828. Psilocin attenuates polyinosinic:polycytidylic acid (Poly I:C)-indued interferon responses in human peripheral blood mononuclear cells

Abstract Background Serotonergic psychedelics have recently re-emerged as promising therapeutic agents in psychiatry, showing positive outcomes in clinical trials for treatment-resistant depression, major depression, and PTSD. However, their effects on the immune system are poorly characterized. It remains unclear whether these compounds exert immunomodulatory effects that contribute to their behavioural and clinical efficacy while maintaining a favourable safety profile. Among these agents, psilocybin, metabolized in vivo to the active compound psilocin, has received the most clinical attention. Aims & Objectives This study aimed to investigate whether psilocin influences antiviral immune signalling in human peripheral blood mononuclear cells (PBMCs) stimulated with the viral mimetic polyinosinic:polycytidylic acid (Poly I:C). Specifically, it sought to determine the timing and extent of psilocin’s immunomodulatory effects on cytokine and interferon responses.

Method: PBMCs from healthy donors were isolated, cultured, and stimulated with Poly I:C (10–80 μg/mL) for 2–72 hours to activate aTLR3-mediated inflammatory, anti-viral response. mRNA expression levels of IFN-α, IFN-β, IL-1β, IL-6, and IDO1 were quantified by real-time quantitative PCR (RT-qPCR). Cell number and viability were assessed via trypan blue exclusion. Psilocin (0.03–30 μM) was added at 2, 6, or 24 hours after Poly I:C stimulation (40 μg/mL for 24 hours), and effects on cytokine gene expression were evaluated.

Results: Poly I:C stimulation induced robust upregulation of IFN-α, IFN-β, IL-1β, IL-6, and IDO1 mRNA expression. At a concentration of 0.1 μM, Psilocin treatment at 2 or 6 hours post-stimulation significantly decreased IFN-α, IFN-β, TNF-α, and IDO1 expression, whereas treatment at 24 hours post-stimulation reduced only IFN-β and IDO1 levels. The lowest effective psilocin concentration (0.1 μM) corresponded to physiologically relevant plasma levels following oral administration of a standard 25 mg psilocybin dose. Discussion & Conclusions These findings indicate that psilocin exerts time-dependent immunomodulatory effects on antiviral signalling pathways in human PBMCs. Direct immunomodulation suggests that psilocin is not only capable of acting in the brain but also of influencing peripheral immune signalling. Notably, the lowest concentration tested (0.1 μM) corresponds to physiologically relevant plasma levels following oral administration of a standard 25 mg psilocybin dose. Future investigations will evaluate psilocin’s effects on immune activation induced by other stimuli, including bacterial lipopolysaccharide (LPS), and determine whether related serotonergic psychedelics such as dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) produce comparable immunomodulatory activity. Immune cells express serotonin receptors including 5-HT2A, so modulation of IFN responses supports a functional role for serotonergic signalling in innate immunity. It will also be important to establish the mechanisms by which serotonergic psychedelics produce these immunomodulatory effects. Moreover, changes in interferon signalling could be one pathway linking psychedelic exposure to downstream effects on mood, inflammation and behaviour.