Piper methysticum / Kawa / Kava Kava

`AWA`Awa is one of the plants brought in their sailing canoes by the earliest Polynesian voyagers arriving in Hawai`i. `Awa (Piper methysticum), a member of the pepper family, grows in the wild now and is also cultivated increasily throughout the Pacific Islands, where it is called Kava or Kava Kava. This plant grows well at low elevations where there is constant moisture and partial sun. More than a dozen varieties of `awa were known in old Hawai`i.The sparingly branched, erect shrub is very hardy and grows up to 12 feet high. It has large, smooth, heart-shaped leaves and green or black jointed stems, with swellings at the joint. The black `awa is the rare one. The flower is an inconspicuous narrow yellow-green spike. The root is thick, soft wooded when fresh, hardening as it dries. It needs to grow for 2 to 3 years minimum to achieve usable potency. It is valued as an intoxicating drink and as a medicine. `Awa is also a sedative, used as a sacred plant for prayer, as well as appreciated for pleasure, especially in the south Pacific islands. It assists in opening communication channels with others and with the elements.

As a medicine, the roots - as well as the leaves, stems and bark - are used for the following: general debility, weary muscles, chills, colds, headaches, lung and other respiratory diseases such as asthma, displacement of the womb, diabetes, congestion of the urinary tract as well as for rheumatism.

To make feverish or restless young children go to sleep, the leaf buds are given to the child after being chewed by the mother. The plant is also used during teething and in rituals at the time of weaning.

`Awa is used principally as a sedative to induce relaxation and sleep, especially when combined with lomi lomi massage. It is also used as a tonic when people feel weak, as it is stimulating and refreshing, unless drunk in large quantities. Over indulgence in `awa use for a period of time can adversely (but temporarily) affect the skin and eyes. The word `awa means bitter.

In the old days, it is said that the chiefs and priests were the principal users of `awa, but in more recent times it has been taken to use by all the people. Those who perform strenuous work especially appreciate its properties as a relief for stiffness, tenseness and fatigue in the muscles. `Awa is a muscle relaxant to weary farmers, fishermen, hunters and paddlers. Spiritual leaders use `awa ceremonially at appointed times, such as at a ritual following a canoe race-meet. It is a social tradition and an offering of gratitude to the divine, both before and after events and festivals in the life of the people.

In a story about the daughters of Haumea, the eldest being Pele, and her family's travels from Tahiti to Hawai`i Nei, throughout the islands, ending in Hawai`i Island where she resides now, there is a chant given, which was chanted upon making an offering of pig and `awa to Laka, the goddess of hula, to receive instruction. The last lines of the translation are:

...Low

accessible is the day whereby knowledge is gained,

Knowledge from the source, knowledge by hearing,

Like the flourishing `awa plant is the knowledge of the gods,

O hear me.

While living in Western Samoa, I learned that the chiefs and talking chiefs use `awa ceremonially. These villagers on the island of Savaii met together periodically to decide the issues of the village. The meetings were preceded by an `awa ceremony, bringing the leaders into one accord and goodwill, as they sat in a decision making circle around the fale.

To prepare the 'awa root, it is sometimes used fresh, sometimes sun-dried. It is washed clean, chopped into small pieces, and then pounded — or in modern times, blended in a blender — with water to create a suspension of kavalactones, which are lipid-soluble. Traditionally, the root pieces were chewed, usually by a young maiden. Now powdered and packaged root is often available.

An `awa drink, good for migraines or P.M.S. can be prepared for one's personal use in the following way. Put a few small pieces of the clean root in the mouth and chew them. Add a few more, until a cud the size of the thumb is formed. When three of these are ready, put them in a bowl and mash with about a cup of fresh water. Strain the liquid through a cloth to remove woody material. This will provide you with a drink that can be used for headaches or cramps. Sugar cane juice or honey can be added to sweeten. Sometimes a spoonful of noni juice is added as a chaser, to counter any unpleasant effects.

