Neuroinflammation, the gut-brain axis, and psychedelic-assisted psychotherapy: A synthesis of emerging paradigms in psychiatric care

Abstract

Psychiatric disorders represent a leading cause of global disability yet current therapeutic strategies, based mainly on monoaminergic modulation, exhibit limited efficacy and high relapse rates for a significant patient population. This has catalyzed a paradigm shift toward understanding the biological underpinnings of mental illness. This review synthesises evidence from three rapidly advancing fields to propose an integrated model for psychiatric pathophysiology and treatment. First, we examine neuroinflammation—the chronic activation of the brain’s innate immune system—as a key transdiagnostic mechanism in disorders such as major depression, anxiety, and schizophrenia. Second, we explore the microbiota-gut-brain axis as a critical bidirectional communication network that regulates systemic immunity and acts as a primary driver of neuroinflammation through mechanisms including increased intestinal permeability and dysbiosis. Finally, we analyze the emerging field of psychedelic-assisted psychotherapy (PAP), positing that its profound therapeutic efficacy extends beyond established psychological and neuroplastic effects. We present compelling preclinical evidence that classic psychedelics function as potent immunomodulatory agents, directly attenuating neuroinflammatory pathways via biased agonism at the serotonin 5-HT2A receptor. This review culminates in a proposed unified, tripartite hypothesis of PAP’s mechanism of action, which integrates a “top-down” psychological reset, a “central” quenching of neuroinflammation, and a “bottom-up” restoration of gut-brain axis homeostasis. This integrated perspective provides a more holistic, biologically grounded framework for understanding and optimising psychedelic medicine, heralding a new, system-level approach to psychiatric care.