We previously reported that both cannabidiol (CBD) and low‑dose naltrexone (LDN) exhibit complex effects on G‑protein coupled receptors, which can impact the expression and function of other members of this superfamily. These receptors feed into and interact with central signalling cascades that determine the ease by which cells engage in apoptosis, and can be used as a way to prime cancer cells to other treatments. The present study was designed to investigate the effect of combining these two agents on cancer cell lines in vitro and in a mouse model, and focused on how the sequence of administration may affect the overall action. The results showed both agents had minimal effect on cell numbers when used simultaneously; however, the combination of LDN and CBD, delivered in this specific sequence, significantly reduced the number of cells, and was superior to the regimen where the order of the agents was reversed. For example, there was a 35% reduction in cell numbers when using LDN before CBD compared to a 22% reduction when using CBD before LDN. The two agents also sensitised cells to chemotherapy as significant decreases in cell viability were observed when they were used before chemotherapy. In mouse models, the use of both agents enhanced the effect of gemcitabine, and crucially, their use resulted in no significant toxicity in the mice, which actually gained more weight compared to those without this pre‑treatment (+6.5 vs. 0%). Overall, the results highlight the importance of drug sequence when using these drugs. There is also a need to translate these observations into standard chemotherapy regimens, especially for common tumour types where treatment is often not completed due to toxicities.
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