High doses of cannabidiol induce neurotoxicity in cell culture systems

Abstract

Abstract Recent studies have demonstrated that cannabinoids are potentially effective in treating various neurological conditions, and cannabidiol (CBD), one of the most studied compounds, has been proposed as a non-toxic option. However, the adverse effects of CBD on neurodevelopmental processes have rarely been studied in cell culture systems. To gain a better understanding of CBD's impact on neuraldevelopment, we exposed neural progenitor cells (NPCs) to different concentrations of CBD (1 µM, 5 µM, and 10 µM) and investigated the morphology, migration, differentiation, cell death, and gene expression in 2D and 3D bioprinted models. Our results showed that CBD was more toxic at higher concentrations (5 µM and 10 µM) and affected the viability of NPCs than at lower concentration (1µM), in both 2D and 3D models. Moreover, our study identified that higher concentrations of CBD drastically reduced the size of neurospheres and the number of NPC within neurospheres, impaired the morphology and mobility of neurons and astrocytes after differentiation, and reduced neurite sprouting. Interestingly, we also found that CBD alters cellular metabolism by influencing the expression of glycolytic and β-oxidative enzymes in the early and late stages of metabolic pathways. Therefore, our study, demonstrated that higher concentrations of CBD promote important changes in cellular functions that are crucial during CNS development.