Biased Signaling in Psychedelic Action

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.

Keywords: GPCR signaling; biased agonism; psychedelics; psychiatric disorders; serotonin.

Figure 1 |. 5-HT_2A receptor signaling pathways.

Signaling components stemming from 5-HT_2A receptor activation include (a) G_q/11 signaling pathways that activate PLC, leading to IP₃ and DAG generation, followed by PKC activation; (b) β-arrestin recruitment, leading to internalization, which is implicated in neuritogenesis and neuroplastic potential and may be due to intracellular sustained signaling; and (c) alternative pathways such as AA generation, which may be due to a pertussis toxin–sensitive or –insensitive G_i/o/z pathway. Abbreviations: 5-HT, 5-hydroxytryptamine; AA, arachidonic acid; DAG, diacylglycerol; ER, endoplasmic reticulum; IP₃, inositol-1,4,5-trisphosphate; PKC, protein kinase C; PIP2, phosphatidylinositol 4,5-bisphosphate; PLA₂, phospholipase A₂; PLC, phospholipase C. Figure created in BioRender; McCorvy J. 2025. https://BioRender.com/zkdc0c4.

Figure 2 |. Structural studies of the 5-HT_2A receptor illuminate mechanisms of psychedelic action and ligand bias.

(a) Structures of the 5-HT_2A receptor in active (light blue, PDB ID 6WHA; https://www.rcsb.org/structure/6WHA), inactive (red, PDB ID 6A93; https://www.rcsb.org/structure/6A93), and noncanonical (green, PDB ID 9ASA; https://www.rcsb.org/structure/9ASA) states. Structural models (top) and simplified schematics highlight differences in overall helical configurations and key motifs and residues. (b) Close-up of the LSD-bound 5-HT_2A receptor (purple) ligand-binding pocket (PDB ID 6WGT; https://www.rcsb.org/structure/6WGT), with lid residues (yellow) sealing LSD in the binding site (top). Schematic illustrating that mutating L229 increases LSD’s off rate and selectively diminishes β-arrestin activity (bottom). Abbreviations: 5-HT, 5-hydroxytryptamine; ECL2, extracellular loop 2; ICL2, intracellular loop 2; LSD, lysergic acid diethylamide; PDB, Protein Data Bank; TM, transmembrane helix; WT, wild type. Images created using the PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC.