CB1 - Cannabinoid Receptor Antagonist Effects on Cortisol in Cannabis-Dependent Men

Background: The endocannabinoid system modulates the hypothalamic–pituitary–adrenal (HPA) axis, but the effect of cannabinoid type 1 (CB1) receptor antagonism following chronic CB1 receptor stimulation in humans is unknown. Objectives: To evaluate effects of the CB1 receptor antagonist rimonabant on the HPA axis in cannabis-dependent individuals. Methods: Fourteen daily cannabis smokers received increasingly frequent 20 mg oral � 9-tetrahydrocannabinol (THC) doses (60–120 mg/day) over 8 days to standardize cannabis tolerance. Concurrent with the last THC dose, double-blind placebo or rimonabant (20 or 40 mg) was administered. Cannabinoid, rimonabant, and cortisol plasma concentrations were measured 1.5 hours prior to rimonabant administration and 2.0, 5.5, and 12.5 hours post-dose. Results: Ten participants completed before premature study termination due to rimonabant’s withdrawal from development. Five participants received 20 mg, three received 40 mg, and two placebo. There was a significant positive association between rimonabant concentration and change in cortisol concentration from baseline (r = .53, p < .01). There also was a borderline significant association between rimonabant dose and cortisol concentrations when the dose-by-time interaction was included. Four of eight participants receiving rimonabant (none of two receiving placebo) had greater cortisol concentrations 2 hours after dosing (at 11:30) than at 08:00, while normal diurnal variation should have peak concentrations at 08:00.