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

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.

This exploratory, open-label pilot study was conducted with institutional ethics approval and registered (ACTRN 12622001315707). Dosing sessions took place in prepared treatment rooms with a therapist dyad (psychiatrist and clinical psychologist) present. Recruitment ran from December 2022 to November 2023; 24 people were phone-screened and nine participants received at least one dose. The sample comprised nine healthy, tertiary-educated adults (five male, four female), aged 32–54 years (mean 40.6, SD 7.5), who all had prior ayahuasca experience (mean prior uses 2.2, SD 1.5) and met extensive medical and psychiatric inclusion/exclusion criteria including absence of current psychiatric disorder, no recent use of contraindicated medications or substances, and normal screening bloods/ECG. The protocol had two parts. In Part 1 participants crossed over to receive two Acacia-derived formulations (A and B), each standardised to 1.0 mg/kg DMT and 4 mg/kg total harmalas; participants, therapists and researchers were blinded to the order of A versus B but the study was otherwise open-label. After interim review, Part 2 evaluated a third formulation (ACL-010, formulation C) produced with additional purification steps to >90% DMT and >90% harmala alkaloids; four participants received formulation C at 1.0 mg/kg DMT and 4 mg/kg harmalas in a first session and were titrated to 1.4 mg/kg DMT and 5.6 mg/kg harmalas in a second session where appropriate. Treatment sessions were separated by at least seven days. Interventions were orally delivered in encapsulated form with a 1:4 ratio of DMT to total harmalas. Formulations A and B were manufactured via extraction and standardisation procedures with alkaloidal levels of ~5% DMT (Acacia A) and ~13% DMT (Acacia acuminata, formula B) and ~48% harmalas in the first formulas; formulation C (ACL-010) was a purified product from Acacia acuminata and Peganum harmala with each capsule containing approximately 20 mg DMT and 80 mg harmalas and reported >90% purity. Participants completed preparatory psychotherapy (90–120 minutes) and were offered integration psychotherapy approximately one week after each session. During dosing, participants were encouraged to use eyeshades and a music playlist; vitals and psychiatric state were monitored during and after sessions. Emergency pharmacological measures were specified but only non-pharmacological interventions were reported as required. Primary outcomes were safety and tolerability (AEs/SAEs, vital signs, pathology), the Integration Difficulties Scale (IDS) and the Mystical Experience Questionnaire (MEQ). Secondary outcomes included acute subjective measures (Five Dimensions of Altered States of Consciousness, modified Short Index of Mystical Orientation, visual analogue scales for mood/anxiety) and four-week follow-up scales (DASS-21, PANAS-SF, K-10, Persisting Effects Questionnaire (PEQ), Insomnia Severity Index, TEPS, PIQ). The analytic approach was descriptive: baseline demographics and outcomes were summarised using frequencies, means, medians, SDs, ranges and individual response reporting. The investigators stated that inferential statistics were inappropriate given the small sample and interindividual variability.

