2. Academic Validation
  3. A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer

A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer

  • J Psychopharmacol. 2025 Oct 16:2698811251378512. doi: 10.1177/02698811251378512.
Gerard J Marek 1,  Soma Makai-Bölöni 2 3,  Daniel Umbricht 1,  Edward P Christian 1,  Jason Winters 1,  Dino Dvorak 1,  Shane Raines 1,  Zoë A Hughes 1,  Eric W Austin 1,  Adam K Klein 1,  William Leong 1,  Fas J Krol 2 3,  Anne J van der Graaf 2,  Maria J Juachon 2,  Marije E Otto 2 4,  Laura G J M Borghans 2 3,  Gabriël Jacobs 2 3 5,  Andrew C Kruegel 1,  Jonathan Sporn 1
Affiliations

Affiliations

  • 1 Gilgamesh Pharmaceuticals Inc., New York, NY, USA.
  • 2 Centre for Human Drug Research, Leiden, The Netherlands.
  • 3 Leiden University Medical Center, The Netherlands.
  • 4 Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.
  • 5 Department of Psychiatry, Leiden University Medical Centre, the Netherlands.
PMID: 41099491 DOI: 10.1177/02698811251378512
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-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. Clinical trial (ISRCTN64428072) registration: https://www.isrctn.com/ISRCTN64428072.

Keywords

5-HT2A receptor; GM-2505; PD; PK; biomarker; healthy volunteers; major depressive disorder; psychedelics; resting-state EEG.

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