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
  • 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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