Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study

A growing body of evidence implicates inflammatory processes in the pathophysiology of stress-related psychiatric disorders including depression, addiction, and PTSD, with elevated circulating concentrations of pro-inflammatory cytokines — including IL-1β, IL-6, and TNF-α — consistently reported in these conditions. Serotonergic psychedelics such as psilocybin have been shown to possess anti-inflammatory properties in vitro and in animal models, yet their effects on immune markers in healthy humans — including the time course and persistence of any changes — had not been systematically characterised. This study aimed to determine whether a single moderate dose of psilocybin produces acute and persisting alterations in inflammatory markers in healthy volunteers, to assess its effects on the HPA axis stress response, and to examine whether psilocybin-induced changes in immune status are associated with alterations in brain neurometabolites and with persisting changes in mood and social behaviour.

Sixty healthy participants were enrolled in a randomised, placebo-controlled, double-blind, parallel-group design conducted at Maastricht University between July 2017 and June 2018. Participants were required to be aged 18–40, have previous experience with a psychedelic drug but not within the preceding three months, and to meet standard health and psychiatric exclusion criteria. Venous blood samples were collected at baseline, acutely (80 minutes post-administration, during peak drug effects), and seven days post-treatment, for assay of plasma IL-1β, IL-6, IL-8, TNF-α, and CRP concentrations. HPA axis activation was assessed via cortisol concentrations at baseline and acutely; the Maastricht Acute Stress Test (MAST) was administered at seven-day follow-up to assess persisting stress reactivity. Proton magnetic resonance spectroscopy (MRS) was used to quantify glutamate and myo-inositol (mI, a glial activity marker) in the medial prefrontal cortex and hippocampus. Mood and sociability were assessed via self-report at seven-day follow-up.

Acutely, psilocybin significantly reduced plasma TNF-α concentrations compared to placebo (p = 0.016), whilst IL-1β, IL-6, IL-8, and CRP were not significantly altered at this time point. Seven days post-treatment, TNF-α had returned to baseline levels in the psilocybin group whilst IL-6 and CRP were significantly reduced relative to placebo — indicating a delayed and persisting anti-inflammatory effect on a different cytokine profile. Psilocybin acutely increased cortisol concentrations above baseline, peaking at 80 minutes post-administration and returning toward baseline by 150 minutes, indicating transient HPA axis activation. At seven-day follow-up, the cortisol response to the MAST did not differ significantly between psilocybin and placebo groups. Psilocybin-induced reductions in IL-6 and CRP at seven days were positively associated with persisting increases in self-reported positive mood and altruistic or prosocial behaviour at follow-up. Acute TNF-α reductions correlated with acute hippocampal glutamate concentrations, which were significantly lower after psilocybin than after placebo, suggesting a glutamate–TNF-α interaction in the hippocampus as a potential acute mechanistic pathway.

The biphasic immune response to psilocybin — characterised by acute TNF-α reduction followed by persisting IL-6 and CRP reductions seven days later — is consistent with in vitro and animal data demonstrating anti-inflammatory serotonergic psychedelic effects and provides the first human in vivo evidence for this property. The temporal dissociation between the two phases suggests distinct early (likely glutamatergic-TNF-α) and later (likely downstream neuroplastic or neuroimmune) mechanisms. The correlation between persisting reductions in IL-6 and CRP and improvements in mood and prosociality positions immune modulation as a candidate mechanism contributing to the therapeutic effects of psilocybin observed in clinical depression trials — alongside the established neuroplasticity and psychological insight mechanisms. The transient HPA axis activation observed acutely — without persisting effects on stress reactivity at seven days — suggests that the acute cortisol response does not translate into sustained hypothalamic-pituitary-adrenal sensitisation. Limitations include the healthy volunteer population, single-dose design, and absence of longer follow-up beyond seven days.

A single moderate dose of psilocybin produces a rapid and persisting decrease in pro-inflammatory cytokine concentrations in healthy volunteers, with acute TNF-α reductions potentially mediated via a hippocampal glutamatergic mechanism and persisting IL-6 and CRP reductions correlating with improvements in mood and prosocial behaviour. These findings identify immune modulation as a candidate mechanism through which psilocybin may exert its therapeutic effects and highlight the immunological dimension of psychedelic pharmacology as a promising avenue for further clinical investigation.