Nine participants received at least one dose and were included in outcome reporting. Baseline characteristics: mean age 40.6 (SD 7.5), five men and four women, all tertiary-educated; prior ayahuasca use averaged 2.2 occasions (SD 1.5) with a mean interval since last use of 5.3 years (SD 8.2, range 0.2–26.4 years). Safety and tolerability: All nine participants (100%) reported at least one adverse event (AE) from consent through study end; there were no serious adverse events (SAEs). A total of 71 AEs were recorded; three events were classified as severe (Influenza A, chest infection secondary to influenza, and agitation). Sixteen AEs were moderate and 52 were mild. Investigators judged 55 of the 71 AEs (78%) to be related to study medication. The most common medication-related AEs were physical (69% of related events), principally nausea (n=11) and headache (n=7); vomiting/retching occurred in 2 of 9 participants. Mental health–related AEs accounted for 31% of medication-related events (17/55); 11 of these mental health events occurred in one participant after the higher-dose ACL-010 (formulation C). Most medication-related AEs resolved during the session or within 24 hours; median duration for medication-related AEs was 4.8 hours (IQR 1.1–12.3), with a range from 15 minutes to 19 days (the latter a mild headache that resolved without medication). Physical examination, vital signs and pathology showed no clinically significant changes over the study; pathology data were reported in appendices. Subjective psychedelic effects: MEQ scores immediately post-session were higher for ACL-010 (formulation C, both low and high doses) than for formulations A and B, and fell within the range characterised as a Complete Mystical Experience on average, though large standard deviations indicated high interindividual variability. On a trial-specific tolerability and differential experience comparison with prior ayahuasca, participants generally rated formulations A and B as weaker than their previous ayahuasca experiences; low-dose ACL-010 was rated similar to ayahuasca and high-dose ACL-010 as stronger. Modified SIMO (mystical orientation) and several 5D-ASC subscales trended higher for ACL-010, particularly at the higher dose, though scores were inconsistent across participants. The single added item assessing extreme fear was generally low after formulations A and B; two participants scored high (8 and 10/10) after ACL-010 high dose. Integration and longer-term effects: Integration Difficulties Scale scores were low overall across formulations, with slightly higher averages for ACL-010. Four-week follow-up measures (DASS-21, PANAS, K-10, ISI, TEPS, PIQ, IDS) showed little systematic change from baseline or between formulations in this healthy sample. The Persisting Effects Questionnaire (PEQ) yielded higher positive than negative subscale responses across formulations, with formulation B and ACL-010 (low and high) tending to score higher than formulation A on positive domains (attitudes about life/self, mood, behaviour, spirituality). Preparation and support ratings were consistently moderate-to-high. Notable individual event: One participant receiving the higher ACL-010 dose experienced several intense emotional–cognitive adverse mental health effects including transient suicidal ideation during the session; these reactions resolved during the session after therapist interventions (breathing techniques, reassurance, physical support and removing hazards). Review of pre-treatment data did not identify predictors for this event.

Bonomo and colleagues interpret these pilot data as indicating a generally acceptable safety and tolerability profile for three encapsulated Acacia-derived DMT–harmala formulations in healthy, ayahuasca-experienced volunteers. No SAEs occurred and most AEs were transient and resolved without pharmacological treatment. The reduced frequency of emesis compared with traditional liquid ayahuasca preparations (2 of 9 participants reported vomiting in this study) is highlighted as potentially favourable for clinical contexts, though the authors note that emesis is traditionally considered integral to therapeutic ayahuasca ceremonies and that the therapeutic implications of reduced gastrointestinal purging remain uncertain. The investigators observed that the highly purified formulation ACL-010 (formulation C) produced stronger mystical-type and altered-state experiences (higher MEQ and trends on 5D-ASC and SIMO) than formulations A and B, and that these subjective intensities are thought from previous literature to predict therapeutic benefit. They therefore suggest ACL-010’s greater purity and consistency, and its capacity for controlled titration, are advantageous for future clinical research. The therapist dyad and structured preparation/integration were described as strengths that supported participant safety. Acknowledged limitations include the small sample size, open-label design, absence of placebo control, and the specialised sample (mental health professionals with prior ayahuasca experience), all of which limit generalisability and increase susceptibility to expectancy bias. The authors note that pharmacokinetic and pharmacodynamic data were not collected in this study to avoid intrusive sampling during therapeutic sessions; a planned Phase I PK/PD study is intended to address this. They further discuss challenges in AE reporting for psychedelic trials because some phenomenology classically considered an AE may form part of the therapeutic process; standardised reporting using MedDRA was used but may be reductive. Cultural and conservation considerations are also mentioned, with the authors recommending engagement with traditional custodians in future protocol design. Overall, the authors contend that these exploratory results justify further controlled, adequately powered trials to confirm safety, define dosing, characterise PK/PD, and evaluate clinical efficacy.

The study reports the first clinical trial, to the authors' knowledge, of encapsulated DMT/harmala formulations in which the DMT component is derived from Acacia species. Findings from this small pilot indicate acceptable safety and tolerability and suggest that the purified ACL-010 (formulation C) elicited stronger mystical-type subjective effects than the less purified formulations A and B. On this basis, the authors propose that an ACL-010 dose intermediate between the low and high doses tested could be appropriate for further study, but emphasise that these preliminary conclusions require verification in adequately powered, placebo-controlled randomised trials.