HERBAL
MEDICINAL
PLANT
----------------------------------------------------------
KAVA
Piper methysticum G. Forster. f. (Piperaceae) ++
BY
RETTODWIKART THENU
KAVA
(kah’vah)
Piper methysticum G. Forster. f. (Piperaceae)
SUMMARY AND PHARMACEUTICAL COMMENT
The chemistry of kava is well documented (see Constituents) and there is strong
evidence that the kavalactone constituents are responsible for the observed
pharmacological activities. Randomised, double-blind, placebo-controlled
clinical trials of certain standardised kava preparations have shown beneficial
effects on measures of anxiety, although because of methodological limitations
of some studies, further welldesigned trials are required to confirm the
anxiolytic effects.
Also, most trials have been carried out with one particular standardised
kava extract (containing 70% kavalactones) and it cannot be assumed that the
effects shown in these studies will be produced by other kava extracts.
Clinical trials involving patients with anxiety have also compared welldefined standardised
kava preparations with certain standard anxiolytic agents. While these studies
have suggested that the kava extracts tested may be as effective as certain
standard anxiolytic agents, further investigation is necessary. Data from pharmacological
studies provide supporting evidence for the anxiolytic effects of kava,
although many of the other traditional uses of kava (see Herbal use) have not been tested
scientifically. Many pharmacological studies involving individual kavalactones
have investigated the effects of the synthetic kavalactone (_)-kavain, rather
than the natural compound (þ)-kavain. Some studies have used both the natural
compound and the synthetic racemate and have reported a lack of stereospecific
effect.
In placebo-controlled clinical trials, standardised kava extracts
generally have been well tolerated; reported adverse events have been mild and
transient and similar in nature and frequency to those reported for placebo.
Clinical trials, however, can provide only limited information on the safety profile
of a medicine. Spontaneous reports of hepatotoxicity associated with the use of
kava preparations have arisen since the year 2000. Although the risk of serious
liver toxicity is thought to be low, the reaction is idiosyncratic. Against
this background, kava was prohibited in unlicensed medicines in the UK in 2003,
and in the EU, all licensed kava products were removed from the market. In 2005
in the UK, evidence relating to hepatotoxicity associated with kava was
reviewed and the Expert Working Group’s report concluded that there was
insufficient new evidence to support a change in the regulatory position, i.e.
the inclusion of kava in unlicensed medicines remains prohibited. Regulatory action
has also been taken in Canada and Australia (voluntary recall), and in the USA,
consumers were warned of the risk of liver toxicity with use of kava-containing
products.
Other adverse reactions documented for kava preparations include
an ichthyosiform (scaly, non-inflammatory) skin condition, termed ’kava dermopathy’,
usually associated with the traditional method of preparing and ingesting kava
(see Side-effects,
Toxicity, Skin reactions).
In view of the documented pharmacological actions of kava and in
view of the reported inhibitory activity against certain cytochrome P450 drug
metabolising enzymes, the potential for preparations of kava root/rhizome to
interfere with other medicines administered concurrently, particularly those
with similar or opposing effects, should be considered. Use of kava should be
avoided during pregnancy and breastfeeding.
Although kava is prohibited in the UK and several other countries,
individuals may obtain kava preparations over the Internet. Healthcare
professionals should be aware that patients may be taking herbal medicinal
products containing kava. Healthcare professionals should enquire about use of kava
in patients presenting with symptoms of hepatotoxicity (see Side-effects, Toxicity, Hepatotoxicity). Adverse reactions have
been reported in association with use of ’herbal ecstasy’ tablets, which often
contain ephedrine alkaloids, although healthcare professionals should be aware
that some products have been stated to contain kava. or many
centuries, Pacific Islanders have used the kava kava root to prepare a beverage used in welcoming ceremonies for important
visitors. Drinking kava kava is not only done to induce pleasant mental states but also to reduce anxiety and
promote socialising. It is believed that the first report about kava kava came
to the West from Captain James Cook during his voyages through the Pacific
region.
TRADE NAMES
Kava
Kava (available from numerous manfacturers) Alcohol Free Kava Kava, Kava Kava
Power,
Kava
Kava Premium, Kava Kava Root
DESCRIPTION
MEDICINAL PARTS: The medicinal
parts are the peeled, dried, cut rhizome, which has normally been freed from
the roots, and the fresh rhizome with the roots.
FLOWER AND FRUIT: The plant has
numerous small flowers in spike-like inflorescences 3 to 9 cm long.
LEAVES, STEM AND ROOT: The plant is a 2
to 3 m high, erect dioecious bush. The leaves are very large, measuring 13 to 28
cm by 10 to 22 cm. They have a deeply cordate base and 9 to 13 main ribs that
are slightly soft on the undersurface. The stipules are large. The plant has a
massive, 2 to 10 kg, branched and very juicy rhizome with many roots. They are blackish-gray
on the outside and whitish on the inside. The fracture is mealy and somewhat
splintery. The central portion is porous with irregularly twisted thin woody bundles,
separated by broad medullary rays, forming meshes beneath the bark.
CHARACTERISTICS: The taste is
pungent and numbing, and the odor is reminiscent of lilac.
HABITAT: The plant is
indigenous to the South Sea Islands and is mainly cultivated there.
PRODUCTION: Kava Kava
rhizome consists of the dried rhizomes of Piper methysticum.
OTHER NAMES: Ava, Ava Pepper,
Intoxicating Pepper, Kawa, Kawa Pepper, Tonga, Kew, Sakau, Yagona
SPECIES (FAMILY)
Piper methysticum Forst. f. (Piperaceae) Fourteen different
varieties are used throughout Oceania
(Polynesia, Melanesia, Micronesia).(1)
RELATED SPECIES
Cultivars of P. methysticum have been developed in some Pacific Islands
from Piper wichmannii C. DC
(syn: Piper erectum C. DC, Piper arbuscula Trelease).(2, 3)
SYNONYM(S)
Intoxicating Pepper, Kava-kava, Kawa, Kawa-kawa, Macropiper methysticum
(G. Forst.) Hook. & Arn., M. latifolium Miq., Waghi, Wati, Bari (Irian
Jaya), Koniak, Keu, Oyo (Papua New Guinea)
ORIGIN
Kava is a shrub found on the
South Sea Islands. Kava is indigenous to the islands
of the South Pacific.
The native Polynesians use the
rhizome to make a mildly intoxicating beverage.
Kava rhizome extract has
anxiolytic and sedative effects.
PHARMACOPODIAL AND OTHER MONOGRAPHS
BHMA 2003(G66)
BHP 1996(G9)
Complete German Commission E 1998(G3)
Expanded German Commission E 2000(G4)
Martindale 35th edition(G85)
WHO volume 2 2002(G70)
LEGAL CATEGORY (LICENSED PRODUCTS)
Prohibited in unlicensed medicines in the UK.(4)
CONSTITUENTS
Kavalactones
Kawalactones, kavapyrones, 2-pyrones, d-lactones with styryl or dihydrostyryl
substituents.(1–3, 5–9,G56) Dried rhizomes should contain at least 3.5%
kavalactones(G56) and good-quality material 5.5–8.3%.(10) Ethanol–water
extracts contain 30% kavalactones, whereas acetone–water extracts contain 70%.(G56)
The kavalactones occur as a complex mixture of at least 18 compounds,(5) which
are of three main types: styryl enolide pyrones (e.g. kawain (= kavain),
dimethoxykawain, methysticin), styryl dienolide pyrones (e.g. yangonin,
desmethoxyyangonin), and dihydrostyryl enolide pyrones (e.g. dihydrokawain,
dimethoxydihydrokawain, dihydromethysticin). The four major kavalactones of the
rhizome are kawain (1–2%), dihydrokawain (0.6–1%), methysticin (1.2–2%) and
dihydromethysticin (0.5–0.8%).(G56) Smaller quantities (<0.1%) of dimeric kavalactones
(e.g. truxyangonins I, II, III) have also been isolated.(2, 3)
Alkaloids/Amides Cepharadione A (aporphine-type) is a minor component
(4 kg yielded 1 mg).(11) Small quantities of Ncinnamoylpyrrolidine and its
O-methoxy analogue are also present.(6, 12, 13)
Chalcones Flavokawains A, B and C.(6, 9, 14)
Flavonoids Pinostrobin, 5,7-dimethoxyflavanone.(14)
Steroids Sitosterol, stigmasterol, stigmastanol.(6,
13)
Esters Bornyl cinnamate(13) and bornyl
3,4-methylenedioxycinnamate.(14)
Aliphatic Alcohols Docosan-1-ol, dodecan-1-ol, eicosan-1-ol, hexacosan-1-ol,
hexadecan-1-ol, octadecan-1-ol, n tetradecanol, transphytol.(6)
Other Constituents Cinnamylideneacetone,(5) long-chain fatty acids.(6)
OTHER PARTS OF THE PLANT
Stem
peelings may be included as raw material in kava commerce due to the high
demand for the rhizome; leaves and branches are used in folk medicine. Pipermethystine
(a piperidone amide) is present in stem peelings (traces to 0.85%).(15)
3a,4a-Epoxy-5bpipermethysticin (0.93%) was isolated from stem peelings of one cultivar,
but was absent from 10 other cultivars, and the related alkaloid awaine was
present in the unopened leaves of 11 cultivars (0.16–2.67%). 7,8-Dihydrokawain,
7,8-dihydromethysticin and 5,6,7,8-tetrahydroyangonin are present in stem
peelings.
OTHER SPECIES
Kavalactones
occur in P. wichmanni and P. sanctum. The latter species contains several
cinnamoyl butenolides (piperolides), e.g. methylenedioxypiperolide and
7,8-epoxypiperolide.(2, 3)
PHARMACOLOGY
·
HERB: Kava rhizome (Piperis methystici rhizoma).
The herb consists of the peeled, cut and
dried rhizomes (usually with the root parts removed) of Piper methysticum G. F. and preparations of the same.
·
IMPORTANT Constituents: Kava lactones (kava pyrones, 5–12 %)
consisting mainly of ()-kavain (1.8 %), ()-methysticin (1.2 %), desmethoxyyangonin (1
%), and yangonin (1 %).
·
PHARMACOLOGICAL PROPERTIES: Kava pyrones have sedative and central
muscle relaxant effects. Anticonvulsive, neuroprotective, narcosis-enhancing,
central muscle relaxant, spasmolytic, analgesic, and local anesthetic effects were
observed in animals. The herb has anxiolytic and soporific effects in humans.
USES
USES
Kava is used as an anxiolytic, antiepileptic,
antidepressant, antipsychotic, and for anxiety, attention defi
cit–hyperactivity disorder, insomnia, restlessness, and headaches. It is also
used as a muscle relaxant and to promote wound healing.
INVESTIGATIONAL USE
Research is underway for use in cancer.
FOOD USE
Kava
is used as an intoxicant drink, on either informal or ceremonial occasions, by
Pacific Islanders e.g. from Fiji, Samoa and Tonga.(1, 7) Some claim that it has
a pleasant, cooling, aromatic taste with numbing on the tongue and is
stimulating, while others refer to great bitterness with a burning sensation in
the mouth. It is reputed to reduce fatigue, allay anxieties and produce a
cheerful and sociable attitude. Unpleasant effects reported include dizziness,
sleeping disorders, stomach pains, lethargy and skin reactions. These reported
effects are taken from a wide geographical area and any differences may be due
to a number of reasons including plant varieties or growing conditions.
HERBAL USE
In
many parts of the Pacific it is believed that kava is beneficial to health by
soothing nervous conditions, inducing relaxation and sleep, counteracting
fatigue, and reducing weight. Medicinal uses also include treatment of urinary
tract infections, asthma, rheumatism, headache, fever, gonorrhoea and syphilis,
and use as a diuretic and stomachic.(1, 7, G34) The medicinal use of kava is now
widespread, e.g. across Europe, North America and Australia, where it is used
to treat anxiety, nervous tension, restlessness, mild depression and menopausal
symptoms.(G9, G32, G50, G56, G60, G67) It has also been adopted by the
Aboriginal community in parts of Australia as an intoxicating drink.(16) The
German Commission E recommended kava for the treatment of nervous anxiety,
stress and restlessness.(G3) Traditional uses listed for kava rhizome in other
standard herbal and pharmaceutical reference texts include cystitis,
urethritis, infection or inflammation of the genitourinary tract, rheumatism
and, topically, for joint pains.(G66)
CLINICAL USE
Kava
kava extracts are popular in Europe and have been investigated in numerous
clinical trials, primarily in European countries. As a result, many research
papers have been published in languages other than English. In order to provide
a more complete description of the evidence available, secondary sources have
been used where necessary. The extract which has been most studied is kava kava
extract WS®1490.
Figure 1. Kava (Piper methysticum).
Figure 2. Kava – dried
drug substance (rhizome).
Anxiety
Evidence from double-blind
clinical studies indicates that kava kava is an effective treatment for anxiety,
repeatedly shown to be as effective as benzodiazepines.
A 2000 Cochrane review of
the scientific literature assessed the results from seven, double-blind, randomised,
placebo-controlled trials and concluded that kava kava extract has significant
anxiolytic activity and is superior to placebo for the symptomatic treatment of
anxiety (Pittler & Ernst 2000).
