Kava Hepatotoxicity Research Articles

The integrated use of in silico methods for the hepatotoxicity potential of Piper methysticum

Herbal products as supplements and therapeutic intervention have been used for centuries. However, their toxicities are not completely evaluated and the mechanisms are not clearly understood. Dried rhizome of the plant kava (Piper methysticum) is used for its anxiolytic, and sedative effects. The drug is also known for its hepatotoxicity potential. Major constituents of the plant were identified as kavalactones, alkaloids and chalcones in previous studies. Kava hepatotoxicity mechanism and the constituent that causes the toxicity have been debated for decades. In this paper, we illustrated the use of computational tools for the hepatotoxicity of kava constituents. The proposed mechanisms and major constituents that are most probably responsible for the toxicity have been scrutinized. According to the experimental and prediction results, the kava constituents play a substantial role in hepatotoxicity by some means or other via glutathione depletion, CYP inhibition, reactive metabolite formation, mitochondrial toxicity and cyclooxygenase activity. Some of the constituents, which have not been tested yet, were predicted to involve mitochondrial membrane potential, caspase-3 stimulation, and AhR activity. Since Nrf2 activation could be favorable for prevention of hepatotoxicity, we also suggest that these compounds should undergo testing given that they were predicted not to be activating Nrf2. Among the major constituents, alkaloids appear to be the least studied and the least toxic group in general. The outcomes of the study could help to appreciate the mechanisms and to prioritize the kava constituents for further testing.

Sesame lignans significantly alleviate liver damage of rats caused by carbon tetrachloride in combination with kava

The aim of this study was to examine if the liver damage caused by CCl 4 in combination with kava (Piper methysticum) could be alleviated via coadministration of sesame lignans. Six groups of male Sprague-Dawley rats were fed with corn oil as a control, kava only, kava plus sesame lignans, CCl4 only, CCl4 plus kava, and CCl4 plus kava plus sesame lignans, respectively. Body weight, diet intake, animal behavior, and serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were recorded along with the course. Four weeks later, organ weights and histopathological data including liver steatosis and fibrosis were obtained after sacrifice. At day 28, both the diet intakes and body weights of rats decreased, and their relative liver weights increased considerably in all three CCl4-treated groups compared to the control group. In accord with the levels of pathological steatosis and fibrosis, the liver damage caused by CCl4 was somewhat worse when kava extract was congested, but significantly attenuated when sesame lignans were coadministrated. No detectable liver damage was observed in the kava or kava plus sesame lignan group. The protective effect of sesame lignans against liver injury caused by CCl4 with or without kava extract was also observed in the relative activities of plasma ALT, AST and ALP. It is concluded that sesame lignans significantly alleviate liver damage of rats caused by carbon tetrachloride with or without kava. The potential risk of kava's hepatotoxicity can be greatly circumvented and the applications of kava may be further extended by coadministration of sesame lignans.

Liver transplantation and the use of KAVA: Case report

BackgroundSelf-medication and the belief that herbal products are free of health risks are common in Brazil. The kava (Piper methysticum), known for its anxiolytic action, has a widespread popular use. Hepatotoxicity of kava is reported, including cases of liver transplantation and death. The kava had its use prohibited or restricted in countries like Germany, France, among others. Toxicity may be related to overdosage; however, factors such as botanical characteristics of the plant, the harvesting, storage, and production process may be associated with the development of hepatotoxic substances, such as triggering idiosyncratic reactions. HypothesisIn this case, there is a suspicion that the toxicide is intrinsic to the drug; however, the possibility of adulterants and contaminants must be ruled out. Study designThis study reports the case of a patient who, after using the herbal kava for 52 days, evolved into acute liver failure and liver transplantation. MethodsThe data were collected directly with the patient and compared with their clinical records. Causality was determined through the RUCAM algorithm. In addition, a phytochemical analysis of the drug used was performed. ResultsAccording to the patient's report, there is no evidence of overdosage. Results from RUCAM algorithm infer causality between liver damage and the use of kava. The analysis chemical constituents did not find any possible contaminants and major changes in the active compounds. Seven months after transplantation, the patient is well and continues to be followed up by a medical team. ConclusionOur investigation indicates that there was kava-induced hepatotoxicity at standard dosages. In Brazil, self-medication by herbal medicines is frequent and many patients and health professionals do not know the risks associated with their use. Diagnosing and notifying cases in which plants and herbal medicine induce liver damage is of paramount importance to increase the knowledge about DILI and to prevent or treat similar cases quickly.

Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat.

The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed.

German Kava Ban Lifted by Court: The Alleged Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics.

Kava, the rhizome and roots of Piper methysticum, are one of the most important social pillars of Melanesian societies. They have been used for more than 1000 years in social gatherings for the preparation of beverages with relaxing effects. During the colonial period, extract preparations found their way into Western medicinal systems, with experience especially concerning the treatment of situational anxiety dating back more than 100 years. It therefore came as a surprise when the safety of kava was suddenly questioned based on the observation of a series of case reports of liver toxicity in 1999 and 2000. These case reports ultimately led to a ban of kava products in Europe - a ban that has been contested because of the poor evidence of risks related to kava. Only recently, two German administrative courts decided that the decision of the regulatory authority to ban kava as a measure to ensure consumer safety was inappropriate and even associated with an increased risk due to the higher risk inherent to the therapeutic alternatives. This ruling can be considered as final for at least the German market, as no further appeal has been pursued by the regulatory authorities. However, in order to prevent further misunderstandings, especially in other markets, the current situation calls for a comprehensive presentation of the cardinal facts and misconceptions concerning kava and related drug quality issues.

Reduction in Colon Cancer Risk by Consumption of Kava or Kava Fractions in Carcinogen-Treated Rats

Epidemiological studies suggest that kava reduces colon cancer risk. However, no experimental studies of the chemopreventive properties of kava toward colon cancer have been reported. Further, there are concerns regarding hepatotoxicity of kava. The goal of this study was to determine whether kava consumption reduces markers of colon cancer in an animal model and to study the safety of kava. An ethanolic extract and polar and nonpolar fractions of the kava extract were fed to rats for 12 days prior to, during, and after administration of dimethylhydrazine, a colon-specific carcinogen. After 14 wk, rats fed the nonpolar extract had a significant reduction in precancerous lesions [aberrant crypt (AC) foci (ACF)] as well as large (≥4 AC/ACF) sialomucin-only expressing foci, an indicator of greater tumorigenic potential, compared to the control group. Groups fed the ethanolic extract and polar kava fraction trended toward reductions in ACF and large sialomucin-only expressing foci. The combined kava groups had significantly fewer total AC, ACF, large ACF, and large sialomucin-only expressing foci compared to the control group. Histological examination found no hepatic lesions in animals consuming the kava diets, suggesting that kava is safe to consume. Our results support that kava may reduce colon cancer risk.

Contaminant Hepatotoxins as Culprits for Kava Hepatotoxicity – Fact or Fiction?

The culprit of kava hepatotoxicity will continue to remain a mystery in humans, if the underlying reaction is of idiosyncratic, unpredictable, and dose-independent nature due potentially to some metabolic aberration in a few individuals emerging from kava use. In addition, kava hepatotoxicity is presently not reproducible experimentally in preclinical models, as demonstrated by studies showing whole kava extracts are not hepatotoxic. This led us to propose our 'working hypothesis' that contaminant hepatotoxins including moulds might have caused rare kava hepatotoxicity in humans. Further studies are now warranted to proof or disproof our working hypothesis, because kava hepatotoxicity possibly based on contaminant hepatotoxins could be a preventable disease. In the meantime, however, for minimizing toxicity risk in kava users, a pragmatic approach should focus on the medicinal use of an aqueous extract derived from peeled rhizomes and roots of a non-mouldy noble kava cultivar, limited to maximum 250-mg kavalactones daily for acute or intermittent use.

Are Mould Hepatotoxins Responsible for Kava Hepatotoxicity?

Previous studies with kava components such as kavalactones, pipermethystine and flavokavain B have demonstrated hepatotoxicity from these constituents. Regardless, there has recently been speculation that adulterants or impurities such as the mould hepatotoxin aflatoxin are a more likely cause of kava hepatotoxicity, despite a paucity of supporting evidence. Although there is limited similarity between acute kava hepatotoxicity and acute aflatoxicosis, and background levels of aflatoxin have been detected in kava samples, unless epidemiological investigations can uncover direct evidence implicating mould hepatotoxins, it remains more likely that chemical constituents of kava are the cause of the hepatotoxicity from kava.

Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited

Kava, a Pacific herb consumed worldwide for medicinal, recreational and cultural purposes, has been associated with rare hepatotoxicity, and there is currently a critical need to determine this causation. The previously proposed Pacific kava paradox was based on the theory that kava hepatotoxicity was not observed following use of traditional aqueous extracts in the Pacific region, but was restricted to use of Western acetonic and ethanolic extracts. Subsequent cases analyzed by the World Health Organization and published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; thus, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may reside in the time before the preparation of the various kava extracts, possibly attributed to poor quality of the raw material caused by mould hepatotoxins. Rigorous testing of kava raw material is urgently advised, in addition to Pan-Pacific kava manufacturing quality standards.

