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

N L Mason; A Szabo; K P C Kuypers; P A Mallaroni; R de la Torre Fornell; J T Reckweg; D H Y Tse; N R P W Hutten; A Feilding; J G Ramaekers

doi:10.1016/j.bbi.2023.09.004

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

Brain Behav Immun. 2023 Nov:114:299-310. doi: 10.1016/j.bbi.2023.09.004. Epub 2023 Sep 7.

Authors

Affiliations

¹ Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: natasha.mason@maastrichtuniversity.nl.
² Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway.
³ Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
⁴ Integrative Pharmacology and Systems Neurosciences Research Group. Neurosciences Program. Hospital del Mar Medical Research Institute. Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra. Dr. Aiguader 88, 08003 Barcelona, Spain.
⁵ The Beckley Foundation, Beckley Park, Oxford, OX3 9SY, United Kingdom.

PMID: 37689275
DOI: 10.1016/j.bbi.2023.09.004

Abstract

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 and persisting (7 day) changes in immune status. 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 (7-Tesla) 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-α (TNF-α), while other inflammatory markers (interleukin (IL)- 1β, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF-α 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-α 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 did not significantly alter the stress response. Results are discussed in regards to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Keywords: Cytokines; Glutamate; Hypothalamic-pituitary-adrenocortical axis; Magnetic resonance spectroscopy; Psilocybin; Psychedelics; Stress.