Does Psilocybin Change Synaptic Density in Amnestic Mild Cognitive Impairment

Sponsor

Centre for Addiction and Mental Health (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06041152

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this 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.

60 participants (30 with aMCI, and 30 sex and age matched healthy volunteers) will:

Be randomized to receive either:

Two 25 mg macrodoses of psilocybin separated by 1 week.
Two placebo doses separated by 1 week.

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.
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.

Condition or Disease	Intervention/Treatment	Phase
Amnestic Mild Cognitive Impairment	Drug: Psilocybin Drug: Placebo	Phase 2

Detailed Description

The proposed study will investigate the effects of on synaptic vesicular density (SVD) levels as measured by the positron emission tomography (PET) radiotracer, 18F-SynVesT-1, and cognition (i.e., global cognition, executive function, and memory domains) in amnestic Mild Cognitive Impairment (aMCI) and healthy participants. Participants will be randomized to receive either two 25mg doses of psilocybin separated by one week, or two placebo doses separated by one week. Brain scans, clinical, and cognitive assessments will be conducted one week before, and one week, four weeks, and 12 weeks post dosing.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Other

Official Title:

Does Psilocybin Change Synaptic Density in the Brains of Patients With Amnestic Mild Cognitive Impairment

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2026

Anticipated Study Completion Date :

Jul 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amnestic Mild Cognitive Impairment Participants Receiving Psilocybin Receiving 2 doses of 25mg of psilocybin separated by 1 week.	Drug: Psilocybin 2 macrodoses of 25mg separated by one week.
Experimental: Healthy Participants Receiving Psilocybin Receiving 2 doses of 25mg of psilocybin separated by 1 week.	Drug: Psilocybin 2 macrodoses of 25mg separated by one week.
Placebo Comparator: Amnestic Mild Cognitive Impairment Participants Receiving Placebo Receiving 2 doses of placebo separated by 1 week.	Drug: Placebo 2 doses of placebo separated by one week.
Placebo Comparator: Healthy Participants Receiving Placebo Receiving 2 doses of placebo separated by 1 week.	Drug: Placebo 2 doses of placebo separated by one week.

Outcome Measures

Primary Outcome Measures

Synaptic Vesicular Density [3 years]
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.

Secondary Outcome Measures

Global Cognition [3 years]
The results of the neuropsychological battery will be combined to a global cognition composite score as a Z-score, the change of which will be a secondary outcome measure. Z-scores will be comprised of the Mini-Mental State Examination, Montreal Cognitive Assessment, Boston Naming Test, Category Fluency Test, Letter Fluency Test, Trail Making Test Parts A and B, Wisconsin Card Sorting Test, Stroop Neuropsychological Test, Executive Interview, Block Design Test, Clock Drawing Test, Grooved Pegboard, Digit Symbol Test, Logical Memory Test, California Verbal Learning Test, and Modified Rey-Osterrieth Complex Figure, and will be calculated based on the performance of the equated comparison group. Each domain will contribute equally to the global cognition composite score.
Memory [3 years]
A memory composite Z-score will be generated using the performance on the following individual tests: Logical Memory Test, California Verbal Learning Test, and Modified Rey-Osterrieth Complex Figure. Z-scores will be calculated based on the performance of the equated comparison group, and each domain will contribute equally to the global cognition composite score.
Executive Function [3 years]
An executive function composite Z-score will be generated using the performance on the following individual tests: Trail Making Test Part B, Wisconsin Card Sorting Test, Stroop Neuropsychological Screening, and the Executive Interview. Z-scores will be calculated based on the performance of the equated comparison group, and each domain will contribute equally to the global cognition composite score.

Other Outcome Measures

Exploratory Cognitive Outcomes [3 years]
If individual cognitive test scores are significantly different between groups, the mean difference of the individual test scores (i.e., Mini-Mental State Examination, Montreal Cognitive Assessment, Boston Naming Test, Category Fluency Test, Letter Fluency Test, Trail Making Test Parts A and B, Wisconsin Card Sorting Test, Stroop Neuropsychological Test, Executive Interview, Block Design Test, Clock Drawing Test, Grooved Pegboard, Digit Symbol Test, Logical Memory Test, California Verbal Learning Test, and Modified Rey-Osterrieth Complex Figure) will be analyzed separately as exploratory outcomes.
Exploratory Primary and Secondary Outcomes [3 years]
Primary and secondary outcomes will be compared between aMCI and healthy control groups. The means of the primary outcome (i.e., volume of distribution) and secondary outcomes (i.e., cognitive composite Z-scores: global cognition, memory, and executive function) will be compared between aMCI and healthy control groups.

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria

The aMCI participant must meet all of the inclusion criteria to be eligible for this clinical trial:

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 (62),

California Verbal Learning Test (63), iii. Modified Rey-Osterrieth Complex Figure (64).

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)

The Healthy Control participant must meet all of the inclusion criteria to be eligible for this clinical trial:

Male or female participants of any race or ethnicity
60 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
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)

Exclusion Criteria

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
Lifetime use of serotonergic psychedelic drugs
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
Disorders of coagulation or taking anticoagulant medication
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)
Female with childbearing potential*, pregnancy (as confirmed by a negative pregnancy test) or breastfeeding
Active gender affirming hormonal treatment
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.
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.