Optimal Cannabinoid-Terpene Combination Ratios Suppress Mutagenicity of Gastric Reflux in Normal and Metaplastic Esophageal Cells

Abstract

BackgroundEsophageal adenocarcinoma (EAC) frequently arises from chronic exposure to acid and bile reflux, with secondary bile acids, such as deoxycholic acid (DCA), contributing to its pathogenesis through mechanisms involving reactive oxygen species (ROS), oxidative DNA damage, and resistance to apoptosis. The human endocannabinoid system (ECS) regulates diverse anti-inflammatory, antioxidant, and analgesic pathways implicated in disease modulation. Despite its therapeutic promise, effective pharmacological activation of the ECS remains challenging. ObjectivesThis study aimed to evaluate whether specific cannabinoid-terpene combinations targeting the ECS could attenuate the mutagenic and cytotoxic effects of bile acid-induced stress in esophageal cell models. Additionally, we assessed the clinical significance of ECS-related protein receptors in the progression of EAC. DesignIn vitro experimental models combined with clinical samples analyses. MethodsWe utilized in vitro models, including human esophageal epithelial cell lines exposed to DCA and a Barretts esophagus gastroesophageal reflux (GER) model subjected to low pH and a bile acid cocktail. Patient-derived samples were analyzed to investigate the clinical association of ECS pathway markers with EAC progression. Experimental models were treated with varying ratios of phyto-cannabinoids and terpenes. Endpoints included assessment of DNA damage, mitochondrial membrane potential, and ROS production to identify optimal compound combinations. Expression of ECS-related protein receptors was evaluated in clinical samples to elucidate their role in EAC development. ResultsA 1:5 ratio of cannabigerol (CBG) to Phytol (Phy) was found to significantly reduce DCA-induced DNA damage, preserve mitochondrial membrane potential, and decrease ROS levels. This combination also enhanced apoptosis in damaged cells and diminished mutagenicity. Analysis of patient samples revealed that the expression of the ECS-associated receptor protein CB1 correlated with EAC progression, suggesting a broader clinical role for ECS modulation in cancer prevention. ConclusionModulation of the ECS through carefully selected cannabinoid-terpene ratios can mitigate bile acid-induced esophageal damage and may reduce carcinogenic progression. These findings support further in vivo investigations and raise the possibility of expanding cannabinoid-terpene therapeutics to other conditions involving similar pathogenic processes.