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

The study addresses whether classic psychedelics with differing pharmacological receptor profiles (mescaline, LSD, psilocybin) produce distinct subjective experiences and physiological effects at psychoactive-equivalent doses. Although all primarily act via 5-HT2A receptor agonism, they differ in potency and pharmacokinetics: mescaline is far less potent and has slower onset; LSD has high 5-HT2A affinity and dopaminergic/serotonergic activity; psilocin (from psilocybin) also inhibits SERT. Prior direct, blinded comparisons are limited, especially for mescaline. The purpose was to directly compare acute subjective effects, autonomic responses, and pharmacokinetics within the same participants using moderate to high, overall intensity-matched doses to inform cross-trial interpretation and dose-finding for research and therapy. The authors hypothesized no major divergences in acute psychological effects across substances and expected differences in temporal profiles (mescaline > LSD > psilocybin) due to pharmacokinetics.

The introduction outlines receptor-binding differences among mescaline (5-HT2A, 5-HT1A, α2-adrenergic), LSD (5-HT2A, 5-HT2B, 5-HT1A, D1–D2), and psilocin (5-HT2A agonism and SERT inhibition). Earlier comparative human studies were sparse and methodologically limited, with one recent modern trial directly comparing LSD and psilocybin. Mescaline’s modern clinical investigation has been neglected despite historical and contemporary use. The study also references ongoing interest in oxytocin and BDNF as potential mechanistic biomarkers in psychedelic therapy, with BDNF implicated in neuroplasticity.

Design: Randomized, double-blind, placebo-controlled, within-subject cross-over trial with four experimental sessions per participant (mescaline, LSD, psilocybin, placebo). Washout intervals were at least 10 days. Allocation to substance conditions was randomized and blinded. Doses: Mescaline hydrochloride 300 mg (participants 1–16) or 500 mg (participants 17–32), LSD base 100 µg, psilocybin 20 mg, and placebo. Allocation to mescaline dose (300 vs 500 mg) was not randomized or blinded (first cohort received 300 mg; second cohort 500 mg) due to dose adjustment during the study. Double-dummy procedures were used with matching capsules/solutions to maintain blinding. Participants: N=32 healthy adults (16 men, 16 women), mean age 29 ± 4 years (25–44). Exclusion criteria included psychiatric disorders (personal/family), interfering medications, significant medical illness, heavy tobacco use, recent illicit drug use, and high lifetime psychedelic exposure (>10 times). Most participants had some prior experience with psychoactive substances, including psychedelics, stimulants, and cannabis. Informed consent obtained; ethics approval and trial registration reported. Procedures: Drug administration in controlled clinical setting with overnight monitoring. Subjective measures: Repeated Visual Analog Scales (VAS) post-dose; Drug Rating Scale (DRS) at baseline, 3, 6, 9, 12, and 24 h; 5D-ASC and MEQ administered 24 h post-dose to retrospectively rate acute psychedelic effects. Onset, time to maximal effect (tmax), offset, and duration derived from individual VAS “any drug effect” time-courses using a 10% of individual maximum threshold. Autonomic measures: Blood pressure, heart rate, and tympanic temperature repeatedly assessed from baseline through 24 h; pupil diameter measured at selected time points. Adverse effects assessed using the List of Complaints (LC) at baseline, 12, and 24 h. Pharmacokinetics: Serial plasma sampling up to 24 h. Concentrations of mescaline, LSD, psilocybin (and metabolites) measured using validated HPLC methods. Non-compartmental PK analysis (Phoenix WinNonlin 8.3) to estimate Cmax, tmax, half-life, AUC, clearance, and volume of distribution. Blinding assessment: Participants guessed the administered condition at ~3 h and after study completion. Statistics: Peak or peak change-from-baseline values analyzed via repeated-measures ANOVA with within-subject factor drug condition, followed by Tukey post hoc tests; significance threshold p<0.05.