In the traditional manner, the chewed `awa is mixed with water or with coconut water, sometimes warmed by putting it in a kanoa, calabash, with hot stones. It is then stirred and strained with a fibrous plant bundle and drunk when it is cool.

Special cups (`apu `awa), made from coconut shell cut lengthwise are often reserved for this brew, and for the ceremony of `awa drinking. Distinctive bowls are also made and set aside for `awa ceremonies throughout Polynesia. `Awa/kava seems to be more widely used outside these Hawai`i islands.

E hanai `awa a ikaika ka makani.

Feed with `awa so that the spirit may gain strength.

One offers `awa and prayers to the dead so that their spirit may grow strong and be a source of help to the family.

When `awa cups are filled, a prayer of gratitude is offered. `Awa is usually gulped rather than sipped, with some of the liquid being left in the container and poured upon the earth, with thanksgiving. A chaser or pupu is sometimes used to offset the bitter taste: a piece of sugar cane, a bite of sweet potato,banana or fish. A numbness in the mouth may be noticed after `awa ingestion.

It is best to harvest the `awa root when the ground is moist from rain, so that it can be easily removed. For propagation, the stalk can be cut into sections that include the top of one knob and the bottom of the next one down. These can be planted right side up, with most of the cane being beneath the moist earth, in a shady place. Another method of planting is to lay a long piece of stem within the earth, allowing several plants to sprout from the knobby sections laid down.

Uit Tyler's herbs of choice: The therapeutic use of phytomedicinals

KavaKava is the dried roots of Piper methysticum Forst., family Piperaceae. Known also as kava-kava, the plant is a large shrub widely cultivated in Oceania. Its underground parts have been extensively used by the indig-enous people of these Pacific islands in the preparation of an intoxicat-ing beverage. Kava beverage drinking predates recorded history and has acquired important significance from a social and ceremonial standpoint among the various island cultures. An overview of kava preparation and ceremonial use as well as kava chemistry and pharmacology has been pre-sented in detail by Singh and Blumenthal.15 Kava was ritually prepared by young men or women who chewed cut pieces of the scraped root, spitting the pieces into a bowl to which coconut milk was added to make an infu-sion. However, for sanitary reasons, pressures by colonizing governments and missionary influence have led to the abandonment of the chewing technique in favor of pounding or grating the root.Kava bars offer the beverage on various Pacific islands, where the muddy-looking liquid is rapidly drunk (not sipped) from coconut shells. It first causes a numbing and astringent effect in the mouth, followed by a relaxed sociable state in which fatigue and anxiety are lessened. Eventually, a deep restful sleep ensues from which the user awakes refreshed and without hangover. Excessive consumption can lead to dizziness and stu-pefaction,16 and use over a prolonged period (a few months) can lead to kava dermopathy, which is characterized by a reversible ichthyosiform scaly skin.17

The CNS activity of kava is due to a group of resinous compounds called kavalactones, kavapyrones, or styrylpyrones. Roots of good quality contain between 5.5 and 8.3 percent of kavalactones, including the major components kawain, dihydrokawain, and methysticin, as well as the minor compounds yangonin, desmethoxyyangonin, and dihydromethysticin.18 Animal studies have demonstrated the ability of kava extracts or purified kavalactones to induce sleep and produce muscle relaxation and analgesia as well as anticonvulsive protection against strychnine and electroshocks.19 At low doses, kavalactones resemble t he phar maco-logic action of benzodiazepines, although they apparently do not bind at either GABA or benzodiazepine binding sites in rat or mouse brain membranes.20 Because of the diverse range of pharmacological activities shown by kava, kavalactones may act nonselectively and remain in the lipid membranes to cause modifications to a variety of receptor domains rather than interacting with any specific receptor binding site. There is evidence that the spasmolytic, analgesic, and anticonvulsant activity of kavalactones might be explained by inhibition of voltage-dependent Na+ chan nels in the brain21; however, the question remains whether this inhibition is also responsible for the anxiolytic and hypnotic action.