Kava and Kava Hepatotoxicity: Requirements for Novel Experimental, Ethnobotanical and Clinical Studies Based on a Review of the Evidence

Kava hepatotoxicity is a well described disease entity, yet there is uncertainty as to the culprit(s). In particular, there is so far no clear evidence for a causative role of kavalactones and non-kavalactone constituents, such as pipermethystine and flavokavain B, identified from kava. Therefore, novel enzymatic, analytical, toxicological, ethnobotanical and clinical studies are now required. Studies should focus on the identification of further potential hepatotoxic constituents, considering in particular possible adulterants and impurities with special reference to ochratoxin A and aflatoxins (AFs) producing Aspergillus varieties, which should be urgently assessed and published. At present, Aspergillus and other fungus species producing hepatotoxic mycotoxins have not yet been examined thoroughly as possible contaminants of some kava raw materials. Its occurence may be facilitated by high humidity, poor methods for drying procedures and insufficient storage facilities during the time after harvest. Various experimental studies are recommended using aqueous, acetonic and ethanolic kava extracts derived from different plant parts, such as peeled rhizomes and peeled roots including their peelings, and considering both noble and non-noble kava cultivars. In addition, ethnobotanical studies associated with local expertise and surveillance are required to achieve a good quality of kava as the raw material. In clinical trials of patients with anxiety disorders seeking herbal anxiolytic treatment with kava extracts, long-term safety and efficacy should be tested using traditional aqueous extracts obtained from peeled rhizomes and peeled roots of a noble kava cultivar, such as Borogu, to evaluate the risk: benefit ratio. Concomitantly, more research should be conducted on the bioavailability of kavalactones and non-kavalactones derived from aqueous kava extracts. To be on the side of caution and to ensure lack of liver injury, kava consuming inhabitants of the kava producing or importing South Pacific islands should undergo assessment of their liver function values and serum aflatoxin levels. The primary aim is to achieve a good quality of kava raw material, without the risk of adulterants and impurities including ochratoxin A and AFs, which represent the sum of aflatoxin B1, B2, G1 and G2. Although it is known that kava may naturally be contaminated with AFs, there is at present no evidence that kava hepatotoxicity might be due to aflatoxicosis. However, appropriate studies have yet to be done and should be extended to other mould hepatotoxins, with the aim of publishing the obtained results. It is hoped that with the proposed qualifying measures, the safety of individuals consuming kava will substantially be improved.

Kava hepatotoxicity solution: A six-point plan for new kava standardization

Kava-induced liver injury has been demonstrated in a few patients worldwide and appears to be caused by inappropriate quality of the kava raw material. When cases of liver disease in connection with the use of kava emerged, this was an unexpected and challenging event considering the long tradition of safe kava use. In order to prevent kava hepatotoxicity in future, a set of quality specifications as standard is essential for the preparation not only of kava drugs and kava dietary supplements in the Western world but also for traditional kava drinks in the South Pacific Islands. For all these purposes a uniform approach is required, using water based extracts from the peeled rhizomes and roots of a noble cultivar such as Borogu with at least 5 years of age at the time of harvest. Cultivated in Vanuatu for centuries, noble varieties (as defined in the Vanuatu Kava Act of December 2002) are well tolerated traditional cultivars with a good safety record. At present, Vanuatu kava legislation is inadequately enforced to meet quality issues for kava, and further efforts are required in Vanuatu, in addition to similar legislation in other kava producing South Pacific Islands. Future regulatory and commercial strategies should focus not only on the standardization of kava drugs, kava dietary supplements, and traditional kava extracts, but also on thorough surveillance during the manufacturing process to improve kava quality for safe human use. The efficacy of kava extracts to treat patients with anxiety disorders is well supported, but further clinical trials with aqueous kava extracts are necessary. We thereby propose a six-point kava solution plan: (1) use of a noble kava cultivar such as Borogu, at least 5 years old at time of harvest, (2) use of peeled and dried rhizomes and roots, (3) aqueous extraction, (4) dosage recommendation of ≤250mg kavalactones per day (for medicinal use), (5) systematic rigorous future research, and (6) a Pan Pacific quality control system enforced by strict policing. In conclusion, at different levels of responsibility, new mandatory approaches are now required to implement quality specification for international acceptance of kava as a safe and effective anxiolytic herb.

