Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants
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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. ClinicalTrials.gov identifier: NCT04227756.
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Compared to other psychedelics such as psilocybin or LSD, the overall experience duration of combined DMT/HAR with this specific administration protocol (3-4 h) is shorter.
“Compared to other psychedelics such as psilocybin (Holze: 5.6 ± 2.2, 6.5 ± 2.4; Ley: 4.9 ± 1.7; Passie 3–6 h) or LSD (Holze: 9.3 ± 3.2, 11 ± 3.7; Ley: 8.2 ± 3.1; Passie: 9–12 h) (39, 76–78), the overall experience duration of combined DMT/HAR with this specific administration protocol (3–4 h) is shorter.”
From Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects (2024) · cites this paper as [77]
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“…have asked participants to rate the intensity of psychedelic effects at regular intervals during the experience, including the overall intensity of drug effects, positive and negative effects, and ego dissolution (Holze et al., 2021; Ley et al., 2023; Straumann et al., 2023; Vogt et al., 2023).”
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- Authors
- 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.
- Affiliations
- University of Basel (CH)
- Corresponding author
- Liechti, Matthias E.
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2023-05-25
- Volume
- 48
- Issue
- 11
- Pages
- 1659-1667
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC10517157
- OpenAlex
- W4378174725
- Cited by
- 130
- References
- 47
- Citations by year
- 2026: 27 · 2025: 57 · 2024: 39 · 2023: 7
- FWCI
- 37.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (32003B_185111)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
- Keywords
- mescaline, lysergic acid diethylamide, psilocybin, psychedelics, autonomic effects, blood pressure, heart rate, pharmacokinetics, plasma half-life, tolerability, adverse effects, oxytocin, brain-derived neurotrophic factor, altered states of consciousness, serotonergic psychedelics, dose comparison
- MeSH terms
- Hallucinogens, Humans, Lysergic Acid Diethylamide, Mescaline, Psilocybin, Cross-Over Studies, Healthy Volunteers
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