An update of this review was published in 2003 and analysed results from 12
clinical studies involving 700 subjects (Pittler & Ernst 2003).
The results of seven studies that used the Hamilton Anxiety Scale (HAM-A) score
were pooled and a significant reduction in anxiety was observed for kava kava
treatment compared with placebo. The results of the five studies that were not
submitted to metaanalysis largely support these findings. The extract most
commonly tested was WS 1490 at a dose of up to 300 mg daily. According to the
authors of the review, none of the trials reported any hepatotoxic events and seven
trials measured liver enzyme levels as safety parameters and reported no
clinically significant changes.
In 2005, Witte et al
published results of another meta-analysis which included data from six
placebo- controlled, randomised trials with the kava kava extract WS®1490. The
endpoints were the change in HAMA during treatment (continuous and binary).
Kava kava significantly improved anxiety with a mean improvement of 5.94 points
on the HAMA scale better than placebo. Interestingly, kava kava seemed to be more
effective in females and in younger patients. The rigorous meta-analysis found no
evidence of publication bias, no remarkable heterogeneity amongst the studies
and concluded that trials had high methodological standards. Based on this
impressive result, authors concluded that kava kava remains as an effective
alternative to benzodiazepines, selective serotonin re-uptake inhibitors (SSRIs)
and other antidepressants in the treatment of non-psychotic anxiety disorders.
GENERALISED ANXIETY DISORDER
An 8-week randomised,
double-blind, multicentre clinical trial involving 129 outpatients with GAD showed
that kava kava LI 150 (400 mg/day) was as effective as buspirone in the acute
treatment of GAD, with about 75% of patients responding to treatment (Boerner
et al 2003).
COMPARATIVE STUDIES
Comparative studies suggest
the absence of significant differences between benzodiazepines and kavain or
kava kava extract as treatments for anxiety. A 1993 double-blind, comparative
study involving 174 subjects over 6 weeks demonstrated that 300 mg/day of a 70%
kava lactone extract produced a similar improvement in anxiety level, as
measured by HAM-A scores, to 15 mg oxazepam or 9 mg bromazepam taken daily (Woelk
et al 1993). D,Lkavain produced equivalent anxiolytic effects to oxazepam in
38 outpatients with neurotic or psychosomatic disturbances, under double-blind
study conditions (Lindenberg & Pitule-Schodel 1990). Benzodiazepine
with drawal Kava kava may have a role in reducing anxiety and improving
subjective wellbeing during benzodiazepine withdrawal, according to a 2001
randomised, double-blind, placebo-controlled study (Malsch
& Kieser 2001). During the first 2 weeks of that study,
kava kava dose was increased from 50 mg/day to 300 mg/day while benzodiazepine
use was tapered off during the same period. Kava kava extract was superior to
placebo in reducing anxiety as measured by the HAM-A scale and improved
subjects’ feelings of wellbeing according to a subjective wellbeing scale (Bf-S
total scores). Lack of tolerance The results from a randomised, double-blind
trial conducted over 25 weeks have found that physical tolerance does not
develop to kava kava extract and it is well tolerated (Volz
& Kieser 1997). Evidence from a randomised, double-blind study conducted with
84 patients has shown that treatment with kavain (one of the active constituents
of kava kava) produces continuous improvements in parameters such as memory function,
vigilance, fluency of mental functions and reaction time. Interestingly, these
effects were reported over a relatively short period of 3 weeks (Scholing
& Clausen 1977). Another randomised, double-blind trial conducted with 52
patients over 28 days not only confirmed anxiolytic activity but also found
that kavain promoted subjective vitality-related performance (Lehmann
et al 1989). Commission E approves the use of kava kava in conditions of nervous
anxiety and restlessness (Blumenthal et al 2000).
Menopausal
and perimenopausal anxiety
A randomised, placebo-controlled
study conducted with 40 menopausal women found that using kava kava extract,
together with hormone replacement therapy (HRT), led to significant reductions in
anxiety, as measured by the HAM-A scale at both 3- and 6-month follow-up (De
et al 2000). A 3-month, randomised, open study of 68 perimenopausal women
showed that treatment with kava kava (100 mg/day) significantly reduced anxiety
(P < 0.001) at 1 month and 3 months. This was significantly greater
than that spontaneously occurring in controls (P < 0.009) (Cagnacci
et al 2003).
Insomnia
The hypnotic activity of kava
kava extract was confirmed in a RCT in which a single dose of 300 mg kava kava
extract was found to improve the quality of sleep significantly (Emser
& Bartylla 1991, as reported by Ernst et al 2001). In vivo experiments with
D,L-kavain have shown that it reduces active wakefulness and significantly
prolongs sleep, compared with placebo (Holm et al 1991).
OTHER USES
Traditionally,
the herb has been used to treat urinary tract infections, asthma, conditions
associated with pain, gonorrhoea and syphilis, and to assist with weight
reduction, muscle relaxation and sleep. Topically, it has been used as a local
anaesthetic and to treat pruritus.
ACTIONS
PHARMACOLOGICAL ACTIONS
Kava
has been investigated mostly for its anxiolytic effects, although other central
nervous system activities, such as anticonvulsant and analgesic properties, and
other effects have been documented following preclinical studies. The
kavalactones are believed to be the major active constituents of kava.
IN VITRO AND ANIMAL STUDIES
Pharmacokinetics Uptake of the kavalactones kavain,
dihydrokavain, yangonin and desmethoxyyangonin into brain tissue has been documented
following intraperitoneal administration of each of these compounds at a dose
of 100 mg/kg to mice.(17) Maximum concentrations of kavain and dihydrokavain
were noted five minutes after administration, and these compounds were rapidly
eliminated. In contrast, yangonin and desmethoxyyangonin were eliminated more slowly.
All four compounds were also detected in mouse brain tissue following
intraperitoneal administration of kava resin 120 mg/kg (containing kavain
36.7%, dihydrokavain 19.2%, yangonin 15% and desmethoxyyangonin 13.3%),
although the concentrations of kavain and yangonin were higher than was noted
following individual administration of these constituents.
Central Nervous System Activities
Anxiolytic properties for kava extract and isolated kavalactones
have been documented in an experimental model of anxiety, the chick social
separation–stress procedure. In a series of experiments, kava extract
(containing 30% kavalactones; 30 mg/mL per kg body weight), dihydrokavain (30
mg/mL per kg body weight) and chlordiazepoxide (5 mg/mL per kg body weight)
administered intraperitoneally 30 minutes before testing significantly reduced the
separation–stress effect (p < 0.05 for each substance).(18) However, the
isolated kavalactones kavain, methysticin, dihydromethysticin, yangonin and
desmethoxyyangonin administered according to the same regimen did not have a
statistically significant effect. Further work using the same experimental
model confirmed these findings and found that total kavalactone content was not
predictive of outcome, but that a dihydrokavain content of at least 15% was necessary
for anxiolytic activity.(19) In this study, the kava samples and fractions that
demonstrated anxiolytic activity were reported to be without sedative effects.
In contrast, previous studies have reported sedative effects for
kava extract. In mice, kava extract (containing 7% kavalactones) at doses of at
least 50 mg/kg body weight (by intraperitoneal injection) reduced spontaneous
motility to a greater extent than did control.(20) The effect was enhanced by
the addition of (_)- kavain (ratio of kava extract to (_)-kavain, 1 : 0.12),
although this compound had no sedative effect when administered alone. In another
experimental model, kava extract 100 mg/kg body weight and (_)-kavain 12 mg/kg
body weight, each administered alone, had no sedative effect, whereas a
combination of the two substances significantly reduced amphetamine (5 mg/kg
body weight subcutaneously)-induced hypermotility. Sedative effects have also
been documented for an ethanolic extract of kava rhizome (containing 50% kavalactones)
100 mg/kg body weight administered by gastric tube and 200 mg/kg body weight intraperitoneally
in the amphetamine-induced hypermotility test and barbiturate-induced sleeping
time, respectively.(21)
In studies utilising the conditioned avoidance response test in rats,
an experimental model used to test for antipsychotic activity, aqueous
(kavalactone-free) kava extract 30–500 mg/kg body weight intraperitoneally had
no statistically significant effect.(22) However, administration of kava resin
at doses of 125 mg/kg intraperitoneally significantly inhibited the conditioned
avoidance response, although to a lesser extent than did chlorpromazine and haloperidol.
In cats, a kava extract in arachis oil (50–100 mg kavalactones per kg body
weight intraperitoneally) and the individual kavalactone (_)-kavain (10–50 mg
per kg body weight intraperitoneally) were reported to be active in the
amygdala complex region of the brain.(23)
Receptor binding studies with kava extracts and individual kavalactones
have reported conflicting results. One series of experiments found that kava resin
and individual kavalactones displayed only weak activity on GABAA- and no
activity on GABAB-binding sites in rat brain membranes in vitro, and that there
was no significant effect on benzodiazepine receptors following intraperitoneal
administration of kava resin 150 mg/kg body weight to mice.(24) A marked effect
of kavain on GABA has also been stated to be unlikely.(25) By contrast, a
kavalactoneenriched ethanol/aqueous extract of kava rhizome (containing 58%
kavalactones and 42% other lipid-soluble compounds) increased the density of
GABA-binding sites in certain brain regions.(26) Other experiments have shown concentration-
and structure-dependent effects of kavalactones on binding of bicuculline methochloride
(BMC) to GABAA receptors from rat cortex preparations.(27) (þ)-Kavain,
(þ)-methysticin and (þ)-dihydromethysticin enhanced BMC binding by 18–28% at a
concentration of 0.1 mmol/L, whereas (þ)-dihydrokavain did so only at a concentration
of 10 mmol/L, and yangonin at a concentration of 1 mmol/L; desmethoxyyangonin
had no effect. Further radioreceptor assays demonstrated that these six kavalactones
had no effect on the binding of flunitrazepam to benzodiazepine receptors in
rat cortex preparations, indicating that the influence of kavalactones on GABAA
receptors was not based upon an
interaction
with benzodiazepine receptors.(27)
Other in vitro studies have investigated the effects of kava extracts
and individual kavalactones on other transmitters in the central nervous system
(CNS). A kavalactone-rich kava rhizome extract (containing 68% kavalactones)
was a reversible inhibitor of monoamine-oxidase B (MAO-B) in intact and
disrupted platelets (inhibitory concentration IC50 24 mmol/L and 1.2 mmol/ L,
respectively), although there were differences in MAO-B inhibition among the
different synthetic kavalactones with desmethoxyyangonin and (_)-methysticin
being the most potent inhibitors.(28) Differences between kavalactones in
inhibition of noradrenaline (norepinephrine) uptake in synaptosomes prepared from
rat cerebral cortex and hippocampus have also been documented: (_)- and
(þ)-kavain gave approximately equal values and both were more potent inhibitors
than (þ)-methysticin, although none of the compounds inhibited serotonin
uptake.(29) It has been suggested, following in vitro studies involving
ipsapirone (a serotonin-1A receptor agonist)-induced field potential changes in
guinea-pig hippocampal slices, that kavain and dihydromethysticin may modulate
serotonin-1A receptor activity, although further work is needed to identify the
precise mechanism for this.(30)
In vivo studies in rats administered a single oral dose of (þ)- dihydromethysticin
100 mg/kg body weight or fed (_)-kavain in the diet over a 78-day period showed
that neither kavalactone regimen affected brain tissue concentrations of
dopamine and serotonin, although since extracellular neurotransmitter concentrations
were not measured in this study, receptor-mediated effects of kavalactones on
dopaminergic and serotonergic neurons could not be excluded.(31) In vivo (rats),
kava extract 20 and 120 mg/kg body weight intraperitoneally increased dopamine
concentrations in the nucleus accumbens, although a dose of 220 mg/kg body weight
led to an initial decrease followed by an increase above baseline values.(32)
It was suggested that this ceiling effect may be due to yangonin which may have
dopamine antagonist activity. The development of physiological tolerance to an
aqueous extract of kava administered intraperitoneally to mice has been documented,
although there was no clear evidence of development of physiological or learned
tolerance to kava resin.(33)
Anticonvulsant And Neuroprotective
Activities
Studies described in the older literature have documented
anticonvulsant effects for kavalactones in several experimental models.(34,
G50) The anticonvulsant properties of (þ)-methysticin in vitro may arise from a
direct membrane action on the excitability of neurons,(34) and in vitro assays
have shown that (þ)-methysti-cin,(35) (þ)-kavain(36) and the synthetic
kavalactone (_)-kavain(34–36) appear to interact with voltage-dependent sodium
channels, and that (_)-kavain also interacts with voltage-dependent calcium channels.(37)
Inhibition by (_)-kavain of veratridine-activated voltage-dependent sodium ion
channels in synaptosomes from rat cerebral cortex,(38) and veratridine-induced
increase in intracellular calcium ion concentrations has been described following
in vitro studies utilising rat cerebrocortical synaptosomes.(39) Reduction in
veratridine-induced glutamate release following (_)-kavain administration has
been reported both in vitro(39) and in vivo in freely moving rats.(40)
Substances which reduce extracellular glutamate concentrations are of interest
for their potential as anticonvulsant agents. Some of the mechanisms described
above documented for certain kavalactones may also be important in neuroprotective
effects reported for the synthetic kavalactone (_)-kavain. For example, the
role of sodium-ion channel blockade in the neuroprotective effect of (_)-kavain
against anoxia in vitro has been described,(41) and (_)-kavain (50, 100 or 200
mg/kg intraperitoneally) has been shown to protect nigrostriatal dopaminergic
neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity
in mice, an experimental model of Parkinson's disease.(42) A neuroprotective
effect against ischaemic brain damage in mice and rats has been demonstrated for
kava extract (WS-1490 containing 70% kavalactones) and the individual
kavalactones methysticin and dihydromethysticin, but not for kavain,
dihydrokavain and yangonin. Kava extract 150 mg/ kg given orally as an emulsion
(polyethyleneglycol 400 and water; 20 : 80) one hour before experimentally
induced ischaemia, and methysticin and dihydromethysticin (both 10 and 30 mg/kg
intraperitoneally 15 minutes before induction of ischaemia), compared with
control, significantly reduced the size of the infarct area in mice brains (p
< 0.05).(43) In rats, kava extract administered according to the same
regimen as used in mice significantly reduced infarct volume compared with
control (p <0.05).
