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Abstract
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 Δ9-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. Conclusion: Rimonabant 20 or 40 mg did not significantly increase plasma cortisol concentrations, consistent with an absence of antagonist-elicited cannabis withdrawal. Scientific Significance: Rimonabant doses >40 mg might elicit cortisol changes, confirming a role for CB1 receptors in modulating the HPA axis in humans.
ACKNOWLEDGEMENTS
We acknowledge the clinical research teams of the NIDA IRP, Johns Hopkins Behavioral Pharmacology Research Unit, and Maryland Psychiatric Research Center (MPRC) Treatment Research Program for their support. This study was funded by the IRP, NIDA, National Institutes of Health, NIDA Residential Research Support Services Contract HHSN271200599091CADB (D. Kelly, PI), and Sanofi-aventis, and conducted under a Cooperative Research and Development Agreement (CRADA) between the National Institutes of Health and Sanofi-aventis.
Declaration of Interest
Drs. Ortemann-Renon and Bonnet are employees of Sanofi-aventis. No other authors have any conflicts of interest to declare. The authors alone are responsible for the content and writing of the paper.