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

British journal of clinical pharmacology

PubMedID: 23278647

Klumpers LE, Roy C, Ferron G, Turpault S, Poitiers F, Pinquier JL, van Hasselt JG, Zuurman L, Erwich FA, van Gerven JM. Surinabant, a selective cannabinoid receptor type 1 antagonist, inhibits ?9-tetrahydrocannabinol-induced central nervous system and heart rate effects in humans. Br J Clin Pharmacol. 2013;76(1):65-77.
AIM
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 ?(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.