Nat Commun
December 15, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
153 citations
Serotonergic psychedelics show therapeutic potential, but the specific roles of 5-HT2A receptor signaling pathways are unclear. Researchers developed selective ligands with varying Gq efficacies, including β-arrestin-biased ones. In male mice, 5-HT2A-Gq recruitment efficacy, not β-arrestin2 recruitment, predicted psychedelic potential measured by head-twitch response magnitude. Disrupting Gq-PLC signaling reduced this response, and a threshold Gq activation level was needed for psychedelic-like effects, explaining why partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists blocked psychedelic effects and caused receptor downregulation and tachyphylaxis. Fine-tuning 5-HT2A Gq-signaling enables development of non-psychedelic 5-HT2A agonists.
Nat Commun
March 19, 2025
Ryan H. Gumpper, Manish K. Jain, Kuglae Kim et al.
31 citations
Classical psychedelics are being studied for treating depression, addiction, anxiety, and cluster headaches. Their therapeutic effects are thought to involve the 5-HT2A serotonin receptor. Seven cryo-EM structures were determined, covering major classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound. These structures reveal both common and distinct molecular interactions between different psychedelics and the receptor. The findings provide a mechanistic understanding of 5-HT2A activation that could aid development of new drugs with fewer side effects.
Nat Commun
December 22, 2020
Elizabeth D. Ballard, Carlos A. Zarate
10 citations
Ketamine produces immediate antidepressant effects and also short-term dissociative effects, where individuals experience altered consciousness and perceptions. Whether these dissociative side effects are necessary for the antidepressant effects remains unclear. This perspective examines the relationship between dissociation and both acute and longer-lasting antidepressant responses to ketamine and other NMDA receptor antagonists. The current literature does not support the conclusion that dissociation is necessary for antidepressant response to ketamine, but further work is needed to explore this relationship at molecular, biomarker, and psychological levels.