Antidepressant effect of psychedelic compounds and mechanisms underlying the G protein-coupled receptors activation psychedelics: Antidepressant action and GPCR signaling.
Amanda Gollo Bertollo, Vinicius Alexandre Wippel, Maiqueli Eduarda Dama Mingoti, Rui Daniel Prediger, Zuleide Maria Ignácio
European journal of pharmacology July 10, 2026 Peer reviewed DOI: 10.1016/j.ejphar.2026.179036 via PubMed
Summary
Psychedelic compounds show promise as rapid-acting antidepressants for treatment-resistant depression (TRD) by activating the 5-HT2A receptor and initiating unique intracellular signaling pathways. These pathways lead to neuroplasticity and changes in neural circuits, particularly in the default mode network. The review discusses how psychedelics also affect glutamatergic transmission and possess anti-inflammatory properties that contribute to their therapeutic effects, while highlighting knowledge gaps and future research directions.
Study at a glance
| Design | review |
|---|---|
| Key finding | Psychedelics, primarily through 5-HT2A receptor activation, trigger intracellular signaling that leads to neuroplasticity and may provide rapid antidepressant effects in treatment-resistant depression. |
Abstract
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-HT2A receptor 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-HT2A receptors, 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.