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Kava, Studies

Anxiety / Mood

Cancer

Cardiovascular Effects

Antithrombotic Action of the Kava Pyrone (+)-Kavain Prepared from *Piper methysticum* on Human Platelets

Immune System Effects

Liver Effects

Neurological Effects

CLINICAL PHARMACOLOGY

Anxiety

At least seven double-blind, controlled clinical studies have assessed the efficacy of two extracts of Kava  for symptomatic treatment of anxiety. Two of these studies were performed with a hydroalcoholic extract standardized to contain 15% kava pyrones , while the other studies used an extract standardized to contain 70% kava pyrones.

Two placebo-controlled trials investigated the effect of both standardized extracts in women with climacteric psychosomatic disturbances. In the first study, 40 such women were treated with either a placebo or 200–400mg extract (30–60 mg kava pyrones) daily for 8–12 weeks. Using the Kuppermann Index and Anxiety Status Index, the extract was found to be superior to the placebo.

In the second study, a further 40 such women were treated with 300mg extract (210mg kava pyrones) daily for 8 weeks in a randomized, placebo controlled, double-blind study. The outcome was assessed using the Hamilton Anxiety Rating Scale; the Depression Status Inventory and the Kuppermann Index were also used. The total score on the Hamilton Anxiety Rating Scale decreased after 1 week of treatment with the extract, and reached a plateau at 4 weeks. The therapeutic response to the extract was significant, as compared with the response to the placebo (P < 0.001) (23). After 8 weeks of treatment with the extract, the mean score on the Hamilton Anxiety Rating Scale decreased from 31.1 to 5.5. In the group which received the placebo, the mean score decreased from 30.15 to 22.50. The mean score on the Depression Status Inventory decreased significantly from 42.5 to 24.8 (P < 0.01). The mean score on the Kuppermann Index also decreased significantly from 20.35 to 3.60 (P < 0.01).

A double-blind, placebo-controlled study of 58 patients with symptoms of anxiety, tension or agitation of non-psychotic origin assessed the effectiveness of the extract containing 70% kava pyrones (equivalent to 210mg kava pyrones) daily for 4 weeks. The outcome was assessed using the total score on the Hamilton Anxiety Rating Scale, and other rating scales (the Erlanger Scale for Anxiety, Clinical Global Impressions and the Fischer Somatic Symptoms). After 1 week, patients treated with the extract showed a reduction in the total score on the Hamilton Anxiety Rating Scale as compared with the placebo group. The difference between the scores of the two groups increased after 4 weeks of treatment.

A randomized double-blind comparative study assessed the efficacy of the extract containing 70% kava pyrones in 172 patients with symptoms of anxiety, tension and agitation of non-psychotic origin. Patients received either 300mg extract (210 mg kava pyrones), 15mg oxazepam or 9mg bromazepam daily for 6 weeks. The main criterion for assessment was the total score on the Hamilton Anxiety Rating Scale. No significant difference was observed between the treatments. In another randomized study which involved several centers, the efficacy of the extract containing 70% kava pyrones was tested in 100 patients with anxiety of non-psychotic origin (as defined in the Diagnostic and statistical manual of mental disorders, 3rd ed.. Patients were treated with either a placebo or 300mg extract (equivalent to 210 mg kava pyrones) daily for 24 weeks and the outcome was assessed using the Hamilton Anxiety Rating Scale. Adjunct rating scales were the Clinical Global Impressions and Von Zerssen mood scale. In patients treated with the extract, the decrease in the Hamilton Anxiety Rating Scale (mean scores of 30.7 and 9.7 at weeks 0 and 24, respectively) was significant as compared with the placebo group (P < 0.005). The scores on the Clinical Global Impressions and Von Zerssen mood scale also improved after 24 weeks of treatment with the extract. A randomized study of 58 patients also assessed the efficacy of the extract containing 70% kava pyrones for the treatment of anxiety of non-psychotic origin. Patients were treated with either a placebo or 300 mg extract (equivalent to 210 mg kava pyrones) daily for 4 weeks and therapeutic efficacy was assessed using the Hamilton Anxiety Rating Scale. After 1 week, there was a significant reduction in the scores (mean scores of 25.6 and 16.2 at weeks 0 and 1, respectively) in the treated group as compared with the placebo group (P = 0.004).

A randomized, double-blind pilot study investigated the effects of the extract containing 15% kava pyrones in 59 patients with pre-operative anxiety. Although improvements in mood were observed using a psychostatus score, only two doses of the extract (equivalent to 60 mg kava pyrones daily) were administered, and thus the clinical significance of this study is questionable.

An additional nine double-blind studies have been performed with (±)-kawain (60, 61). Two of the studies were comparative studies and seven were placebo-controlled. Therapeutic anxiolytic activity was achieved with doses of 200–600 mg (±)-kawain daily (60). Kawain is available in Germany and Switzerland as an over-the-counter medication.

