The Effect of Psilocybin on MDD Symptom Severity and Synaptic Density

Inclusion Criteria: Individuals eligible to be randomized in this protocol are those who meet all of thefollowing criteria:

1. Are 20 to 65 years old at the time of written informed consent at the In-PersonScreening visit
2. Are able to read, speak, and understand Swedish
3. Are able and willing to adhere to study requirements, including attending all studyvisits, preparatory and follow-up sessions, and completing all study evaluations
4. Are able to swallow capsules
5. Women of childbearing potential (WOCBP) must agree to practice an effective means ofbirth control throughout the duration of the study, from Screening through the Day 42assessment
6. Meet ICD-10 criteria for a diagnosis of remitting major depressive disorder and arecurrently experiencing a major depressive episode of
7. at least a 30-day duration at the time of the Screening
8. less than 5 years at time of Screening
9. Have sustained moderate-severe depression symptoms at Screening and Baseline, asdefined by a Screening MADRS total score ≥ 22 and ≤30% and ≤7 point improvement (i.e.decrease) in MADRS total score from web-screening to screening visit (assuming 3points on item 1 at web screening).
10. Have an identified support person a. Agree to be driven/accompanied home (or to an otherwise safe destination) by the supportperson, or another responsible party, following dosing

Exclusion Criteria: Individuals not eligible to be randomized in this protocol are those who meet any of thefollowing criteria:

1. Women who are pregnant, as indicated by a positive urine pregnancy test at Screeningor Baseline. Women who intend to become pregnant during the study or who are currentlynursing.
2. Current depressive episode lasting >5 years
3. Unwilling or unable to discontinue formal psychotherapy 3. Ongoing antidepressant drugtreatment 4. Have previously during the current episode received the followingnon-medication treatments: a. deep brain stimulation (DBS) b. vagus nerve stimulation (VNS) 5. Currently receivingelectroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) 6. Unable orunwilling to discontinue any current medications that are known uridine diphosphate (UDP)or glucuronosyltransferase (UGT) enzyme modulators (eg valproate)

• Note: Any prohibited agents must have been stopped at least 5x the eliminationhalf-life of the specific drug at the time of Baseline. See Appendix A for a full listof prohibited medications.

7. Report psychedelic substances use ever

• Note: Psychedelic substances include psilocybin, Lysergic acid diethylamide (LSD),mescaline (and natural products containing mescaline including peyote and San Pedrocactus), N,N-Dimethyltryptamine (DMT), natural products containing DMT includingayahuasca and 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine, 2C compounds, 3,4-methylenedioxy- methamphetamine (MDMA), methylone or other psychedelics.

8. Have the following cardiovascular conditions: a. coronary artery disease, congenital long QT syndrome (prior diagnosis), cardiachypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction (priordiagnosis); b. tachycardia (defined as heart rate > 100 beats per minute); c. aclinically significant Screening ECG abnormality (e.g., atrial fibrillation); oNote: AQTcF interval > 450 milliseconds is considered a clinically significant ECGabnormality d. artificial heart valve; or e. any other significant current or historyof cardiovascular condition, based on the clinical judgment of study physician, thatwould make a participant unsuitable for the study 9. At Screening or Baseline haveelevated blood pressure as defined as: a. Screening blood pressure SBP >135 mmHg or DBP > 85 mmHg on three separate readings;or b. Baseline blood pressure SBP >140 mmHg or DBP > 90 mmHg on three separatereadings 10. Have a history of stroke or Transient Ischemic Attack (TIA) 11. Havemoderate to severe hepatic impairment, as indexed by a Child-Pugh score ≥ 7 12. Haveepilepsy 13. Have insulin-dependent diabetes

• Note: Participants who are taking oral hypoglycemic agent and have a history ofhypoglycemia requiring medical intervention will be excluded 14. Are unable orunwilling to adhere to the following medication requirements:

1. Agree to suspend sildenafil (Viagra®), tadalafil, or similar medications at least 72 hours prior to dosing
2. If taking any supplement containing >20 mg of niacin, agrees to suspend use forthe duration of the study 15. Have a positive urine drug test includingAmphetamines, Barbiturates, Buprenorphine, Benzodiazepines, Cocaine, Cannabis,Methamphetamine, MDMA, Methadone, Opiates (Morphine, Oxycodone), Phencyclidine (PCP), and Tetrahydrocannabinol (THC). Exceptions are made for prescribedBenzodiazepines (stable dose for sleep or anxiety).

• Note: Benzodiazepine medications for sleep and non-benzodiazepine sleeping medicationswill be allowed to continue through the study period for participants who have been ona stable dose of such a medicine for at least 6 weeks prior to Screening, asdetermined during review of concomitant medications
• Note: Participants using cannabis, including legal cannabis, for any purposes will beexcluded
• Note: Participants who are taking prescription maintenance methadone or buprenorphinenaloxone will be excluded
• Note: Prescription opiates must have been stopped at least 5x the elimination half-life of the specific drug at the time of inclusion, as confirmed with a negative urinedrug screen.

16. Nicotine dependence that would disallow an individual to be nicotine free for the 7-10 hours during the dosing period 17. Meet ICD-10 criteria for schizophreniaspectrum or other psychotic disorders, including MDD with psychotic features (exceptsubstance/medication-induced or due to another medical condition), or Bipolar IDisorder, Bipolar II Disorder and bipolar disorder NOS.

• Note: Participants with any lifetime diagnosis of schizophrenia spectrum or otherpsychotic disorders will be excluded 18. Meet ICD-10 criteria for antisocialpersonality disorder 19. Meet ICD-10 criteria for a moderate or severe alcohol or druguse disorder (excluding caffeine)
• Note: Participants with a diagnosis of alcohol or drug use disorder within the past 12months will be excluded 20. Have presence of any psychiatric condition or symptomjudged by the PI (or designee) to be a more significant clinical problem than MDD forthe participant.

21. Have a first-degree relative with schizophrenia spectrum or other psychoticdisorders (except substance/medication-induced or due to another medical condition),or Bipolar I Disorder 22. Have a psychiatric condition judged to be incompatible withestablishment of rapport with the Facilitators or safe exposure to psilocybin 23.Report the following suicidal ideation or suicidal thoughts defined as: a. Have a score of ≥ 5 on Item 10 (suicidal thoughts) of the central-rater or computeradministered MADRS at Screening or Baseline; or b. Have any suicidal ideation orthoughts, in the opinion of the study physician or PI, that presents a serious risk ofsuicidal or self-injurious behavior at any time prior to randomization 24. Have anysuicidal ideation or thoughts, in the opinion of the study physician or PI, thatpresents a serious risk of suicidal or self-injurious behavior 25. Have any physicalor psychological symptom, medication or other relevant finding at Screening orBaseline, based on the clinical judgment of clinical/medical study personnel, thatwould make a participant unsuitable for the study.
22. Have an allergy or intolerance to any of the materials contained in either drugproduct 27. Have Hepatitis B, C or HIV 28. Have one or more pathological blood testresults as defined in 5.6.3 (as determined by a study physician; with the exception ofCRP).
23. Have peptic ulcer (ICD 10 K25 or K26)