Biased Signaling in Psychedelic Action.
Annu Rev Pharmacol Toxicol August 12, 2025 Daniel Wacker, John D. Mccorvy 4 citations
Psychedelics are promising for treating psychiatric disorders, pain, and migraine, but which signaling mechanisms produce their rapid and lasting therapeutic effects remains uncertain. Activation of the serotonin 5-HT2A receptor is key for their psychoactive effects, yet the specific signaling pathways and receptor shapes involved are still being studied. This review summarizes progress on 5-HT2A signaling, the development of biased agonist tools to separate therapeutic from adverse effects, and structural insights for designing tailored psychedelic-derived compounds. It also discusses other 5-HT receptors that may shape therapeutic outcomes and draws lessons from opioid research, emphasizing the need for rigor and reproducibility to advance novel psychedelic pharmacotherapies.