Aspects of tolerance to and dependence on cannabis.

Tolerance at all levels of complexity in the brain involves "learning" in the sense of the acquisition of compensatory adaptations to the consequences of the presence of a drug-produced disturbance in function. Depending on the function, species, and dose of cannabis, "tissue tolerance," behaviorally augmented (to provide the presence of the disturbed function) or not, develops at different rates or not all (e.g., to impairment of the logical sequence of thoughts, to which no tolerance has yet been demonstrated). "Dispositional tolerance" (increased rate of metabolism of delta 9-THC due to enzyme induction) may play a role in the development of tolerance or "reverse tolerance" to cannabis in man. There is evidence that for the label "high," placebo effects may account for the "reverse tolerance" seen in experienced users on smoking (but not on ingestion of delta 9-THC or placebo) along with evidence of residual tolerance to other not-so-labeled effects of the drug. Dependence on cannabis, in the sense of abstinence phenomena on abrupt withdrawal of delta 9-THC, has been demonstrated in monkeys made tolerant to delta 9-THC given four times daily for about 1 month. In man, physiologic marijuana abstinence signs have not been demonstrated, but behavioral (and some physiologic) abstinence phenomena have been reported in heavy users of hashish or ganja. The between-dose hyperirritability and dysphoria reported to occur in experimental studies on chronic marijuana intoxication may actually be early and short-lived abstinence changes. In the West, where marijuana with relatively low delta 9-THC content is widely smoked, dependence in the sense of drug-seeking behavior appears to be less a function of any pharmacologic reinforcing properties the drug may have than of secondary (conditioned) reinforcement derived from the social milieu in which the marijuana is smoked. In cultures where marijuana of higher delta 9-THC content, hashish, or ganja is used, pharmacologic reinforcement (through suppression of abstinence changes) may play a greater role in maintaining drug-seeking behavior.