Study of Psilocybin Under Anesthesia Controlled by EEG

INCLUSION CRITERIA: A participant will be eligible for inclusion when all of the following criteria are met: 1. People 25 to 65 years of age at screening; 2. Able to read, understand, and provide dated, informed consent, either in writing or electronically, prior to screening. Patients will be deemed likely to comply with study protocol and communicate with study staff about adverse events and other clinically important information; 3. Fluent in English; 4. Able to commit to attend all study visits and participate in all remote data collection procedures; 5. Be stable in background psychotherapy for at least 4 weeks prior to enrollment outside of the study and able to access mental healthcare for the duration of the study; 6. Body mass index between 17-35 kg/m2. 7. Participant has a current diagnosis of MDD during a current Major Depressive Episode (MDE) (single or recurrent episode as defined by DSM-5-TR \[if single episode, duration of ≥4 weeks\] and verified after evaluation by a qualified member of the investigative team using the QuickSCID-5 (Quick Structured Clinical Interview for DSM-5 Disorders). 8. Able to physically tolerate general anesthesia, as determined by American Society of Anesthesiologists (ASA) Physical Status Class I or II. ASA Class III participants whose functional impairment is directly related to a psychiatric diagnosis (depression) will be included. 9. Agree that for one week preceding the psilocybin sessions and throughout the study, they will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the study staff. Exceptions will be evaluated by the study staff and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals. 10. Agree not to consume any food or drink after midnight preceding dosing days. 11. Agree not to consume alcoholic beverages for 48 hours prior to and 24 hours following the dosing sessions. 12. Agree not to use cannabis in any form for the duration of the study. 13. Non-smoker, or abstained at least 6 weeks. 14. For people who can become pregnant: agree to use highly effective contraception from entry into the trial through the end of the study. a. A person with a uterus is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterilized (i.e. has had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). b. A person with a uterus who is not of childbearing potential is considered to be postmenopausal after at least 12 months without menstruation. c. Highly effective contraception (typical use failure rate of less than 1%) is defined i. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation <!-- --> 1. oral 2. intravaginal 3. Transdermal 4. Double-barrier method ii. progestogen-only hormonal contraception associated with inhibition of ovulation: 1\. oral 2. injectable 3. implantable iii. intrauterine device (IUD) iv. intrauterine hormone-releasing system (IUS) v. bilateral tubal occlusion vi. vasectomized partner vii. sexual abstinence d. Periodic abstinence (i.e., calendar, symptothermal, or postovulation methods, and tubal ligation/occlusion) are not an acceptable form of contraception for this study. e. The PI will use his judgement and familiarity with the participant's preferred and usual lifestyle to understand if reporting of abstinence may be trusted to achieve 100% effectiveness. 15\. Negative urinary pregnancy test at screening and again immediately before dosing sessions. EXCLUSION CRITERIA: A potential participant will NOT be eligible for participation in this study if any of the following criteria are met: 1. Has any ongoing legal or disability claim such as Worker's Compensation 2. Is taking a medication belonging to any of the following classes: a. TCAs, MAOIs, SSRIs, SNRIs. (Other antidepressants including mirtazapine, nefazodone, trazodone, vilazodone, vortioxetine, and bupropion are allowed.) b. Typical or atypical antipsychotics c. Anticonvulsants such as valproate, topiramate, oxcarbazepine, carbamazepine. (Gabapentinoids and lamotrigine are allowed.) d. Other agents that may be associated with serotonin syndrome: i. St. John's Wort ii. S-adenosyl-methionine (SAM-e) iii. 5-Hydroxytryptophan (5-HTP) iv. Lithium v. Dextromethorphan vi. Linezolid vii. Buspirone viii. Efavirenz ix. Lorcaserin e. Agents that may interact with psilocybin metabolism/effects: i. Modulators of uridine diphosphate (UDP) or glucuronosyltransferase (UGT) (e.g., COMT inhibitors, ethinyl estradiol, valproate, diclofenac, mefenamic acid, verapamil, ketoconazole, itraconazole, probenecid, phenobarbital, protease inhibitors) ii. L-Methylfolate (\>/= 7.5mg/day) iii. Alcohol or aldehyde dehydrogenase inhibitors 3. Is taking benzodiazepine medication such that patient cannot tolerate withholding doses 8 hours before through 6 hours after planned study intervention 4. Is taking agents that may interact with psilocybin metabolism effects such that the patient cannot tolerate withholding doses 8 hours before through 6 hours after planned study intervention. 5. For individuals who can become pregnant: a. Currently pregnant (confirmed or suspected) b. Currently breastfeeding c. Positive urinary pregnancy test at screening or immediately before dosing d. Unwilling or unable to use highly effective contraception (defined as methods with failure rate \<1% per year) from the time of consent through 30 days following the last dosing session e. Planning to become pregnant within 30 days following the psilocybin or placebo administration sessions 6. Participation in a clinical trial within 30 days of entry into this trial, or during the trial, or treatment with another investigational drug or other intervention within 30 days or 5 half-lives, whichever is longer, that may interfere with psilocybin metabolism/effects. 