Kava

Victor Babalola &

Natalee Gautam

Taxonomy[1]

Scientific name:

Kingdom: PlantaeDivision: MagnoliophytaClass: MagnoliopsidaOrder: PiperalesFamily: PiperaceaeGenus: PiperSpecies: Piper

methysticum Forster f.

Common names: kava, kava-kava, kawa, ava (Samoa), awa (Hawaii) , yaqona (Fiji) Piper methysticum means

"intoxicating pepper”

History [1]

First classified by J.G.A. Forster Kava has been consumed heavily as a beverage in the south Pacific for around

3000 years. Documented by Capt. James Cook from his South Seas Voyage of 1768

-used ceremonially in the form of an intoxicating beverage that reduced anxiety and fatigue- cultivate through South Pacific from Hawaii to New Guinea - In Hawaii used to treat asthma Alternative herbal supplement to synthetic products such as Xanax or Valium

non-addictive antidote for stress relief In Vanuatu alone natives are known to classify kava into 247 types! The name kava or its alternative names reflects the vernacular used for the

plant and the beverage prepared from it throughout Polynesia. Piper wichmanii, native to Vanuatu, the Solomon Islands, and New Guinea.

Products containing kava are sold under

Botanical description[1,3]

Has only male flower and devoid of seeds and fruit Always cultivated and does not reproduce sexually Believe to have originated from semi-domesticated clones of a wild

progenitor Slow growing perennial Height over 3 meters. Knotty, thick stump, often containing holes and cracks Roots consist of ligneous fibers that are more than 60 percent

starch The root stock color varies from white to dark yellow

large ovate to heart-shaped leaves. The flower spikes are opposite the leaves Male and female flowers occur on separate plants.

Botanical description[1,3]

Prefers a loose, rich soil with good drainage and frequent watering. It does well on stony ground. The best crops are grown on virgin soil. If two consecutive crops are

raised on the same soil the second crop will be poor. The plant rarely produces seeds and is generally propagated by

cuttings of the firm wood. These are susceptible to fungus diseases because of the high humidity the plant requires.

Rootstocks usually reach maximum growth at about 6 years, but the older the plant the more potent it will be.

Roots may be dug and used fresh or dried in the sun. The lower stems are also active. Before drying, the rootstocks and lower stems should be scraped of their outer coating and cut into pieces.

Macroscopic description[3]

Several rhizome components and lactones have been isolated in the kava root. Of the fifteen lactones isolated from kava, there are six major lactones (kavalactones) known to provide psychoactive activity:

Kawain Methysticin Demethoxy-yangonin Dihydrokawain Dihydomethysicin Yongonin.

All kavalactones are physiologically active, though it is the fat-soluble kavalactones derived from kava resin have the greatest effect on the central nervous system.

Kava also has a direct effect on muscle tension similar to tranquilizers. The activity of the kava rhizome is related to several arylethylene pyrones similar in structure to myristicin, which is found in nutmeg.

Commercial sources and handling [6]

A relaxing mildly psychoactive beverage prepared from the roots The rootstock or stump contains the psychoactive substances, they are

prepared by pounding, chewing or grinding them and soaking them in

cold water.

ProcessingStorage[6]

Dried kava can be stored at any temperature below 50°C if it is kept in moisture-proof containers.

The moisture content must be monitored and tested by smell, looking for mould, and noticing if the roots bend rather than break.

When stored as powder,

less attention needs to be paid.

AdulterantsPreparations[8, 19]

Kava has been successfully combined with valerian, St. Johns wort, hops, and passionflower in relaxing herbal formulas.

Potency can increase in specific preparation with St. John’s Wort.

More experimental (and experienced) user might want to try combining kava with cannabis or nutmeg

Constituents[14]

Isolated Chemicals: DHM Dihydrokawain Kawain Methysticin Yangonin

Yangonin

Chromatogram[17]

Rising concern over these cases of liver toxicity. - A separation method using high performance centrifugal

partition chromatography (HPCPC) has been developed for the isolation of each kava lactone from

a CO2 extract of P. methysticum in a single chromatographic run

Results: The HPCPC method are substantially better than those from the conventional column chromatography in terms of peak resolution.

- Traditional chromatography using silica gel does not always afford fractions of purified kavalactones since the lactones frequently coelute.

* Research was funded in part by the United States Department of Agriculture*

Therapeutics[3,7]

Kava was, and still is in many regions of the Pacific, an important medicine being used in the treatment of

rheumatism menstrual problems local anesthetic anticonvulsant venereal disease tuberculosis Leprosy Tension Restlessness Have been shown to be effective as alternative treatments, at

least in mild to moderate cases of anxiety.

