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The roots of the plant are used to produce a drink with sedative and anesthetic properties. Kava is consumed throughout the Pacific Ocean cultures of Polynesia, including Hawaii, Vanuatu, Melanesia and some parts of Micronesia. Kava is sedating and is primarily consumed to relax without disrupting mental clarity. Its active ingredients are called kavalactones.
A Cochrane Collaboration systematic review of its evidence concluded it was likely to be more effective than placebo at treating short-term social anxiety. Safety concerns have been raised over liver toxicity, largely due to the use of stems and leaves by supplement makers, as opposed to solely the root of the plant as dictated by traditional uses. However, based on a retrospective study of retained P. methysticum drug materials in Germany, the alkaloid pipermethystine, occurring to about 0.2% in the leaves, is an unlikely cause for the observed hepatotoxicity. Whether kava hepatotoxicity may be due to contamination with aflatoxins or other mould hepatotoxins, requires further studies. Heavy use of kava with comorbid alcohol consumption or an existing liver condition appears to lead to malnutrition, weight loss, liver damage (causing elevated serum γ -glutamyltransferase and high-density lipoprotein cholesterol levels), renal dysfunction, rashes, pulmonary hypertension, macrocytosis of red cells, lymphocytopenia, and decreasing platelet volumes.
Preparation and consumption
Kava is consumed in various ways throughout the Pacific Ocean cultures of Polynesia, Vanuatu, Melanesia and some parts of Micronesia and Australia. Traditionally, it is prepared by either chewing, grinding or pounding the roots of the kava plant. Grinding is done by hand against a cone-shaped block of dead coral; the hand forms a mortar and the coral a pestle. The ground root/bark is combined with only a little water, as the fresh root releases moisture during grinding. Pounding is done in a large stone with a small log. The product is then added to cold water and consumed as quickly as possible.
The extract is an emulsion of kavalactone droplets in starch. The taste is slightly pungent, while the distinctive aroma depends on whether it was prepared from dry or fresh plant, and on the variety. The colour is grey to tan to opaque greenish.
Kava prepared as described above is much more potent than processed kava. Chewing produces the strongest effect because it produces the finest particles. Fresh, undried kava produces a stronger beverage than dry kava. The strength also depends on the species and techniques of cultivation. Many find mixing powdered kava with hot water makes the drink stronger.
In Vanuatu, a strong kava drink is normally followed by a hot meal or tea. The meal traditionally follows some time after the drink so the psychoactives are absorbed into the bloodstream quicker. Traditionally, no flavoring is added.
In Papua New Guinea, the locals in Madang province refer to their kava as waild koniak ("wild cognac" in English).
Fijians commonly share a drink called grog made by pounding sun-dried kava root into a fine powder, straining and mixing it with cold water. Traditionally, grog is drunk from the shorn half-shell of a coconut, called a bilo. Grog is very popular in Fiji, especially among young men, and often brings people together for storytelling and socializing. Drinking grog for a few hours brings a numbing and relaxing effect to the drinker; grog also numbs the tongue and grog drinking typically is followed by a "chaser" or sweet or spicy snack to follow a bilo.
In Western countries, kava beverage is usually made from kava root powder. The root is dried and then finely ground into powder before being exported. Generally, one tablespoon of powder is added per cup of water, but sometimes as much as a half a cup of powder (eight tablespoons) is added per cup of water to increase potency. The powder is then soaked in water for about 30 minutes to allow the water to completely soak through the powdered fibers. Lecithin is often added to aid in the process of emulsifying the kavalactones with water. The kava powder, water, and lecithin are blended in a blender for several minutes then strained into a straining cloth. Nylon, cheesecloth, and silk screen are common materials for straining. The remaining liquid is squeezed from the pulp and the rest is discarded. As an alternative to the blender method, with the powdered pulp enclosed within the straining material, the pulp is massaged for five to 30 minutes in water, then the liquid is wrung out. As more pressure is applied to the wet powdered pulp while wringing it out, more kavalactones will be released from it. Finally, the pulp resin is discarded and the beverage is enjoyed. Often, coconut water, coconut milk, lemongrass, cocoa, sugar, or soy milk is added to improve flavor.
