Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects

Interest in ayahuasca, the Amazonian brew containing N,N-dimethyltryptamine (DMT) plus reversible monoamine oxidase inhibitors (MAO-Is) such as harmine, has grown because of signals that it can reduce symptoms of depression, anxiety and addiction. The brew’s combination of β-carbolines and DMT produces orally active, multi-hour psychedelic states characterised by increased introspection, vivid imagery, emotional release and reported psychological insights. However, botanical ayahuasca poses challenges for clinical research and therapy: batch-to-batch variability in alkaloid content, variable oral bioavailability due to first-pass MAO metabolism, common side effects such as nausea/vomiting, cultural and ecological concerns, and difficulty in standardising dosing and delivery for biomedical settings. Aicher and colleagues developed an ayahuasca-inspired, standardised formulation combining harmine and intranasal DMT with incremental dosing to improve controllability and tolerability. The study aimed to characterise the acute subjective phenomenology, psychological mechanisms (insight, emotional breakthrough), safety/tolerability, and persisting effects of the combined DMT + harmine (DMT/HAR) formulation compared with harmine-only (HAR) and placebo (PLA) in healthy male participants. The authors hypothesised that DMT/HAR—but not harmine alone—would produce psychedelic phenomena and foster psychological insights and emotional breakthroughs with low levels of challenging experiences and no lasting increases in psychopathology, and that acute effects would relate to positive persisting outcomes.

The investigators ran a randomised, double-blind, placebo-controlled crossover trial with three intervention days per participant and at least a two-week washout between sessions. Thirty-seven healthy males were recruited and 31 completed all three intervention days (mean age 25.39 ± 4.21 years). Inclusion criteria included male sex (to avoid menstrual-cycle effects on blood chemistry), age 20–40, BMI 18.5–30 kg/m2, absence of current or past major somatic, neurological or psychiatric disorders, no family history of psychosis or bipolar disorder, minimal prior psychedelic exposure (≤15 lifetime uses), and absence of medications or substance use that could interact with study drugs. Participants abstained from caffeine on test days, alcohol the day before, and from psychoactive substances for two weeks prior and during the study. The trial had local ethics approval and informed consent was obtained. Each intervention day followed a standardised protocol in a soundproof, temperature-controlled laboratory room with a relaxed, living-room ambience and a standardised instrumental playlist. A medically and psychologically trained investigator remained in the room throughout. Harmine HCl (100 mg) or matching placebo was given as an orodispersible buccal tablet; after 30 minutes, intranasal DMT or placebo spray was administered intermittently in ten nominal 10 mg doses spaced every 15 minutes (total planned cumulative DMT 100 mg over 150 minutes). Participants could decline subsequent DMT doses or accept only 5 mg at a time; two participants skipped one dose and thus received 90 mg total. Physiological monitoring (EEG, ECG, blood sampling) and acute experience sampling were performed across the day; retrospective questionnaires were completed around t300 (minutes after first DMT/placebo), and follow-ups occurred at 1 and 4 months. Primary subjective measures included dynamic experience-sampling items (single-word and sentence ratings on 0–100 VAS) and validated psychometric instruments: the 5D-ASC (altered states), Psychological Insights Questionnaire (PIQ), Emotional Breakthrough Inventory (EBI), Challenging Experience Questionnaire (CEQ), Symptom Checklist-90-Revised (SCL-90-R), Persisting Effects Questionnaire (PEQ) and Griffiths significance ratings (GSR). Several trait measures were assessed at baseline and follow-ups (AAQ2, CFI, NR6, WHO-5, IPIP openness/neuroticism). Questionnaires not available in German were translated using back-translation. Data were analysed in R. Mixed-model ANOVAs (Type 3 tests, Satterthwaite’s method) with post-hoc estimated marginal means and Tukey correction assessed drug effects; non-parametric tests (Wilcoxon, Friedman with Dunn-Bonferroni) were used where appropriate for timepoint comparisons. Correlations (Pearson or Spearman per normality tests) examined associations between acute and persisting effects. A median split of peak subjective intensity in the DMT/HAR condition defined low vs high sensitivity subgroups for some analyses. Incomplete datasets were excluded from specific timepoint comparisons (notably some PEQ and SCL-90-R data). Significance was set at p = 0.05.

