Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects

Mescaline (3,4,5-trimethoxyphenethylamine) is a classic serotonergic psychedelic with a long ethnomedical history but relatively little contemporary clinical characterisation compared with LSD, psilocybin and DMT. Earlier work described subjective effects historically and a recent study compared dose equivalence between mescaline, LSD and psilocybin, but no modern within-subject data exist on the acute dose–response relationship, tolerability, pharmacokinetics and human mechanism of action for mescaline across a broad dose range. Klaiber and colleagues set out to fill these gaps by administering placebo and four oral mescaline doses (100, 200, 400, 800 mg) in a double-blind, placebo-controlled, crossover design in healthy volunteers, and by adding a condition in which 800 mg mescaline was given together with the 5-HT2A receptor antagonist ketanserin (40 mg). The study aimed to characterise dose-dependent subjective, autonomic and adverse effects, to define pharmacokinetic parameters for each dose, and to test whether acute effects are mediated primarily by 5-HT2A receptor activation. The authors hypothesised dose-dependent effects that would be blocked by ketanserin.

The investigators used a randomised, double-blind, placebo-controlled, crossover design with six experimental sessions per participant: placebo, 100 mg mescaline, 200 mg, 400 mg, 800 mg, and 800 mg mescaline plus 40 mg ketanserin. Sessions were counter-balanced and each test session lasted 31 hours; the extracted text reports that sessions were separated by at least 14 days. Drugs were administered at 09:00 during sessions that began at 08:00, and outcomes were repeatedly assessed for up to 30 hours after dosing. During the first 16 hours the participant was never left alone; one investigator was present in the room for each session. Sixteen healthy volunteers (8 men, 8 women; mean age 33 ± 10 years, range 25–55) were enrolled. Exclusion criteria included age <25 or >65 years, pregnancy, personal or first-degree relative psychotic disorders, current or past major psychiatric disorders, medications that could interfere with the study drugs, significant medical illness, heavy tobacco smoking (>10 cigarettes/day), extensive lifetime hallucinogen use (>20 times except for THC), recent illicit drug use and illicit drug use during the study (verified by random urine tests). Most participants had limited prior psychedelic experience; one was drug-naive. Mescaline hydrochloride was supplied in GMP-produced opaque capsules in 100 mg units. Ketanserin (marketed Ketensin 20 mg tablets) was encapsulated to yield the 40 mg dose; placebo capsules contained mannitol. Participants retrospectively guessed treatment assignment at the end of each session and at study end to assess blinding. Subjective drug effects were measured repeatedly using visual analogue scales (VAS) and the Adjective Mood Rating Scale (AMRS); the 5 Dimensions of Altered States of Consciousness (5D-ASC) and the States of Consciousness Questionnaire including MEQ43/MEQ30 were administered at 30 h to capture retrospective peak experiences. Autonomic measures included blood pressure, heart rate, tympanic temperature and pupil size; adverse effects were assessed with a List of Complaints at baseline, 14 h and 30 h. Blood was collected at multiple time points up to 30 h for mescaline and ketanserin plasma concentrations; assays used HPLC–tandem mass spectrometry. For repeated measures, peak effects (Emax/Emin), peak change from baseline (ΔEmax/ΔEmin) and area under the effect curve (AUEC) were derived. Repeated-measures ANOVA with dose as the within-subject factor and order as an additional between-subject factor was used, with Tukey post hoc testing where appropriate; significance was set at p < 0.05. Pharmacokinetic parameters were estimated non-compartmentally (Phoenix WinNonlin); onset, Tmax, offset, effect duration and AUEC for effect–time plots were assessed using a threshold of 10% of the individual maximum response. The extracted text does not clearly report whether an intention-to-treat approach was used for statistical analyses.

