Biased Signaling in Psychedelic Action

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.