Drug and Alcohol Dependence
June 1, 1998
Gerard J. Marek, George K. Aghajanian
39 citations
Psychedelic hallucinogens fall into three chemical groups: ergolines (e.g., LSD), simple indoleamines (e.g., DMT and psilocybin), and ring-substituted phenethylamines (e.g., mescaline). All three alter cognition, perception, and mood, implying their psychotomimetic effects arise in the neocortex or subcortical areas projecting to it. Evidence suggests that both indoleamine and phenethylamine hallucinogens bind to the 5-HT2A serotonin receptor, and activation of this receptor mediates their psychotomimetic effects. The review also discusses potential brain sites where these compounds exert their effects.
Journal of Psychopharmacology
October 16, 2025
Gerard J. Marek, Soma Makai‐bölöni, Daniel Umbricht et al.
2 citations
A single intravenous dose of GM-2505, a novel 5-HT2A receptor agonist, was safe and well tolerated in 48 healthy volunteers at doses up to 20 mg. The drug produced mild, transient increases in blood pressure and pulse, no significant electrocardiograph changes, and a half-life of 40–50 minutes. Dose-dependent effects appeared on neuroendocrine hormones, neuropsychological and neurophysiological measures, subjective drug effects, and resting-state electroencephalography, with decreased theta and alpha power and increased slow and fast gamma power. These pharmacodynamic effects resembled those of other 5-HT2A agonists, but GM-2505's shorter duration of cardiovascular and subjective effects than psilocybin and longer than DMT suggests a more practical temporal profile for supervised clinical use, with an optimal dose range of 10–15 mg IV.
bioRxiv (Cold Spring Harbor Laboratory)
June 30, 2026
Blake A Fordyce, Yi-Ting Chiu, Nicholas A. Wright et al.
Activation of mGluR2, the primary presynaptic autoreceptor for glutamate in the brain, attenuates the behavioral and electrophysiological effects of psychedelics. The mechanisms behind this are debated, with two competing hypotheses: direct actions via mGluR2/5-HT2A heterodimers, or presynaptic inhibition of glutamate release. In mice expressing tagged receptors, mGluR2 agonist pretreatment reduced the head twitch response induced by the psychedelic DOI. Multiple orthogonal in vivo and in vitro approaches found no evidence for receptor colocalization or oligomerization under basal or agonist-exposed conditions, nor for mGluR2-mediated modulation of 5-HT2A ligand binding. The findings support models where mGluR2 signaling modulates 5-HT2A receptor activity in layer V pyramidal neurons rather than requiring mGluR2/5-HT2A multimers.