Your Mind Matters More Than the Molecule

Self-transcendent and mystical experiences may be key mechanisms underlying psychedelics' therapeutic effects, yet how these experiences differ across substances remains unclear. This study compared mystical and self-transcendent experiences across psilocybin, 3,4-Methylenedioxymethamphetamine (MDMA), and cannabis in a diverse, community-based sample, while accounting for covariates. Additionally, we examined the relative contributions of pharmacological versus psychological factors in shaping self-transcendent and mystical experiences. Adults aged 18 years and older (N = 397) were recruited with general, non-psychedelic-targeted advertisements on a crowdsourcing platform, and randomized to report on their most intense use experience with either cannabis, psilocybin or MDMA in the past five years. Participants completed measures of self-transcendent and mystical experiences, emotions, and variables previously found to predict mystical experiences (e.g., personality traits, motivations for use, intentions/expectations for the experience). Hierarchical multiple linear regressions examined the effects of substance type (cannabis/psilocybin/MDMA) on outcomes, both alone and while adjusting for contextual (set/setting) variables. Most of the sample reported recreational reasons for use (83%) and concurrently used other substances (75%). Psilocybin and MDMA corresponded to greater self-transcendent and mystical experiences than cannabis, even after controlling for contextual factors. However, effect sizes were generally small (standardized regression coefficients β = 0.14 - 0.34, ps < 0.05) and attenuated when covariates were included (βs = 0.03 - 0.20). Effects on self-transcendent experiences characterized by 'self-loss' were weaker overall, and nonsignificant when covariates were added (ps > .33). Notably, mindset-particularly surrendering to the experience and having spiritual/prosocial motivations-emerged as the strongest predictors, with models including these variables accounting for up to 58% of variance (compared to ≤ 10% for substance alone). Findings indicate a "mindset-over-molecule" pattern wherein psychological context ("set") is more strongly associated with psychedelic outcomes than substance type alone.