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

Mescaline produces dose-dependent subjective and physiological effects in healthy people, with doses above 100 mg increasing blood pressure and heart rate. Subjective effects lasted from 6.4 hours at 100 mg to 14 hours at 800 mg, and the drug reached peak concentration in blood after about 2 hours with a half-life of 3.5 hours. Nausea and vomiting were common at the highest dose. Blocking serotonin 5-HT2A receptors with ketanserin reduced the effects of 800 mg mescaline to levels similar to lower doses, indicating that mescaline's acute effects are primarily mediated by these receptors.

Study at a glance

Abstract

Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.