Surinabant, a selective cannabinoid receptor type 1 antagonist, inhibits Δ 9 ‐tetrahydrocannabinol‐induced central nervous system and heart rate effects in humans

Aim Cannabinoid receptor type 1 ( CB 1 ) antagonists have been developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB 1 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). I C 50 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 CB 1 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.