This study is testing a single oral dose of an investigational drug, psilocybin, for the treatment of MDD. We will evaluate the effectiveness and safety of the treatment when compared to a placebo treatment to determine if psilocybin helps end participants’ current depressive episodes, and potentially prevent or lessen future major depressive episodes.

You may qualify for this study if you meet the following criteria.

Inclusion Criteria:

• Experiencing moderate to severe depression symptoms
• Willing to discontinue any current medications used for depression (e.g. antidepressants)
• If in therapy for depression, have been at a stable frequency and duration for at least 3 months
• Willing to use effective means of birth control for duration of study

Exclusion Criteria:

• Active PTSD or substance use disorder
• Have been diagnosed (or have a first-degree relative) with schizophrenia spectrum or other psychotic disorders; or bipolar disorder (types 1 or 2)
• Pregnant, breastfeeding, or planning to become pregnant
• Cardiovascular conditions or elevated blood pressure
• Neurological conditions such as stroke, including transient ischemic attack, epilepsy, neurodegenerative disease (e.g., dementia, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, etc.), or brain tumor
• Severe hepatic or renal impairment
• Hepatitis or HIV
• Have used a psychedelic substance
• Ketamine or esketamine use in the last 30 days

The entire study lasts 64 weeks. Once enrolled, the study involves:

Screening Period

This period includes two in-person visits: a Screening visit and a Baseline visit. The visits involve:

• Informed Consent Form
• Assessments to determine eligibility for the study
• Review current medications and start to taper off any medications not suitable for the study
• Have demographic and medical information collected, a physical and mental status exam, undergo laboratory tests—including blood test, urinalysis, drug test, and a pregnancy test, if applicable—and an ECG (Screening only).

Study Treatment Period (6 Weeks)

• Preparation: Meet with your assigned study facilitators to discuss your current symptoms and life circumstances, as well as your expectations and intentions for the dosing session. These preparation sessions last for around 6 hours total, which can be split up over multiple visits, only one of which must occur in-person.
• Attend the full-day in-person dosing session, in which you are randomly assigned one of the three study drugs.
• Follow-up visits in which you meet with your study facilitators to discuss your dosing experience, which occur one day after dosing (must be in-person), one week after dosing, and two weeks after dosing.
• Two more in-person follow-up visits, at four weeks and six weeks post-dose, in which you undergo medical tests and complete psychiatric assessments.

Long Term Follow Up Period (1 Year)

• Remote telephone check-ins every two weeks
• Remote Psychosocial Support Group Sessions (2/month for first 3 months, then 1/month for months 4-12)
• In-clinic visits every 3 months and a final in-clinic visit to complete the Follow-up Period
• If you meet eligibility criteria, you may receive psilocybin (25 mg) up to four times during the Follow-up Period. Re-administration visits will follow the same schedule as the Study Treatment Period.

You will be paid $49.00 per visit except on prep and dosing visits (4 in total) which you will then be paid $98.00 for those visits. You will also be paid $15.00 for each phone call and $30.00 for each psychosocial call. You will be paid after each visit. If you do not complete the study, you will be paid for each study visit you complete.

Other reasonable expenses (e.g., travel) may be reimbursed (paid back to you), after receipts for the payments are provided, and in agreement with the Study Doctor or study staff.

There is no cost for you to participate in our research study.