title: Surinabant, a selective cannabinoid receptor type 1 antagonist, inhibits Δ9-tetrahydrocannabinol-induced central nervous system and heart rate effects in humans.
abstract: OBJECTIVE
  Cannabinoid receptor type 1 (CB1 ) antagonists have been developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB1 antagonist in vitro. The aim of this study was to assess the magnitude of inhibition by surinabant of CNS effects and heart rate induced by Δ(9) -tetrahydrocannabinol (THC) in humans.
  
  
  METHODS
  This was a double-blind, placebo-controlled, randomized, four period six sequence crossover study. Thirty healthy young male occasional cannabis users (<1 per week) were included. A single oral dose of surinabant (5, 20 or 60 mg) or placebo was administered followed 1.5 h later by four intrapulmonary THC doses (2, 4, 6 and 6 mg) or vehicle, administered at 1 h intervals. The wash-out period was 14-21 days. Subjective and objective pharmacodynamic (PD) measurements were performed. A population PK-PD model for THC and surinabant quantified PK and PD effects.
  
  
  RESULTS
  Surinabant 20 and 60 mg inhibited all THC-induced PD effects in a similar range for both doses with inhibition ratios ranging from 68.3% (95% CI = 32.5, 104.2; heart rate) to 91.1% (95% CI = 30.3, 151.8; body sway). IC50 ranged from 22.0 ng ml(-1) [relative standard error (RSE) = 45.2%; body sway] to 58.8 ng ml(-1) (RSE = 44.2%; internal perception). Surinabant 5 mg demonstrated no significant effects.
  
  
  CONCLUSIONS
  The dose-related inhibition by surinabant, without any effect of its own, suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations. A single surinabant dose between 5 to 20 mg and above was able to antagonize THC-induced effects in humans.
authors.affiliation: Centre for Human Drug Research, Zernikedreef 10, Leiden, the Netherlands. klumpers@gmail.com
authors.forename: Linda E
authors.initials: LE
authors.lastname: Klumpers
authors.forename: Christine
authors.initials: C
authors.lastname: Roy
authors.forename: Geraldine
authors.initials: G
authors.lastname: Ferron
authors.forename: Sandrine
authors.initials: S
authors.lastname: Turpault
authors.forename: Franck
authors.initials: F
authors.lastname: Poitiers
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pinquier
authors.forename: Johan G C
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: Lineke
authors.initials: L
authors.lastname: Zuurman
authors.forename: Frank A S
authors.initials: FA
authors.lastname: Erwich
authors.forename: Joop M A
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D000293:Adolescent; D000328:Adult; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol; C492668:surinabant