Kava beverages, made from dried roots of the shrub Piper methysticum, have been used ceremonially and socially in the South Pacific and in Europe since the 1700s. The drink is reported to have pleasant mild psychoactive effects, similar to alcoholic beverages. In the United States, kava kava is an herbal product used extensively as an alternative to anti-anxiety drugs such as Xanax® and Valium®. It has also been reported as being used to help children with hyperactivity and as a skin-conditioning agent in cosmetics. Kava kava was nominated by the National Cancer Institute for study because of its increasing use as a dietary supplement in the mainstream United States market and reports of liver toxicity among humans. Male and female F344/N rats and B6C3F1 mice received kava kava extract in corn oil by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.
2-WEEK STUDY IN RATSGroups of five male and five female rats were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg body weight, 5 days per week for 16 days. One female rat administered 2.0 g/kg kava kava extract died on day 3 of the study. Mean body weights of all dosed groups of rats were similar to those of the vehicle controls. Clinical findings included abnormal breathing, ataxia, and lethargy in the 2.0 g/kg groups of males and females and ataxia and lethargy in the 1.0 g/kg group of females. Liver weights were significantly increased in 1.0 and 2.0 g/kg males and in 0.5 g/kg or greater females compared to the vehicle controls. Minimal hepatocellular hypertrophy occurred in all 2.0 g/kg males and in all females administered 0.25 g/kg or greater.
There was a dose-related increase in the incidences of interstitial cell adenoma in the testis with increased incidences of bilateral neoplasms.
The incidences of hepatocellular hypertrophy in 1.0 g/kg males and females were significantly greater than those in the vehicle controls. Increased γ-glutamyltransferase activity and/or bile salt concentrations in males and females may represent a cholestatic event related to the hepatocellular hypertrophy observed in rats. Enzyme induction may have played a role in the increased γ-glutamyltransferase activity. Significantly increased incidences of centrilobular fatty change occurred in 0.1 and 1.0 g/kg males. The incidences of inflammation, ulcer, and epithelial hyperplasia in the forestomach were significantly increased in 1.0 g/kg males and females. The severity of nephropathy was increased in 1.0 g/kg male rats, and the incidence of nephropathy was significantly increased in 1.0 g/kg females. Incidences of transitional epithelial hyperplasia of the pelvis of the kidney were significantly increased in 1.0 g/kg males and 0.3 and 1.0 g/kg females. The incidences of retinal degeneration in the eye were significantly increased in 1.0 g/kg males and females. The incidences of metaplasia of pancreatic acinar cells to a hepatocytic morphology increased in 1.0 g/kg males and females, and the increase in males was significant.
Significantly decreased incidences of pars distalis adenoma in the pituitary gland occurred in 1.0 g/kg males and in 0.1 and 1.0 g/kg females. The incidence of fibroadenoma of the mammary gland in 1.0 g/kg females was significantly less than that in the vehicle control group.
The incidences of hepatoblastoma in 0.5 and 1.0 g/kg males were significantly increased compared to the vehicle controls. The incidences of hepatocellular carcinoma or hepatoblastoma (combined) were significantly increased in 0.5 g/kg males. Incidences of hepatocellular carcinoma were increased in all dosed groups of females, and the increase was significant in the 0.25 g/kg group. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in 0.25 and 0.5 g/kg females.
In the liver, the incidences of centrilobular hypertrophy in all dosed groups of males and females were significantly greater than those in the vehicle control groups. Significantly increased incidences of eosinophilic foci occurred in 0.5 g/kg males and in 1.0 g/kg males and females, and the incidence of angiectasis was significantly increased in the 1.0 g/kg males. The incidences of hepatocellular necrosis were significantly increased in 0.25 and 1.0 g/kg males.
In the forestomach, the incidences of chronic inflammation, epithelial hyperplasia, and erosion were significantly increased in 0.5 and 1.0 g/kg females, and the incidence of ulceration was significantly increased in 1.0 g/kg females.
Kava kava extract administration resulted in increased incidences of nonneoplastic lesions in the liver, forestomach, kidney, eye, and pancreas of male and female rats, liver of male and female mice, and forestomach of female mice.