Risk of Kava Hepatotoxicity and the FDA Consumer Advisory

IN EARLY 2002, THE US FOOD AND DRUG ADMINISTRAtion (FDA) began advising consumers of the potential risk of severe liver injury associated with the use of kava-containing dietary supplements. Kava (Piper methysticum) is a plant indigenous to the South Pacific Islands, where it is commonly used to prepare a traditional beverage for social and recreational purposes. Dietary supplements containing the herbal ingredient kava are promoted for relaxation to relieve stress, anxiety, and tension, as well as for sleeplessness and menopausal symptoms. Kava-containing products have been associated with rare liver injuries in Western countries, and the FDA urged consumers and health care professionals to report any case of liver injury that may be related to the use of kava-containing dietary supplements. The FDA also announced its intention to further investigate the relationship, if any, between the use of dietary supplements containing kava and liver injury, which included attempting to determine a biological explanation for the relationship and to identify the different sources of kava in the United States and Europe. Subsequent analyses by the World Health Organization have shown that the use of kava was associated with the development of liver disease in rare cases, confirmed by structured, quantitative, and liver-specific causality assessment methods. There is now sound evidence that liver injury was caused by both the traditional water-based kava extracts of the South Pacific and the medicinal solvent-based kava extracts of Western countries, with flavokavain B as one of the possible culprits. It remained unclear, however, to what extent the use of ethanol or acetone as solvents might have increased the hepatotoxic risks in patients who consumed medicinal kava extracts. Further assessments of the pathogenetic factors of kava hepatotoxicity revealed the use of inappropriate kava varieties and plant parts. Previously, the existence of more than 200 kava varieties, also called cultivars, had not been considered from the aspects of safety concerns and pharmacovigilance issues. Consequently, in Western countries as well as in the South Pacific region, there has been no regulatory definition advising which of the various kava cultivars should preferentially be used for kava beverages, drugs, and dietary supplements. Specific issues also emerged regarding the peeled kava rhizome that should have been used, but evidence suggests also the use of the kava plant’s aerial parts, which may contain the hepatotoxic alkaloid pipermethysticin. Considering the poor quality of kava raw material used for this small number of kava products, liver injury by kava is basically a preventable disease. Legal steps to improve safety of kava products had already been initiated at about the same time as the FDA consumer advisory was issued. The Vanuatu Kava Act No. 7 of 2002 describes some protection rules of kava for export, which include kava drugs and kava dietary supplements. The Vanuatu legislation differentiates 4 groups of kava cultivars with the noble cultivars as the only group with the option for export. The legislation explicitly excludes other groups of kava cultivars, such as medicinal cultivars and 2-day cultivars, which have previously been used for kava drugs. Excluded from export are plant parts such as stumps, shoots, growing buds, and lateral branches. Kava or kava products may only be exported when each of the following is clearly marked: name of the variety, island of origin, distinct organs of the kava, and the words “Original Vanuatu Kava.” Kava quality requirements for export purposes include a minimum maturation time for the kava plant at harvest of 5 years. It appears that legislation-enforced quality standards for kava products are a first step for increasing their safety in human use. The group of exportable kava varieties consists of 28 noble kava cultivars, but the Vanuatu legislation provides no preference for one single cultivar. In Vanuatu, the major kava producer and exporter, the traditional kava beverage is prepared by cold water extraction of its roots. Historic use shows that kava is safe under the strict control of the rituals of Pacific cultures. The traditional beverage is consumed on a daily basis without apparent adverse effects, and kava cultivars considered as noble ones have a long tradition of safe use.

Regulatory causality evaluation methods applied in kava hepatotoxicity: Are they appropriate?

Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.

Does inflammation play a role in kava hepatotoxicity?

The pathophysiology of kava hepatotoxicity remains inconclusive. There is circumstantial evidence for the roles of toxic metabolites, inhibition of cyclooxygenase (COX) enzymes and depletion of liver glutathione. Pharmacogenomic effects are likely, particularly for Cytochrome P450 genes. Experimental and clinical cases of hepatotoxicity show evidence of hepatitis. The question remains whether this inflammation is caused by components of kava directly, or indirectly due to the downstream effects.

