Blockade of effects of smoked marijuana by the CBl-selective cannabinoid receptor antagonist SR141716

Background: SR141716, a recently developed CB1 cannabinoid receptor antagon ist, blocks acute effects of Delta -9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists invitro and in animals. These findings suggest tha t CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. Methods: Sixty-three healthy men with a history of marijuana use were rando mly assigned to receive oral SR141716 or a placebo in an escalating dose (1 , 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64%; THC) or placebo marijuana cigarette 2 hours later. Psychological effects associa ted with marijuana intoxication and heart rate were measured before and aft er antagonist and marijuana administration. Results: Single oral doses of SR141716 produced a significant dose-dependen t blockade of marijuana-induced subjective intoxication and tachycardia. Th e 90-mg dose produced 38% to 43%; reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong. is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psy chological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by a ll subjects. Conclusions: SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.