Inclusion Criteria
The aMCI participant must meet all of the inclusion criteria to be eligible for this clinical trial:
1. Male or female participants of any race or ethnicity
2. Inpatients or outpatients 60 to 75 years of age (on day of randomization)
3. Diagnosis of MCI based on DSM 5 diagnostic criteria of Minor Neurocognitive Disorder
4. Categorization of episodic memory impairment based on scores ≥ 1.0 SD lower on any of the following measures in comparison to normative data i. Logical Memory Test, ii. California Verbal Learning Test, iii. Brief Visual Memory Test
5. Non-smoker/Non-nicotine user
6. Montreal Cognitive Assessment (MoCA) score = \< 26 and MMSE score \> = 24
7. Capable of consenting to participate in the research study
8. On a stable dose of medication for at least 2 months \[see section 5.6\], and unlikely to undergo changes in dose during the study
9. Availability of a study partner who has regular contact with the participant
10. Ability to read and communicate in English (with corrected vision and hearing, if needed)
The Healthy Control participant must meet all of the inclusion criteria to be eligible for this clinical trial:
1. Male or female participants of any race or ethnicity
2. 60 to 75 years of age (on day of randomization)
3. Does not meet SCID-5 criteria for Mild Neurocognitive Disorder, Alzheimer's disease, or other major neurocognitive disorder
4. Non-smoker/Non-nicotine user
5. Capable of consenting to participate in the research study
6. On a stable dose of medication for at least 2 months \[see section 5.6\], and unlikely to undergo changes in dose during the study
7. Availability of a study partner who has regular contact with the participant
8. Ability to read and communicate in English (with corrected vision and hearing, if needed)
Exclusion Criteria
An individual who meets any of the following criteria will be excluded from participation in this clinical trial:
1. Unwilling or incapable to consent to the study
2. Unstable medical or any concomitant major medical or neurological illness, including presence of a relative or absolute contraindication to psilocybin, i.e. 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.
3. History of head trauma resulting in loss of consciousness \> 30 minutes that required medical attention.
4. DSM-5 diagnosis, with active symptoms in the last three months, of major depression; lifetime diagnosis of bipolar disorder; intellectual disability; Alzheimer's Disease; or a psychotic disorder
5. DSM-5 substance dependence (except caffeine) within 12 months of entering the study
6. Anticonvulsant, antidepressant, antipsychotic, mood stabilizer, opioid, or benzodiazepine use
7. Use of serotonergic psychedelic drugs within the past 10 years
8. Positive urine drug screen at the screening visit
9. Having taken a cognitive enhancer (acetylcholinesterase inhibitor or memantine) within the past 6 weeks
10. Acute suicidal or homicidal ideation
11. Receiving treatment with medications such as levetiracetam that blocks SV2a binding, and/or inability to discontinue the following medications before study drug dosing: inhibitors of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A9 and (UGT)1A10, and ALDH inhibitors and alcohol dehydrogenase (ADH) inhibitors.
12. Exceeding allowed annual radiation exposure levels (20 mSv), as outlined by our PET Centre guidelines
13. Having completed multiple PET scans in the past, such that participation in this study would cause participant to exceed lifetime limit (8 PET scans)
14. Metal implants or pacemaker precluding an MRI scan or other contraindications to MRI (e.g., claustrophobia)
15. Female with childbearing potential\*, pregnancy (as confirmed by a negative pregnancy test) or breastfeeding
16. Active gender affirming hormonal treatment
17. 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.
18. Allergies to hydroxypropyl methylcellulose \*A woman/female or person who is not of childbearing potential is considered to be postmenopausal after at least 12 months without menstruation. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Females/people of childbearing potential are those who have experienced menarche and do not meet the criteria for women not of childbearing potential.
