Use, Abuse, and Addiction

Cannabinoid Tolerance

Tolerance readily develops to most of the effects of cannabinoids in humans and is largely attributed to pharmacodynamic (brain neuroadaptation) rather than pharmacokinetic (metabolic or distribution) changes. Chronic cannabinoid administration leads to profound downregulation of cannabinoid receptors in humans, suggesting one of several mechanisms for tolerance (see below for other mechanisms). Tolerance is reflected by changes in the increases in heart rate or subjective high. In an inpatient study of 30 subjects who smoked marijuana, the mean heart rate and subjective “high” decreased over a 94 day smoking period (Figure 8.10). Tolerance to subjective effects but not the effects on food intake have been observed in some studies. Tolerance has also been observed to the effects of Δ9-THC on intraocular pressure, cardiovascular measures other than heart rate, sedative effects, and autonomic and sleep changes.

FIGURE 8.9 Percentage of patients with various DSM-III-R dependence symptoms, among those dependent on cannabis (n = 180), alcohol (n = 186), or cocaine (n = 51). [Taken with permission from Crowley TJ, Macdonald MJ, Whitmore EA, Mikulich SK. Cannabis dependence, withdrawal, and reinforcing effects among adolescents with conduct symptoms and substance use disorders. Drug and Alcohol Dependence, 1998, (50), 27–37.]

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