Kava Uses and Pharmacology
Chewing kava causes numbness in the mouth because of the local anesthetic action of the kavalactones, which is similar to that produced by cocaine, and lasts longer than benzocaine. 43 In addition, it produces a mild euphoria characterized by feelings of contentment and fluent and lively speech. Sight, smell, and sound are also heightened. 4 Higher doses may lead to muscle weakness, especially in the legs, although some observers relate this to sitting for long periods during the “kava ceremony” rather than to kava itself. Very high doses may induce a deep sleep. CNS effects appear to be mediated by the blockage of voltage-gated sodium and calcium channels ultimately suppressing glutamate release. The kavalactones desmethoxyyangonin and methysticin are believed to block the metabolism of monoamine oxidase-B, producing psychotropic effects. 44 , 45 Sedative and antianxiety properties may result from kava's effects on facilitating gamma-aminobutyric acid (GABA)ergic transmission. 46
The molecular mechanism of action of kavalactones and kava is not entirely clear.
Kavalactones at concentrations from 0.1 to 100 mcM enhanced the binding of bicuculline to the GABA receptor by only 20% to 30%. 47 Another study found weak displacement of diazepam from rat brain membranes by kavalactones but no effect on binding of GABA or of baclofen. 48 The observation that strychnine-induced convulsions are effectively antagonized by several kavalactones supports a possible effect on the glycine receptor. 49 Kava extract and methysticin also were found to protect rats against ischemic brain damage, although several kavalactones were not active in this model. 50 This protection might operate through antagonism of the excitatory amino acids glutamate and aspartate. Inhibition of uptake of norepinephrine, but not serotonin, by kavalactones at high doses was observed. 48 No effect on dopamine or serotonin levels was found in a chronic experiment with kavalactones in rats. 51
A somewhat more persuasive mechanism involves kavalactone inhibition of various neuronal sodium channels. Patch clamp experiments with voltage-gated sodium channels of rat hippocampal neurons found that kavalactones could rapidly and reversibly lower peak amplitudes of sodium currents. 52 A noncompetitive inhibition of the binding of batrachotoxinin benzoate to voltage-gated sodium channels by kavalactones was demonstrated in saturation-binding experiments. 53 Less potently, kavalactones blocked veratridine-activated sodium channels, but had no effect on glutamate release from brain slices. 54 In rat brain synaptosomes, kavalactones appeared to interact with voltage-dependent sodium and calcium channels. 48 , 51 , 55 High concentrations of synthetic kawain relaxed evoked contractile activity in a guinea pig ileum preparation, showing that smooth muscle also is affected by kavalactones. 56 A fluorescently labeled kawain derivative was studied using fluorescence correlation spectroscopy and bound specifically and saturably to cultivated human cortical neurons. 57
Neurophysiological studies of sleep/wakefulness in cats showed decreased muscle tone and duration of wakefulness, marked changes in electroencephalogram (EEG), and increased sleep with kava. Involvement of the amygdala and other limbic structures of the brain was deduced. 58 These effects were distinct from those of tricyclic antidepressants and benzodiazepines.
