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.