Kava

This article is about the kava plant. For the class of pharmacological derivatives, see Kavalactone. For other uses, see Kava (disambiguation).
Kava
Piper methysticum leaves
Scientific classification
Kingdom: Plantae
(unranked): Angiosperms
(unranked): Magnoliids
Order: Piperales
Family: Piperaceae
Genus: Piper
Species: P. methysticum
Binomial name
Piper methysticum
G.Forst.

Kava or kava-kava (Piper methysticum: Latin "pepper" + Latinized Greek "intoxicating") is a crop of the western Pacific.

The name kava(-kava) is from Tongan and Marquesan;[1] other names for kava include ʻawa (Hawaiʻi),[2] ava (Samoa),[3] yaqona (Fiji),[4] sakau (Pohnpei),[5] and malok or malogu (parts of Vanuatu).[6]

The roots of the plant are used to produce a drink with sedative, anesthetic, and entheogenic properties. Kava is consumed throughout the Pacific Ocean cultures of Polynesia, including Hawaii, Vanuatu, Melanesia and some parts of Micronesia. (See canoe plants.) 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.[7]

Characteristics

The several cultivars of kava vary in concentrations of primary and secondary psychoactive alkaloids. 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 70–95 °F (21–35 °C) 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. 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

A painting showing women preparing kava

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.

Composition

Fresh kava root contains on average 80% water. Dried root contains approximately 43% starch, 20% dietary fiber, 15% kavalactones,[8] 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 (1.5 to 5 inches (38 to 127 mm) 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.

Pharmacology

Constituents

A total of 18 different kavalactones (or kavapyrones) have been identified to date, at least 15 of which are active.[9] However, six of them, including kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, have been determined to be responsible for about 96% of the plant's pharmacological activity.[9] Some minor constituents, including three chalcones, flavokavain A, flavokavain B, and flavokavain C, have also been identified,[9] as well as a toxic alkaloid, pipermethystine.[10]

Pharmacodynamics

The following pharmacological actions have been reported for kava and/or its major active constituents:[11]

Receptor binding assays with botanical extracts have revealed direct interactions of leaf extracts of kava (which appear to be more active than root extracts) with the GABA (i.e., main) binding site of the GABAA receptor, the D2 receptor, the μ- and δ-opioid receptors, and the H1 and H2 receptors.[13][14] Weak interaction with the 5-HT6 and 5-HT7 receptors and the benzodiazepine site of the GABAA receptor was also observed.[13]

Potentiation of GABAA receptor activity may underlie the anxiolytic effects of kava, while elevation of dopamine levels in the nucleus accumbens likely underlie the moderately psychotropic effects the plant can produce. Changes in the activity of 5-HT neurons could explain the sleep-inducing action [15] However, failure of the GABAA receptor inhibitor flumazenil to reverse the anxiolytic effects of kava in mice suggests that benzodiazepine-like effects are not contributing to the pharmacological profile of kava extracts.[16]

Heavy, long-term use of kava has been found to not reduce ability in saccade and cognitive tests, but has been associated with elevated liver enzymes.[17]

Detection

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.[18]

Preparation and consumption

Kava root drying in Lovoni village, Ovalau, Fiji

Traditional preparation

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 and buttermilk. 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.[19]

Kava root being prepared for consumption in Asanvari village on Maewo Island, Vanuatu

Supplements and pharmaceutical preparations

Pharmaceutical and herbal supplement companies extract kavalactones from the kava plant using solvents such as supercritical carbon dioxide,[20] acetone and ethanol to produce pills standardized with between 30% and 90% kavalactones.

Kava culture

A sign showing a "Kava licence area" at Yirrkala, in the Northern Territory of Australia
Main article: Kava culture

Kava is used for medicinal, religious, political, cultural and social purposes throughout the Pacific. These cultures have a great respect for the plant and place a high importance on it. In Fiji, for example, a formal yaqona (kava) ceremony will often accompany important social, political, religious, etc. functions, usually involving a ritual presentation of the bundled roots as a sevusevu (gift), and drinking of the yaqona itself.[21]

A traditional Fijian yaqona bundle of roots

Effects of consumption

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 experiences sleepiness 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.[22]

Efficacy

Kava is renowned for its many health benefits, but the chiefly among them is its anxiolytic properties. A journal article titled ""Kava: A Comprehensive Review of Efficacy, Safety, And Psychopharmacology." from the Australian & New Zealand Journal of Psychiatry, reviewed all scholarly journal articles related to kava found in scholarly electronic databases, they found that "The current weight of evidence supports the use of kava in treatment of anxiety with a significant result occurring in four out of six studies reviewed" [23]

