A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer
In a randomized, placebo‑controlled ascending‑dose study in 48 healthy volunteers, single IV doses of GM‑2505 up to 20 mg were well tolerated and showed dose‑proportional pharmacokinetics (t1/2 40–50 min) with dose‑dependent neuroendocrine, neurophysiological and subjective psychedelic effects, including decreased theta/alpha and increased gamma EEG power. The duration of cardiovascular and subjective effects was intermediate between psilocybin and DMT, indicating a practical 10–15 mg IV dose range for supervised clinical use.
Authors
- Marek, G. J.
- Makai-Bölöni, S.
- Umbricht, D.
Published
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.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- APA Citation
Marek, G. J., Makai-Bölöni, S., Umbricht, D., Christian, E. P., Winters, J., Dvorak, D., Raines, S., Hughes, Z. A., Austin, E. W., Klein, A. K., Leong, W., Krol, F. J., Graaf, A. J. V. D., Juachon, M. J., Otto, M. E., Borghans, L. G. J. M., Jacobs, G., Kruegel, A. C., & Sporn, J. (2025). A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer. Journal of Psychopharmacology. https://doi.org/10.1177/02698811251378512
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