smoked (2% or 3.5% THC) 0.25-0.50 mg/kg" Not measured Enough to feel psychological effects of THC Ohlsson and co-workers (1980)118 19-mg THC cigarette smoked (about 1.9'% THC) About 0.22 mg/kg1 100 ng/ml Subjects felt "high"   5 mg of THC injected intravenously About 0.06 mg/kgb 100 ng/ml Subjects felt "high"   Chocolate chip cookie containing 20 mg of THC About 0.24 mg/kg 8 ng/ml Subjects rated "high" as only about 40"%, Lindgren and co-workers (1981)95 19-mg THC cigarette smoked to "desired high" 12 mg smoked (7 mg remained in cigarette butt) 85 ng/ml after 3 min., 35 ng/ml after 15 min. Subjects felt "high" after 3 min., and maximally high after 10-20 min. (average self-ratings of 5.5 on 10-point scale)   5 mg of THC injected intravenously 0.06 mg/kg' 300 ng/ml after 3 min., 65 ng/ml after 15 min. Subjects felt maximally "high" after 10 min. (average self ratings of 7.5 on a 10-point scale) aSubjects' weights and cigarette weights were not given. Calculation based on 85-kg bodyweight and 1-g cigarette weight. Note that some THC would have remained in the cigarettebutt and some would have been lost in sidestream smoke, so these represent maximal possible doses. Actual doses would have been slightly less. bBased on estimated average 85-kg weight of 11 men 18-35 years old. cBased on approximate 80-kg weight of subjects (including men and women).

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Page 86 Box 3.1 Definitions Addiction. Substance dependence. Craving refers to the intense desire for a drug and is the most difficult aspectof addiction to overcome. Physiologcal dependence is diagnosed when there is evidence of either tolerance or withdrawal; it is sometimes, but not always, manifested in substance dependence. Reinforcement. A drug-—or any other stimulus—is referred to as a reinforcer if exposure to it is followed by an increase in frequency of drug-seeking behavior. The taste of chocolate is a reinforcer for biting into a chocolate bar. Likewise, for many people the sensation experienced after drinking alcohol or smoking marijuana is a reinforcer. Substance dependence is a cluster of cognitive, behavioral, and physiological symptoms indicating that a person continues use of the substance despite significant substance-related problems. Tolerance is the most common response to repetitive use of a drug and can be defined as the reduction in responses to the drug after repeated administrations. Withdrawal. The collective symptoms that occur when a drug is abruptly withdrawn are known as withdrawal syndrome and are often the only evidence of physical dependence. dence, and withdrawal symptoms if the drug is stopped abruptly rather than gradually. For example, a hypertensive patient receiving a beta-adrenergic receptor blocker, such as propranolol, might have a good therapeutic response; but if the drug is stopped abruptly, there can be a withdrawal syndrome that consists of tachycardia and a rebound increase in blood pressure to a point that is temporarily higher than before administration of the medication began. Because it is an illegal substance, some people consider any use of marijuana as substance abuse. However, this report uses the medical definition; that is, substance abuse is a maladaptive pattern of repeated substance use manifested by recurrent and significant adverse consequences.3 Substance abuse and dependence are both diagnoses of pathological substance use. Dependence is the more serious diagnosis and implies compulsive drug use that is difficult to stop despite significant substancerelated problems (see Box 3.2).

