Transcriptomic comparison on the mechanism of action of four major constituent cannabinoids in hemp extract.

BACKGROUND: A variety of health benefits have been claimed, but not scientifically confirmed, for cannabidiol (CBD) and other nonintoxicating cannabinoids in hemp extracts such as cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN). On the other hand, CBD has been reported to cause hepatotoxicity in clinical trials and research studies, while little is known about the safety of other cannabinoids. In the current study, we set out to understand the mechanism(s) of action of these cannabinoids, beneficial or adverse, through a comprehensive functional analysis of a recently published transcriptomic dataset. METHODS: iPSC-derived hepatocytes were exposed to 40 µM CBC, 20 µM CBD, 40 µM CBG, and 10 µM CBN, respectively, for 24 h. Gene expression changes were profiled using Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Functional analysis was conducted using Ingenuity Pathway Analysis. RESULTS: Each compound impacted a unique list of canonical pathways, upstream regulators, diseases and biological functions, toxicity functions, and gene interaction networks with distinctive activation/inhibition patterns. Overall, the cannabinoids were predicted to affect metabolism and to have some beneficial effects on cardiovascular disease but adverse effects on the neural system. In addition, CBC and CBN, similar to but more potently than CBD, displayed liver toxicity and the potential to cause cancer while CBG protected from these adverse effects. CONCLUSION: This study provides a comprehensive comparison across the four cannabinoids and points to the directions for further research on the therapeutic effects and potential toxicities associated with long-term use of these cannabinoids.