Effect of SSRIs on Response to Psilocybin Therapy

Inclusion Criteria: 1. Male or female, 19 to 65 years of age 2. Fluent in English 3. Currently receiving treatment with an SSRI (consistent dose for at least 6 weeks), with no changes anticipated throughout the duration of the study 4. QIDS-SR-16 score ≥6 5. Clinically diagnosed Major Depressive Disorder by a psychiatrist prior to screening 5a. Diagnosis defined as meeting the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria (American Psychiatric Association, 2013) for MDD 6. MADRS score 7-34 inclusive (mild-moderate) 7. Be medically stable as determined by screening for medical problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests 8. Concurrent psychotherapy is allowed if the type and frequency of the therapy has been stable for at least two months prior to screening and is expected to remain stable during participation in the study. 9. Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of the drug session day. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on session days. 10. Agree that for one week before the drug session, he/she will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement (specifically SAM-e, 5-HTP, L-tryptophan, St John's Wort) except when approved by the study Investigator. Exceptions will be evaluated by the Investigator and may include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals. 11. Agree to refrain from consuming alcohol within two days prior to drug administration. 12. Agree not to take any "as needed" medications on the morning of the drug session. 13. Agree to use of highly effective methods of contraception during the study (females) 14. Normal body mass index (BMI 18.5-24.9) 15. Own an Android or iOS device compatible with the fitness tracker software (Apple iOS 13 or higher, Android OS 7.0 or higher) 16. Able to have a friend or family member pick them up after the dosing session 17. Estimated glomerular filtration rate (eGFR) above 40 mL/min/1.73m2 and all other blood-work values Within Normal Limits Exclusion Criteria: 1. Current or past history of schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), bipolar disorder, delusional disorder, dissociative disorder, paranoid personality disorder, schizoaffective disorder, borderline personality disorder, anorexia nervosa, bulimia nervosa or substance abuse, as assessed by medical history 2. Currently diagnosed psychotic disorder in first-degree relatives, not including psychotic disorders secondary to an apparent medical reason, e.g. brain injury, dementia, or lesions of the brain, as assessed by medical history. 3. History of seizures 4. Uncontrolled diabetes, insulin-dependent diabetes, or history of hypoglycemia on oral hypoglycemic agent(s) 5. Paraneoplastic syndrome 6. History of traumatic brain injury within the last 2 years 7. Significantly intrusive PTSD as determined by the Investigator 8. Significant suicide risk as defined by C-SSRS within the past two years 9. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, vascular or any other major concurrent illness that, in the opinion of the Investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if he/she takes part in the study 10. Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e., QTc \> 450msec), artificial heart valve, or TIA in the past year 11. Psychoactive substance use within the previous two months. 11a. The following criteria are preferred: lifetime total psychoactive substance use less than 10 times. 12. Pregnant, nursing or breastfeeding women. Females of childbearing potential must be on a highly effective or double barrier method of contraception, or abstinent. 13. Participation in another clinical trial (currently or within the last 30 days) 14. Current use of rifamycins (rifampin, rifabutin, rifapentine), anticonvulsants (carbamazepine, phenytoin, phenobarbital), nevirapine, efavirenz, taxol, dexamethasone); cytochrome P450 Inhibitors - including all HIV protease inhibitors, verapamil, diltiazem, itraconazole, ketoconazole, erythromycin, clarithromycin, azithromycin, and troleandomycin; ergot alkaloids, pimozide, midazolam, triazolam, lovastatin, simvastatin, fentanyl, warfarin, metoprolol, propranolol, buspirone, tramadol, selegiline, sumatriptan. 15. Current use of inhibitors of UGT1A9 and 1A10, monoamine oxidase inhibitors (MAOIs), Tricyclic antidepressants, aldehyde dehydrogenase inhibitors (ALDHs) and alcohol dehydrogenase inhibitors (ADHs). 16. Use of steroids within the past two weeks. 17. Resting blood pressure \>140 mmHg systolic and \>90 mmHg diastolic at screening