Psilocybin for Treatment-Resistant Depression in Autism

Inclusion Criteria:

1. Must be aged 18 to 65 years old;

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

3. Ability to read and communicate in English;

4. Must sign and date the informed consent form;

5. Stated willingness to comply with all study procedures;

6. Intellectually able: Either 1) the participant has a previous report showingintelligence quotient (IQ) ≥ 70 on the General Abilities Index of the Wechsler AdultIntelligence Scale-Fourth Edition (WAIS-IV) or any other standardized intelligencescales, or 2) the participant scores >10 percentile on the nine-item form of theRaven's Standard Progressive Matrices Test (RSPM).

7. Clinical diagnosis of autism spectrum disorder (ASD), based on the DSM-5 or ICD-11

8. Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the MiniInternational Neuropsychiatric Interview (MINI) administered at the first screeningvisit (V1);

9. Participants diagnosed with treatment-resistant depression defined as individualswith a baseline GRID-HAMD-17 score > 14 and that have not responded to two or moreseparate trials of antidepressants at an adequate dosage and duration based on theAntidepressant Treatment History Form; there is no upper limit on the number oftreatment failures;

10. Ability to take oral medication;

11. Individuals who are capable of becoming pregnant: use of highly effectivecontraception for at least 3 months prior to screening and agreement to use such amethod during study participation;

12. 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 whose physician confirms that it is safe for them to do so; and

13. A clean urine drug screen and negative urine pregnancy test (in females).

14. Agreement to adhere to Lifestyle Considerations (see below) throughout studyduration

Exclusion Criteria:

1. Pregnant as assessed by a urine pregnancy test or individual's that intend to becomepregnant during the study or are breastfeeding;

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

3. The presence of an unstable seizure disorder as defined by having not beenseizure-free for at least 6 months or anticonvulsant treatment has not been stablefor at least 4 weeks;

4. The presence of any clinically significant or unstable medical conditions, includingcardiovascular, liver, kidney, pulmonary disease, presence of known congenital brainmalformation, as per investigator assessment based on medical history and chartreview;

5. Moderate or severe DSM-5 diagnosis of an alcohol or substance use disorder in thepast 12 months;

6. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder, psychoticdisorder (unless substance induced or due to a medical condition), bipolar I or IIdisorder, paranoid personality disorder, or neurocognitive disorder as determined bymedical history and the MINI 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. Substantial lifetime use (>10 years total) or recent use (past 6 months) ofketamine, psychedelics, or MDMA and positive urine toxicological screen at Screening (V1) and Baseline (V2);

10. 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;

11. Have active suicidal ideation with intent and plan as determined by SBQ-ASC.

12. Have initiated new psychotherapy within 12 weeks prior to Screening

13. Contraindication to MR imaging or a previous history of claustrophobia.

Lifestyle considerations:

During this clinical trial, participants are asked to:

• Abstain from alcohol for 24 hours before the intervention or the day of theintervention (V3, V4).

• Abstain from the use of any prescribed opioids, benzodiazepines, or sleep aids (Z-drugs) within 12 hrs prior to the intervention (V3, V4) and for up to 6 hrs afteradministration.

• Abstain from any illicit drugs (e.g. cocaine, ecstasy/MDMA, hallucinogens) for theduration of the study.

• Abstain from any cannabinoids within 3 weeks prior to the intervention (V3, V4) anduntil the completion of the 2nd integrative therapy session (V6).

• Abstain from driving or operating heavy machinery for up to 24 hours after theintervention (V3, V4).