Abstract

Tetrahydrocannabinol (THC), a major constituent of marijuana, and several of its metabolites are psychoactive in humans. Cannabidiol (CBD), a nonpsychoactive cannabinoid, inhibits hepatic microsomal THC metabolism and also modulates subjective psychological responses to THC in humans. Treatment of mice with CBD markedly decreased the hepatic microsomal in vitro formation of the major THC metabolites, 6 alpha-OH-THC and 7-OH-THC and increased formation of the minor metabolite 6 beta-OH-THC. THC blood levels were modestly elevated after CBD pretreatment and THC administration, compared with untreated controls, and area under the curve (AUC) of THC increased 50% as a function of decreased clearance. CBD pretreatment modestly increased the Cmax, AUC, or t1/2 of the major THC metabolites in the blood, whereas those kinetic parameters for 6 beta-OH-THC were dramatically increased. Changes in brain concentrations and kinetic parameters of the major THC metabolites did not reflect the relatively modest changes found in blood levels after CBD pretreatment, but exhibited large increases in AUC (7- to 15-fold) and t1/2 (2- to 4-fold), as well as in tmax. Changes in brain concentrations and kinetic parameters for 6 beta-OH-THC reflected the marked changes observed in blood levels after CBD pretreatment. Thus, CBD pretreatment resulted in large increases in AUC and t1/2 of all THC metabolites in brain, with a modest increase in AUC of THC. These changes in THC metabolite brain pharmacokinetics may contribute to the modulation of psychological responses to THC observed after CBD treatment.