Thirty-one participants completed all three intervention conditions. The DMT/HAR condition produced clearly detectable subjective drug effects, whereas harmine alone produced minimal or negligible experiential changes. In the DMT/HAR condition, participants’ retrospective overall intensity peaked on average around t90 after the first DMT dosing, with earlier peaks in psychedelic-type imagery (around t60) and a somewhat later peak for empathogenic qualities (around t120). Experience-sampling showed relatively strong ratings of liking, relaxation and letting go, together with elementary and complex imagery and reports of reduced perceived body boundaries. Reports of disliking, frightening experiences and loss of control were generally low; the average peak of disliking occurred at a timepoint associated with a behavioural task and may have been task-related. Descriptively, some positive empathogenic aspects remained into the afterglow at t300, but group differences were not significant at that late timepoint. Harmine alone (100 mg buccal) did not produce notable psychedelic effects; the largest difference from placebo was a trend for increased empathogenic phenomenology at t60 (EMM = 8.94, p = 0.062). Two participants elected to skip one 10 mg DMT dose, receiving 90 mg total. Vomiting occurred in one participant. On measures of persisting effects, participants reported substantially stronger positive than negative changes on PEQ domains at both 1-month (n = 26) and 4-month (n = 28) follow-ups. The study reports strong positive associations for PEQ domains when comparing positive versus negative persisting effects (attitude toward life r = 0.83, mood r = 0.57, social effects r = 0.46, behaviour change r = 0.78; all p < 0.001 as reported). Participants also attributed personal and spiritual significance to the experience on GSR items at follow-up. Trait questionnaires completed by a subset (n = 22 completed all trait follow-ups) showed no significant changes from baseline to 1 and 4 months for psychological flexibility (AAQ2), cognitive flexibility (CFI), nature relatedness (NR6), well-being (WHO-5), openness (IPIP), or neuroticism (IPIP), either for the whole sample or for sensitivity subgroups. Correlational analyses indicated positive associations between acute retrospective measures (5D-ASC, PIQ, EBI) and persisting effects (PEQ) and significance ratings (GSR). The CEQ did not correlate significantly with other measures, likely reflecting generally low CEQ scores. Within DMT/HAR sessions, greater progression of intensity correlated with higher ratings of disliking (rho = 0.664), frightening (rho = 0.577), and loss of control (rho = 0.633), all p < 0.001. Safety and tolerability outcomes were favourable in this healthy sample and supportive setting: acute anxiety and impaired cognition/control subscales of the 5D-ASC were low, CEQ scores were low, and no increases in psychopathology on the SCL-90-R were observed post-session; some SCL-90-R subscales showed main effects of time but the extraction does not clearly report direction or magnitude for all. The intermittent intranasal dosing and buccal harmine delivery were associated with a relatively shorter overall experiential duration (reported around 3–4 hours) compared with some other classical psychedelics, and the authors note the dosing regimen allows flexible interruption which may increase controllability.

Aicher and colleagues interpret their findings as showing that a standardised, ayahuasca‑inspired DMT + harmine formulation produces a phenomenological profile with both psychedelic and empathogenic characteristics in healthy males, while harmine alone produces little effect. The combined formulation elicited reported psychological insights (PIQ) and emotional breakthroughs (EBI), which the investigators regard as therapy-relevant processes potentially important for lasting mental-health benefits. They argue that incremental intranasal dosing and buccal harmine improved controllability and tolerability, producing mostly moderate psychedelic effects, low levels of acute anxiety and challenging experiences, and a relatively short session duration that may be advantageous in clinical settings. The authors situate these results within prior literature indicating ayahuasca and other serotonergic psychedelics can produce rapid antidepressant and anxiolytic effects and lasting positive changes in attitudes and behaviour. They highlight that the DMT/HAR formulation reproduced several core phenomenological features of ayahuasca while mitigating some limitations of botanical brews, such as inter-batch variability and uncontrolled first-pass metabolism. Persisting positive effects at 1 and 4 months—especially behavioural changes and endorsed personal/spiritual significance—are emphasised as evidence of potential transformative outcomes even in a pharmacology‑oriented study setting without formal therapeutic preparation or integration. The authors acknowledge several important limitations. The trial included only male, WEIRD participants—which limits generalisability—and excluded people with extensive prior psychedelic use. Blinding may have been imperfect given the noticeable subjective effects of DMT/HAR, introducing expectancy effects. The study did not include a DMT‑only arm in this report, so the precise contribution of intranasal DMT versus harmine activation remains to be fully disentangled; a subsequent study including a DMT‑only condition is noted as underway. The experimental protocol emphasised pharmacological and neurobehavioural assessment, requiring participants to perform tasks and experience repeated measurements that likely reduced introspective focus and may have attenuated the subjective intensity and trait-change potential. Only 22 of 31 participants completed all trait follow-ups, limiting conclusions about long-term personality change. The authors also caution about possible drug–drug interactions with MAO‑Is and call for further safety work, including physiological and PK–PD data to be reported separately. For future research and clinical translation, the investigators recommend trials in patient populations within therapeutic frameworks that include preparation and integration, consider individualised dosing, and monitor physiological safety closely. They suggest that the flexible, incremental dosing approach and the standardised formulation may support precision-medicine–style, individualised psychedelic-assisted interventions, but stress more work is needed to determine efficacy, optimal context and integration procedures, and interaction risks.

The study concludes that a standardised ayahuasca‑inspired formulation combining intranasal DMT with buccal harmine induced psychedelic and empathogenic subjective effects, psychological insights and emotional breakthroughs in healthy male participants, while harmine alone produced minimal effects. Positive persisting outcomes and generally favourable psychological safety and tolerability were observed in a controlled, supportive setting. The authors posit that the formulation’s controllability and shorter session duration could be advantageous for clinical application, but they emphasise the need for further physiological safety data, trials in patient populations, and attention to integration and contextual factors before therapeutic efficacy can be established.