CBD for Individuals at Risk for Alzheimer's Disease

Study Overview
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Brief Summary
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This is a double-blind, randomized controlled trial designed to test the effects of cannabidiol (CBD) on validated biomarkers of Alzheimer's disease (AD) progression, behavioral and clinical measures, with putative mechanisms of CBD action.

Detailed Description
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To better understand the effects of hemp-derived CBD with and without a small amount of THC, we propose a Phase II randomized clinical trial (RCT) to examine the clinical effects of Full Spectrum CBD (fsCBD, contains less than 0.3% THC) vs. Broad Spectrum CBD (bsCBD, does not contain THC), vs. a matching placebo in a population of individuals diagnosed with mild cognitive impairment (MCI). This is a double-blind, placebo-controlled, parallel group study designed to assess the efficacy of fsCBD and bsCBD, compared to a placebo control, on biomarkers of Alzheimer's disease progression, cognitive function, pain, sleep quality, anxiety, oxidative stress, and inflammation. If eligible for the study, subjects will be randomized to receive one of the conditions for 24 weeks. The current study will test the hypothesis that a moderate dose of CBD will improve measures of Alzheimer's disease progression, cognitive function, pain, sleep quality, anxiety, oxidative stress, and inflammation as compared to placebo. The study will also test whether endocannabinoids mediate the effects of CBD on these outcomes.

Official Title
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Cannabidiol for Individuals at Risk for Alzheimer's Disease: A Randomized Placebo Controlled Trial

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Cannabidiol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be between the ages of 55 - 85 and provide valid informed consent. Participant must receive a diagnosis of Mild Cognitive Impairment after a careful cognitive and functional evaluation by a clinician at the Memory Disorder Clinic at the University of Colorado School of Medicine Participant must have a CDR score of .5 on the Clinical Dementia Rating scale (CDR), which includes an assessment of function and is often used to distinguish MCI from dementia. A score of 0.5 (indicating mild cognitive impairment but not dementia) is required for inclusion. Exclusion Criteria: Any other central nervous system disease that would be expected to affect cognition, Parkinson's disease, multiple sclerosis. Any history of brain injury (e.g., concussion with significant loss of consciousness) Any significant systemic illness or unstable medical condition Current use of Parkinson's medications, antipsychotic medications, anti-seizure medications, or anticholinergic medications Current or lifetime diagnosis of a schizophrenia spectrum disorder, psychotic disorder, bipolar disorder type I & II, cluster B personality disorders (antisocial, borderline, narcissistic, histrionic), eating disorders, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022) Participation in other clinical studies involving neuropsychological measures being collected more than one time per year. Reported use of other drugs (cocaine, opiates, methamphetamine, MDMA) in the past 60 days or test positive on a urine test for those drugs of abuse at baseline. Daily nicotine user Report using cannabis or CBD more than once per month over the last 12 months. Recent history of a psychotic disorder, bipolar disorder or meet criteria for major depression with suicidal ideation. Liver function enzymes (AST, ALT) that are greater than 2x normal. Currently taking medications known to be contraindicated with Epidiolex (buprenorphine, leflunomide, levomethadyl acetate, lomitapide, mipomersen, pexidartinib, propoxyphene, sodium oxybate, teriflunomide, clobazam, lamotrigine, valproate). Pregnant at the time of study enrollment or unwilling to use contraception through the duration of the study (if not yet post-menopausal) Individuals with potentially reversible causes of mild cognitive impairment (hypothyroidism, Vitamin B12 deficiency).

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a double-blind, placebo-controlled, parallel group study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Full Spectrum Cannabidiol<br>200mg/day of full-spectrum cannabidiol, containing less than 0.3% THC. | Drug: Cannabidiol<br>* The current study will directly test the hypothesis that a moderate dose of CBD improves markers of Alzheimer's progression, cognitive function, sleep, pain, anxiety, oxidative stress, and inflammation.<br>* Other names: CBD;|
| Active Comparator: Broad Spectrum Cannabidiol<br>200mg/day of full-spectrum cannabidiol, containing 0.0% THC. | Drug: Cannabidiol<br>* The current study will directly test the hypothesis that a moderate dose of CBD improves markers of Alzheimer's progression, cognitive function, sleep, pain, anxiety, oxidative stress, and inflammation.<br>* Other names: CBD;|
| Placebo Comparator: Hemp Seed Oil<br>200mg/day of hemp seed oil with no cannabinoids present. | Other: Placebo<br>* Placebo arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Dementia Rating Scale (CDR-SB) score | The Clinical Dementia Rating Scale is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias. Higher scores indicate worse cognitive impairment. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Changes in Plasma N-p-tau181 | Changes in plasma levels of N-p-tau181 will be measured. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in plasma Aβ42/Aβ40 ratio | Changes in plasma Aβ42/Aβ40 ratio will be measured. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in plasma Neurofilament Light (Nfl) | Changes in plasma Neurofilament Light (Nfl) will be measured. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in Cognitive Function | The CogState Brief Battery will be used to create domain scores used to inform an aggregate measure of cognition. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma lipid biomarkers of inflammation and oxidative stress | Change in plasma levels of 5-iso PGF2αVI, 16-HETE, PGD2 will be measured. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in plasma endocannabinoids | Change in plasma levels of endocannabinoids will be measured. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in pain | The PROMIS Pain Intensity questionnaire consists of two items asking about the participant's level of pain on average and at its worst in the past 7 days. Participants are asked to rate their pain on a scale from 0 (no pain) to 10 (worst imaginable pain). | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in anxiety | The Depression Anxiety Stress Scale is a 21-item self-report instrument for measuring the three related negative emotional states of depression, anxiety, and tension/stress. Higher scores indicate worse anxiety. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in sleep | The PROMIS Sleep Disturbance assesses self-reported perceptions of sleep quality, sleep depth, and restoration associated with sleep. Higher scores indicate worse sleep outcomes. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in physical activity | The Stanford 7-Day Physical Activity recall will be used to monitor patterns in physical activity type, frequency, and intensity. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 
| Change in diet | The NIH EATS Fruits & Vegetables questionnaire will be used to measure patterns in diet composition. | Week 0 to Week 12, Week 12 to Week 24, Week 0 to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognition, Cannabidiol, Aging, Memory, Alzheimer's Disease