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National Institutes of Health -- Workshop on the Medical Utility of Marijuana
Ad Hoc Group of Experts
Feb. 19-20, 1997
Over the past 18 months there has been wide-ranging public discussion on the potential medical uses of marijuana, particularly smoked marijuana. To contribute to the resolution of the debate
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Mental and Behavioral Effects

Common Acute Effects

Usually the mental and behavioral effects of marijuana consist of a sense of well-being (often termed euphoria or a high), feelings of relaxation, altered perception of time and distance, intensified sensory experiences, laughter, talkativeness, and increased sociability when taken in a social setting. Impaired memory for recent events, difficulty concentrating, dreamlike states, impaired motor coordination, impaired driving and other psychomotor skills, slowed reaction time, impaired goal-directed mental activity, and altered peripheral vision are common associated effects (Adams and Martin 1996; Fehr and Kalant 1983; Hollister 1988a; Institute of Medicine 1982; Tart 1971).

With repeated exposure, varying degrees of tolerance rapidly develops to many subjective and physiologic effects (Fehr and Kalant 1983; Jones 1987). Thus, intensity of acute effects is determined not only by THC dose but also by past experience, setting, expectations, and poorly understood individual differences in sensitivity. After a single moderate smoked dose most mental and behavioral effects are easily measurable for only a few hours and are usually no longer measurable after 4 to 6 hours (Hollister 1986a, 1988a). A few published reports describe lingering cognitive or behavioral changes 24 hours or so after a single smoked or oral dose (Fehr and Kalant 1983; Institute of Medicine 1982; Yesavage et al. 1985). Venous blood levels of THC or other cannabinoids correlate poorly with intensity of effects and character of intoxication (Agurell et al. 1986; Barnett et al. 1985; Huestis et al. 1992a).

Adverse Mental Effects

Large smoked or oral marijuana doses or even ordinary doses taken by a sensitive, inexperienced, or predisposed person can produce transient anxiety, panic, feelings of depression and other dysphoric mood changes, depersonalization, bizarre behaviors, delusions, illusions, or hallucinations (Adams and Martin 1996; Fehr and Kalant 1983; Hollister 1986a, 1988a; Institute of Medicine 1982). Depending on the mix of symptoms and behaviors, the state has been termed an acute panic reaction, toxic delirium, acute paranoid state, or acute mania. The unpleasant effects are usually of sudden onset, during or shortly after smoking, or appear more gradually an hour or two after an oral dose, usually last a few hours, less often a few days, and completely clear without any specific treatment other than reassurance and a supportive environment. A subsequent marijuana dose, particularly a lower one, may be well tolerated. In a large survey of regular marijuana users, 17 percent of young adult respondents reported experiencing at least one of the preceding symptoms during at least one occasion of marijuana use, usually early in their use (Tart 1971).

Whether marijuana can produce or trigger lasting mood disorders (depression or mania) or schizophrenia is less clearly established (Fehr and Kalant 1983; Gruber and Pope 1994; Hollister 1986a, 1988a; Institute of Medicine 1982). A psychotic state with schizophrenic-like and manic features lasting a week or more has been described. Marijuana can clearly worsen schizophrenia. Chronic marijuana use can be associated with behavior characterized by apathy and loss of motivation along with impaired educational performance even without obvious behavioral changes (Pope and Yurgelun-Todd 1996; Pope et al. 1995). The explanation and mechanisms for this association are still not well established.

Cardiovascular and Autonomic Effects

A consistent, prominent, and sudden effect of marijuana is a 20 to 100 percent increase in heart rate lasting up to 2 to 3 hours (Hollister 1986a, 1988a; Jones 1985). After higher smoked or oral doses postural hypotension and associated faintness or dizziness can occur upon standing up from a supine or prone position. Tolerance to these effects appears after only a few days of two to three times per day dosing (Benowitz and Jones 1981; Jones 1985). Typical is a modest increase in supine blood pressure. Cardiac output can increase 30 percent when supine. Peripheral vascular resistance decreases with the greatest drop in resistance in skeletal muscles. Skin temperature drops are large; 4 to 6 degrees centigrade, even after a modest smoked dose and roughly parallel to plasma norepinephrine increases. With a few days of repeated exposure to frequent doses of oral THC or marijuana extract, supine blood pressure falls, the sometimes marked initial orthostatic hypotension disappears, blood volume increases, and heart rate slows (Benowitz and Jones 1981). Thus like other system effects, the intensity and character of many hemodynamic effects of single smoked doses in humans are a function of recent marijuana exposure, dose, and even body position.