Several relatively short-term clinical studies have provided favorable evidence that kava is effective in treating anxiety and insomnia22; how-ever, the first long-term clinical trial investigating safety and efficacy of kava in anxiety patients was only recently published. In this study, 101 outpatients with anxiety of nonpsychotic origin, determined on the basis of the American Psychiatric Association anxiety disorder classification, were included in a twenty-five-week multicenter, randomized, placebo-controlled, double-blind trial using a lipophilic kava extract standardized to contain 70 percent kavalactones. Patients were administered either 100 mg of extract (70 mg kavalactones) or placebo three times daily, and the main outcome criterion utilized the Hamilton Anxiety Scale.Adverse effects were rare and distributed evenly in both groups, and there were no problems with tolerance, dependence, or withdrawal symp-toms—adverse effects often associated with long-term benzodiazepine use. The long-term efficacy (after the eighth week of treatment) of the kava extract was superior to that of placebo. In addition, kava extract was not associated w i t h d e p r e s s e d c o g n i t i v e f u n c t i o n , d r o w s i n e s s , o r i m p a i r m e n t i n m e n t a l r e a c-tion time, problems found in the side-effect profile of benzodiazepines.23

The German Commission E has approved kava for conditions of nervous anxiety, stress, and restlessness; the recommended dosage is 70 mg of kavalactones, usually in the form of a standardized extract two to three times daily.24

As a sleep aid, 180–210 mg of kavalactones can be taken one hour before bedtime. It is important to note that ethanol and other CNS depressants can potentiate the effects of kava; therefore, they should not be taken concomitantly. In this regard, a drug interaction between kava and the benzodiazapine alprazolam that caused a semicomatose state in a patient has been reported.25

In June 2002, the German Federal Institute of Drugs and Medical Devices decided to withdraw all drug registrations for all products con-taining kava, on account of reports of liver toxicity associated with the herb. However, in May 2005, the German government repealed the ban on kava products, pending evaluation of new data. An article by Anke and Ramzan in 2004 reviewed the kava hapatotoxicity controversy and summarized the major theories advanced to explain the case reports of liver failure but reached no satisfactory conclusion.26 An intriguing hypothesis has been recently proposed implicating a kava metabolite with the potential for reacting with glutathione in the liver, supported by an adduct identified in urine.27 Nonetheless, German herbal medicine experts, including former members of Commission E and officials of the Society of Medicinal Plant Research, regard kava extracts and kavalactones as “quite safe.”

Water-Based Kava Extract for Generalized Anxiety Disorder Shows No Adverse Effects in Liver Function

by Heather S. Oliff, PhD HerbalGram. 2013; American Botanical Council

Reviewed: Sarris J, Stough C, Teschke R, Wahid ZT, Bousman CA, Murray G, Savage KM, Mouatt P, Ng C, and Schweitzer I. Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects. Phytother Res. January 2013; [epub ahead of print]. doi: 10.1002/ptr.4916.

Empirical observations and clinical trial evidence suggest that preparations made from the root of kava (Piper methysticum, Piperaceae) are efficacious in the treatment of anxiety; however, cases of hepatotoxicity associated with kava use have led to its withdrawal or restricted use in many Western countries. Considering that kava has anxiolytic effects, questions arise as to whether kava is addictive, has adverse sexual side effects, or has withdrawal effects that might be similar to pharmaceutical anxiolytic drugs such as the benzodiazepines (drugs with an anti-anxiety effect). Uncertainty regarding the cause of the liver toxicity centers on poor-quality raw material, plant cultivars, and extraction solvents. Hence the purpose of this randomized, double-blind, placebo-controlled study was to evaluate adverse events (AEs), withdrawal/addiction effects, and liver function effects associated with kava use in patients with generalized anxiety disorder (GAD). Also, genetic polymorphism (when more than one different phenotype exists in the same species) of the liver enzyme cytochrome P450 2D6 (CYP2D6), which metabolizes compounds in kava, was evaluated to determine whether subjects who were poor or extensive metabolizers have different AEs using water-extracted kava from noble cultivars (that is, kava cultivars with higher levels of kavain and lower levels of dihydromethysticin).1

