title: Antagonist-elicited cannabis withdrawal in humans.
abstract: Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Gorelick
authors.forename: Robert S
authors.initials: RS
authors.lastname: Goodwin
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: Robert P
authors.initials: RP
authors.lastname: McMahon
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
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: D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D002189:Marijuana Abuse / Q000503:physiopathology*; D013058:Mass Spectrometry; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013375:Substance Withdrawal Syndrome / Q000209:etiology* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C001427:11-hydroxy-delta(9)-tetrahydrocannabinol; D013759:Dronabinol; D000077285:Rimonabant