Cannabidiol and Cannabigerol Cooperatively Regulation Autophagy affect Caco-2 Cell Viability

Abstract Cannabidiol (CBD) and Cannabigerol (CBG) are non-psychoactive cannabinoids known to affect both cancerous and non-cancerous cells. Autophagy is a critical regulator of cell survival and death; however, the impact of CBD and CBG on cell viability through autophagy remains limited. In this study, we show that low-dose combinations of CBD and CBG synergistically enhance Caco-2 cell proliferation, achieving effects comparable to those observed at higher doses. Both cannabinoids—whether applied individually at high concentrations or in low-dose combinations—activate autophagy. Correlation analyses between cell viability and autophagic flux, along with comparative assessments of wild-type and ATG9-deficient Caco-2 cells, demonstrate that the survival-promoting effects of CBD and CBG are closely associated with autophagy activation. Overall, these findings reveal that both individual and combined treatments significantly modulate Caco-2 cell viability under conditions with or without autophagy activation, emphasizing the substantial role of cannabinoid-regulated autophagy in influencing cell survival. Highlights Low-dose combinations of CBD and CBG synergistically enhance Caco-2 cell proliferation. Both high-dose individual treatments and low-dose combinations of CBD and CBG activate autophagy. CBD- and CBG-mediated autophagy paly beneficial role in supporting Caco-2 cell survival. Competing Interest Statement The authors have declared no competing interest.