In 2009, Vanuatu Beverage launched Lava Cola (also called Kava Cola), a soft drink containing a kavalactone additive, marketed for its relaxing properties and described as an "anti-energy drink". It was described also as "produc[ing] the calming effect of kava without the muddy taste", in the hopes of eventually reaching an international market.
Other ready-to-drink kava beverages include:
Kalm with Kava produced in San Jose, CA is a ready-to-drink Kava beverage that is a spin on classical Kava preparations. It combines Kava with fruit juice purees in a two serving bottle.
Pharmaceutical and herbal supplement companies extract kavalactones from the kava plant using solvents such as supercritical carbon dioxide, acetone and ethanol to produce pills standardized with between 30% and 90% kavalactones. Some kava herbal supplements have been accused of contributing to very rare but severe hepatotoxic reactions (see section on safety) such may have been due to the use of plant parts other than the root, such as stems or peelings that are known to have been exported to European manufacturers. A kava pill usually has anywhere from 60 mg to 150 mg of kavalactones. By comparison the typical bowl of traditionally prepared kava beverage has around 250 mg of kavalactones.
Kava is chewed by some to relieve symptoms of throat pain, as it produces a "numbing" effect on the tongue and throat. The kava is first chewed in the back of the mouth for five to 10 minutes while swallowing the saliva and kavalactones released from the process. It produces an effect similar to that of Chloraseptic spray (an over-the-counter medicine to alleviate sore throat by numbing it, via pump-spraying it into the mouth).
PharmacologyKava's active principal ingredients are the kavalactones, of which at least 15 have been identified and are all considered psychoactive. Only six of them produce noticeable effects, and their concentrations in kava plants vary. Different ratios can produce different effects.
Effects of kavalactones include mild sedation, a slight numbing of the gums and mouth, and vivid dreams. Kava has been reported to improve cognitive performance and promote a cheerful mood. Kava has similar effects to benzodiazepine medications, including muscle relaxant, anaesthetic, anticonvulsive and anxiolytic effects. They are thought to result from direct interactions of kavalactones with voltage-gated ion channels. Research currently suggests kavalactones potentiate GABAA activity, but do not alter levels of dopamine and serotonin in the CNS. It is thought to do this via modulating GABA activity via altering the lipid membrane structure and sodium channel function. However, it has also been shown that administration of the GABA antagonist Flumazenil does not have an antagonistic effect on kavalactones, suggesting that an alternative pathway may be involved. Heavy, long-term kava use does not cause any reduction of ability in saccade and cognitive tests, but is associated with elevated liver enzymes.
Desmethoxyyangonin, one of the six major kavalactones, is a reversible MAO-B inhibitor (Ki 280 nM) and is able to increase dopamine levels in the nucleus accumbens. This finding might correspond to the slightly euphoric action of kava.
Kavain, in both enantiomeric forms, inhibits the reuptake of norepinephrine at the transporter (NAT), but not of serotonin (SERT). An elevated extracellular norepinephrine level in the brain may account for the reported enhancement of attention and focus.
Yangonin, another major kavalacatone, has been demonstrated to act as a CB1 agonist. This mechanism is also responsible for the effects of THC and likely contributes to the psychoactive effects of kava.
Medical literature sometimes claims kava has a "potential for addiction" because "it produces mild euphoria and relaxation". In a traditional setting, a moderately potent kava drink causes effects within 20–30 minutes that last for about two and a half hours, but can be felt for up to eight hours. Some report longer-term effects up to two days after ingestion, including a feeling of mental clarity, patience, and an ease of acceptance. The effects of kava are most often compared to alcohol, or diazepam.
The sensations, in order of appearance, are slight tongue and lip numbing (the lips and skin surrounding may appear unusually pale), mildly talkative and sociable behavior, clear thinking, calmness, relaxed muscles, and a sense of well-being. As with other drugs that affect the GABA receptors, there can also be paradoxical dysphoria. The numbing of the mouth is caused by the two kavalactones kavain and dihydrokavain, which cause the contraction of the blood vessels in these areas, acting as a local topical anesthetic. These anesthetics can also make one's stomach feel numb. Sometimes, this feeling has been perceived as nausea.
