The follPrepared by Candice Cryne, M.Sc., Scientific Regulatory Associate, Dicentra Inc.
What is Kava?
Kava is the South Pacific herb Piper methysticum G. Forster, and the parts most commonly used are the dried rhizomes and roots, which contain the psychoactive compound kavalactones (1). Kava is known for its tranquilizing, sedative and anxiolytic properties, and has been part of the social and ceremonial life in the South Pacific for centuries (2). For a more detailed review regarding kava, a paper was published by The American Herbal Products Association titled “Kava and the risk of Liver Toxicity: Past, Current, and Future” in the March 2011 issue of the AHPA Report, which provides an in-depth assessment of kava.
Where is Kava now?
Kava exists in more than 200 variant strains or cultivars, categorized as noble cultivars, medicinal cultivars, Two-Day cultivars, and wild species Piper wichmannii C.DC (11-12) and can be chemotyped into 6 major kavalactones; kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin and desmethoxyyangonin (13).
Several clinical trials have been conducted over the years with varying extracts of kava to assess its potential in treating anxiety (3-9) with inconsistent results of efficacy. However, research has indicated that oral kava ingestion can result in rare hepatotoxicity, although the causation is not known (10). Originally, the scientific community agreed that consumption of traditional aqueous kava extracts consumed in the South Pacific Islands were safe, however in that same year case reports appeared showing toxic liver disease in two individuals from New Caledonia in the Southwest Pacific due to kava ingestion in the form of the traditional aqueous kava beverage derived from an unknown kava cultivar (14). Following, other clinical studies also found elevated levels of liver enzymes (15-18). Toxicity was associated with ingestion of traditional aqueous extracts, acetonic and ethanolic drugs, and dietary supplements in kava combinations. This ultimately led to other case reports and regulatory health agency recommendations regarding kava toxicity and in 2002 kava products were removed from sale in Switzerland and Germany (19); The FDA issued a consumer advisory in the US (20); and Australia issued a practitioner alert, consumer advisory and voluntary recall.
However, in January 2003, the Therapeutic Goods Administration in Australia established an expert committee, named the Kava Evaluation Group (KEG), to review the safety of kava-containing medicines and to report to the Complementary Medicines Evaluation Committee (CMEC) as to whether it was appropriate to allow kava (Piper methysticum) to be used as an ingredient in ‘Listed’ (or low risk) medicines (21). Upon review of the report from KEG the CMEC recommended to the TGA that only certain forms of kava were suitable for use in Listed Medicines. The TGA subsequently accepted this recommendation and amended Schedule 4, Part 4, Division 2 (plant material from which herbal substances may be derived for listable goods that are consistent with certain qualifications), Item 35. There is a limit on the maximum amount of Piper methysticum permitted per dosage form; for a tablet or a capsule, there is a limit of 125mg of kavalactones (a group of consistuents found in Piper methysticum); and for a tea bag, there is a limit of 3g of dried rhizome (of Piper methysticum). In addition, all products containing Piper methysticum (any dosage form) must comply with a maximum daily dose of not more than 250mg of kavalactones (21). Furthermore, kava is classified as a prohibited import under the Customs Regulations. There have been no published reports of kava liver toxicity in Australia since its return to the marketplace for anxiety treatment (21).
The Republic of Vanuatu in the South Pacific, created an act titled “Republic of Vanuatu Kava Act No. 7” of 2002, which stated that only noble kava cultivars are to be used in kava drugs or dietary supplements, as only these have a history of long-term safe use (22). Furthermore, medicinal cultivars, Two-Day cultivars and wichmannii varieties are prohibited for export from Vanuatu (22).
In Canada and the U.S., kava is often sold as a natural health product or dietary supplement and in pharmaceutical preparations for anxiety patients. However, due to recent safety concerns, in Canada kava is listed in the “Health Products and Food Branch Inspectorate – Annex to the Natural Health Products (NHPs) Compliance and Enforcement Policy for Exempt NHPs under the Natural Health Products (Unprocessed Product Licence Applications) Regulations (UPLAR)” as a substance that has been subject to stop sale and recalls and will not be issued Exemption Numbers under the UPLAR. As such, unauthorized products with this ingredient are subject to a risk-based approach to compliance. Currently in Canada, there is only one natural health product currently licensed with kava as a homeopathic drug and there are no listed exempted natural health products containing kava.
The UK has banned kava for import or sale for the purpose of ingestion and is only allowed for external use (23). Recent reports still indicate that kava is banned for sale in Switzerland, France and the Netherlands and is found in the form of kavalactones as a prescription drug in Germany.