Patients (n=58; aged 18-65 years) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) diagnosed with GAD were recruited from the Greater Melbourne area in Victoria, Australia, via mass media. Patients were excluded if they had any of the following conditions: major depressive disorder or elevated depressive symptomatology (greater than 17 on the Montgomery-Asberg Depression Rating Scale); a DSM-IV diagnosis of a psychotic or bipolar disorder; significant suicidal ideation in the previous six months; current use of antidepressants, mood stabilizers, antipsychotics, opioid analgesics, or St. John’s wort (Hypericum perforatum, Clusiaceae); diagnosed hepatobiliary disease/inflammation; substance abuse or dependency disorder in the previous six months; a previous adverse reaction to kava or benzodiazepines; kava or benzodiazepine use in the previous 12 months; or abnormal baseline liver function. The study began with a one-week run-in phase to identify placebo responders. Any subject who showed a 50% improvement on the Hamilton Anxiety Scale (HAM-A) score during this placebo phase was excluded from the study.

For six weeks, patients received placebo or an aqueous kava extract with the equivalent of 120 mg of kavalactones/day, which was titrated to 240 mg/day in patients showing no response at three weeks. The kava was formulated from pressed, dried, aqueous peeled rootstock of kava (Medi-Herb, Integria Healthcare; Eight Mile Plains, Queensland, Australia). The kava extract was independently analyzed at Southern Cross University at Lismore, Australia, and was determined to contain various kavalactones: dihydrokavain (15.5 mg, 26%), kavain (12.5 mg, 21%), dihydromethysticin (11 mg, 18%) methysticin (8.5 mg, 14%), yangonin (8 mg, 13%), and desmethoxygangonin (5mg, 8%); the alkaloid pipermethystine, which has been implicated in some kava extracts associated with cases of liver dysfunction, was not detected.

At weeks two and seven, AEs were assessed via questionnaire, and blood was drawn for liver function tests and to determine polymorphisms.

No significant AEs were reported. One case of dermatitis and one case of minor stomach upset were associated with kava intake. Withdrawal was assessed by treating all patients with placebo for one week at study end. There was no significant increase in AEs in either treatment group. Addiction was assessed by evaluating the number of patients who said that they wanted an increase in dose. Both treatment groups had the same number of patients who wanted to increase the dosage. There were no significant differences from baseline in liver function tests, and no patients developed clinical signs of hepatic abnormality. However, gamma-glutamyl transpeptidase (GGT) showed a trend toward elevation in kava-treated patients compared with those who took placebo at week seven (P=0.08). This finding may be due to an outlier; one patient (an extensive CYP2D6 metabolizer) had isolated increases in GGT and alanine aminotransferase (ALT) that both returned to baseline levels after the study. However, intermediate or extensive CYP2D6 metabolizer status had no significant impact on the type or frequency of AEs or abnormal liver function tests. Kava did not diminish sexual performance or enjoyment in men or women. However, there was a trend for kava-treated men to have more difficulty reaching orgasm (P=0.067). Kava-treated women had a significant increase in sex drive (P=0.04).

The authors conclude that water-extracted kava from noble cultivars has no deleterious effects on sexual function and pleasure, has no addictive qualities or withdrawal issues, and is safe for patients with GAD when taken for six weeks. The researchers also wrote that patients with GAD would require treatment for longer than six weeks, so a larger, longer-term study is needed to confirm the findings. Nonetheless, this study contributes to the growing body of evidence that water-soluble, standardized formulations of kava from noble cultivars are safe. The authors conclude that these data may assist in the reintroduction of kava in restricted markets. This study uses a medicinal dose of kava, and the results cannot be extrapolated to traditional recreational use with higher doses of kavalactones.

