Intentions, Spirituality, Set, and Setting Are Associated with Mystical Experiences in Psilocybin-Assisted Therapy

Objective: Emerging evidence suggests that mystical experiences mediate the therapeutic effects of psychedelic-assisted therapy. The current study examines associations between mystical experiences and components of “set” (positive mindset, participant intentions, and spirituality) and “setting” (perceived positivity of the dosing environment) in the context of psilocybin-assisted therapy for alcohol use disorder (AUD). Methods: Twenty adults with moderate-to-severe AUD participated in a 10-week psilocybin-assisted therapy protocol including two open-label 25 mg psilocybin sessions (Session 1 at week 3; Session 2 at week 7) and weekly counseling. Mystical experiences were assessed via the Mystical Experience Questionnaire (MEQ). Precursor variables—participant spirituality, spiritual intentions, clarity of intentions, mindset, and perceptions of the treatment setting—were measured using validated self-report scales. Spearman correlations were used to evaluate associations between precursor variables and MEQ scores and between spirituality and spiritual intentions. Changes across sessions were examined using Wilcoxon signed-rank tests. Results: Intensity of mystical experiences was significantly associated with spirituality (Session 1: r s = 0.76, p < 0.0001), spiritual intentions (Session 1: r s = 0.71, p < 0.001; Session 2: r s = 0.66, p < 0.001), positive mindset (Session 2: r s = 0.52, p = 0.024), and positive perceptions of setting (Session 2: r s = 0.46, p = 0.046). Spirituality was significantly correlated with spiritual intentions at both sessions (Session 1: r s = 0.77, p < 0.0001; Session 2: r s = 0.63, p < 0.005). Mystical experience intensity significantly increased from Session 1 to Session 2 (Wilcoxon S = 48.5, p = 0.033), while no significant changes were observed in precursor variables across sessions (Wilcoxon S = [−8, 33], p = [0.192, 0.953]). Change in MEQ scores was not significantly associated with changes in any of the precursor variables across sessions (r s = [−0.28, 0.18], p = [0.268, 0.804]). Conclusion: Findings suggest that multiple aspects of set and setting—particularly, spiritual intentions, spirituality, mindset, and perceptions of the treatment setting—may be important predictors of mystical experience intensity during psychedelic-assisted therapy. While spirituality was more strongly associated with mystical experiences during the initial dosing session, mindset and setting became more strongly associated in the subsequent session. Future research should evaluate strategies for optimizing environmental and psychological factors—including structured intention-setting exercises—to enhance therapeutic outcomes.