The effects of a kava drink vary widely with the particular selection of kava plant(s) and amount. A potent drink results in a faster onset with a lack of stimulation; the user's eyes become more sensitive, the person soon becomes somnolent and then has deep, dreamless sleep within 30 minutes. Sleep is often restful and pronounced periods of sleepiness correlate to the amount and potency of kava consumed. Kava drinkers are often perceived as having lazy days after consumption of kava the night before, which can be expected as many active kavalactones have half lives of approximately 9 hours. Although heavy doses can cause deep, dreamless sleep, many people reportedly experience lighter sleep and rather vivid dreams after drinking moderate amounts of kava.
Several adverse interactions with drugs have been documented, both prescription and nonprescription – including, but not limited to, anticonvulsants, alcohol, antianxiety medications (CNS depressants such as benzodiazepines), antipsychotic medications, levodopa, diuretics, and drugs metabolized by the liver.
Australian studies focused on populations with heavy concomitant consumption of alcohol and overall poor health. In one study, heavy kava use in an Aboriginal community in Arnhem Land was associated with overall poor health, a puffy face, scaly rash, and a slight increase in patellar reflexes.
Detection in biological fluids
Recent usage of kava has been documented in forensic investigations by quantitation of kavain in blood specimens. The principal urinary metabolite, conjugated 4'-OH-kavain, is generally detectable for up to 48 hours.
- Main article: Kava culture
Correspondingly, the paraphernalia surrounding the traditional kava ceremony are expertly crafted. Traditionally designed kava bowls are made from a single piece of wood, with multiple legs. More modern examples are also highly decorated, often carved and inlaid with mother of pearl and shell.
Kava is used primarily at social gatherings to increase amiability and to relax after work. It has great religious significance, being used to obtain inspiration. Among some Christian denominations and sects in the Western Pacific, the drink has been seen as a vice to some, and some young members of these religions often reject its traditional and nontraditional uses. However, among many mainline Christian denominations, i.e. the Roman Catholic, Methodist, and Anglican churches, kava drinking is encouraged where it replaces alcohol.
Botany and agronomy
The several cultivars of kava vary in concentrations of primary and secondary psychoactive substances. The largest number are grown in the Republic of Vanuatu, and so it is recognised as the "home" of kava. Kava was historically grown only in the Pacific islands of Hawaii, Federated States of Micronesia, Vanuatu, Fiji, the Samoas and Tonga. Some is grown in the Solomon Islands since World War II, but most is imported. Kava is a cash crop in Vanuatu and Fiji.
The kava shrub thrives in loose, well-drained soils where plenty of air reaches the roots. It grows naturally where rainfall is plentiful (over 2,000 mm/yr). Ideal growing conditions are Template:Convert/-Template:Convert/test/A and 70–100% relative humidity. Too much sunlight is harmful, especially in early growth, so kava is an understory crop.
Kava cannot reproduce sexually. Female flowers are especially rare and do not produce fruit even when hand-pollinated. Its cultivation is entirely by propagation from stem cuttings.
Traditionally, plants are harvested around four years of age, as older plants have higher concentrations of kavalactones. In the past two decades, though, farmers have been harvesting younger and younger plants, as young as 18 months. After reaching about 2 m height, plants grow a wider stalk and additional stalks, but not much taller. The roots can reach a depth of 60 cm.
Strains and origins
One of the most potent strains is called "Isa" in Papua New Guinea, and also called "Tuday" in Hawaii. In Vanuatu, it is considered a type of "Tudei" kava, pronounced as "two-day" because it is said to have effects lasting two days due to its chemical profile being high in the kavalactone dihydromethysticin. The plant itself is a strong, very hardy, fast-growing variety with multiple light to dark green stems covered with raised dark spots.