—Heather S. Oliff, PhD

Reference

1. Sarris J, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol. 2013;33(5):1-6.

Planta Med 2015; 81(18): 1647-1653

Georg Thieme Verlag KG Stuttgart · New York

German Kava Ban Lifted by Court: The Alleged Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics

Kava, the rhizome and roots of Piper methysticum, are one of the most important social pillars of Melanesian societies. They have been used for more than 1000 years in social gatherings for the preparation of beverages with relaxing effects. During the colonial period, extract preparations found their way into Western medicinal systems, with experience especially concerning the treatment of situational anxiety dating back more than 100 years. It therefore came as a surprise when the safety of kava was suddenly questioned based on the observation of a series of case reports of liver toxicity in 1999 and 2000. These case reports ultimately led to a ban of kava products in Europe – a ban that has been contested because of the poor evidence of risks related to kava. Only recently, two German administrative courts decided that the decision of the regulatory authority to ban kava as a measure to ensure consumer safety was inappropriate and even associated with an increased risk due to the higher risk inherent to the therapeutic alternatives. This ruling can be considered as final for at least the German market, as no further appeal has been pursued by the regulatory authorities. However, in order to prevent further misunderstandings, especially in other markets, the current situation calls for a comprehensive presentation of the cardinal facts and misconceptions concerning kava and related drug quality issues.

The current state of ethnopharmacological and phytochemical research still does not confirm a causal relationship between the consumption of kava preparations and the occurrence of adverse liver reactions. With the assumption of the (albeit very rare) existence of such a type of reaction, manufacturers should seek guidance for the quality of plant material known to be safe through centuries of traditional experience. The problem of possible hepatotoxicity of kava preparations was potentially caused by ill-defined herbal drug identity, a lack of appropriate quality control, and misguided regulatory politics.

Thus, in order to re-establish “noble” kava to its rightful place as an essential anxiolytic drug in the European market, its botanical and phytochemical differentiation from the “non-noble” kava varieties has to be established by pharmacopoeial regulations. This should be a minor problem, as there are already several plant drugs where the pharmacopoeia does already differentiate between closely related and easily misidentified species (e.g.,Illicium verum vs. Illicium anisatum). With the circumstantial evidence supporting a raw drug identity/quality issue at the base of the problem of hepatotoxicity, the definition of appropriate quality standards should, in any case, be helpful.

There is, however, not much time to act on the problem of drug identity of pharmaceutically suitable kava varieties. In the past 10 years, kava exports from the South Pacific islands have again multiplied, reaching the same level as at the time before the kava ban in 2001. The United States have especially evolved as a kava market, with currently more than 90 kava bars serving kava of frequently highly doubtful quality. Similarly, the market of New Caledonia has shifted to the import of large quantities of two-day kava roots and (mainly) peelings from Vanuatu, with the argument that the higher kavalactone concentrations and, at the same time, relatively low costs allow for the production of more kava drinks at lesser expenses. If the flavokavins or other as yet non-identified constituents of non-noble kava are truly responsible for liver toxicity, this could be playing with fire. There are already isolated reports of liver toxicity related to kava use from New Caledonia – cases that are now discussed in the context of potential mould-related toxicity [54], but even this aspect would have to be part of quality specifications.

With the revocation of the German kava “ban” by the Administrative Court of Cologne and the Upper Administrative Court of Münster, a major hurdle for a constructive discussion and a potential comeback of kava has been overcome. Therefore, now is the time to act to prevent the problem of kava-related hepatotoxicity from reoccurring by introducing appropriate regulatory standards concerning its drug quality and, even more so, drug identity.

