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Pharmacokinetics of N,N-dimethyltryptamine in Humans.

Meghan Good, Zelah Joel, Tiffanie Benway, Carol Routledge, Chris Timmermann, David Erritzøe, Richard Weaver, Graham Allen, Charlotte Hughes, Helen Topping, Amy Bowman, Ellen James

European Journal of Drug Metabolism and Pharmacokinetics May 1, 2023 DOI: 10.1007/s13318-023-00822-y (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial Randomized Peer reviewed
Sample size 24
Population Healthy adults
Intervention DMT fumarate (SPL026)
Dose 9-21.5 mg (DMT freebase)
Duration Single escalating doses administered as a 10-min infusion
Topics 5-MeO-DMT DMT
Keywords Psychedelics Mental health Pharmacology Drug metabolism
Citations 54
Registration NCT04673383
Key findings DMT is rapidly cleared from the body (mean elimination half-life 9–12 minutes) and all tested doses were safe and well tolerated, with no relationship between peak plasma concentration and body weight or BMI.

Abstract

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. 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. 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. 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. Registered on ClinicalTrials.gov (NCT04673383).

Comparable studies

Other randomized controlled trials on 5-MeO-DMT, most cited first.

Study Year Design Participants
Dose-Response Study of N,N-Dimethyltryptamine in Humans Experienced hallucinogen users 1994 Double-blind, saline placebo-controlled, randomized study n = 12
Psychological Effects of (S)-Ketamine and N,N-Dimethyltryptamine (DMT): A Double-Blind, Cross-Over Study in Healthy Volunteers Healthy volunteers 2005 Double-blind crossover study n = 9
Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans Experienced hallucinogen users 1996 Randomized controlled trial n = 13
Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis Healthy volunteers 2007 Double-blind crossover study n = 15
Phase 1, placebo-controlled, single ascending dose trial to evaluate the safety, pharmacokinetics and effect on altered states of consciousness of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine benzoate) in healthy participants. Healthy psychedelic-naïve participants 2024 Double-blind, placebo-controlled single ascending dose study n = 44

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