A novel psychedelic 5-HT 2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer

A single intravenous dose of GM-2505, a novel 5-HT2A receptor agonist, was safe and well tolerated in 48 healthy volunteers at doses up to 20 mg. The drug produced mild, transient increases in blood pressure and pulse, no significant electrocardiograph changes, and a half-life of 40–50 minutes. Dose-dependent effects appeared on neuroendocrine hormones, neuropsychological and neurophysiological measures, subjective drug effects, and resting-state electroencephalography, with decreased theta and alpha power and increased slow and fast gamma power. These pharmacodynamic effects resembled those of other 5-HT2A agonists, but GM-2505's shorter duration of cardiovascular and subjective effects than psilocybin and longer than DMT suggests a more practical temporal profile for supervised clinical use, with an optimal dose range of 10–15 mg IV.

Study at a glance

Abstract

Background: The treatment of major depressive disorder (MDD) with available antidepressant drugs is characterized by considerable ineffectiveness. Classical psychedelics such as psilocybin and N,N-dimethyltryptamine (DMT), which act primarily as 5-hydroxytryptamine 2A (5-HT 2A ) receptor agonists, have shown preliminary efficacy for inducing long-term remission in MDD after one or two doses. GM-2505 is a novel, 5-HT 2A receptor agonist, developed for treating MDD. Methods: In this single-ascending dose, randomized, placebo-controlled, double-blind study, we characterized GM-2505’s safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) profile in 48 healthy participants. Results: Single intravenous (IV) doses up to 20 mg demonstrated an acceptable safety profile of mild transient adverse events, short-term, non-clinically significant increases in blood pressure and pulse, and no significant changes in electrocardiographs, consistent with other 5-HT 2A receptor agonists. In general, GM-2505 C max and AUC last increased dose proportionally, with t 1/2 of 40–50 minutes. Generally, dose-dependent effects were observed for neuroendocrine hormones, several neuropsychological and neurophysiological measures, and subjective drug effects. Dose-related effects were also observed in resting-state electroencephalography (rsEEG), with decreased power in the low frequency rsEEG bands (theta and alpha), and increased in the high frequency bands (slow and fast gamma). Conclusions: These PD findings were similar in nature and magnitude to other 5-HT 2A receptor agonists that have been studied clinically. In line with the GM-2505 PK profile, the duration of cardiovascular and subjective effects was shorter than psilocybin but longer than DMT, demonstrating a potentially more practical temporal profile for use in a supervised clinical setting compared to longer-acting 5-HT 2A receptor agonists, with an optimal dose range of 10–15 mg IV. Clinical trial (ISRCTN64428072) registration: https://www.isrctn.com/ISRCTN64428072.