Bookshelf

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

Kava Kava

Last Update: April 10, 2018 .

OVERVIEW

Introduction

Kava kava is an herbal derived from roots of the plant Piper methysticum, which has been used for centuries as a recreational and ceremonial drink in Oceania and more recently in concentrated forms in herbal medications to treat anxiety and insomnia. Products labeled as kava have been linked to the development of clinically apparent acute liver injury which can be severe and even fatal.

Background

Kava kava is an herbal derived from roots of the plant Piper methysticum (“intoxicating Pepper” plant), a member of the pepper family found in the Western and South Pacific. More commonly referred to simply as “kava” (bitter), it has been used for centuries as a recreational and ceremonial drink in Oceania (Polynesia, Micronesia and Macronesia). It is prepared from the roots of the plant which are ground into a fine pulp to which water is added. The active ingredients are kavapyrones (kavalactones), which have effects similar to alcohol, such as relaxation, talkativeness, and euphoria, while reportedly maintaining mental clarity. For these reasons, kava has been proposed to be anxiolytic and used in patients with anxiety disorders and as treatment for insomnia, premenstrual syndrome and stress. Kava appears to have an abuse potential, but it is rare with conventional doses. Recently, concerns have arisen regarding the safety of kava products, in particular due to reports of liver injury. For this reason, the use of kava has been banned or restricted in many countries of the world such as Germany, Switzerland, France, Canada, and Great Britain. However, several groups have disputed the evidence for hepatotoxicity, suggesting that responsibility for liver injury lies with adulterants or concomitant drugs or herbals. Furthermore, the literature on liver injury from kava has included several incomplete or overlapping reports, and causality was rarely well shown. Nevertheless, there are a small number of cases of severe hepatic injury arising during therapy that are convincing. Kava in many formulations remains available from nutrition stores and the Internet.

The kava pyrones are believed to have anxiolytic, analgesic, muscle relaxing, and anticonvulsant effects, mediated by effects on the limbic system, the part of the brain linked to emotions. The mechanism of action of the pharmacological effects of kava has yet to be elucidated. Research has demonstrated that several factors, including concentration, type of preparation, kava pyrone content, and kava variety used may affect pharmacologic activity. Therapeutic uses of kava include the treatment of anxiety, insomnia, and stress. Its abuse potential is low, but not absent. Suggested dosage for treatment of nonpsychotic anxiety is 105 to 210 mg daily for three to four weeks. The most common side effects of kava are headache, dizziness, drowsiness, depression, diarrhea, and occasionally dermatologic manifestations.

Hepatotoxicity

The frequency of adverse reactions to kava, particularly liver injury, is not known. Based upon reported cases, the estimated frequency of clinically apparent liver injury due to kava is less than 1:1,000,000 daily doses. However, spontaneous reporting is believed to capture less than 1% of severe adverse events from the use of dietary supplements. Between 50 and 100 cases of clinically apparent liver injury have been published or discussed in the literature. Advocates of the herbal have strongly rejected these numbers, disputing both their accuracy and the causality assessment process. Still, there seem to be convincing evidence in some cases of severe hepatitis ending in fulminant hepatic failure, requiring liver transplantation, and even leading to death. Patients typically present with fatigue, nausea, elevations in serum aminotransferase levels, and jaundice 2 to 24 weeks after starting use of the product. The pattern of enzyme elevations is hepatocellular with marked elevations in serum aminotransferase and minimal increases in alkaline phosphatase levels. In some cases, features of immunoallergic hepatitis (rash, fever, eosinophilia, and recurrence on reexposure) are present. Liver biopsy findings include focal hepatocellular necrosis, lobular inflammation and intrahepatic cholestasis. In more severe cases there is massive or submassive necrosis.

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Injury

The cause of hepatotoxicity from kava is unclear. In vitro studies suggest that the kavalactones are not intrinsically cytotoxic, although other components of kava preparations may be. Kava can also cause herb-drug interaction. Although in vitro studies suggest that kavalactones inhibit several cytochrome P450 isoenzymes, human studies suggest that it is a inhibitor of CYP 2E1 alone, and that its effects are modest. Clinical cases of hepatotoxicity due to kava suggest an idiosyncratic or immunoallergic pathogenesis. The possibility of mislabeling or adulteration with hepatotoxic herbals is always an issue.

Outcome and Management

The severity of liver injury ranges from transient and moderate enzyme elevations to symptomatic acute hepatitis to acute liver failure. In most instances, the liver injury subsides within 1 to 3 months of discontinuing the herbal product, but if fulminant hepatitis develops, a liver transplant may be required. Rechallenge leads to prompt recurrence and should be avoided.

Other Names: Intoxicating pepper, kavain, kawa pepper

CASE REPORTS

Case 1. Acute liver failure treated with liver transplantation after kava use.

