The phenomenology of psilocybin’s experience mediates subsequent persistent psychological effects independently of sex, previous experience or setting

Background Recent studies have intensively explored the potential antidepressant effects of psilocybin. However, important variables such as previous experience, repeated administration, setting and sex remain underexplored. This study describes the acute psilocybin experience and long-term effects in a small sample of healthy individuals. Methods In a double-blind, placebo-controlled, cross-over study, 40 healthy participants (20 females, mean age 38, sd 8) received two doses of psilocybin 0.26 mg/kg per os at least 56 days apart (mean 354 days) in two study arms (EEG and fMRI). Near half of participants had experience with psychedelics. The Altered State of Consciousness Scale (ASC) and a visual analogue scale (VAS) on emotional valence of the phenomenology assessed acute phenomenology. The Persisting Effects Questionnaire (PEQ) assessed long- term effects. Venous blood samples were taken to measure serum psilocin levels. Results All results were independent of previous experience, sex, EEG or fMRI arm/setting. Acute psychedelic effects were of moderate intensity on ASC. The VAS showed mostly pleasant and fluctuating, and only one unpleasant only experience. All experiences resolved in a positive or neutral state at the end of the session. Psilocybin induced sustained positive effects on all domains of the PEQ, with negligible negative effects. Oceanic Boundlessness and Visual Restructuralization were associated with positive effects on PEQ. Contrary to expectations, Dread of Ego Dissolution, typically associated with fearful experiences, was not associated with PEQ negative outcomes. The type of experience (pleasant or mixed) did not correlate with the intensity or direction of the lasting effect; however, peak experiences culminating in a positive mood were associated with positive long- term effects. Conclusion In our sample repeated administration of psilocybin to healthy volunteers, induces positive, lasting effects. This underscores the psychological safety of psilocybin in a laboratory setting and supports its repeated use in clinical trials. In particular, challenging or anxiety-provoking experiences in controlled environments did not lead to adverse long-term outcomes. Clinical trial registration: EudraCT 2012-004579-37, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004579-37/CZ.