A novel psychedelic 5-HT_2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer.

IF 5.5 3区医学 Q1 CLINICAL NEUROLOGY

Journal of Psychopharmacology Pub Date : 2025-10-16 DOI:10.1177/02698811251378512

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

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引用次数: 0

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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一种新型迷幻5-HT2A受体激动剂GM-2505：健康志愿者随机试验的药代动力学、安全性和药效学特征

背景：现有抗抑郁药物治疗重度抑郁症（MDD）的特点是相当无效。经典致幻剂，如裸盖菇素和N，N-二甲基色胺（DMT），主要作为5-羟色胺2A （5-HT2A）受体激动剂，已经显示出在1或2次剂量后诱导MDD长期缓解的初步疗效。GM-2505是一种新型的5-HT2A受体激动剂，用于治疗重度抑郁症。方法：在这项单次递增剂量、随机、安慰剂对照、双盲研究中，我们在48名健康参与者中表征了GM-2505的安全性、耐受性、药代动力学（PK）和药效学（PD）特征。结果：单次静脉注射（IV）剂量高达20mg，与其他5-HT2A受体激动剂一致，显示出轻度短暂不良事件、短期、非临床显著的血压和脉搏升高以及心电图无显著变化的可接受安全性。一般情况下，GM-2505 Cmax和AUClast剂量成比例增加，40-50分钟为1/2。一般来说，神经内分泌激素、一些神经心理和神经生理指标以及主观药物效应都存在剂量依赖效应。静息状态脑电图（rsEEG）也观察到剂量相关效应，低频rsEEG波段（θ和α）功率下降，高频波段（慢速和快伽马）功率增加。结论：这些PD的发现在性质和程度上与其他临床研究的5-HT2A受体激动剂相似。根据GM-2505的PK概况，心血管和主观效应的持续时间比裸盖菇素短，但比DMT长，与长效5-HT2A受体激动剂相比，在有监督的临床环境中使用的潜在更实用的时间概况，最佳剂量范围为10- 15mg IV。临床试验（ISRCTN64428072）注册：https://www.isrctn.com/ISRCTN64428072。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Psychopharmacology 医学-精神病学

CiteScore

8.60

自引率

4.90%

发文量

126

审稿时长

3-8 weeks

期刊介绍： The Journal of Psychopharmacology is a fully peer-reviewed, international journal that publishes original research and review articles on preclinical and clinical aspects of psychopharmacology. The journal provides an essential forum for researchers and practicing clinicians on the effects of drugs on animal and human behavior, and the mechanisms underlying these effects. The Journal of Psychopharmacology is truly international in scope and readership.