Establishment of a point of departure for CBD hepatotoxicity employing human HepaRG spheroids.

The United States Food and Drug Administration recently approved the use of Cannabis sativa derived cannabidiol (CBD) in the treatment of Dravet Syndrome and Lennox-Gastaut Syndrome, under the trade name, Epidiolex. In double-blinded, placebo-controlled clinical trials, elevated ALT levels were observed in some patients, but these findings could not be uncoupled from the confounds of potential drug-drug interactions with co-administration of valproate and clobazam. Given the uncertainty of the potential hepatatoxic effects of CBD, the objective of the present study was to determine a point of departure for CBD, using human HepaRG spheroid cultures, followed by transcriptomic benchmark dose analysis. Treatment of HepaRG spheroids with CBD for 24 and 72 h, resulted in EC50 concentrations for cytotoxicity of 86.27 µM and 58.04 µM, respectively. Subsequent transcriptomic analysis at these timepoints demonstrated little alteration of gene and pathway data sets at a CBD concentration at or below 10 µM. Although this current analysis was conducted using liver cells, interestingly the findings at 72 h post CBD treatment showed suppression of many genes more commonly associated with immune regulation. Indeed, the immune system is a well-established target for CBD based on immune function assays. Collectively, in the present studies a point of departure was derived using transcriptomic changes produced by CBD in a human cell-based model system, which has been shown to accurately translate to human hepatotoxicity modeling.