Analgesic Activity
Antinociceptive activity in vivo (mice) in the tail immersion
test has been documented for kava resin (150 mg/kg intraperitoneally) and for
the individual kavalactones dihydrokawain, dihydromethysticin, kavain and
methysticin at doses of 150, 275, 300 and 360 mg/kg (intraperitoneally),
respectively, compared with controls.(44) Yangonin, tetrahydroyangonin,
desmethoxyyangonin and dehydroyangonin had no or only a weak effect. Both kava
resin (200 mg/kg, orally) and aqueous kava extract (250 mg/ kg, intraperioneally)
displayed antinociceptive activity in the acetic acid-induced writhing test,
also in mice. In further tests using both models, naloxone failed to reverse
the antinociceptive effects of kava resin or aqueous kava extract, indicating
that analgesic activity of kava is achieved via non-opiate pathways.(44) Analgesic
activity of dihydrokawain and dihydromethysticin has been reported
previously.(45)
Other Activities
Kava extract has been reported to have a muscle relaxant effect
in isolated frog muscles, thought to be due to a direct effect on muscle
contractility.(46) Reductions in contractions of isolated guinea-pig ileum induced
by carbachol and by raised extracellular potassium ion concentrations have been
documented for the synthetic kavalactone (_)-kavain, although the compound had
no effect on caffeine-induced contractions of ileum strips or on calcium
ion-induced contractions of skinned muscles.(47) (_)- Kavain has also been
reported to relax maximally contracted murine airway smooth muscle and to reduce
carbachol- and potassium chloride-induced airway smooth muscle contraction.(48)
Further investigation indicated that nitric oxide and
cyclooxygenase- mediated events did not play a role in kavain-induced relaxation.
In contrast, a previous study found that (þ)-kavain inhibited human platelet
aggregation in a concentration-dependent manner in vitro.(49) The formation of
prostaglandin E2 and thromboxane B2 was also inhibited in a concentration-dependent
manner, suggesting that (þ)-kavain is an inhibitor of cyclooxygenase.
An ethanol extract of kava and the isolated kavalactones dehydrokavain,
dihydrokavain, kavain, yangonin and methysticin inhibited tumour necrosis
factor alpha (TNFa) release in vitro from BALB/3T3 cells incubated with okadaic
acid and suppressed lipopolysaccharide-induced TNFa production in vivo in
diabetic mice following intraperitoneal administration.(50) Antifungal activity
against several microorganisms, including Candida albicans, has been described
for a 10% aqueous kava extract.(51)
CLINICAL STUDIES
Clinical trials of kava preparations have focused on
investigating anxiolytic effects in various patient groups. Several trials have
assessed effects in healthy volunteers, and others have explored the effects of
kavain, a constituent of kava. A Cochrane systematic review of monopreparations
of kava for the treatment of anxiety included 12 randomised, double-blind, placebo-controlled
trials involving a total of 700 participants.(52) All but one of these trials
tested the effects of a standardised (70% kavalactones) preparation of kava
rhizome (WS-1490) at various dosages but typically equivalent to 60–240 mg
kavalactones daily for four weeks. Only two trials were conducted for longer
than four weeks; both used a dose equivalent to 210 mg kavalactones daily given
for eight weeks in one study(53) and 24 weeks in the other.(54)
Seven of the 12 trials, involving a total of 380 participants,
used the total score on the Hamilton Anxiety Scale as their primary outcome
measure, and provided data suitable for meta-analysis. Meta-analysis showed a
reduction in anxiety scale scores in kava recipients, compared with placebo
recipients (weighted mean difference: 3.9; 95% confidence interval (CI), 0.1–7.7;
p = 0.05). All except one of these trials included participants with
nonpsychotic anxiety; one study involved women with anxiety associated with the
climacteric (perimenopausal period). Removing this trial and the trial that did
not assess the kava extract WS-1490 from the meta-analysis indicated a statistically
significant reduction in anxiety scores for kava recipients compared with placebo
recipients (weighted mean difference: 3.4; 95% CI, 0.5– 6.4; p = 0.02).(52)
The five studies not included in the meta-analysis reported statistically
significant improvements for kava recipients, compared with placebo recipients,
on outcomes (e.g. response rates, reduction in scores on various anxiety
scales).(52) These five studies were heterogeneous in that they involved
different patient groups, such as women with anxiety associated with the perimenopausal
period, individuals with preoperative anxiety, and outpatients with neurotic
anxiety. Consequently, dosage regimens of kava varied widely (e.g. equivalent
to kavalactones 60 mg in the evening and 1 hour preoperatively, to 140 mg kavalactones
daily for four weeks). The conclusions of the review were that kava extract is
an effective symptomatic treatment for anxiety, but that limitations of the
studies included meant that further rigorous trials were needed.(52) A similar
meta-analysis, which included six rando-mised, double-blind, placebo-controlled
trials assessing the effects of the kava extract WS-1490 in patients with
non-psychotic anxiety disorders reached a similar conclusion.(55)
Some other research has been published, but has added little to the
evidence base because of methodological issues. In a randomised, double-blind,
placebo-controlled, multicentre trial, 61 patients with sleep disturbances
associated with anxiety, tension and restlessness states of non-psychotic origin
received a kava extract (WS-1490) 200 mg daily, or placebo, for four weeks.(56)
At the end of the study, statistically significant improvements in the two primary
outcome measures quality of sleep and recuperative effect after sleep were
observed for kava recipients, compared with the placebo group (p = 0.007 and
0.018, respectively; intention-to-treat analysis).
In a randomised, double-blind, placebo-controlled trial
conducted entirely over the Internet, 391 adults who scored at least 40 points
on the State-Trait Anxiety Inventory (STAI) State scale and who reported having
sleeping problems on at least two occasions received capsules containing kava
extract (each containing total kavalactones 100 mg) one three times daily, two
capsules containing valerian extract (each containing valerenic acids 3.2 mg;
no further details of preparation provided) one hour before bedtime, or
placebo, for 28 days.(57) At the end of the study, there were no
statistically significant differences between kava and placebo
with respect to the primary outcome measures changes from baseline in STAI-state
anxiety scores and Insomnia Severity Index scores.
For example, a study involving 68 perimenopausal women reported
that kava extract 100 mg (containing 55% kavain) or 200 mg daily improved
anxiety compared with no treatment, but participants were not masked as to
their treatment allocation.(58) Results from some clinical studies have
suggested that kava extracts may be as effective as certain standard anxiolytic
agents, although this requires further investigation and confirmation. In a six-week,
randomised, double-blind trial involving 172 patients with non-psychotic
anxiety, the standardised kava extract WS- 1490 (containing 70% kavalactones)
100 mg three times daily was as effective as oxazepam 5mg and bromazepam 3 mg,
each taken three times daily.(59) Another randomised, double-blind, multicentre
trial, involving 129 outpatients with generalised anxiety disorder, reported
that the kava extract LI-150 400 mg (standardised to 30% kavapyrones = 120 mg)
each morning for eight weeks was as effective as buspirone 5mg twice daily and opipramol
(a tricyclic antidepressant) 50 mg twice daily.(60)
A randomised, placebo-controlled study involving 40 postmenopausal
women with anxiety assessed the effects of a kava extract 100 mg daily
(containing 55% kavain) given in addition to hormone replacement therapy (oestrogens
plus progestogens or oestrogens alone).(61) It was reported that women who received
kava showed greater reductions in anxiety scores than women who received
placebo. However, the study had various methodological limitations.
In a randomised, controlled study involving 54 healthy volunteers,
kava extract (LI-150, equivalent to 120 mg kavalactones; n = 18) and valerian
extract 600 mg (LI-156; n = 18), taken daily for one week, significantly reduced
systolic blood pressure following mental stress tests, compared with baseline
values, whereas no such reduction was observed in the no-treatment control
group (p < 0.001 for both kava and valerian).(62) No effect on diastolic
blood pressure was recorded for either herbal preparation, and valerian, but
not kava, appeared to reduce heart rate following mental stress tests. These
findings require confirmation in placebo-controlled studies, and their
relevance to everyday stress needs to be investigated.(62)
Several other randomised, double-blind, controlled trials involving
patients with anxiety have compared the effects of the synthetic kavalactone, (_)-kavain,
administered at a dose of 200 mg three times daily for 3–4 weeks, with those of
placebo,(63) or benzodiazepines, such as oxazepam.(64) One trial assessed the effects
of kavain, or placebo, 200 mg three times daily for three weeks in 83
outpatients who had been treated with benzodiazepines for at least six weeks
and who were undergoing benzodiazepine withdrawal.(65) Generally, these studies
have reported beneficial effects for kavain, but typically have involved only
small numbers of patients.
A preliminary study involving healthy individuals assessed the effects
of a single 300 mg dose of a kava extract on cognitive performance and mood in
a randomised, double-blind, placebocontrolled trial.(66) Some improvements in
mood (in trait cheerful participants only) and cognitive performance were
observed during the study, although further assessment of the effects of kava on
these parameters is required. A case series described improvements after
administration of a kava extract (WS-1490) in extrapyramidal side-effects
experienced by 42 patients with various psychiatric diagnoses who were receiving
neuroleptic drugs.(67) The hypothesis that kava extract can reduce
extrapyramidal side-effects requires testing in rigorous randomised controlled
trials.
Pharmacokinetics Little is known about the clinical
pharmacokinetics of kava preparations. Several metabolites of kavalactones have
been detected and identified in human urine following ingestion of around 1 L
of kava (prepared by the traditional method of aqueous extraction of kava
rhizome) over 1 hour by healthy male volunteers before sleeping.(68) Urine
samples were collected before sleeping and on rising in the morning. Kawain, dihydrokawain,
desmethoxyyangonin, tetrahydroyangonin, dihydromethysticin, 11-methoxytetrahydroyangonin,
yangonin, methysticin and dehydromethysticin were detected unchanged in human
urine; metabolic transformations observed included reduction of the 3,4-double
bond and/or demethylation of the 4 methoxyl group of the kavalactone ring. The
C12 hydroxy analogue of yangonin (12-hydroxy-12-desmethoxyyangonin) was also
detected, and it may have been formed by demethylation of yangonin and/or C12 hydroxylation
of desmethoxyyangonin. Dihydroxylated metabolites of the kavalactones and
products from ring opening of the kavalactone ring were not detected.(68)
MAIN ACTION
Central
Nervous System (CNS) Effects
The kava lactones reach a
large number of targets that influence CNS activity and act centrally and
peripherally. They interact with dopaminergic, serotonergic, GABA-ergic and glutamatergic
neurotransmission, seem to inhibit monoamine oxidase B and exert multiple effects
on ion channels, according to in vitro and in vivo research (Grunze
et al 2001). Additionally, animal studies show that kava lactones are
chiefly responsible for these effects that give rise to many of the herb’s
clinical actions (Cairney et al 2002).
Hypnotic
Although the exact mechanism
of action is not yet understood, it has been observed that sleep promotion may
be due to the preferential activity of D,L-kavain and kava kava extract on the
limbic structures and, in particular, the amygdalar complex (Holm
et al 1991) in the brain. In an electroencephalogram (EEG) brainmapping study
it was demonstrated that D,Lkavain could induce a dose-dependent increase in delta-,
theta- and alpha-1 power, as well as a decrease in alpha-2 and beta power. These
results indicate a sedative effect at the higher dose range (Frey
1991).
Anxiolytic Effects
A recent study showed that
kava kava extract produces a statistically significant dose-dependent anxiolytic-like
behavioural change in rat models of anxiety (Garrett et al 2003).
The effect is not mediated through the benzodiazepine binding site on the
GABA-A receptor complex, as flumazenil, a competitive benzodiazepine receptor
antagonist, did not block this effect. Meta-analyses confirm that the
anxiolytic effect is clinically significant and comparable to benzodiazepines.
Analgesic
And Local Anaesthetic
Both the aqueous and
lipid-soluble extracts of kava kava exhibit antinociceptive properties in
experimental animal models (Jamieson & Duffield
1990). The effect is not mediated by an opiate pathway, as naloxone
does not reduce the effects when administered in doses that reverse the effects
of morphine. More recently, in vitro research has identified several compounds
found in kava kava that have the ability to inhibit COX-1 and to a lesser
extent COX-2 enzyme activities (Wu et al 2002). The
local anaesthetic effect of kava kava is well known for topical use and has
been described as similar to procaine and cocaine (Mills
& Bone 2000).