In Vanuatu, exportation of kava is strictly regulated. Only strains they deem as "noble" varieties that are not too weak or too potent are allowed to be exported. Only the most desirable strains for everyday drinking are selected to be noble varieties to maintain quality control. In addition, their laws mandate that exported kava must be at least five years old and farmed organically. Their most popular noble strains are "Boroguu" or "Boronggoru" from Pentecost Island. "Melomelo" from Ambae island, (called sese in North Pentecost) and "Palarasul" kava from Espiritu Santo Island. In Vanuatu, Tudei (two-days) kava is reserved for special ceremonial occasions and exporting it is not allowed. "Palisi" is a popular Tudei variety.
In Hawaii, there are many other strains of kava. Some of the most popular strains are the "Mahakea," "Mo'i," "Hiwa" and "Nene" varieties. The Ali'i (kings) of old Hawaii coveted the special kava they called "Mo'i" that had a strong cerebral effect due to a predominant amount of the kavalactone kavain. This sacred variety was so important to them that no one but royalty could ever experience it, "lest they suffer an untimely death". The reverence for Hiwa in old Hawai‘i is evident in this portion of a chant recorded by N.B. Emerson and quoted by Handy and Handy. "This refers to the cup of sacramental‘awa brewed from the strong, black ‘awa root (‘awa hiwa) which was drunk sacramentally by the kumu hula":
The day of revealing shall see what it sees: A seeing of facts, a sifting of rumors, An insight won by the black sacred ‘awa, A vision like that of a sacred god!
Winter describes a hula prayer for inspiration which contains the line, He ‘ike pū ‘awa hiwa. Pukui and Elbert translated this as "a knowledge from kava offerings". Winter explains that ‘awa, especially of the Hiwa variety, was offered to hula deities in return for knowledge and inspiration. [pg. 34, Hawaiian 'Awa, Views of an Ethnobotanical Treasure, 2006].
Other strains are found in Fiji, Tonga, and Samoa.
Fresh kava root contains on average 80% water. Dried root contains approximately 43% starch, 20% dietary fiber, 15% kavalactones, 12% water, 3.2% sugars, 3.6% protein, and 3.2% minerals. Kavalactone content is greatest in the roots and decreases higher up the plant. Relative concentrations of 15%, 10% and 5% have been observed in the root, stump, and basal stems, respectively.
The mature roots of the kava plant are harvested after a minimum of four years (at least five years ideally) for peak kavalactone content. Most kava plants produce around 50 kg (110 lb) of root when they are harvested. Kava root is classified into two categories: crown root (or chips) and lateral root. Crown roots are the large-diameter pieces that look like (Template:Convert/toTemplate:Convert/test/A diameter) wooden poker chips. Most kava plants consist of approximately 80% crown root upon harvesting. Lateral roots are smaller-diameter roots that look more like a typical root. A mature kava plant is about 20% lateral roots. Kava lateral roots have the highest content of kavalactones in the kava plant. "Waka" grade kava is made of lateral roots only.
Basic research on anti-cancer potential
Side effects and safety
Toxicology of pill from kava extracts with stems and leaves
The legal intervention of several countries stimulated research, and hepatotoxic substances were found in the stems and leaves of the plant. Researchers from the University of Hawaii at Manoa found an alkaloid called pipermethystine (formula 1), contained in stem peelings and leaves but not in the roots, had toxic effects on liver cells in vitro and in vivo. In rats fed with 10 mg/kg pipermethystine for two weeks, indications of hepatic toxicity were found. Comparable signs of toxicity were not detected with kava rhizome extracts (100 mg/kg, 2 weeks), (73 mg/kg, 3 months).
Flavokavain B, found in the plant's rhizome (large horizontal underground stem), may also contribute to toxic effects. It is also known that some of the kavapyrones block several subtypes of the enzyme cytochrome P450, which can result in adverse interactions with other drugs used concomitantly.
Hawaiian researchers learned from a trader in Fijian kava that European pharmaceutical companies eagerly bought up the stem and leaves peelings when demand for kava extract soared in Europe in 2000 and 2001. Before 2002, substantial amounts of aerial parts of the kava plant were being exported to North America and Europe and obviously used for the production of commercial pill extracts. For traditional use in the South Pacific, stem peelings and leaves are discarded, and only the rhizomes are used and extracted with water. This may explain why native populations who make heavy use of kava experience side effects that are mild, temporary, and confined to the skin, whereas industrialized countries that have newly adopted kava occasionally show severe, acute responses.