Subjective effects: Mescaline produced dose-dependent acute subjective effects that became evident at the 200 mg dose on VAS and AMRS measures. Responses increased with dose from 200 to 800 mg without a clear ceiling within that range. Negative or “bad drug” effects were significant only at 800 mg. Alterations of consciousness on the 5D-ASC and mystical-type experiences on the MEQ30 increased dose-dependently starting at 200 mg; anxiety on the 5D-ASC rose significantly only at 800 mg. Ketanserin co-administration with 800 mg mescaline markedly reduced and shortened subjective effects, bringing responses to levels comparable with the 100–200 mg doses. Individual reductions in mescaline effects correlated with measured ketanserin plasma levels in supplementary data. Autonomic and adverse effects: Mescaline raised systolic and diastolic blood pressure and body temperature at 200–800 mg compared with placebo, with relatively similar magnitude across those doses. Heart rate increased more clearly in a dose-dependent manner. Ketanserin reversed mescaline-induced elevations in blood pressure and heart rate overall, although peak blood pressure responses were not significantly lowered because ketanserin’s onset occurred after the initial mescaline-induced pressure rise. Mescaline dose-dependently dilated pupils and reduced the light reflex; ketanserin transiently attenuated these pupillary changes. On the List of Complaints, mescaline produced dose-dependent acute (0–14 h) and subacute (14–30 h) adverse effects; common acute complaints were fatigue, headache, difficulty concentrating and nausea. Emesis occurred in 2 subjects at 400 mg and 7 subjects at 800 mg; co-administration with ketanserin reduced emesis to 2 subjects. One subject reported a single flashback after the 800 mg session. Spontaneously reported events included headaches (3 subjects), stomachache (1), dizziness (1) and a nosebleed (1). Pharmacokinetics and blinding: Plasma mescaline concentrations increased proportionally with dose overall, consistent with linear elimination kinetics and an estimated plasma elimination half-life of about 3.5–3.6 h. Maximal concentrations were reached after approximately 2 h, and peak subjective responses occurred later (reported peak-response times of roughly 3.2–4.0 h). The 400 mg and 800 mg conditions showed slightly lower-than-expected concentrations, likely because vomiting at onset reduced oral bioavailability; when ketanserin reduced emesis, 800 mg concentrations were in the expected range. Blinding was imperfect: at study end 16 participants correctly identified the 800 mg dose and 15 identified the 400 mg dose; two participants mistook 100 mg for placebo. The mescaline+ketanserin condition was correctly identified by 12 participants and sometimes mistaken for lower mescaline doses.

Klaiber and colleagues interpret their findings as showing that oral mescaline produces robust, dose-dependent psychedelic effects in healthy volunteers that, within the tested range (100–800 mg), increase with dose and do not reach a ceiling up to 800 mg. The authors conclude that acute subjective and many physical effects of mescaline are primarily mediated by 5-HT2A receptor activation because co-administration of ketanserin strongly attenuated both subjective and autonomic responses. They note that ketanserin was given concurrently with mescaline rather than as a pretreatment, which explains why some initial mescaline effects occurred before ketanserin concentrations were sufficient to antagonise the response; when ketanserin reached peak levels, most mescaline effects were markedly reduced, and only minimal residual subjective effects remained, implying a minor contribution of other receptors. The pharmacokinetic profile is interpreted as dose-proportional with linear elimination and a plasma half-life shorter than earlier reports (about 3.5–3.6 h). The authors attribute mescaline’s relatively long subjective duration largely to slower absorption and a longer time to reach peak plasma concentration compared with LSD, rather than to slower elimination. They compare effect durations with previous mescaline and LSD data and provide tentative equivalence estimates (for example, suggesting 800 mg mescaline could correspond approximately to 160 µg LSD base or 32 mg psilocybin dihydrate in that study’s context), while emphasising that higher doses may reduce tolerability. Strengths highlighted include the within-subject, multi-dose design under double-blind controlled conditions, inclusion of a ketanserin condition to probe mechanism, sex balance, standardised psychometric instruments and detailed pharmacokinetic sampling up to 30 h. Limitations acknowledged are the absence of doses above 800 mg, the concurrent (not pre-) administration of ketanserin, prior psychedelic exposure in most participants (although limited in frequency), and the restricted generalisability because the study involved healthy volunteers in a controlled laboratory setting. The authors suggest the dose–response and pharmacokinetic data will be useful for dose selection in future experimental and clinical research and that the results support 5-HT2A receptor involvement in mescaline’s acute effects.

The study characterised acute subjective, autonomic and pharmacokinetic effects of four oral mescaline doses in healthy volunteers and found dose-dependent psychedelic effects beginning at 200 mg and increasing through 800 mg without a clear ceiling. The 800 mg dose produced notable adverse effects, including nausea and emesis. Co-administration of ketanserin attenuated mescaline’s acute responses, supporting predominant mediation by 5-HT2A receptors. Plasma mescaline concentrations rose roughly dose-proportionally and showed an elimination half-life of approximately 3.5–3.6 h; lower-than-expected concentrations at some higher doses were likely due to vomiting, which was reduced by ketanserin.