Safety pharmacology of acute mescaline administration in healthy participants

Mescaline is a classical psychedelic alkaloid with a long ethnomedicinal history but limited contemporary controlled clinical data. Earlier research established that mescaline, like other serotonergic psychedelics, can raise blood pressure, heart rate and body temperature, but systematic dose–response data across a broad range of pure mescaline doses are scarce. In recent years psychedelic research has resumed and mescaline has been included in Phase I and Phase II programmes for psychiatric indications, yet safety pharmacology information from standardised clinical trials remains limited. Klaiber and colleagues therefore pooled data from two double-blind, placebo-controlled Phase I trials to describe the acute safety pharmacology of single oral doses of pure mescaline across a wide dose range. The pooled analysis aimed to characterise dose-dependent subjective effects, autonomic responses and adverse events up to 30 h after administration, to report proportions of participants who exhibited extreme cardiovascular stimulation (rather than only group means), and to examine blood chemistry and haematology from screening to end-of-study visits.

The analysis combined data from two double-blind, placebo-controlled, cross-over studies conducted at the University Hospital Basel. In total 48 healthy participants (24 female, 24 male) were enrolled and received 96 mescaline administrations in aggregate. Study 1 (n = 32) compared single doses of LSD (100 μg), psilocybin (20 mg), mescaline (300 or 500 mg) and placebo in a within-subject design; the first 16 participants received 300 mg mescaline and the next 16 received 500 mg, so different subjects received those two mescaline doses and allocation between those two doses was ordered rather than random. Study 2 (n = 16) used a counterbalanced block-randomised within-subject design in which each participant received 100, 200, 400 and 800 mg mescaline and placebo (an additional ketanserin + 800 mg condition was collected but not used here). The washout between sessions was at least 10 days in both studies. Screening included medical, psychiatric and laboratory assessments; people with major psychiatric disorders or a first-degree relative with a psychotic disorder were excluded and the PQ-16 was applied to screen for prodromal psychotic tendencies. Study sessions began at 08:00 with baseline measures and administration of drug or placebo at 09:00, followed by repeated measures over 25 h (Study 1) or 31 h (Study 2). Repeated measures included visual analogue scales (VASs) for "any drug effect", "good drug effect", "bad drug effect", "nausea" and "anxiety", the 5D-ASC completed at 24 or 30 h to rate peak effects, continuous vital signs (blood pressure, heart rate, tympanic temperature) and pupil diameter, blood sampling for pharmacokinetics, and the 66-item List of Complaints (LC) to capture acute and subacute adverse effects. Grouping criteria for extreme cardiovascular responses were pre-specified (for example, diastolic blood pressure >90 and >100 mmHg, systolic >140, >160 and >180 mmHg, tachycardia >100 beats/min, hyperthermia >38.0 °C). Blood chemistry and haematology were measured at screening and at the end-of-study visit to assess kidney and liver function and blood cell counts. Statistical analyses used ANOVAs with dose as factor and Tukey post hoc tests for continuous outcomes, Fisher's exact tests for proportions, paired t-tests for pre/post laboratory comparisons, and Spearman correlations to examine associations between good and bad drug effects. Significance was set at P < .05. The extracted text does not reproduce the demographic table in full.

