Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study

Egger and colleagues situate the study in the context of ayahuasca research, noting that traditional brews commonly contain N,N-dimethyltryptamine (DMT) together with β-carbolines such as harmine and harmaline that inhibit monoamine oxidase A (MAO-A). Previous work has shown that MAO-A inhibition is crucial for oral psychoactivity of DMT by preventing first-pass deamination, but the precise pharmacokinetic and pharmacodynamic interactions between isolated DMT and specific β-carbolines remain incompletely characterised. The authors also highlight translational challenges posed by variable botanical preparations and common gastrointestinal effects of ayahuasca that complicate standardised dosing and regulatory development. This study set out to characterise systematically the PK/PD interaction between DMT and harmine using an oromucosal, fast-disintegrating tablet (TIP™) formulation. Employing a within-subject, factorial dose-escalation design, the investigators tested seven DMT:harmine dose combinations (DMT 0–120 mg; harmine 0–180 mg) to evaluate whether increasing harmine would raise DMT bioavailability, alter DMT half-life and metabolite profiles (notably reducing indole-3-acetic acid (3-IAA) and shifting formation toward DMT-N-oxide), reduce interindividual variability in DMT exposure, and identify tolerable dose ratios suitable for further clinical development. The authors emphasise that this is the first human study to administer DMT and harmine transmucosally via TIP™ orodispersible tablets and to integrate dense serial blood sampling with repeated subjective and safety assessments to delineate exposure–response relationships.

A single-blind, randomised, balanced crossover design was used in which 16 healthy volunteers (7 female, 9 male; mean age 35 ± 5.4 years; mean BMI 22.9 ± 2.1 kg/m²) completed six to seven dosing days each. Participants had to be aged 25–45 years and have at least five prior psychedelic experiences; standard psychiatric, medical and medication exclusions applied. Study sessions were usually separated by a 7-day washout (range 2–51 days). The dosing environment was a supervised, group clinical setting with background music and mattress rest; participants received monetary compensation and provided informed consent. Seven dose conditions were administered across two counterbalanced sequences so that each participant received the same five combined DMT+harmine combinations and either a DMT-only or harmine-only condition depending on sequence. Doses per condition (DMT:harmine in mg) included 0:120, 60:120, 90:120, 120:120, 120:0, 120:60, and 120:90, with actual tablet strengths designed so three successive tablets given 20 min apart delivered the target total dose. The repeated-intermittent schedule (three equal doses at 0, 20 and 40 min) was chosen to moderate onset and improve tolerability. The investigational products were high-purity DMT (formulated as DMT succinate) and harmine hydrochloride, each prepared into TIP™ calcium phosphate microparticles and compacted into fast-disintegrating orodispersible tablets with taste-masking excipients. Blood sampling for pharmacokinetics was intensive: 15 plasma draws per session from baseline through 1440 min post-first dose (frequent sampling in the first 3 h), processed and stored at −80 °C. The analysed analytes were DMT, DMT-N-oxide (DMT-NO), indole-3-acetic acid (3-IAA), harmine and harmol. Pharmacokinetic analysis used non-compartmental analysis (NCA) in R with the 'ncappc' package to derive Cmax, Tmax, terminal half-life (t1/2), AUC metrics (AUClast, AUC0-540, AUCinf), apparent oral clearance (CL/F), and apparent volume of distribution (Vz/F). Quality-control rules were applied for estimation of terminal-phase parameters and AUCinf (excluding estimates where extrapolated area exceeded 20%). Because λ (elimination rate constant) could not be estimated in all series, an alternative clearance proxy (CL/F_alt, using AUC0-540) was constructed to retain sample size for clearance comparisons. Bioanalysis was performed by LC–MS/MS with internal standards; calibration and QC ranges are reported in the methods. Acute subjective effects were assessed repeatedly by brief single-item VAS ratings (0–10) for intensity, liking, arousal, emotionality, visuals and challenging effects, and by the 5D-ASC (94 items, scored as percentages) at 300 min. Safety monitoring included continuous presence of study staff, regular vital signs, 12-lead ECGs (QTcF reported), and systematic documentation of adverse events. Statistical analysis was descriptive; only one inferential test (Pearson correlation between DMT AUC0-540 and subjective intensity) was performed per the statistical analysis plan.

