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
{"title":"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","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","doi":"10.1177/02698811251378512","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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<sub>2A</sub>) 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<sub>2A</sub> receptor agonist, developed for treating MDD.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sub>2A</sub> receptor agonists. In general, GM-2505 <i>C</i><sub>max</sub> and AUC<sub>last</sub> increased dose proportionally, with <i>t</i><sub>1/2</sub> 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).</p><p><strong>Conclusions: </strong>These PD findings were similar in nature and magnitude to other 5-HT<sub>2A</sub> 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<sub>2A</sub> receptor agonists, with an optimal dose range of 10-15 mg IV. Clinical trial (ISRCTN64428072) registration: https://www.isrctn.com/ISRCTN64428072.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251378512"},"PeriodicalIF":5.5000,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A novel psychedelic 5-HT<sub>2A</sub> receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer.\",\"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\",\"doi\":\"10.1177/02698811251378512\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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<sub>2A</sub>) 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<sub>2A</sub> receptor agonist, developed for treating MDD.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sub>2A</sub> receptor agonists. In general, GM-2505 <i>C</i><sub>max</sub> and AUC<sub>last</sub> increased dose proportionally, with <i>t</i><sub>1/2</sub> 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).</p><p><strong>Conclusions: </strong>These PD findings were similar in nature and magnitude to other 5-HT<sub>2A</sub> 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<sub>2A</sub> receptor agonists, with an optimal dose range of 10-15 mg IV. Clinical trial (ISRCTN64428072) registration: https://www.isrctn.com/ISRCTN64428072.</p>\",\"PeriodicalId\":16892,\"journal\":{\"name\":\"Journal of Psychopharmacology\",\"volume\":\" \",\"pages\":\"2698811251378512\"},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2025-10-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/02698811251378512\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/02698811251378512","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer.
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.
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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.
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