Antispasmodic
Activity
Antispasmodic activity for
skeletal muscle has been observed in vitro and in vivo for both kava kava extract
and kava lactones (Mills & Bone 2000). In vivo research suggests
that kavain impairs vascular smooth muscle contraction, likely through
inhibition of calcium channels (Martin et al 2002).
OTHER ACTIONS
Cytochrome
Inhibition
In
vitro studies published in 2002 suggested that whole kava kava extract and kava
lactones have widespread inhibitory effects on various cytochrome enzymes, such
as CYP3A4 (Unger et al 2002), whereas in vivo tests found no
effects on CYP3A4/5, CYP1A2 or CYP2D6, but did demonstrate significant
inhibition (approximately 40%) of CYP2E1 (Gurley et al 2005).
Clinical tests confirm no significant effect on CYP2D6 (Gurley
et al 2008).
Animal
studies found that kava kava extract decreased the expression of CYP2D1 (human CYP2D6
homolog) at a dose of 2.0 g/kg in females and increased the expression of
CYP1A2, 2B1 and 3A1 in 1.0 and 2.0 g/kg groups of both sexes (Clayton et
al 2007). The clinical relevance of these findings is unclear, as the
doses used were extremely large and not clinically relevant. Kava
acts as a sedative, an analgesic, and an anxiolytic. It has been used for
ceremonial purposes in Micronesia and Polynesia for thousands of years in the
place of alcoholic beverages, which have not always been available.
Sedative Action
The sedative action of kava is unlike any other. It appears
to act directly on the limbic system. Kava lactones may actually modify
receptor areas rather than bind to receptor binding sites (Holm et al, 1991).
Anxiolytic
Action
There appears to be no lack of effectiveness, even at
large doses over time. Several studies confi rm the ability of kava to decrease
anxiety. One study used 84 volunteers with anxiety conditions who received
kavain, a kava lactone, in doses of 400 mg/day. In the experimental group, the
result was an increase in memory and reaction time (Scholing et al, 1977). A
more recent study showed a signifi cant reduction of anxiety symptoms with the
use of kava (Pittler et al, 2000). One group of volunteers was given 100 mg of
kava extract three times daily, while the other received a placebo. After 4
weeks, when the subjects were evaluated using the Hamilton Anxiety Scale, the
kava group reported a signifi cant decrease in anxiety symptoms (Kinzler et al,
1991).
Analgesic,
Antiinfl ammatory Action
The analgesic effect of kava appears to be unrelated to
that of other pain relievers. Kava does not bind to opiate receptors and does
not block pain impulses in the central nervous system. Its mechanism of action
is unknown at present. One study (Folmer et al, 2006) identifi ed kava as
possessing TNF-alpha–induced activation of a nuclear factor. This information
leads the researcher to believe that kava could be used for antiinfl ammatory
conditions.
ACTIVITIES
Allergenic
(1; CRC); Analgesic (1; APA; FNF; WAM); Anaphrodisiac (f; MAD); Anesthetic (1;
BGB; CRC; MAB; MAD; PH2); Antiaggregant (1; MAB); Antibacterial (1; MAB; MAD);
Anticonvulsant (1; FNF; KOM; PH2; SHT); Antidepressant (1; APA); Antidopamine (1;
MAB); Antiepileptic (1; BGB); Antifatigue (f; PNC); Antiischemic (1; MAB);
Antipyretic (1; MAB); Antirheumatic (1; FNF); Antiseptic (1; FNF; MAD); Antispasmodic
(1; APA; BGB; CRC; PH2; WAM); Antithrombic (1; PH2); Anxiolytic (1; KOM; MAB;
PHR; PH2; WAM); Aperitif (1; MAD); Aphrodisiac (f; APA; CRC); Climacteric (f;
BGB); CNS-Depressant (1; APA); Contraceptive (f; MAB); Cyclooxygenase Inhibitor
(1; PH2); Diaphoretic (f; CRC; MAD); Diuretic (1; APA; MAB; MAD; PNC);
Dopaminergic (1; PH2); Expectorant (f; CRC); Fungicide (1; CRC; MAB); Hypnotic
(1; MAB; PH2); Hyporeflexic (1; BGB); Lactagogue (f; CRC); Memorigenic (1;
MAB); Myorelaxant (1; APA; FNF; KOM; PH2; SKY); Narcotic (1; CRC);
Neuroprotective (1; HH2); Psychotropic (f; PH2); Sedative (2; FNF; KOM; PH2;
WAM); Serotoninergic (1; PH2); Sobering (1; MAB); Stimulant (f; CRC; PNC);
Tonic (f; CRC; MAD; PNC); Tranquilizer (1; APA).
INDICATIONS
Anorexia
(1; MAB; MAD); Anxiety (2; APA; KOM; MAB; PHR; PH2; WAM); Arthrosis (f; MAD);
Asthma (f; BGB; PH2); Backache (f; CRC); Bacteria (1; MAB; MAD); Blennorrhea
(f; MAD); Bronchosis (f; PNC); Catarrh (f; MAB); Chill (f; CRC); Cholecystosis (f;
MAB); Cold (f; CRC; MAB); Colic (f; MAB); Congestion (f; MAD); Convulsion (1;
FNF; KOM; PH2; SHT); Cough (f; CRC; MAB); Cramp (1; APA; BGB; CRC; MAB; PH2; WAM);
Cystosis (f; MAD; PH2); Debility (f; CRC; MAB); Depression (1; APA; BGB);
Dermatosis (f; CRC; MAB; MAD); Despondency (f; MAB); Dizziness (1; APA; MAB;
MAD); Dysmenorrhea (1; FNF; SHT; WAM); Dyspepsia (1; APA; PH2); Dysuria (1;
WAM); Earache (1; MAB; MAD); Eczema (f; MAD); Elephantiasis (f; CRC);
Encephalosis (f; MAD); Enterosis (1; WAM); Enuresis (f; MAB); Epilepsy (1; BGB;
MAB); Fatigue (1; MAB); Fever (1; CRC; MAD; MAB); Filariasis (f; MAB); Fungus
(1; CRC; MAB); Gastrosis (f; PH2); Gonorrhea (f; CRC, MAB; MAD; PH2); Gout (f;
APA; PNC); Headache (1; APA; CRC; FNF; MAD); Heart (f; CRC); Hemorrhoid (f;
MAB); Herpes (f; MAD); Hot Flash (f; BGB); Hyperactivity (1; APA; WAM); Ichthyosis
(f; MAD); Incontinence (f; MAB); Infection (1; CRC; MAB); Insomnia (2; APA; FNF;
KOM; MAB; PHR; PH2; WAM); Leprosy (f; MAB); Leukorrhea (f; CRC; MAB); Menopause
(1; APA; BGB; MAB); Menstrual Cramp (1; FNF); Migraine (1; APA); Myalgia (1;
MAB); Mycosis (1; CRC; MAB); Nephrosis (f; CRC; MAB); Nervousness (2; APA; FNF;
KOM; PHR; PH2; WAM); Neuralgia (f; MAB); Neurasthenia (f; CRC; MAD); Obesity (f;
PH2); OCD (1; WAF); Ophthalmia (f; MAB); Pain (1; APA; BGB; CRC; FNF; MAB; MAD;
PH2; WAM); Palpitation (1; APA); Prolapse (f; MAB); Prostatosis (f; MAD);
Psoriasis (f; MAD); Pulmonosis (f; CRC); Restlessness (2; APA; KOM); Rheumatism
(1; CRC; FNF; PH2; PNC); Sore Throat (f; MAB); Stomachache (1; APA); Stress (2;
APA; KOM; PH2; SHT); Syphilis (f; PH2); Thrombosis (1; PH2); Toothache (1; MAB;
MAD); Tuberculosis (f; CRC); Urethrosis (f; CRC; MAD; PH2); UTI (f; BGB; MAB);
Vaginosis (f; CRC; MAB); VD (f; APA; CRC; MAD; PH2); Vertigo (f; MAB); Water
Retention (1; APA; MAB; MAD; PNC); Wet Dream (f; CRC).
INDICATIONS AND USAGE
• Nervousness and insomnia
Kava Kava is used for nervous
tension, stress and agitation.
Unproven Uses: In folk medicine,
the herb is used as a sleeping agent and sedative; for asthma, rheumatism,
dyspeptic symptoms, chronic cystitis, syphilis, gonorrhea and weight reduction.
Homeopathic Uses: Kava Kava is
used for states of excitement and exhaustion. It is also used for gastritis and
pain in the urethra.
INDICATIONS
Nervous tension, states of tension and anxiety.
PRODUCT AVAILABILITY
Capsules, beverage, extract,
tablets, tincture
PLANT PARTS USED: Dried rhizome, dried roots (sometimes referred to
incorrectly as the root)
DOSAGES
DOSAGES
Anxiolytic
·
Adult PO extract, standardized: 45-70 mg kava lactones tid (Murray,
Pizzorno, 1998)
Depression
·
Adult PO extract, standardized: 45-70 mg kava lactones tid (Murray,
Pizzorno, 1998)
General Use
·
Adult PO extract, standardized: 70 mg kava lactones tid (Foster, 1998)
·
Adult PO capsules/tablets:
400-500 mg up to 6 times/day (Foster, 1998)
·
Adult PO tincture: 15-30 drops (dilution 1:2 ) taken tid in water (Foster,
1998)
Sedative
·
Adult PO extract, standardized: 190-200 mg kava lactones 60 min at bedtime
DOSAGES
Dosages
for oral administration (adults) for treatment of anxiety recommended in older
and contemporary standard herbal reference texts are given below.
·
Dried Rhizome 1.5–3 g per day.(G50) Equivalent to 60–120 mg
kavalactones per day.(G3)
·
Liquid Extract 3–6mL per day (1 : 2 liquid extract,
unspecified solvent).(G50)
Standardised Preparations
·
100–200 mg kavalactones per day.(G50)
·
60 mg kavalactones 2–4 times per day in tablet form.(G50)
·
60–120 mg kavalactones per day.(G3)
Kava exists in numerous varieties of differing potency (7) and only
preparations with standardised kavalactone content should be used for medicinal
purposes. Medicinal extracts prepared with ethanol–water yield dry extracts
with about 30% kavalactones content, whereas acetone–water prepared dry
extracts contain about 70% kavalactones.(G56)
Dosages
(adults) used in clinical trials have varied widely, but typically
are those equivalent to 60–240 mg kavalactones daily by oral
administration in divided doses (see Pharmacological Actions, Clinical
studies). Duration of use of kava extracts generally should not exceed three
months.(G3, G4, G56)
DOSAGES
·
1 tsp cup/night (JAD); 1.5–3 g
dry root/day (MAB); 100–300 mg root several x/day (MAD); 2–4 g powdered root 1–3 x /day (AHP; PNC); 2–4 ml liquid root extract (PNC);
·
3–6 ml fluid extract (1:2)/day
(MAB); 1–3 ml tincture/day (SKY); 60–600 mg kavalactones/day (AHP);
·
ca 250 ml kavalactones/day
(24–70 mg 3 x /day) (APA); 180–210
kavalactones 1 hour before bedtime (APA);
·
1 (525 mg) capsule (StX with
250 mg certified potency kava-kava root extract with at least 75 mg
kavalactone) 3 x /day (NH).
DOSAGES RANGE
·
Cut Rhizome: 1.7–3.4 g/day.
·
Dried Rhizome: 1.5–3 g/day in divided doses
or equivalent to 60–120 mg kavapyrones daily.
·
Fluid Extract (1:2): 3–8.5 mL/day in divided
doses.
Ideally,
ethanolic extracts should contain > 20 mg/ mL kava lactones.
According to
clinical studies
·
Anxiety: generally
doses up to 300 mg daily of kava kava extract WS 1490 providing 105–210 mg
kavalactones. A kava kava extract LI 150 (400 mg/day) was used successfully in
generalised anxiety disorder.
·
Insomnia — a single dose
of 300 mg kava kava extract.
·
Benzodiazepine with drawal —
300 mg/day of kava kava extract.
DOSAGES
AND DURATION OF USE
Daily
dose: 60–120 mg of herb
preparations.
DOSAGES
Mode of Administration:
Comminuted
rhizome and other galenic preparations for oral use.
How Supplied:
Capsules — 100 mg, 125 mg, 128 mg, 150 mg, 250
mg, 390 mg, 400 mg, 425 mg, 455 mg, 500 mg
Liquid — 1:1, 1:2
Preparation: There are a
number of different extraction recipes depending on the pharmaceutical
companies.
Daily Dosage:
Capsules — The root extract is taken 150 mg to
300 mg twice daily, with a daily dosage of kava pyrones 50 to 240 mg (Herberg,
1996; Lehmann, 1996).
Tincture — The tincture is taken as 30 drops
with water three times daily (Chavallier, 1996).
Infusion — Take 1/2 cup twice daily (Chavallier.
1996).
