Cannabinoid receptor 1 agonists and antagonists are in development for neurological, metabolic and psychiatric disorders. The effects of cannabinoid antagonists in healthy volunteers are mostly unknown, hampering the design and interpretation of early pharmacology studies in humans with these compounds. Cannabinoid antagonist activity can be demonstrated, by showing inhibitory activity on the effects of the cannabinoid receptor 1 agonist tertrahydrocannabinol (THC). This study addresses the dose-response-relationships for THC. This information can be used as the basis for pharmacological proof-of-mechanism studies of cannabinoid antagonists (counteraction studies) and agonists (as a positive control). The study was also set up to identify by which pharmacodynamic parameters the effects of THC are most accurately quantified.

THC was purified from Cannabis sativa according to GMP-compliant procedures (Farmalyse BV, Zaandam, The Netherlands). Twelve healthy males (average 23.3 years, range 21-27) with a history of mild cannabis use for at least 1 year were included in the study. On one study day, r ising doses of THC (2, 4, 6 and 8 mg) were administered by inhalation at 90 min intervals using a Volcano® vaporizer (Storz-Bickel GmbH, Tuttlingen, Germany). On a separate, randomized occasion, vehicle was administered in the same way, as a double-blinded placebo. Pharmacodynamic measurements were obtained frequently after each consecutive dose, including visual analogue scales (VAS) according to Bond & Lader, psychotomimetic VAS according to Bowdle, saccadic eye movements, smooth pursuit eye movements, pupil size, body sway, adaptive tracking, pharmaco-EEG and heart rate. Blood samples were taken to measure plasma THC concentrations.

Analysis was performed using mixed model anova with baseline values as covariate. After THC administration, significant dose-related changes compared with placebo were seen in body sway (58.9%, 95% CI 33, 89.7) and VAS alertness (– 33.6 %, 95% CI – 41.6, – 25.7). Significant dose-related changes were also seen in pharmaco-EEG, in which Pz-Oz delta- and beta activity decreased (– 12.0%: 95% CI – 19.1%, – 4.4% and – 8.0%: 95% CI – 13.8%, – 1.8% respectively). Heart rate increased significantly compared with placebo with a maximum of 24 beats min^-1 (19.4%: 95% CI 13.3, 25.5). Plasma THC concentrations showed little interindividual variation. The average initial half-life was 4 min and the terminal half-life was 70 min.

This study provides a model for pharmacological proof-of-mechanism studies of cannabinoid antagonists (inhibitory activity) and agonists (positive control).