► Rare cases of hepatotoxicity emerged in association with the use of the anxiolytic herb kava as drug and dietary supplement. ► To overcome this toxicity problem, strict kava quality ...standardizations are required. ► We therefore analyzed existing quality standards of traditional aqueous kava beverages and kava drugs and dietary supplements. ► Quality shortcomings emerged in the chemical, agricultural, manufactural, nutritional, regulatory, and legislation areas. ► A Kava Quality Standardization Code for farmers, manufacturers, regulators, and legislators for safe kava use is suggested.
Rare cases of hepatotoxicity emerged with the use of kava drugs and dietary supplements prepared from rhizomes and roots of the South Pacific plant kava (Piper methysticum). Their psychoactive, anxiolytic, relaxing, and recreational ingredients are the kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, but there is little evidence that these kavalactones or the non-kavalactones pipermethystine and flavokavain B are the culprits of the adverse hepatic reactions. It rather appears that poor quality of the kava material was responsible for the liver toxicity. Analysis of existing kava quality standardizations with focus on chemical, agricultural, manufacturing, nutritional, regulatory, and legislation backgrounds showed major shortcomings that could easily explain quality problems. We therefore suggest a uniform, internationally accepted device for kava quality standardizations that are in the interest of the consumers because of safety reasons and will meet the expectations of kava farmers, pharmaceutical manufacturers, regulators of agencies, and legislators. The initial step resides in the establishment of Pan-Pacific kava quality legislation as an important part of the proposed Kava Quality Standardization Code. In conclusion, a sophisticated approach to establish kava quality standardizations is needed for safe human use of kava as relaxing traditional beverages, the anxiolytic drugs, and recreational dietary supplements.
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.
To study the possible hepatotoxicity of aqueous kava extracts of the South Pacific Islands.
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).
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.
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.
The aqueous extract of kava (Piper methysticum) root is known as a traditional beverage for daily intake in the Western Pacific Islands, such as Fiji, Tonga, and Vanuatu, to induce relaxation and ...health-beneficial effects. In this study, the antioxidant, anti-hyperuricemia, and antibacterial properties of kava root were investigated through the isolation and purification of bioactive compounds in ten fractions separated by column chromatography (CC). They included six flavonoids, 5-hydroxy-4′,7-dimethoxyflavanone (C1), matteucinol (C2), isosakuranetin (C3), 5,7- dimethoxyflavanone (C4), 2′,4′-dihydroxy-6′-methoxydihydrochalcone (in MC5) and alpinetin (C10), and seven kavalactones, 5,6-dehydrokawain (DK) (in MC5 and C6), kavain (in MC7), yangonin (in MC7 and C8), dihydro-5,6-dehydrokavain (DDK) (in MC9), 7,8-dihydromethysticin (in MC9), dihydromethysticin (in MC9), methysticin (in MC9). The chemical structures of the compounds were illustrated by the analyses of gas chromatography–mass spectrometry (GC–MS), electrospray ionization–mass spectrometry (ESI–MS), nuclear magnetic resonance (sup.1 H and sup.13 C-NMR), and X-ray diffraction. The evaluation of the free radical scavenging activity of the isolated substances via the DPPH and ABTS assays revealed that C3 (ICsub.50 : ABTS = 76.5; DPPH = 74.8 µg/mL) possessed the strongest antioxidant property. In terms of anti-hyperuricemia activity evaluated via the xanthine oxidase inhibitory in vitro assay, the compound C10 was the most promising inhibitor, revealing an ICsub.50 of 134.52 µg/mL. The two kavalactone mixtures in MC5 and a pure compound C6 inhibited the growth of bacteria Listeria monocytogenes, while MC7 can constrain the development of Klebsiella pneumoniae. This is the first study to isolate, purify, and identify the flavonoids isosakuranetin, 2′,4′-dihydroxy-6′-methoxydihydrochalcone and alpinetin in kava root and report their pharmaceutical potential. The identified bioactive compounds showed potent antioxidant, anti-hyperuricemia, and antibacterial activity and thus can enhance the value of beverages and foods derived from kava root.