References

1 Anonymous Kava-Kava: Eine Lücke, die keiner wollte. Interview mit Prof. Volker Faust. Natura Med 2002; 17: 14

2 Ernst E. Marktrücknahme des pflanzlichen Anxiolytikums Kava: Nutzen unter-, Risiken überschätzt?. Münchn Med Wschr 2003; 144: 40

3 Loew D, Gaus W. Kava-Kava. Tragödie einer Fehlentscheidung. Z Phytother 2002; 23: 267-281

4 Loew D. Zum Widerruf von Kava-Extrakten. Politikum oder fachliche Fehlbeurteilung?. Ärzteztsch Naturheilverf 2003; 44: 884-896

5 Loew D. Widerruf der Zulassung von Kava-Extrakten. War die Entscheidung des BfArM gerechtfertigt?. Dt Apotheker Ztg 2005; 145: 5362-5364

6 Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 2003; (1) CD003383

7 Schmidt M, Nahrstedt A. Ist Kava lebertoxisch? Eine Analyse der bekannten Daten zum Leberrisiko von Kava-Präparaten. Dtsch Apoth Ztg 2002; 142: 1006-1011

8 Schmidt M. Are kavalactones the hepatotoxic principle of kava extracts? The pitfalls of the glutathione theory. J Altern Complement Med 2003; 9: 183-187 author reply 187–188

9 Stevinson C, Huntley A, Ernst E. A systematic review of the safety of kava extract in the treatment of anxiety. Drug Saf 2002; 25: 251-261

10 Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomedicine 2003; 10: 440-446

11 Teschke R. Kava-induzierte Leberschäden – Was ist gesichert?. Dtsch Apoth Ztg 2003; 143: 4011-4021

12 Teschke R. Nicht einmal eine Verschreibungspflicht. FAZ 2003; 54: 8

13 Singh YN, Devkota AK. Aqueous kava extracts do not affect liver function tests in rats. Planta Med 2003; 69: 496-499

14 Bauer R, Kopp B, Nahrstedt A. Relevant hepatotoxic effects of kava still need to be proven. A statement of the Society for Medicinal Plant Research. Planta Med 2003; 69: 971-972

15 Schmidt M. German court ruling reverses kava ban; German regulatory authority appeals decision. HerbalGram 2014; 103: 38-43

16 Kraft K. Verwaltungsgericht Köln kippt das Kava-Verbot. Z Phytother 2014; 35: 186-189

17 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; 205: 399-407

18 Sarris J, Kavanagh DJ, Deed G, Bone KM. St. Johnʼs wort and Kava in treating major depressive disorder with comorbid anxiety: a randomised double-blind placebo-controlled pilot trial. Hum Psychopharmacol 2009; 24: 41-48

19 Sarris J, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I.Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2013; 33: 643-648

20 Sarris J, Stough C, Teschke R, Wahid ZT, Bousman CA, Murray G, Savage KM, Mouatt P, Ng C, Schweitzer I.Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects. Phytother Res 2013; 27: 1723-1728

21 Sarris J, Scholey A, Schweitzer I, Bousman C, Laporte E, Ng C, Murray G, Stough C. The acute effects of kava and oxazepam on anxiety, mood, neurocognition; and genetic correlates: a randomized, placebo-controlled, double-blind study. Hum Psychopharmacol 2012; 27: 262-269

22 Schmidt M, Nahrstedt A, Lüpke NP. Piper methysticum (Kava) in der Diskussion: Betrachtungen zu Qualität, Wirksamkeit und Unbedenklichkeit. Wien Med Wochenschr 2002; 152: 382-388

23 Teschke R, Schwarzenboeck A, Hennermann KH. Causality assessment in hepatotoxicity by drugs and dietary supplements. Br J Clin Pharmacol 2008; 66: 758-766

24 Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol 2008; 20: 1182-1193

25 Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol 2013; 19: 2864-2882

26 Teschke R, Fuchs J, Bahre R, Genthner A, Wolff A. Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment. J Clin Pharm Ther 2010; 35: 545-563

27 Teschke R, Wolff A. Kava hepatotoxicity: regulatory data selection and causality assessment. Dig Liver Dis 2009; 41: 891-901

28 Teschke R, Wolff A. Regulatory causality evaluation methods applied in kava hepatotoxicity: are they appropriate?. Regul Toxicol Pharmacol 2011; 59: 1-7

