Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. 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 changes in immune status, and 7 days after drug administration. Seven days post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity 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-alpha (TNF-a), while other inflammatory markers (interleukin (IL)-1a, IL-1b, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF-a concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF-a were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin blunted the cortisol response compared to placebo. Such acute and persisting changes may contribute to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

The authors have declared no competing interest.

Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007

This study is part of the Beckley/Maastricht Research Programme. The Beckley Foundation made a financial contribution to the study. The authors report no other relevant funding, and all authors report no potential conflicts of interest.

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