Pharmacokinetics It has been shown that several kavalactones, the assumed active

principles of kava extracts, are potent inhibitors of several enzymes of the CYP 450 system (CYP1A2, 2C9, 2C19, 2D6, 3A4 and 4A9/11).

Has the potential to interact with so many different medications because it inhibits several different types of liver enzymes.

The pharmacological properties of kava are postulated to include:-blockade of voltage-gated sodium ion channels which

enhances ligand binding to gamma-aminobutyric acid (GABA) type A receptors,

-diminished excitatory neurotransmitter release due to calcium ion channel blockade,

-reduced neuronal reuptake of noradrenaline (norepinephrine),

-reversible inhibition of monoamine oxidase B

Pharmacodynamics

Desmethoxyyangonin, one of the six major kavalactones, is a reversible MAO-B inhibitor (Ki 280 nM)[11]- which are a class of powerful antidepressant drugs prescribed for the treatment of depression; and is able to increase dopamine levels in the nucleus accumbens -collection of neurons within the forebrain. This finding might correspond to the slightly euphoric action of kava.[4]

Clinical studies Effect of Extraction Methods[18]

Several cases of hepatotoxicity have been reported following consumption of commercial preparation, whereas no serious side affects had been documented from traditional use.

Trials were carried out comparing extraction methods using acetone, ethanol, methanol, or traditional aqueous revealing differences in ratio of kavalactones.

Extracts were compared for their inhibition of the major drug metabolizing P450 enzymes.

Results: In all cases the inhibition was more pronounced in commercial preparation.

-Commercial available caplets are

usually prepared by ethanolic or

acetonic extraction of entire plant,

unlike traditional, where roots are

only used.

Clinical Trial Hospital based survey [14]

To assess the kava-drinking habits of current-day-Vanuatu,

150 people were surveyed at Vila Central Hospital, (50 medical and 50 surgical patients plus 50 staff). 35% of those surveyed drank kava, (9% daily). 59% of men and 15% of women drank kava (approximately 4:1). 51% of all men drank kava at least weekly, compared to 11% of women. For any given kava-drinking episode men drank more than women, (4.3 +/- 2 vs. 3.3 +/- 1.3 shells).

There was no significant difference in age between drinkers and non-drinkers or in usage rates between patient groups or staff. Women attaining higher levels of education and women resident on Vanuatu's main island were more likely to drink kava. Of the women surveyed who were resident on outer islands none drank kava.

This study reveals that the consumption of fresh kava on a regular basis is very common in Vanuatu. If this is the case it also suggests that whilst much is written about the dermopathy, weight loss and, more recently, possible liver disease associated with kava use that these and other health problems are of doubtful significance. This is also supported by field experience

Clinical Trial Meta-Analysis [16]

All publications describing randomized, double-blind, placebo-controlled trials of kava extract for anxiety were sought through electronic searches on EMBASE, MEDLINE, AMED (British Library), CISCOM (Research Council for Complementary Medicine, London), Central/CCTR and CCDANCTR. Additionally, manufacturers of kava preparations and experts on the subject were contacted and asked to contribute published and unpublished material. Hand-searches of relevant medical journals, Complementary Therapies and our own files were conducted. The searches were updated to August 2002. No restrictions regarding the language of publication were imposed.

Studies were required to be randomized, controlled trials (RCTs), i.e. trials with a randomized generation of allocation sequences, and conducted placebo-controlled and double-blind

Trials using single constituents of kava extract alone, assessing kava extract as one of several active components in a combination preparation or as a part of a combination therapy were excluded.

Eleven trials with a total of 645 participants met the inclusion criteria. The meta-analysis of six studies using the total score on the Hamilton Anxiety scale as a common outcome measure.

Results:Compared with placebo, kava extract appears to be an effective symptomatic treatment option

for anxiety. The data available from the reviewed studies suggest that kava is relatively safe for short-term treatment (1 to 24 weeks)

Animal studies [10]

Extracts of Kava induce acute anxiolytic - like behavioral changes in mice.

-Various doses, 125mg/kg and 88mg/kg, of an ethanolic extract of kava root or diazepam (derivative drug of Valium) were administered intraperitoneally to BALB inbred mice. Behavioral changes were measured in the mirrored chamber avoidance assay and elevated plus-maze assay.

-Sedation was defined as decrease locomotive activity in arena.

