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

ABSTRACT The increasing therapeutic incorporation of cannabis has expanded phytocannabinoid application, yet peripheral adverse effects like xerostomia raise concerns regarding emerging biotechnological formulations. This study evaluated the effects of cannabis‐based lipid nanoemulsions on the rat submandibular gland parenchyma. Forty male Wistar rats were distributed into five daily oral treatment groups for 21 days: vehicle control, CBD and THC (2.5 and 5 mg/kg), and isolated CBD (2.5 and 5 mg/kg). Submandibular glands were assessed via histopathology (H&E), acinar histomorphometry, periodic acid‐Schiff (PAS) histochemistry, immunohistochemistry for 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), cleaved caspase‐3, and cyclooxygenase‐2 (COX‐2) and collagen birefringence under polarized light. All treated groups exhibited significant histopathological alterations versus control ( p < 0.05). Isolated CBD groups displayed the most pronounced tissue injury, with extensive cytoplasmic vacuolization, hemorrhage, and severe acinar disorganization, although acinar density remained comparable among groups. PAS reactivity was significantly reduced only in CBD and THC groups, whereas oxidative DNA damage (8‐OHdG) was significantly increased in the CBD 2.5‐mg/kg group. All treated groups demonstrated enhanced periductal collagen deposition: isolated CBD groups showed a predominance of mature type I collagen fibers, whereas CBD and THC 5 mg/kg exhibited a higher proportion of immature type III fibers, indicating distinct extracellular matrix remodeling patterns. In conclusion, cannabis‐based lipid nanoemulsions induced histopathological injury, oxidative stress, and extracellular matrix remodeling in rat submandibular glands. Notably, isolated CBD produced more severe glandular damage than the CBD and THC combination, suggesting a protective modulatory effect of THC against CBD‐induced toxicity in salivary tissue, consistent with a pharmacodynamic interaction between these phytocannabinoids.