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Kava

 

Kava (Piper methysticum) is an ancient crop of the western Pacific. Other names for kava include `awa (Hawaii), 'ava (Samoa), yaqona (Fiji), and sakau (Pohnpei). Kava is related to the black pepper; both have heart-shaped leaves and flowers similar to the flower spike of the anthurium. Kava also has a peppery taste. Kava has long been a part of religious, political, and cultural life throughout the Pacific.

Species

Family:
Piper methysticum Forst. f. (Piperaceae)
Fourteen different varieties are used throughout Oceania (Polynesia, Melanesia, Micronesia).

Related species
Cultivars of P. methysticum have been developed in some Pacific Islands from Piper wichmanni C.DC (syn: Piper erectum C.DC, Piper schlecteri C.DC, Piper arbuscula Trelease). Piper sanctum (Miqu.) Schlect. is native to Mexico.

Synonyms and Part Used

Synonyms
Intoxicating Pepper, Kava-kava, Kawa, Kawa-kawa

Part Used
Peeled dry rhizome (sometimes referred to incorrectly as the root)

Constituents

Kavalactones
Kavalactones, kavapyrones, 2-pyrones, δ-lactones with styryl or dihydrostyryl substituents. Dried rhizomes should contain at least 3.5% kavalactones and good-quality material 5.5–8.3%.Ethanol–water extracts contain 30% kavalactones, whereas acetone–water extracts contain 70%. The kavalactones occur as a complex mixture of at least 18 compounds,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%).Smaller quantities (less than 0.1%) of dimeric kavalactones (e.g. trux-yangonins I, II, III) have also been isolated.

Alkaloids/amides
Cepharadione A (aporphine-type) is a minor component (4 kg yielded 1 mg).Small quantities of N-cinnamoylpyrrolidine and its o-methoxy analogue are also present.

Chalcones
Flavokawains A, B and C.

Flavonoids
Pinostrobin, 5,7-dimethoxyflavanone.

Steroids
Sitosterol, stigmasterol, stigmastanol.

Esters
Bornyl cinnamate and bornyl 3,4-methylenedioxycinnamate.

Aliphatic alcohols
Docosan-1-ol, dodecan-1-ol, eicosan-1-ol, hexacosan-1-ol, hexadecan-1-ol, octadecan-1-ol, n-tetradecanol,transphytol.

Other constituents
Cinnamylideneacetone,long-chain fatty acids.

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%). 3α,4α-Epoxy-5β-pipermethysticin (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 epoxypiperolide.

Uses

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. 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.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.It has also been adopted by the Aboriginal community in parts of Australia as an intoxicating drink.

The German Commission E recommended kava for the treatment of nervous anxiety, stress and restlessness.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.

Dosage
For treatment of anxiety (adults) by oral administration.
Dried rhizome:1.5–3 g per day.Equivalent to 60–120 mg kavalactones per day.

Liquid extract:3–6 mL per day (1 : 2 liquid extract, unspecified solvent).

Standardised preparations:100–200 mg kavalactones per day.60 mg kavalactones 2–4 times per day in tablet form.60–120 mg kavalactones per day.

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.

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 Clinical studies). Duration of use of kava extracts generally should not exceed three months.

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.Maximum concentrations of kavain and dihydrokavain were noted 5 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).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.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.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 arbiturate-induced sleeping time, respectively.

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.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.

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.A marked effect of kavain on GABA has also been stated to be unlikely.By contrast, a kavalactone-enriched 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.Other experiments have shown concentration- and structure-dependent effects of kavalactones on binding of bicuculline methochloride (BMC) to GABAA receptors from rat cortex preparations.(+)-Kavain, (+)-methysticin and (+)-dihydromethysticin enhanced BMC binding by 18–28% at a concentration of 0.1 μmol/L, whereas (+)-dihydrokavain did so only at a concentration of 10 μmol/L, and yangonin at a concentration of 1 μmol/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.

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 μmol/L and 1.2 μmol/L, respectively), although there were differences in MAO-B inhibition among the different synthetic kavalactones with desmethoxyyangonin and (±)-methysticin being the most potent inhibitors.Differences between kavalactones in inhibition of noradrenaline (norepinephrine) uptake in synaptosomes prepared from rat cerebral cortex and hippocampus have also been documented: (±)- and (+)-kavain gave approximately equal values and both were more potent inhibitors than (+)-methysticin, although none of the compounds inhibited serotonin uptake.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.

In vivo studies in rats administered a single oral dose of (+)-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.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.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.

