This reanalysis of a single-blind, randomized study (n=16) using DMT (0-120mg) with harmine (0-180mg) in an ayahuasca-inspired (‘pharmahuasca’) formulation found that harmine significantly enhanced DMT bioavailability and prolonged absorption, resulting in higher sustained plasma concentrations and increased subjective psychedelic effects, with population pharmacokinetic/pharmacodynamic modeling revealing substantial interindividual variability in clearance, bioavailability, and sensitivity to psychedelic effects.
Abstract of Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects
“N,N-dimethyltryptamine (DMT) is a psychedelic compound commonly co-administered with the monoamine oxidase inhibitor harmine in ayahuasca-inspired formulations. However, the impact of harmine on DMT pharmacokinetics (PK) and pharmacodynamics (PD) remains insufficiently characterized. In this single-blind, randomized, two-arm, factorial, dose-finding study, 16 healthy participants (9 males, 7 females) received six combinations of buccal DMT (0–120 mg) and harmine (0–180 mg) via a microcarrier-based transmucosal delivery system. Plasma concentrations and subjective intensity ratings of psychedelic effects were collected and analyzed using nonlinear mixed-effects modeling in NONMEM. A one-compartment model with delayed absorption, incorporating three transit compartments, best described the PK of DMT. Allometric scaling based on body weight improved the model fit, revealing significant interindividual variability in clearance and bioavailability. Harmine markedly enhanced DMT bioavailability and prolonged its absorption, resulting in higher and more sustained plasma concentrations. The relationship between DMT plasma concentrations and subjective drug effect intensity was captured by a sigmoidal maximum effect model, which demonstrated considerable variability in individual sensitivity to psychedelic effects. Model-based simulations showed a clear dose-dependent increase in subjective intensity for both DMT and harmine, with a potentiating effect observed at higher DMT doses when combined with escalating harmine doses. These findings provide a comprehensive population PK/PD framework that elucidates how harmine influences DMT exposure and subjective effects. By quantifying key sources of variability, this work provides a proof-of-concept approach applied to a specific population and dosing regimen, which lays the foundation for more precise, personalized dosing strategies in psychedelic-assisted therapy.”
Authors: Angela Äbelö, John W. Smallridge, Robin von Rotz, Dario A. Dornbierer, Klemens Egger, Michael Ashton & Milan Scheidegger
Summary of Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects
Ayahuasca, a traditional Amazonian preparation, combines the psychedelic N,N-dimethyltryptamine (DMT) with plant-derived monoamine oxidase A (MAO‑A) inhibitors such as harmine. MAO‑A normally breaks down DMT very rapidly in the gut and liver; inhibiting the enzyme allows DMT to become active when taken orally. Although interest in ayahuasca and ayahuasca‑inspired treatments has grown—driven by exploratory work in mood, anxiety, and substance use disorders—its clinical translation is hampered by unpredictable plant composition, variable absorption, and frequent nausea and vomiting. These practical drawbacks have prompted a shift toward standardised, synthetic combinations of DMT with harmine delivered by alternative routes (for example, transmucosal/buccal dosing) that might improve tolerability and make dosing more consistent.
Earlier research using non‑compartmental analysis (a descriptive approach that summarises data using measures such as peak concentration, time to peak, and total exposure) suggested that adding harmine increases DMT bioavailability and prolongs its half‑life, while also dampening some of the person‑to‑person variation seen when DMT is given alone. However, non‑compartmental methods cannot readily account for factors such as differences in enzyme activity between individuals, nor can they link changing blood concentrations over time to changes in subjective psychedelic intensity. Quantitative population pharmacokinetic‑pharmacodynamic (PopPK/PD) modelling can address these gaps by simultaneously characterising how the body handles a drug (pharmacokinetics: absorption, distribution, metabolism, elimination) and how the resulting concentrations relate to effects (pharmacodynamics). In the present work, Äbelö and colleagues set out to build a PopPK/PD model for buccally administered DMT with co‑administered harmine, incorporating covariates (notably body weight) and explicitly testing how harmine alters DMT exposure and perceived psychedelic intensity. The aim was to generate a framework that could support precision dosing in future psychedelic‑assisted therapies.
Materials and methods
Clinical trial
Find this paper
https://doi.org/10.1016/j.biopha.2025.118329
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Cite this paper (APA)
Äbelö, A., Smallridge, J. W., von Rotz, R., Dornbierer, D. A., Egger, K., Ashton, M., & Scheidegger, M. (2025). Population pharmacokinetic-pharmacodynamic modeling of co-administered N, N-dimethyltryptamine and harmine in healthy subjects. Biomedicine & Pharmacotherapy, 189, 118329.
Study details
Compounds studied
DMT
Ayahuasca
Topics studied
Healthy Subjects
Neuroscience
Study characteristics
Original Re-analysis
Single-Blind
Within-Subject
Randomized
Re-analysis
Bio/Neuro
Participants
16
Humans
Compound Details
The psychedelics given at which dose and how many times
DMT 60 - 120mg | 6x
Linked Clinical Trial
Dose-finding Study for the Combination of DMT and Harmine in Healthy Subjects (DHTP)This clinical trial (n=16) aims to compare the pharmacokinetic and pharmacodynamic profiles of DMT and Harmine and their safety and tolerability through six study days with varying doses. Participants will be closely monitored for adverse events and receive continuous psychological support in a controlled environment.