29 Strahl S, Ehret V, Dahm HH, Maier KP. Nekrotisierende Hepatitis nach Einnahme pflanzlicher Heilmittel. Dtsch Med Wochenschr 1998; 123: 1410-1414

30 Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001; 135: 68-69

31 Johnson BM, Qiu SX, Zhang S, Zhang F, Burdette JE, Yu L, Bolton JL, van Breemen RB. Identification of novel electrophilic metabolites of Piper methysticum Forst (Kava). Chem Res Toxicol 2003; 16: 733-740

32 Olsen LR, Grillo MP, Skonberg C. Constituents in kava extracts potentially involved in hepatotoxicity: a review. Chem Res Toxicol 2011; 24: 992-1002

33 Hänsel R, Lazar J. Kawapyrone. Inhaltsstoffe des Rauschpfeffers in pflanzlichen Sedativa. Dtsch Apoth Ztg 1985; 125: 2056-2058

34 Gaedcke F. SL-49: Pharmaceutical characterization of Kava-Kava extracts and their formulations. Phytomed 2000; 7 (Suppl. 02) 27

35 Anonymous Assessment of the risk of hepatotoxicity with kava products. Geneva: World Health Organization; 2007

36 Lewin L. Über Piper methysticum (Kawa-Kawa). Berl Klin Wschr 1886; 1: 7-10

37 Zhou P, Gross S, Liu JH, Yu BY, Feng LL, Nolta J, Sharma V, Piwnica-Worms D, Qiu SX. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways. FASEB J 2010; 24: 4722-4732

38 Li X, Liu Z, Xu X, Blair CA, Sun Z, Xie J, Lilly MB, Zi X. Kava components down-regulate expression of ar and ar splice variants and reduce growth in patient-derived prostate cancer xenografts in mice. PLoS One 2012; 7: e31213

39 Dragull K, Yoshida WY, Tang CS. Piperidine alkaloids from Piper methysticum . Phytochemistry 2003; 63: 193-198

40 Nerurkar PV, Dragull K, Tang CS. In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones. Toxicol Sci 2004; 79: 106-111

41 Lechtenberg M, Quandt B, Schmidt M, Nahrstedt A. Is the alkaloid pipermethystine connected with the claimed liver toxicity of Kava products?. Pharmazie 2008; 63: 71-74

42 Teschke R, Qiu SX, Xuan TD, Lebot V. Kava and kava hepatotoxicity: requirements for novel experimental, ethnobotanical and clinical studies based on a review of the evidence. Phytother Res 2011; 25: 1263-1274

43 Teschke R, Lebot V. Proposal for a kava quality standardization code. Food Chem Toxicol 2011; 49: 2503-2516

44 Schmidt M, Carreno I, Vergano P. Technical assistance to the integration to the multilateral trading system and support to the integrated framework. Ref: 9 ACP RPR 140‐039/11: Establishment of health and safety standards for the production and export of kava-based products. Brussels: ACP-EU-TBT; 2012

45 Lebot V. The quality of kava consumed in the South Pacific. HerbalGram 2006; 71: 34-37

46 Schmidt M. Quality criteria for kava. HerbalGram 2007; 73: 44-49

47 Lebot V, Merlin M, Lindstrom L. Kava, the Pacific elixir. New Haven: Yale University Press; 1992

48 Siméoni P, Lebot V. Buveurs de kava. Port Vila, Vanuatu: Géo-consulte; 2014

49 Lebot V. Kava in the Pacific. High Level Conference on Kava: Port Vila, Vanuatu; 2012

50 Kaul PN, Joshi S. Alternative medicine: herbal drugs and their critical appraisal, Part II. Chapter 2: Kava-Kava. In: Jucker E, editor Progress in drug research, Vol. 57. Basel: Springer; 2001: 5-24

51 Narayanapillai SC, Leitzman P, OʼSullivan MG, Xing C. Flavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice. Chem Res Toxicol 2014; 27: 1871-1876

