Major Depressive Disorder (MDD) is a debilitating mental health condition that significantly impacts quality of life. Despite available pharmacological treatments, response rates remain suboptimal, with a considerable number of patients experiencing treatment-resistant depression (TRD). Indeed, classical antidepressants, primarily targeting monoaminergic systems, exhibit a therapeutic delay due to complex neuroadaptive changes. On the other hand, psychedelic compounds have recently emerged as promising, rapid-acting antidepressant agents, demonstrating efficacy particularly in TRD. This review explores the antidepressant effects of psychedelics, focusing on the underlying mechanisms involving G protein-coupled receptors (GPCRs). It is discussed how psychedelics, predominantly through 5-HTreceptor activation, trigger distinct intracellular signaling cascades (e.g., Gq/11 and β-arrestin pathways) leading to neuroplasticity, synaptogenesis, and functional remodeling of neural circuits, such as the default mode network (DMN). The review also examines their modulatory effects on glutamatergic transmission and anti-inflammatory properties, highlighting how these mechanisms contribute to their rapid and sustained therapeutic effects. Furthermore, the review examines the impact of psychedelics on key transcription factors (e.g., EGR1, CREB, NF-κB) and epigenetic modifications, which underpin enduring changes in gene expression and neuronal function. Finally, the central and predominant role of GPCRs, especially 5-HTreceptors, in mediating the antidepressant effects of psychedelics is discussed, acknowledging the complementary involvement of other receptors and neurotransmitter systems. This review aims to highlight existing knowledge gaps, particularly concerning the intricate interactions between different mechanistic pathways, and to propose future research directions to fully elucidate the therapeutic potential and safety of psychedelics in depression treatment. 2A2A