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Page 87 Box 3.2 DSM-IV Criteria for Substance Dependence A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period: (1) Tolerance, as defined by either of the following: (a) A need for markedly increased amount of the substance to achieve intoxication or desired effect. (b) Markedly diminished effect with continued use of the same amount of the substance. (2) Withdrawal, as defined by either of the following: (a) The characteristic withdrawal syndrome for the substance. (b) The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms. (3) The substance is often taken in larger amounts or over a longer period than was intended. (4) There is a persistent desire or unsuccessful efforts to cut down or control substance use. (5) A great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), to use the substance (e.g., chain-smoking), or to recover from its effects. (6) Important social, occupational, or recreational activities are given up or reduced because of substance use. (7) The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression or continued drinking despite recognition that an ulcer was made worse by alcohol consumption). Substance abuse with physiological dependence is diagnosed if there is evidence of tolerance or withdrawal. Substance abuse without physiological dependence is diagnosed if there is no evidence of tolerance or withdrawal. Reinforcement Drugs vary in their ability to produce good feelings in users, and the more strongly reinforcing a drug is, the more likely it will be abused (G. Koob, Institute of Medicine (IOM) workshop). Marijuana is indisputably reinforcing for many people. The reinforcing properties of even so mild a

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Page 88 stimulant as caffeine are typical of reinforcement by addicting drugs (reviewed by Goldstein54 in 1994). Caffeine is reinforcing for many people at low doses (100-200 mg, the average amount of caffeine in one to two cups of coffee) and is aversive at high doses (600 mg, the average amount of caffeine in six cups of coffee). The reinforcing effects of many drugs are different for different people. For example, caffeine was most reinforcing for test subjects who scored lowest on tests of anxiety but tended not to be reinforcing for the most anxious subjects. As an argument to dispute the abuse potential of marijuana, some have cited the observation that animals do not willingly self-administer THC, as they will cocaine. Even if that were true, it would not be relevant to human use of marijuana. The value in animal models of drug selfadministration is not that they are necessary to show that a drug is reinforcing but rather that they provide a model in which the effects of a drug can be studied. Furthermore, THC is indeed rewarding to animals at some doses but, like many reinforcing drugs, is aversive at high doses (4.0 mg/ kg).93 Similar effects have been found in experiments conducted in animals outfitted with intravenous catheters that allow them to selfadminister WIN 55,212, a drug that mimics the effects of THC.100 A specific set of neural pathways has been proposed to be a "reward system" that underlies the reinforcement of drugs of abuse and other pleasurable stimuli.51 Reinforcing properties of drugs are associated with their ability to increase concentrations of particular neurotransmitters in areas that are part of the proposed brain reward system. The median forebrain bundle and the nucleus accumbens are associated with brain reward pathways.88 Cocaine, amphetamine, alcohol, opioids, nicotine, and THC144 all increase extracellular fluid dopamine in the nucleus accumbens region (reviewed by Koob and Le Moal88 and Nestler and Aghajanian110 in 1997). However, it is important to note that brain reward systems are not strictly "drug reinforcement centers." Rather, their biological role is to respond to a range of positive stimuli, including sweet foods and sexual attraction. Tolerance The rate at which tolerance to the various effects of any drug develops is an important consideration for its safety and efficacy. For medical use, tolerance to some effects of cannabinoids might be desirable. Differences in the rates at which tolerance to the multiple effects of a drug develops can be dangerous. For example, tolerance to the euphoric effects of heroin develops faster than tolerance to its respiratory depressant effects, so heroin users tend to increase their daily doses to reach their desired level of euphoria, thereby putting themselves at risk for respiratory arrest. Because tolerance to the various effects of cannabinoids might

