Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults
Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults
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DOI：
10.1007/s40262-017-0540-6
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发表时间：
2017-12-01
影响因子：
4.5
通讯作者：
Hutson, Paul R.
中科院分区：
文献类型：
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作者：
Brown, Randall T.;Nicholas, Christopher R.;Hutson, Paul R.
裸盖菇素是一种迷幻色胺，在最近的临床试验中显示出治疗抑郁症和药物使用障碍的前景。这项裸盖菇素药代动力学的开放式研究被用来描述裸盖菇素在12名健康成人中的药代动力学和安全性，剂量依次为0.3、0.45和0.6 mg/kg。在受试者的控制环境中，大约每月一次口服裸盖菇素剂量的递增，并对受试者进行24小时的监测。在24小时内采集血液和尿样，并通过高效液相色谱-串联质谱仪(LC-MS/MS)分析裸盖菇素和活性代谢物裸盖菇素。用室内法(NONMEM)和非室内法(WinNonlin)测定裸盖菇素的药代动力学，在血浆和尿液中均未发现裸盖菇素，完整裸盖菇素的肾清除量占总清除量的不到2%。裸鼠李素在两倍剂量范围内线性关系良好，消除半衰期为3h(标准差1.1)。在一些受试者中，延长的消除阶段表明psiLocin葡萄糖醛酸化物的代谢物被水解。在受试者中，体重并不能预测psiLocin清除量的变化，也没有发生严重的不良事件。少量的psiLocin从肾脏排泄，表明对于轻、中度肾损害的受试者，无需减少剂量。使用药代动力学参数对固定剂量的模拟表明，25毫克的口服剂量应近似于0.3毫克/公斤的裸盖菇素口服剂量的药物暴露。虽然0.6毫克/公斤的剂量超过了可能的治疗剂量，但在任何剂量期间或在任何剂量后30天内，都没有发生严重的身体或心理事件。
Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods.No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied.The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose.