Psilocybin for Treatment-Resistant Depression in Autism with Pre-Post Brain and Cognitive Measurement to Understand Mechanisms

Inclusion Criteria:

• Autistic adult, ages 18-65

• Must be deemed to have capacity to provide informed consent;

• Must sign and date the informed consent form;

• Stated willingness to comply with all study procedures;

• 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).

• 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;

• Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on theStructured Clinical Interview for DSM-5 (Clinician Version; SCID-5-CV) administeredat the first screening visit (V1);

• Participants diagnosed with treatment-resistant depression defined as individualswith a baseline GRID-HAMD-17 score > 14 and that have not responded to two ormore separate trials of antidepressants at an adequate dosage and duration based onthe Antidepressant Treatment History Form (ATHF; Appendix C2); there is no upperlimit on the number of treatment failures;

• Ability to take oral medication;

• 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;

• 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

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

Exclusion Criteria:

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

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

• 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;

• 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;

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

• 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 SCID-5-CV clinical interview;

• 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;

• 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;

• Substantial lifetime use (>10 years total) or recent use (past 6 months) ofketamine, psychedelics, or MDMA;

• 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;

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

• Are currently undergoing psychotherapy or have undergone psychotherapy within 12weeks prior to Screening.

• Contraindication to MR imaging: with shrapnel or other metal or electronic implantsin their bodies (such as pacemakers, aneurysm clips, surgical devices, metallictattoos on the head, etc.) or a previous history of claustrophobia.