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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Drugs and Herbal Products. Lyon (FR): International Agency for Research on Cancer; 2016. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 108.)
The kava plant is indigenous to Oceania (Lebot et al., 1997; Ramzan & Tran, 2004) and has been used both ceremonially and recreationally in certain cultures of the South Pacific for at least 1500 years. Europeans documented its use when they travelled to Polynesia in the 18th century (WHO, 2007). The cultural history of the use of kava has been reviewed by Singh (1992).
In the past, traditional use of kava was widespread, but, in certain cultures, custom determined who could use kava and for what purposes. In recent years, as part of the processes of modernization, major changes have occurred with regard to who uses kava, and where and how it is consumed. In some places, kava is now being consumed much like alcohol in western countries, as a beverage that is drunk socially (McDonald & Jowitt, 2000).
1.1. Identification of the agent
1.1.1. Botanical data
(a) Nomenclature
- Chem. Abstr. Serv. Reg. No.: 9000-38-8
- Chem. Abstr. Name: Kava-kava resin (8Cl)
- Botanical name: Piper methysticum G. Forst
- Family: Piperaceae
- Genus: Piper
- Plant part: Rhizome
(WHO, 2004; O’Neil et al., 2006; NTP, 2012; and SciFinder, 2013)
According to WHO (2007), some other species such as Piper wichmanni, Piper aduncum and Piper auritum have also been marketed as “kava.”
Common names: Kava; Kava-kava; Ava-ava; Antares; Ava; Ava pepper; Ava pepper shrub; Ava root; Awa; Fijian kava; Gea; Gi; Grog; Intoxicating long pepper; Intoxicating pepper; Kao; Kava kava rhizome; Kava root; Kavapiper; Kavapyrones; Kavarod; Kavasporal forte; Kave-kave; Kawa; Kawa kawa; Kawa pepper; Kawa Pfeffer; Kew; Long pepper; Macropiper latifolium; Malohu; Maluk; Maori kava; Meruk; Milik; Pepe kava; Piperis methystici rhizome; Rhizoma piperis methystici; Sakaua; Sakau; Tonga; Yagona; Yangona; Yaqona; Yongona
(b) Description
See Fig. 1.1
Fig. 1.1
Piper methysticum G. Forst
The tropical shrub Piper methysticum is a hardy, fairly succulent, slow-growing perennial that is widely cultivated in Oceania. The species is sterile and reproduces asexually. Due to its traditional use as a ritual beverage known for promoting relaxation and a sense of well-being, the kava plant spread widely throughout Oceania, in Polynesia, Melanesia, and the Federated States of Micronesia (Norton & Ruze, 1994; NTP, 2012).
The leaves are heart-shaped, pointed, 8–25 cm in length, and smooth and green on both sides. Kava is cultivated for its rootstock (rhizome), also referred to as the stump. The stump is knotty, thick, and sometimes tuberous and often contains holes or cracks created by partial destruction of the parenchyma. A fringe of lateral roots up to 2–3 m in length extends from the pithy rhizome. The roots comprise a multitude of ligneous fibres and consist of > 60% starch. Rhizome colour varies from white to dark yellow, depending upon the amount of kavalactones contained in the lemon-yellow resin. The plant is usually harvested when it is about 2–2.5 m in height (Singh, 1992; Lebot et al., 1997; NTP, 2012).
The cultivation and selection of kava has produced numerous varieties or cultivars recognized by differences in the internodes (space between stem joints), colour of stems, intensity of leaf colour, and quality of the root. Different varieties are classified, named, and used for different purposes by the indigenous people (NTP, 2012).
The dried rhizome consists of irregular, transverse and longitudinal pieces, varying considerably in size and shape: 3–20 cm in length and 1–5 cm in diameter. The outer surface is light yellowish or greyish-brown, longitudinally wrinkled, with large, whitish, circular root scars. The fracture is coarsely fibrous, the inner surface is yellow-white, with thin bark, radiate xylem, and large pith (WHO, 2004).
1.1.2. Chemical constituents and their properties
Analysis of the composition of kava rhizome indicates that the fresh material is on average 80% water. When dried, the rhizome consists of approximately 43% starch, 20% fibres, 12% water, 3.2% sugars, 3.6% proteins, 3.2% minerals, and 15% kavalactones, although the kavalactone component can vary between 3% and 20% of the dry weight of the rhizome, depending on the age of the plant and the cultivar. The bioactive principles of kava rhizome are mostly, if not entirely, contained in the lipid-soluble resin. The compounds of greatest pharmacological interest are the substituted α-pyrones or kavapyrones, commonly known as kavalactones. At least 15 lactones have been isolated from kava rhizome. The following six compounds are present in the highest concentrations and account for approximately 96% of the lipid resin: kavain, dihydrokavain, yangonin, desmethoxyyangonin, methysticin, and dihydromethysticin (see Fig. 1.2). Other constituents of kava include chalcones and other flavanones, and conjugated diene ketones (Shulgin, 1973; Dentali, 1997; WHO, 2004; NTP, 2012).
