Biased agonism in psychopharmacology: an opportunity to improve efficacy and safety of treatments.
Gia Han Le, Sabrina Wong, Stavroula Bargiota, Swainson Jennifer, Heidi K.y. Lo, Diana Orsini, Kayla M Teopiz, Hernán F Guillen-Burgos, Poh Khuen Lim, Roger S McIntyre
CNS Spectrums August 12, 2025 DOI: 10.1017/s109285292510045x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative literature review Peer reviewed |
|---|---|
| Keywords | G-protein coupled receptors Glp-1 Gpcr Antagonism Biased agonism Efficacy Psychedelics Psychopharmacology Safety |
| Citations | 3 |
| Key findings | Biased agonism enables selective intracellular signaling (e.g., G protein- versus β-arrestin-mediated) and has demonstrated potential for improved efficacy and safety in preclinical studies of psychopharmacologic agents. |
Abstract
G protein-coupled receptors (GPCRs) are involved in many physiological and pathophysiological processes. Conventional pharmacological models categorize the typology of pharmacologic ligands as agonists or antagonists. Biased agonism is a relatively newer pharmacodynamic characteristic that has potential to optimize therapeutic efficacy while minimizing adverse effects in psychiatric and neurological treatments. We conducted a narrative literature review of articles obtained from PubMed, Embase, and MEDLINE from inception to April 2025, focusing on pharmacologic antagonism (i.e., competitive, noncompetitive, uncompetitive) and agonism (i.e., full, partial, inverse, superagonism, biased). Primary and secondary articles defining these concepts were included, provided they addressed pharmacologic (rather than chemical) antagonism and agonism. Distinct mechanisms of antagonism and agonism were identified, each contributing nuanced receptor modulation beyond the conventional models. Notably, biased agonism facilitates targeted intracellular signaling (e.g., G protein- versus β-arrestin-mediated). Use cases demonstrate relatively greater efficacy (e.g., incretin receptor agonist, tirzepatide) and improved safety (e.g., serotonergic psychedelics, opioids). Biased agonism provides a potential avenue for future drug development, with emerging preclinical evidence suggesting potential to differentially activate intracellular pathways and thereby improve efficacy and safety profiles of psychopharmacologic agents-pending clinical validation. Future research vistas should aim to rigorously assess the long-term outcomes of biased agonism, explicitly addressing individual variability in receptor signaling and therapeutic response.