Sixteen participants completed the dosing sessions and contributed 1390 of 1440 planned plasma samples (96.5%). DMT plasma exposure increased with both higher DMT and higher harmine doses. Across DMT-containing conditions mean DMT Cmax ranged from 4.5 ng/mL (Tmax ≈ 68 min for 90 mg DMT without harmine) to 32.7 ng/mL (Tmax ≈ 174 min for 90 mg DMT with 180 mg harmine), with Tmax generally delayed at higher harmine doses. DMT AUC0-540 rose dose-dependently, from 3.6 ng·hr/mL (90 mg DMT alone) to 82.5 ng·hr/mL (90 mg DMT with 180 mg harmine); AUCinf showed a similar pattern (5.0 to 103 ± 49.6 ng·hr/mL). Mean DMT t1/2 varied (≈31–52 min) with considerable interindividual variability and was not calculable for all participants. Apparent clearance (CL/F) and the alternative proxy CL/F_alt decreased with increasing harmine dose and increased with higher DMT doses; CL/F estimates spanned wide ranges (e.g., lowest ≈5.6 L/min in high harmine conditions to highest ≈114 L/min in DMT-only conditions). Apparent volume of distribution (Vz/F) for DMT decreased with higher harmine doses (range ≈348–3351 L across conditions). Harmine pharmacokinetics showed dose-dependent increases in exposure. Harmine Cmax ranged from 4.9 ng/mL to 48.6 ng/mL, with Tmax values often later when co-administered with DMT; harmine t1/2 was ~81–93 min. Harmine AUC increased with harmine dose (AUC0-540 and AUCinf from ~15–187 ng·hr/mL and ~20–239 ng·hr/mL, respectively), and harmine AUC was largely unaffected by increasing DMT dose. When harmine was given alone (0(D)-120(H)), 3-IAA levels (a principal DMT deamination product) decreased from ~200 ng/mL to ~150 ng/mL between 70 and 300 min post-dose. Metabolite patterns indicated that harmine co-administration reduced formation of the deaminated metabolite 3-IAA and increased relative formation of DMT-N-oxide, consistent with partial MAO-A inhibition shifting DMT metabolism toward CYP-mediated pathways. Despite higher harmine doses, residual 3-IAA formation persisted, suggesting incomplete competitive inhibition. Acute subjective and physiological effects tracked exposure. Combined DMT+harmine conditions produced moderate-to-strong psychedelic effects with mean peak intensity scores of 6.1–8.8/10 and durations of about 4–5 h; DMT-only and harmine-only conditions produced only mild subjective effects (e.g., mean peak intensity ≈1.5–2/10, ASC subscale maxima <15%). The area under the subjective intensity curve correlated strongly with DMT AUC0-540: Pearson r = 0.85 (harmine escalation conditions, p < 10^-15) and r = 0.55 (DMT escalation conditions, p < 10^-4). Autonomic effects were generally moderate and transient. Combined dose conditions produced systolic blood pressure increases of ~10–15 mmHg and smaller diastolic increases, peaking 120–180 min after first administration; rate pressure product increased in combined conditions and returned to baseline by 300 min. QTcF showed a transient mean increase up to ~13 ms at 85 min (maximum increases did not exceed clinically relevant thresholds). Across 96 drug administrations there were 17 adverse events judged related to study medication; headaches and nausea were the most common (headache reported in 33% of administrations, mostly mild; nausea in 27%, predominantly mild). One participant experienced a challenging emotional episode lasting two weeks. Overall tolerability was described as favourable.

Egger and colleagues interpret the findings as clear evidence that harmine acts as a dose-dependent pharmacokinetic enhancer of transmucosally administered DMT, increasing DMT plasma exposure and prolonging subjective psychedelic effects. The investigators underline that the TIP™ orodispersible formulation and the repeated-intermittent dosing produced observable, durable psychedelic states of about 4–5 h, with exposure–response relationships showing that integrated DMT plasma concentrations predict subjective intensity. The authors note a metabolic shift induced by harmine: co-administration reduced formation of the MAO-A-mediated metabolite 3-IAA and increased relative production of DMT-N-oxide, consistent with partial MAO-A blockade and greater reliance on CYP-mediated metabolism. They highlight that residual 3-IAA at high harmine doses indicates incomplete competitive inhibition, which has potential implications for drug–drug interactions with other serotonergic or pressor agents. Limitations acknowledged by the investigators include constraints of the dosing scheme and PK estimation: the repeated-intermittent dosing (three doses 20 min apart) may have delivered insufficient early harmine to fully block systemic MAO-A prior to initial DMT exposure, complicating estimation of terminal-phase parameters such as t1/2 and CL/F. The authors also note substantial interindividual variability in PK parameters, possibly reflecting genetic polymorphisms in metabolic enzymes (e.g., CYP2D6), and the fact that λ could not be estimated for some profiles reduced the sample for conventional clearance estimates, motivating use of an alternative clearance proxy (CL/F_alt) which may overestimate true clearance. Other caveats discussed are contextual and generalisability concerns: participants knew they would receive active drug on each day (single-blind), the dosing occurred in a group setting which may have influenced later subjective reports, and the sample comprised Western European individuals only. Safety observations are summarised as reassuring: autonomic effects were moderate and transient, QTcF prolongation was minor, and adverse events were mostly mild. Finally, the authors propose that the TIP™ formulation and the characterised harmine:DMT ratios warrant further evaluation in Phase II trials for therapeutic applications, particularly in supportive group settings, while recommending further studies to probe metabolite consequences and drug–drug interaction risks.

The study characterised PK/PD interactions of DMT and harmine administered via a novel TIP™ orodispersible tablet across seven dose ratios in healthy volunteers. Harmine consistently enhanced DMT exposure in a dose-dependent manner, shifting DMT metabolism away from MAO-A-mediated deamination toward CYP-related pathways and increasing subjective psychedelic intensity and duration. The formulation exhibited a favourable safety and tolerability profile under controlled conditions. The authors conclude that these findings support further clinical investigation, including Phase II trials, while recognising the need to examine potential drug–drug interactions and to refine dosing strategies.