Toxicity of traditional kava beverage preparations
Two studies still allege changes in liver function, with the first describing the effects as temporary and reversible when discontinuing kava use. There is evidence of health concerns for kava use among heavy alcohol drinkers, including poor nutrition and a rise in liver enzymes typically associated with liver damage.
Another study published in the journal Phytochemistry in 2003 indicated traditional aqueous preparations of kava also extract glutathione, which alcoholic extracts lack when made with high concentrations of alcohol. The authors discovered the glutathione in traditional preparations interacts with the kavalactones and prevents cell death. They claim that in all standardized extracts that contributed to liver damage, there were only the kavalactones without any glutathione.
Allergic reactions are usually mild and include itchy skin or itchy throat, and hives on the skin usually prevalent on the user's belly region.
Currently, following the lifting of the ban on kava imports by the EU in 2008, Poland and Portugal are the only countries in the European Union (and probably in the world) that explicitly ban sale, cultivation and possession of kava in any form and for any purpose.
In 2001, concerns were raised about the safety of commercial kava products. There were allegations of liver toxicity in people who had used dietary supplements containing kava extract (but not in anyone who had drunk kava the traditional way). The allegations of liver damage consequently prompted action of many regulatory agencies in European countries where the legal precautionary principle so mandated. In the UK, the "Medicines for Human Use (Kava-kava) (Prohibition) Order 2002" prohibits the sale, supply or import of most derivative medicinal products. The sale of kava is regulated in Switzerland, France, and the Netherlands.
The health agency of Canada issued a stop-sale order for kava in 2002. But legislation in 2004 made the legal status of kava murky to many, especially since not everyone is aware that a stop-sale order does not constitute a ban such as that applies in several European countries. Kava is not illegal in Canada and does not fall under any of the Food and Drugs Act regulations. Many retailers had been ignoring the no-sale order without further consequence than having Health Canada issue warnings about the product's safety. At least one US manufacturer of kava products who had suspended export to Canada in 2002 has since lifted the restriction and resumed shipping kava to Canada after obtaining confirmation that it was not illegal for Canadians to import kava. In February 2012, retail sale of Kava was made legal again in Canada.
The United States CDC has released a report expressing reservations about the use of kava and its possibly adverse side effects (specifically severe liver toxicity), as has the Food and Drug Administration (FDA). The aviation medicine branch of the FAA has strongly recommended against any use of kava by pilots. In Australia, the supply of kava is regulated through the National Code of Kava Management. The sale and supply of kava is prohibited in Western Australia and the Northern Territory. The Australian Therapeutic Goods Administration has recommended no more than 250 mg of kavalactones be taken in a 24 hour period. According to the Medicines Control Agency in the U.K., there is no safe dose of kava, as there is no way to predict which individuals would have adverse reactions, if any.
In a 2009 study by the University of Queensland, Australia, researchers found the study's participants did not show any signs of potential liver damage, contrary to concerns that prompted European, British and Canadian authorities to ban kava sales in 2002. Kava products sold in those countries were based on ethanol or acetone extracts of the kava plant, not the water-soluble extracts used traditionally by Pacific islanders and approved for sale in Australia.
With regard to the mechanism of the discussed hepatotoxicity, the data for now indicate an intrinsic toxicity, and possibly also an idiosyncratic metabolic toxicity in isolated cases. Hepatotoxic effects cannot be excluded with elevated doses and abuse of kava or isolated kava lactones, as in the case of other drugs, since this medicinal plant has a pronounced pharmacological activity. Kava is an herbal drug that must be taken within a defined dosage range. Higher than recommended doses and extensive use over a longer time period are therefore not only unnecessary, but also generally increase the risk. From the reviewed adverse events, three possible mechanisms for kavalactone hepatotoxicity were considered: inhibition of cytochrome P450, reduction in liver glutathione content and, more remotely, inhibition of cyclooxygenase enzyme activity. The direct toxicity of kava extracts is relatively small under any analysis, yet the potential for drug interactions and/or the potentiation of the toxicity of other compounds is large.
