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

Abstract

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.

Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

“…As an example, several hundred kava varieties exist [8][9][10][11] , but specific information on kava variety identification was missing in all spontaneous reports and case report publications of suspected hepatotoxicity. This leaves open which kava variety had to be incriminated [9][10][11][12][13][14][15][16][17] .…”

“…This leaves open which kava variety had to be incriminated [9][10][11][12][13][14][15][16][17] . On the other hand, the regulatory recommendation for kava drugs was to use its peeled rhizome [8,11,15] .…”

“…This leaves open which kava variety had to be incriminated [9][10][11][12][13][14][15][16][17] . On the other hand, the regulatory recommendation for kava drugs was to use its peeled rhizome [8,11,15] . In various HILI cases, it remained unclear, whether unpeeled rhizomes, peeled and unpeeled roots, and/or stem peelings were also used [8,11,16,17] .…”

“…On the other hand, the regulatory recommendation for kava drugs was to use its peeled rhizome [8,11,15] . In various HILI cases, it remained unclear, whether unpeeled rhizomes, peeled and unpeeled roots, and/or stem peelings were also used [8,11,16,17] . This again hampered any evaluation of the causative agent of kava hepatotoxicity [16,17] .…”

“…For both the United States Food and Drug Administration and the Australian Therapeutic Goods Administration, peeled kava rhizomes were recommended for kava supplements [18,19] . Another point of interest focuses on solvents and solubilizers without regulatory advice [8,11,15,16] , as well as on adulterants, impurities, contaminants, or misidentified herbs [4,7,8,11] . These key issues of herbal product quality are rarely addressed in publications related to herbal hepatotoxicity [1,4,[8][9][10][11][12][13][14][15][16][17][20][21][22][23][24][25][26][27][28][29][30][31][32][33] .…”