The cardiovascular effects of smoked or oral marijuana have not presented any health problems for healthy and relatively young users. However, marijuana smoking by older patients, particularly those with some degree of coronary artery or cerebrovascular disease, is likely to pose greater risks because of the resulting increased cardiac work, increased catecholamines, carboxyhemoglobin, and postural hypotension (Benowitz and Jones 1981; Hollister 1988a). Such issues have not been well addressed in past marijuana research.

Respiratory System Effects

Pulmonary effects associated with marijuana smoking include transient bronchodilation after acute exposure. Chronic bronchitis and pharyngitis are associated with repeated exposure with an increased frequency of pulmonary illness. With chronic marijuana smoking, large-airway obstruction is evident on pulmonary function tests, and cellular inflammatory histopathological abnormalities appear in bronchial epithelium (Adams and Martin 1996; Hollister 1986a). These effects appear to be additive to those produced by tobacco smoking.

Endocrine System

Endocrine system effects include a moderate depression of spermatogenesis and sperm motility and a decrease in plasma testosterone in males. Prolactin, FSH, LH, and GH levels are decreased in females. Although suppressed ovulation and other ovulatory cycle changes occur in nonhuman primates, a study of human females smoking marijuana in a research hospital setting did not find hormone or menstrual cycle changes like those in the monkeys given THC (Mendelson and Mello 1984; Mendelson et al. 1984a). Relatively little research has been done on experimentally administered marijuana effects on human female endocrine and reproductive system function.

Immune System

THC and other cannabinoids in marijuana have immunosuppressant properties producing impaired cell-mediated and humoral immune system responses. A large literature describes the results of experiments with animal and animal tissue in in vivo and in vitro model systems. THC and other cannabinoids suppress antibody formation, cytokine production, leukocyte migration and natural killer-cell activity. Cannabinoids decrease host resistance to infection from bacterial and viral infection in animals. Marijuana smokers show evidence of impaired immune function: for example, decreased leukocyte blastogenesis in response to mitogens. Marijuana smokers, when compared to nonmarijuana smokers, have more respiratory illness (Polen et al. 1993).

The cannabinoids have been characterized as immunomodulators because although they generally suppress, they occasionally enhance some immune responses (Friedman et al. 1995). Reviews of marijuana immune system effects have characterized the effects as complicated or conflicting or controversial (Adams and Martin 1996; Hollister 1988b). The clinical significance or relevance of these findings remains uncertain. Much of the complexity and controversy results from the use of mostly in vitro animal models, or in vitro animal and human cell cultures, or in vivo animal studies. Generally in most studies the cannabinoid doses or concentrations used have been quite high when compared to reasonable levels of exposure in human marijuana smoking.

Suppressed or impaired immune mechanisms would likely have negative effects on health by increasing susceptibility to infection or to tumors. People with compromised immune systems or existing malignancies may be at higher risk than healthy people. For example, the risk of developing AIDS may be higher with HIV infection, with a higher risk for infection by opportunistic bacteria, fungi, or viruses. On the other hand, some have suggested that the immunosuppressive effects of cannabinoids might be useful clinically; for example, in treating multiple sclerosis, mostly reasoning from theoretical assumptions or experimental disease models in animals.

In summary, there is good evidence that THC and other cannabinoids can impair both cell-mediated and humoral immune system functioning, leading to decreased resistance to infection by viruses and bacteria. However, the health relevance of these findings to human marijuana use remains uncertain. Conclusive evidence for increased malignancy, or enhanced acquisition of HIV, or the development of AIDS, has not been associated with marijuana use.

