Population pharmacokinetic/pharmacodynamic modelling of the psychedelic experience induced by N,N‐dimethyltryptamine – implications for dose considerations

N,N-dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data were obtained from 13 healthy subjects after intravenous administration of DMT. The data were analyzed using nonlinear mixed-effects modeling in NONMEM. DMT plasma concentrations were described by a two-compartment model with first-order elimination leading to formation of the major metabolite indole 3-acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid maximum effect (E-max) response. DMT clearance was estimated at 26 L/min, a high value indicating elimination of DMT to be independent of blood flow. Higher concentrations of DMT were associated with a more intense experience with the concentration of DMT at the effect site required to produce half of the maximum response estimated at 95 nM. The maximum achievable intensity rating was 10 and the simulated median maximum rating was zero, 2, 4, 8, and 9 after doses of 1, 4, 7, 14, and 20 mg, respectively. The model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience.