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Marilyn A. Huestis, PhD; David A. Gorelick, MD, PhD; Stephen J. Heishman, PhD; Kenzie L. Preston, PhD; Richard A. Nelson, MD; Eric T. Moolchan, MD; Richard A. Frank, MD, PhD

Arch Gen Psychiatry. 2001;58:322-328.

Background  SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of -9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that 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 randomly 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 associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration.

Results  Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 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 psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all 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.

From the Clinical Pharmacology and Therapeutics Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Md (Drs Huestis, Gorelick, Heishman, Preston, Nelson, and Moolchan); and Sanofi-Synthelabo Inc, Malvern, Pa (Dr Frank).

Corresponding author and reprints: Marilyn A. Huestis, PhD, National Institute on Drug Abuse Intramural Research Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 (e-mail: mhuestis{at}intra.nida.nih.gov).

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