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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.

Target Enrollment
36 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

The study tests whether blocking the glucocorticoid stress response with metyrapone alters the acute and protracted effects of psilocybin in healthy participants.

Thirty-six psychiatrically healthy adults (22–65) will complete four randomized crossover dosing sessions: 25 mg psilocybin ± metyrapone and 1 mg psilocybin ± metyrapone; outcomes include self-report, biochemical (cortisol, ACTH, BDNF), and psychophysiological measures at acute and 1-week/1-month follow-ups.

Psilocybin is administered as oral PEX010 capsules; metyrapone is given as two 750 mg oral doses to achieve cortisol suppression.

Study Protocol

Preparation

sessions

Dosing

4 sessions

Integration

sessions

Study Arms & Interventions

High-dose + placebo

active comparator

25 mg psilocybin with oral placebo (crossover condition).

Interventions

  • Psilocybin25 mg
    via Oral• single dose

    PEX010 capsule (high-dose).

  • Placebo
    via Oral• single dose

    Oral inactive placebo.

Low-dose + placebo

inactive

1 mg psilocybin (active control) with oral placebo.

Interventions

  • Psilocybin1 mg
    via Oral• single dose

    PEX010 capsule (low-dose).

  • Placebo
    via Oral• single dose

    Oral inactive placebo.

High-dose + metyrapone

experimental

25 mg psilocybin with metyrapone (cortisol suppression).

Interventions

  • Psilocybin25 mg
    via Oral• single dose

    PEX010 capsule (high-dose).

  • Compound750 mg
    via Oral• two doses (pre and +180 min)• 2 doses total

    Metyrapone 750 mg administered in 2 doses (not a listed compound reference).

Low-dose + metyrapone

active comparator

1 mg psilocybin with metyrapone (cortisol suppression).

Interventions

  • Psilocybin1 mg
    via Oral• single dose

    PEX010 capsule (low-dose).

  • Compound750 mg
    via Oral• two doses (pre and +180 min)• 2 doses total

    Metyrapone 750 mg administered in 2 doses (not a listed compound reference).

Participants

Ages
22 – 65
Sexes
Male & Female

Inclusion 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

  • 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

Study Details

Locations

University of Calgary — Calgary, Alberta, Canada

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