title: CB1 - cannabinoid receptor antagonist effects on cortisol in cannabis-dependent men.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Rimonabant 20 or 40 mg did not significantly increase plasma cortisol concentrations, consistent with an absence of antagonist-elicited cannabis withdrawal.
  
  
  CONCLUSIONS
  Rimonabant doses >40 mg might elicit cortisol changes, confirming a role for CB1 receptors in modulating the HPA axis in humans.
authors.affiliation: Chemistry and Drug Metabolism Section, Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Goodwin
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.forename: David A
authors.initials: DA
authors.lastname: Gorelick
authors.forename: Eugene
authors.initials: E
authors.lastname: Schwilke
authors.forename: David M
authors.initials: DM
authors.lastname: Schwope
authors.forename: William D
authors.initials: WD
authors.lastname: Darwin
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kelly
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Schroeder
authors.forename: Catherine
authors.initials: C
authors.lastname: Ortemann-Renon
authors.forename: Denis
authors.initials: D
authors.lastname: Bonnet
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
mesh_terms: D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D002189:Marijuana Abuse / Q000097:blood*; D010880:Piperidines / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol; D000077285:Rimonabant; D006854:Hydrocortisone