Acute experiences and persisting psychological effects associated with an encapsulated DMT-harmala alkaloid combination: results of a phase 1 study

This Phase I proof-of-concept study tested two partially purified formulations (A and B) and one highly purified formulation (C) of an encapsulated DMT-harmala product in healthy volunteers with prior oral DMT-harmala (ayahuasca or analogue) experience. The study had ethical approval and was prospectively registered. Manufacturing followed GMP standards; DMT was extracted from Acacia material and harmala alkaloids from Peganum harmala seeds, and formulations were standardised to contain the same DMT:harmala ratio (1:4). Formulations A and B were partially purified; formulation C was >92% DMT and >93% harmalas. Dosing was by weight: standard doses were 1.0 mg/kg DMT and 4.0 mg/kg harmalas, and a high dose tested for formulation C was 1.4 mg/kg DMT and 5.6 mg/kg harmalas. Capsule rounding meant total mg per session ranged approximately 65–115 mg DMT across participants weighing 61–85 kg. Nine participants completed 17 administrations (eight participants had two sessions; one withdrew after a single dose). Part one comprised blinded comparisons of formulations A and B (four participants received both; one received A only). Part two comprised open-label ascending-dose administrations of formulation C (four additional participants received two administrations, one of which was a higher dose). Acute subjective experience instruments completed after dosing were the MEQ-30, the 5D-ASC, and a modified nine-item Short Index of Mystical Experience (SIME) adapted from prior work to capture acute mystical elements. Persisting effects were assessed one week post-session using the Persisting Effects Questionnaire (PEQ) summary items and individual questions about meaningfulness, spiritual significance, challenge, insightfulness and life changes; personal insights were quantified with the Personal Insights Questionnaire (PIQ). Statistical analysis used Pearson correlations to examine simple associations and linear mixed-effects models (LMMs) to assess dose, formulation and instrument predictors while accounting for repeated measures. LMMs included participant as a random intercept, and models adjusted for session and treatment formulation. Interaction terms tested dose×high/standard dose and dose×purification effects; a subgroup model restricted to formulation C removed these interaction and treatment terms. Model selection considered AIC and BIC. Missing data (two participants missing two 5D-ASC items) were imputed using an Expectation-Maximization algorithm. Internal consistency of MEQ, 5D-ASC and SIME was assessed with McDonald's Omega. The study also compared SIME scores with subsamples from the Global Ayahuasca Survey (people with up to three lifetime ayahuasca uses in church, traditional shamanic or other settings) and compared MEQ and 5D-ASC total scores with published studies that used those scales.

