DMT and harmala alkaloids: an exploratory study of oral Acacia based formulations in healthy volunteers

Introduction

Ayahuasca is a traditional Amazonian plant brew whose principal psychoactive constituents are N,N-dimethyltryptamine (DMT) and harmala b-carbolines (harmine, harmaline, tetrahydroharmine). The harmala alkaloids act as reversible monoamine oxidase inhibitors (MAOIs) that allow orally administered DMT to reach the brain and engage serotonergic (5-HT2A) pathways. Earlier research has linked ayahuasca use to a range of psychological effects and possible therapeutic mechanisms — for example, increased cognitive flexibility, emotional regulation, decentring, and facets of mindfulness — and to changes in personality traits (increased openness and agreeableness; reduced neuroticism). At the same time, use of DMT–harmala preparations can produce transient adverse events (AEs) such as nausea, vomiting, headache, anxiety or autonomic changes, and rarely more serious psychiatric reactions. There is growing interest in standardised, pharmaceutical-grade DMT–harmala formulations that might offer scalable, conserved-supply alternatives to traditional brews. Bonomo and colleagues set out to pilot test safety, tolerability, and subjective psychedelic effects of three encapsulated Acacia-derived DMT plus Peganum harmala formulations in healthy volunteers with prior ayahuasca experience. The study compared two formulations derived from different Australian Acacia species (formulations A and B, both dosed at 1.0 mg/kg DMT with 4 mg/kg total harmalas) in a cross-over open-label design, and evaluated a third, highly purified formulation (ACL-010 / formulation C) at 1.0 mg/kg and an escalated dose of 1.4 mg/kg DMT (with proportional harmala dosing). The pilot aimed to inform subsequent Phase I pharmacokinetic/pharmacodynamic work and a planned randomized trial in clinical populations, while exploring whether differing alkaloidal profiles or purification affected safety or psychoactive properties.