Mueller Lorenz, Klaiber Aaron, Ley Laura, Becker Anna M, Thomann Jan, Luethi Dino, Schmid Yasmin, Liechti Matthias E
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel and University of Basel, Schanzenstrasse 55, CH-4056, Basel, Switzerland.
Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Clin Pharmacokinet. 2025 Jul 14. doi: 10.1007/s40262-025-01544-x.
Mescaline is a classic serotonergic psychedelic with a long history of human use. The present study analyzed the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship, and urinary recovery of oral mescaline hydrochloride.
Data from 105 single-dose administrations (100-800 mg) in 49 participants from two phase I trials were analyzed with compartmental pharmacokinetics and pharmacokinetic-pharmacodynamic modeling. A one-compartment model with first-order absorption, elimination, and a lag time was used to describe mescaline plasma concentrations. Acute subjective effects, assessed by visual analog scales (range 0-100%), were modeled using a sigmoid E model linked to plasma concentrations via a first-order rate constant (k).
Mescaline showed dose-proportional increases in total exposure and maximal concentrations, with a peak concentration reached within 2.0 h (geometric mean) and a half-life of 3.5 h across all doses. Mean model-predicted onset of "any drug effect" occurred around 1 hour post-dose. Maximum predicted effect intensity and duration increased with dose, from 13% and 2.8 h at 100 mg to 89% and 15 h at 800 mg. Over all conditions, 53% of the dose was excreted into urine unchanged, and 31% was excreted as the main metabolite 3,4,5-trimethoxyphenylacetic acid over 24-30 h.
These findings provide the first detailed pharmacokinetic-pharmacodynamic characterization of mescaline in humans and indicate an oral bioavailability of at least 53%, limited by first-pass metabolism to 3,4,5-trimethoxyphenylacetic acid, followed by predominant renal elimination of both analytes.
ClinicalTrials.gov identifier: NCT04227756 and NCT04849013.
三甲氧苯乙胺是一种经典的血清素能致幻剂，人类使用历史悠久。本研究分析了口服盐酸三甲氧苯乙胺的药代动力学、药代动力学-药效学关系及尿回收率。
对来自两项I期试验的49名参与者的105次单剂量给药（100 - 800毫克）数据进行房室药代动力学和药代动力学-药效学建模分析。采用具有一级吸收、消除和滞后时间的单室模型描述三甲氧苯乙胺血浆浓度。通过视觉模拟量表（范围0 - 100%）评估的急性主观效应，使用通过一级速率常数（k）与血浆浓度相关联的S型E模型进行建模。
三甲氧苯乙胺的总暴露量和最大浓度呈剂量比例增加，所有剂量下的峰值浓度在2.0小时（几何均值）内达到，半衰期为3.5小时。模型预测的“任何药物效应”平均起效时间在给药后约1小时。最大预测效应强度和持续时间随剂量增加，从100毫克时的13%和2.8小时增加到800毫克时的89%和15小时。在所有情况下，53%的剂量以原形排泄到尿液中，在24 - 30小时内，31%以主要代谢物3,4,5 - 三甲氧基苯乙酸的形式排泄。
这些发现首次提供了人类三甲氧苯乙胺详细的药代动力学-药效学特征，表明口服生物利用度至少为53%，受首过代谢为3,4,5 - 三甲氧基苯乙酸的限制，随后两种分析物主要经肾脏消除。
ClinicalTrials.gov标识符：NCT04227756和NCT04849013。
