The Role of the Subjective Experience in Supporting Positive Effects Following Psilocybin: a Randomized, Controlled Clinical Trial Using Risperidone in Healthy Adults

The purpose of this study is to determine the importance of the acute subjective experience induced by psilocybin (the primary component of "magic mushrooms") in facilitating positive outcomes. Participants in this study will be given psilocybin in combination with either a placebo or risperidone, an atypical antipsychotic that block the subjective effects of psilocybin. The overall goal of this clinical trial is to systematically explore the relationship between the subjective psychedelic experience, improvements in well-being, and the stress response following psilocybin administration. The investigators aim to determine whether blocking the acute subjective effects (via risperidone) will influence the acute or protracted effects of psilocybin as measured via self-report, biochemical, or psychophysiological measures. The study also aims to determine if individual variability in stress reactivity or regulation predicts acute (day of dosing) or protracted (1-week later) effects of psilocybin. A single site will recruit 128 participants aged 18 to 65 who do not meet criteria for any psychiatric diagnoses. A series of questionnaires, blood labs, and medical exams including electrocardiogram will determine inclusion into the study. Once accepted into the study, participants will complete baseline measures assessing biomarkers such as cortisol and brain-derived neurotrophic factor (BDNF) levels, cognitive flexibility, mood, well-being, personality traits, and anxiety levels. Participants will then be randomly assigned into one of the following groups: i) high dose psilocybin in combination with placebo pretreatment ii) high dose psilocybin in combination with risperidone pretreatment iii) low dose psilocybin in combination with placebo pretreatment iv) low dose psilocybin in combination with risperidone pretreatment Outcome measures will be assessed at 1-week and 1-month after each dosing session.