The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties
The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties
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DOI：
10.1038/npp.2013.135
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发表时间：
2013-11-01
影响因子：
7.6
通讯作者：
Schetz, John A.
中科院分区：
文献类型：
--
作者：
Gatch, Michael B.;Kozlenkov, Alexey;Schetz, John A.
关于艾滋病毒患者和未感染艾滋病毒的青少年滥用艾滋病毒抗逆转录病毒药物依法韦仑（（4S）-6-氯-4-（2-环丙基乙炔基）-4-（三氟甲基）-2，4-二氢-1H-3，1-苯并恶嗪-2-酮）的轶事报道已经浮出水面，他们压碎药丸并吸食粉末以获得其精神作用。依法韦仑受体药理学的分子特征分析确定了与其他已知滥用药物（包括儿茶酚胺和吲哚胺转运蛋白以及GABA（A）和5-HT 2A受体）的多个既定作用位点的相互作用。在啮齿类动物中，与麦角酸二乙胺（LSD）的主要作用位点5-HT 2A受体的相互作用似乎主导了依法韦仑的行为特征。LSD和依法韦仑在一个新的开放领域的环境中减少amplitude。依法韦仑在大鼠中引起区分LSD和盐水的药物杠杆反应，并且这种作用通过选择性阻断5-HT 2A受体而消除。与LSD类似，依法韦仑在野生型小鼠中诱导头部抽搐反应，但在5-HT 2A敲除小鼠中不诱导。尽管具有GABA（A）增强作用（如苯二氮卓类和巴比妥类药物），并与多巴胺转运体，5-羟色胺转运体和囊泡单胺转运体2（如可卡因和甲基苯丙胺）相互作用，依法韦仑未能在自我施用可卡因的大鼠中维持反应，并且未能产生条件性位置偏好。虽然它的分子药理学是多种多样的，依法韦仑在啮齿动物中的主要行为效应与通过5-HT 2A受体介导的LSD样活性一致。这一发现部分与滥用依法韦仑的人的主观体验以及特定剂量依赖性不良神经精神事件（如幻觉和夜惊）相关，这些事件由服用依法韦仑作为药物的艾滋病毒患者报告。
Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)- 4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABA(A) and 5-HT2A receptors. In rodents, interaction with the 5-HT2A receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT2A-knockout, mice. Despite having GABA(A)-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT2A receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.