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 showing intelligence quotient (IQ) ≥ 70 on the General Abilities Index of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) or any other standardized intelligence scales, or 2) the participant scores \>10 percentile on the nine-item form of the Raven'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 Mini International Neuropsychiatric Interview (MINI) administered at the first screening visit (V1);
9. Participants diagnosed with treatment-resistant depression defined as individuals with a baseline GRID-HAMD-17 score \> 14 and that have not responded to two or more separate trials of antidepressants at an adequate dosage and duration based on the Antidepressant Treatment History Form; there is no upper limit on the number of treatment failures;
10. Ability to take oral medication;
11. Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 3 months prior to screening and agreement to use such a method during study participation;
12. Individuals who are willing to taper off current antidepressant and antipsychotic medications for a minimum of 2-weeks (or more depending on the medication) prior to Baseline (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 study duration
Exclusion Criteria:
1. Pregnant as assessed by a urine pregnancy test or individual's that intend to become pregnant during the study or are breastfeeding;
2. Treatment with another investigational drug or other intervention within 30 days of Screening (V1);
3. The presence of an unstable seizure disorder as defined by having not been seizure-free for at least 6 months or anticonvulsant treatment has not been stable for at least 4 weeks;
4. The presence of any clinically significant or unstable medical conditions, including cardiovascular, liver, kidney, pulmonary disease, presence of known congenital brain malformation, as per investigator assessment based on medical history and chart review;
5. Moderate or severe DSM-5 diagnosis of an alcohol or substance use disorder in the past 12 months;
6. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, or neurocognitive disorder as determined by medical 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); or bipolar I or II disorder as determined by the family medical history form and discussions with the participant;
8. Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment;
9. Substantial lifetime use (\>10 years total) or recent use (past 6 months) of ketamine, psychedelics, or MDMA and positive urine toxicological screen at Screening (V1) and Baseline (V2);
10. Any other clinically significant physical illness, including chronic infectious diseases 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 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 the intervention (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 after administration.
* Abstain from any illicit drugs (e.g. cocaine, ecstasy/MDMA, hallucinogens) for the duration of the study.
* Abstain from any cannabinoids within 3 weeks prior to the intervention (V3, V4) and until the completion of the 2nd integrative therapy session (V6).
* Abstain from driving or operating heavy machinery for up to 24 hours after the intervention (V3, V4).