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Does Psilocybin Change Synaptic Density in Amnestic Mild Cognitive Impairment

This Phase II interventional trial (n=60) aims to investigate whether psilocybin affects synaptic vesicular density (SVD) in individuals with amnestic Mild Cognitive Impairment (aMCI) compared to healthy participants.

Target Enrollment
60 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

Randomised, quadruple-blind, parallel-group Phase II study (n=60; 30 aMCI, 30 healthy controls) comparing two 25 mg oral doses of psilocybin separated by one week versus two placebo doses.

Primary outcome is change in synaptic vesicular density measured with 18F-SynVesT-1 PET before and one week after the last dose; additional PET with [18F]T807 for tau, and cognitive testing at 1, 4, and 12 weeks.

Study Protocol

Preparation

sessions

Dosing

2 sessions

Integration

sessions

Study Arms & Interventions

aMCI Psilocybin

experimental

aMCI participants receiving two 25 mg oral doses of psilocybin separated by 1 week.

Interventions

  • Psilocybin25 mg
    via Oral• two doses (1 week apart)• 2 doses total

Healthy Psilocybin

experimental

Healthy matched participants receiving two 25 mg oral doses of psilocybin separated by 1 week.

Interventions

  • Psilocybin25 mg
    via Oral• two doses (1 week apart)• 2 doses total

aMCI Placebo

inactive

aMCI participants receiving two placebo doses separated by 1 week.

Interventions

  • Placebo
    via Oral• two doses (1 week apart)• 2 doses total

    Placebo comparator

Healthy Placebo

inactive

Healthy participants receiving two placebo doses separated by 1 week.

Interventions

  • Placebo
    via Oral• two doses (1 week apart)• 2 doses total

    Placebo comparator

Participants

Ages
60 – 75
Sexes
Male & Female

Inclusion Criteria

  • 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, 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, 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

  • Exclusion Criteria
  • 1. Unwilling or incapable to consent to the study
  • 2. Unstable medical or any concomitant major medical or neurological illness, including contraindication to psilocybin (allergy, recent stroke, uncontrolled hypertension, recent myocardial infarction, cardiac arrhythmia, severe coronary artery disease, 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 medications including UGT1A9/1A10 inhibitors, ALDH inhibitors and ADH inhibitors before dosing
  • 12. Exceeding allowed annual radiation exposure levels (20 mSv)
  • 13. Having completed multiple PET scans such that participation would exceed lifetime limit (8 PET scans)
  • 14. Metal implants or pacemaker precluding MRI or other contraindications to MRI (e.g., claustrophobia)
  • 15. Female with childbearing potential, pregnancy or breastfeeding
  • 16. Active gender affirming hormonal treatment
  • 17. Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder, psychotic disorder, or bipolar I or II disorder
  • 18. Allergies to hydroxypropyl methylcellulose

Study Details

Locations

Centre for Addiction and Mental Health — Toronto, Ontario, Canada

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