52 Lebot V, Do TK, Legendre L. Detection of flavokavins (A, B, C) in cultivars of kava (Piper methysticum) using high performance thin layer chromatography (HPTLC). Food Chem 2014; 151: 554-560

53 Schmidt M. “Noble” vs. “Two-day” Phytochemical quality and analytical specifications. High Level Conference on Kava: Port Vila, Vanuatu; 2012

54 Teschke R, Sarris J, Schweitzer I. Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited. Br J Clin Pharmacol 2012; 73: 170-174

55 Kraft M, Spahn TW, Menzel J, Senninger N, Dietl KH, Herbst H, Domschke W, Lerch MM. Fulminant liver failure after administration of the herbal antidepressant kava-kava. Dtsch Med Wochenschr 2001; 126: 970-972

Kava

The use of Kava originated in the “Oceana” island communities encompassed by Polynesia, Melanesia, and Micronesia (Singh and Blumenthal, 1997). In these cultures “Kava” (also known as “Kava-Kava,” “Ava,” and “Awa”) refers to an intoxicating beverage used in rituals and ceremonies, which is produced from the mashed rhizome and roots of the woody shrub, Piper methysticum. However, Kava is now used as the common name forP. methysticum as well as the phytomedicine produced from root/rhizome extracts. Worldwide, Kava is receiving considerable attention for its use as a treatment for anxiety, nervous tension, agitation, and/or insomnia. Clinical studies have shown an effectiveness of Kava that is comparable with sedatives such as benzodiazapines but without the development of either physical or psychological dependency (Singh and Blumenthal, 1997; Schulz et al., 1998).

From intensive chemical and pharmacological studies conducted on Kava root/rhizome extracts over the past century, several key active constituents have been identified (Bruneton, 1995; Singh and Blumenthal, 1997). The pharmacological activity of this plant appears to be associated with a family of styrylpyrones called “kavapyrones” (or “kavalactones”) that have effects on several neurotransmitter systems including those involving Gln, GABA, dopamine, and serotonin (Schulz et al., 1998). Whereas the kavapyrones shown in Figure4represent the predominant pharmacologically active components in Kava root extracts, a total of 18 have been identified at present (He et al., 1997). These remaining kavapyrones appear to be derivatives of either kawain, yangonin, or dihydromethysticin (Bruneton, 1995; He et al., 1997). Although details regarding kavapyrone biosynthesis are still lacking, evidence from other systems such asEquisetum arvense gametophytes suggest that styrylpyrones may arise from a triketide produced by successive condensation of two malonyl-coenzyme A (CoA) molecules with a phenylpropanoid CoA-ester (Schröder, 1997 and references therein). This is similar to reactions catalyzed by chalcone synthase except that two, rather than three, successive condensations involving malonyl CoA are involved. Recent studies have shown that kavapyrone levels in Kava roots are influenced by environmental factors. In cultivated Kava plants, kavapyrone levels appear to increase with irrigation and mineral nutrient supplementation and decrease with shading (Lebot et al., 1999). Moreover, varietal differences in Kava also appear to have a role in determining the overall level of kavapyrone production (Lebot et al., 1999).

Fig. 4.

Examples of kavapyrones from P. methysticum (Kava) (adapted from Bruneton, 1995).

It is quite interesting that Kava plants are sterile and plantation production involves propagation from stem cuttings (Singh and Blumenthal, 1997). From genetic studies, it has been suggested that Kava likely represents a sterile relative of Piper wichmannii (native to New Guinea), which became distributed across the South Pacific islands with human migration and through somatic mutation became sterile (Lebot et al., 1999 and references therein). Kava's sterility combined with its limited growth habitat range (South Pacific Tropics), time required for growth before root harvest (approximately 8 years), and high world demand have raised concerns about potential over harvesting. Although attempts have been made to grow Kava in tissue culture for propagation and possible in vitro phytochemical production, little success has been achieved (Taylor and Taufa, 1998).