Kava Study 2002

Kava safety questioned due to possible link to liver toxicity

(from HerbalGram www.herbalgram.org, 2002)

Expert analysis of case reports says there is insufficient evidence to make causal connection

by Mark Blumenthal

The biggest subject on the front burner in the herb community in the past six months is the potential hepatotoxicity of kava. European regulatory officials have begun investigating kava based on case reports of liver toxicity associated with the popular South Pacific herb. News stories first began surfacing in November, increasing in December culminating at the end of the year with a front-page article in USA Today (Rubin, 2001); in mid-January after The New York Times (Burros, 2002) and Washington Post (Packer-Tursman, 2002) published articles, things started picking up again, culminating in an Associated Press article that was carried in presumably hundreds of papers across the country (Neergard, 2002).

The American Botanical Council (ABC), has been very interested in the issue surrounding the case reports of hepatotoxicity associated with ingestion of kava since isolated reports became known in 1999 (Strahl, 1998). Subsequently, news of possible European regulatory action began to surface as increased reports became available last fall. ABC has been collecting an extensive volume of data on this subject and has been in contact with German regulatory officials, leading scientists at universities and phytomedicine manufacturers here and in Europe, and industry trade organizations in Germany and the United States. What follows is an attempt to put some of the kava situation into a chronological perspective. This article will not, however, attempt to evaluate the safety issue itself; since that task is being addressed by more qualified experts.

Kava is the traditional ritual tranquilizing beverage from the rootstock of Piper methysticum Forst., a plant in the family Piperaceae (pepper family). It has long enjoyed a reputation as the most revered medicinal and ritual herb in Polynesia, where it is used for ceremonial purposes, as a symbolic welcome for VIPs, as a beverage for culminating the marriage ceremony, and as a medicine for relaxation and also used to treat urinary tract infections (Singh and Blumenthal, 1997). There have been at least 13 clinical studies conducted on 619 participants demonstrating kava’s positive effects for indications including anxiety, mental function, reaction time, sleep quality, and peri-menopausal symptoms (Blumenthal et al., 2002), with a meta-analysis demonstrating that kava is more effective than placebo in treating symptoms of anxiety (Pittler and Ernst, 2000). Because of its historical use and modern scientific data to demonstrate safety and efficacy, the German Commission E, a special expert committee of the German Federal Institute for Drugs and Medical Devices (BfArM), analogous to the U.S. Food and Drug Administration, has approved kava preparations as nonprescription drugs for the treatment anxiety disorders, stress and restlessness (Blumenthal et al., 1998).

Kava in Europe

At least 28 cases of liver toxicity associated with the use of kava have been reported in Switzerland (4) and Germany (24), prompting regulatory actions by authorities (Hagemann, 2001). The hepatic adverse event reports (AERs) in these cases include cholestatic hepatitis (inflamed liver with obstruction of bile flow), icterus (jaundice), increased liver enzymes (a sign of liver dysfunction), liver cell impairment, severe hepatitis with confluent necrosis, irreversible liver damage (required transplant in four cases), etc. Several additional cases have been reported in Switzerland.

Based on the initial four case reports in 2000, Swiss officials banned a trademarked, acetone-based kava extract called Laitan®. This was a highly concentrated product, standardized to 70% kavalactone content (also sometimes referred to as kavapyrones, manufactured by a leading German phytomedicine company, W. Schwabe (Karlsuhe, Germany). While only the acetonic extracts were removed from the Swiss market at this time, the government gave manufacturers of ethanolic extracts three years to market these products and monitor their safety to see if any liver problems were reported. In addition, all manufacturers of ethanolic extracts in Switzerland have been asked to substantiate safety by conducting new toxicological and clinical trials (this may pose a significant financial challenge to these mostly small companies).

It should come as no surprise that the initial reports in Switzerland pertain to the acetone extract; since it dominates the market there with an approximately 80%-85% share. Ethanolic extracts comprise the balance. Ironically, the acetone extract has been the subject of the most scientific scrutiny; with at least seven controlled clinical trials on this product indicating its safety and efficacy compared to placebo (Pittler and Ernst, 1999; Blumenthal et al., 2002). Interestingly, the decision by the Swiss authorities was made despite the fact that in three cases other potentially hepatotoxic drugs had been taken (e.g. diclofenac), and concurrent viral infections and alcohol use or abuse could not be ruled out.

