Pharmacokinetics of N,N-dimethyltryptamine in Humans.

Abstract

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).

• Authors: Meghan Good, Zelah Joel, Tiffanie Benway, Carol Routledge, Chris Timmermann, David Erritzoe, Richard Weaver, Graham Allen, Charlotte Hughes, Helen Topping, Amy Bowman, Ellen James
• Journal: European journal of drug metabolism and pharmacokinetics (Eur J Drug Metab Pharmacokinet) Vol. 48 Issue 3 Pg. 311-327 (May 2023) ISSN: 2107-0180 [Electronic] France
• PMID: 37086340 (Publication Type: Randomized Controlled Trial, Clinical Trial, Phase I, Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• N,N-Dimethyltryptamine
• Cytochrome P-450 CYP2D6
• Monoamine Oxidase

Topics

• Adult
• Humans
• N,N-Dimethyltryptamine
• Depressive Disorder, Major (drug therapy)
• Cytochrome P-450 CYP2D6 (metabolism)
• Monoamine Oxidase (metabolism)
• Kinetics
• Double-Blind Method
• Dose-Response Relationship, Drug