There is a need for further research, particularly in circumstances where long-term administration of marijuana might be considered for therapeutic purposes; for example, in individuals who are HIV-positive or who have tumors, malignancies, or diseases where immune system function may be important in the genesis of the disease. Clinical studies with smoked marijuana in patients with compromised immune systems may offer a sensitive index of adverse immune system effects associated with cannabinoid exposure. Direct measures of viral load and other sensitive indices of immune system function are now more practical than in past years when most of the cannabinoid immune system research was carried out. The possibility that frequent and prolonged marijuana use might lead to clinically significant impairments of immune system function is great enough that such studies should be part of any marijuana medication development research, particularly when marijuana will be used by patients with compromised immune systems.

Tolerance and Physical Dependence
After repeated smoked or oral marijuana doses, marked tolerance is rapidly acquired (after a day or two) to many marijuana effects, e.g., cardiovascular, autonomic, and many subjective effects. After exposure is stopped, tolerance is lost with similar rapidity (Jones et al. 1981). Measurable tolerance or tachyphalaxis is evident for some hours after smoking even a single marijuana cigarette.

Withdrawal symptoms and signs appearing within hours after cessation of repeated marijuana use have been occasionally reported by patients in clinical settings (Duffy and Milin 1996; Mendelson et al. 1984b). A withdrawal syndrome was reliably produced by as little as 5 days of modest but frequent oral doses of THC or marijuana extract in double-blind, placebo-controlled experiments (Jones et al. 1981). THC decreased or relieved the symptoms. Typical symptoms and signs were restlessness, insomnia, irritability, salivation, tearing, nausea, diarrhea, increased body temperature, anorexia, weight loss, tremor, sweating, sleep brainwave rapid eye movement rebound, and subjective sleep disturbance. Increased dreaming contributing to the sleep disturbance sometimes persisted for weeks, but the other signs and symptoms were gone or markedly diminished within 48 hours after the last oral marijuana dose.

Drug Interactions With Marijuana
Tobacco, ethanol, and other psychoactive and therapeutic drugs commonly consumed together with marijuana share metabolic pathways with cannabinoids, so metabolic interactions are likely. Both THC and CBD inhibit the metabolism of drugs metabolized by hepatic mixed-function oxidase enzymes (Benowitz and Jones 1977; Benowitz et al. 1980; Hollister 1986b).

The absorption or clearance of other drugs taken with marijuana may be slowed or hastened depending on timing and sequence of drug ingestion and past exposure. For example, ethanol consumed just after smoking a marijuana cigarette produces a much lower peak blood level than the same dose of ethanol taken an hour before marijuana smoking because THC slows gastric emptying time, thus slowing absorption of ethanol.

THC is highly bound to plasma proteins (97 percent to 99 percent) and thus is likely to interact with other highly bound drugs because of competition for binding sites on plasma proteins.

Finally, there is experimental evidence for drug interactions at the functional (neural) adaptation level (Adams and Martin 1996).

By those and possibly by other mechanisms, recent or concurrent THC or CBD exposure measurably alters the pharmacokinetics and/or effects of ethanol, barbiturates, nicotine, amphetamines, cocaine, phencyclidine, opiates, atropine, and clomipramine (Fehr and Kalant 1983; Institute of Medicine 1982). Marijuana use is likely to alter the pharmacology of some concurrently used therapeutic drugs, e.g., cancer chemotherapeutic agents or anticonvulsants.

Cannabinoid Receptors
Mechanisms of psychoactive cannabinoid action were long suspected to be through interactions of/with lipid components of cell membranes (Adams and Martin 1996; Hollister 1988a). The discovery of cannabinoid receptors in the human brain in the late 1980s led to renewed interest in the pharmacology and potential therapeutic uses of cannabinoids (Adams and Martin 1996; Herkenham 1992). The mechanisms of action of THC are now assumed to be mainly receptor mediated. So far, it still is a relatively simple receptor family (CB 1 and CB 2). Receptors are abundant in brain areas concerned with memory, cognition, and motor coordination. An endogenous ligand, a fatty acid derivative named anandamide, has been identified but not yet studied in humans (Thomas et al. 1996). A specific THC antagonist, SR141716A, provokes intense withdrawal signs and behaviors in rodents that have been exposed to THC for even relatively brief periods (Adams and Martin 1996). The clinical pharmacology of the antagonist has not been studied in humans.

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