In response to the potential for hepatoxicity, the German Federal Institute for Drugs and Medical Devices (BfArM), in 2000, called for labeling of such potential risk on package inserts in kava products (BfArM, 2000). Then, on November 8, 2001, officials at the BfArM sent letters to kava manufacturers proposing withdrawal of drug licenses for kava (Hagemann, 2001). Although hava is approved as a safe and effective nonprescription drug by the German Commission E, much of the kava sold in Germany also is prescribed, as many physicians consider it a safe and effective first-line remedy to treat symptoms associated with anxiety, a condition for which it is approved. The action proposed in the November 8 letter from BfArM is pending evaluation of data submitted by the companies. These submissions originally were to be made within four weeks; however, an extension was granted to December 21. During this time, the pharmaceutical giant Merck permanently ceased sales of its kava products Kavadura® and Kytta-Kava®, according to a story attributed to the Financial Times (Anon, 2001).

On December 18, the German Nonprescription Drug Manufacturers Association (BAH) and the German Pharmaceutical Industry Association (BPI) filed comments with BfArM (BAH-BPI, 2001) as did several individual parties (Schmidt, 2002; Schulz and Siegers, 2001). The BAH-BPI comments noted the following: “in most of the reported cases, the causality between kava intake and liver reactions is not clear because further medication was used which might have caused liver toxicity. Furthermore, in many cases, detailed information on the patients’ history, co-medication, consumption of alcohol and further particulars are missing, thus not permitting a sound evaluation of these cases.” Some of these comments proposed that kava remain on the market as a prescription drug to be used under the supervision of a physician, where the patient’s medical history and potential susceptibility to liver disease and liver enzyme levels could be monitored to help reduce the potential risk of hepatotoxicity. Discussing the already-existing disclosure of potential hepatic risk in kava package inserts, as required by BfArM in 2000, Barbara Steinhoff, Ph.D. of the BAH, stated that the BAH submission “comes to the conclusion that the data presented [i.e., to the BfArM] on the benefit/risk assessment of Kava- and Kavain-containing medicinal products does not justify the withdrawal of marketing authorizations. The companies have already included risk information in their package leaflets and expert information and consider control of patients applying Kava products by a physician as an appropriate means.” (Steinhoff, 2001).

Some comments submitted to BfArM evaluated the details of the AERs, showing that many were related to the concomitant use of conventional drugs with potential hepatotoxic effects, and other issues that raised doubts about the validity of some of the reports (Schmidt, 2001). It is not certain when the BfArM will complete its review of the industry’s comments. The fate of kava is on the German market has been slightly clarified at the time of this writing (mid February, 2002). In late January 2002, a special committee of the BfArM that evaluates drugs for prescription use recommended that BfArM approve kava as a prescription drug (Busse, 2002). This approval was consistent with some of the comments from German manufacturers who would rather see kava be retained on the market than to see it be banned from use whatsoever. It is likely that kava will be approved as Rx starting in July, 2002.

Meanwhile, the German situation has set off a chain reaction of scrutiny by other governments and a spate of articles in Europe, the United States, and elsewhere. In early December, members of four major U.S. dietary supplement trade associationsñthe American Herbal Products Association (AHPA); the Council for Responsible Nutrition (CRN); the National Nutritional Foods Association (NNFA); and the Utah Natural Products Alliance (UNPA)ñ initiated a meeting with Christine Lewis Taylor of the Center for Food Safety and Applied Nutrition of the U.S. Food and Drug Administration (FDA) and other FDA officials to apprise them of the situation in Europe and the actions being taken by the U.S. industry, i.e., retaining a professional toxicologist to review to European AERs. On December 18, in a second meeting with the industry groups, the FDA announced that it was sending a letter to physicians requesting that they submit reports of cases of liver toxicity associated with the herb to the FDA’s MedWatch system (Taylor, 2002). The FDA letter was not intended as a public warning but was merely a fact-finding measure. The letter was posted on the FDA website (www.fda.gov) and began to generate inquiries from the media during the following days.

On December 19, the dietary supplement industry in the United Kingdom, working with officials at the Medicine Controls Agency, agreed to voluntarily suspend kava sales until such time as the question of liver toxicity is resolved (Woodfield, 2001). Boots, a leading drug chain in the UK, had previously suspended sales. According to reports from the UK, there are no published cases of liver toxicity associated with kava.

In January, the French government banned kava products. The Belgian government reportedly has required kava warnings to be posted in drugstores, and the Dutch government has reportedly worked out an arrangement with industry to require more detailed label warnings on kava products. In February, the Irish government has reportedly banned the sale of kava products.

Review of Kava Adverse Event Reports

A review of the cases reported in Germany and Switzerland, based on the information available so far, is instructive. Of the 30 cases reported, 18 appear to be associated with the concomitant use of prescription medications, some of which are known or suspected to be hepatotoxic. In some instances, people consumed kava at higher than the doses recommended by the Commission E (60-120 mg kavalactones per day); one report shows that the subject exceeded this dose by 400%. Experts point to other potentially confounding co-factors that raise questions about kava’s culpability. Whether some of these AERs are results of the conventional drugs, the interaction of kava and the conventional drugs, or the kava products used still remains to be determined. Adequate information is lacking for a proper assessment at the time of this writing although a review of the AERs by a toxicologist for AHPA is imminent (mid-February).