Moving forward:
The causation of liver toxicity from kava is difficult to establish, although some contributing facts have been identified, such as prolonged kava use, overdose, and combination with other drugs or natural health products (10). The possibility of other factors contributing such as poor kava quality, adulteration, misidentification, and the presence of impurities and mold hepatotoxins still needs to be evaluated (24). Furthermore, during the skyrocketing success of kava before the ban, vendors were also selling the leaves and peelings of kava, which contains the hepatotoxic compound pipermenthystine and various other bacteria and may have contributed to the liver toxicities reported, as the long term safety of kava only supports the use of the roots and rhizomes.
An international working group is working to reintroduce kava into the global market. Leading world kava experts Dr. Jerome Sarris from the University of Melbourne, Australia; Professor Rolf Teschke from Wolfgang Goethe-University, Frankfurt, Germany; and Dr. Vincent Lebot from CIRAD, Port-Vila, Vanuatu, have proposed a six-point plan that is intended to become the framework to assist in the re-introduction of kava to restricted countries. The framework will ensure only high quality kava to be consumed throughout the Pacific and the rest of the world. The use of the plant as a treatment for generalised anxiety is part of two human trials currently being conducted by Dr. Sarris in Melbourne, Australia, where it is available over the counter (25). An article was published in the British Journal for Clinical Pharmacology and Phytomedicine by Teschke, in which a six point plan was proposed (25, 26, and 27):
1) Ideally use one of several noble kava cultivars (those having a certain chemotype signature and high amounts of kavain and dihydrokavain and low amounts of methysticin and desmethoxyyangonin) that have a history of safe traditional use and are at least five years old. Make regulatory kava standardizations for the best noble cultivars mandatory.
2) Use only the peeled and dried rhizome and underground roots of the kava plant, as opposed to its leaves and/or aerial parts. Establish legislation to ensure that only these are exported for use in kava medicines and dietary supplements, and ensure that requirements for use in the South Pacific and in international exports are the same.
3) Give water-soluble kava extracts preference over those extracted using alcohol or a chemical solution.
4) Define and establish standards for a recommended daily dosage of kavalactones (the primary active compounds) and duration of treatment.
5) Conduct systematic and rigorous research into kava’s safety issues, such as using poorly stored and manufactured kava material and/or incorrect cultivar and plant material, and conduct human clinical trials using noble cultivars prepared through good pharmaceutical manufacturing practices.
6) Enforce a Pan-Pacific quality control system.
The response to the potential reintroduction of kava has been mixed. The United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) would not re-evaluate its current position on kava and will keep it banned in the UK. The political situation in Germany on kava has to do with differing views between the German Commission E, German Federal Institute for Drugs and Medical Devices, kava manufactures and the kava steering group, on the safety and efficacy of kava and perhaps a decision will be reached soon, as the herb is still considered banned. The United States does not have a ban on kava; however, most products carry the risk statement about potential liver injury (28).
References
1. World Health Organization. Assessments of the risk of hepatotoxicity with kava products. WHO Document Production Services: Geneva, Switzerland; 2007
2. Sarris J, LaPorte E, Schweitzer I. Kava: a comprehensive review of efficacy, safety, and psychopharmacology. Aust N Z J Psychiatry 2011; 45: 36-44
3. Sarris J, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl). 2009 Aug;205(3):399-407.
4. Sarris J, Kavanagh DJ, Deed G, Bone KM. St. John’s wort and Kava in treating major depressive disorder with comorbid anxiety: a randomised double-blind placebo-controlled pilot trial. Hum Psychopharmacol. 2009 Jan;24(1):41-8.
5. Connor KM, Payne V, Davidson JR. Kava in generalized anxiety disorder: three placebo-controlled trials. Int Clin Psychopharmacol. 2006 Sep;21(5):249-53.
6. Lehrl S. Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with anxiety disorders. Results of a multicenter, randomized, placebo-controlled, double-blind clinical trial. J Affect Disord. 2004 Feb;78(2):101-10. Erratum in: J Affect Disord. 2004 Dec;83(2-3):287.
7. Gastpar M, Klimm HD. Treatment of anxiety, tension and restlessness states with Kava special extract WS 1490 in general practice: a randomized placebo-controlled double-blind multicenter trial. Phytomedicine. 2003 Nov;10(8):631-9.
8. Boerner RJ, Sommer H, Berger W, Kuhn U, Schmidt U, Mannel M. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalised Anxiety Disorder–an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients. Phytomedicine. 2003;10 Suppl 4:38-49.