Note: The drug should
be administered with food or liquid due to its lipid solubility (Fachinfo
Antares 120 (R). 1996). The activity of the herb is enhanced when mixtures of
the kava pyrones are taken instead of a single pyrone (Jamieson,1989).
Homeopathic Dosage:
The
herb is taken as 5 to 10 drops, 1 tablet or 5 to 10 globules 1 to 3 times daily,
or 1 ml injection solution sc twice weekly (HAB1).
Storage: The herb should
be stored away from direct light, moisture and heat at room temperature.
PRECAUTIONS AND ADVERSE REACTIONS
GENERAL: No health hazards
are known in conjunction with the proper administration of designated
therapeutic dosages. Administration of the herb leads to rare cases of allergic
reactions and gastrointestinal complaints. Slight morning tiredness can appear
at the beginning of the therapy. Motor reflexes and judgment when driving may
be reduced while taking the herb.
CENTRAL NERVOUS SYSTEM: Dyskinesia and
choreoathetosis of the limbs, trunk, neck and facial musculature have been reported
secondary to the administration of kava (Schelosky, 1995; Spillane, 1997).
ENDOCRINE: Following long-term
use of high doses of Kava extract, weight loss was reported (Mathews, 1988).
HEPATOTOXICITY: Increase in
gamma-glutamyl transferase (GGT) levels have been associated with high doses of
Kava extract (Mathews, 1988). Two cases of acute hepatitis with an increase of
liver enzymes were reported. Necrotizing hepatitis was determined after a liver
biopsy, and upon discontinuation of Kava, liver tests normalized (Stahl, 1998).
MUSCULOSKELETAL: Minor inhibition
of movement and impaired motor reflexes have been observed with the use of Kava
(Jamieson, 1990).
OCULAR: Increase in
pupil diameter, reduction of the near point of accommodation and near point of
convergence, and disturbance to the oculomotor balance have been reported with
Kava (Garner, 1985). Eye irritation has been reported with the heavy
consumption of Kava (Ruze, 1990).
SKIN: Heavy chronic
consumption of Kava is associated with a peculiar, scaly rash suggestive of
ichthyosis (Ruze, 1990). A reversible, slight yellowing of the skin has been
associated with long-term use of Kava. Sebotropic drug reactions resulting from
Kava-Kava extract therapy has been reported (Jappe, 1998). The drug should not
be taken for longer than three months without a doctor's supervision.
DRUG INTERACTIONS:
ALCOHOL — Concomitant use of Kava Kava with
alcohol results in an increase in each other's hypnotic action. The alcohol
also increases the possibility for kava toxicity (Jamieson, 1990).
ALPRAZOLAM —- Kava used simutaneously with
alprazolam has resulted in coma (Almeida, 1996).
CNS Depressants,
such as Barbituates — The herb may potentiate
the effectiveness of substances that act on the central nervous system.
PSYCHOACTIVE AGENTS
— The intensity of psychoactive agents may be intensified with kava (Jamieson,
1990).
DOPAMINE — Kava Kava has been reported to
antagonize the effect of dopamine. Patients with Parkinson's Disease taking levodopa
should avoid the use of the herb (Baum, 1998; Cupp, 1999; Schelosky, 1995).
PREGNANCY: the drug is
contraindicated during pregnancy.
NURSING MOTHERS: The drug is
contraindicated in nursing mothers.
ADVERSE
EFFECTS: The prolonged use
of high doses of kava can, in rare cases, lead to gastrointestinal complaints,
oculomotor equilibrium disorders, pupil dilation, and insufficiency of
accommodation. Slight morning fatigue can occur in the initial phase of
treatment. Disorders of complex movement with otherwise unimpaired
consciousness are initial signs of overdose, followed by fatigue and a tendency
to fall asleep. Kava increases the action of substances that affect the central
nervous system, e. g., alcohol, barbiturates, and other psychoactive drugs. A
few studies yielded some indication of hepatotoxicity in relation to administration
of kava. Though this information is limited to date and still awaits scientific
evaluation, it is recommended to consider the following when using kava
products.
WARNING: Kava should not be taken on a daily basis
for more than 4 weeks.
WARNING: Use of kava should be discontinued if
symptoms of jaundice appear.
WARNING: Patients with a history of liver problems
or who suspect possible liver problems or who are taking pharmaceutical drugs
should use kava only with the advice of a professional health care provider.
WARNING: See p. 212 for cautions in the use of kava
in disorders of the nervous system.
HERB–DRUG
INTERACTIONS: Kava should not be
used by anyone who has liver problems, is taking any drugs with known adverse
effects on the liver, such as NSAIDS, or is a regular consumer of alcohol.
ADVERSE REACTIONS
In RCT, the incidence of
adverse effects to kava kava has been found to be similar to placebo. Two postmarketing
surveillance studies involving more than 6000 patients found adverse effects in
2.3% and 1.5% of patients taking 120–240 mg standardised extract (Ernst
2002). The most common side effects appear to be gastrointestinal
upset and headaches when used in recommended doses.
Hepatotoxicity
A systematic review
assessing the safety of kava kava which included a total of 7078 patients
taking kava kava extract equivalent to 10 mg to 240 mg kava lactones per day
for 5–7 weeks identified no cases of hepatotoxicity (Stevinson
et al 2002). Considering that case reports of hepatotoxicity exist, they should
be considered a very rare event based on the evidence. In 2008, a quantitative
causality assessment of 26 critical cases came to a similar conclusion stating kava
kava taken as recommended is associated with rare hepatotoxicity, whereas
overdose, prolonged treatment, and co-medication may carry an increased risk (Teschke
et al 2008). Importantly, a recent World Health Organization report
identified that liver toxicity risk is associated with kava kava acetonic and ethanolic
extracts, whereas the traditional kava kava preparation which has been prepared
for centuries in water does not have the same risk of liver injury. To put the
risk into perspective, estimates from case reports and the sales figures of
kava kava extracts (using data from Germany) show an incidence rate of one potential
case in 60–125 million patients for liver toxicity (Sorrentino
et al 2006).
Possible
Mechanisms for Kava-Kava-Induced Hepatotoxicity
The exact cause remains
elusive; however, several mechanisms have been proposed. Genetic polymorphism of
cytochrome enzymes, leading to interindividual variation in drug metabolism,
may be one important factor in the marked discrepancy in hepatotoxic response
to kava kava (Singh 2005). Other possible mechanisms are inhibition of cytochrome P450 by
kava kava, reduction in liver glutathione content and, more remotely,
inhibition of cyclooxygenase enzyme activity. The direct toxicity of kava kava
extracts is quite small under any analysis; yet, the potential for drug
interactions and/or the potentiation of the toxicity of other compounds is
larger (Clouatre 2004). Recent animal tests with three
different kava kava extracts (a methanolic and an acetonic root and a methanolic
leaf extract) indicate that the these kava kava extracts are toxic to mitochondria,
leading to inhibition of the respiratory chain, increased reactive oxygen
species (ROS) production, a decrease in the mitochondrial membrane potential and
eventually to apoptosis of exposed cells. In predisposed patients,
mitochondrial toxicity of kava kava extract may provide another explanation for
hepatotoxic reactions (Lude et al 2008). It has also been suggested that
reactions are immunologically mediated (Schulze et al 2003). Considering that
the toxic reactions are limited to methanolic and ethanolic extracts, it is possible
that chemicals other than kava lactones, such as alkaloids not bioavailable in water
extracts, may be responsible for hepatotoxicity.
Long-Term
Use
Heavy kava kava drinkers acquire
a reversible ichthyosiform eruption, known as kanikani in Fijian or ‘kava dermopathy’
in English-speaking countries. This condition is characterised by yellow
discolouration of the skin, hair and nails. This temporary condition reverses once
kava kava use is discontinued. A 2003 report found no evidence of brain
dysfunction in heavy and long-term kava kava users (Cairney
et al 2003).
SIGNIFICANT INTERACTIONS
Alcohol
Potentiation of CNS sedative
effects has been reported in an animal study; however, one doubleblind, placebo
controlled study found no additive effects on CNS depression or safety related
performance (Herberg 1993). Alternatively, a study of 10 subjects
found that when alcohol and kava kava were combined, kava kava potentiated both
the perceived and measured impairment compared to alcohol alone (Foo
& Lemon 1997). Caution is advised when taking this combination together.
Barbiturates
Additive effects are
theoretically possible. Use with caution and monitor drug dosage. However, interaction
may be beneficial under professional supervision.
Benzodiazepines
Additive effects are theoretically
possible. Use with caution and monitor drug dosage. However, interaction may be
beneficial under professional supervision. The combination has been used
successfully to ease symptoms of benzodiazepine withdrawal. Antagonistic
effects are theoretically possible, thereby reducing the effectiveness of l-dopa.
Avoid concurrent use unless under professional supervision until safety is
confirmed.
Methadone and
morphine
Additive effects with increased CNS depression are theoretically possible, so use
with caution, although interactions may be beneficial under professional
supervision.
Substrates for
CYP2E1
Inhibition of CYP2E1 has been
demonstrated in vivo — serum levels of CYP2E1 substrates may become elevated — use
caution.
OVERDOSAGE
Overdosage can result in disorders
of complex movement, accompanied by undisturbed consciousness, later tiredness and
tendency to sleep.
CONTRAINDICATIONS, INTERACTIONS, AND SIDE
EFFECTS
CLASS 2B,
2C, 2D. Contraindicated for
endogenous depression (AHP). Maximum tolerated doses for dogs was 60 mg/kg, for
rats 320 mg/kg StX (70% kavapyrones). Perversely, if the authors didn’t
misspeak, the dogs tolerated 24 mg/kg/day. Of >4000 patients taking 105
mg/day StX (70% kavapyrones), 1.5% had objectionable side effects (allergy,
dizziness, GI distress, and headache). At levels 100 times the therapeutic dose
(roughly 13 liters kava beverage a day or 300–400 mg rhizome per week) caused
anorexia, ataxia, dyspnea, hair loss, red eyes, skin rash, visual problems, and
yellow skin. “There is no potential for physical or psychological dependency.
Use should not exceed 3 months.” (AHP) Germans limit use to 1–3 months (AHP).
Commission E reports contraindications: esophageal and gastrointestinal
stenoses; adverse effects: allergic reactions (rarely). Other sources report
intestinal obstruction (AEH). Many reports suggest a yellowing of the skin in
chronic users. “Chronic ingestion may lead to ‘kawism’ characterized by dry,
flaking, discolored skin, and reddened eyes” (LRNP, May 1987). Persistent rumors
suggest that overdoses can cause intoxication. Commission E warns against the
concomitant use of kava with barbituates, antidepressant medications, and CNS
agents. Lactating or pregnant women should not use kava (WAM). “Not permitted
as a non-medicinal ingredient in oral use products in Canada” (Michols, 1995).
Abuse by Australian Aborigines suggest links to hematuria, infectious disease,
neurological abnormalities, pulmonary hypotension, nephrosis, visual disturbances,
ischemic heart disease, thrombosis, and sudden heart attacks (MAB). The
following quote might scare abusers, as it should, “Full consciousness is
maintained with even fatal doses” (APA, quoting Weiss, 1988).
CONTRA-INDICATIONS, WARNINGS
It has been stated that kava is contra-indicated in endogenous depression.(G3,
G4) Even when administered in accordance with recommended dosage regimens, kava
may adversely affect motor reflexes, and may affect ability to drive and/or
operate machinery.( G3,G4) It has been reported that there is no evidence that
use of kava extracts has the potential for physical or psychological dependency
to develop.(G56) However, as most clinical studies of kava extracts have been
of short duration, typically around four weeks (maximum 24 weeks) and/or usually
have involved only small numbers of participants, further study is required
before definitive statements are made on the potential for dependency with
kava.
Drug interactions There is an isolated report of a 54-year-old man
who was taking alprazolam, cimetidine and terazosin and who became lethargic
and disoriented three days after he began taking kava purchased from a health-food
store (no further details of the kava preparation were provided).(106) The man
was hospitalised and his symptoms resolved after several hours. He tested
negatively for alcohol, and positively for benzodiazepines; the man stated he
had not taken overdoses of either alprazolam or kava. The clinical importance
and role of kava in this reaction is not known, although there is a view that
concurrent use of kava and substances
with central nervous system effects could lead to enhanced activity.(G3, G4)
The effects on performance of a kava extract given in combination
with bromazepam have been explored in a randomised, double-blind, controlled
crossover trial involving 18 healthy volunteers. Participants received a kava
extract (Antares) equivalent to 120 mg kavalactones twice daily, or bromazepam 4.5
mg twice daily, or both agents, for 14 days.(107) Significant reductions in
indicators of performance, such as motor coordination, were reported for
recipients of both kava and bromazepam, compared with recipients of kava alone,
but there was no difference between kava plus bromazepam compared with bromazepam
alone. Isolated case reports of extrapyramidal symptoms associated with use of
kava extracts have led to the suggestion that constituents of kava may have
dopamine antagonist effects (see Side-effects, Toxicity, Central nervous system
effects).(88) On this basis, the potential for kava to interact with dopamine
agonists or antagonists should be considered.
