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 of Pharmacokinetics, Pharmacodynamics, and Urinary Recovery of Oral Mescaline Hydrochloride in Healthy Participants
“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.“
Authors: Lorenz Mueller, Aaron Klaiber, Laura Ley, Anna M. Becker, Jan Thomann, Dino Luethi, Yasmin Schmid & Matthias E. Liechti
Summary of Pharmacokinetics, Pharmacodynamics, and Urinary Recovery of Oral Mescaline Hydrochloride in Healthy Participants
Mescaline is a naturally occurring psychedelic compound classified as a phenethylamine alkaloid. It is found in several cactus species, most notably peyote and San Pedro. As a classic serotonergic psychedelic, mescaline shares its mechanism of action with substances like LSD, psilocybin, and DMT, primarily by activating the serotonin 5-HT₂A receptor. However, mescaline exhibits the weakest affinity for this receptor among these substances and demonstrates limited permeability across the blood–brain barrier. Consequently, higher oral doses—typically between 300 to 800 mg of mescaline hydrochloride—are required to produce full psychedelic effects compared to lower-dose substances like psilocybin or LSD.
Despite the long-standing cultural use of mescaline, especially in ceremonial contexts, it has received relatively little attention in contemporary clinical research. Recent years have seen renewed interest in psychedelic research, particularly regarding their therapeutic applications. Most studies, however, have focused on psilocybin and LSD, leaving a gap in understanding the pharmacology of mescaline in humans. Previous investigations into mescaline’s metabolism have been sparse, with only a single earlier study using radiolabelled mescaline in healthy males. The current research aims to address this gap by analysing pharmacokinetics (how the body processes mescaline), pharmacodynamics (how mescaline affects the body), and urinary excretion using data from two Phase I clinical trials.
Methods
Study Design
This analysis utilised data from two previously published Phase I clinical trials conducted in healthy volunteers. Study 1 included 32 participants who received either 300 mg or 500 mg of oral mescaline HCl. Study 2 involved 17 participants who were administered four different single doses of mescaline HCl (100, 200, 400, and 800 mg) and, in one session, a combination of 800 mg mescaline with 40 mg of ketanserin—a 5-HT₂A receptor antagonist. Both studies were designed as randomised, double-blind, crossover trials. Only mescaline conditions were included in the primary analysis, although ketanserin data were retained for certain pharmacokinetic evaluations. A washout period of at least 10–14 days was observed between sessions to prevent carry-over effects.
Participants
Find this paper
https://doi.org/10.1007/s40262-025-01544-x
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Cite this paper (APA)
Mueller, L., Klaiber, A., Ley, L., Becker, A. M., Thomann, J., Luethi, D., ... & Liechti, M. E. Pharmacokinetics, Pharmacodynamics, and Urinary Recovery of Oral Mescaline Hydrochloride in Healthy Participants. Clinical Pharmacokinetics.
Study details
Compounds studied
Mescaline
Topics studied
Neuroscience
Healthy Subjects
Study characteristics
Original Re-analysis
Placebo-Controlled
Double-Blind
Within-Subject
Randomized
Bio/Neuro
Participants
49
Humans
Compound Details
The psychedelics given at which dose and how many times
Mescaline 300 - 500mg | 2x Mescaline 100 - 800
mg | 5x
Linked Clinical Trial
Role of the Serotonin 5-HT2A Receptor in Mescaline-induced Altered States of ConsciousnessThe present MDR-study will characterize the subjective effects of different doses of mescaline using modern psychometric instruments and examine the contribution of the 5-HT2A receptor in the mescaline-induced alterations of consciousness.
Comparative Acute Effects of LSD, Psilocybin and Mescaline
The LPM-Study compares the acute effects of LSD, psilocybin, mescaline and placebo in a double-blind, placebo-controlled, 4-period cross-over design with four treatment conditions: 1) 100 μg LSD, 2) 20 mg psilocybin, 3) 300 or 500 mg mescaline, and 4) placebo.