Clinical trial NCT06626139: Investigating the Interaction of Psilocybin and Context of Its Administration in Healthy Volunteers
Official title: 2 x 2 Factorial, Double-blind, Randomized Trial of 'Set and Setting': a Translational Study in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Healthy Participants With Lower-than-average Mental Well-being
Keywords: well-being
psilocybin
psychedelic
neuroimaging
healthy volunteers
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2024-10-03
Enrollment: 120
Sex: ALL
Minimum age (years): 21
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: 2 x 2 Factorial Design Factor 1: Drug (Psilocybin vs Placebo) Factor 2: Context (Context 1 vs Context 2)
Primary purpose: BASIC_SCIENCE

Brief summary: One hundred twenty healthy participants, ages 21 to 70, who experience moderate-to-lower-than-average mental well-being will be evenly randomized into four different study arms, using a 2x2 factorial design. Depending on the study arm, participants will either receive an inactive placebo or up to 25mg psilocybin (oral dose), in one of two set and setting conditions; drug administration contexts that are predicted to modulate drug effects.

The purpose of this study is to evaluate any interaction effects between an oral dose of psilocybin and the surrounding context (set and setting).

Detailed description: Recent research posits that psychedelic medicine is best employed as a combination treatment, i.e., as drug x psychological support or psychotherapy referred to for simplicity as 'psychedelic therapy'. It is assumed that positive outcomes via psychedelic therapy critically depend on a synergistic relationship between drug-induced brain and mind plasticity and supportive contextual factors (Carhart-Harris et al., 2018; Carhart-Harris and Friston, 2019). These contextual factors have been referred to as 'set and setting' (Leary et al., 1963) or 'extrapharmacological'- highlighting elements beyond the drug that contribute to relevant outcomes (Hartogsohn, 2016).

The proposed experiment is a double-blind, randomized between-subjects 2 x 2 factorial study in 120 volunteers who experience low psychological well-being at baseline and have limited prior experience with psychedelics (1:1:1:1, n = 30 per condition). The main aim of the study is to assess the contribution of a select number of pre-defined contextual variables (both 'set' and 'setting') on the nature and trajectory of effects linked to a single dosing session with either psilocybin (oral, 25mg) or placebo (oral, inert).

The study will have four primary outcomes, two pertaining to mental health, namely: changes in psychological well-being - as measured via the Warwick-Edinburgh Mental Wellbeing Scales (WEMWBS), from baseline to 4 weeks post dosing session (primary endpoint) and changes in the Watts Connectedness Scale (WCS) at consistent timepoints. The two primary outcomes indexing the quality of the acute experience will be: Emotional Breakthrough - measured via mean scores on the Emotional Breakthrough Inventory (EBI), and Challenging experience (CE) - defined and measured here as scores on the following four sub-factors of the Challenging Experience Questionnaire (CEQ): fear, insanity, isolation, and paranoia.

Eligibility criteria: If you are interested in participating in this study, please follow this link to check your eligibility: https://tiny.ucsf.edu/setsettingscreener

Inclusion Criteria:

Participants will be considered for inclusion if they:

1. Are between 21 and 70 years of age
2. Are fluent in speaking and reading English
3. Are able to swallow pills/capsules
4. If able to become pregnant, must be non-lactating, have a negative pregnancy test at study entry and prior to each Experimental Session and must agree to an adequate form of birth control over the course of the study. Adequate forms of birth control include intrauterine device (IUD), injected, implanted, intravaginal, or transdermal hormonal methods, abstinence, oral hormones plus a barrier contraception, vasectomized sole partner, or double barrier contraception. Two forms of contraception are required with any barrier method or oral hormones (i.e., condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal contraceptives plus spermicide or condom). Unable to become pregnant is defined as documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, and/or tubal ligation), permanently sterile by medical device such as Essure, postmenopausal, or assigned male sex at birth.
5. Able and willing to provide informed consent
6. Able and willing to use computers and tablets or phones to enter electronic data
7. Agree to inform the investigators within 48 hours of any new or changed medical conditions.
8. Have an identified support person
9. For those dosed with psilocybin, their prior consent to be accompanied home (or to an otherwise safe destination) by a support person, chosen by them - ahead of time, or by a member of the study team.
10. Willing to provide contact details for a friend or family member, should there be an inability to make direct contact with the participant

Exclusion Criteria:

Participants will be excluded if they:

1. Have a current diagnosed psychiatric disorder that, in the opinion of the study clinician or PI, renders to person psychologically unstable or unduly vulnerable, or interferes with activities of daily living, or could impact attendance at or participation in study activities
2. Have a medically significant condition that renders the person unsuitable for the study
3. Give a positive alcohol breathalyzer test result on any study visit
4. A positive urine drug screen to any excluded substances prior to an Experimental Session, which warrants exclusion based on concerns that it may compromise safety or confound outcomes
5. Are breastfeeding, or have a positive pregnancy test at screening or at any point during the course of the study
6. Systolic and diastolic BP values exceeding 139 SBP and exceeding 89 DBP and heart rate exceeding 90 bpm would result in exclusion from the study.
7. Present with a exceeding 450 msec or with evidence of cardiac damage, ischemia, or heart disease.
8. Have received an investigational drug within 30 days of the screening visit
9. Have an allergy or intolerance to any of the materials contained in either drug product or setting components, such as certain scents.
10. Have MRI contraindications (e.g., metal implants, pacemakers, claustrophobia etc.)
11. Have any current problem which, in the opinion of the investigator or clinician, might interfere with participation.

Primary outcomes:
measure: Challenging Experience Questionnaire (CEQ) subscales score
timeFrame: Eight hours post-dose.
measure: Change in Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) score from Baseline to 28 days post-dose
timeFrame: Baseline to 28 days post-dose.
measure: Change in Watts Connectedness Scale (WCS) scores from Baseline to 28 days post-dose
timeFrame: Baseline to 28 days post-dose.
measure: Emotional Breakthrough Inventory (EBI) score
timeFrame: Eight hours post-dose.
Secondary outcomes:
measure: Changes in resting state BOLD activity viafunctional magnetic resonance imaging (fMRI)
timeFrame: Baseline to 28 days post-dose.
measure: Changes in BOLD activity during emotional processing via functional magnetic resonance imaging (fMRI)
timeFrame: Baseline to 28 days post-dose.
measure: Changes in white matter organization via magnetic resonance imaging (MRI)
timeFrame: Baseline to 28 days post-dose.
measure: Structural brain changes via magnetic resonance imaging (MRI)
timeFrame: Baseline to 28 days post-dose.
measure: Acute Lempel Ziv Complexity (LZC) via Electroencephalography (EEG)
timeFrame: Pre-dose; 2, 4, and 6 hours post-dose
measure: Spectral power in traditional frequency bands via Electroencephalography (EEG)
timeFrame: Pre-dose; 2, 4, and 6 hours post-dose
measure: Transfer entropy and integrated information via Electroencephalography (EEG)
timeFrame: Pre-dose; 2, 4, and 6 hours post-dose
measure: Synergistic and redundant activity patterns via Electroencephalography (EEG)
timeFrame: Pre-dose; 2, 4, and 6 hours post-dose
measure: Travelling waves via Electroencephalography (EEG)
timeFrame: Pre-dose; 2, 4, and 6 hours post-dose
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Mission Bay
state: California
Study officials:
affiliation: University of California, San Francisco
name: Robin Carhart-Harris, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Jennifer Mitchell, PhD
role: PRINCIPAL_INVESTIGATOR
References: