A Phase 1 single ascending dose study of pure oral harmine in healthy volunteers.

Background: Harmine is a component of the hallucinogenic brew, Ayahuasca, which also contains the psychoactive compound, N, N-dimethyltryptamine. Whether pharmaceutical-grade harmine hydrochloride (HCl) has psychoactive effects, the doses at which these might occur, and the dose-response relationship to side effects and safety in humans are unknown.

Methods: We conducted a Phase 1, open-label single ascending dose trial in healthy adults with normal body mass index and no prior psychiatric illness. The primary goal was to determine the maximum tolerated dose (MTD) of oral pharmaceutical-grade harmine HCl and to characterize safety and tolerability. A secondary goal was to ascertain whether any oral dose has psychoactive effects.

Results: Thirty-four adult participants, aged 18-55 years, were screened for study eligibility. Twenty-five participants met eligibility criteria and were randomized to a single dose of 100, 200, 300, or 500 mg of harmine HCl, respectively, using a continuous reassessment method. The most common adverse events (AEs) observed were gastrointestinal and/or neurological, dose-related, and of mild to moderate severity. The MTD was determined to be between 100 and 200 mg and is weight-based, with 90% of those participants receiving >2.7 mg/kg experiencing a dose-limiting toxicity. No serious AEs of harmine HCl were identified.

Conclusions: Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no AEs. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity. This study is the first to systematically characterize the psychoactive effects of pharmaceutical quality harmine in healthy participants.