Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants

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).

Ley and colleagues conducted a randomized, double-blind, placebo-controlled, within-subject crossover trial with four experimental sessions per participant: mescaline, LSD, psilocybin, and placebo. Washout periods were at least 10 days. The planned mescaline dose was initially 300 mg for participants 1–16 and was increased to 500 mg for participants 17–32 after early sessions suggested 300 mg was subequivalent; this allocation to mescaline dose cohorts was neither randomised nor blinded to those participants. LSD was administered as 100 µg (oral solution) and psilocybin as 20 mg (capsules). A double-dummy approach ensured each session involved capsules and a solution so that the administration format was consistent across conditions. Thirty-two healthy adults (16 men, 16 women; mean age 29 ± 4 years, range 25–44) were enrolled. Key exclusion criteria included age outside 25–65 years, pregnancy or breastfeeding, personal or first-degree family history of major psychiatric disorders, use of interfering medications, significant medical illness, heavy tobacco use (>10 cigarettes/day), lifetime psychedelic exposure >10 times, recent illicit drug use (past 2 months, except cannabis), and alcohol limits around sessions. Most participants had prior recreational drug experience, including previous psychedelic and MDMA use. Sessions took place in a controlled hospital room with one or two investigators present. Drugs were administered at 09:00 following a standardised breakfast and baseline measures. Subjective effects were repeatedly assessed using visual analogue scales (VASs) at frequent timepoints up to 24 h, the 5-Dimensions of Altered States of Consciousness (5D-ASC) scale and the Mystical Experience Questionnaire (MEQ) at 24 h, and the Adjective Mood Rating Scale (AMRS) at several post-dose timepoints. Effect onset, Tmax, offset and duration were derived from individual VAS "any drug effect" curves using a threshold of 10% of the individual maximum response. Autonomic variables (blood pressure, heart rate, tympanic temperature) and pupil diameter were repeatedly measured across the 24-h period. Adverse effects were assessed with a standardised List of Complaints at baseline, 12 h and 24 h. Blood samples were collected for plasma mescaline, LSD, and psilocin quantification by validated HPLC–tandem mass spectrometry, and for oxytocin and BDNF assays at prespecified timepoints. Pharmacokinetic parameters were estimated with non-compartmental methods using Phoenix WinNonlin. Repeated-measures ANOVA with drug as the within-subjects factor and Tukey post hoc tests were used for statistical comparisons, with p < 0.05 as the significance threshold.

Subjective peak effects: Peak subjective responses on VAS, 5D-ASC, MEQ and AMRS were comparable for 500 mg mescaline, 100 µg LSD and 20 mg psilocybin. The lower 300 mg mescaline dose produced weaker effects across these psychometrics than the higher mescaline dose, LSD and psilocybin. On the AMRS, the 300 mg mescaline condition produced greater ratings of "inactivity" compared with psilocybin and placebo. Time course and durations: Effect-duration analyses showed mescaline effects lasted longer than LSD (n = 32, p < 0.05) and psilocybin (n = 32, p < 0.001), and LSD effects lasted longer than psilocybin (n = 32, p < 0.001). The longer duration for mescaline was attributable to a slower onset (p < 0.001), a longer time to maximal effect (Tmax) (p < 0.001), and a broader peak plateau, while the subjective comedown rate was similar to LSD. Interindividual variability in onset and Tmax was larger for the 500 mg mescaline condition compared with LSD and psilocybin. Pharmacokinetics: For mescaline, geometric mean Cmax was 858 ng/mL (range 600–1284) for 300 mg and 1217 ng/mL (range 721–1822) for 500 mg; Tmax for both doses was 2.3 h (range 1.5–4.0 h). Mescaline elimination half-life (t1/2) was approximately 3.6 h. For LSD (100 µg), Cmax was 2.1 ng/mL (range 1.1–3.6), Tmax 1.4 h (range 0.5–3.5), and t1/2 about 3.5 h. For psilocybin (20 mg), Cmax (psilocin) was 17 ng/mL (range 9.6–34), Tmax 2.1 h (range 1.0–5.0), and t1/2 about 2.3 h. The mescaline and LSD elimination half-lives were similar, but mescaline had a later Tmax, which explains its longer subjective duration despite comparable elimination kinetics. Autonomic effects and tolerability: All active drug conditions produced moderate, transient increases in systolic and diastolic blood pressure, heart rate, tympanic temperature and pupil size compared with placebo. Psilocybin produced a significantly higher diastolic blood pressure response than LSD, whereas LSD showed a trend toward greater heart-rate increases than psilocybin. When measured by rate pressure product (heart rate × systolic blood pressure), overall cardiovascular stimulation was comparable across the three substances. Mescaline (both doses), LSD and psilocybin increased acute (0–12 h) adverse-effect scores relative to placebo; only mescaline showed significant subacute (12–24 h) adverse effects versus placebo. Reported adverse events included severe headaches (three after mescaline, one after LSD, one after psilocybin), fatigue (two after mescaline), ear congestion (one after LSD), nosebleed (one after mescaline), muscle twitches (one after psilocybin), transient depressive symptomatology in two participants (one after psilocybin, one after all three substances) that resolved spontaneously, and four flashback phenomena (two occurrences after mescaline in one participant, two after LSD in one participant). No serious adverse events occurred. Oxytocin and BDNF: Plasma oxytocin increased significantly after mescaline and LSD compared with placebo; oxytocin was higher after mescaline than after psilocybin. No substance altered plasma BDNF levels. Blinding: Participants did not reliably distinguish between the three active substances during the session or at study end. Correct identification rates during sessions were: 53.3% for 500 mg mescaline, 58.1% for LSD, 48.4% for psilocybin and 96.7% for placebo. After study completion the correct identification rates rose (e.g. 81.2% for 500 mg mescaline), but no condition was identified correctly in all cases. The most common misattributions were mescaline mistaken for LSD and LSD and psilocybin mistaken for each other.