9. Connor KM, Davidson JR. A placebo-controlled study of Kava kava in generalized anxiety disorder. Int Clin Psychopharmacol. 2002 Jul;17(4):185-8.
10. Teschke R. Kava hepatotoxicity: pathogenetic aspects and prospective considerations. Liver Int 2010; 30: 1270-1279.
11. Vanuatu Legislation: Republic of Vanuatu Kava Act No. 7 of 2002. Available at: http://www.paclii.org/vu/legis/num_act/toc- K.html. Accessed March 28, 2011
12. Food Standards Australia New Zealand. Kava. A human health risk assessment. Technical report Series No.30. 2005. Available at: http://www.foodstandards.gov.au/scienceandeducation/publications/technicalreportserie1338.cfm. Accessed March 28, 2011
13. Lebot V, Lévesque J. Genetic control of kavalactone chemotypes in Piper methysticum cultivars. Phytochemistry 1996; 43: 397-403.
14. Russmann S, Barguil Y, Cabalion P, Kritsanida M, Duhet D, Lauterburg BH. Hepatic injury due to traditional aqueous extracts of kava root in New Caledonia. Eur J Gastroenterol Hepatol 2003; 15: 1033-1036
15. Clough AR, Bailie RS, Currie B. Liver function test abnormalities in users of aqueous kava extracts. J Toxicol Clin Toxicol 2003; 41: 821-829
16. Clough AR, Jacups SP, Wang Z, Burns CB, Bailie RS, Carney SJ, Collie A, Guyula T, McDonald SP, Currie BJ. Health effects of kava use in an eastern Arnhem Land community. Intern Med 2003; 33: 336-340
17. Brown AC, Onopa JO, Holck P, Kaufusi P, Kabasawa D, Craig WJ, Dragull K, Levine AM, Baker JD. Traditional kava beverage consumption and liver function tests in a predominantly Tongan population in Hawaii. Clin Toxicol 2007; 45: 549-556
18. Mathews JD, Riley MD, Fejo L, Munoz E, Milns NR, Gardner ID, Powers JR, Ganygulpa E, Gununuwawuy BJ. Effects of the heavy usage of kava on physical health: summary of a pilot survey in an aboriginal community. Med J Aust 1988; 148: 548-555
19. BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn. Federal Institute for Drugs and Medicinal Products in Germany). Rejection of Drug Risks, Step II. As related to: Kava-Kava (Piper methysticum)- containing, and kavain-containing drugs, including homeopathic preparations with a final concentration up to, and including D4. June 14, 2002. Available at: http://www.spc.int/cis/documents/02_0714_BfArM_Kava_Removal.pdf Accessed March 28, 2011
20. FDA (U.S. Food and Drug Administration): Consumer advisory: Kava-containing dietary supplements may be associated with severe liver injury. Issued March 25, 2002. Available at: http://www.fda.gov/Food/ResourcesForYou/Consumers/ucm085482.htm Accessed March 28, 2011
21. Therapeutic Goods Administration (TGA), Australian Government, Department of Health and Aging. Kava fact sheet, April 2005. Web page last updated September 20, 2010. Available at: http://www.tga.gov.au/cm/kavafs0504.htm Accessed March 28, 201122. Vanuatu Legislation: Republic of Vanuatu Kava Act No. 7 of 2002. Available at: http://www.paclii.org/vu/legis/num_act/toc- K.html Accessed March 28, 2011
23. Statutory Instrument 2002 No.3170 : The Medicines for Human Use (Kava-kava) (prohibition) Order 2002 :The Stationery Office Ltd , UK Government E1856 12/02. Kava Ban Update
24. Teschke R. Kava and the Risk of Liver Toxicity: Past, Current, and Future Aspects. AHPA Report. 2011. Vol. 26, No.3
25. Experts propose global guidelines for safe use and production of Kava. The University of Melbourne Newsroom. February 27, 2011. Available at: http://newsroom.melbourne.edu/news/n-469 . Accessed April 8, 2011
26. Kava trade and use restrictions may be based on inadequate information [press release]. American Herbal Products Association; Silver Spring, MD. March 8, 2011. Available at: www.ahpa.org/Default.aspx?tabid=69&aId=644. Accessed April 8, 2011
27. Teschke R, Sarris J, Glass X, Schulze J. Kava, the anxiolytic herb: back to basics to prevent liver injury? Br J Clin Pharmacol. 2011. 71;3:445–448.
28. Stafford L. Global response to kava reintroduction proposal. HerbalEGram: Volume 8, Number 4, April 2011. Accessed April 8, 2011.