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Page 89 develop at different rates, it is important to evaluate independently their effects on mood, motor performance, memory, and attention, as well as any therapeutic use under investigation. Tolerance to most of the effects of marijuana can develop rapidly after only a few doses, and it also disappears rapidly. Tolerance to large doses has been found to persist in experimental animals for long periods after cessation of drug use. Performance impairment is less among people who use marijuana heavily than it is among those who use marijuana only occasionally,29,104,124 possibly because of tolerance. Heavy users tend to reach higher plasma concentrations of THC than light users after similar doses of THC, arguing against the possibility that heavy users show less performance impairment because they somehow absorb less THC (perhaps due to differences in smoking behavior).95 There appear to be variations in the development of tolerance to the different effects of marijuana and oral THC. For example, daily marijuana smokers participated in a residential laboratory study to compare the development of tolerance to THC pills and to smoked marijuana.61,62 One group was given marijuana cigarettes to smoke four times per day for four consecutive days; another group was given THC pills on the same schedule. During the four-day period, both groups became tolerant to feeling "high" and what they reported as a "good drug effect." In contrast, neither group became tolerant to the stimulatory effects of marijuana or THC on appetite. "Tolerance" does not mean that the drug no longer produced the effects but simply that the effects were less at the end than at the beginning of the four-day period. The marijuana smoking group reported feeling "mellow" after smoking and did not show tolerance to this effect; the group that took THC pills did not report feeling "mellow." The difference was also reported by many people who described their experiences to the IOM study team. The oral and smoked doses were designed to deliver roughly equivalent amounts of THC to a subject. Each smoked marijuana dose consisted of five 10-second puffs of a marijuana cigarette containing 3.1% THC; the pills contained 30 mg of THC. Both groups also received placebo drugs during other four-day periods. Although the dosing of the two groups was comparable, different routes of administration resulted in different patterns of drug effect. The peak effect of smoked marijuana is usually felt within minutes and declines sharply after 30 minutes68, 95; the peak effect of oral THC is usually not felt until about an hour and lasts for several hours.118 Withdrawal A distinctive marijuana and THC withdrawal syndrome has been

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Page 90 identified, but it is mild and subtle compared with the profound physical syndrome of alcohol or heroin withdrawal.31,74 The symptoms of marijuana withdrawal include restlessness, irritability, mild agitation, insomnia, sleep EEG disturbance, nausea, and cramping (Table 3.2). In addition to those symptoms, two recent studies noted several more. A group of adolescents under treatment for conduct disorders also reported fatigue and illusions or hallucinations after marijuana abstinence (this study is discussed further in the section on "Prevalence and Predictors of Dependence on Marijuana and Other Drugs").31 In a residential study of daily TABLE 3.2 Drug Withdrawal Symptoms Nicotine Alcohol Marijuana Cocaine Opioids (e.g., heroin or morphine)           Restlessness   Restlessness   Restlessness Irritability Irritability Irritability   Irritability Impatience, hostility   Mild agitation     Dysphoria     Dysphoria Dysphoria Depression     Depression   Anxiety       Anxiety Difficulty concentrating           Sleep disturbance Insomnia Sleepiness, fatigue Insomnia               Sleep EEG disturbance                 Nausea Nausea   Nausea     Cramping   Cramping Decreased heart rate Tachycardia, hypertension   Bradycardia               Sweating     Muscle aches   Seizures     Increased sensitivity to pain             Alcohol craving   Cocaine craving  Opioid craving Increased appetite or weight gain Delirium tremensa                             Tremor         Perceptual distortion                 aSevere agitation, confusion, visual hallucinations, fever, profuse sweating, nausea, diarrhea, dilated pupils. SOURCE: O'Brien (1996).113

