Stress Experience Following Psilocybin

The purpose of this study is to determine the importance in the acute stress response induced by psilocybin (the primary component of "magic mushrooms") in facilitating positive outcomes. Participants in this study will be given psilocybin in combination with a placebo or metyrapone, a cortisol synthesis inhibitor medication, on four different occasions.

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.

Eligibility Criteria:
Inclusion Criteria:

* Individuals of all sexes, gender identities, and ethnicities
* Ages 22 to 65 years of age at the time of screening
* Ability to read/write in English
* No serotonergic psychedelic use in the past 6 months (e.g. psilocybin, LSD, DMT, mescaline)
* Agree not to consume psychoactive drugs 24 hours before dosing sessions or consume psychedelics during duration of study participation
* At least one self-reported positive experience with a mind-altering substance (e.g., psychedelics or cannabis) or experience with altered states of consciousness
* No serious adverse events following previous psychedelic use

Exclusion Criteria:

* Any notable abnormality on electrocardiogram, physical examination, or routine medical blood or urinalysis laboratory tests
* Psychiatric diagnoses: major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder, moderate to severe substance use disorders, personality disorders, or schizophrenia or psychotic disorders
* Endocrine disorders or dysfunction
* Family history: a first- or second degree relative with a history of schizophrenia or other psychotic disorders, bipolar I or II
* Medications: tricyclic antidepressants, lithium, SSRIs, MAOIs, haloperidol, benzodiazepines
* Currently pregnancy or nursing, trying to become pregnant, or unwilling to use acceptable method of contraception during the study
* Any sensitivity or adverse reaction to previous use of a hallucinogen
* Suffered a mild traumatic brain injury (TBI) within the last 6 months, or a moderate/severe TBI at least once in lifetime
* Any other circumstances that, in the opinion of the investigators, compromises participant safety