The pharmacokinetics of kavalactones have been explained to some extent. In rats, dihydrokawain was completely excreted within 48 hours, primarily through urinary excretion of hydroxylated metabolites. Bile and feces did not appear to be important routes of excretion. However, lactones (eg, kawain) with poorer oral absorption than dihydrokawain were found unchanged in feces. The octanol-water partition coefficient for yangonin is 1,500; thus, these compounds are quite nonpolar and water-insoluble. This accounts in part for their poor oral absorption. 59 Because the metabolites of kavalactones are different in humans than in rats, 37 the pharmacokinetics also may differ. Kavalactones have a half-life of 9 hours and achieve peak plasma levels 1.8 hours after administration. 14 Kinetics of entry of kavalactones into mouse brains after intraperitoneal injection have been studied, and kawain and dihydrokawain were rapidly absorbed and quickly eliminated within several minutes, while yangonin and desmoethoxyyangonin were more slowly incorporated and eliminated. 38
Concerns about impaired performance under the influence of kava have motivated several studies in humans. One small study found insignificant decreases in cognitive function when using kava, with only the extent of body sway showing an increase. Subjects' rating of intoxication under kava was low to moderate, while respiration, heart rate, and blood pressure were unaffected. Kava lowered arousal rating without affecting stress rating, although the decrease was not statistically significant. 60 Another small study of 12 patients compared the effects of kava and oxazepam on behavior and event-related potentials in a word recognition task. While oxazepam produced pronounced negative effects on performance, no effects were seen with kava. 61 A study of reaction time by the same authors concluded that kava may increase attention slightly, in contrast to oxazepam, which impaired attention. 62 Kawain in EEG studies showed mild sedation at high doses (600 mg) but not at lower doses (200 mg). 63 Kava had no effect on alertness and long-term memory in a subsequent trial. 64 Minor changes in vision and balance were detected with kava in one subject. 65
Clinical studies of kava have produced evidence of substantial efficacy in mild to moderate anxiety.
Research reveals no animal data regarding the use of kava for anxiety.
In Germany, several investigations have reviewed kava in comparison with other CNS-active herbal products. 66 Kawain was compared with oxazepam in a double-blind study of 58 patients and was equally effective and safe. 67 Over 4 weeks, kava extract progressively reduced anxiety compared with placebo in 60 patients with no reported adverse reactions. 68 A longer 25-week, double-blind, placebo-controlled study of 101 patients with anxiety disorders found that Hamilton Anxiety Scale (HAMA) scores decreased faster with kava than with placebo. 69 A similar 4-week study found kava extract effective using both HAMA and Clinical Global Impression Scale scores. 70
The first US study of kava in anxiety was reported at a conference but has not been published. The study found similar therapeutic effects of kava extract under double-blind, placebo-controlled conditions. 71 A combination of kava and hormone replacement therapy for menopause symptoms was undertaken in Italy over a period of 6 months. Kava with hormone therapy accelerated the improvement in anxiety scores over single treatments alone. 72
Positive results in a sleep study involving 12 patients were found with kava extract WS 1490, as measured by EEG, electromyography, and subjective measures. No adverse effects on rapid eye movement sleep were found. 73 A clinical study of kava's ability to moderate cardiac symptoms in generalized anxiety disorder found that it improved baroreflex control (BRC) of heart rate, but not respiratory sinus arrhythmia, and improvement in BRC was associated with overall clinical improvement in kava-treated patients. 74
The effects of kava extract WS 1490 were assessed on sleep disturbances associated with anxiety disorders. After 4 weeks of double-blind treatment, the assessment of quality of sleep and recuperative effect after sleep were statistically significant in comparison with placebo. Thus, a potential role for kava in improving sleep in patients with anxiety was suggested. 75
The transition from benzodiazepines to kava extract WS 1490 in treatment of anxiety was monitored in a 5-week study involving 40 patients. While symptoms of benzodiazepine withdrawal were not controlled by kava, anxiety was reduced and symptoms decreased after kava treatment compared with during benzodiazepine therapy. 76 A meta-analysis of clinical trials of kava extracts in anxiety has been conducted. Seven trials met the acceptance criteria for inclusion and found kava superior to placebo in the treatment of anxiety as noted by a reduction in the total score of the HAMA. 77
A randomized, double-blind, placebo-controlled study was conducted to assess the effects of kava (total kavalactones 100 mg 3 times daily for 4 weeks) on anxiety. When compared with placebo, there were no statistically significant differences (+2.6 [95%, confidence interval (CI) −0.8 to +6.2]) in reductions of anxiety as measured by the State subtest of the State-Trait Anxiety Inventory. Kava also does not appear to improve measures of insomnia. 78
Additionally, data from 3 randomized, double-blind, placebo-controlled trials assessing the efficacy of kava for the treatment of generalized anxiety disorder were analyzed. From these studies, it did not appear that kava was efficacious for the treatment of generalized anxiety disorder. 79
Kavalactones are purportedly used to relieve anxiolytic effects associated with menopause through modulation of GABA-A receptors in nerve endings. 80
Research reveals no animal data regarding the use of kava for the treatment of menopausal symptoms.