INSOMNIA

Two single-blind and four double-blind, placebo-controlled clinical trials investigated the effect of a rhizome extract standardized to contain 70% kava pyrones on EEG recordings, and intellectual and motor functions of healthy volunteers. Changes in EEG recordings and psychomotor test results showed no evidence of a decrease in vigilance or responsiveness in volunteers treated with 600 mg extract (equivalent to 420mg kava pyrones) daily for 5 days . Examination of EEG recordings during sleep of healthy volunteers given a single dose of 300 mg extract (equivalent to 210mg kava pyrones) showed an increased sleep spindle density of 20% and an increase in slow-wave sleep (i.e. deep sleep), but the rapid eye movement phase was not suppressed. Daily doses of 300 or 600 mg extract (equivalent to 210 or 420mg kava pyrones), respectively, for 1 week increased the beta/alpha index typical for the pharmaco-EEG profile of anxiolytics. The increase in beta activity was most marked in the beta2 range . In two studies, administration of 300mg extract (equivalent to 210 mg kava pyrones) daily for either 8 or 14 days, taken with or without ethanol, had no influence on the safety-related performance of healthy volunteers.

In a randomized, double-blind crossover study involving 12 healthy volunteers, administration of daily single doses of a rhizome extract standardized to contain 30% kava pyrones (400 mg extract containing 120mg kava pyrones) was compared with daily single doses of diazepam (10 mg) or a placebo in a 7-day trial. Changes in EEG recordings and psychometric test results showed no evidence of a decrease in vigilance in the group treated with the extract .

Safety-related performance was assessed in another study after administration of an extract standardized to contain 30% kava pyrones, bromazepam or a combination of extract and bromazepam. Safety-related performance remained

unaffected in healthy volunteers treated daily with 400 mg extract (equivalent to 120 mg kava pyrones for 14 days), whereas it was impaired after treatment with bromazepam (9mg daily) or the extract/bromazepam combination. No differences were observed following treatment with bromazepam or the combination, indicating that the extract did not have an additive effect when given in combination with bromazepam.

BEHAVIORAL EFFECTS

Intraperitoneal administration of an aqueous extract of Kava (62.5 mg/kg body weight) decreased the spontaneous activity of mice. This effect lasted for 2 hours without loss of muscle tone. The same extract, however, was not active in mice or rats when administered orally in single doses of 0.5–2.5 g/kg body weight. A dichloromethane extract of the rhizome (150 mg/kg body weight, administered intraperitoneally) decreased spontaneous motility by 46%, and markedly reduced motor control (by 50%), in mice . At this dose, the extract also induced hypnosis and analgesia. Intraperitoneal administration of aqueous, dichloromethane and lyophilized aqueous extracts of the rhizome (62.5–250mg/kg body weight) reduced spontaneous activity in mice and rats. Intraperitoneal administration

of an aqueous or dichloromethane extract of the rhizome (120mg/kg body weight) suppressed apomorphine-induced hyperactivity in rats.

Intraperitoneal administration of a lipid-soluble fraction of an aqueous rhizome extract (doses up to 300 mg/kg body weight) decreased the conditioned avoidance response in rats. An aqueous extract, however, was inactive at doses up to 500mg/kg body weight . Intraperitoneal administration of an extract of the rhizome (equivalent to 50–100mg kava pyrones/kg body weight) or(±)-kawain, a synthetic kava lactone (10–50mg/kg body weight), reduced muscle tone in cats.

ANALGESIC ACTIVITY

Intraperitoneal administration of a dichloromethane extract of the rhizome (150 mg/kg body weight) produced analgesia in mice. Intraperitoneal or intragastric administration of an aqueous or lipid extract of the rhizome (150–250 mg/kg body weight) produced analgesia in mice, as measured by tailflick reaction times and suppression of acetic acid-induced writhing . Both dihydrokawain and dihydromethysticin exhibited analgesic effects when administered intraperitoneally to rats (140 mg/kg body weight), as determined by an increase in tail-flick reaction times.

NEUROLOGICAL EFFECTS

Depression of the central nervous system was observed in rodents after intraperitoneal administration of an aqueous rhizome extract (50–170mg/kg body weight) . Intraperitoneal administration of an aqueous extract (300 mg/kg body weight) or a chloroform extract (140mg/kg body weight) of the rhizome depressed the central nervous system and potentiated the effects of barbiturates in mice. Administration of dihydromethysticin to mice potentiated pentobarbital-induced sleeping time by 400%, while dihydrokawain, yangonin and kawain were only moderately active (150–235%). A dichloromethane extract of the rhizome administered intraperitoneally to mice (150 mg/kg body weight) induced hypnosis . The hypnotic and sedative effects of a dichloromethane rhizome extract (300mg/kg body weight, administered intraperitoneally) were significantly prolonged in mice by the concurrent administration of ethanol (2 g/kg body weight; P < 0.001). A saline extract of the rhizome had an effect on crayfish abdominal ganglia in vitro (0.05 g/ml) . Intraperitoneal administration of an extract of the rhizome (equivalent to 50–100 mg kava pyrones/kg body weight) to cats had a significant effect on EEG recordings, inducing high-amplitude delta waves, spindlelike formation, and continuous alpha- or beta-synchronization in amygdala recordings (P < 0.001). Hippocampal responses, following stimulation of the amygdala nucleus, increased significantly in amplitude in cats treated intraperitoneally with the rhizome extract (equivalent to 100 mg kava pyrones/kg body weight; P < 0.01) or (±)-kawain (50 mg/kg body weight; P < 0.05).

