Endocannabinoid-Based Interventions in Alzheimer’s Disease: From Basic Mechanisms to Clinical Translation — A Systematic Review
DOI:
https://doi.org/10.62051/mwqw1j53Keywords:
Endocannabinoid system; Alzheimer’s disease; Neuroinflammation; CB2 receptor; Microglia; Phytocannabinoids; Cannabidiol; MAGL inhibitor; Amyloid-beta; Clinical translation.Abstract
In Alzheimer’s disease (AD)—a progressive neurodegenerative disorder featuring cognitive impairment, synaptic loss, and neuroinflammation—the endocannabinoid system (ECS) (including CB1R/CB2R receptors, endogenous ligands AEA/2-AG, and metabolic enzymes FAAH/MAGL) acts as a key modulator of inflammatory processes, synaptic function, and neuronal resilience. Here, we present a systematic review integrating preclinical and clinical studies from the last three years (2023–2026), highlighting the multifaceted roles of the ECS in AD pathology. Both clinical and preclinical studies have identified ECS dysregulation in Alzheimer’s disease—specifically, altered CB1R/CB2R expression and disturbed 2-AG/AEA signaling. Importantly, activating CB2R exerts neuroprotective and anti-inflammatory effects by controlling microglial activation, promoting autophagy, and attenuating amyloid-β (Aβ) and tau pathology. Inhibitors of MAGL and FAAH have shown promise in restoring ECS tone and reversing cognitive deficits in AD models. Phytocannabinoids such as CBD, CBG, and β-caryophyllene, as well as synthetic CB2R agonists (e.g., JWH-133), have demonstrated therapeutic potential through pathways involving PPAR-γ, NRF2, BDNF/TrkB, and NLRP3 inflammasome regulation. Clinical studies remain limited but suggest benefits for neuropsychiatric symptoms in AD. Emerging evidence also points to the retina as a potential site for early ECS-based diagnosis. Challenges such as CB1R-mediated psychotropic effects, receptor selectivity, and translational gaps remain. This review synthesizes multi-level (molecular, cellular, and systems) evidence to call for continued pursuit of ECS-targeted therapies, which represent a hopeful tactic for addressing AD.
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