A PhD thesis from 2011 suggests that a synthetic kavain enantiomer is likely to have played a role in the liver toxicity in Europe. Many German kava kava products comprised a synthetic kavain for economic reason, like, e.g., in Laitan®. The synthetic kavain is a racemic mixture of kavain(+) and kavain(-) (noted also D/L kavain). Kava kava contains only kavain(+). In the PhD work, it is shown that kavain(-) is metabolized in toxic para hydroxy-kavalactones. This would explain why the liver toxicity has mainly taken place in the German speaking part of Europe while it is unknown in the Pacific. Moreover, contradictory results in scientific studies would simply come from the fact that most authors do not disclose if the kavain used in their study is natural or synthetic. In any case, in 2006 Germany lifted its ban on kava imports recognizing that the problems concerned only specific pharmaceutical products and not the kava root itself.
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- Kava culture
- List of herbs with known adverse effects
- Samoa 'ava ceremony
- Samoan plant names
- ↑ kava. (2010). In Merriam–Webster Online Dictionary.
- ↑ Pittler MH, Ernst E (2003). Kava extract for treating anxiety. Cochrane database of systematic reviews (Online) (1): CD003383.
- ↑ 3.0 3.1 3.2 Lim ST, Dragull K, Tang CS, Bittenbender HC, Efird JT, Nerurkar PV (May 2007). Effects of kava alkaloid, pipermethystine, and kavalactones on oxidative stress and cytochrome P450 in F-344 rats. Toxicol. Sci. 97 (1): 214–21.
- ↑ 4.0 4.1 Sorrentino L, Capasso A, Schmidt M (September 2006). Safety of ethanolic kava extract: Results of a study of chronic toxicity in rats. Phytomedicine 13 (8): 542–9.
- ↑ Lechtenberg M, Quandt B, Schmidt M, Nahrstedt A (2008). "Is the alkaloid pipermethystine connected with the claimed liver toxicity of Kava products?" Pharmazie 63 (1) : 71–74. PMID 18271308
- ↑ Teschke R., Qiu S.X., Lebot V. "Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits" [Article in Press] Digestive and Liver Disease 2011
- ↑ Fu PP, Xia Q, Guo L, Yu H, Chan PC (2008). Toxicity of kava kava. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 26 (1): 89–112 .
- ↑ Kevin Cassell (2005). Fiji: A Visitor's Guide. URL accessed on 2007-04-25.
- ↑ "Van Beverage releases new kava drink", Vanuatu Daily Post, 4 October 2009
- ↑ "Vanuatu has high hopes for new Kava based Lava Kola", ABC Radio Australia, 18 March 2010
- ↑ "Kava cola, Vanuatu's answer to energy drinks", Australia News Network, 18 March 2010
- ↑ Advertisement for Lava Cola, focusing on its relaxing effect, on the official YouTube channel of the Vanuatu Kava Store
- ↑ http://www.vice.com/read/king-kava-a-savage-journey-into-the-dark-heart-of-brooklyns-alt-beverage-industry
- ↑ http://kingkava.com/
- ↑ http://DrinkKalm.com
- ↑ Viorica, Lopez-Aila Supercritical fluid extraction of kava lactones from Piper methysticum (kava) herb. Hüthig GmbH. URL accessed on 5 September 2012.
- ↑ Thompson, R et al. (2004). Enhanced cognitive performance and cheerful mood by standardized extracts of Piper methysticum (Kava-kava). Hum Psychopharmacol. 19 (4): 243–250.
- ↑ Cairney, S et al. (2002). The neurobehavioural effects of kava. Aust N Z J Psychiatry 36 (5): 657–652.
- ↑ Hunter, A (2006). Kava (Piper methysticum) back in circulation. Australian Centre for Complementary Medicine 25 (7).
- ↑ Teschke, Rolf, Qiu SX, Lebot V (2011). Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B and mould hepatotoxins as primarily assumed culprits. Digestive and Liver Disease 43 (9): 676–681.