The neuroprotective effects of an acetone extract of the rhizome and kavapyrones have been demonstrated both in vivo and in vitro. A standardized acetone extract of the rhizome, methysticin and dihydromethysticin protected rodents against hypoxia or ischaemia-induced cerebral damage . The standardized extract also protected against neuronal damage in cultured neurons from chick embryo cerebral hemispheres.

Although the neuroprotective mechanisms of the rhizome are not well understood, recent investigations have indicated that kava pyrones may exert their effects by activating several neurotransmitter systems, such as the adrenergic , mesolimbic dopaminergic , gabaminergic , glutamatergic , and serotonergic receptor systems . An extract of the rhizome containing 58% kava pyrones enhanced the binding of [3H]muscimol to g-aminobutyric acid-A receptors in a concentration-dependent manner in rat hippocampus, amygdala and medulla oblongata in vitro (ED50 200–300mmol/l). However, another study found no significant interaction in vitro or in vivo of a dichloromethane rhizome extract or kava pyrones with g-aminobutyric acid (A and B) or benzodiazepine receptor binding sites . Both kawain and dihydromethysticin (10–100mmol/l) reduced the field potential changes induced by the serotonin-1A agonist, ipsapirone, in the CA1 and CA3 areas of guinea-pig hippocampal slices in vitro. These results suggest that both compounds may modulate serotonin-1A receptor activity. Methysticin and kawain inhibited the uptake of 3H-labelled norepinephrine, but not of 3Hlabelled serotonin, in synaptosomes prepared from the cerebral cortex and hippocampus of rats . Intragastric administration of (+)-dihydromethysticin in a single dose (100 mg/kg body weight), or chronic intragastric administration of (±)-kawain (10.8 mg/kg body weight) daily for 78 days to rats did not alter dopamine or serotonin levels in the striatal or cortical brain regions.

ANTICONVULSANT ACTIVITY

Intraperitoneal administration of an aqueous extract (300mg/kg body weight) or a chloroform extract (140 mg/kg body weight) of the rhizome to mice inhibited strychnine-induced convulsions. The anticonvulsant activity of methysticin and other kava pyrones against electroshock- and chemically induced seizures has been demonstrated in mice and rats. Intraperitoneal administration of dihydromethysticin and dihydrokawain inhibited electroshock-induced seizures at doses of 25 and 60mg/kg body weight, respectively, in mice and rats . Methysticin (10–100mmol/l) was also active in different in vitro models of seizure-like events using extracellular recordings in rat temporal cortex slices containing the hippocampus and entorhinal cortex. Methysticin suppressed epileptiform activity independent of the stimulus (low calcium or magnesium, or high potassium perfusion medium), suggesting a direct effect of the compound on neuron membranes, thus inhibiting neuron excitability. Other studies have demonstrated that (+)-kawain and (±)-kawain inhibited voltage-dependent calcium and sodium channels of rat cerebrocortical synaptosomes. In these synaptosomes, it was also shown that (±)-kawain inhibited the increase in intracellular calcium and glutamate release induced by veratridine and potassium chloride (49). Both (±)- kawain and methysticin inhibited voltage-dependent sodium channels in rat CA1 hippocampal neurons in vitro (1–400mmol/l).

ANTISPASMODIC ACTIVITY

An aqueous rhizome extract, kawain, dihydrokawain, methysticin and dihydromethysticin inhibited serotonin and nicotine-induced contractions of guinea-pig ileum in vitro . The antispasmodic effects were attributed to a direct musculotropic action. Dihydromethysticin also inhibited contractions of rat colon and uterus in vitro induced by serotonin, acetylcholine and barium. Desmethoxyyangonin, dihydromethysticin and kawain inhibited serotonin-induced contractions of rat uterus in vitro at concentrations of 3.2, 7.5 and 10.0mg/ml, respectively. Aqueous, dichloromethane and lyophilized extracts of the rhizome induced relaxation of rat uterus in vitro (ED50 22.5mg/ml). The effects of an aqueous extract of the rhizome on muscle contractility and neuromuscular transmission were investigated in mouse hemidiaphragms and frog sartorius muscles in vitro using twitch tension and intracellular recording techniques. The extract (2–5 mg/ml) induced muscle relaxation by direct action on muscle contractility rather than by inhibition of neuromuscular transmission.

ANTIMICROBIAL ACTIVITY

A hydroalcoholic extract of the rhizome inhibited the growth in vitro of Aspergillus fumigatus, A. niger, Penicillium digitatum, Rhizopus nigricans, Trichophyton mentagrophytes, Candida albicans and Saccharomyces pastorianus .

However, an aqueous extract of the rhizome did not inhibit the growth in vitro of Trichophyton rubrum, Microsporum canis or Epidermophyton floccosum.