Subjective Experience Following Psilocybin (SEP-1)

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.

Study Overview

• Status: Recruiting
• Conditions: Investigating the Importance of the Subjective Psychedelic Experience
• Intervention / Treatment: Drug: Placebo; Drug: Risperidone 1 MG; Drug: Psilocybin high-dose; Drug: Psilocybin low-dose

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 128
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ana Deutsch, MSc; Phone Number: 587-893-0257; Email: ana.deutsch@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Recruiting
      • University of Calgary
      • Principal Investigator: Leah Mayo, PhD
      • Contact: Ana Deutsch, MSc; Phone Number: 587-893-0257; Email: pactlab@ucalgary.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Individuals of all sexes, gender identities, and ethnicities
• Ages 18 to 65 years of age at the time of screening
• Ability to read/write in English
• Agree not to consume psychoactive drugs 24 hours before dosing sessions or consume psychedelics during duration of study participation

Exclusion Criteria:

• Any notable abnormality on electrocardiogram or routine medical blood or urinalysis laboratory tests
• Current psychiatric diagnoses, such as: major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, moderate to severe substance use disorders, eating disorders, personality disorders, post-traumatic stress disorder
• Lifetime or current psychiatric diagnoses of: psychosis, schizophrenia, bipolar disorder
• Family history: a first- or second degree relative with a history of schizophrenia or other psychotic disorders, bipolar I or II
• Medication: Any medication with the potential to interact with the investigational medicinal products, especially those with serotonergic mechanisms of actions like SSRIs, SNRIs or MAO-Inhibitors as well as other antipsychotics
• Currently pregnancy or nursing, trying to become pregnant, or unwilling to use acceptable method of contraception during the study
• Current or recent (within 12 weeks) participation in a clinical trial involving medication administration
• Cognitive impairment (Folsetin Mini Mental State Exam score < 24)
• A disorder that may interfere with drug absorption, distribution, metabolism, or excretion (including gastrointestinal surgery).
• Suffered a traumatic brain injury with one of the following symptoms Loss of consciousness >30min Alteration of consciousness/mental state >24h Post-traumatic amnesia >1 day Glasgow Coma Scale (best available score in first 24 hours) <13
• Any other circumstances that, in the opinion of the investigators, compromises participant safety

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High-dose psilocybin + placebo; placebo + psilocybin (+60 min)	Drug: Placebo; inactive placebo; Drug: Psilocybin high-dose; The drug product (DP) PEX010 is a capsule for oral administration and is manufactured with DS PYEX (12.5-14.0% psilocybin), excipients, and HPMC capsules. The product is manufactured in two product strengths, and this represents the high-dose; Other Names: PEX010; high-dose psilocybin
Active Comparator: Low-dose psilocybin + placebo; placebo + psilocybin (+60 min)	Drug: Placebo; inactive placebo; Drug: Psilocybin low-dose; The drug product (DP) PEX010 is a capsule for oral administration and is manufactured with DS PYEX (12.5-14.0% psilocybin), excipients, and HPMC capsules. The product is manufactured in two product strengths, and this represents the low-dose.; Other Names: PEX010; low-dose psilocybin
Experimental: High-dose psilocybin + risperidone; risperidone + psilocybin (+60 min)	Drug: Risperidone 1 MG; risperidone 1mg capsules; Other Names: Risperdal; Drug: Psilocybin high-dose; The drug product (DP) PEX010 is a capsule for oral administration and is manufactured with DS PYEX (12.5-14.0% psilocybin), excipients, and HPMC capsules. The product is manufactured in two product strengths, and this represents the high-dose; Other Names: PEX010; high-dose psilocybin
Active Comparator: Low-dose psilocybin + risperidone; risperidone + psilocybin (+60 min)	Drug: Risperidone 1 MG; risperidone 1mg capsules; Other Names: Risperdal; Drug: Psilocybin low-dose; The drug product (DP) PEX010 is a capsule for oral administration and is manufactured with DS PYEX (12.5-14.0% psilocybin), excipients, and HPMC capsules. The product is manufactured in two product strengths, and this represents the low-dose.; Other Names: PEX010; low-dose psilocybin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive effects	Persisting Effects Questionnaire (PEQ) - 145 questions rated using a 6-point Likert scale from 0 to 6. There are 12 sub-scale themes assessing positive and negative changes in Attitudes About Life, Attitudes About Self, Mood Changes, Social Effects, Behavioural Changes, and Spirituality. Higher scores in the positive sub-scales indicate a better outcome, while higher scores in the negative sub-scales indicate a worse outcome.	One week and one month post-dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stress reactivity	Stress reactivity will be assessed through heart rate variability	From start of dosing session to end of dosing session
Biomarkers of stress and plasticity	cortisol, ACTH, BDNF	from baseline to dosing session (one week post-baseline) to follow-up 1 (one week post doing session) to follow-up 2 (one month post dosing session)
Mood	Mood will be assessed using the Positive and Negative Affect Schedule. The questionnaire has two sub-scales: the positive affect score (scores range from 10-50, higher scores represent better outcome) and the negative affect score (scores range from 10-50, higher scores represent worse outcome)	from baseline to one week and one month post-dosing
Well-being	Well-being will be assessed using the Warwick-Edinburgh Mental Wellbeing Scale. The total score ranges from 14-70; a higher score represents a better outcome.	from baseline to one week and one month post-dosing
Anxiety	Anxiety will be measured using the State-Trait Anxiety Inventory. The total score ranges from 20-80; a higher score represents a worse outcome.	from baseline to one week and one month post-dosing
Cognitive Flexibility	The Berg Card Sorting Task is a set-shifting measure of cognitive flexibility modeled after the Wisconsin Card Sorting task. Participants must select the stimulus that is different from others based on feedback and adapt their responses once the criteria for correct choice switches. Perseverative errors are defined as the number of instances in which three incorrect responses are made based on a previous rule, and they are thought to reflect less cognitive flexibility (or cognitive rigidity).	from baseline to one week and one month post-dosing
Spontaneous Thought	To measure spontaneous thought, participants will complete a Think Aloud task where they narrate their stream of thought in real time.	from baseline to one week and one month post-dosing
Reinforcement Learning	Reinforcement learning will be assessed using a three-armed bandit task. This is a decision-making task in which participants must choose between three alternative targets whose values (probability of reward) changes over the trials.	from baseline to one week and one month post-dosing

Collaborators and Investigators

• Sponsor: University of Calgary
• Investigators: Principal Investigator: Leah Mayo, PhD, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: December 16, 2024
• First Submitted That Met QC Criteria: January 6, 2025
• First Posted (Actual): January 10, 2025

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: risperidone; stress response; cortisol; psilocybin; psychedelics; subjective effects; healthy participants
• Additional Relevant MeSH Terms: Wounds and Injuries; Fractures, Bone; Fractures, Stress; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Pyrimidines; Pyrimidinones; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin; Risperidone
• Other Study ID Numbers: REB24-1121

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No