Other than its anxiolytic uses, kava also has a few therapeutic qualities. Kava is known for having a sleep inducing effect and is good for common restlessness and more serious insomnia.[24][25] Another study found that kava consumption may reduce colon cancer risk based on their results with carcinogen (a substance capable of causing cancer in living tissue) treated rats.[26]

A few studies have shown that kava extracts possessed efficacious anxiolytic activity compared to placebo for the symptomatic treatment for anxiety.[27] As well, kava extracts may be an effective alternative to tricyclic antidepressants and benzodiazepines for the treatment of anxiety disorders.[28]

One study showed that 150 mg/day of the standardized WS 1490 Kava extract in divided doses for four weeks was effective at decreasing anxiety symptoms but was not superior to the alternative dose of 300 mg/day in divided doses used in other studies.[29]

Most of these studies used a standardized WS 1490 Kava extract formulation, which is composed of 70% kavalactones.[30]

Toxicity and safety

In 2001, concerns were raised about the safety of kava, which led to restrictions and regulations in several countries,[31] as well as reports by the United States CDC [32] and FDA.[33] Most of the concerns were related to a small number of reports indicating potential cases of hepatotoxicity caused by consumption of various commercial products derived from kava. A number of scientists and medical practitioners criticized the poor quality of the reports by pointing out that most of the reported rare cases of hepatotoxicity involved patients with a history of alcohol or prescription drugs abuse or concomitant use of medicines known as potentially hepatotoxic.[34] On June 10, 2014, the German Administrative Court overturned the 2002 ban reinstating the regulatory requirements of 2001. The court stated that risk from kava exposure had not been clearly demonstrated, nor does it appear unusually high, an opinion presumably driven by the very small number of cases of reported toxicity (n ~ 3) with even a certain degree of causality linked to kava in a global kava-consuming community that may number in the millions of doses consumed daily.[35]

According to a recent comprehensive review of the relevant literature by Showman et al. (2014): "Despite the link to kava and liver toxicity demonstrated in vivo and in vitro, in the history of Western kava use, toxicity is still considered relatively rare. Only a fraction of the handful of cases reviewed for liver toxicity could be, with any certainty, linked to kava consumption and most of those involved the coingestion of other medications/supplements. That means that the incident rate of liver toxicity due to kava is one in 60-125 million patients."[35]

Various components of the plant have been labelled as potentially capable of causing toxicity, particularly pipermethystine and flavokavain B. Yet, based on a retrospective study in Germany, the alkaloid pipermethystine is an unlikely cause for the observed hepatotoxicity, as, although it occurs in qualities up to 0.2% of the leaves, it is found in quantities a hundred-fold less in Western extracts.[36] Another suggested culprit, Flavokavain B, is also found in various preparations in the plant, although not in ethanol extracts of noble cultivars, and never in large enough amounts to cause any liver damage.[37] The very rare cases of kava hepatotoxicity may have been due to contamination with aflatoxins or other mold hepatotoxins, but this requires further study.[38]

Other data suggests that the rare cases of toxicity may be due to an intrinsic metabolic cause. Three possible mechanisms for kavalactone hepatotoxicity have been theorized: inhibition of cytochrome P450, possible 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.[39]

In line with this reasoning, several adverse interactions with drugs have been documented, both prescription and nonprescription – including, but not limited to, anticonvulsants, alcohol, anxiolytics (CNS depressants such as benzodiazepines), antipsychotics, levodopa, diuretics, and drugs metabolized by CYP450 in the liver.[40]

A few notable potential drug interactions are, but are not limited to:

Alcohol
It has been reported that combined use of alcohol and kava extract can have additive sedative effects in mice.[41] However, this additive effect has not been studied in humans. But separately kava has been shown to induce sedation.[42] Regarding cognitive function, kava has been shown to have additive cognitive impairments while taken with alcohol when compared to taking placebo and alcohol alone.[43]
Anxiolytics (CNS depressants such as benzodiazepines and barbiturates)
Kava may have potential additive CNS depressant effects (such as sedation and anxiolytic effects) with benzodiazepines and barbiturates.[43]
Dopamine Agonist - Levodopa
One of levodopa’s chronic side effects that Parkinson’s patients experience is the "on-off phenomenon" of motor fluctuations where there will be periods of oscillations between "on" where the patient experiences symptomatic relief and "off" where the therapeutic effect wears off early.[44] When taking levodopa and kava together it has been shown that there is an increased frequency of this "on-off phenomenon".[45]

