Patients with stress-related disorders, like depression, exhibit elevated pro-inflammatory cytokines and an overactive HPA axis. Although psychedelics show promise in treating these disorders, the underlying therapeutic mechanisms remain unclear. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel-group design comprising of 60 healthy participants who received either placebo (n = 30) or 0.17 mg/kg psilocybin (n = 30). Blood samples were taken to assess acute and persisting (7 day) immune changes, and seven days post-administration, participants underwent further stress induction or control protocols. Ultra-high field (7-Tesla) magnetic resonance spectroscopy was used to assess whether acute changes in glutamate were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. 

Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin (IL)- 1β, IL-6, and C-reactive protein (CRP)) remained unchanged.  After seven days, TNF-α returned to baseline, while IL-6 and CRP concentrations reduced. Acute TNF-α reduction correlated with lower hippocampal glutamate concentrations, whereas greater decreases in IL-6 and CRP correlated with persistent positive mood and social effects. Regarding the stress response, after a psychosocial stressor, psilocybin did not significantly alter the stress response. Results will be discussed in regards to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.