This randomized, double-blind, placebo-controlled, cross-over study (n=32) investigated the effects of mescaline, LSD, and psilocybin at psychoactive-equivalent doses. The acute subjective effects of these substances were comparable, and all had moderate autonomic effects with minor differences in diastolic blood pressure and heart rate. Mescaline induced slightly more subacute adverse effects, and differences were found in the duration of action, with mescaline lasting the longest.
Abstract of Comparative acute effects of mescaline, LSD, and psilocybin
“Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin. The tolerability of mescaline, LSD, and psilocybin was comparable, with mescaline at both doses inducing slightly more subacute adverse effects (12–24 h) than LSD and psilocybin. Clear distinctions were seen in the duration of action between the three substances. Mescaline had the longest effect duration (mean: 11.1 h), followed by LSD (mean: 8.2 h), and psilocybin (mean: 4.9 h). Plasma elimination half-lives of mescaline and LSD were similar (approximately 3.5 h). The longer effect duration of mescaline compared with LSD was due to the longer time to reach maximal plasma concentrations and related peak effects. Mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. None of the substances altered plasma brain-derived neurotrophic factor concentrations. In conclusion, the present study found no evidence of qualitative differences in altered states of consciousness that were induced by equally strong doses of mescaline, LSD, and psilocybin. The results indicate that any differences in the pharmacological profiles of mescaline, LSD, and psilocybin do not translate into relevant differences in the subjective experience.”
Authors: Laura Ley, Friederike Holze, Denis Arikci, Anna M. Becker, Isabelle Straumann, Aaron Klaiber, Fabio Coviello, Sophie Dierbach, Jan Thomann, Urs Duthaler, Dino Luethi, Nimmy Varghese, Anne Eckert & Matthias E. Liechti
Summary of Comparative acute effects of mescaline, LSD, and psilocybin
Mescaline, lysergic acid diethylamide (LSD), and psilocybin are psychedelic substances that induce exceptional alterations of consciousness. They are used for ethnomedical and spiritual rituals, and are also used recreationally around the world. Mescaline, LSD, and psilocybin are considered “classic hallucinogens” because they stimulate serotonin 5-HT2A receptors. However, they also exhibit differences in their pharmacological receptor profiles and pharmacokinetic properties. Mescaline is 30 times less potent than psilocybin and 1000 – 3000 times less potent than LSD, and has a delayed onset of action. Its subjective effect duration is similar to that of LSD.
A randomized, double-blind, placebo-controlled, crossover study was conducted in healthy participants to directly compare the acute effects of mescaline, LSD, and psilocybin. The results suggest that there may be pharmacological, physiological, and subjective/phenomenological differences between these three substances.
The authors hypothesized that the acute psychedelic effects induced by mescaline, LSD, and psilocybin would not be distinguishable using established psychometrics, and that the acute effects of mescaline > LSD > psilocybin would be longer due to pharmacokinetic differences.
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https://doi.org/10.1038/s41386-023-01607-2
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Cite this paper (APA)
Ley, L., Holze, F., Arikci, D., Becker, A. M., Straumann, I., Klaiber, A., ... & Liechti, M. E. (2023). Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants. Neuropsychopharmacology, 1-9.
Study details
Compounds studied
Mescaline
LSD
Psilocybin
Topics studied
Healthy Subjects
Study characteristics
Original
Placebo-Controlled
Double-Blind
Within-Subject
Randomized
Participants
30
Humans
Authors
Authors associated with this publication with profiles on Blossom
Matthias LiechtiMatthias Emanuel Liechti is the research group leader at the Liechti Lab at the University of Basel.
Institutes
Institutes associated with this publication
University of BaselThe University of Basel Department of Biomedicine hosts the Liechti Lab research group, headed by Matthias Liechti.
Compound Details
The psychedelics given at which dose and how many times
Mescaline 300 - 500mg | 2x LSD 100 μg | 1x Psilocybin 20 mg | 1x
Linked Research Papers
Notable research papers that build on or are influenced by this paper
Safety pharmacology of acute psilocybin administration in healthy participantsThis pooled analysis (n=85; doses=113) of three randomized crossover studies evaluates the safety pharmacology of psilocybin (15-30mg). Psilocybin induced stronger effects at higher doses, with 25 mg and 30 mg doses showing increased anxiety. However, overall, psilocybin was found to be safe in terms of acute psychological and physical harm, with no serious adverse reactions reported, suggesting its potential safety for controlled research settings.
Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects
This RCT (n=28) compared the effects of LSD (100 & 200µg) and psilocybin (15 & 30mg) to placebo. Findings include that the doses of 100 & 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. LSD at both doses had longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. Ultimately, any differences between LSD and psilocybin are dose-dependent rather than substance-dependent.
Linked Clinical Trial
Comparative Acute Effects of LSD, Psilocybin and MescalineThe 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.