- ↑ Garrett, KM et al. (2003). Extracts of kava (Piper methysticum) induce acute anxiolytic-like behavioral changes in mice.. Psychopharmacology 170 (1): 389–396.
- ↑ Cairney, S et al. (2003). Saccade and cognitive function in chronic kava users. Neuropsychopharmacology 28 (2): 389–396.
- ↑ Uebelhack R, Franke L, Schewe HJ (September 1998). Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava). Pharmacopsychiatry 31 (5): 187–92.
- ↑ Baum SS, Hill R, Rommelspacher H (October 1998). Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 22 (7): 1105–20.
- ↑ Seitz U, Schüle A, Gleitz J (December 1997). [3H]-monoamine uptake inhibition properties of kava pyrones. Planta Med. 63 (6): 548–9.
- ↑ PMID 22525682 (PMID 22525682)
- ↑ 27.0 27.1 http://www.health.gov.au/internet/drugstrategy/publishing.nsf/Content/545C92F95DF8C76ACA257162000DA780/$File/indigenous-background.pdf
- ↑ 28.0 28.1 .
- ↑ McDonald, D (2000). Kava in the Pacific Islands: a contemporary drug of abuse?. DRUG ALCOHOL REV 19: 217–227.
- ↑ University of Maryland Medical Center (2011). Kava Kava. URL accessed on 2011-12-18.
- ↑ Clough A (2001). Enough! or too much. What is 'excessive' kava use in Arnhem Land?. Drug Alcohol Rev 22 (1): 43–51.
- ↑ Mathews JD, Riley MD, Fejo L, et al. (June 1988). Effects of the heavy usage of kava on physical health: summary of a pilot survey in an aboriginal community. Med. J. Aust. 148 (11): 548–55.
- ↑ Kava R (March 2001). The adverse effects of kava. Pac Health Dialog 8 (1): 115–8.
- ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 803–804.
- ↑ There are many variations to this ceremony; one of which is described in: (2001) My Village, My World: Everyday Life in Nadoria, Fiji, 17–20, Suva, Fiji: Institute of Pacific Studies, University of the South Pacific. There are numerous anthropological studies, one example being: (2007). Everything and Its Opposite: Kava Drinking in Fiji. Anthropological Quarterly 80 (4): 1065–81.Template:Synthesis-inline
- ↑ Naumov, P., Dragull, K., Yoshioka, M., Tang, C.-S., Ng, S. W. Structural Characterization of Genuine (—)-Pipermethystine, (—)-Epoxypipermethystine, (+)-Dihydromethysticin and Yangonin from the Kava Plant (Piper methysticum), Natural Product Communications(2008), 3(8) 1333—1336.
- ↑ (2005). Anticancer activities of constituents of kava (Piper methysticum). The South Pacific Journal of Natural Science 23: 26.
- ↑ (2009). Kava High Safety Record. (PDF) Kava Zen. URL accessed on 2010-03-05.
- ↑ Pratibha V. Nerurkar et al. (2004): "In Vitro Toxicity of Kava Alkaloid, Pipermethystine, in HepG2 Cells Compared to Kavalactones", Toxicological Sciences 79, 106-111. Fulltext.
- ↑ Jhoo JW, Freeman JP, Heinze TM, et al. (April 2006). In vitro cytotoxicity of nonpolar constituents from different parts of kava plant (Piper methysticum). J. Agric. Food Chem. 54 (8): 3157–62.
- ↑ a)Mathews JM, Etheridge AS, Valentine JL, et al. (October 2005). Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro. Drug Metab. Dispos. 33 (10): 1555–63.
b)Mathews JM, Etheridge AS, Black SR (November 2002). Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab. Dispos. 30 (11): 1153–7.
- ↑ Clough AR, Bailie RS, Currie B (2003). Liver function test abnormalities in users of aqueous kava extracts. J. Toxicol. Clin. Toxicol. 41 (6): 821–9.
- ↑ Dr Joji Malani (2002). Evaluation of the effects of Kava on the Liver. (PDF) URL accessed on 2008-01-05.
- ↑ AC Brown (2007). Traditional kava beverage consumption and liver function tests in a predominantly Tongan population in Hawaii revealed no liver impairment.. URL accessed on 2009-03-17.
