Narrating the psychoneuroimmunomodulatory properties of serotonin 5-HT2A receptor psychedelics from a transdiagnostic perspective

Objective: By synthesising findings from both clinical and preclinical research, this review aims to provide an understanding of the interplay between 5-HT 2A receptor psychedelics and the immune system and considers how their immunomodulatory effects associate with neuronal and behavioural changes. Methods: A PubMed literature search covering the past 30 years was conducted using keywords such as “5-HT2A receptor,” “psychedelics,” “immune system,” and “HPA axis.” Studies were included if they addressed the effects of 5-HT2AR psychedelics on immune function, neuroimmune interactions, or HPA axis involvement. This narrative review synthesises evidence highlighting the bi-directional effects of 5-HT 2A R psychedelics between the immune and nervous systems, identified through this search process. Results: Preclinical and clinical studies report that 5-HT 2A R psychedelics have some direct immunomodulatory properties with downregulation of gene regulators like NF-κB, and reduced cytokine expression such as TNF-α, IL-6, and IL-1β at a central and peripheral level, accompanied by modulation of corticotrophin releasing hormone (CRH), adrenocorticotrophic hormone (ACTH), and cortisol. Direct immunomodulatory effects are mediated by pathways involving serotonin receptors, the Sigma-1 receptor, and the TrkB receptor. Immunomodulation is further mediated indirectly via the HPA axis. Conclusion: Further studies will determine the molecular and cellular mechanisms underlying these immunomodulatory effects. There is growing interest in the potential of 5-HT 2A R psychedelics for treating a range of mental health and brain disorders. In keeping with their immunomodulatory actions, the likely modulation of brain glia and glial-neuronal interaction remains to be determined, representing a promising direction of further research on the therapeutic potential of 5-HT 2A R psychedelics.