Does Psilocybin Change Synaptic Density in Amnestic Mild Cognitive Impairment

NCT06041152 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: 101-2021
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this pilot, exploratory, clinical trial is to investigate the effects of psilocybin on synaptic vesicular density (SVD) as measured by the positron emission tomography (PET) radiotracer, 18F-SynVesT-1, in participants with amnestic Mild Cognitive Impairment (aMCI) and healthy participants. The investigators hypothesize that SVD levels in the brain will be higher following the ingestion of psilocybin in comparison to placebo, and that increases in SVD will be associated with improvements in cognition. 10 participants (6 with aMCI, and 4 sex and age matched healthy volunteers) will:

• Receive a baseline 18F-SynVesT-1 PET scan, clinical, and neuropsychological assessments.
• Receive a 18F-SynVesT-1 PET scan one week after the last dose of treatment.
• Depending on available funds, receive a third PET scan at any time within 4 weeks of the screening visit to quantify tauopathy with the \[18F\]T807 radiotracer.
• Receive clinical and neuropsychological testing 1, 4, and 12 weeks after the last treatment. Researchers will compare placebo vs. experimental groups to see if psilocybin will increase SVD, and if increases in SVD are associated with cognitive improvements.

Conditions

Amnestic Mild Cognitive Impairment

Keywords

amnestic mild cognitive impairment; psilocybin; SV2A; positron emission tomography; synaptic vesicular density

Outcome Measures

Primary Outcomes (1)

• Synaptic Vesicular Density

  Synaptic vesicular density will be assessed with PET imaging by measuring the volume of distribution (i.e., defined as the ratio of the radioligand concentration in tissue target region (CT, kBq·cm-3) to that in plasma (CP, kBq·mL-1) at equilibrium) of the \[18F\]SynVesT-1 radioligand in the cortical and subcortical gray matter regions in the whole brain and more specifically, the hippocampus and dorsolateral prefrontal cortex.

  3 years

Secondary Outcomes (3)

• Global Cognition

  3 years

• Memory

  3 years

• Executive Function

  3 years

Other Outcomes (2)

• Exploratory Cognitive Outcomes

  3 years

• Exploratory Primary and Secondary Outcomes

  3 years

Study Arms (4)

Amnestic Mild Cognitive Impairment Participants Receiving Psilocybin

EXPERIMENTAL

Receiving 2 doses of 25mg of psilocybin separated by 1 week.

Drug: Psilocybin

Healthy Participants Receiving Psilocybin

EXPERIMENTAL

Receiving 2 doses of 25mg of psilocybin separated by 1 week.

Drug: Psilocybin

Amnestic Mild Cognitive Impairment Participants Receiving Placebo

PLACEBO COMPARATOR

Receiving 2 doses of placebo separated by 1 week.

Drug: Placebo

Healthy Participants Receiving Placebo

PLACEBO COMPARATOR

Receiving 2 doses of placebo separated by 1 week.

Drug: Placebo

Interventions

Psilocybin DRUG

2 macrodoses of 25mg separated by one week.

Amnestic Mild Cognitive Impairment Participants Receiving Psilocybin; Healthy Participants Receiving Psilocybin

Placebo DRUG

2 doses of placebo separated by one week.

Amnestic Mild Cognitive Impairment Participants Receiving Placebo; Healthy Participants Receiving Placebo

Eligibility Criteria

• Age: 60 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participants of any race or ethnicity
• Inpatients or outpatients 60 to 75 years of age (on day of randomization)
• Diagnosis of MCI based on DSM 5 diagnostic criteria of Minor Neurocognitive Disorder
• 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
• Non-smoker/Non-nicotine user
• Montreal Cognitive Assessment (MoCA) score = \< 26 and MMSE score \> = 24
• Capable of consenting to participate in the research study
• 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
• Availability of a study partner who has regular contact with the participant
• Ability to read and communicate in English (with corrected vision and hearing, if needed)
• Male or female participants of any race or ethnicity
• to 75 years of age (on day of randomization)
• Does not meet SCID-5 criteria for Mild Neurocognitive Disorder, Alzheimer's disease, or other major neurocognitive disorder
• Non-smoker/Non-nicotine user
• Capable of consenting to participate in the research study

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this clinical trial:
• Unwilling or incapable to consent to the study
• 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.
• History of head trauma resulting in loss of consciousness \> 30 minutes that required medical attention.
• 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
• DSM-5 substance dependence (except caffeine) within 12 months of entering the study
• Anticonvulsant, antidepressant, antipsychotic, mood stabilizer, opioid, or benzodiazepine use
• Use of serotonergic psychedelic drugs within the past 10 years
• Positive urine drug screen at the screening visit
• Having taken a cognitive enhancer (acetylcholinesterase inhibitor or memantine) within the past 6 weeks
• Acute suicidal or homicidal ideation
• 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.
• Exceeding allowed annual radiation exposure levels (20 mSv), as outlined by our PET Centre guidelines
• Having completed multiple PET scans in the past, such that participation in this study would cause participant to exceed lifetime limit (8 PET scans)
• Metal implants or pacemaker precluding an MRI scan or other contraindications to MRI (e.g., claustrophobia)

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead

Study Sites (1)

Centre for Addiction and Mental Health

Toronto, Ontario, M5T 1R8, Canada

Location

Related Links

• The Centre for Addiction and Mental Health (CAMH) is the leading mental health and addictions research facility in Canada, and one of the largest in the world.

MeSH Terms

Interventions

Psilocybin

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines

Study Officials

• Philip Gerretsen, MD, PhD

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinician Scientist

Study Record Dates

• First Submitted: August 1, 2023
• First Posted: September 18, 2023
• Study Start: November 27, 2023
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: February 25, 2026

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)