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). Supplementary Information The online version contains supplementary material available at 10.1007/s13318-023-00822-y.

The risk of chronic psychedelic and MDMA microdosing for valvular heart disease

“…Various clinical studies of DMT have been performed, but all were single doses or short series of doses that would not be adequate to assess the risk of VHD (e.g., Good et al, 2023;Riba et al, 2015;Timmermann et al, 2019;Vogt et al, 2023;Strassman, 1994aStrassman, , 1994b. The health status of long-term ritualistic users of ayahuasca has also been assessed (e.g., Barbosa et al, 2012), but with significant limitations.…”

“…The PK data following inhaled DMT are very limited (Riba et al, 2015), although the PK of IV administration has been studied fairly extensively in recent years (Good et al, 2023;Timmermann et al, 2019;Vogt et al, 2023). A dose-ranging study showed that a 0.05 mg/kg IV bolus of DMT fumarate resulted in an effect intensity equivalent to a microdose and a plasma C max value of approximately 10 ng/mL (Strassman, 1994a(Strassman, , 1994b.…”

“…Although DMT microdoses are generally administered in an inhaled fashion, we can assume that users would titrate their dose to a similar C max value. Considering an unbound plasma fraction of 0.677 (Good et al, 2023), the free C max would be 6.8 ng/mL (36 nM). Compared to the lowest reported K i value of 101 nM (Blair et al, 1999), the safety margin of this unbound C max is 2.8.…”

“…DMT-N-oxide plasma C max values were approximately 60-fold lower than those of parent DMT following an IV bolus dose (Vogt et al, 2023), and so are not likely to represent much risk. Concentrations of indole-3-acetic acid (IAA) can reach much higher levels than DMT (Good et al, 2023; Vogt et al, 2023). However, this molecule is also part of normal tryptophan metabolism and a typical serum level in healthy subjects was reported to be 1.9 µM (Dou et al, 2015).…”

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

“…10 Recently, infusions of DMT over varying lengths of time have been evaluated in the clinic. 11,12 The subjective intensity score used in the aforementioned study 7 is a discrete outcome variable that can only assume integer values within certain boundaries. However, the published model treats the intensity ratings as being continuous which means that predictions of non-integer values can also occur.…”