The Australian studies that drove this debate focused on populations with heavy concomitant consumption of alcohol and overall poor health. In these studies, 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.[46][47][48] A 2012 analysis of cases worldwide proposed that mold was the primary cause of hepatotoxicity in kava products.[49]

Regulation

In 2002 the EU imposed a ban on imports of kava-based pharmaceutical products.[50] The sale of kava plant is regulated in Switzerland, France, and the Netherlands.[51] Some Pacific Island States who had been benefiting from the export of kava to the pharmaceutical companies have attempted to overturn the EU ban on kava-based pharmaceutical products by invoking international trade agreements at the WTO: Fiji, Samoa, Tonga and Vanuatu argued that the ban was imposed with insufficient evidence.[52] The pressure prompted Germany to reconsider the evidence base for banning kava-based pharmaceutical products.[53] On June 10, 2014, the German Administrative Court overturned the 2002 ban making selling kava as a medicine legal (personal possession of kava has never been illegal), albeit strictly regulated. In Germany, Kava-based pharmaceutical preparations are currently prescription drugs. Furthermore, patient and professional information brochures have been redesigned to warn from potential hepatotoxic side effects.[54] These strict measures have been opposed by some of the leading kava scientists. In early 2016 a court case has been filed against the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM/German Federal Institute for Drugs and Medical Devices) arguing that the new regulatory regime is too strict and not justified.[55]

Poland is the only EU country with an "outright ban on kava" and where the mere possession of kava is prohibited and may result in a prison sentence.[50]

In the United Kingdom it is a criminal offence to sell, supply or import any medicinal product containing kava.[56] At the same time it is still legal to possess kava (for personal use) or import it for purposes other than human consumption.

In 2002 Health Canada issued an order prohibiting the sale of any product containing kava.[57] While the restrictions on kava were lifted in 2012,[58] Health Canada has not licensed any kava products for sale in Canada.[59]

In Australia, the supply of kava is regulated through the National Code of Kava Management. The importation and licensing of kava is prohibited in Western Australia.[60][61] In the Northern Territory, the police say that "the sale and, in majority of circumstances, possession of kava [...] is illegal".[62] The Australian Therapeutic Goods Administration has recommended no more than 250 mg of kavalactones be taken in a 24‑hour period.[63]

Legislation has been proposed to require that kava products be derived only from noble cultivars, which may be less toxic.[64][65] Other acts have been passed based on the assumption that aqueous solutions are less harmful.[37][65] Exclusion of certain aerial parts of the plant are also often required by law or convention, which contain less pipermethystine and other toxic compounds.[65]