Several analyses have turned a critical eye on these reports (Schmidt, 2002; Schulze and Siegers, 2002). The most impressive, from Professors Johanne Schulze and Claus-Peter Siegers of the Medical University of Luebeck in Germany, concludes that although the association of kava and hepatotoxicity was reported as early as 1990, this issue did not attract much scientific or medical attention until 1999. Despite the fact that numerous spontaneous adverse event reports suggest the potential of kava hepatotoxicity, a definite causal relationship has been confirmed in one case only. The increase in the number of spontaneous reports may be dueñin addition to possible intrinsic kava hepatotoxicityñto increased awareness of medical and regulatory officials, chronological association and aggravated pre-existing liver disease. They also point out that duplicate reports and erroneous association of kava in cases of pre-existing liver damage has occurred. The most suitable therapeutic alternatives are the class of conventional drugs known as benzodiazepines (e.g., Valium) and antidepressants, which in some cases are known to exert drug toxicity including hepatotoxicity. These researchers acknowledge that kava preparations can produce adverse reactions (as noted by the Commission E monograph), and may be associated with rare serious liver toxicity. Schulz and Siegers suggest that the current data support idiosyncratic reactions as the possible mechanism rather than dose-dependent direct toxicity. They conclude that despite the wave of AERs, kava still appears to be a reasonable alternative for long-term treatment of anxiety; although suitable precautions should be taken to minimize patient risks.

An analysis of the approximately 30 hepatic AERs from Europe and 5 submitted to the U.S. FDA from May 1998 and September 2001 by an American toxicologist concluded that there is “no clear evidence that the liver damage reported in the U.S. and Europe was caused by the consumption of kava” and that those cases in which there is a possible association between the use of a kava extract and liver dysfunction “appear to have been hypersensitivity or idiosyncratic base responses.” (Waller, 2002). However, the report’s author acknowledged that he did not have adequate medical information on all the case reports to adequately assess them. Two U.S. case reports suggest relative safety of kava. In one case in which four prescription drugs plus relatively high levels of kava were used (300 pills or 45,000 mg per day!) there was no liver damage observed; in another case a 13 year-old girl consumed 8-10 500mg tablets in a suicide attempt, but recovered the following morning. “From a toxicologist perspective, these two cases provide some evidence that kava itself is not a direct hepatotoxin even in extremely high concentrations.” (Waller, 2002).

The report concludes:

“Kava, when taken in appropriate doses for reasonable periods of time, has no scientifically established potential for causing liver damage. However as with any pharmacologically active agent, there is always the possibility of drug interactions, preexisting disease conditions and idiosyncratic or hypersensitivity reactions, which can exacerbate the toxicity of such an agent. Increased surveillance or reports of adverse effects and judicious use of kava-derived products under the conditions recommended by the natural products industry would be a most prudent approach to confirm its safety and minimize any risk of liver damage. The medical community and the general public should be made aware that concomitant intake of prescription drugs associated with liver damage, excessive alcohol consumption and preexisting liver disease or hepatitis with compromised liver function are conditions which may preclude any kava consumption (Waller, 2002).

AERs in the USA

Regarding kava in North America, the information is somewhat confusing. In November 2001, both the ABC and AHPA checked the FDA database of AERs related to herbals and dietary supplements and found no reports of adverse liver effects associated with kava in the United States. There were, however, 35 AERs suggesting other types of adverse effects purportedly associated with kava use (as of November 26, 2001). A closer inspection of those AERs reveals that 29 of them are based on the infamous “fX” case in which a young man doled out ersatz “kava” doses at a New Year’s Eve rave in Los Angeles in 1996. The fraudulent products contained 1,4-butanediol and contained no kava or any other herbs or natural dietary supplement ingredients (Anon., 1997). This case received widespread publicity, the perpetrator’s parents’ business (where he stealthily manufactured the illicit product) was closed by health authorities, and he served a prison sentence. Thus, these AERs have nothing to do with kava and should not even be reported as kava AERs in the FDA database. AHPA has contacted FDA and asked the agency to remove these erroneous and highly misleading reports (McGuffin, 2002b), FDA’S Dr. Christine Taylor has advised AHPA that the FDA press office has been directed to inform the press that these are not kava-related cases.