Kava beverages are typically prepared from the root of Piper methysticum. They have been consumed among Pacific Islanders for centuries. Kava extract preparations were once used as herbal drugs to ...treat anxiety in Europe. Kava is also marketed as a dietary supplement in the U.S. and is gaining popularity as a recreational drink in Western countries. Recent studies suggest that kava and its key phytochemicals have anti-inflammatory and anticancer effects, in addition to the well-documented neurological benefits. While its beneficial effects are widely recognized, rare hepatotoxicity had been associated with use of certain kava preparations, but there are no validations nor consistent mechanisms. Major challenges lie in the diversity of kava products and the lack of standardization, which has produced an unmet need for quality initiatives. This review aims to provide the scientific community and consumers, as well as regulatory agencies, with a broad overview on kava use and its related research. We first provide a historical background for its different uses and then discuss the current state of the research, including its chemical composition, possible mechanisms of action, and its therapeutic potential in treating inflammatory and neurological conditions, as well as cancer. We then discuss the challenges associated with kava use and research, focusing on the need for the detailed characterization of kava components and associated risks such as its reported hepatotoxicity. Lastly, given its growing popularity in clinical and recreational use, we emphasize the urgent need for quality control and quality assurance of kava products, pharmacokinetics, absorption, distribution, metabolism, excretion, and foundational pharmacology. These are essential in order to inform research into the molecular targets, cellular mechanisms, and creative use of early stage human clinical trials for designer kava modalities to inform and guide the design and execution of future randomized placebo controlled trials to maximize kava's clinical efficacy and to minimize its risks.
Here, we aim to evaluate the chemopreventive efficacy of kava root extracts (KRE) in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and investigate potential molecular targets of ...kavalactones, the main components of kava.
TRAMP mice were administrated with KRE formulated food for different periods of time, and then the incidences of high-grade prostatic intraepithelial neoplasia (HG-PIN) and adenocarcinomas and tumor burdens were compared between vehicle control and KRE food fed groups. In addition, the inhibitory effect of the KRE and kavalactones on monoamine oxidase A (MAO-A) and lysine-specific demethylase 1 (LSD1) enzyme activities were examined by commercially available inhibitor screening kits. Histone H3 lysine 9 dimethylation was also evaluated in prostate cancer cells and tumor tissues using Western blotting analysis.
Dietary feeding of 0.3% and 0.6% KRE to TRAMP mice from ages of 6 weeks to 12 weeks inhibited HG-PIN by 43.5% and 59.7%, respectively, and prostate adenocarcinoma by 53.5% and 66.4%, respectively. In addition, 0.6% KRE fed TRAMP mice from ages of 6 weeks to 24 weeks exhibited a significant reduction of genitourinary weight (a surrogate of tumor burden) by 54.5% and reduced body weight gain. Furthermore, the KRE and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities.
Our results suggest that consumption of kava products through diet can delay prostate cancer development and progression and that kavalactones may be a new structure model for developing a potent dual inhibitor of LSD1 and MAO-A.
Before 1998, extracts of kava kava,
Piper methysticum, were considered to be very safe alternatives to anxiolytic drugs and to possibly exert a wide range of other benefits. Major reviews published ...through the end of 2002 continued to confirm kava’s safety and efficacy. Nevertheless, by January 2003 kava extracts had been banned in the entire European Union and Canada, and were subject to cautions and advisories by the US FDA as a result of 11 cases of hepatic failure leading to liver transplants, including four deaths. A total of 78 cases of hepatotoxicity reputedly linked to kava ingestion are available for review from various databases. Of these adverse events, four probably are linked to kavalactones taken alone and another 23 are potentially linked to kava intake, but also involve the concomitant ingestion of other compounds with potential hepatotoxicity. Three possible mechanisms for kavalactone hepatotoxicity are known: inhibition of cytochrome P450, reduction in liver glutathione content and, more remotely, inhibition of cyclooxygenase enzyme activity. The direct toxicity of kava extracts is quite small under any analysis, yet the potential for drug interactions and/or the potentiation of the toxicity of other compounds is large. Presently, kava toxicity appears to be “idiosyncratic.” The risk-to-benefit ratio of kava extracts, nevertheless, remains good in comparison with that of other drugs used to treat anxiety.
