Researchers will also compare whether one treatment or two treatments help improve symptoms more for participants. conditions: Refractory Depression conditions: Treatment Resistant Depression studyType: INTERVENTIONAL phases: PHASE3 allocation: RANDOMIZED interventionModel: PARALLEL interventionModelDescription: Participants are randomized into one of two groups and will receive either one single treatment of psilocybin-assisted therapy with follow-up therapy and assessments or two treatments spaced two weeks apart with follow-up therapy and assessments. primaryPurpose: TREATMENT masking: SINGLE maskingDescription: 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. whoMasked: OUTCOMES_ASSESSOR count: 20 type: ESTIMATED name: psilocybin measure: Change in HAM-D-17 Scores between Baseline and 2 Weeks after Treatment measure: Change in QIDS SR-16 Scores between Baseline and 2 Weeks after Treatment measure: Number of Participants Achieving Remission 2 Weeks after Treatment measure: Number of Participants Achieving Response 2 weeks after treatment measure: Number of Participants Achieving Remission at 6 Weeks measure: Number of Participants Achieving Response at 6 Weeks measure: Number of Participants Achieving Remission at 3 Months measure: Number of Participants Achieving Response at 3 Months measure: Number of Participants Achieving Remission at 6 Months measure: Number of Participants Achieving Response at 6 Months measure: Number of Participants Achieving Remission at 9 Months measure: Number of Participants Achieving Response at 9 Months measure: Number of Participants Achieving Remission at 12 Months measure: Number of Participants Achieving Response at 12 Months measure: Time to Relapse in Participants Who Showed Remission at 2 weeks measure: Time to Relapse in Participants Who Showed Response at 2 Weeks measure: Change in HAM-D-17 Scores between Baseline and 6 Weeks after Treatment measure: Change in HAM-D-17 Scores between Baseline and 3 Months after Treatment measure: Change in HAM-D-17 Scores between Baseline and 6 Months after Treatment measure: Change in HAM-D-17 Scores between Baseline and 9 Months after Treatment measure: Change in HAM-D-17 Scores between Baseline and 12 Months after Treatment measure: Change in QIDS SR-16 Scores between Baseline and 6 Weeks after Treatment measure: Change in QIDS SR-16 Scores between Baseline and 3 Months after Treatment measure: Change in QIDS SR-16 Scores between Baseline and 6 Months after Treatment measure: Change in QIDS SR-16 Scores between Baseline and 9 Months after Treatment measure: Change in QIDS SR-16 Scores between Baseline and 12 Months after Treatment sex: ALL minimumAge: 18 Years maximumAge: 70 Years stdAges: ADULT stdAges: OLDER_ADULT facility: UNC Chapel Hill Medical Center status: RECRUITING city: Chapel Hill state: North Carolina zip: 27514 country: United States name: Mary Pruden, BA role: CONTACT name: Robert K McClure, MD role: PRINCIPAL_INVESTIGATOR name: Amanda Tow, MD, PhD role: SUB_INVESTIGATOR name: Lindley Reynolds, MSW role: SUB_INVESTIGATOR lat: 35.9132 lon: -79.05584 hasResults: False