Subchronic Exposure to Cannabis-Based Nanoemulsions Induces Histopathological and Molecular Alterations in the Rat Submandibular Gland.

Bullo L.; de Aguiar G.; Souza D.; Dos Anjos Rosário B.; de Oliveira F.; Magalhaes F.; Ricardo N.; Silveira E.; Zampieri D.; de Barros Viana M. et al. · Journal of applied toxicology : JAT · 2026

**Background & Methods** This experimental study investigated the histopathological effects of cannabis-based lipid nanoemulsions on rat submandibular glands. Forty male Wistar rats received daily oral treatment for 21 days across five groups: vehicle control, CBD and THC combination (2.5 and 5 mg/kg), and isolated CBD (2.5 and 5 mg/kg), with comprehensive histopathological and molecular analysis performed. **Key Findings** • All cannabis-treated groups exhibited significant histopathological alterations compared to control, with isolated CBD demonstrating the most severe tissue injury including extensive cytoplasmic vacuolization, hemorrhage, and acinar disorganization. Acinar density remained comparable across all groups. • Oxidative stress markers were elevated selectively in treated groups, with significantly increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) oxidative DNA damage in the CBD 2.5-mg/kg group. PAS reactivity was significantly reduced only in CBD and THC groups, indicating altered carbohydrate metabolism in salivary tissue. • Enhanced periductal collagen deposition occurred in all treated groups with distinct remodeling patterns: isolated CBD groups showed predominance of mature type I collagen fibers, while CBD and THC 5-mg/kg combination exhibited higher proportions of immature type III fibers, suggesting differential extracellular matrix remodeling mechanisms. **Dosage & Administration** CBD and THC combination: 2.5 mg/kg and 5 mg/kg daily oral administration. Isolated CBD: 2.5 mg/kg and 5 mg/kg daily oral administration. Treatment duration: 21 days. **Safety & Adverse Effects** Dose-dependent histopathological injury to submandibular gland tissue was observed across all treatment groups. Isolated CBD produced more severe glandular damage including tissue necrosis, inflammatory changes, and oxidative stress compared to CBD and THC combination, suggesting potential dose-dependent toxicity in salivary tissue. No systemic adverse effects or animal mortality were explicitly reported. **Evidence Quality** This is a preclinical animal study with inherent limitations for human extrapolation. The findings suggest potential xerostomia (dry mouth) risk with cannabis nanoemulsion formulations. The study provides novel mechanistic data on cannabinoid effects on salivary glands but lacks clinical translation. The apparent protective effect of THC against CBD-induced toxicity is noteworthy and warrants further investigation. Evidence quality is moderate for preclinical research; human safety data in cannabis product development remains limited.

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