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.