Across the pooled sample (96 mescaline administrations), subjective positive effects increased dose-dependently up to 800 mg without an observed ceiling. "Good drug effect" ratings >50% of the VAS maximum were reported by 13%, 25%, 69%, 69%, 81% and 100% of participants at 100, 200, 300, 400, 500 and 800 mg, respectively. Negative subjective effects ("bad drug effect", nausea, and the AED dimension of the 5D-ASC) also rose with dose but reached lower maxima and increased more slowly; "bad drug effect" >50% occurred in 0%, 0%, 19%, 6%, 25% and 38% of participants across the same dose levels, and clinically significant nausea (>50% VAS) occurred in 0%, 6%, 19%, 19%, 25% and 56% at 100–800 mg respectively. A weak positive correlation was observed between the AUEC for good and bad drug effects (Spearman r = 0.25, P < .01). Mescaline produced dose-dependent but generally moderate autonomic stimulation. Systolic blood pressure exceeded 140 mmHg in 38% of all administrations and exceeded 160 mmHg in 2%; the highest systolic value recorded was 166 mmHg and no instance exceeded 180 mmHg. Diastolic pressure exceeded 90 mmHg in 36% of administrations and exceeded 100 mmHg in 6%, with a maximum of 105 mmHg. Heart rate was >80 beats/min in 64% of administrations and >100 beats/min in 3%, the highest recorded heart rate being 108 beats/min. Tympanic body temperature exceeded 38.0 °C in 5% of administrations, with a maximum of 39.0 °C; no hyperpyrexia (>40 °C) occurred. Adverse effects on the LC increased with dose, with a notable rise in overall acute adverse-effect scores for doses >300 mg and a significant elevation of the total LC score at 800 mg. Nevertheless, some specific complaints such as headache, tiredness and increased need to sleep were reported even at the lowest 100 mg dose. Vomiting was observed: in Study 1 three participants vomited (two after 300 mg, one after 500 mg; one of those also vomited during an LSD session) and in Study 2 six participants (38%) vomited, all after 800 mg. Within 48 h after discharge, the most frequently reported adverse events were headache (8% after mescaline, 10% after placebo) and strong exhaustion (2% after mescaline, 2% after placebo); a single mild self-limiting depressive episode (0.9% after mescaline) and rare dizziness (0.9%) were recorded. Two participants (2%) reported transient "flashbacks"; no persistent perceptual alterations and no serious adverse events occurred. Pharmacokinetic measures (Cmax and AUC) increased roughly dose-proportionally, but peak plasma concentrations after 800 mg were lower than expected, likely reflecting incomplete absorption due to vomiting in six participants. Kidney and liver function tests and blood cell counts showed no meaningful changes between screening and end-of-study visits according to the extracted supplementary summary.

Klaiber and colleagues interpret the pooled data as indicating that single oral doses of mescaline from 100–800 mg are generally well tolerated in psychiatrically and physically healthy young adults in a controlled laboratory setting. Subjective responses were predominantly positive, with greater "good drug effect" and Oceanic Boundlessness than negative ratings; no ceiling effect was observed for positive or negative subjective experiences across the studied dose range. The investigators note that this contrasts with some dose–response patterns reported for LSD and psilocybin, where a ceiling for positive acute effects has been observed at lower dose ranges. The authors emphasise that adverse effects were dose dependent and that nausea and vomiting were the principal dose-limiting problems, particularly at 800 mg where nearly 40% of participants vomited. Cardiovascular and thermogenic effects were moderate, with no episodes of severe hypertension, hyperpyrexia or arrhythmic tachycardia recorded. The discussion compares these sympathomimetic responses to similarly conducted studies with LSD and psilocybin and concludes there were no relevant differences in cardiovascular stimulation between these classic psychedelics within comparable experimental settings. Potential mechanisms for the relatively prominent emetic response to mescaline are considered but remain uncertain; the authors mention serotonergic pathways including 5-HT3 receptors as plausible contributors and note that prior reports of nausea after cactus-derived preparations implicated other alkaloids, but here only pure mescaline was administered. Strengths of the pooled analysis include the use of two randomised controlled studies with standardised measures, precisely defined doses and balanced sex representation. Important limitations highlighted by the investigators are the restriction to psychiatrically healthy and mostly younger participants, the modest sample size (48 participants, 96 administrations) which limits detection of rare adverse events, ordered rather than fully random allocation for the 300/500 mg doses in Study 1, and the lack of long-term follow-up. The authors conclude these data support further clinical research with mescaline but caution that risks may differ in patient populations or older individuals and that additional study of long-term safety is needed.

The investigators conclude that single oral doses of mescaline between 100 and 800 mg were safe with respect to acute psychological and physical harm in healthy participants in a controlled clinical setting. Acute subjective effects were largely positive, while transient negative effects—principally nausea, vomiting and anxiety—occurred mainly at the highest 800 mg dose and may limit tolerability at very high doses. Mild cardiovascular stimulation was observed but no severe hypertensive or hyperthermic events occurred. The authors recommend further research to examine risks and benefits of mescaline in patient populations and over longer follow-up periods.