A Phase 2 interventional study of Psilocybin and Context 1 in Healthy Participants With Lower-than-average Mental Well-being, sponsored by Robin Carhart-Harris, PhD, MA. Recruiting at 1 site in United States. Open to participants aged 21 Years to 70 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-06-04.
Sponsored by Robin Carhart-Harris, PhD, MA · Phase 2, Interventional, and Basic science
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).
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.
Robin Carhart-Harris, PhD, MA is the lead sponsor of 2 studies on the registry; 1 is open to participants now.
Counted across the registry records on this site, refreshed daily.
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:
Exclusion Criteria:
Participants will be excluded if they:
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.
Drug: Psilocybin · Behavioral: Context 1
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.
Drug: Psilocybin · Behavioral: Context 2
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.
Behavioral: Context 1 · Drug: Placebo
Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.
Behavioral: Context 2 · Drug: Placebo
Healthy participants will receive up to 25 mg psilocybin.
Drug administration will take place in a context (Context 1) that is expected to modulate acute and post-acute drug effects.
Drug administration will take place in a context (Context 2) that is expected to modulate acute and post-acute drug effects.
Healthy participants will receive an inactive placebo.
Challenging Experience Questionnaire (CEQ) subscales score
The Challenging Experience Questionnaire is designed to measure challenging psychological experiences associated with the acute effects of psilocybin. For this study, the combined score across four our of its seven subscales will be used as a primary outcome: Fear, Insanity, Isolation, and Paranoia, excluding Grief, Physical Distress, and Death subscales. Scaled scores range from 0 to 100. Higher scores indicate higher levels of challenging experience (worse outcome).
Time frame: Eight hours post-dose.
Change in Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) score from Baseline to 28 days post-dose
The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) was developed to enable the monitoring of mental wellbeing in the general population and the evaluation of projects, programmes and policies which aim to improve mental wellbeing. Scores range form 14 to 70. Higher scores indicate higher levels of mental well-being (better outcome).
Time frame: Baseline to 28 days post-dose.
Change in Watts Connectedness Scale (WCS) scores from Baseline to 28 days post-dose
The WCS is a 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. Scores range from 0 to 100. Higher scores indicate higher levels of connectedness (better outcome).
Time frame: Baseline to 28 days post-dose.
Emotional Breakthrough Inventory (EBI) score
The Emotional Breakthrough Inventory was developed to assess emotional breakthrough, an important and distinct component of the acute psychedelic experience. Scores range from 0 to 100. Higher scores indicate higher levels of emotional breakthrough (better outcome).
Time frame: Eight hours post-dose.
Changes in resting state BOLD activity viafunctional magnetic resonance imaging (fMRI)
Assessment parameters include: Eyes-closed resting state fMRI
Time frame: Baseline to 28 days post-dose.
Changes in BOLD activity during emotional processing via functional magnetic resonance imaging (fMRI)
Assessment parameters include: BOLD response during an emotional processing task
Time frame: Baseline to 28 days post-dose.
Changes in white matter organization via magnetic resonance imaging (MRI)
Assessment parameters include: Diffusion Tensor Imaging (DTI)
Time frame: Baseline to 28 days post-dose.
Structural brain changes via magnetic resonance imaging (MRI)
Assessment parameters include: T1- and T2-weighted imaging
Time frame: Baseline to 28 days post-dose.
Acute Lempel Ziv Complexity (LZC) via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include: Lempel Ziv Complexity (LZC)
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Spectral power in traditional frequency bands via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include: Spectral power in traditional frequency bands
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Transfer entropy and integrated information via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include: Transfer entropy and integrated information
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Synergistic and redundant activity patterns via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Analytic approaches include: Partial information decomposition
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Travelling waves via Electroencephalography (EEG)
Electroencephalography is a method to record an electrogram of the spontaneous electrical activity of the brain. Assessment parameters include: Travelling waves
Time frame: Pre-dose; 2, 4, and 6 hours post-dose
Plan to share: No
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Robin Carhart-Harris, PhD, MA