Long term exposure to dietary cannabinoids inhibits rapid functional tolerance to ethanol in Drosophila melanogaster adults

In rodents, exposure to cannabidiol (CBD) was shown to alter responses to alcohol, primarily via CB1/CB2 signaling. However, CBD also targets non-canonical receptors whose potential roles in modulating CBD-alcohol interactions remain unknown. We used a simple behavioral assay to compare responses to ethanol in <i>Drosophila melanogaster</i> , which lacks CB1/CB2 genes but has orthologs for non-canonical targets. Flies fed with a CBD-enriched diet retain baseline ethanol sensitivity but fail to develop rapid functional tolerance to ethanol. These findings support using <i>Drosophila</i> as a model to study non-canonical CBD signaling in ethanol behaviors relevant to the development of alcohol use disorder.