Overview
- Background
Normal aging, as well as dementias such as Alzheimer s disease, can cause changes in the brain that affect memory, attention, and thinking. Researchers want to know if regular mental tasks (cognitive training) can improve brain function in older adults. They also want to know if psilocybin, a compound found in certain mushrooms, can further support improved brain function.
- Objective
To learn how regular cognitive training, with or without psilocybin, can improve brain health in older adults.
- Eligibility
People aged 65 years and older with mild cognitive impairment or early-stage Alzheimer s disease. Healthy older adults with normal cognition are also needed.
- Design
Participants will be screened. They will have a test of their heart function and an imaging scan. They will have mental health screening and tests of their thinking and memory. They will practice brain-training tasks on a tablet.
Participants will be divided into 2 groups: 1 will have cognitive training plus psilocybin; 1 will have cognitive training only.
Those having cognitive training only will have 5 or 6 clinic visits. They will take the tablet home to practice brain training daily. They will wear a device to measure brain waves as they sleep; they may have 1 overnight stay in the clinic, or they may wear the device at home. Imaging scans and other tests will be repeated at each visit.
Those taking psilocybin will have up to 9 clinic visits. In addition to the visits for cognitive training, they will take 1 psilocybin capsule by mouth 2 weeks apart (the second dose is optional). They will remain in the clinic for 24 hours after each dose.
Description
Study Description:
A randomized, open-label, parallel-group clinical trial with two arms aimed at evaluating whether psilocybin enhances the neuroplastic and cognitive benefits of cognitive training in two populations: older adults with normal cognition and individuals with early-stage Alzheimer s disease (AD). Participants in both populations will be randomized to receive either two oral doses of 25 mg of psilocybin, administered two weeks apart, plus cognitive training for four weeks or cognitive training alone for four weeks. The primary outcome will be the change from baseline in a novel Neuroplasticity Composite Score (NPCS) assessed four weeks after the first psilocybin session or the onset of cognitive training. Secondary outcomes include the assessment of safety and tolerability, cognitive performance on TabCAT, RBANS, and autobiographical memory; psychological well-being; quality of life; and sleep. Additional outcomes will include MRI/fMRI/MRS measures of neuroplasticity, brain network connectivity and neurochemistry; EEG during sleep; and plasma and plasma extracellular vesicle (EV)-associated biomarkers of synaptic integrity, serotonergic transmission, neurodegeneration, mitochondrial function, and inflammation. Screening will include clinical and cognitive assessments, assessment of suicidal ideation and behavior, biomarker confirmation of AD pathology, neuroimaging eligibility screening, and laboratory tests for metabolic, hepatic, and renal function. A urine drug screen will confirm the absence of illicit substances, and a urine pregnancy test will be required for female participants of childbearing potential. By simultaneously assessing cognitive and brain function and structure at multiple levels, this study will provide proof-ofconcept for psilocybin s potential to promote neuroplasticity, enhance cognition, improve emotional well-being, and mitigate neurodegenerative processes in aging and AD. Additionally, the inclusion of understudied geriatric populations will address critical gaps in psilocybin s safety and efficacy profile in older adults.
- Objectives
Primary Objective:
-Determine whether psilocybin enhances neuroplasticity four weeks after the first psilocybin session compared to cognitive training alone.
Secondary Objectives:
- Assess the safety and tolerability of psilocybin in cognitively healthy older adults and individuals with early-stage AD.
- Assess whether psilocybin enhances cognitive performance on TabCAT, RBANS and autobiographical memory, compared to cognitive training alone.
- Evaluate whether psilocybin enhances neuroplasticity-related changes on MRI, resting state fMRI, and MRS (i.e., changes in microanatomy, structural \& functional connectivity, neurotransmitter levels) compared to cognitive training alone.
- Evaluate whether psilocybin enhances neuroplasticity-related changes on EEG during sleep (sleep architecture, spectral power) compared to cognitive training alone.
- Investigate whether psilocybin followed by cognitive training changes plasma and plasma EV-associated biomarkers, compared to cognitive training alone, focusing on synaptic, neurodegenerative, mitochondrial, and inflammatory markers.
- Characterize salivary stress-related biomarkers (e.g., cortisol and related hormones) and explore their association with acute psilocybin response and longer-term outcomes, and their longitudinal changes.
- Evaluate changes in psychological well-being (anxiety, depressive symptoms, trauma-related symptoms, alcohol craving/misuse, broader dimensions of well-being such as autonomy, purpose in life, personal growth); overall quality of life; and sleep with psilocybin followed by cognitive training compared to cognitive training alone.
- Assess differences between the first and second psilocybin session.
- Endpoints
Primary Endpoint:
-Change in NPCS four weeks after the first psilocybin session and initiation of cognitive training compared to cognitive training alone.
Secondary Endpoints:
- Safety \& Tolerability: Incidence of adverse events.
- Change in NPCS, four days after the first psilocybin session and initiation of cognitive training, compared to cognitive training alone.
- Cognitive Outcomes: Change in TabCAT Brain Health Assessment (TabCAT-BHA) global composite score and individual task scores, RBANS total score, autobiographical memory performance (Reminiscence Functions Scale, Autobiographical Event Recall Test, DRM Paradigm), and performance in individual cognitive tests with psilocybin followed by cognitive training, in the short- (i.e., four days) and mid-term (i.e., four weeks), compared to cognitive training alone.
- Neuroimaging Outcomes: Changes in MRI, resting state fMRI, and MRS measures, including changes in microstructure and myelin and axonal integrity, BrainAGE, brain network connectivity, and neurotransmitter concentrations with psilocybin followed by cognitive training, compared to cognitive training alone.
- EEG Outcomes: Changes in sleep architecture and quantitative EEG spectral power with psilocybin and cognitive training, compared to cognitive training alone.
- Biomarkers: Changes in plasma and plasma EV-associated markers of synaptic function and neuroplasticity, neurodegeneration, mitochondrial function, and inflammation, with psilocybin and cognitive training, compared to cognitive training alone.
- Salivary Stress Biomarkers: Association of salivary cortisol and related hormones with acute psilocybin response and longer-term outcomes, and their longitudinal changes.
- Psychological and Quality of Life Outcomes: Changes in State- Trait Anxiety Inventory-State (STAI-State), Montgomery(SqrRoot) sberg Depression Rating Scale Self report (MADRS-S), PTSD Checklist for DSM-5 (PCL-5), Penn Alcohol Craving Scale (PACS), National Institutes of Health-Healing Experience of All Life Stressors (NIH-HEALS), Ryff Psychological Well-Being Scales, Neuropsychiatric Inventory Questionnaire (NPI-Q), Quality of Life in Alzheimer s Disease (QOL-AD) Scale, Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) with psilocybin followed by cognitive training, compared to cognitive training alone.
- Subjective Effects Questionnaires: Scores on the Mystical Experience Questionnaire (MEQ30), Challenging Experience Questionnaire (CEQ-Challenge), Ego-Dissolution Inventory (EDI), and Drug Effects Questionnaire (DEQ) following each psilocybin session.
Eligibility
- Pending Web Eligibility
