G protein-coupled receptors (GPCRs) represent key drug targets, with approximately 30%-40% of all medications acting on these receptors. Recent advancements have uncovered the complexity of GPCR signaling, including biased signaling, which allows selective activation of specific intracellular pathways—primarily mediated by G proteins and β-arrestins. Among aminergic GPCRs, the serotonin 5-HT₂A receptor has garnered attention for its potential to generate therapeutic effects without adverse outcomes, such as hallucinations, through biased agonism. This review delivers a comprehensive overview of 5-HT₂A receptor-biased signaling and its significance in developing safer mental health therapeutics, particularly for depression and anxiety. We provide a critical evaluation of methodologies for assessing biased signaling, spanning from traditional radioligand binding assays to advanced biosensor technologies. Furthermore, we review structural studies and computational modeling that have identified key receptor residues modulating biased signaling. We also highlight novel biased ligands with selective pathway activation, presenting a promising avenue for developing targeted antidepressant therapies without psychedelic effects. Additionally, we explore the 5-HT₂A receptor's role in memory processes and stress response regulation. Ultimately, advancing our understanding of 5-HT₂A receptor-biased signaling could drive the development of next-generation GPCR-targeted therapies, maximizing therapeutic efficacy while minimizing side effects in psychiatric treatment.

5-HT_2A receptor  /  Biased agonism  /  Biased signaling  /  G protein-coupled receptors  /  Mental health disorders  /  Psychedelics