Treatment With Psilocybin for Chronic Neuropathic Pain and Depression (TRANSCEND)

Inclusion Criteria:

1. Adults 18 to 65 years old;

2. Are outpatients;

3. Must be deemed to have capacity to provide informed consent;

4. Must sign and date the informed consent form;

5. Stated willingness to comply with all study procedures;

6. Ability to read and communicate in English, such that their literacy andcomprehension is sufficient for understanding the consent form and studyquestionnaires, as evaluated by study staff obtaining consent;

7. Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on theStructured Clinical Interview for DSM-5 (SCID-5) administered at the first screeningvisit;

8. Participants diagnosed with treatment-resistant depression defined as individualswith a baseline HamD-17 score > 14 and that have not responded to two or moreseparate trials of antidepressants at an adequate dosage and duration (anantidepressant resistance rating score of three or more is considered an adequatetrial) based on the Antidepressant Treatment History Form (ATHF) (Sackeim & Sackeim, 2001); there is no upper limit on the number of treatment failures;

9. Diagnosis of chronic neuropathic pain as determined by a pain specialist andconfirmed with the standardized Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaire25

10. Moderate-to-severe neuropathic pain determined by Patient Reported OutcomesMeasurement Information System (PROMIS) Pain Interference score of > 6026, as wellas mean pain intensity scores > 5 on a numeric rating scale27

11. Previous trials of at least two medications recommended in the Canadian consensusguidelines on the management of neuropathic pain with no self-reported meaningfulimprovement in symptoms

12. Ability to take oral medication;

13. Individuals with an eGFR above 40mL/min/1.73m2 and all blood work on clinicallaboratory tests assessed as not clinically significant by study delegate physicianat Screening (V1)

14. Individuals who are capable of becoming pregnant: use of highly effectivecontraception for at least 1 month prior to screening and agreement to use such amethod during study participation;

15. Individuals who are willing to taper off current antidepressant and antipsychoticmedications for a minimum of 2-weeks (or more depending on the medication) prior toBaseline (V2) and for the duration of the study and whose physician confirms that itis safe for them to do so; and

16. Agreement to adhere to Lifestyle Considerations (section 4.5) throughout studyduration.

Exclusion Criteria:

1. Pregnant as assessed by a urine pregnancy test at Screening (V1) or individual'sthat intend to become pregnant during the study or are breastfeeding;

2. Treatment with another investigational drug or other intervention within 30 days ofScreening (V1);

3. Have initiated psychotherapy in the preceding 12 weeks prior to Screening (V1);

4. Have a DSM-5 diagnosis of substance use disorder (recreational use of tobacco,alcohol, cannabis and prescribed opioids are permitted) within the preceding 6months;

5. Have active suicidal ideation with intent and plan as determined by item 3 of theHamD-17;

6. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder;obsessive-compulsive disorder, psychotic disorder (unless substance induced or dueto a medical condition), bipolar I or II disorder, paranoid personality disorder,borderline personality disorder, or neurocognitive disorder as determined by medicalhistory and the SCID-5 clinical interview;

7. Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder;psychotic disorder (unless substance-induced or due to a medical condition); orbipolar I or II disorder as determined by the family medical history form anddiscussions with the participant;

8. Presence of a relative or absolute contraindication to psilocybin, including a drugallergy, recent stroke history, uncontrolled hypertension, low or labile bloodpressure, recent myocardial infarction, cardiac arrhythmic, severe coronary arterydisease, or moderate to severe renal or hepatic impairment.

9. Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or ahistory of long QTc syndrome or related risk factors;

10. Individuals who are currently taking methadone, buprenorphine or > 100 milligrams ofmorphine (or morphine equivalents).

11. Any other clinically significant physical illness including chronic infectiousdiseases or any other major concurrent illness that, in the opinion of theinvestigator, may interfere with the interpretation of the study results orconstitute a health risk for the participant if they take part in the study.