Experiments investigating the possible interaction of tetrahydrocannabinol (THC) and cannabidiol (CBD), two major components of marihuana, were conducted under controlled laboratory conditions in a double-blind manner. In one study, 15 male volunteers were given placebo or 25 mug/kg of THC together with either placebo or 150 mug/kg of CBD by inhalation of the smoke of a single cigarette. All four treatments were assigned to each subject according to a series of Latin-square designs. CBD significantly attenuated the subjective euphoria of THC. Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD, but a trend indicating a decrease in THC-like effects was observed after the combination. When administered alone CBD was inactive for all the parameters measured. In a second study, 8 male subjects were given CBD (0 or 150 mug/kg) by smoke inhalation 30 min before THC (0 or 25 mug/kg) in a second cigarette. In contrast to the simultaneous administration of both drugs, CBD pretreatment did not alter the effects of THC on the parameters observed.

Delta(9)-Tetrahydrocannabinol (the major active component of marihuana) administered intravenously to normal human volunteers persists in plasma for more than 3 days (t(1/2) = 56 hours). Its metabolites appear in plasma within 10 minutes after administration and persist along with the precursor compound. Delta(9)-Tetrahydrocannabinol is completely metabolized in man, and the radioactive metabolites are excreted in urine and feces for more than 8 days.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of both imipramine and desipramine as much as tenfold and prolonged half-life as much as fourfold. Desipramine oral clearance values were 289, 112, and 27 L/hr alone, after a single fluoxetine dose, and after multiple fluoxetine doses, respectively. Correspondingly, imipramine oral clearance values were 181, 87, and 51 L/hr. These kinetic changes resulted in significantly higher plasma tricyclic concentrations after fluoxetine administration. The amount of parent drug excreted unchanged in urine increased and imipramine or desipramine clearance to their respective 2-hydroxy metabolites decreased. Metabolic conversion of imipramine to desipramine appeared to be unaffected. The findings indicate that fluoxetine causes an inhibition of tricyclic 2-hydroxylation and may decrease first-pass and systemic metabolism. When imipramine or desipramine are to be coadministered with fluoxetine, a lower dosage may be needed to maintain steady-state concentrations and to avoid undesirable side effects caused by excessive tricyclic concentrations.