Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716.
BACKGROUND
SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-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.
Huestis
M A
MA
National Institute on Drug Abuse Intramural Research Program, 5500 Nathan Shock Dr, Baltimore, MD 21224, USA. mhuestis@intra.nida.nih.gov
Gorelick
D A
DA
Heishman
S J
SJ
Preston
K L
KL
Nelson
R A
RA
Moolchan
E T
ET
Frank
R A
RA
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D013759:Dronabinol / Q000037:antagonists & inhibitors* / Q000097:blood; D005059:Euphoria / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D002189:Marijuana Abuse / Q000097:blood / Q000503:physiopathology / Q000523:psychology*; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010919:Placebos; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013610:Tachycardia / Q000139:chemically induced / Q000503:physiopathology
D002186:Cannabinoids; D010880:Piperidines; D010919:Placebos; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; D000077285:Rimonabant