Pharmacokinetics of N,n-Dimethyltryptamine Fumarate in Humans

Abstract

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.

Psychedelic Therapy: A Primer for Primary Care Clinicians—N,N-Dimethyltryptamine and Ayahuasca

“…Intravenous or smoked DMT is very short-acting, with an elimination half-life of 9-12 minutes, because of its rapid metabolism through oxidase deamination into the primary metabolite indole-3-acetic acid. [10][11][12][13][14] Up to 50% of DMT is recovered as indole-3-acetic acid, whereas less than 1% of DMT is excreted unchanged in human urine. 15,16 As with other classical psychedelics, the hallucinogenic effect of DMT is mainly achieved by stimulating the 5-HT 2A receptor.…”

The changing outlook of psychedelic drugs: The importance of risk assessment and occupational exposure limits

“…Because of the short‐term potent effect, smoked DMT was referred to as the “businessman's lunch trip” in the 1960s (Cameron & Olson, 2018). When administered parenterally or inhaled/smoked, DMT is believed to be metabolized by cytochrome P450 (CYP)2D6 and CYP2C19, and 5‐MeO‐DMT is believed to be metabolized by CYP2D6 (Good et al, 2022; Shen et al, 2010).…”

“…The elimination half‐lives ( T ½) of psilocybin and LSD are in the same range (2 to 3 h) (European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2022b; Dinis‐Oliveira, 2017). Compared with psilocybin and LSD, DMT and 5‐MeO‐DMT have more rapid elimination half‐lives of 5 to 16 min for DMT and 6 to 19 min for 5‐MeO‐DMT (Ermakova et al, 2022; Good et al, 2022; Vogt et al, 2023).…”

Optimized infusion rates for N,N‐dimethyltryptamine to achieve a target psychedelic intensity based on a modeling and simulation framework

“…However, whereas most published studies with DMT so far have used intravenous bolus doses to investigate its effects, 4,8,9 a continuous infusion of DMT rather than bolus doses has been proposed as a suitable way forward to extend the psychedelic experience 10 . Recently, infusions of DMT over varying lengths of time have been evaluated in the clinic 11,12 …”