Fig. 1.2
Structures of the major kavalactones occurring in kava rhizome
In the past, “kavain” has been used to indicate a racemic mixture resulting from chemical synthesis, and “kawain” for the naturally occurring compound, which is a dextro-isomer. Currently, the two terms, kavain and kawain, are frequently used interchangeably in the scientific literature, but the term kavain has started to supersede kawain (Singh, 2004a).
The chemistry of kava and kavalactones has been reviewed in detail by Ramzan & Tran (2004).
1.1.3. Technical and commercial products
Kava biomass is normally sold as the rhizome, with the periderm and roots removed. The peeled rhizome is also the desired material for solvent extraction to produce kava extracts. Kava may also be sold as an unpeeled rhizome covered with the cork or with the roots attached. Peelings from the root and stump have also been used in commerce (Morgan et al., 2005). Powdered forms of rhizome are available in commercial markets in Fiji and have been described to be adulterated to the extent that they only contain 71–78% of the expected active constituents (Clough et al., 2000). Singh (2004a) mentioned adulteration with sawdust, flour, or soil. Adulteration of kava with plants resembling the genuine kava, but lacking the kavalactones and the distinct kava odour has also been reported. The main “false kava” species are P. auritum and P. aduncum (Singh, 2004b).
Very few data exist on kava contamination by bacteria or with mycotoxins (Teschke et al., 2011). A study on ochratoxin A contamination found concentrations of 3.0 ng/g in one sample of kava root (Trucksess et al., 2006). The level of contamination with aflatoxin B1 in four samples of ground kava was 0.5 ng/g (Weaver & Trucksess, 2010).
The part of the plant used, processing techniques, and specifically the extraction solvent and the ratio between solvent/plant material in the case of kava extracts, may have considerable influence on the chemical composition of the end product. For example, the alkaloid pipermethystine was not detectable in some commercial kava extracts (Teschke et al., 2011).
[The Working Group noted that the influences on composition mentioned above may hinder the comparison of studies, especially if the applied kava material was not specified exactly.]
1.2. Analysis
The chemical analysis and quality control of both kava and its extracts obtained by aqueous acetone or aqueous methanol, and supercritical fluid extraction – typically with carbon dioxide modified with methanol as solvent – were reviewed by Bilia et al. (2004). Both gas chromatography (GC) and high-performance liquid chromatography (HPLC) can be used for the analysis of kavalactones with some advantages and disadvantages for each method. Using GC analysis, methysticin and yangonin, which are two of the major components, are generally not separated. In addition, the high temperature of the injection port causes the decomposition of methysticin. Concerning HPLC analyses, reversed-phase separation is generally better because it is highly reproducible with a very low detection limit for all compounds even if the quantitative analysis of the kavalactones by HPLC needs to be carried out in the absence of light to prevent the cis/trans isomerization of yangonin (Bilia et al., 2004). Besides various chromatographic approaches reviewed by Bilia et al. (2004), near infrared spectroscopy and nuclear magnetic resonance spectroscopy have been suggested to directly determine kavalactones without the need for separation (Table 1.1).
Table 1.1
Selected methods of analysis of constituents of kava in various matrices.
1.3. Use
1.3.1. Indications
(a) Medicinal use
According to WHO (2004), the medicinal uses supported by clinical data are short-term symptomatic treatment of mild states of anxiety or insomnia due to nervousness, stress or tension; the medicinal uses described in pharmacopoeias and in traditional systems of medicine are to induce relaxation, reduce weight, and treat fungal infections. Uses described in traditional medicine, but not supported by experimental or clinical data, are treatment of asthma, common cold, cystis, gonorrhoea, headaches, menstrual irregularities, urinary infections, and warts.
The German Commission E has approved kava for use in conditions of nervous anxiety, stress, and restlessness (Anonymous, 2000).
(b) Traditional food and recreational use
A local traditional drink, also known under the name kava, is obtained from the root or rhizome of the kava plant. The kava drink is made from water extracts, with water-insoluble substances made available to the drinker by emulsification, which may be accomplished by pounding or chewing of the rhizome (WHO, 2007).
