Endocannabinoid system dysregulation in oral diseases: mechanistic insights and therapeutic modulation

Abstract Background Chronic inflammatory and neoplastic diseases of the oral cavity, including periodontitis, oral lichen planus (OLP), oral squamous cell carcinoma (OSCC), and oral mucositis, represent a significant global health burden. Current therapeutic strategies face limitations such as disease recurrence, adverse effects, and incomplete restoration of tissue homeostasis. The endocannabinoid system (ECS), a ubiquitous lipid signaling network comprising endocannabinoids, cannabinoid receptors, and metabolic enzymes, has emerged as a master regulator of inflammation, immune responses, and tissue repair. Main body This narrative review synthesizes current evidence on ECS dysregulation in oral diseases and evaluates the therapeutic potential of cannabinoid-based interventions. In periodontitis, dysfunction of the cannabinoid receptor type 2, driven by sustained inflammatory stress, amplifies neutrophil recruitment, matrix metalloproteinase production, and osteoclast differentiation, accelerating alveolar bone loss. OLP exhibits an imbalance between anti-inflammatory N-acylethanolamines and pro-inflammatory prostaglandins. In OSCC, conflicting prognostic associations of cannabinoid receptor type 2 expression and altered endocannabinoid metabolism suggest complex, context-dependent roles. Preclinical evidence suggests that phytocannabinoids such as cannabidiol and cannabigerol reduce pro-inflammatory cytokines, inhibit periodontal pathogens, protect against chemotherapy-induced oral mucositis via antioxidant pathways, and induce oral cancer cell death. Preliminary clinical evidence suggests that topical cannabidiol formulations may improve gingival inflammation, although data remain limited. Furthermore, compositions including extra virgin olive oil, xylitol, and betaine may modulate endocannabinoid system gene expression through epigenetic mechanisms, offering non-cannabinoid therapeutic avenues. Conclusion The ECS is emerging as a relevant regulatory network in oral medicine, integrating immune modulation, inflammatory signaling, oxidative stress, and cellular proliferation. Evidence from periodontitis, OLP, and OSCC suggests that ECS dysregulation may contribute to both chronic inflammation and tumor-related pathways. However, current knowledge remains largely derived from experimental and observational studies, and clinical evidence is still limited. Future research should focus on mechanistic studies, standardized methodologies, and well-designed clinical trials to clarify the therapeutic potential of ECS modulation.