Huestis M A, Gorelick D A, Heishman S J, Preston K L, Nelson R A, Moolchan E T, Frank R A
National Institute on Drug Abuse Intramural Research Program, 5500 Nathan Shock Dr, Baltimore, MD 21224, USA.
Arch Gen Psychiatry. 2001 Apr;58(4):322-8. doi: 10.1001/archpsyc.58.4.322.
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.
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.
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.
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.
SR141716是一种最近研发的CB1大麻素受体拮抗剂，可在体外和动物实验中阻断Δ-9-四氢大麻酚（THC）及其他CB1大麻素激动剂的急性效应。这些发现表明CB1受体介导了大麻的许多效应，但尚未在人体中得到评估。
63名有大麻使用史的健康男性被随机分配，按照剂量递增（1、3、10、30和90毫克）设计接受口服SR141716或安慰剂。两小时后，每位受试者吸食一支活性（2.64% THC）或安慰剂大麻烟。在给予拮抗剂和大麻前后，测量与大麻中毒相关的心理效应及心率。
单次口服SR141716可显著剂量依赖性地阻断大麻诱发的主观中毒和心动过速。90毫克剂量使“你现在感觉有多嗨？”“你现在吸食大麻有多迷糊？”和“你现在感觉药物效果有多强烈？”的视觉模拟量表评分降低了38%至43%，并使心率降低了59%。单独使用SR141716未产生显著的生理或心理效应，也未影响THC血浆峰值浓度或时间-浓度曲线下面积。所有受试者对SR141716耐受性良好。
SR141716可阻断吸食大麻的急性心理和生理效应，而不改变THC的药代动力学。这些发现在人体中首次证实了CB1受体在介导大麻效应中的核心作用。