Synonyms: Antares, ava; ava pepper; ava pepper shrub; ava root; awa; bornyl cinnamate; cavain; (+)-dihydrokawain-5-ol; Fijian kava; flavokavines A and B; 6-dihydroyangonin; gea; gi; grog; intoxicating long pepper; intoxicating pepper; kao; kava kava extract LI 140; kava kava rhizome; kava root; kavain; kavakava; kavalactones; kavapiper; kavapyrones; kavarod; kavasporal forte; kave-kave; kawa; kawa kawa; kawa pepper; Kawa Pfeffer; kew; LI150; long pepper; Macropiper latifolium; malohu; maluk; maori kava; meruk; 11-methoxy-5, 5-hydroxydihydrokawain; milik; olanzapine; pepe kava; piperis methystici rhizome; pipermethystine; Rauschpfeffer; rhizoma piperis methystici; rhizome di kava-kava sakaua; risperidone; sakau; tonga; WS 1490; wurzelstock; yagona; yangona; yaqona; yongonaBotanical name: Piper methysticum
|Doses in corn oil by gavage||0, 0.1, 0.3, or 1.0 g/kg||0, 0.1, 0.3, or 1.0 g/kg||0, 0.25, 0.5, or 1.0 g/kg||0, 0.25, 0.5, or 1.0 g/kg|
|Body weights||1.0 g/kg group 10% less than the vehicle control group after week 65||1.0 g/kg group 10% less than the vehicle control group after week 41||Dosed groups generally similar to the vehicle control group||1.0 g/kg group 11% less than the vehicle control group after week 21|
|Survival rates||34/49, 35/50, 34/50, 31/50||34/50, 35/50, 24/50, 34/50||34/50, 33/50, 35/50, 36/50||38/50, 34/50, 45/50, 37/50|
|Nonneoplastic effects||Liver: hepatocyte, hypertrophy (0/49, 2/50, 2/50, 22/50); centrilobular, fatty change (1/49, 7/50, 4/50, 21/50)
Stomach, Forestomach: inflammation (8/49, 4/50, 9/50, 22/50); ulcer (4/49, 0/50, 6/50, 13/50); epithelium, hyperplasia (6/49, 4/50, 11/50, 27/50)
Kidney: severity of nephropathy (1.4, 1.2, 1.8, 3.1); pelvis, transitional epithelium, hyperplasia (0/49, 1/50, 1/50, 15/50)
Eye: retina, degeneration (6/49, 6/50, 10/50, 16/50)
Pancreas: acinus, metaplasia, hepatocyte (0/49, 0/50, 0/50, 6/50)
| Liver: hepatocyte, hypertrophy (5/50, 2/50, 3/50, 33/50)
Stomach, Forestomach: inflammation (5/49, 7/50, 7/50, 13/50); ulcer (1/49, 1/50, 3/50, 7/50); epithelium, hyperplasia (5/49, 6/50, 8/50, 19/50)
Kidney: nephropathy (34/50, 35/50, 37/50, 43/50)
Eye: retina, degeneration (5/50, 5/50, 5/50, 12/50)
Pancreas: acinus, metaplasia, hepatocyte (0/49, 1/50, 0/50, 4/50)
|Liver: centrilobular, hypertrophy (0/50, 34/50, 30/50, 39/50); eosinophilic focus (28/50, 32/50, 42/50, 43/50); angiectasis (3/50, 6/50, 7/50, 10/50); necrosis (3/50, 10/50, 7/50, 13/50)|| Liver: centrilobular, hypertrophy (0/50, 20/50, 48/50, 49/50); eosinophilic focus (9/50, 7/50, 16/50, 26/50)
Stomach, Forestomach: inflammation, chronic (3/50, 6/50, 21/50, 22/50); epithelium, hyperplasia (3/50, 6/50, 23/50, 24/50); erosion (0/50, 1/50, 14/50, 11/50); ulcer (0/50, 2/50, 3/50, 6/50)
|Neoplastic effects||None||None||Liver: hepatoblastoma (0/50, 4/50, 9/50, 12/50)||Liver: hepatocellular carcinoma (3/50, 13/50, 8/50, 8/50); hepatocellular adenoma or carcinoma (10/50, 21/50, 20/50, 13/50)|
|Equivocal findings||Testes: interstitial cell, adenoma (37/49, 44/50, 49/50, 46/50)||None||None||None|
|Level of evidence of carcinogenic activity||Equivocal evidence||No Evidence||Clear evidence||Some evidence|
|Bacterial gene mutations:
||Negative in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535 with and without S9; negative in Escherichia coli WP2 uvrA/pKM101 with and without S9|
Mouse peripheral blood in vivo:
|Negative in males and females|
Date: March 2012