On some islands in the South Pacific, fresh kava root or rhizome is used to prepare the traditional drink, while on others it is the dried and ground roots or rhizomes that are used. For fresh preparations, the root is chewed by young women, who spit the juice into the kava bowl without swallowing it themselves. The juice is then mixed with water or coconut milk and further processed. Most people drink only the water extracts of kava. This is obtained by adding water to kava roots which are finely ground and then filtered using cheese-cloth (WHO, 2007).
The kava drink has been described to have a psychoactive activity, and potency can vary considerably. Kava drinking initially produces a slight numbing of the tongue. Delayed effects have been described as relief of fatigue, reduction of anxiety, and production of a pleasant, cheerful, and sociable attitude in the drinker (WHO, 2007).
The consumption of kava is part of everyday life on islands such as Fiji, Tonga, and Vanuatu, and occurs during important events or social gatherings (Singh, 1992).
It is difficult to compare the psychopharmacological effects of kava between published studies as methods of preparation, means of ingestion, and the potency and quantity of dosages actually consumed vary considerably (Cairney et al., 2002).
Kava bars, at which prepared kava can be purchased to drink on the spot or to take away, are an increasingly common feature throughout Oceania (McDonald & Jowitt, 2000).
(c) Non-traditional food use
Non-traditional kava products are marketed in Europe and North America typically as food or dietary supplements in tablet form (Morris & Avorn, 2003; Teschke & Lebot, 2011). Interestingly, these food supplements are often marketed over the internet (Morris & Avorn, 2003). In some countries this may be due to difficulties with regulatory acceptance. For example, in Europe this practice is illegal, but kava products are nevertheless available (Monakhova et al., 2013).
(d) Cosmetic use
Kava extracts from various parts of the plant may be used as skin-conditioning agents in cosmetics. However, the USA Cosmetic Ingredient Review expert panel concluded that the available data were insufficient to support the safety of kava extracts for cosmetic use (Robinson et al., 2009).
1.3.2. Dosage
(a) Medicinal use
The comminuted crude drug and extracts are used for oral use. Daily dosage for crude drug and extracts is equivalent to 60–210 mg of kavalactones (WHO, 2004). The recommended oral dose for use of commercial kava extracts as an anxiolytic is 50–70 mg of kavalactones, two to four times per day and, as a hypnotic, 150–210 mg in a single oral dose before bedtime (Bilia et al., 2002b).
The pharmaceutical industry was primarily interested in the organic solvent (such as 95% ethanol or acetone) extracts of kava containing the organic compounds of commercial interest. Some marketed products, referred to as “synthetic,” consist of a single kavalactone, l-kavain (WHO, 2007).
A review of standardized kava brands in the USA found an approximate equivalence of actual [measured] and labelled amounts of kavalactones in 13 products that listed amounts of constituents. Kavalactones per tablet or capsule ranged from 50 to 110 mg. Two brands that did not label amounts of constituents contained 10–15 mg per tablet or capsule (Ulbricht et al., 2005).
Typical usage has ranged from 70 to 280 mg of kavalactones per day as a single bedtime dose or divided doses (60–120 mg of kavalactones per day). Many practitioners allegedly start at a lower dose and titrate up as needed (Ulbricht et al., 2005).
(b) Traditional food and recreational use
Only rough estimations exist on the dosage of traditional food and in recreational use of kava. Heavy consumers may drink the equivalent of at least 610 g/week of kava powder, which, with an estimated kavalactone content of 12.5%, may equate to approximately 76 g of lactones per week or more than 50 times the recommended therapeutic dose (Cairney et al., 2002).
In Arnhem Land, Australia, weekly per capita consumption was estimated as 145 g of powder for 1989–90 and 368 g of powder for 1990–91. When seven cups of 100 mL are consumed in 1 hour, about 3.8 g of lactones may be consumed. In a detailed review of the literature on weekly consumption levels and possible lactone contents, the estimations encompassed a wide variation from 39 to 1840 g of kava powder consumed, and from 4.1 g to 188.6 g of lactones consumed per week (Clough et al., 2000).
Typical dosage of dried root or by decoction was reported to be 6–12 g per day (Morgan et al., 2005).
(c) Non-traditional food use
The Dietary Supplements Label Database lists 11 products that contain kava as active ingredient in amounts of 60–1000 mg. Of the 11 products, 4 are listed as discontinued (NLM, 2012).
Kava food supplements, illegally sold over the internet in Germany, contained 8–10 mg of kavalactones per capsule (Monakhova et al., 2013).
(d) Cosmetic use
The Cosmetic, Toiletry, and Fragrance Association (CTFA) provided a use concentration of 0.0001–0.01% for leaf/root/stem extract, and of 0.1% for root extract (Robinson et al., 2009).