See also

References

  1. ↑ kava. (2010). In Merriam–Webster Online Dictionary.
  2. ↑ Hawaiian Dictionary
  3. ↑ Fitisemanu, Jacob (2007) Samoan social drinking: perpetuation and adaptation of 'Ava ceremonies in Salt Lake County, Utah B. A. Thesis, Westminster College] p. 2.
  4. ↑ Yaqona, kava drinking ceremony
  5. ↑ Balick, Michael J. and Leem, Roberta (2002) Traditional use of sakau (kava) in Pohnpei: lessons for integrative medicine Alternative Therapies, Vol. 8, No.4. p. 96
  6. ↑ Lebot, Vincent et al (1997) Kava: The Pacific Elixir: The Definitive Guide to Its Ethnobotany, History, and Chemistry Rochester, Vt.: Healing Arts Press. ISBN 9780892817269. page 98.
  7. ↑ Pittler MH, Ernst E (2003). Pittler, Max H, ed. "Kava extract for treating anxiety". Cochrane database of systematic reviews (Online) (1): CD003383. doi:10.1002/14651858.CD003383. PMID 12535473.
  8. ↑ 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.
  9. 1 2 3 Sarris J, LaPorte E, Schweitzer I (2011). "Kava: a comprehensive review of efficacy, safety, and psychopharmacology". Aust N Z J Psychiatry 45 (1): 27–35. doi:10.3109/00048674.2010.522554. PMID 21073405.
  10. ↑ Olsen LR, Grillo MP, Skonberg C (2011). "Constituents in kava extracts potentially involved in hepatotoxicity: a review". Chem. Res. Toxicol. 24 (7): 992–1002. doi:10.1021/tx100412m. PMID 21506562.
  11. ↑ Singh YN, Singh NN (2002). "Therapeutic potential of kava in the treatment of anxiety disorders". CNS Drugs 16 (11): 731–43. doi:10.2165/00023210-200216110-00002. PMID 12383029.
  12. ↑ Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V (2012). "Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand". Pharmacol. Res. 66 (2): 163–9. doi:10.1016/j.phrs.2012.04.003. PMID 22525682.
  13. 1 2 Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W (2001). "Interaction of various Piper methysticum cultivars with CNS receptors in vitro". Planta Med. 67 (4): 306–11. doi:10.1055/s-2001-14334. PMID 11458444.
  14. ↑ Amitava Dasgupta; Catherine A. Hammett-Stabler (21 March 2011). Herbal Supplements: Efficacy, Toxicity, Interactions with Western Drugs, and Effects on Clinical Laboratory Tests. John Wiley & Sons. pp. 57–. ISBN 978-0-470-92275-0.
  15. ↑ Baum SS, Hill R, Rommelspacher H (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. doi:10.1016/s0278-5846(98)00062-1. PMID 9829291.
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  17. ↑ Cairney S, Clough AR, Maruff P, Collie A, Currie BJ, Currie J (2003). "Saccade and cognitive function in chronic kava users". Neuropsychopharmacology 28 (2): 389–96. doi:10.1038/sj.npp.1300052. PMID 12589393.
  18. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 803–804.
  19. ↑ Kevin Cassell (2005). "Fiji: A Visitor's Guide". Retrieved 25 April 2007.
  20. ↑ Viorica, Lopez-Aila. "Supercritical fluid extraction of kava lactones from Piper methysticum (kava) herb". Hüthig GmbH. Retrieved 5 September 2012.
  21. ↑ There are many variations to this ceremony; one of which is described in: Biturogoiwasa, Solomoni; Walker, Anthony R. (2001). My Village, My World: Everyday Life in Nadoria, Fiji. Suva, Fiji: Institute of Pacific Studies, University of the South Pacific. pp. 17–20. ISBN 978-982-02-0160-6. There are numerous anthropological studies, one example being: Tomlinson, Matt (2007). "Everything and Its Opposite: Kava Drinking in Fiji". Anthropological Quarterly 80 (4): 1065–81. doi:10.1353/anq.2007.0054.
  22. ↑ McDonald, D (2000). "Kava in the Pacific Islands: a contemporary drug of abuse?". DRUG ALCOHOL REV 19: 217–227. doi:10.1080/713659319.
  23. ↑ Jerome, Sarris; et al. (2011). "Kava: A Comprehensive Review Of Efficacy, Safety, And Psychopharmacology". Australian and New Zealand Journal of Psychiatry 45: 27–35. doi:10.3109/00048674.2010.522554. PMID 21073405.
  24. ↑ [<https://umm.edu/health/medical/altmed/herb/kava-kava>. "Kava kava"] Check |url= value (help).
  25. ↑ "Hava". Annals of Psychotherapy & Integrative Health. 2011.
  26. ↑ Triolet; et al. (2012). "Reduction In Colon Cancer Risk By Consumption Of Kava Or Kava Fractions In Carcinogen-Treated Rats". Nutrition & Cancer 64: 838–846. doi:10.1080/01635581.2012.689917.
  27. ↑ Pittler MH, Ernst E (2000). "Efficacy of kava extract for treating anxiety: systematic review and meta-analysis". J Clin Psychopharmacol 20: 84–89. doi:10.1097/00004714-200002000-00014.
  28. ↑ Volz HP, Kieser M (1997). "Kava-kava extract WS 1490 versus placebo in anxiety disorders--a randomized placebo-controlled 25-week outpatient trial". Pharmacopsychiatry 30: 1–5. doi:10.1055/s-2007-979474.
  29. ↑ 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: 10(8):631-9.
