Neuroprotective Effects and Mechanisms of Cannabinoids in In Vitro Cell Models of Neurodegenerative Diseases: A Scoping Review

Background: Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Multiple sclerosis (MS) collectively affect millions of people worldwide, and substantial unmet needs remain for therapies that preserve neuronal structure and function. Current treatments can alleviate symptoms or modify selected disease processes, but they do not comprehensively target the interconnected cellular mechanisms that drive neuronal and axonal injury. Natural, semisynthetic, and synthetic cannabinoids have shown neuroprotective activity in preclinical models, but most remain at an early experimental stage, and their mechanisms of action have not been systematically mapped across disease contexts. Objective: This scoping review maps preclinical evidence, predominantly in vitro, with select studies incorporating in vivo validation, on exogenous cannabinoids and their neuroprotective mechanisms across cellular models of AD, PD, HD, and MS. The compounds examined include phytocannabinoids, synthetic cannabinoid receptor agonists, and cannabinoid-active phytochemicals (e.g., β-amyrin, as described by the original study authors). Methods: This review followed JBI methodological guidance and PRISMA-ScR reporting standards. The protocol was prospectively registered on the Open Science Framework (OSF; 10.17605/OSF.IO/TAQ9F). PubMed, MEDLINE, CINAHL, PsycINFO, and Web of Science were searched, yielding 8484 records (2844 after deduplication). Following two-stage screening in Rayyan, 194 reports were sought for full-text retrieval; 176 were assessed for eligibility, and 26 preclinical studies (2015–2025) met the inclusion criteria. Results: Most included studies were exclusively in vitro (n = 17); six combined in vitro and in vivo methods, and three combined in vitro methods with in silico or ex vivo components. The studies addressed AD (n = 11), PD (n = 8), general neuroinflammation models (n = 5), HD (n = 1), and MS (n = 1). Cannabidiol (CBD) was the most frequently studied compound (n = 9), followed by the synthetic agonists JWH-133 and ACEA (n = 6 combined), THC and its analogs (n = 5), and WIN 55,212-2 (n = 4). Evidence converged on three mechanistic domains: (1) anti-neuroinflammatory signaling in microglia and astrocytes; (2) antioxidant, anti-apoptotic, and mitochondrial pathways; and (3) protein aggregate clearance, autophagy, myelination, and neurotransmitter modulation. Receptor pharmacology emerged as a cross-cutting axis linking these domains, rather than a fourth, parallel mechanism. It spanned canonical cannabinoid receptor type 1 and type 2 (CB1R/CB2R) signaling, non-canonical receptors (peroxisome proliferator-activated receptor γ (PPARγ), G protein-coupled receptor 55 (GPR55), adenosine A2A receptor [A2AR], and transient receptor potential vanilloid 1 (TRPV1)), and receptor heteromerization. Conclusions: Cannabinoid-mediated neuroprotection in AD, PD, HD and MS cannot be explained by canonical receptor pharmacology alone. Three of 26 studies also reported receptor-independent or off-target mechanisms and formulation-dependent effects, highlighting potentially important but under-investigated contributors to cannabinoid-mediated neuroprotection. Translation priorities include systematic dose-response characterization, development of central nervous system (CNS)-penetrant CB2R agonists, and target-deconvolution studies to establish the prevalence of receptor-independent mechanisms and direct molecular effects.