The New York Times’ article on January 16 stated that the FDA had 60 kava-related adverse event reports since 1998 (Burros, 2002). The ABC contacted the FDA and was told that the agency has only 26 AERs related to kava-containing products, with only a few related to liver (Cianci, 2002). Fortunately, the story on January 22 in the Washington Post correctly reported the 26 cases (Packer-Tursman, 2002. A group of 25 AERs reflecting reports to the FDA from March 1998 to August 2001 implicating products in which kava is an ingredient (some contain multiple ingredients, raising questions regarding the effect kava may have had on the reported adverse event) were obtained through the Freedom of Information Act process by AHPA president Michael McGuffin. Of these 25 reports, only four reported some type of liver disorder (McGuffin, 2002a).

How, then, can one resolve the apparent discrepancy in the FDA’s reports on kava, from the 35 on the FDAës website in November (including the “fX” reports), to the 25 obtained by AHPA in January, to the 60 reported by The New York Times in January? The answer lies in the fact that the reports on the FDA website had not been updated since October 1998; that is, they were over three years old with no additional revisions! And, to complicate matters more, the Times article included the 29 “fX” cases, even though the reporter had been told previously by this writer that the “fX” cases were not associated with kava and should not be listed on the FDA database under “kava.”

Kava Safety and Precautions

The kava-liver safety issue comes as somewhat of a surprise to most industry members, health professionals and consumers familiar with the history and clinical use of kava. There is little evidence in the scientific literature to suggest liver toxicity; and the herb has enjoyed safe use for centuries in Polynesia. A meta-analysis on clinical trials on the acetone-based kava extract from Germany does not mention liver toxicity as one of the adverse effects noted in clinical trials, concluding that kava appears to be a safe and effective remedy for anxiety (Pittler and Ernst, 1999). In October, a Duke University clinical trial to assess the adverse effects profile of an American kava extract (KavaPure®, PureWorld, South Hackensack, New Jersey) found only insignificant elevations of liver enzymes in 3 of the 38 subjects in the trial (one already with elevated levels at the beginning), concluding that kava is relatively safe (Connor et al., 2001).

No one seems to be certain what’s going on. Contamination has been ruled out as the products implicated come from various sources. No definitive mechanism explains the alleged toxicity although several are speculated. Polynesians blame the European extracts, saying that the traditionally used kava beverages do not produce liver problems. This assertion has not been proven scientifically. Some have suggested that the acetone solvent used to make the leading European kava extract may be at fault, but analysis of the case reports shows that five of the six most serious cases are related to ethanolic (alcohol) extracts. This writer cautions all concerned not to suggest that differences in products have any toxicological significance until all the evidence has been properly evaluated.

Because of the confusion and the potential seriousness of the issue, on December 20 the American Botanical Council (ABC) issued a press release explaining the situation at the time and suggesting that the public adhere to the following cautions:

  • Kava should not be used by anyone who has any liver problems, or by anyone who is taking any drug products with known adverse effects on the liver, or anyone who is a regular consumer of alcohol.
  • Since the reports so far are associated with chronic use, kava should not be taken on a daily basis for more than four weeks (without the advice of a qualified professional).
  • In addition, consumers should discontinue use if symptoms of jaundice (e.g., dark urine, yellowing of the eyes) occur.
  • Consumers should consult their primary health care provider if they have a history of liver problems or suspect possible liver problems before using kava or continuing its use.

The ABC precautions have been noted in the USA Today and the AP articles. ABC deemed these cautions reasonable and prudent, based on the information available at the time ABC issued the precautions (December). (The complete text, plus new information, can be viewed on the ABC website: www.herbalgram.org). AHPA has issued similar information for consumers (www.ahpa.org). AHPA retained a highly regarded professional toxicologist from a leading university to ascertain the nature of the relationship between kava consumption and liver problems (AHPA et al., 2002). AHPA president Michael McGuffin was quoted as saying, “Despite the fact that the kava products under scrutiny are ones manufactured and sold in Europe, we believe that it is critical that kava’s long history of safe use be re-affirmed by a review of the information.” In February AHPA released a summary of this review, available on its website.

Despite the relatively good safety profile that kava has in the United States, these actions by the German and other European governments are must being taken very seriously by members of the U.S. industry. Germany has led the world in clinical research and rational regulation of herbal medicines. If its regulators think there’s a problem, then this is something that the U.S. herb industry and the FDA must deal with carefully and forthrightly. What is becoming somewhat clear, however, is that kava is being anecdotally linked to reports of liver dysfunction without any confirming scientific evidence. An expert evaluation of the medical case reports and all relevant scientific literature is warranted to determine the extent of the problem and the necessary steps for the appropriate labeling and regulation of kava.

There are many issues to be reviewed and resolved on the kava situation. This is one of the most serious challenges ever experienced by the herb and dietary supplement community in recent memory. More information on this issue will be posted on the ABC website as new developments arise.

This article was revised and expanded from two previous versions published in Whole Foods and Texas Pharmacy, March 2002.

 

References

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Website: www.herbalgram.org.