- Subjective effects: At approximately intensity-equivalent doses (mescaline 500 mg, LSD 100 µg, psilocybin 20 mg), subjective effects were comparable across VAS, 5D-ASC, MEQ, and mood scales. The 300 mg mescaline dose produced weaker effects than the higher mescaline dose, LSD, and psilocybin. - Time course: Mescaline exhibited slower onset and later peak with the longest duration of subjective effects, followed by LSD, then psilocybin. From VAS-derived metrics: mean effect duration ~11.1 h for mescaline 500 mg, ~8.2 h for LSD 100 µg, and ~4.9 h for psilocybin 20 mg; mescaline onset and tmax were significantly later than LSD and psilocybin. - Autonomic effects: All three increased systolic/diastolic blood pressure vs placebo. Psilocybin produced a significantly higher diastolic BP increase than LSD; LSD showed a trend toward higher heart rate compared with psilocybin. All increased pupil size; body temperature increases were comparable. Autonomic effects followed each drug’s duration of action and were moderate and transient. - Adverse effects: All active drugs increased adverse effects vs placebo. Mescaline (both doses) showed slightly more subacute adverse effects (12–24 h) than LSD or psilocybin. - Pharmacokinetics: Mescaline and LSD had similar plasma elimination half-lives (~3.6 h and ~3.5 h, respectively), whereas psilocybin had a shorter half-life (~2.3 h). Typical tmax values: mescaline ~2.3 h, LSD ~1.4 h, psilocybin ~2.1 h. Differences in subjective effect duration were attributed mainly to onset and time-to-peak/plateau rather than elimination half-life. - Oxytocin and BDNF: Mescaline and LSD significantly increased plasma oxytocin vs placebo; oxytocin levels were higher after mescaline vs psilocybin. None of the substances altered plasma BDNF concentrations. - Blinding: Participants generally could not unequivocally distinguish mescaline, LSD, and psilocybin during sessions or post-study; misidentifications among active conditions were common, supporting similarity of subjective effects at equivalent intensities.

The study directly addressed whether pharmacologically distinct classic psychedelics produce different acute phenomenology when administered at intensity-equivalent doses. Findings showed no qualitative differences in altered states of consciousness between mescaline (500 mg), LSD (100 µg), and psilocybin (20 mg) across multiple psychometric instruments, suggesting that distinct receptor-binding profiles do not translate to materially different subjective experiences at matched intensities. The principal differences lay in pharmacokinetics and time course: mescaline had slower onset and longer effect duration than LSD, which exceeded psilocybin, consistent with dose- and PK-driven effects. Autonomic stimulation was moderate across substances, with minor differences (psilocybin > LSD for diastolic BP; LSD trend for higher heart rate vs psilocybin). Mescaline and LSD, but not psilocybin, increased circulating oxytocin, while none changed plasma BDNF. Blinding results further indicated high phenomenological overlap across active conditions. These findings inform dose-equivalence across psychedelics and support the view that 5-HT2A receptor agonism predominantly drives the shared psychedelic experience, with clinical implications for dosing and study design in psychedelic-assisted therapies.

Equivalent-intensity doses of mescaline (500 mg), LSD (100 µg), and psilocybin (20 mg) produced comparable acute subjective effects in healthy participants, with primary differences in onset and duration of action (mescaline > LSD > psilocybin). Autonomic effects were moderate and transient; mescaline elicited slightly more subacute adverse effects. Mescaline and LSD increased oxytocin; none affected plasma BDNF. The study establishes practical dose equivalences to guide research and therapeutic applications and underscores that pharmacokinetic differences, rather than qualitative phenomenology, distinguish these classic psychedelics. Future work should examine patient populations, explore nuanced phenomenological differences with more sensitive instruments, and assess longer-term therapeutic and biomarker outcomes.

- Mescaline dose equivalence was not achieved initially; the mescaline dose was increased mid-study from 300 mg to 500 mg. Consequently, two mescaline doses were tested against single doses of LSD and psilocybin. - Allocation to mescaline dose (300 vs 500 mg) was neither randomized nor blinded, introducing potential cohort effects and between-subject comparisons for mescaline dose. - Controlled clinical (hospital-like) setting and a healthy sample with substantial prior drug experience may limit generalizability to patient populations undergoing psychedelic therapy. - Psychometric instruments may lack sensitivity to detect subtle qualitative differences among substances; nuanced phenomenological distinctions cannot be fully excluded. - Minor textual inconsistencies in reported units/doses/time values reflect OCR or reporting artifacts but do not alter the main conclusions.