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.
Classical serotonergic psychedelics like psilocybin show emerging evidence of therapeutic potential across depression, anxiety, and substance use disorders, with indications of transdiagnostic efficacy. Early-phase studies yielded encouraging results, but recent larger-scale phase 3 trials for treatment-resistant depression have shown more modest effects. No regulatory approvals from the U.S. FDA or EMA exist, though a few countries permit psychedelic therapies in regulated clinical settings. The long-term trajectory and real-world impact within public health systems remain uncertain. This paper examines challenges for integrating psychedelic therapies into Ireland's public healthcare system, covering regulatory approval, Health Technology Assessment, service implementation, workforce capacity, and evaluation of long-term patient outcomes.