EFFECTS IN MAN Acute Effects Acute Physical Toxicity Chronic Physical Effects Genetics and Birth Defects Cannabis and Psychiatric Illness EFFECTS IN MAN ACUTE EFFECTS The acute effects of marihuana intoxication vary considerably due to several factors which can be classified as related to the marihuana itself, the dose and route of administration, the individual's rate of metabolism, his past experience with the drug, his expectations as well as the environmental and social setting in which the intoxication takes place. As synthetic trans-delta-9-tetrahydrocannabinol (henceforth referred to as THC) has become available (mainly through the national marihuana program of NIMH), it has been possible to study the basic chemistry and pharmacology of marihuana and to obtain the first data on the human metabolism of this psychoactive ingredient of marihuana. These will be discussed in the next few sections in detail. The role of expectations and setting are best discussed in relation to the endpoint of the effects studied, i.e., the physiological, biochemical, neurological, cognitive psychomoter and subjective aspects. The Question of the Active Ingredient There is no doubt that the major active ingredient of marihuana, as far as the typical euphoriant effect in man is concerned, is Delta-9-THC (59,67,95,96). At least the major psychological effects of marihuana can be reproduced by the administration of synthetic Delta-9-THC. There are, however, other ingredients in marihuana that may play a role in its biological activity. In freshly harvested marihuana there are comparatively large amounts of cannabinoid acids which are rapidly converted when heated, and slowly when stored, into decarboxylated neutral cannabinoids, including the active Delta-9-THC (95). Delta-8-THC, which occurs in much smaller concentration than Delta-9-THC, is also active (5) but no detailed analysis of its psychological effect in man is available as yet (61). It has been suggested that cannabidiol, occurring in variable but sometimes significant concentration in marihuana may be converted to Delta-9-THC during smoking (101), but this suggestion needs confirmation. The psychotropic activity of the other ingredients of natural marihuana, whether neutral (cannabinol, cannabiogerol, cannabicyclol, cannabichromene, etc.), acidic (cannabiodiolic acid, canabinolic acid, cannabichromenic acid, etc.) or alkaloid (82) has not been investigated (95). It is quite possible that some of these materials have psychotropic or biological activity different from that of Delta-9-THC or may play a role either in modifying the effect of Delta-9-THC or pro 1 Numbers in parentheses indicate references at end of chapter. ducing some side effects. Further research comparing the natural material with the synthetic THC is under way to shed some light on this problem (41,104,131). Dose and Route of Administration There are two major ways of consuming marihuana: smoking and oral ingestion. When smoked, THC is rapidly absorbed and effects appear within seconds to minutes. If marihuana is of low potency, effects may be subtle and brief (139). Seldom do they last longer than 2 to 3 hours after a single cigarette, although users may prolong the effects by repeated smoking (59). When the material is smoked, an uncertain and variable fraction of THC is lost by smoke escaping into the air or exhaled from the respiratory dead space. Investigators, in trying to control this variable, have adopted either a standardized routine of inhaling, holding the breath and finishing the cigarette within a given period of time (81), or using a spirometer to deliver the smoke and bringing the time variable of inhalation under stimulus control (113). Since no method for the quantitative estimation of THC concentration in blood or urine is available by conventional chemical techniques, radioactive labeled THC has been used to obtain such data. C 14-labeled Delta-9-THC was administered to chronic marihuana users by the smoking route by Galanter et al. There was a marked variability in the amount of Delta-9-THC absorbed. This was reflected both in plasma concentrations and in urinary excretion of the tracer (extractable by heptane and consisting mostly of unchanged Delta-9-THC). From these data it was estimated that the percentage of THC absorbed can vary between 1 and 41 percent (43) in contrast to the earlier estimate of about 50 percent absorption based on using a mechanical smoking device to imitate human smoking and measuring the delivered THC in the smoke (91). These data suggest that quantitative comparisons across subjects in studies of smoked marihuana must be made with extreme caution. Oral ingestion usually delays the onset of the psychological effect for from 30 minutes to over 2 hours (63). The effects peak at approximately three hours and have a duration greater than four hours (87). This delay occurs because synthetic THC, as well as marihuana extracts, require nonpolar vehicles, usually alcohol or vegetable oil. These apparently delay the absorption of the THC from the gastrointestinal tract (63). The importance of the vehicle for the rate of absorption from an oral dose of labeled material for three oral vehicles-alcohol, sesame oil and aqueous glycocholic acid solution has been demonstrated by Perez-Reyes and Lipton (107). It was found that THC in doses of 37 mg. (total dose) is very poorly absorbed from an alcoholic solution as indicated by: (1) A low plasma level of total radioactivity; (2) a large portion (70 percent) of radioactivity recovered from the feces in the first 3 days after administration; (3) slow onset and relatively moderate intensity of the psychological effects. In contrast to this result, THC was absorbed much better from sesame oil solution and even faster from the glycocholic acid preparation of THC. This was evidenced by high plasma levels, lower recovery rate of radioactivity from feces, and faster onset with higher intensity of the psychological effects after administration in these |