- ↑ Peter A. Whittona, Andrew Laua, Alicia Salisburyb, Julie Whitehousec, Christine S. Evans (2003). Kava lactones and the kava-kava controversy. Phytochemistry 64 (3): 673–679.
- ↑ (2008). Europe lifts ban on kava. Fiji Times Limited.. URL accessed on 2008-11-12. ).
- ↑ Blumenthal, Mark (2002). Kava safety questioned due to case reports of liver toxicity. American Botanical Council (55): 26–32.
- ↑ C.I.J.M. Ross-van Dorp (2003). Besluit van 23 april 2003, houdende wijziging van het Warenwetbesluit Kruidenpreparaten (verbod op Kava kava in kruidenpreparaten). (PDF) Sdu Uitgevers. Staatsblad van het Koninkrijk der Nederlanden. URL accessed on 2007-02-07.
- ↑ konakavafarm.com/kava-canada-banned.
- ↑ 
- ↑ United States Centers for Disease Control and Prevention (2002). Hepatic Toxicity Possibly Associated with Kava-Containing Products – United States, Germany, and Switzerland, 1999 2002. Morbidity & Mortality Weekly Report 51 (47): 1065–1067.
- ↑ Center for Food Safety and Applied Nutrition (2002). Kava-Containing Dietary Supplements May Be Associated with Severe Liver Injury.
- ↑ http://aviationmedicine.com/articles/index.cfm?fuseaction=displayArticle&articleID=48
- ↑ http://www.nt.gov.au/justice/licenreg/kava.shtml
- ↑ (2005). Kava fact sheet. Therapeutic Goods Administration, Government of Australia. URL accessed on 2006-07-10. (Download PDF 44KB).
- ↑ (2003). Kava: A supplement to avoid. Consumer Reports. URL accessed on 2006-07-17.
- ↑ Kava good for anxiety. Stuff. URL accessed on 2009-05-12.
- ↑ Zhou P., Gross S., Liu J.-H., Yu B.-Y., Feng L.-L., Nolta J., Sharma V., Piwnica-Worms D., Qiu S.X. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-κB and MAPK signaling pathways FASEB Journal 2010 24:12 (4722-4732)
- ↑ On the Risk of Liver Damage Due to KAVASEDON® and the Current Risk-Benefit Ratio of the Preparation in context with the Hearing in the drug safety protocol for Kava (In accord. with the BfArM communication from 8 Nov. 2001), translated by JB & ML
- ↑ Clouatre DL.(2004)"Kava kava: examining new reports of toxicity" Toxicol Lett. 150(1):85-96. PMID 15068826
- ↑ Barguil, Yann. Etude de trois plantes psychotropes consommées en Nouvelle-Calédonie: kava, cannabis et datura. Dissertation, Universite de la Nouvelle-Calédonie. 4 March 2011.
- ↑ synthetic kavain BfArM
- ↑ 
53. Hawaiian 'Awa Views of an Ethnobotanical Treasure (2006)
- Lindstrom, Lamont; Lebot, Vincent; Merlin, Mark David (1992). Kava: The Pacific Elixir – The Definitive Guide to its Ethnobotany, History and Chemistry, New Haven, Conn: Yale University Press.
- The Mars Trilogy by Kim Stanley Robinson, Spectra, 1993. ISBN 0-553-09204-9. Contains many references to Kava, and "Kavajava" – kava mixed with coffee. The book uses kava as the social drink of choice for the "Martians" (human colonizers of Mars).
- The Sex Lives of Cannibals: Adrift in the Equatorial Pacific by J. Maarten Troost, Broadway Books, New York, 2004. ISBN 0-7679-1530-5.
- Getting Stoned with Savages: A Trip Through the Islands of Fiji and Vanuatu by J. Maarten Troost, Broadway Books, New York, 2006. ISBN 978-0-7679-2199-2. ISBN 0-7679-2199-2.
- Kava ban documents
- Piper methysticum information from the Hawaiian Ecosystems at Risk project (HEAR)
- Template:Cite EB9