ORIGINAL ARTICLE: Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment

Ingestion of the medicinal herb kava has been associated with hepatotoxicity. We aimed to compare two different quantitative methods of causality assessment of patients with assumed hepatotoxicity by the herb. We assessed causality in 26 patients from Germany and Switzerland, using two structured quantitative analytical methods: the system of Maria and Victorino (MV) and that of the Council for International Organizations of Medical Sciences (CIOMS). In all 26 patients, regulatory ad hoc evaluation had suggested a causal relationship between liver disease and kava use. Assessment with the MV scale resulted in no or low graded causality for kava in the 26 patients with liver disease. Causality was probable (n=1), possible (n=2), unlikely (n=7), and excluded (n=16). Causality for kava was more evident with the CIOMS scale: highly probable (n=1), probable (n=2), possible (n=6), unlikely (n=2) and excluded (n=15). However, the results of both quantitative causality assessments are not supportive for most of the regulatory ad hoc causality assessments of the 26 patients. Grades of causality for suspected hepatotoxicity by kava were much lower when evaluated by structured quantitative causality assessment scales than by regulatory ad hoc judgements. The quantitative CIOMS scale is the preferable tool for causality assessment of spontaneous reports of hepatotoxcity involving kava.

Kavalactones Yangonin and Methysticin Induce Apoptosis in Human Hepatocytes (HepG2) In Vitro

While cases of severe kava hepatotoxicity have been reported, studies examining the toxicity of individual kavalactones are limited. The present study examined the in vitro hepatotoxicity of kavain, methysticin and yangonin on human hepatocytes (HepG2) and the possible mechanism(s) involved. Cytotoxicity was assessed using lactate dehydrogenase (LDH) and ethidium bromide (EB) assays. The mode of cell death was analysed with acridine orange/ethidium bromide dual staining with fluorescence microscopy. Glutathione oxidation was measured using the ortho-phthalaldehyde (OPT) fluorescence assay. Kavain had minimal cytotoxicity, methysticin showed moderate concentration-dependent toxicity and yangonin displayed marked toxicity with ~ 40% reduction in viability in the EB assay. Acridine orange/ethidium bromide staining showed the predominant mode of cell death was apoptosis rather than necrosis. No significant changes were observed in glutathione levels, excluding this as the primary mechanism of cell death in this model. Further studies may elucidate the precise apoptotic pathways responsible and whether toxic kavalactone metabolites are involved.

Kava hepatotoxicity: pathogenetic aspects and prospective considerations

Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.

Role of ethanol in kava hepatotoxicity

Kava is known for its recreational, ceremonial and medicinal use in the Pacific. The aqueous non-alcoholic drink of kava rhizome produces intoxicating, relaxing and soothing effects. While kava's medicinal effects receive worldwide recognition, kava-containing products came under scrutiny after over 100 reports of spontaneous adverse hepatic effects. Many mechanisms have been postulated to explain the unexpected toxicity, one being pharmacokinetic interactions between kavalactones and co-administered drugs involving cytochrome P450 enzyme system. Alcohol is often co-injested in kava hepatotoxicity cases. This review evaluates the possible hepatotoxicity mechanisms involving alcohol and kava.

Kava hepatotoxicity: Regulatory data selection and causality assessment

Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster. We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts. The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation. The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation. The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.

Kava hepatotoxicity: Comparison of aqueous, ethanolic, acetonic kava extracts and kava–herbs mixtures

Ethnopharmacological relevance Ethanolic and acetonic kava extracts have previously been causally related to rare hepatotoxicity observed in patients from Germany and Switzerland, but causality assessment was not performed in cases of patients having taken the traditional aqueous kava extracts of South Pacific islands or kava–herbs mixtures. Aim of the study To study the possible hepatotoxicity of aqueous kava extracts of the South Pacific Islands. Materials and methods Causality of hepatotoxicity by aqueous kava extracts and kava–herbs mixtures was assessed, using the updated score of the quantitative CIOMS (Council for the International Organizations of Medical Sciences). Results Causality was established in five patients from New Caledonia, Australia, the United States and Germany for aqueous kava extracts and kava–herbs mixtures. A comparison with 9 patients from Germany and Switzerland with established causality of hepatotoxicity by ethanolic and acetonic kava extracts reveals that the clinical picture in all 14 patients is similar, independently whether aqueous, ethanolic and acetonic kava extracts or kava–herbs mixtures were used. Conclusions Kava hepatotoxicity occurs also with traditional aqueous kava extracts of the South Pacific islands and thereby independently from ethanol or acetone as chemical solvents, suggesting that the toxicity is linked to the kava plant itself with a possibly low quality of the used kava cultivar or kava plant part rather than to chemical solvents.