Background and Objective N , N -dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects. Methods The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability. Results In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9–21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9–12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight. Conclusion This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD. Clinical Trial Registration Registered on ClinicalTrials.gov (NCT04673383). Supplementary Information The online version contains supplementary material available at 10.1007/s13318-023-00822-y.

Aim: N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the in vitro metabolism and clinical pharmacokinetics (PK) of DMT fumarate (SPL026) in healthy subjects. Methods: Results are from the Phase I component of an ongoing Phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial. Healthy adults received escalating doses of SPL026 via a 2-phase intravenous (IV) infusion. Dosing regimens were calculated based on PK modelling and predictions, with progression to each subsequent dose level according to safety and tolerability. In vitro experiments assessed hepatic clearance and metabolism of DMT by monoamine oxidase (MAO) and cytochrome P450 enzymes. Results: 24 healthy subjects received escalating doses of SPL026 which were safe and well-tolerated. Dose-proportional increases in DMT exposure were observed over the range of 9–21.5 mg. For all doses, median time to peak plasma concentration was ~10 min and mean elimination half-life was 9–12 min. There was no relationship between peak DMT plasma concentration and body mass index, weight or age. In vitro hepatic mitochondrial fraction clearance of SPL026 was inhibited by MAO-A, but not MAO-B, inhibition. CYP2D6 and CYP2C19 modified SPL026 clearance in vitro. The unbound fraction of SPL026 was approximately 70%. Conclusion: This is the first study to determine, in detail, the full PK profile of DMT in humans, confirming rapid attainment of peak plasma concentrations followed by accelerated clearance. These findings provide evidence which support the development of novel DMT infusion regimens for the treatment of MDD.