Pathway-selective signaling of serotonergic psychedelics at 5-HT receptors: Implications for psychoactivity, safety, and therapeutic potential
European Neuropsychopharmacology April 10, 2026 Deborah Rudin, Jan Valenta, Helene Rolli et al. 2 citations
Serotonergic psychedelics primarily activate the serotonin 2A receptor, but their full effects involve multiple receptor subtypes and signaling pathways. Using stable cell lines and bioassays measuring phospholipase C activation via inositol monophosphate formation, phospholipase A2 activation, β-arrestin2 recruitment, and Gαi-protein dissociation across 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors, the study found that inositol monophosphate formation provides the most robust measure of 5-HT2 receptor activation and correlates strongly with known psychoactive doses. Most psychedelics showed signaling bias toward the PLC-IP1 or PLA2-AA pathway at the 5-HT2A receptor. The 5-HT2A/5-HT1A activation ratio may indicate seizure risk and therapeutic potential. Low activation at the 5-HT2B receptor suggests reduced cardiac risk with intermittent use, while strong 5-HT2C receptor activation aligns with low abuse potential.