[Modified from: Brauer RB, Stangl M, Stewart JR, Pfab R, Becker K. Acute liver failure after administration of herbal tranquilizer kava-kava (Piper methysticum). J Clin Psychiatry 2003; 64: 216-8. PubMed Citation]

A 22 year old woman presented with a 3 week history of nausea and fatigue, followed by jaundice 4 months after starting kava kava (240 mg daily). Her other medications included oral contraceptives (norgestimate, 180-250 μg and ethinyl estradiol, 35 μg) for a year and a half, and rizatriptan (10 mg) and acetaminophen (500 mg) approximately twice a month as needed for migraine headaches. She was initially found to be jaundiced with a serum bilirubin of 10.4 mg/dL. She was told to stop kava. A week later she was hospitalized for worsening jaundice and mental slowing. At that point, serum bilirubin was 40 mg/dL, ALT 2442 U/L, alkaline phosphatase 246 U/L, and the prothrombin time index

Key Points

Laboratory Values

Comment

This patient developed a severe acute hepatitis-like syndrome 4 months after starting kava kava for depression. Other causes of acute liver injury were appropriately excluded. Progressive hepatic failure followed and led to emergency liver transplantation. Because at least a dozen instances of acute liver failure have been reported in patients taking kava, the agent has been banned in many countries as an over-the-counter product for therapy of anxiety or mood disorders. The argument that prescription anxiolytic agents have a similar rate of severe hepatic reactions is not correct. Prescription medications with the number of published instances of severe hepatic injury attributed to kava would be similarly withdrawn from use.

Case 2. Death from acute liver failure after kava kava use.

[Modified from: Gow PJ, Connelly NJ, Hill RL, Crowley P, Angus PW. Fatal fulminant hepatic failure induced by a natural therapy containing kava. Med J Aust 2003; 178: 442-3. PubMed Citation]

In July 2002, a 56 year old Australian woman who had been taking a kava product for three months developed nausea and jaundice. The product was provided by a naturopath for anxiety to be taken three times daily: Kava 1800 Plus was labeled as containing 60 mg of kavalactones, 50 mg of Passiflora incarnata (maypop, passion flower) and 100 mg of Scutellaria laterifloria (blue skullcap). She had no previous major medical problems except for benign monoclonal gammopathy. She had initially been seen with a two week history of fatigue, nausea and increasing jaundice. She had no risk factors for viral hepatitis, no history of liver disease and drank minimal amounts of alcohol. She had also been taking some vitamin and mineral supplements, but no other prescription medications. Examination upon hospital admission revealed deep jaundice, but no fever, rash or signs of chronic liver disease. Laboratory tests showed a total bilirubin of 12.2 mg/dL, ALT 4539 U/L, alkaline phosphatase 190 U/L, albumin 3.4 g/dL and INR 2.3 (Table). Tests for acute hepatitis A, B, and C were negative as were serology of acute Epstein Barr virus and cytomegalovirus infection. Serum copper and ceruloplasmin levels were normal. Antinuclear antibodies were present in a titer of 1:160, without smooth muscle antibodies and with stable serum immunoglobulin levels. Plasma acetaminophen levels were negative. An abdominal ultrasound revealed a small liver with normal flow in the hepatic arteries, hepatic veins and portal veins and no evidence of extrahepatic obstruction. A trans-jugular liver biopsy showed severe acute hepatitis with marked parenchymal necrosis and collapse. Over the next week, she developed deepening jaundice, coagulopathy and hepatic encephalopathy and was listed for transplantation which was performed on hospital day 17. The surgery was complicated by massive bleeding that did not correct following implantation of the donor liver, and the patient died of circulatory failure. Histological examination of the explanted liver confirmed the presence of massive hepatic necrosis.

Key Points

Laboratory Values

Comment

This patient developed a severe acute hepatitis-like syndrome, followed by acute liver failure three months after starting a kava containing combination herbal medication. Other causes of acute liver injury were excluded. This case occurred after a warning was made by the Australian Regulatory agency and stresses the difficulty of managing risks that are very rare, but nevertheless potentially profound. While the herbal medication that she was taking included multiple components, the association of hepatic injury with kava has been far stronger than with the other listed herbals. The possibility of mislabeling or contamination of the herbal preparation was raised with the case, but these concerns affect all herbals that are not formally regulated.

Case 3. Acute hepatitis attributed to kava.

[Modified from: Bujanda L, Palacios A, Silvarino R, Sanchez A, Munoz C. [Kava-induced acute icteric hepatitis], Gastroenterol Hepatol 2002; 25: 434-5. PubMed Citation]

A 55 year old man using kava extract (250 mg capsule, 3 times daily) for 2 weeks began to experience weakness, fatigue and right upper quadrant discomfort. He continued taking the extract for 3 months when he developed jaundice. He denied taking any other medications and denied alcohol use or risk factors for viral hepatitis. Liver tests were known to have been normal in the past. On physical examination, he was jaundiced but had no signs of chronic liver disease, rash or fever. Laboratory tests showed a total serum bilirubin of 6.5 mg/dL, ALT 2300 U/L, AST 1506 U/L, alkaline phosphatase 514 U/L and GGT 874 U/L (Table). The prothrombin index was 60%. Tests for hepatitis A, B and C were negative as were routine autoantibodies. Abdominal ultrasound and magnetic resonance cholangiography showed no evidence of extrahepatic obstruction. A liver biopsy showed centrilobular hemorrhagic necrosis without steatosis, fibrosis, or cholestasis and with minimal mixed inflammatory infiltrates. Two weeks after stopping the kava product, liver tests began to improve and were near normal when he was seen four months later.

Key Points