Safety Assessment of a Hemp Extract using Genotoxicity and Oral Repeat-Dose Toxicity Studies in Sprague-Dawley Rats

Dziwenka, Margitta; Coppock, Robert; Alexander, McCorkle; Palumbo, Eddie; Ramirez, Carlos; Lermer, Stephen

Reported rodent studies have differing findings on hepatotoxicity when CBD is orally administered in high doses [4, 26] . Hepatocellular hypertrophy with a centrilobular pattern was observed in rat livers in the study being reported. This pattern of hepatocellular hyperplasia is frequently observed in rats and other animals exposed to agents that induce the CYP family of enzymes and can be associated with activation of peroxisome proliferator-activated receptors (PPAR) [27] . THC has affinity for PPARα, and CBD has very low to no affinity for PPARα and high affinity for PPARγ [28] . Interaction with the PPARγ is one of the mechanisms of action for CBD. In our study, we did not show the mechanism of action for the hepatocellular hypertrophy. We did show that the activities of liver enzymes in serum were not significantly changed by treatment with the test article and the hepatocellular hypertrophy was reversed during the 28-day recovery period. In the study reported by Marx et al. [4] , no histopathological changes were observed in the livers from the treated and control rats and the liver weights in the male and female rats in the 360 and 720 mg/kg body weight/day were significantly increased (p < 0.05) at 90 days. The 28-day recovery males and females receiving 720 mg/kg/day retained the significantly increased in hepatic weights. The induction of hepatic drug metabolizing enzymes (HDMEs) can be associated with increased liver weights, and hepatocellular hypertrophy and hyperplasia (increased number of cells) and elevation of hepatic-source enzymes in serum. The evidence in the scientific literature supports a conclusion that the centrilobular pattern of hepatocellular hypertrophy and increased liver weights observed in our study was due to induction of HDMEs and/or peroxisomes. No hepatocellular necrosis and changes in the clinical chemistries occurred which is evidence that liver damage did not occur. This conclusion is further supported by not observing hepatocellular hypertrophy and increased liver weights in the 28-day recovery groups that received the test article. Studies in laboratory animals have shown CBD to protect the liver from toxic insults [8, 29, 30] .