Pharmacokinetics, Pharmacodynamics, and Urinary Recovery of Oral Mescaline Hydrochloride in Healthy Participants
Becker, A. M., Klaiber, A., Ley, L., Liechti, M. E., Luethi, D., Mueller, L., Schmid, Y., Thomann, J.
This pharmacokinetic-pharmacodynamic analysis (n=46) of two Phase I trials of oral mescaline (100-800 mg) showed dose-proportional exposure with peak concentrations at 2 hours, a half-life of 3.5 hours, onset of effects around 1 hour post-dose, maximum effect intensity and duration ranging from 13% and 2.8 hours (100 mg) to 89% and 15 hours (800 mg), with 53% urinary excretion unchanged and 31% as the main metabolite, indicating at least 53% oral bioavailability.
Abstract
Background and objective: 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.Methods: 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 Emax model linked to plasma concentrations via a first-order rate constant (ke0).Results: 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.Conclusions: 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.