Article date: July 2013
By: Linda E. Klumpers, Christine Roy, Geraldine Ferron, Sandrine Turpault, Franck Poitiers, Jean‐Louis Pinquier, Johan G. C. Hasselt, Lineke Zuurman, Frank A. S. Erwich, Joop M. A. Gerven, in Volume 76, Issue 1, pages 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 Δ9‐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.
DOI: 10.1111/bcp.12071
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