Inhibition of certain cytochrome P450 (CYP) drug metabolising enzymes
has been shown in vitro and in vivo for kava extracts and individual
kavalactones. In a randomised, open-label, crossover study, 12 healthy
volunteers received kava root extract 1000 mg twice daily (subsequently found
to be equivalent to total kavalactones 138 mg daily) for 28 days; probe drugs
were administered before and after kava administration to assess effects on CYP
enzymes.(108) Administration of the kava extract according to this dosage regimen
inhibited CYP2E1, but not CYP3A4/5, CYP2D6 and CYP1A2. In in vitro studies,
methanolic, acetone and ethyl acetate extracts of kava rhizome significantly
inhibited CYP3A4 activity, compared with control, at concentrations as low as
10 mg/mL (ethyl acetate extract).(109) In other in vitro experiments, several individual
kavalactones were tested for their effects on the activities of CYP1A2, CYP2C9,
CYP2C19 and CYP2D6, as well as CYP3A4. Desmethoxyyangonin, dihydromethysticin
and methysticin produced a concentration-dependent inhibition of one or more of
the CYP isoforms at concentrations of <10 mmol/ L, considered as 'potent'
inhibition (e.g. IC50 values for desmethoxyyangonin, dihydromethysticin and
methysticin for CYP2C19 were 0.51, 0.43 and 0.93 mmol/L, respectively, and for dihydromethysticin
and methysticin for CYP3A4 under certain assay conditions were 2.49 and 1.49
mmol/L, respectively).(110) In several cases, this degree of inhibition was
greater than that shown by positive controls which are known to produce
clinically significant drug interactions. Similar results have been reported for
an ethanolic kava root extract and the individual kavalactones desmethoxyyangonin,
dihydromethysticin and yangonin: in two in vitro models, both the extract and
the individual kavalactones inhibited CYP1A2, CYP2C9, CYP2C19, CYP2E1 and
CYP3A4 with IC50 values of around 10 mmol/L.(104)
Differences in CYP enzyme inhibition have been described for commercial
preparations (acetone, methanol and ethanol extracts) and traditional aqueous
extracts, with commercial preparations having a greater inhibitory effect than
traditional preparations on CYP3A4, CYP1A2, CYP2C9 and CYP2C19.(111) Desmethoxyyangonin
and dihydromethysticin induced the expression of CYP3A23 by approximately
seven-fold in an in vitro system; other experimental results suggested that the
inductive effect of these kavalactones is additively or synergistically
enhanced by the presence of other kavalactones.(112) Other in vitro experiments
have demonstrated that kava root extract and the individual kavalactones
kavain, dihydrokavain, methysticin, dihydromethysticin and desmethoxyyangonin
inhibit the efflux transporter Pglycoprotein.( 113)
The clinical relevance of these findings is not known, although the
potential for kava extracts to interact with concurrently administered drugs
metabolised mainly by the CYP enzymes mentioned above should be considered. There
are conflicting results from in vitro studies regarding the effects of the
kavalactone (þ)-kavain on cyclooxygenase activity.(48, 49) One study reported
that (þ)-kavain inhibited human platelet aggregation in vitro (see In vitro and
animal studies, Other activities], although the clinical relevance of this, if
any is not known. At present, there is insufficient evidence to warn against
the concurrent use of kava preparations and antiplatelet agents. The
kavalactones kavain, methysticin, yangonin and desmethoxyyangonin did not
inhibit alcohol dehydrogenase in vitro when applied to the system at
concentrations of 1, 10 and 100 mmol/L.(114)
ALCOHOL The
effects of concurrent use of kava extract and alcohol have undergone some
investigation. In a randomised, doubleblind, controlled trial, 20 healthy participants
received kava extract (WS-1490; Laitan) 300 mg daily (equivalent to 210 mg kavalactones),
or placebo, for eight days.(115) Alcohol was ingested on days one, four and
eight in quantities sufficient to achieve a blood alcohol concentration of 50
mg%; participants underwent a series of tests designed to assess psychomotor performance
before and after alcohol consumption. The results indicated that there was no
difference in performance between the kava and placebo groups, apart from one
test (concentration) in which the kava group was reported to be superior to the
placebo group.(115)
A small study involving 40 healthy participants found that the
concurrent ingestion of a kava beverage (350mL of aqueous extract of Fijian
kava) and alcohol 0.75 g/kg led to a greater reduction in cognitive performance,
as assessed by a series of tests, compared with that observed with ingestion of
alcohol alone; ingestion of kava alone did not affect cognitive performance.(116)
Studies in mice given ethanol (3.5 and 4 g/kg, intraperitoneally) and kava
resin 200 or 300 mg/kg orally have demonstrated a prolongation of hypnotic
effects.(117)
Pregnancy and lactation There is a lack of information on the use
of kava preparations during pregnancy and breastfeeding. Given the lack of
data, kava should be avoided during these periods.
CONTRAINDICATIONS AND PRECAUTIONS
Endogenous
depression — according to Commission E (Blumenthal et al 2000). Although
clinical studies indicate no adverse effects on vigilance, the herb’s CNS effects
may slow some individuals’ reaction times, thereby affecting ability to drive a
car or operate heavy machinery.
Additionally,
it should not be used by people with preexisting liver disease and long-term
continuous use should be avoided unless under medical supervision. It should be
used with caution in the elderly and in those with Parkinson’s disease.
PREGNANCY USE
Safety
is unknown.
CONTRAINDICATIONS
Pregnancy category is 2;
Breastfeeding category is 3A.
Kava should not be given to children younger than 12
years of age. This herb should not be used by persons with major depressive
disorder or Parkinson’s disease, or by those with hypersensitivity to it.
SIDE
EFFECTS/ADVERSE REACTIONS
Most side effects and adverse reactions occur when high
doses are taken for a long period.
CNS: Increased
refl exes, drowsiness
EENT: Blurred
vision, red eyes
GI: Nausea,
vomiting, anorexia, weight loss, hepatic damage
SIDE
EFFECTS/ADVERSE REACTIONS—CONT’D
GU: Hematuria
HEMA: Decreased platelets, lymphocytes, bilirubin, protein,
and albumin; increased red blood cell volume
INTEG: Hypersensitivity reactions; skin yellowing and scaling
(high doses)
RESP: Shortness of breath, pulmonary hypertension
INTERACTIONS
Drug
Antiparkinsonians
(carbidopa,
levodopa): Antiparkinsonian drugs may
increase symptoms of parkinsonism when used with kava; do not use concurrently.
Antipsychotics (chlorpromazine,
fl uphenazine, loxapine, mesoridazine, molindone, perphenazine, prochlorperazine,
promazine, thioridazine, thiothixene, trifl uoperazine, trifl upromazine): Antipsychotics taken
with kava may result in neuroleptic movement disorders.
Barbiturates (amobarbital,
aprobarbital, butabarbital, phenobarbital, secobarbital): Barbiturates taken with kava may result in increased sedation.
Benzodiazepines:
Increased sedation and coma
(theoretical) may result when kava is used with benzodiazepines, including
alprazolam; do not use concurrently.
CNS depressants:
CNS depressants such as
alcohol, benzodiazepines, and barbiturates may cause increased sedation when
used with kava; avoid concurrent use.
Cytochrome P450
1A2, 2C9, 2C19, 2D6, 3A4 substrates: Kava
signifi cantly decreases these substrates; use cautiously in patients taking
these agents.
Food
Increased absorption of kava occurs when it is taken
with food.
Lab Test
AST, ALT, LDH,
bilirubin: Kava may increase hepatic
function tests.
SIDE-EFFECTS, TOXICITY
In
randomised, placebo-controlled trials involving different patient groups with
anxiety, kava extracts generally have been well tolerated; adverse events reported,
and their frequencies, are similar to those reported for placebo. However,
clinical trials have the statistical power only to detect common, acute adverse
effects.
Spontaneous
reports of suspected adverse drug reactions associated with kava preparations
have raised concerns over hepatotoxic reactions (see Hepatotoxicity). A
systematic review of eight placebo-controlled trials of kava extracts
administered at doses equivalent to 55–240 mg kavalactones daily for two days
to 24 weeks found that adverse events
reported
for both kava and placebo were most commonly gastrointestinal symptoms, tiredness,
restlessness, tremor and headache.(69) Three trials included in the review, one
of which tested kava extract 100 mg daily (equivalent to 55 mg kavalactones) for
24 weeks,(61) reported that adverse events were not observed in either the kava
or placebo groups.
A
similar finding was reported by a more recent Cochrane systematic review of
monopreparations of kava for the treatment of anxiety (see Clinical
studies).(52) This review comprised seven of the eight placebo-controlled
trials from the earlier review(69) (the other trial was excluded from the
Cochrane review because it tested kava extract in addition to hormone
replacement therapy)(61) and five new trials.
Four
of the trials, involving 30% of the total number of participants in the trials
included in the review, reported that adverse events were not observed during
treatment with kava extract.(52) Randomised, double-blind clinical trials comparing
kava extracts with certain benzodiazepines and other anxiolytic agents have
also found kava to be well tolerated. In a six-week trial involving 172
patients with non-psychotic anxiety, gastrointestinal disturbances occurred in
one of 57 participants who received WS-1490 100 mg three times daily
(equivalent to 210 mg kavalactones daily), whereas tiredness, vertigo and
pruritus occurred in seven of the remaining 115 participants who received oxazepam
5mg or bromazepam 3 mg, both taken three times daily.(59) In an eight-week
trial involving 129 outpatients with generalised anxiety disorder, 14 of 43
(33%) participants who received the kava extract LI-150 400 mg (standardised to
30% kavalactones = 120 mg) each morning experienced adverse events, compared with
10 (24%) and 11 (26%) participants who received buspirone 5mg twice daily and
opipramol 50 mg twice daily, respectively.(60) A total of 27 adverse events was
reported in the kava group, compared with 16 and 14 for buspirone and opipramol,
respectively. Adverse events reported for kava included upper respiratory tract
infections, gastrointestinal disorders, weight changes, skin reactions and
tachycardia, all of which were also reported for buspirone and/or opipramol. These
clinical trials and systematic reviews, however, provide only limited evidence
to support the safety of kava extracts since they involved only small numbers
of participants, involved different patient groups, tested different doses of
kava extract (typically equivalent to 60–240 mg kavalactones daily), and most were
of relatively short duration, usually around four weeks.
Further,
most trials investigated preparations of the kava extract WS-1490, and other
standardised extracts of kava and kava preparations supplied by herbal medicine
practitioners have undergone considerably less assessment. Two post-marketing
surveillance studies published in the early to mid-1990s involving patients
treated in one study with WS-1490 150 mg daily (equivalent to 105 mg
kavalactones; n = 4049) and in the other with Antares 120 (equivalent to 120 mg
kavalactones; n = 3029) reported that the frequencies of adverse events were
1.5% and 2.3%, respectively.(69) In both studies, adverse events commonly
reported were mild gastrointestinal disorders and allergic reactions and, in
the latter study, headaches and vertigo, which stopped when kava treatment was
discontinued. A rather higher frequency of adverse events was reported during a
postmarketing surveillance study carried out in Brazil.(70) Among 850 participants
with anxiety who received WS-1490 100 mg three times daily (equivalent to 210
mg kavalactones daily), 16.7% reported adverse events, most commonly
fatigue/tiredness, nausea, confusion and gastrointestinal upset.
The
World Health Organization's Uppsala Monitoring Centre (WHO-UMC; Collaborating
Centre for International Drug Monitoring) receives summary reports of suspected
adverse drug reactions from national pharmacovigilance centres of over 70 countries
worldwide. To the end of the year 2005, the WHOUMC's Vigisearch database contained
a total of 91 reports, describing a total of 189 adverse reactions, for
products reported to contain P. methysticum only as the active ingredient (see Table
1).(71) This number may include some of the case reports described in the
sections below. Reports originated from nine different countries. The total
number of reactions included reports describing a total of 55 reactions
associated with liver and biliary system disorders (see Table 1), including
three cases of hepatic failure and two of hepatic coma. (These data were
obtained from the Vigisearch database held by the WHO Collaborating Centre for
International Drug Monitoring, Uppsala, Sweden. The information is not
homogeneous at least with respect to origin or likelihood that the pharmaceutical
product caused the adverse reaction. Any information included in this report
does not represent the opinion of the World Health Organization.)
Table 1
Summary of spontaneous reports (n = 91) of suspected adverse drug reactions associated with
single-ingredient Piper methysticum preparations held in the Vigisearch database of the World Health
Organization’s Uppsala Monitoring Centre for the period up to end of 2005(71,
a, b)
a Specific
reactions described where n =
3 or more
bCaveat
statement. These data were obtained from the Vigisearch database held by the
WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
The information is not homogeneous at least with respect to origin or
likelihood that the pharmaceutical product caused the adverse reaction. Any
information included in this report does not represent the opinion of the World
Health Organization
Hepatotoxicity
Clinical data None of the clinical trials and post-marketing surveillance
studies described above reported hepatotoxicity as an observed adverse event,
although not all studies carried out liver function tests on participants.