  30. ↑ Malsch U, Kieser M. "Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Psychopharmacology (berl). (2001)
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  32. ↑ 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. Retrieved 16 September 2005.
  33. ↑ Center for Food Safety and Applied Nutrition (2002). "Kava-Containing Dietary Supplements May Be Associated with Severe Liver Injury". United States Food and Drug Administration. Archived from the original on 25 March 2008. Retrieved 16 June 2005.
  34. ↑ Baker, Jonathan (2011). "Tradition and toxicity: Evidential cultures in the kava safety debate". Social Studies of Science 41: 361–384. doi:10.1177/0306312710395341.
  35. 1 2 Showman; et al. (2014). "Contemporary Pacific and Western perspectives on `awa (Piper methysticum) toxicology.". Filoterapia 100: 56–67. doi:10.1016/j.fitote.2014.11.012. PMID 25464054.
  36. ↑ Lechtenberg, M.; Quandt, B.; Schmidt, M.; Nahrstedt, A. (2008). "Is the alkaloid pipermethystine connected with the claimed liver toxicity of Kava products?". Die Pharmazie 63 (1): 71–74. PMID 18271308.
  37. 1 2 Teschke, Rolf; Samuel Qiu; Vincent Lebot (September 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. doi:10.1016/j.dld.2011.01.018. PMID 21377431.
  38. ↑ Teschke R., Qiu S.X., Lebot V. "Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mold hepatotoxins as primarily assumed culprits" [Article in Press] Digestive and Liver Disease 2011
  39. ↑ Clouatre, D. L. (2004). "Kava kava: Examining new reports of toxicity". Toxicology Letters 150 (1): 85–96. doi:10.1016/j.toxlet.2003.07.005. PMID 15068826.
  40. ↑ University of Maryland Medical Center (2011). "Kava Kava". Retrieved 18 December 2011.
  41. ↑ Jamieson, D. D. and Duffield, P. H. "Positive interaction of ethanol and kava resin in mice. Clin Exp Pharmacol Physiol 1990;17(7):509-514
  42. ↑ Cairney S., Maruff P., Clough A. R., Collie A., Currie J., Currie B. J. (2003). "Saccade and cognitive impairment associated with kava intoxication". Hum.Psychopharmacol 18 (7): 525–533. doi:10.1002/hup.532.
  43. 1 2 Spinella M (2002). "The importance of pharmacological synergy in psychoactive herbal medicines". Altern Med Rev 7 (2): 130–137.
  44. ↑ Lees AJ. "The on-off phenomenon. J Neurol Neurosurg Psychiatr. 1989;Suppl:29-37.
  45. ↑ Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review" Drugs 2001;61(15):2163-75.
  46. ↑ Clough A (2001). "Enough! or too much. What is 'excessive' kava use in Arnhem Land?". Drug Alcohol Rev 22 (1): 43–51. doi:10.1080/0959523021000059820. PMID 12745358.
  47. ↑ 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. PMID 3374423.
  48. ↑ Kava R (March 2001). "The adverse effects of kava". Pac Health Dialog 8 (1): 115–8. PMID 12017812.
  49. ↑ Teschke, Rolf; Sarris, Jerome; Schweitzer, Isaac (2012). "Kava hepatotoxicity in traditional and modern use: The presumed Pacific kava paradox hypothesis revisited". British Journal of Clinical Pharmacology 73 (2): 170–4. doi:10.1111/j.1365-2125.2011.04070.x. PMC 3269575. PMID 21801196.
  50. 1 2 "Europe Explains Its Stand on Kava from the Pacific". Radio Australia. March 2012. Retrieved 10 October 2013.
  51. ↑ 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. Retrieved 7 February 2007.
  52. ↑ "Fiji takes kava ban fight to WTO". The World Trade Review. August 2005. Retrieved 26 October 2013.
  53. ↑ Bowman, Chakriya. "The Pacific Island Nations: Towards Shared Representation". WTO. Retrieved 26 October 2013.
  54. ↑ Comeback unter strengen Auflagen(in German). PHARMAZEUTISCHE ZEITUNG online 16/2015. Retrieved February 28, 2016.
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  56. ↑ "The Medicines for Human Use (Kava-kava) (Prohibition) Order 2002". Retrieved 26 October 2013.
  57. ↑ "Marketed Health Products Directorate Heath Products and Foods Branch". Canadian Adverse Reaction Newsletter (Health Canada) 12 (4). 2002.
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  59. ↑ http://www.healthlinkbc.ca/healthtopics/content.asp?hwid=tn7356spec
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  61. ↑ "Kava". Government of the Northern Territory of Australia. Archived from the original on 8 January 2013. In accordance with the Australian Government National Emergency Response in the Northern Territory the commercial importation and licensing of kava is prohibited.
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  63. ↑ "Kava fact sheet". Therapeutic Goods Administration, Government of Australia. April 2005. Retrieved 10 July 2006. (Download PDF 44KB).
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Literature

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