This Phase 2 clinical trial investigates whether cannabidiol (CBD) can prevent or delay the onset of Alzheimer's Disease in individuals at elevated genetic risk for AD. The trial is conducted by researchers at the University of Colorado and represents a novel preventive therapeutic approach targeting the endocannabinoid system in at-risk populations.
| Parameter |
Value |
| NCT Number |
NCT05822362 |
| Phase |
Phase 2 |
| Enrollment |
236 participants |
| Sponsor |
University of Colorado |
| Intervention |
Cannabidiol (CBD) |
| Purpose |
Prevention |
| Study Type |
Interventional |
| Allocation |
Randomized, controlled |
- Individuals at genetic risk for Alzheimer's Disease
- May include carriers of Apolipoprotein E (APOE) ε4 allele or other known AD risk genetic variants
- Cognitively normal at baseline
The rationale for CBD-based prevention in at-risk populations includes:
- Genetic predisposition — APOE ε4 carriers and other genetic risk factors increase AD susceptibility by 3-12x
- Neuroprotective mechanisms — CBD exerts multiple neuroprotective effects through the endocannabinoid system
- Early intervention opportunity — Preventive approaches before clinical symptoms may be more effective than symptomatic treatment
- Safety profile — CBD has demonstrated an acceptable safety profile in previous clinical trials
CBD is a non-psychoactive phytocannabinoid that exerts neuroprotective effects through multiple pathways:
-
Anti-inflammatory effects
- CB2 receptor activation on microglia shifts polarization from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype
- Suppression of NLRP3 inflammasome assembly
- Reduction in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)
-
Antioxidant properties
- Direct scavenging of reactive oxygen species (ROS) through phenolic ring structure
- Activation of Nrf2-dependent antioxidant gene expression
- Protection against lipid peroxidation
-
Anti-excitotoxic effects
- Modulation of glutamate release
- Protection against NMDA receptor-mediated excitotoxicity
- Calcium homeostasis maintenance
-
Neurotrophic support
- Enhancement of BDNF expression
- Support of synaptic plasticity
- Promotion of neurogenesis
-
Amyloid and tau modulation
- Reduction of Aβ production through APP processing modulation
- Inhibition of tau hyperphosphorylation
- Enhancement of Aβ clearance
- Randomized, double-blind, placebo-controlled design
- Parallel-group comparison
- Dose-finding components may be included
Primary Endpoints:
- Cognitive performance measures
- Biomarker changes indicative of AD progression
Secondary Endpoints:
- Brain imaging biomarkers
- Fluid biomarker panels
- Clinical conversion rates
Participants will undergo comprehensive assessments at baseline and follow-up visits:
- Cognitive testing batteries
- Neuroimaging (MRI/PET)
- Fluid biomarker collection (blood, CSF)
The endocannabinoid system represents a promising therapeutic target for AD prevention:
- CB1R downregulation in AD cortex correlates with cognitive decline
- CB2R upregulation on microglia surrounding plaques represents an endogenous anti-inflammatory response
- Endocannabinoid deficiency in AD brain may contribute to disease progression
- MAGL and FAAH enzymes represent additional therapeutic targets
| Target |
Advantage of CBD |
| CB1R agonists |
CBD acts as negative allosteric modulator — avoids psychoactivity |
| CB2R-selective |
CBD provides anti-inflammatory effects without immunosuppression |
| FAAH inhibitors |
CBD has mild FAAH inhibitory activity |
| Direct antioxidants |
CBD provides direct ROS scavenging |
- Generally well-tolerated at doses up to 1500-3000 mg/day
- Most common adverse events: diarrhea, fatigue, weight changes
- Drug interactions via CYP450 enzymes
- Minimal psychoactivity compared to THC
- Liver function tests
- Drug interaction screening
- Adverse event tracking
- Concomitant medication review