Blockade of effects of smoked marijuana by the CBl-selective cannabinoid receptor antagonist SR141716
Blockade of effects of smoked marijuana by the CBl-selective cannabinoid receptor antagonist SR141716
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DOI：
10.1001/archpsyc.58.4.322
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发表时间：
2001-04-01
影响因子：
--
通讯作者：
Frank, RA
中科院分区：
文献类型：
--
作者：
Huestis, MA;Gorelick, DA;Frank, RA
背景：SR141716是最近开发的CB1大麻素受体拮抗剂，可阻断δ -9-四氢大麻酚（THC）和其他CB1大麻素激动剂在体外和动物体内的急性作用。这些发现表明，CB1受体介导了大麻的许多影响，但这还没有在人类中进行评估。方法：63名有大麻使用史的健康男性被随机分配到口服SR141716或递增剂量安慰剂组（1、3、10、30和90 mg）。每名受试者在2小时后抽一支有活性（2.64%；THC）或安慰剂的大麻烟。在服用拮抗剂和大麻前后测量大麻中毒和心率相关的心理影响。结果：单次口服SR141716对大麻诱导的主观中毒和心动过速具有明显的剂量依赖性阻断作用。90毫克的剂量产生38%到43%；视觉模拟量表“你现在感觉有多高？”“你现在吸食大麻有多嗨？”以及“你有多强壮？”你现在感觉到药物的作用了吗？”并使心率降低了59%。单独使用SR141716不会产生明显的生理和心理影响，也不会影响THC峰值血浆浓度和时间x浓度曲线下面积。所有受试者对SR141716耐受良好。结论：SR141716在不改变四氢大麻酚药代动力学的情况下，阻断了吸食大麻的急性心理和生理效应。这些发现首次在人类身上证实了CB1受体在调节大麻作用中的核心作用。
Background: SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta -9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists invitro 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.