•A LC-ESI-MS/MS method was developed for the quantification of kavain in mice plasma.•This simple and fast method was fully validated according to regulatory guidelines.•Isotopically labeled kavain ...was used as internal standard for the developed method.•Pharmacokinetic profiles of kavain isolated and in kava-kava extract were compared.•Higher bioavailability for kavain present in the extract was observed due to pharmacokinetic synergism.
A simple and fast bioanalytical method for the quantification of kavain in mice plasma was developed using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). A full method validation was performed, according to regulatory guidelines, employing isotopically labeled kavain as the internal standard (racemic-kavain-d3). For the quantification, M+H+ was formed using an electrospray ionization (ESI) source in the positive ion mode and multiple reaction monitoring (MRM) was employed using a quadrupole-linear ion trap (4000 QTRAP®) instrument. The monitored MRM transitions were 231.0 → 115.1 and 231.0 → 152.8 for kavain; and 234.2 → 199.2 for the internal standard. A linear response was obtained at the concentration range of 10 to 200 ng/mL with intra- and inter-day variations within the acceptable criteria for all quality control samples. After validation, the method was successfully applied for the quantification of kavain in mice plasma after oral administration of the kavain standard and Kava-kava extract. The plasma concentration over time results were applied for a pharmacokinetics study. The obtained pharmacokinetic parameters indicated a considerably higher bioavailability for kavain when Kava-kava extract was administered due to a pharmacokinetic synergism between the analyte and the other compounds present in the extract.
Kava (Piper methysticum G. Forst. f.) is by far the most important plant used in the islands of Melanesia, Polynesia and Micronesia for its relaxing effects. Kava drinking is a pillar of South ...Pacific societies and is also the foundation of their economies. Preparations of kava extract as herbal medicinal drugs were banned in Germany in 2002 and again in 2019, with dramatic consequences for the South Pacific economies. In 2002, the major regulatory argument for the ban of kava was safety issues. In 2019, the assessment report of the European Medicines Agency's Herbal Medicinal Product Committee (HMPC) justified a negative benefit-to-risk ratio by a supposed lack of efficacy of ethanolic extracts for an indication of which kava extract preparations never had an approval. In this HMPC report the efficacy in the approved indications ‘nervous anxiety, tension and restlessness’ was attributed to the extract branded as ‘WS 1490’, which was assumed to have been prepared with acetone as an extraction solvent. In addition to this change of indication and the attribution of efficacy to acetone kava extract alone, the German health authorities and the HMPC still refuse to discuss quality issues as a likely factor impacting drug safety. The first case reports of liver toxicity were observed with an acetone extract in a timely relationship with the introduction of ‘two-day kava’ instead of ‘noble kava’ as used in ethanolic kava extracts.
The correlation between clinical benefits and the type of extract preparation was examined.
In order to identify the types of kava material and extracts used in clinical trials, the respective publications were compared with regulatory databases and protocols of a German regulatory advisory board.
The comparison reveals inconsistencies in the regulatory decisions. In all studies with WS 1490, the evidence points to the use of an ethanolic extract. The efficacy of kava extract for the approved indication was clearly demonstrated. The HMPC report and the recent renewed German regulatory ban of kava therefore require major revision, which should include the impact of the use of “two-day kava” on drug safety. Such a revision could contribute to restoring the reputation of “noble kava” on the international markets.
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•Kava extract preparations are efficacious in nervous anxiety, tension and restlessness.•The HMPC’s assumption of generalized anxiety as the indication of kava is unfounded.•The attribution of the clinical evidence to acetone extracts must be questioned.•There is evidence that the branded extract “WS 1490” was prepared with ethanol.•There are inconsistencies in the procedures, which led to the prohibition of kava.•The substitution of noble with two-day kava has never been examined.
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