Results: Kava induced increases in time spent in both chamber and open arena. Caused a profound decrease in loco motor activity.

Flumazenil, a competitive benzodiazepine receptor antagonist, blocked sedative effects of diazepam, but had no effects on kava’s behavioral actions.

Kava extracts produce significant anxiolytic like behavioral changes that are not mediated through benzodiazepine binding site on GABA receptor.

Animal StudiesToxicity [12]

The aim of this study was to test chronic toxicity in rats by oral application of an ethanolic kava full extract.

- Wistar rats of both sexes were fed 7.3 or 73 mg/kg body weight of ethanolic kava extract for 3 and 6 months. The animals were examined for changes in body weight, hematological and liver parameters, and macroscopical and microscopical histological changes in the major organs.

- No signs of toxicity could be found. - The results are in accordance with the medical experience

regarding the use of kava preparations and the long tradition of kava drinking in the South Pacific island states. Specifically, the results do not back the suspicion of potential liver toxicity.

In vitro [13]

The aim of this study was to test the in vitro effects of a major kava alkaloid, piper methystine (PM), found mostly in leaves and stem peelings, and kavalactones such as 7,8-dihydromethysticin (DHM) and desmethoxyyangonin (DMY), which are abundant in the roots.

Exposure of human hepatoma cells, HepG2, to 100 micro M PM caused 90% loss in cell viability within 24 h, while 50 micro M caused 65% cell death. Similar concentrations of kavalactones did not affect cell viability for up to 8 days of treatment.

Mechanistic studies indicate that, in contrast to kavalactones, PM significantly decreased cellular ATP levels, mitochondrial membrane potential, and induced apoptosis as measured by the release of caspase-3 after 24 h of treatment.

These observations suggest that PM, rather than kavalactones, is capable of causing cell death, probably in part by disrupting mitochondrial function. Thus, PM may contribute to rare but severe hepatotoxic reactions to kava.

Indications[2]

Determined 70mg dose of kavalactones (active compound in roots) administered 3 times daily reduced symptoms of patients diagnosed with anxiety disorders

Can be taken as a tablet, capsule, tinctures (alcoholic extract) and dried roots. Pill usually has anywhere from 75 mg to 150 mg of kavalactones.

Lecithin is often added to aid in the process of emulsifying the kavalactones with water.

Hepatic failure in female adolescent taking kava[20]

- A 14-year-old female with no previous medical history developed fulminant hepatitis and hepatic failure after taking the herbal preparation kava (piper methysticum) over a three-month period for treatment of anxiety.

- The patient presented with nausea lasting one week in duration, vomiting, malaise and poor oral intake, but without fever or diarrhea.

- Initial workup showed markedly abnormal liver function tests, later confirmed by a liver biopsy

to be fulminant hepatitis with extensive centrilobular necrosis. - The patient underwent successful liver transplantation. - This first report of kava-induced hepatotoxicity in a child suggests that

kava use can have grave consequences in children, even when used according to the recommended guidelines, say the authors. “Kava use in childhood cannot be recommended in the absence of additional research and a better understanding of drug delivery and potential toxicities,” they conclude.

Toxicology[5,3]

Do not exceed 100mg 2-3 times daily Excessive use for more than 6 months could result in skin

damage, liver dysfunction and muscle fatigue Long term use of the herb can contribute to hypertension,

reduced protein levels, blood cell abnormalities, or liver damage.

Alcohol consumption increases the toxicity of the pharmacological constituents.

It is not recommended for those who intend on driving or where quick reaction time is required.

Do not use if pregnant, nursing, or being treated for depression.

Toxicology The United States Food and Drug Administration (FDA) has warned

that very rare cases of liver damage or fulminant liver failure may be caused by kava-containing supplements. However, these injuries might result from pipermethystine, an alkaloid present in portions of the plant used industrially but normally discarded in traditional preparations

Researchers from the University of Hawaii at Manoa found that pipermethystine (formula 1), contained in stem peelings and leaves but not in the roots, had toxic effects on liver cells in vitro [4] and in vivo.[5] 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)[5], (73 mg/kg, 3 months).[6]

Found in the plant's rhizome (large horizontal underground stem), may also contribute to toxic effects.[17] And, it is known that some of the kavapyrones block several subtypes of the enzyme cytochrome P450[18], which can result in adverse interactions with other drugs used concomitantly.

Contraindications[7]

Occasionally higher doses can lead to muscle weakness, visual impairment, dizziness and drying of the skin

Pregnancy lactation endogenous depression

Adverse effects[3]

By putting kava leaves in the vagina, abortions were said to be provoked.

