Narrating the psychoneuroimmunomodulatory properties of serotonin 5-HT2A receptor psychedelics from a transdiagnostic perspective.
Acta neuropsychiatrica – July 25, 2025
Source: PubMed
Summary
Psychedelics targeting the 5-HT2A receptor have demonstrated significant immunomodulatory effects, potentially influencing treatment for psychiatric disorders. A review of 30 years of literature revealed that these substances can downregulate key inflammatory markers like TNF-α and IL-6, impacting both the immune and nervous systems. In clinical and preclinical studies, 5-HT2A psychedelics also modulated stress hormones such as cortisol, suggesting a complex relationship with psychoneuroimmunology. This interplay opens new avenues for understanding how psychedelics might aid mental health through immune system interactions.
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.