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Page 91 marijuana users, withdrawal symptoms included sweating and runny nose, in addition to those listed above.62 A marijuana withdrawal syndrome, however, has been reported only in a group of adolescents in treatment for substance abuse problems31 and in a research setting where subjects were given marijuana or THC daily.62,74 Withdrawal symptoms have been observed in carefully controlled laboratory studies of people after use of both oral THC and smoked marijuana.61,62 In one study, subjects were given very high doses of oral THC: 180-210 mg per day for 10-20 days, roughly equivalent to smoking 9-10 2% THC cigarettes per day.74 During the abstinence period at the end of the study, the study subjects were irritable and showed insomnia, runny nose, sweating, and decreased appetite. The withdrawal symptoms, however, were short lived. In four days they had abated. The time course contrasts with that in another study in which lower doses of oral THC were used (80-120 mg/day for four days) and withdrawal symptoms were still near maximal after four days.61,62 In animals, simply discontinuing chronic heavy dosing of THC does not reveal withdrawal symptoms, but the "removal" of THC from the brain can be made abrupt by another drug that blocks THC at its receptor if administered when the chronic THC is withdrawn. The withdrawal syndrome is pronounced, and the behavior of the animals becomes hyperactive and disorganized.153 The half-life of THC in brain is about an hour.16,24 Although traces of THC can remain in the brain for much longer periods, the amounts are not physiologically significant. Thus, the lack of a withdrawal syndrome when THC is abruptly withdrawn without administration of a receptor-blocking drug is probably not due to a prolonged decline in brain concentrations. Craving Craving, the intense desire for a drug, is the most difficult aspect of addiction to overcome. Research on craving has focused on nicotine, alcohol, cocaine, and opiates but has not specifically addressed marijuana. 115 Thus, while this section briefly reviews what is known about drug craving, its relevance to marijuana use has not been established. Most people who suffer from addiction relapse within a year of abstinence, and they often attribute their relapse to craving.58 As addiction develops, craving increases even as maladaptive consequences accumulate. Animal studies indicate that the tendency to relapse is based on changes in brain function that continue for months or years after the last use of the drug. 115 Whether neurobiological conditions change during the manifestation of an abstinence syndrome remains an unanswered question in drug abuse research.88 The "liking" of sweet foods, for example, is

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Page 92 mediated by opioid forebrain systems and by brain stem systems, whereas "wanting" seems to be mediated by ascending dopamine neurons that project to the nucleus accumbens.109 Anticraving medications have been developed for nicotine and alcohol. The antidepressant, bupropion, blocks nicotine craving, while naltrexone blocks alcohol craving."l5 Another category of addiction medication includes drugs that block other drugs' effects. Some of those drugs also block craving. For example, methadone blocks the euphoric effects of heroin and also reduces craving. Marijuana Use and Dependence Prevalence of Use Millions of Americans have tried marijuana, but most are not regular users. In 1996, 68.6 million people —32% of the U.S. population over 12 years old—had tried marijuana or hashish at least once in their lifetime, but only 5% were current users.132 Marijuana use is most prevalent among 18- to 25-year-olds and declines sharply after the age of 34 (Figure 3.1).77,132 Whites are more likely than blacks to use marijuana in adolescence, although the difference decreases by adulthood.132 Most people who have used marijuana did so first during adolescence. Social influences, such as peer pressure and prevalence of use by peers, are highly predictive of initiation into marijuana use.9 Initiation is not, of course, synonymous with continued or regular use. A cohort of 456 students who experimented with marijuana during their high school years were surveyed about their reasons for initiating, continuing, and stopping their marijuana use.9 Students who began as heavy users were excluded from the analysis. Those who did not become regular marijuana users cited two types of reasons for discontinuing. The first was related to health and well-being; that is, they felt that marijuana was bad for their health or for their family and work relationships. The second type was based on age-related changes in circumstances, including increased responsibility and decreased regular contact with other marijuana users. Among high school students who quit, parental disapproval was a stronger influence than peer disapproval in discontinuing marijuana use. In the initiation of marijuana use, the reverse was true. The reasons cited by those who continued to use marijuana were to "get in a better mood or feel better." Social factors were not a significant predictor of continued use. Data on young adults show similar trends. Those who use drugs in response to social influences are more likely to stop using them than those who also use them for psychological reasons.80 The age distribution of marijuana users among the general popula-

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Page 93 Figure 3.1  Age distribution of marijuana users among the general population. tion contrasts with that of medical marijuana users. Marijuana use generally declines sharply after the age of 34 years, whereas medical marijuana users tend to be over 35. That raises the question of what, if any, relationship exists between abuse and medical use of marijuana; however, no studies reported in the scientific literature have addressed this question. Prevalence and Predictors of Dependence on Marijuana and Other Drugs Many factors influence the likelihood that a particular person will become a drug abuser or an addict; the user, the environment, and the drug are all important factors (Table 3.3).114 The first two categories apply to potential abuse of any substance; that is, people who are vulnerable to drug abuse for individual reasons and who find themselves in an environment that encourages drug abuse are initially likely to abuse the most readily available drug—regardless of its unique set of effects on the brain. The third category includes drug-specific effects that influence the abuse

