Biased Signaling in Psychedelic Action.

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.

Study at a glance

Abstract

Psychedelics show tremendous promise for treating psychiatric disorders and other illnesses, including pain and migraine. Despite decades of research, there is uncertainty which signaling mechanisms are necessary for rapid-acting and durable therapeutic effects of psychedelics. Although activation of the serotonin 5-HT 2A receptor is critical for their psychopharmacological effects, the precise signaling pathways and receptor conformations responsible are still under investigation. This review summarizes progress in studying 5-HT 2A signaling mechanisms and recent developments in the discovery of biased agonist tool compounds to disentangle therapeutic from adverse effects. Moreover, we review insights from structural studies regarding the design of psychedelic-derived compounds with tailored pharmacology and briefly discuss other 5-HT receptors that may be important for shaping therapeutic effects. Finally, by drawing parallels between 5-HT 2A biased signaling and the opioid field, we conclude with lessons learned and discuss the need for more rigor and reproducibility to facilitate the development of novel psychedelic-based pharmacotherapies.