Seven of the 11 trials included in the Cochrane review of the kava extract
WS-1490 for the treatment of anxiety (see Clinical studies) did involve
monitoring participants' liver function (e.g. serum aspartate transaminase and
alanine transaminase concentrations) and
did not report any abnormalities or clinically significant changes in values
obtained.(52)
Over the years 2000 and 2001, a safety concern arose regarding cases
of hepatoxicity reported in association with the use of kava extracts. The
signal first emerged in Switzerland, following a cluster of spontaneous reports
to the medicines' regulatory authority, and was strengthened a year or so later
following further spontaneous reports from Switzerland and Germany. By July
2002, a total of 68 reports of liver toxicity associated with use of kava had
been received by regulatory authorities in Canada, France, the UK and USA, as
well as in Switzerland and Germany,(72) and by the end of January 2005, 79
cases of liver damage associated with use of kava had been identified
worldwide.(73) The severity of the liver damage described in the reports
varied from abnormal liver function test results to irreversible
liver failure and death; at least six patients received liver transplants, one
of whom, as well as at least two other individuals, subsequently died. Cases
reported in the UK included two of raised liver function test values in men
aged 40 and 48 who had taken unspecified kava preparations for three months and
eight years, respectively.(74) Both stopped taking kava and their liver
function test values normalised. Another UK case related to a woman (age not
stated) who had taken kava 150 mg three times daily for two months, in addition
to fluoxetine, and who experienced jaundice and raised liver function test
values and was hospitalised for seven weeks.
In the UK, evidence relating to the hepatotoxicity associated with
kava was reviewed in 2005 in a public consultation and later that year by the
Expert Working Group set up to consider the evidence. The Expert Working
Group's report was published in July 2006 and concluded that there was
insufficient new evidence to support a change in the regulatory position, hence
the inclusion of kava in unlicensed medicines in the UK remains prohibited.(75)
The report also identified several new questions and issues that may be
important with respect to hepatotoxicity of kava, including the possibility that
other alkaloid and/or amide constituents may be present, and their possible
contribution to hepatotoxicity, and the need for a systematic evaluation of all
marketed kava products and their source material, and of the variation in the
phytochemistry of kava cultivars.(75) Earlier reviews of German data relating
to hepatotoxicity associated with kava have produced conflicting opinions on causality.
One review emphasised that there was no dose–response relationship for
kava-associated hepatotoxicity, and that crude estimates of incidence based on
primary care data suggest that any risk of hepatotoxicity is similar to that of
benzodiazepines.(76)
However, this conclusion is questionable since estimates of this
nature can be inaccurate and misleading. By contrast, a review of seven
previously published and 29 unpublished case reports of kava-associated
hepatotoxicity concluded that these data clearly showed the potential for
severe, unpredictable kava-related hepatotoxicity.(77) Cases included nine individuals
who developed fulminant hepatic failure, of whom six underwent successful liver
transplantation (one only after retransplantation), two died after
transplantation due to postoperative infectious complications, and one who was
too old to undergo transplantation also died. All other cases, which comprised
mostly cholestatic or necrotising hepatitis, underwent full recovery after
withdrawal of kava treatment. Among these 36 reports, the relationship between
kava ingestion and hepatotoxicity was considered 'certain' in three cases and
'probable' in 21.(77) Most individuals were concurrently using other medication
and several were regular consumers of alcohol.
A case report from Australia describes a 56-year-old woman who
developed fatigue, nausea and jaundice after taking a preparation named 'Kava
1800 Plus' one tablet three times daily for around 10 weeks.(78) Each tablet
was stated to contain kavalactones 60 mg, Passiflora incarnata 50 mg and Scutellaria
lateriflora 100 mg, although the latter ingredient was not identified in the
product, so the precise composition of the product is unknown. She presented
two weeks after first experiencing these symptoms and was hospitalised. Five
days later, a biopsy revealed non-specific severe acute hepatitis with pan-acinar
necrosis and collapse of hepatic lobules. She underwent liver transplantation
on day 17 after admission, but the procedure was complicated and she died from
progressive blood loss and circulatory failure. Subsequent examinations
confirmed massive hepatic necrosis. Until the year 2003, it was thought that
kava-associated hepatoxicity occurred only with ethanolic and acetonic kava extracts.
However, recent reports described hepatoxic effects associated with consumption
of traditional aqueous extracts of kava root.
Two cases in New Caledonia involved women aged in their fifties
who started consuming kava prepared in the traditional manner as an aqueous
preparation.(79) Both women developed signs and symptoms of hepatotoxicity,
including icterus and raised liver function test values four or five weeks
after starting kava. Neither patient consumed alcohol. Kava consumption was
stopped; both patients recovered and liver function test values normalised over
the following three months.(79) Subsequently, in a cross-sectional study, blood
samples were collected from 27 individuals who were chronic kava drinkers,
recruited from kava bars in New Caledonia. Participants had been consuming kava
regularly for at least five years and had a mean intake equivalent to around 32
g kavalactones weekly or 70 mg/kg daily; 12 participants also consumed
alcohol.(79) Transaminase concentrations were more than 1.5 times the upper
limit of normal in three participants, and 23 participants had increases in concentration
of GGT (which is not necessarily a specific marker of liver injury); alkaline
phosphatase and bilirubin concentrations were within normal ranges for all
subjects. Another crosssectional study, involving indigenous people from an
Arnhem Land community (Northern Territory, Australia), included 98 participants,
of whom 36 had never used kava.(80) Of the 62 kava users, 14 had ingested kava
within the previous 24 hours, and 10 and 15 had used kava within the previous
one or two weeks, or one or two months, respectively. Investigation of liver
function test values indicated that changes appeared to be reversible and
started to normalise after one or two weeks of kava abstinence.(80)
Inhibition of certain cytochrome P450 (CYP) drug metabolising enzymes
has been shown in vitro and in vivo for kava extracts and individual
kavalactones (see Contra-indications, Warnings). The relevance of this for the
hepatotoxic effects described for kava is not known; further work is needed to
determine whether the inhibition of CYP enzymes by kava can lead to raised
plasma concentrations of concurrently ingested drugs with hepatotoxic effects.
Skin Reactions
An
ichthyosiform (scaly, non-inflammatory), usually yellowish or whitish, skin
condition termed kava dermopathy has been documented among kava users in
Polynesia, Micronesia and Melanesia where powdered kava rhizome is prepared as
a drink with cold water or coconut milk.(81) The condition is reversible on stopping
kava. Initially, it was thought that the condition was related to niacin
deficiency, but this hypothesis was rejected following a small randomised,
placebo-controlled trial of nicotinamide 100 mg daily for three weeks which
showed no difference between groups.(82)
Measures
of health among 39 users of kava (prepared as a cold water infusion of powdered
kava rhizome) were compared with those of 34 age-matched non-users of kava in
an Aboriginal community in the Northern Territory in Australia.(83) Most (n = 35)
were 'heavy' or 'very heavy' users of kava (310 g or more per week). It was
reported that kava users were more likely to complain of poor health, and to have
a scaly skin rash. However, the study had several methodological limitations
(e.g. no correction for multiple statistical tests) and potential biases.
Several
cases of allergic skin reactions have been reported in association with kava use.
One case described a man who presented with oedema and severe non-pruritic
erythema involving his upper body, head and neck, the morning after drinking several
cups of 'kava tea'.(84) It was reported that the man had previously had a
similar reaction to kava tea three months earlier whilst overseas and for which
he was hospitalised and treated with intravenous corticosteroids. A case of
systemic contact-type dermatitis following several weeks' use of kava extract
(Antares), chlorprothixene (an antipsychotic agent with properties similar to those
of chlorpromazine) and diazepam has been described.(85)
Two
further cases described a 70-year-old man and a 52-year-old woman who
experienced skin eruptions (erythematous plaques and/or papules) in sebaceous
gland-rich areas after using kava extract (no further details provided) for two
to three weeks.(86) Both patients were reported to display reactions to kava in
diagnostic allergy or skin patch tests. Generalised erythema and papules with
severe itching were described in a 36-year-old woman who had taken kava extract
(Antares) 120 mg daily for three weeks.(87) The rash, but not the itching,
responded to short-term treatment with systemic corticosteroids, and six weeks
later, patch test results for Antares were positive one day after application.
Central Nervous System Effects
Four
cases of involuntary movements and dyskinesia associated with use of kava
extracts have been reported, although causality has not been established; it
has been stated that these symptoms suggest that constituents of kava may have
antagonistic effects on central dopaminergic pathways.(88) In three cases,
involuntary movements involving the neck, head and/or trunk, and involuntary oral
and lingual dyskinesia began within a few minutes to 4 hours after ingestion of
kava extracts (Laitan 100 mg or Kavasporal forte 150 mg) for anxiety. One of
these cases involved a 28-year-old man who had previously experienced three
episodes of acute dystonic reactions following exposure to promethazine and
fluspirilene, although he denied having used these medicines in relation to the
current episode. The fourth case report described a 76-year-old woman being
treated with levodopa 500 mg and benserazide 125 mg for Parkinson's disease and
who experienced an increase in the duration and frequency of her 'off' periods
10 days after starting Kavasporal forte 150 mg twice daily, prescribed by her physician
for tension. (The 'on–off' phenomenon – sudden swings in mobility–immobility –
occurs with long-term use of levodopa.) In all four cases, symptoms resolved on
stopping kava or following treatment with biperiden administered intravenously.
Two
other cases describe neurological symptoms following excessive use of
traditional preparations of kava, i.e. as a beverage. A 27-year-old Aboriginal
Australian man experienced generalised severe choreoathetosis (characterised by
chorea and athetosis, a form of dyskinesia) without impairment of consciousness
on three occasions after drinking large amounts of kava (precise quantity not
specified).(89) Routine investigations were normal, apart from raised liver
function test values (serum alkaline phosphatase 162 IU/L, normal range 35–135 IU/L;
gamma-glutamyltransferase 426 IU/L, normal range <60 IU/L). His symptoms
responded to treatment with diazepam administered intravenously. Disorientation
was reported in a 34-year-old Tongan man, a heavy user of kava (40 bowls daily
for 14 years), who had ingested further excessive amounts of kava over the
previous 12 hours.(90) The man was treated in hospital with Plasmalyte
intravenously and intramuscular thiamine and five hours after admission his symptoms
had resolved. In a controlled study, individuals intoxicated following kava consumption
(205 g powder) experienced ataxia, tremors, sedation, blepharospasm and reduced
accuracy performing a visual search task, when compared with control subjects
who had not ingested kava. These results suggest that kava intoxication results
in specific abnormalities of movement co-ordination and visual attention, but
normal performance of complex cognitive functions.(91)
Effects On Mental Performance
The
effects of kava extracts and the synthetic kavalactone (_)- kavain on mental
performance have been explored in studies involving healthy volunteers. Preliminary
studies involving small numbers of volunteers have suggested that kava extract
(WS-1490 200 mg three times daily for five days) did not appear to impair memory
as assessed by certain tests (e.g. word recognition) carried out under
laboratory conditions.(92) In another series of tests, designed to assess
mental alertness, volunteers received kava extract, Antares 120 (standardised
to 120 mg kavalactones per tablet), one tablet daily, diazepam 10 mg daily, or
placebo.(93) It was reported that the experiments provided evidence that kava
did
not
cause drowsiness or lack of concentration, for example, reaction time was
reduced in placebo recipients, but not kava recipients. Other research
involving volunteers found that a single dose of kava extract 600 mg (LI-158;
drug–extract ratio, 12.5 : 1) led to a 'moderate' increase in tiredness,
compared with placebo, and as assessed using visual analogue scale scores,
although statistical analysis was not reported.(94) Confirmation of these findings
is required. In a battery of psychometric and other tests following
administration of a range of single doses of the synthetic kavalactone (_)-kavain
(200, 400 and 600 mg) and clobazam 30 mg to healthy volunteers, (_)-kavain
appeared to have a sedative effect which was stated to be different to that observed
with clobazam.(95) Compared with placebo, (_)-kavain, but not clobazam,
improved intellectual performance, attention, concentration and reaction time.
Other Reactions
There are isolated reports of myopathy and myoglobinuria associated
with the use of kava preparations, although causality in these cases has not
been established. One report described dermatomyositis associated with use of kava
for anxiety by a 47-year-old woman.(96) The woman, who had also been taking
valproic acid for 18 months and sertraline occasionally over two years for
bipolar disorder, developed a rash involving her back, neck and face, as well
as muscle weakness, two weeks after taking kava (dosage not specified). She
improved initially following treatment with methylprednisolone, but then developed
a fever which prompted her to attend a hospital emergency department. Investigations
revealed a raised serum creatine kinase concentration (8654 U/L, normal values
stated as 24–170 U/L) and myopathic patterns in various muscles, and biopsy
samples showed changes indicative of dermatomyositis.
The woman was treated initially with parenteral prednisone, after
which her creatine kinase concentration returned to normal, and also received
methotrexate for five months and hydroxychloroquine. Prednisone treatment was
reduced over the following year, and at one year of follow-up the woman remained
symptom-free.
Another isolated report describes a 29-year-old man who experienced
severe muscle pain and passed dark urine one morning a few hours after having
taken a herbal product said to contain kava 100 mg, Ginkgo biloba extract 200
mg and guarana (which contains methylxanthines) 500 mg (daily dosage was not
stated), for the first time.(97) The man was admitted to an intensive care unit
and was found to have highly elevated serum creatine kinase (100 500 IU/L, normal
range given as 0–195 IU/L) and myoglobin (10 000 ng/mL, normal range stated as
0–90 ng/ mL) concentrations, but no renal complications. Investigations excluded
metabolic myopathy as a possible cause; his signs and symptoms subsided over
six weeks.
