Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants
In a randomised, double‑blind, placebo‑controlled crossover study (n=32) in healthy volunteers, mescaline (300/500 mg), LSD (100 µg), and psilocybin (20 mg) produced comparable acute subjective effects with no qualitative differences in altered states of consciousness at psychoactive‑equivalent doses. Pharmacokinetic differences explained duration differences (mescaline ≈11.1 h, LSD ≈8.2 h, psilocybin ≈4.9 h), with modest autonomic and oxytocin effects (mescaline and LSD increased oxytocin) and similar tolerability apart from slightly more subacute adverse effects after mescaline.
Authors
- Matthias Liechti
- Friederike Holze
- Lukas Ley
Published
Abstract
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.
Research Summary of 'Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants'
Blossom's Take
As the only study directly comparing psilocybin, LSD, and mescaline, this study providers interesting details both the acute experience as well as the duration of these psychedelics (mescaline > LSD > psilocybin).
Introduction
Psychedelic substances such as mescaline, lysergic acid diethylamide (LSD), and psilocybin produce pronounced alterations of consciousness and share primary agonism at serotonin 5-HT2A receptors, yet they differ in other receptor interactions and pharmacokinetic properties. Ley and colleagues note that mescaline binds 5-HT2A, 5-HT1A and adrenergic α2A receptors, LSD additionally engages several serotonin and dopamine receptors, and psilocin (the active metabolite of psilocybin) also inhibits the serotonin transporter. Historical reports suggest mescaline is substantially less potent than LSD and psilocybin, with a reportedly slower onset and longer subjective duration, but modern, blinded, direct comparisons across these three classic psychedelics are lacking. This study aimed to directly compare acute subjective, autonomic, and pharmacokinetic effects of mescaline, LSD, and psilocybin at doses judged to be psychoactive-equivalent. The investigators tested the hypotheses that the three drugs would produce indistinguishable subjective effects on established psychometric instruments and that their durations of action would follow the order mescaline > LSD > psilocybin. The study also examined peripheral markers of putative therapeutic mechanisms, specifically circulating oxytocin and brain-derived neurotrophic factor (BDNF).
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topic
- Authors
- APA Citation
Ley, L., Holze, F., Arikci, D., Becker, A. M., Straumann, I., Klaiber, A., Coviello, F., Dierbach, S., Thomann, J., Duthaler, U., Luethi, D., Varghese, N., Eckert, 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, 48(11), 1659-1667. https://doi.org/10.1038/s41386-023-01607-2
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