This Phase I single-ascending dose, randomised, placebo-controlled, double-blind study (n=48) found that GM-2505, a novel 5-HT2A receptor agonist, demonstrated an acceptable safety profile with mild transient adverse events at intravenous doses up to 20 mg, a half-life of 40-50 minutes, and dose-dependent effects on neuroendocrine hormones, neuropsychological measures, and resting-state electroencephalography similar to other 5-HT2A receptor agonists but with a duration of effects shorter than psilocybin and longer than DMT.
Abstract of A novel psychedelic 5-HT2A receptor agonist GM-2505
“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-HT2A) receptor agonists, have shown preliminary efficacy for inducing long-term remission in MDD after one or two doses. GM-2505 is a novel, 5-HT2A 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-HT2A receptor agonists. In general, GM-2505 Cmax and AUClast increased dose proportionally, with t1/2 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-HT2A 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-HT2A receptor agonists, with an optimal dose range of 10–15 mg IV.”
Authors: Gerard J. Marek, Soma Makai-Bölöni, Daniel Umbricht, Edward P. Christian, Jason Winters, Dino Dvorak, Shane Raines, Zoë A. Hughes, Eric W. Austin, Adam K. Klein, William Leong, Fas J. Krol, Anne J. van der Graaf, Maria J. Juachon, Marije E. Otto, Laura G. J. M. Borghans, Gabriël Jacobs, Andrew C. Kruegel & Jonathan Sporn
Summary of A novel psychedelic 5-HT2A receptor agonist GM-2505
Major depressive disorder (MDD) imposes a large global burden and current antidepressants often fail to deliver remission for most patients, with typical remission rates hovering around 30–40%. Even when benefits emerge, they commonly take weeks to materialise and adverse effects are frequent, leaving many with residual symptoms. Against this backdrop, rapid-acting treatments are being pursued.
Classical psychedelics such as psilocybin and DMT act chiefly at the 5-HT2A receptor (a serotonin receptor subtype widely expressed in cortex) and can produce durable improvements after one or two administrations in early clinical work. The 5-HT2A mechanism differentiates them from conventional antidepressants and is thought to engage neuroplasticity processes relevant to mood disorders. GM-2505 is a novel compound designed as a 5-HT2A receptor agonist with additional 5-HT releasing properties. Preclinical work suggested a short plasma half-life (~45 minutes) with psychedelic-like effects lasting ~90 minutes—shorter than psilocybin or LSD but longer than DMT—potentially improving the practicality of supervised dosing sessions. This first-in-human, randomised, placebo-controlled, single-ascending-dose study in healthy volunteers characterises the pharmacokinetics (PK), safety, and pharmacodynamics (PD) of intravenous (IV) GM-2505.
Methods
Study design and oversight
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https://doi.org/10.1177/02698811251378512
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Cite this paper (APA)
Marek, G. J., Makai-Bölöni, S., Umbricht, D., Christian, E. P., Winters, J., Dvorak, D., ... & Sporn, J. A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer. Journal of Psychopharmacology, 02698811251378512.
Study details
Participants
48
Humans
Linked Clinical Trial
A study on the safety, tolerability, and effects of GM-2505This adaptive, randomised, double-blind, placebo-controlled trial (n=48) evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending intravenous doses of GM-2505 (second-gen, shorter duration, 5-HT2A agonist) in healthy volunteers.