Psilocybin Assisted Psychotherapy for Treatment Resistant Depression and Co-occurring Substance Use Disorder

The goal of this clinical trial is to learn if a single dose of psilocybin (5mg Vs 10mg Vs 25mg) alongside psychotherapy is safe and can help treat treatment resistant depression (TRD) with co-occurring substance use disorder (SUD). The participant sample will be enriched for veterans and first responders. Investigators seek to answer: * Whether 5mgs, 10mgs and 25mgs of psilocybin are safe in individuals with co-occurring TRD and SUD * Whether psilocybin assisted psychotherapy will reduce substance use severity and depression symptoms * What neurobiological processes are associated with the effects of psilocybin assisted psychotherapy. The researchers will compare the effects of a single dose of psilocybin (either 5mgs or 10mgs or 25mg) alongside psychotherapy on substance use severity and depression symptoms over six weeks in a sample of individuals with TRD and co-occurring SUD. In this 14-week study, participants will: * Visit the clinic for two intake sessions * Complete seven psychotherapy sessions. This will include three sessions before psilocybin administration, an 8 to 10 hour dosing session, and three sessions following psilocybin administration * Complete short, repeated daily assessments for six weeks, in total, before and after psilocybin administration * Complete two brain scans before and after psilocybin administration

Inclusion Criteria: * Men and Women 18 years or over (veterans and first responders encouraged) * Meets criteria for TRD (current major depressive episode without psychotic features by the Mini-International Neuropsychiatric Interview - MINI, with failure to respond to 2 or more evidence-based anti-depressants in the current episode) * Meets moderate to severe use criteria for one primary substance (alcohol, cocaine, opioids/heroin, or cannabis). Moderate to severe co-use of nicotine also acceptable, as well as mild/recreational use of other substances * Able to read English and complete study evaluations and consent * In good health as verified by screening examination and medical history * Able to safely receive MRI Exclusion Criteria: * Exclusionary psychiatric conditions include schizophrenia, schizoaffective disorder, bipolar disorder, current post-traumatic stress disorder, or history of medically serious suicide attempt * Actively/imminently suicidal (QIDS-SR question 12 score \>2, Hamilton Depression Scale (HAM-D) question 3 score \>3, or Montgomery-Åsberg Depression Rating Scale (MADRS) question 10 \>4) * A family history of schizophrenia or schizoaffective disorder (first- or second-degree relatives), or bipolar disorder type 1 (first degree relatives) * Use of selective serotonin reuptake inhibitors (SSRIs) and other medications are acceptable if dose has remained stable for 6 months and is not contra-indicated with psilocybin, as per the study physician * Any prior use of classic psychedelics, including psilocybin * Medical conditions that would preclude safe participation in the trial (e.g., seizure disorder, significantly impaired liver function, coronary artery disease, heart failure, history of cerebrovascular accident, severe asthma, hyperthyroidism, narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, or bladder-neck obstruction) * Sitting blood pressure below 90/50 mmHg or above 165/95 mmHg * EKG evidence of any clinically significant conduction abnormalities, including a Bazett's corrected QT interval (QTc) of \>450 msec for men and QTc \>470 msec for women * Women who are pregnant or lactating