1.4. Production, sales, and consumption
1.4.1. Production
(a) Production process
Kava production including cultivation, diseases and pests, harvesting and processing has been reviewed by Singh (2004b).
(b) Production volume
Kava was one of the most extensively used herbal products in the USA in the 1990s (NTP, 2012). According to Morris & Avorn (2003), sales of kava were US$ 69 million in 2000. In 2003, 62 retail sites were identified that sold kava over the internet (Morris & Avorn, 2003).
In Australia, trade in kava rhizome in Arnhem Land was approximately 28 tonnes in 1992, and between 27 and 36 tonnes in 1997. At the end of 1999, by which time trade in kava was illegal, trade was estimated to be 20 tonnes, while in 2000 the trade was approximately 15 tonnes (Clough, 2003).
1.4.2. Sales
By the mid 1990s, North Americans, Europeans, and Australians had begun using kava products as an alternative medicine and herbal relaxant. Commercial kava bars promoted recreational kava drinking, which can often occur for extended periods. Drug stores and supermarkets offered a variety of kava products in pill, capsule, tea, and liquid form. In addition, powdered kava root was available by mail order from several internet sites. Most of this exported kava derived from Fiji and Vanuatu, and to a lesser extent, Samoa and Tonga (Lindstrom, 2004). Kava abuse has been reported, especially in Pacific Island nations, leading to significant health and social problems (McDonald & Jowitt, 2000; Rychetnik & Madronio, 2011).
Current use in North America, Europe, and Australia may have been influenced by regulatory measures (see Section 1.6) and reports of adverse events in the popular press.
According to the 2012 Nutrition Business Journal Annual Report, kava was the 36th best-selling dietary supplement in the USA in 2011. There has been a considerable decline in kava sales in the USA from US$ 52 million in 2000 to US$ 17 million in 2004. Sales remained at a similar level between US$ 18 and 22 million during 2005–2011, and then increased to US$ 31 million in 2011 (Fig. 1.3; Nutrition Business Journal, 2010, 2012). Total global sales of kava (Piper methysticum) as an herbal supplement were US$ 8 million in 2012, and appreciable sales volumes occurred in the USA (US $3 million), Brazil (US$ 2 million), and Hungary (US$1 million) (IMS Health, 2012).
Fig. 1.3
Sales of kava as a dietary supplement in the USA
[The Working Group suggested that prohibition in some countries may have resulted in increases in unrecorded sales of kava, e.g. unrecorded individual imports, or illegal sales.]
1.4.3. Consumption
Consumers of products specified in Section 1.3 are exposed to kava. No literature about the degree of population-based exposure to kava was available to the Working Group. [The Working Group estimated that current exposure to kava was expected to be a fraction of what it was in the previous decade due to withdrawal of marketing authorization in many countries (see Section 1.6).]
1.5. Occupational exposure
No specific studies on occupational exposure were available to the Working Group. It can be assumed that workers in kava production for food, cosmetic, or medicinal use may be exposed.
1.6. Regulations and guidelines
Several cases of liver damage have been associated with exposure to kava in Europe, and have led to withdrawal of the product license (NTP, 2012). Reviews on the cases of adverse effects potentially caused by exposure to kava have been compiled by Schmidt et al. (2005) (detailed analysis of 83 cases), as by WHO (2007) (analysis of 93 cases). Speculations about the causes of the adverse effects included the use of less expensive stem peelings in commercial materials instead of the usual peeled rhizomes (Teschke et al., 2011).
Sales of kava have been suspended or withdrawn in several countries, including Australia, Canada, France, Germany, Spain, and Switzerland, and due to reported association with hepatotoxicity in humans (Russmann et al., 2001, 2003; Campo et al., 2002; De Smet, 2002; Parkman, 2002; Clough et al., 2003; Humberston et al., 2003; Teschke et al., 2003; Ulbricht et al., 2005; NTP, 2012).
Although sales of kava were not regulated or controlled in the USA in 2012 (NTP, 2012), the Food and Drug Administration (FDA) had issued a public warning in 2001 that kava might be be associated with serious liver damage, including hepatitis, cirrhosis, and liver failure (FDA, 2002). The regulatory action taken by various countries around the world from the year 2000 after concerns about hepatotoxicity is summarized in WHO (2007). Current regulatory status was summarized by Teschke & Lebot (2011), and included suggested chemical standards and agricultural standardizations. WHO (2004) provided some guidelines for the quality control of kava (see Table 1.2).
Table 1.2
Guidelines for dried kava rhizome.
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