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Page 126 the influence of marijuana to operate any equipment that might put the user or others in danger (such as driving or operating complex equipment). Most people can be expected to show impaired performance of complex tasks, and a minority experience dysphoria. People with or at risk of psychiatric disorders (including substance dependence) are particularly vulnerable to developing marijuana dependence, and marijuana use would be generally contraindicated for them. The short-term immunosuppressive effects are not well established; if they exist at all, they are probably not great enough to preclude a legitimate medical use. The acute side effects of marijuana use are within the risks tolerated for many medications. The chronic effects of marijuana are of greater concern for medical use and fall into two categories: the effects of chronic smoking and the effects of THC. Marijuana smoke is like tobacco smoke in that it is associated with increased risk of cancer, lung damage, and poor pregnancy outcome. Smoked marijuana is unlikely to be a safe medication for any chronic medical condition. The second category is that associated with dependence on the psychoactive effects of THC. Despite past skepticism, it has been established that, although it is not common, a vulnerable subpopulation of marijuana users can develop dependence. Adolescents, particularly those with conduct disorders, and people with psychiatric disorders, or problems with substance abuse appear to be at greater risk for marijuana dependence than the general population. As a cannabinoid drug delivery system, marijuana cigarettes are not ideal in that they deliver a variable mixture of cannabinoids and a variety of other biologically active substances, not all of which are desirable or even known. Unknown substances include possible contaminants, such as fungi or bacteria. Finally, there is the broad social concern that sanctioning the medical use of marijuana might lead to an increase in its use among the general population. No convincing data support that concern. The existing data are consistent with the idea that this would not be a problem if the medical use of marijuana were as closely regulated as the use of other medications that have abuse potential, but we acknowledge a lack of data that directly address the question. Even if there were evidence that the medical use of marijuana would decrease the perception that it can be a harmful substance, this is beyond the scope of laws regulating the approval of therapeutic drugs. Those laws concern scientific data related to the safety and efficacy of drugs for individual use; they do not address perceptions or beliefs of the general population. Marijuana is not a completely benign substance. It is a powerful drug with a variety of effects. However, except for the harm associated with smoking, the adverse effects of marijuana use are within the range toler-

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Page 127 ated for other medications. Thus, the safety issues associated with marijuana do not preclude some medical uses. But the question remains: Is it effective? That question is covered here in two chapters: chapter 2 summarizes what has been learned about the biological activity of cannabinoids in the past 15 years through research in the basic sciences, and chapter 4 reviews clinical data on the effectiveness of marijuana and cannabinoids for the treatment of various medical conditions. Three factors influence the safety of marijuana or cannabinoid drugs for medical use: the delivery system, the use of plant material, and the side effects of cannabinoid drugs. (1) Smoking marijuana is clearly harmful, especially in people with chronic conditions, and is not an ideal drug delivery system. (2) Plants are of uncertain composition, which renders their effects equally uncertain, so they constitute an undesirable medication. (3) The side effects of cannabinoid drugs are within the acceptable risks associated with approved medications. Indeed, some of the side effects, such as anxiety reduction and sedation, might be desirable for some patients. As with many medications, there are people for whom they would probably be contraindicated. CONCLUSION: Present data on drug use progression neither support nor refute the suggestion that medical availability would increase drug abuse. However, this question is beyond the issues normally considered for medical uses of drugs, and it should not be a factor in the evaluation of the therapeutic potential of marijuana or cannabinoids. CONCLUSION: A distinctive marijuana withdrawal syndrome has been identified, but it is mild and short lived. The syndrome includes restlessness, irritability, mild agitation, insomnia, sleep EEG disturbance, nausea, and cramping. CONCLUSION: Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory disease. RECOMMENDATION: Studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent.

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