Antidepressant effect of psychedelic compounds and mechanisms underlying the G protein-coupled receptors activation psychedelics: Antidepressant action and GPCR signaling.
European Journal of Pharmacology July 10, 2026 Amanda Gollo Bertollo, Vinicius Alexandre Wippel, Maiqueli Eduarda Dama Mingoti et al.
Psychedelic compounds show promise as rapid-acting antidepressants, especially for treatment-resistant depression. Their effects are primarily mediated through 5-HT2A receptor activation, which triggers intracellular signaling cascades involving Gq/11 and β-arrestin pathways, leading to neuroplasticity, synaptogenesis, and remodeling of neural circuits like the default mode network. These compounds also modulate glutamatergic transmission and have anti-inflammatory properties. Key transcription factors and epigenetic modifications contribute to enduring changes in gene expression. While 5-HT2A receptors play a central role, other receptors and neurotransmitter systems are also involved. The review identifies knowledge gaps regarding interactions between these mechanisms and suggests future research directions.