Abstract
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 Drosophila melanogaster , 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 Drosophila as a model to study non-canonical CBD signaling in ethanol behaviors relevant to the development of alcohol use disorder.