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

This narrative review synthesizes clinical and preclinical research on how 5-HT2A receptor psychedelics interact with the immune system. The evidence shows these compounds have direct immunomodulatory properties, including downregulation of gene regulators like NF-κB and reduced expression of cytokines such as TNF-α, IL-6, and IL-1β in both the central and peripheral nervous systems. These effects are accompanied by modulation of corticotrophin releasing hormone, adrenocorticotrophic hormone, and cortisol. The immunomodulation occurs through pathways involving serotonin receptors, the Sigma-1 receptor, and the TrkB receptor, as well as indirectly via the HPA axis. The review identifies that modulation of brain glia and glial-neuronal interactions remains to be determined, representing a promising direction for future research on the therapeutic potential of these psychedelics for mental health and brain disorders.

Study at a glance

Abstract

By synthesising findings from both clinical and preclinical research, this review aims to provide an understanding of the interplay between 5-HT2A receptor psychedelics and the immune system and considers how their immunomodulatory effects associate with neuronal and behavioural changes. 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-HT2AR psychedelics between the immune and nervous systems, identified through this search process. Preclinical and clinical studies report that 5-HT2AR 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. Further studies will determine the molecular and cellular mechanisms underlying these immunomodulatory effects. There is growing interest in the potential of 5-HT2AR 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-HT2AR psychedelics.