Dosing and internal reliability: Total DMT doses per session ranged from about 65 to 115 mg. McDonald's Omega indicated high internal consistency for the scales in this sample: MEQ ω = 0.99, 5D-ASC ω = 0.97, and SIME ω = 0.94 (the authors note possible inflation given small sample size). Bivariate correlations: Pearson correlations across administrations showed significant, positive associations between total DMT dose and MEQ (r = 0.52, p < 0.05) and between total dose and SIME (r = 0.56, p < 0.05). The correlation between total dose and 5D-ASC was moderate but not statistically significant (r = 0.35, p = 0.16). Formulation C (combined high and standard doses) had a moderate significant positive correlation with SIME and a moderate non-significant positive correlation with MEQ; formulations A and B exhibited non-significant moderate negative correlations with all three instruments. High dose (1.4 mg/kg) showed a moderate, borderline-significant positive correlation with SIME (r = 0.46, p < 0.06). Inter-instrument correlations were strong for MEQ–SIME (r = 0.85, p < 0.001) and moderate for MEQ–5D-ASC (r = 0.64, p < 0.01); the SIME–5D-ASC correlation was moderate but not significant (r = 0.47, p = 0.06). Mixed-effects models and dose-response: In contrast to bivariate results, LMMs across the full dataset did not find total dose (mg) to be a significant predictor of MEQ (p = 0.109), 5D-ASC (p = 0.736) or SIME (p = 0.810), though a trend toward significance was noted for MEQ. In the subgroup analysis restricted to formulation C, no significant dose-dependent relationships emerged for MEQ (p = 0.106) or SIME (p = 0.273), though MEQ again trended toward significance; however, 5D-ASC total scores were significantly associated with dose in this subgroup (estimate = 1.17, SE = 0.41, p < 0.05). The model for PIQ (insight) with dose as predictor was not significant (p = 0.304). The authors attribute some null mixed-model findings to limited statistical power from the small sample. Persisting psychological effects: LMMs examining predictors of one-week persisting outcomes found that MEQ and SIME total scores significantly predicted PIQ personal insight scores (MEQ p < 0.05; SIME p < 0.01); 5D-ASC showed a similar non-significant trend (p = 0.059). MEQ and 5D-ASC significantly predicted all positive PEQ dimensions reported (meaningfulness, spiritual significance, insightfulness, wellbeing, positive attitudes about life and self, positive mood change, positive behavioural change and altruistic/positive social effects). SIME significantly predicted the same positive PEQ dimensions except altruistic/positive social effect, which showed a non-significant trend (p = 0.051). None of the three instruments significantly predicted the negative PEQ dimensions (negative attitudes about life/self, negative mood, negative behavioural or social changes), with the exception that MEQ predicted negative behavioural change (p < 0.05) while also predicting a stronger positive behavioural change (p < 0.01). Acute psychological challenge was positively predicted by SIME (p < 0.05) and trended positively with MEQ (p = 0.086) and 5D-ASC (p = 0.081). Comparisons with naturalistic and published data: Mean SIME scores from Global Ayahuasca Survey subsamples (people with 1–3 lifetime ayahuasca uses) were about 63/90. In this study, formulation C produced mean SIME scores of 70.8 for the high dose and 53.8 for the standard dose. The proportion of formulation C administrations rated among participants' top five lifetime spiritually significant experiences at one week was 62.5% (combined doses), compared with 63.1% (other contexts), 60.5% (traditional shamanic) and 56.0% (ayahuasca church) in the survey subsamples. For the MEQ, mean total scores were 76 (high-dose formulation C) and 68 (standard dose); the high dose exceeded MEQ means reported in most other clinical and naturalistic studies included in the comparison, with exceptions noted for a 50 mg 5-MeO-DMT study (mean MEQ 83) and DMT-alone consumed with therapeutic intent (~78). For the 5D-ASC, formulation C produced mean totals of 56 (high) and 49 (standard), both higher than mean totals reported in the other studies surveyed.

The researchers interpret these Phase I findings as evidence that an encapsulated, standardised DMT-harmala product can reliably induce strong mystical-type acute experiences in healthy, ayahuasca-experienced volunteers in a clinical setting, and that those acute experiences are robustly associated with a range of beneficial persisting psychological effects measured one week later. A key innovation the authors highlight is the explicit standardisation of not only DMT but also the three primary harmala alkaloids to predetermined levels and ratios (DMT:harmalas 1:4), distinguishing this product from prior clinical studies that used botanical extracts with variable harmala composition. The authors note that bivariate correlations suggested positive dose–response relationships for MEQ and SIME, while mixed-effects models did not detect significant dose effects across the full sample; visual inspection showed dose-dependent trends. The divergence between analytic approaches is attributed chiefly to the small sample size and consequent limited statistical power. Formulation C (highly purified) tended to show positive correlations with mystical experience measures while less-purified formulations tended toward negative correlations, though mixed models did not confirm formulation effects. Comparison with naturalistic ayahuasca users and with other psychedelic studies suggested the high-dose formulation C produced mystical and altered-state scores comparable with or exceeding most prior reports. The authors acknowledge several important limitations: the small sample size limits statistical power and generalisability; the open-label element and lack of placebo control restrict causal inference; participants were healthy and had prior ayahuasca experience, which may not reflect responses in patient groups or psychedelic-naïve individuals and may have reduced incidence of negative reactions; and differences in source materials and purification across formulations represent potential confounds when comparing formulations. They indicate qualitative data will be reported separately. The authors conclude that, notwithstanding these limitations, the findings support further controlled clinical trials of this purified oral DMT-harmala combination to assess therapeutic potential and safety.

In this Phase I proof-of-concept study, an encapsulated DMT-harmala drug product standardised for precise levels and ratios of DMT and three harmala alkaloids produced robust mystical experiences in healthy volunteers, as measured by MEQ, 5D-ASC and an adapted SIME instrument. These acute experiences were strongly associated with a range of beneficial persisting psychological effects at one week. While the small sample size and study design limit conclusions, the results indicate the purified oral DMT-harmala formulation merits further investigation in controlled clinical trials to evaluate therapeutic potential and safety.