The goal of this clinical trial is to test how well psilocybin-assisted therapy works in treating people with depression. The main questions this study aims to answer are:

• Does psilocybin with assisted therapy help improve symptoms for people with depression?
• How long do the effects of this treatment last?

Participants will:

• Take part in a couple of screening and preparation visits.
• Be given psilocybin in one or two treatment sessions.
• Attend a series of follow-up sessions over the following year.
• Complete forms and surveys to test how their symptoms have changed and what they thought of their experience.

Researchers will also compare whether one treatment or two treatments help improve symptoms more for participants.

Major depressive disorder (MDD) ranks fourth in global disease burden and has significant morbidity, mortality, societal and financial costs. However, few adequate and effective treatments exist with 60% of MDD patients not responding sufficiently to an initial oral antidepressant treatment. These patients who experience treatment resistant depression (TRD), defined as an intolerance or lack of response to two antidepressants of different classes, have limited treatment options beyond the antidepressant treatments that often yield insufficient results or relapse. Psilocybin, a novel treatment, has been found to relieve symptoms of TRD, but there are limited studies on specific dosing and long term treatment follow-up. In this study, the investigators will look closer at the effectiveness of one treatment with psilocybin versus two treatments with psilocybin, as well as the long term effectiveness over the first 12 months after treatment.

Inclusion Criteria:

• Provision of signed and dated informed consent form.
• Willingness to comply with all study procedures and availability for the study.
• Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-V) diagnosis of major depressive disorder.
• Currently experiencing a major depressive episode, lasting at least 3 months
• Failure to respond or inability to tolerate at least 2 guideline-concordant pharmacological treatments from different pharmacologic classes during the current major depressive episode
• Good health evidenced by medical history and routine lab tests
• No central nervous system (CNS) or neurocognitive impairment
• Ability to take oral medication and to follow to the psilocybin-assisted therapy protocol
• Identified support person to accompany patient home after dosing
• Use of effective contraception throughout the study by those with child-bearing potential
• Use of condoms or other effective contraceptive methods by males with reproductive potential
• Fully vaccinated and up to date on vaccination against COVID-19, as defined by Center for Disease Control guidelines
• Following Lifestyle Considerations throughout study (no nicotine containing products in clinical unit, refrain from operating heavy machinery for the duration of treatment day, no more than two servings 8 hours prior to treatment, no psychoactive drugs 72 hours before treatment, refrain from consuming foods that would interfere with drug absorption, minimize interaction with household immunocompromised contacts)

Exclusion Criteria:

• Family history (first- or second-degree relatives) or diagnosis of bipolar disorder with psychotic features, schizophrenia, schizoaffective disorder, hallucinogen-induced psychosis, anti-social personality disorder, or other psychotic disorder.
• Borderline personality disorder, defined by DSM-V criteria, that in the judgement of the Investigator is likely to complicate the assessment of clinical response to study treatments or limits the patient's ability to comply with study procedures.
• Alcohol or other substance use disorder (except tobacco/nicotine) that has been active within the 6 months prior to enrollment.
• Recent use (within past 4 weeks) of esketamine, ketamine or classic hallucinogens (psilocybin-containing mushrooms or LSD) or use of psychedelics within the past 6 months or more than 10 times in lifetime.
• Participants with active suicidal ideation or plan with a Columbia Suicide Severity Rating Scale (C-SSRS) score greater than or equal to 4.
• Current active self-injurious behavior, requiring medical attention or per investigator discretion.
• Diagnosis of Obsessive-compulsive disorder or post-traumatic stress disorder.
• Within 72 hours of psilocybin administration, use of nicotine, alcohol, or other controlled substances (use related to over-the-counter or prescribed medications may be allowed per the Primary Investigator's discretion).
• Current delirium, dementia, amnestic disorder, or other cognitive disorders.
• Any current or past medical or neurological illness (including chronic pain syndromes and/or history of cerebrovascular event (excluding migraine)) that, in the opinion of the investigator, may confound the interpretation of study assessments
• Known allergic reactions to components of psilocybin.
• Medically instability at screening, including hepatic, renal, circulatory, cardiac (arrhythmia, uncontrolled hypertension, systolic BP > 140 mmHg or diastolic BP > 90 mmHg, abnormal QTc), pulmonary or CNS (seizure disorder or treatment with antiepileptic drugs) impairment.
• Current pregnancy or lactation.
• Febrile illness in last 3 weeks.
• Current use or use within 4 weeks of psilocybin administration of Monoamine oxidase inhibitors (MAOIs), alcohol dehydrogenase inhibitors and antipsychotics (concomitant medications will be allowed per investigator discretion).
• Current treatment with buproprion greater than 300mg/day.
• Current use of tramadol.
• Prior participation in psilocybin-assisted therapy trial and or regular use of hallucinogens
• Treatment with another investigational drug or other intervention during study period.

Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

Data will be provided beginning 9 and continuing for 36 months following publication.

Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with UNC.

Due to the nature of the study and limitations of study staffing, only those conducting assessments and ratings throughout the study will be masked to the treatments. All others, including participants, therapists, investigators, and study coordinator, will not be masked to the number of treatments a participant receives.