Changes in blood chemistry Dry, flaking, discolored skin Exaggerated kneecap reflex Pulmonary hypertension Reddened eyes Shortness of breath Weight loss Liver Toxicity- long term

Interactions[14]

Pharmaceutical companies and herbal supplement companies extract kavalactones using solvents such as acetone and ethanol and 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 such may have been due to the use of plant parts other than the root, such as stems or peelings.

It should be assumed that kava will interact will any medication, until proven otherwise.

References [1] Wilton, Peter A., Lau, Andrew, Salisbury Alicia, Whitehouse Julie, Evans Christine

A.(2003) Kava lactones and the kava-kava Controversy. Photochemistry 64; 673-679 [2] Title: Kava, take me away. Osorio, Carolina, Marandino, Cristin, Vegetarian Times,

01648497, Oct98, Issue 254.-- Endorsed by Dr. Sahelian [3]Singh YN, Singh NN. Therapeutic potential of kava in the treatment of anxiety

disorders. CNS Drugs. 2002;16(11):731-43. PMID: 12383029 [PubMed - indexed for MEDLINE]

[4] 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. PMID 9829291

[5] Seitz U, Schule A, Gleitz J (1997): "[3H]-monoamine uptake inhibition properties of kava pyrones." Plant Med. 63(6):548-9. PMID 9434608

[6 ]Sorrentino L et al. (2006): "Safety of ethanolic kava extract: Results of a study of chronic toxicity in rats", Phytomedicine, 13(8):542-549. PMID 16904878

[7] Jhoo JW et al. (2006): "In vitro cytotoxicity of nonpolar constituents from different parts of kava plant (Piper methysticum)", J. Agric. Food Chem. 54(8):3157-62. PMI 16608246

[8] a) J.M. Mathews et al. (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. PMID 16033948

References

[10]Psychopharmacology(2003) 170:33-4; Original investigation: Extracts of Kava(Piper methysticum) induce acute anxiolytic-like behavioral changes in mice. Kennon M. Garrett, Garo Basmadjian, Ikhlas A. Khan, Brian T. Schaneberg, Thomas W. Seale; Revised: 16 Sept 2002/ Accepted 16 April 2003/ Published online 4July 2003; Copywrite Springer- Verlag 2003.

[11]Uebelhack R, Franke L, Schewe HJ (1998): “Inhibition of platelet MAO-B by kava pyrone -enriched extract from kava-kava.” Pharmacopsychiatry 31(5):187-92.

[12]Sorrentino L, Capasso A, Schmidt M. Safety of ethanolic kava extract: Results of a study of chronic toxicity in rats. Phytomedicine. 2006 Sep;13(8):542-9. Epub 2006 Aug 14.

[13]Nerurkar PV, Dragull K, Tang CS; In vitro toxicity of kava alkaloid, piper methystine, in HepG2 cells compared to kavalactones. Toxicol Sci. 2004 May;79(1):106-11. Epub 2004 Jan 21.

[14]Grace, R.F. Kava consumption and its health effects. Pac Health Dialog. 2006 Sep;13(2):131-5. Review. PMID: 18181402 [PubMed - indexed for MEDLINE]

[15] Lim ST et al. (2007): "Effects of Kava Alkaloid, Pipermethystine, and Kavalactones on Oxidative Stress and Cytochrome P450 in F-344 Rats." Toxicol Sci. PMID 17329236

[16]Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst. Rev. 2003;(1):CD003383. PMID: 12535473 [PubMed - indexed for MEDLINE]

Reference [17]Mikell, J.; Schaneberg, B.; Khan, I. Isolation and purification of kava lactones by

high performance centrifugal partition chromatography. Journal of Liquid Chromatography & Related Technologies. 2003, 26 (18), 3069‑3074.

[18]Xuan TD, Fukuta M, Wei AC, Elzaawely AA, Khanh TD, Tawata S.Efficacy of extracting solvents to chemical components of kava (Piper methysticum) roots.Nat Med (Tokyo). 2008 Apr;62(2):188-94. Epub 2007 Nov 28. PMID: 18404321 [PubMed - in process]

[19]Singh YN. Potential for interaction of kava and St. John's wort with drugs.J Ethnopharmacol. 2005 Aug 22;100(1-2):108-13

[20] Campo JV, McNabb J, Perel JM, et al.: Kava-induced fulminant hepatic failure. Journal of the American Academy of Child and Adolescent Psychiatry 2002; 41(6):631-632.