EFFECT OF CANNABIDIOL PRETREATMENT ON THE KINETICS OF TETRAHYDROCANNABINOL METABOLITES IN MOUSE-BRAIN

Tetrahydrocannabinol (THC), a major constituent of marijuana, and seve ral of its metabolites are psychoactive in humans, Cannabidiol (CBD), a nonpsychoactive cannabinoid, inhibits hepatic microsomal THC metabol ism and also modulates subjective psychological responses to THC in hu mans, Treatment of mice with CBD markedly decreased the hepatic micros omal in vitro formation of the major THC metabolites, 6 alpha-OH-THC a nd 7-OH-THC and increased formation of the minor metabolite 6 beta-OH- THC, THC blood levels were modestly elevated after CBD pretreatment an d THC administration, compared with untreated controls, and area under the curve (AUG) of THC increased 50% as a function of decreased clear ance, CBD pretreatment modestly increased the C-max, AUC, or t(1/2) of the major THC metabolites in the blood, whereas those kinetic paramet ers for 6 beta-OH-THC were dramatically increased, Changes in brain co ncentrations and kinetic parameters of the major THC metabolites did n ot reflect the relatively modest changes found in blood levels after C BD pretreatment, but exhibited large increases in AUC (7- to 15-fold) and t(1/2) (2- to 4-fold), as well as in t(max), Changes in brain conc entrations and kinetic parameters for G beta-OH-THC reflected the mark ed changes observed in blood levels after CBD pretreatment. Thus, CBD pretreatment resulted in large increases in AUC and t(1/2) of all THC metabolites in brain, with a modest increase in AUC of THC, These chan ges in THC metabolite brain pharmacokinetics may contribute to the mod ulation of psychological responses to THC observed after CBD treatment .