Disturbances of visual function have been reported following a study
involving a 30-year-old kava-naïve male volunteer who ingested 600 mL of
aqueous extract of pulverised kava 'root' (rhizome).(98) Measurements involving
the man's right eye only indicated reductions in near point of accommodation
and convergence, an increase in pupil diameter, and disturbance of oculomotor
balance, but no effects on visual or stereoacuity or ocular refractive error.
The experiment was not carried out according to a double-blind, controlled
design and, therefore, the findings require further investigation.
A case of hypokalaemic renal tubular acidosis due to Sjögren's syndrome
(a symptom complex of unknown aetiology, marked by keratoconjunctivitis sicca,
xerostamia, with or without lachrymal and salivary gland enlargement,
respectively, and presence of connective tissue disease, usually rheumatoid
arthritis, but sometimes systemic lupus erythematosus, scleroderma or
polymyositis) has been reported in a 36-year-old woman.(99) She was stated to
have begun taking kava, echinacea and St John's wort two weeks before becoming
ill, but the report does not provide any further details of the echinacea
species contained in the product(s), nor of the types of preparations,
formulations, dosages and routes of administration of any of the herbal
medicines listed.
The woman was hospitalised with severe generalised muscle weakness
and tests revealed she had a serum potassium ion concentration of 1.3 mEq/L.
She was given electrolyte replacement for four days after which the muscle
weakness resolved, and was started on hydroxychloroquine 200 mg daily for
'probable' Sjögren's syndrome. The authors suggested that ingestion of echinacea
may have aggravated an autoimmune disorder (see Echinacea, Side-effects,
Toxicity) although causality has not been established.(99)
No clear evidence of an association between kava consumption and
ischaemic heart disease (IHD) was found in a case–control study (using up to
four randomly selected control subjects) involving 83 individuals from Aboriginal
communities in Arnhem Land (Northern Territory, Australia) who were diagnosed
with IHD for the first time during 1992–1997.(100) In a similar case– control
study involving 115 individuals (and 415 control subjects) with pneumonia, no
association between kava use and pneumonia was found.(101)
Toxicology
Incubation of the kava alkaloid pipermethystine, which occurs mostly
in kava leaves and stem peelings, with human hepatoma cells resulted in a 90%
loss in cell viability within 24 hours when applied at a concentration of 100 mmol/L
and 65% cell death at a concentration of 50 mmol/L.(102) Further experiments
indicated that pipermethystine causes cell death in part by disrupting mitochondrial
function. It has been suggested that pipermethysticine could be involved in
hepatoxicity associated with kava root extracts,(102) although since hepatotoxicity
has been associated both with authorised commerical products (therefore made according
to the principles of good manufacturing practice) and traditional aqueous extracts
(which might be more easily contaminated with leaves and stem peelings) this
suggestion requires further examination.
A study involving small numbers of rats administered an aqueous
(water) extract of kava 'root' equivalent to kavalactones 200 or 500 mg/kg/day
for 2–4 weeks found that serum concentrations of the enzymes alanine
aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate
dehydrogenase were not elevated following kava administration, compared with control.(103)
The clinical relevance of these findings is not known.
In other toxicological studies, LD50 values for a standardised kava
extract containing 70% kavalactones have been reported as 370 mg/kg and 16 g/kg
for intraperitoneal and oral administration, respectively, in rats, and 380
mg/kg and 1.8 g/kg for intraperitoneal and oral administration, respectively,
in mice.(G50)
An ethanolic extract of kava root was reported to be cytotoxic (EC50
approximately 50 mmol/L) in an in vitro system assessing viability of human
hepatocytes. The kavalactones methysticin, desmethoxyyangonin and yangonin also
displayed cytotoxicity in this system, with methysticin having the greatest
cytotoxic activity.(104) In vitro cytotoxicity of kavalactones has also been described
in a human lymphoblastoid cell line; the cytotoxic effect appears to be due to
the parent compound and not as a result of activation of kava constituents to
toxic metabolites.(105)
CLIENT CONSIDERATIONS
ASSESS
·
Assess the reason the client is
using kava.
·
Assess for hypersensitivity
reactions. If present, discontinue the use of kava and administer an
antihistamine or other appropriate therapy.
·
Assess for use of other central
nervous system depressants, including alcohol, barbiturates, benzodiazepines,
antianxiety medications, and sedatives/hypnotics (see Interactions).
ADMINISTER
·
Instruct the client to store
kava products in a cool, dry place, away from heat and moisture.
·
Instruct the client not to use
kava for longer than 3 months unless under the direction of an herbalist. This
herb may be habit forming.
·
Inform the client that kava
absorption is increased when kava is taken with food.
TEACH
CLIENT/FAMILY
·
Inform the client that
pregnancy category is 2 and breastfeeding category is 3A.
·
Caution the client not to give
kava to children younger than 12 years of age.
·
Inform the client that
excessive doses may result in daytime drowsiness. Advise the client not to
operate heavy machinery or engage in hazardous activities if drowsiness occurs.
·
Caution the client not to use
kava with other central nervous system depressants (see Interactions).
PRACTICE
POINTS/PATIENT COUNSELLING
·
Kava
kava is a scientifically proven treatment for the symptoms of anxiety and
stress states. Its anxiety-reducing effects are similar to those of 15 mg oxazepam
or 9 mg bromazepam; yet, physical tolerance and reduced vigilance have not been
observed.
·
It
also reduces symptoms of anxiety related to menopause when used together with
HRT, and reduces withdrawal symptoms associated with benzodiazepine
discontinuation.
·
It
has anxiolytic, sedative, antispasmodic, analgesic and local anaesthetic
activities.
·
Although
the herb is considered to have a low incidence of adverse effects, long-term
use should be carefully supervised because of the possibility of developing
adverse reactions.
·
Rare
hepatotoxic effects have been reported for methanolic and ethanolic extracts, whereas
traditional aqueous extracts are considerably safer. The mechanism responsible remains
elusive.
PATIENTS’
FAQs
What will this herb do for me?
Kava
kava is an effective herbal relaxant that reduces symptoms of anxiety and
restlessness. It is also used to relieve anxiety in menopause, insomnia and symptoms
of benzodiazepine withdrawal.
When will it start to work?
Anxiety-relieving
effects are usually seen within the first few weeks of use.
Are there any safety issues?
Taking
high doses long term has been associated with a number of side effects and
should be avoided.
CLINICAL
NOTE
COMMERCIAL KAVA
KAVA PRODUCTS AND LINKS TO HEPATOTOXICITY
Conflicting reports abound. On 15 August 2002, the Therapeutic
Goods Administration (TGA) initiated a voluntary recall of all products
containing kava kava. The response was undertaken due to incoming details from
European countries of case reports of hepatotoxicity apparently associated with
the use of commercial kava kava products.
The decision to remove kava kava from the market has been viewed as
controversial and questioned by many people. Toxicological and clinical studies
have shown that kava kava extracts are virtually devoid of toxic effects and,
when assessed primarily by the British regulatory authority (MCA) and a German
research group, a critical analysis of the suspected cases in Germany reveals
that a very probable causal relationship could be established in only one
patient (Teschke et al 2003). It is suspected that a
rare, immunologically mediated, idiosyncratic mechanism may be responsible
(Schulze et al 2003) and the extraction process used to produce kava kava
products also had an influence. It now appears that the aqueous method results
in extraction of glutathione, in addition to kava lactones, an important factor
for protecting the liver from potential damage, whereas the acetone extraction
method does not (Whitton et al 2003). As a result, kava kava products
made with the acetone extraction process are more toxic than those produced via
aqueous extraction methods. This is an important distinction to make, as most
European products were made using acetone extraction, whereas Australian
products were chiefly made via aqueous extraction.
Interestingly, fulminant hepatic failure has not been documented
with traditional use either in Pacific countries or in the Northern Territory, where
Aboriginal kava kava drinkers consume kava lactones in doses estimated to be
10–50-fold the recommended levels (Currie & Clough 2003).
Several reports published in 2003 have found no evidence of aqueous kava kava
extracts inducing irreversible liver toxicity in vivo (Singh
& Devkota 2003) or in humans (Clough et al 2003).
One study involving long-term users of aqueous kava kava extracts found that
although changes to liver function could occur at moderate levels of
consumption, they are reversible and begin to return to baseline after 1–2 weeks’
abstinence from kava kava. A recent animal study testing large concentrations
of kava lactones (7.3 or 73 mg/kg of kava lactones/day) over 3 months and 6 months
found no signs of toxicity. In addition, no behavioural or physiological
changes were observed on discontinuation of kava lactone feeding after 3 months
(Sorrentino et al 2006).
Australia was not alone, and other countries also issued health advisory
cautions or banned kava kava-containing products from sale. Although these
actions effectively removed kava kava products from the market, the traditional
kava kava beverage continued to be consumed in the Pacific Islands and the kava
kava-producing countries of the Pacific found the controversy surprising, given
the long history of apparent safe use in the Pacific. The impact of European
and UK withdrawal of kava kava was devastating to the South Pacific economies.
In January 2003, the Kava Evaluation Group was established in Australia to
review the accumulating safety data and by August that same year the Complementary
Medicine Evaluation Committee recommended to the TGA that certain forms of kava
kava could be considered safe. The TGA accepted these recommendations and amended
the regulations accordingly. Currently in Australia, there is a maximum limit
of 125 mg kava lactones allowable per tablet or capsule, 3 g of dried rhizome
per tea bag and all products containing kava kava must not provide more than
250 mg kava lactones in the recommended daily dose. The World Health
Organization published a report in May 2007 entitled Assessment of the risk
of hepatotoxicity with kava products (WHO 2007).
It evaluated data from 93 case reports of which 8 were determined
to have a close association between the use of kava kava and liver dysfunction;
53 cases were classified as having a possible relationship, but they could not
be fully assessed due to insufficient data or other potential causes of liver
damage; 5 cases had a positive rechallenge. Most of the other case reports
could not be evaluated due to lack of information. It concluded that there is
‘significant concern’ for a cause and effect relationship between kava kava
products and hepatotoxity, especially for organic extracts. Other risk factors
appear to include heavy alcohol intake, preexisting liver disease, genetic
polymorphisms of cytochrome P450 enzymes, excessive dosage and co-medication
with other potentially hepatotoxic drugs and potentially interacting drugs.
PREPARATIONS
PROPRIETARY
SINGLE-INGREDIENT PREPARATIONS
Brazil: Ansiopax; Calmonex; Farmakava; Kavakan; Kavalac; Kavasedon;
Laitan; Natuzilium. Czech Republic: Antares; Kavasedon; Leikan. Venezuela:
Kavasedon.
PROPRIETARY
MULTI-INGREDIENT PREPARATIONS
USA: Calming Aid.
EXTRACTS
Increase GABA in the synaptic cleft by increasing
GABA secretion and inhibiting its reuptake (SHT). LD50 dihydrokavain = 920
mg/kg orl mouse (MAB), LD50 dihydromethysticin = 1050 mg/kg orl mouse (MAB),
LD50 StX (70% kavalactones) = 16,000 mg/kg orl rat, 1800 mg/kg orl mouse, 370
mg/kg ipr rat, 380 mg/kg ipr mouse (MAB). This indicates that the mix is safer
than the individual lactone, at least orally in rats and mice (MAB). Kava slows
hyperactivity in mice, but not as much as antipsychotic drugs. When chewed, the
root produces numbness in the mouth similar to what one would experience with
cocaine and longer-lasting than what one would experience with benzocaines
(APA). In a traditional Hawaiian remedy, leaves were chewed and given to
anxious or restless children for its calming effect, and to induce sleep. And
for the old reprobates “kava tends to lower one’s interest in sexual
activities.” ( = ) lactones are 10 times more anticonvulsant than mephenesin against
strychnine; the mixture of lactones was synergistic; the potency of the mix was
equal to that of pure dihydromethysticin; synergy more pronounced with oral
than ivn administration; lactones better absorbed in mix than as isolated
silver bullets (MAB). Lactones = cocaine and procaine as analgesic and
anesthetic; dihydromethysticin better than aspirin but inferior to morphine as
analgesic (MAB).
REFERENCE
Barnes, J., Anderson, L. A., and Phillipson, J. D.
2007. Herbal Medicines Third Edition. Pharmaceutical
Press. Auckland and London.
Braun, L and Cohen, M. 2010. Hebs and Natural
Supplements An Evidence Based Guide 3R D Edition. Elsevier Australia.
Australia.
Duke, J. A. with Mary Jo Bogenschutz-Godwin, Judi
duCellier, Peggy-Ann K. Duke. 2002. Handbook of Medicinal Herbs 2nd
Ed. CRC Press LLC. USA.
Gruenwald, J., Brendler, T., Jaenicke, Ch. 2000. PDR for
Herbal Medicines. Medical Economics Company, Inc. at
Montvale, NJ 07645-1742. USA
Kraft, K and Hobbs, C. 2004 . Pocket
Guide to Herbal Medicine. Thieme. Stuttgart New York.
Linda S-Roth. 2010. Mosby’s Handbook Of
Herbs & Natural Supplements, Fourth Edition. Mosby Elsevier. USA
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