Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model.

Igor Koturbash,Laura E Ewing,Charles M Skinner,Stefanie Kennon-Mcgill,Mitchell R Mcgill,Bill J Gurley,Mahmoud A Elsohly,Charles M Quick,Larry A Walker

doi:10.3390/molecules24091694

Abstract

The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-week-old male B6C3F1 mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in EPIDIOLEX® (20 mg/kg). In the acute study, significant increases in liver-to-body weight (LBW) ratios, plasma ALT, AST, and total bilirubin were observed for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metabolism pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways associated with lipid and xenobiotic metabolism raises serious concerns about potential drug interactions as well as the safety of CBD.

Highlights

Cannabidiol (CBD) is a non-psychotropic phytochemical present in Cannabis sativa that has gained significant popularity over the last decade
A dose of 246 mg/kg was chosen as an initial dose as this is a mouse equivalent doses (MED). Analogous to those used in recent clinical trials (MED of 20 mg/kg CBD) [1,2]
We used analogous to those used in recent clinical trials (MED of 20 mg/kg CBD) [1,2]

Summary

Introduction

Cannabidiol (CBD) is a non-psychotropic phytochemical present in Cannabis sativa that has gained significant popularity over the last decade It is a major component of EPIDIOLEX® , a drug indicated for the treatment of drug-resistant epileptic seizures associated with Dravet and Lennox-Gastaut. The authors of a large clinical trial that utilized CBD (dose regimen 2.5–30 mg/kg/day) to treat 278 patients with Dravet syndrome reported adverse events in 93% of subjects [15]. Another recent study inferred a strong genotoxic potential for CBD at concentrations commonly detected in human blood [16]. CBD may have a high drug interaction potential as it modulates numerous cytochrome P450 enzymes responsible for xenobiotic metabolism [17,18,19,20,21]

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Conclusion