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.

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.

Research staff will be masked in reference to the Drug condition but not the Context condition. Participants will be briefed only on the Context condition they are randomized to, and masked in reference to Drug condition.