The sub-acute toxicity of kavalactone in rats: a study of the effect of oral doses and the mechanism of toxicity in combination with ethanol

Kava is a herbal supplement and beverage made from the Piper methysticum plant, which is known for its recreational use as a mood enhancer, relaxation, as well as pain relief for centuries. Kava is widely used among alcoholics, but it is dangerous and potentially fatal. The objectives of this study were to examine the sub-acute toxicity effects of different doses of 70% kavalactone (KL) in rats by oral application, as well as to elucidate the mechanisms of toxicity alone and in combination with ethanol (EtOH). The most common side effects observed were abnormal breathing, ataxia, lethargy, loss of appetite, indigestion, and loss of coordination, especially in the 800 mg/kg bw, po bodyweight dosage of kava treatment group alone, and in combination with EtOH. In the sub-acute study, there were dose-related decreases in body weight, feed intake, and water consumption rates. Gross and histopathological findings revealed that the liver was abnormal in color, size, consistency, and the weight significantly increased at a dose of 800 mg/kg bw, po, with KL alone and a greater increase in combination with EtOH. Hepatocellular hypertrophy (HP) and necrosis with Kupffer cells hyperplasia were observed in the periacinar zone of all rats dosed with KL (800 mg/kg bw, po) alone, and extensive changes were observed in combination with EtOH. The periportal (Z1) and mid-zonal (Z2) areas of hepatocytes were less affected as compared to the periacinar zone. These results demonstrate that EtOH exacerbated the sedative and hypnotic activity of KL, and markedly increased toxicity. The histopathological results supported the clinical and biochemical findings and the severity of hepatic damage in a dose-dependent manner.