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


Web link: onlinelibrary.wiley.com/doi/abs/1...

Pages: article 13410, 10 pages

Abstract

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 was obtained from 13 healthy subjects after intravenous administration of DMT. The data was analyzed using nonlinear mixed-effects modelling 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 Emax 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 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 0, 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. Study Highlights: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? N,N-dimethyltryptamine (DMT) is a psychedelic compound being investigated as a therapeutic option in psychiatric disorders. Very little is known about its pharmacokinetic/pharmacodynamic properties. WHAT QUESTION DID THIS STUDY ADDRESS? This study aimed to investigate the pharmacokinetics of DMT and to quantify the relationship between DMT concentrations and intensity of the psychedelic experience after intravenous administration of DMT to 13 healthy subjects. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? DMT pharmacokinetics were characterized, showing a large DMT clearance of 26 L/min. The relationship between DMT concentrations and psychedelic intensity was also described. The applicability of the model was demonstrated through simulations of obtained intensity at different dose levels, illustrating what doses may be required for suboptimal and maximal responses, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This is the first time the pharmacokinetics/pharmacodynamics of DMT has been modeled. We believe this model can be useful in guiding DMT dosing in future clinical research. Further, the work demonstrates the benefits of using a quantitative pharmacokinetic/pharmacodynamic approach in future clinical development of psychedelics in general.