Stress Experience Following Psilocybin (SEP-1)

This quadruple-blind, placebo-controlled trial (n=36) will investigate the role of stress response in shaping the positive effects of psilocybin (25mg or 1mg) by using metyrapone (750mg) to suppress cortisol production.

Conducted by the University of Calgary, this Phase II study will recruit healthy adults aged 22 to 65 with prior experience of altered states of consciousness. Participants will undergo four dosing sessions in random order, receiving either high-dose psilocybin (25mg) or low-dose psilocybin (1mg) in combination with metyrapone or a placebo. The study aims to determine whether suppressing the glucocorticoid stress response influences the acute or lasting effects of psilocybin, assessed through self-reports, physiological measures, and biomarkers such as cortisol, ACTH (adrenocorticotropic hormone), and BDNF (brain-derived neurotrophic factor).

Primary outcomes include changes in well-being, mood, and personality traits, measured one week after each session. Secondary outcomes will assess stress reactivity via heart rate variability, cognitive flexibility, and spontaneous thought processes. The study is expected to run from February 2025 to October 2027.

Trial Details

The overall goal of this double-blind, placebo-controlled clinical trial is to systematically explore the relationship between the stress response, improvements in well-being, and the subjective psychedelic experience following psilocybin administration. The investigators aim to determine whether blocking the glucocorticoid stress response (via metyrapone-mediated cortisol suppression) 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 36 participants aged 22 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 hormone levels (cortisol, adrenocorticotropin hormone (ACTH), and brain-derived neurotrophic factor (BDNF)), cognitive flexibility, mood, well-being, personality traits, and anxiety levels. Participants will then complete the following sessions in a randomized order: i) high dose psilocybin (25mg; "active dose") in combination with placebo treatment ii) high dose psilocybin (25mg; "active dose") in combination with metyrapone treatment (2X 750mg) iii) low dose psilocybin (1mg "active control") in combination with placebo treatment, iv) low dose psilocybin (1mg "active control") in combination with metyrapone treatment (2X 750mg) Outcome measures will be assessed at 1-week and 1-month after each dosing session.

Trial Number NCT06768944

Data attribution

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