Anticonvulsant and neuroprotective activities
Studies described in the older literature have documented anticonvulsant effects for kavalactones in several experimental models.The anticonvulsant properties of (+)-methysticin in vitro may arise from a direct membrane action on the excitability of neurons,and in vitro assays have shown that (+)-methysticin,(+)-kavain and the synthetic kavalactone (±)-kavain appear to interact with voltage-dependent sodium channels, and that (±)-kavain also interacts with voltage-dependent calcium channels.Inhibition by (±)-kavain of veratridine-activated voltage-dependent sodium ion channels in synaptosomes from rat cerebral cortex,and veratridine-induced increase in intracellular calcium ion concentrations has been described following in vitro studies utilising rat cerebrocortical synaptosomes.Reduction in veratridine-induced glutamate release following (±)-kavain administration has been reported both in vitro and in vivo in freely moving rats. 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,and (±)-kavain (50, 100 or 200 mg/kg intraperitoneally) has been shown to protect nigrostriatal dopaminergic neurons against -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice, an experimental model of Parkinson’s disease. 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) 1 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).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.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.Analgesic activity of dihydrokawain and dihydromethysticin has been reported previously.

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.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.(±)-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. 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 (+)-kavain inhibited human platelet aggregation in a dose-dependent manner in vitro.The formation of prostaglandin E2 and thromboxane B2 was also inhibited in a dose-dependent manner, suggesting that (+)-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 (TNFα) release in vitro from BALB/3T3 cells incubated with okadaic acid and suppressed lipopolysaccharide-induced TNFα production in vivo in diabetic mice following intraperitoneal administration.

Antifungal activity against several microorganisms, including Candida albicans, has been described for a 10% aqueous kava extract.

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 11 randomised, double-blind, placebo-controlled trials involving a total of 645 participants. All 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 and 24 weeks in the other.

Kava extract is an effective symptomatic treatment for anxiety, but that limitations of the studies included meant that further rigorous trials were needed.Some new research has been published since, but has added little to the evidence base because of methodological issues.

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 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).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.

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.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.

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.

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.Three trials included in the review, one of which tested kava extract 100 mg daily (equivalent to 55 mg kavalactones) for 24 weeks,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.This review comprised seven of the eight placebo-controlled trials from the earlier review (the other trial was excluded from the Cochrane review because it tested kava extract in addition to hormone replacement therapy) and four new trials. One of the new trials (unpublished) reported that adverse events were not observed during four weeks’ treatment with kava extract 200 mg daily (equivalent to 140 mg kavalactones).

Hepatotoxicity
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. Six 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 in values obtained.

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.The severity of the liver damage described in the reports varied from abnormal liver function test results to irreversible liver failure and death; six patients received liver transplants, one of whom, as well as two other individuals, subsequently died.

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.However, this conclusion is questionable since estimates of this nature can be inaccurate and misleading.

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.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.

Inhibition of the cytochrome P450 drug metabolising enzyme CYP3A4 has been shown in vitro 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 CYP3A4 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.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.

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’. 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. 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. 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.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.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).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 less than 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. The man was treated in hospital with Plasmalyte intravenously and intramuscular thiamine and 5 hours after admission his symptoms had resolved.

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.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 although causality has not been established.

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.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.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.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.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.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.

Toxicology
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.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.

Contra-indications, Warnings
It has been stated that kava is contra-indicated in endogenous depression.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.

It has been reported that there is no evidence that use of kava extracts has the potential for physical or psychological dependency to develop. 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.

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). 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.

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.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).On this basis, the potential for kava to interact with dopamine agonists or antagonists should be considered.

There are conflicting results from in vitro studies regarding the effects of the kavalactone (+)-kavain on cyclooxygenase activity. One study reported that (+)-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.

Inhibition of the cytochrome P450 drug metabolising enzyme CYP3A4 by kava extracts and individual kavalactones has been described following 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 μg/mL (ethyl acetate extract).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 dose-dependent inhibition of one or more of the CYP isoforms at concentrations of less than 10 μmol/L, considered as ‘potent’ inhibition (e.g. IC50 values for desmethoxyyangonin, dihydromethysticin and methysticin for CYP2C19 were 0.51, 0.43 and 0.93 μmol/L, respectively, and for dihydromethysticin and methysticin for CYP3A4 under certain assay conditions were 2.49 and 1.49 μmol/L, respectively).In several cases, this degree of inhibition was greater than that shown by positive controls which are known to produce clinically significant drug interactions.

The clinical relevance of these findings is not known, although the potential for kava extracts to interact with concurrently administered drugs metabolised mainly by CYP3A4 should be considered.

Alcohol The effects of concurrent use of kava extract and alcohol have undergone some investigation. In a randomised, double-blind, controlled trial, 20 healthy participants received kava extract (WS-1490; Laitan) 300 mg daily (equivalent to 210 mg kavalactones), or placebo, for eight days.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.

A small study involving 40 healthy participants found that the concurrent ingestion of a kava beverage (350 mL 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.

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.

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.



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 well-designed 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 well-defined 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 (+)-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. 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).

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, and in view of the reported inhibitory activity against certain cytochrome P450 drug metabolising enzymes, be vigilant to the potential for drug interactions (see Contra-indications, Warnings, Interactions). 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.

 

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