7. Currently receiving electroconvulsive therapy (ECT). Previous treatment with ECT is permitted; last treatment must be at least 30 days prior to entry into this trial. 8. History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms, mania, or bipolar affective disorder 9. A positive urine toxicology screen including amphetamines, cocaine, MDMA, cannabis, opioids, ketamine, and benzodiazepines at screening visit and on the morning of the dosing session. 10. Use of psychedelics in the previous 6 months prior to screening (psilocybin, LSD, DMT, 5-Meo-DMT, MDMA, Ibogaine). 11. History of meeting DSM-5 criteria for Hallucinogen Use Disorder (Moderate or Severe) or Hallucinogen Persisting Perception Disorder (HPPD),or has ever had a negative reaction to or experience with a psychedelic (e.g., "bad trip"). 12. Current diagnosis of a Substance Use Disorder over the last 12 months (SUD; Abuse or Dependence, as defined by DSM-V) per QuickSCID-5. Participants who are at risk of alcohol or cannabis withdrawal will be excluded (e.g. those who endorse tolerance or who have experienced previous withdrawal). The following categories of SUD will NOT be excluded: nicotine dependence; alcohol or cannabis substance use disorder rated "mild". 13. Current diagnosis of a psychiatric disorder or mental health status that in the judgement of the study staff increases the risk of the intervention or would interfere with the patient's ability to engage in the intervention at any time within the six months prior to screening. 14. History of suicide attempt requiring hospitalization or suicidal ideation with intent in the last 10 years. 15. In the judgment of the study staff, the participant is at significant risk for suicidal behavior during the course of their participation in the study per Columbia Suicide Severity Rating Scale (C-SSRS), rated 'High Risk'. 16. A neurological disorder including: 1. Dementia, delirium, amnestic, or any other cognitive disorder. 2. Lifetime history of surgical procedures involving the brain or meninges, 3. Encephalitis, meningitis, degenerative central nervous system disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation 4. Any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system (CNS), 5. History of significant head trauma within the past two years. 17. A cardiovascular disorder including: a. Elevated blood pressure defined as systolic blood pressure (SBP) \>140 or diastolic blood pressure (DBP) \>90 averaged over two separate measurements taken during the screening period b. Tachycardia defined as heart rate (HR) \>90 beats per minute averaged over two separate measurements taken during the screening period c. Bradycardia defined as heart rate (HR) \<50 beats per minute averaged over two separate measurements taken during the screening period d. Angina e. Clinically significant EKG abnormality (e.g., atrial fibrillation, QTcF \>450 ms for males or \>470 ms for females) f. Any other significant current or history of a cardiovascular condition that would preclude safe participation in the study based on the clinical judgment of the investigators. 18. Clinically significant pulmonary/respiratory disorder including a. History of difficult airway or difficult mask ventilation, or predictors of difficult airway such as Mallampati Score 3 or 4, limited mouth opening, thyromental distance \<6cm, restricted neck mobility, or significant retrognathia. b. COPD requiring systemic steroid use. c. Obstructive Sleep Apnea, moderate or severe (Apnea-Hypopnea Index \>=15), or requiring regular CPAP use 19. Clinically significant liver disease, determined by Liver Function Tests (LFTs) within the past 6 months: Hepatic dysfunction as indicated by any of the following values: 1. AST \> 3 x upper limit of normal 2. ALT \> 3 x upper limit of. Normal 3. Total bilirubin \> 3.0 mg/dl 20. Known allergy or hypersensitivity to propofol or any of its components (unless they have a documented propofol exposure without complication), including: 1. Eggs or egg products 2. Soybeans, soy products, or soy lecithin 3. Peanuts or other legumes 4. History of anaphylaxis, angioedema, bronchospasm, or other serious allergic reaction to any of the above substances. 21. Known allergy or hypersensitivity to psilocybin or its metabolites. 22. History of severe lipid disorder or recent pancreatitis 23. Is taking a GLP-1 agonist class drug like tirzepatide, or has taken a dose within the past 7 days prior to propofol dosing. 24. Has symptomatic gastroesophageal reflux disease, or other delayed gastric emptying conditions. 25. Clinically significant kidney disease determined by creatinine/glomerular filtration rate within the past 6 months. Renal insufficiency (creatinine clearance \< 40 ml/min using Cockraft and Gault equation) 26. Any endocrine disorder or any thyroid disorder treated (medically or surgically) within the past 6 months prior to screening: 1. Uncontrolled diabetes, type 1 or 2 (well-controlled diabetes is allowed). 2. Hyperthyroidism or hypothyroidism diagnosed within the past six months prior to screening (stable treatment with a thyroid hormone replacement therapy is allowed). 27. Other medical condition(s) or diagnosis, physical exam finding, EKG or laboratory abnormality that precludes participation in study procedures due to safety concerns at the discretion of the study staff. \-