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Kava
Victor Babalola &
Natalee Gautam
Taxonomy
[1]
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Scientific name:
Kingdom: Plantae
Division: Magnoliophyta
Class: Magnoliopsida
Order: Piperales
Family: Piperaceae
Genus: Piper
Species: 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
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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
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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.
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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.
Processing
Storage
[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.
Adulterants
Preparations[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 kavadrinking 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 metaanalysis 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 plusmaze 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 Studies
Toxicity [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 caspase3 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
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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
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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
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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
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[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
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[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
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[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.