Menopause-related anxiety was successfully treated with kava extract in an 8-week study of 40 women, with rapid onset of efficacy. 81 A 12-week study also found improvement in menopausal symptoms; however, poor compliance in the placebo group confounded interpretation. 82 In a randomized, prospective study, 68 perimenopausal women requiring therapy for climacteric symptoms were randomized to receive 3 months of calcium 1 g/day plus either kava 100 mg/day (kavapyrones 55 mg), 200 mg/day (kavapyrones 110 mg), or no other therapies. Perimenopause was defined as amenorrhea for 6 to 24 months in women between 47 and 53 years of age with hot flushes occurring at least 3 times daily for at least 1 week and a follicle-stimulating hormone level of greater than 30 units/L. In the control group, there were no differences with regard to anxiety, depression, or climacteric symptoms after 1 and 3 months. Patients treated with kava 100 mg/day had a significant decline in anxiety after 1 and 3 months of therapy ( P < 0.025). A similar effect was noted in patients treated with kava 200 mg/day for anxiety at 1 and 3 months ( P < 0.0003). Patients treated with both doses of kava experienced improvements in depression after 1 and 3 months of treatment as compared with baseline ( P < 0.002). Climacteric symptoms were also reduced in both kava treatment groups after 1 and 3 months ( P < 0.006). The authors concluded that kava may be an effective short-term alternative for improving mood disturbances and climacteric symptoms in women with perimenopausal symptoms. 83
In another study, the effects of hormone replacement therapy with and without kava were assessed for a total of 6 months in 40 women with menopausal anxiety. Subjects with physiological menopause were randomized to receive 50 mcg/day of estrogen with progestin plus either kava extract 100 mg/day or placebo. Subjects with surgically induced menopause were randomly assigned to receive estrogen 50 mcg/day plus either kava 100 mg/day or placebo. A reduction in anxiety scores as measured by the HAMA was noted after 3 and 6 months of treatment for all 4 treatment groups. However, the groups receiving kava extract had a larger reduction in anxiety scores compared with those who did not. Specifically, after 6 months of therapy, HAMA scores were reduced 55% compared with baseline for the patients with physiologically induced menopause receiving kava and hormone placement therapy ( P < 0.05) and reduced 23% for those receiving only hormone replacement therapy. In the surgically induced menopause group, HAMA scores were reduced 53% for those receiving hormone replacement therapy and kava, compared with baseline, and reduced 26% for those receiving only hormone replacement therapy. 72
Kavalactones, especially kawain, have modest anticonvulsant activity in electroshock and metrazol models. 84 Kawain showed an antithrombotic effect on platelets, dose-dependently blocking platelet aggregation, adenosine 5′-triphosphate release and synthesis of prostaglandins at high micromolar concentrations. 85 Despite a reputation as an antimicrobial agent in urinary tract infections, kava extracts demonstrated very minimal antifungal and no antimicrobial or antiviral activity. 86
Preliminary data collected from the Pacific Islands suggest that kava consumption is possibly associated with a lower incidence of cancer. 87
The German Commission E recommends dosages of kavalactones 60 to 120 mg daily for no longer than 3 months without medical evaluation. 88 However, clinical studies have reported that dosages of kavalactones 60 to 240 mg/day are effective. 13 Kava does not appear to be addictive at therapeutic dosages. 89 An aqueous extract can be prepared by chopping 30 g of the kava roots and extracting with 300 mL of cold water. The traditional extract was derived from 10 g of powdered crude drug and 100 mL of water to yield a product containing kavapyrones 72.6 mg, representing a daily dose of kavapyrones 210 mg when 300 mL are consumed. 12 A study using a special extract of kava containing 70% kavalactones found a dosage of 150 mg/day to be effective for the treatment of anxiety. 43 When used as a sedative, kavalactones 180 to 210 mg may be given 1 hour before bedtime. 4