Ley and colleagues interpret their findings as showing no qualitative differences in the altered states of consciousness produced by psychoactive-equivalent doses of mescaline (500 mg), LSD (100 µg), and psilocybin (20 mg). The comparable peak subjective effects across multiple validated psychometric instruments support the view that these classic psychedelics produce similar phenomenology when matched for overall intensity, consistent with a shared primary mechanism via 5-HT2A receptor agonism. The study further identified clear pharmacokinetic distinctions: mescaline had a delayed Tmax and longer subjective duration than LSD and psilocybin, while mescaline and LSD shared similar elimination half-lives of approximately 3.5–3.6 h, and psilocybin exhibited a shorter half-life. Autonomic responses were moderate and transient for all substances, with psilocybin producing a higher diastolic blood pressure response compared with LSD and LSD showing a trend for greater heart-rate increases. Tolerability was judged comparable across substances, although mescaline produced more subacute (12–24 h) adverse effects, plausibly related to its later onset and longer duration. Mescaline and LSD but not psilocybin increased circulating oxytocin; none of the substances altered plasma BDNF, and the authors note uncertainty about measuring BDNF in plasma versus serum. The investigators highlight several strengths: a within-subject, double-blind, placebo-controlled design comparing three psychedelics at equivalent psychoactive intensity, balanced sex distribution, frequent plasma sampling and validated analytical methods. They also acknowledge limitations: the mid-study increase of the mescaline dose from 300 mg to 500 mg created non-randomised, non-blinded allocation between the two mescaline dose cohorts and required a between-subjects comparison for mescaline dose effects. The controlled hospital setting and enrolment of healthy, mostly experienced psychedelic users limits generalisability to patient populations undergoing psychedelic therapy. Finally, the authors concede that standard psychometric instruments may not capture subtle qualitative differences in phenomenology, so small substance-specific subjective distinctions cannot be fully excluded. Overall, Ley and colleagues conclude that the principal clinically relevant distinctions among these three classic psychedelics at equivalent psychoactive doses are pharmacokinetic—primarily differences in onset and duration—rather than qualitative differences in the acute subjective experience. They present a pragmatic dose equivalence for future research and therapeutic dose-finding: 500 mg mescaline hydrochloride ≈ 100 µg LSD base ≈ 20 mg psilocybin dihydrate.

No evidence was found for qualitative differences in altered states of consciousness induced by 500 mg mescaline, 100 µg LSD, and 20 mg psilocybin. The three substances differed primarily in their durations of action, with mescaline lasting longest, followed by LSD and then psilocybin. These results provide a basis for dose-equivalence guidance in future psychedelic research and for dose-finding in psychedelic-assisted therapy.