Kava Kava (Piper Mthysticum) Supplements Exposed
Kava kava (Piper methysticum) is a perennial shrub with a heart-shaped leaf. It was discovered by Captain Cook, who named the plant “intoxicating pepper.” Ceremonially, kava kava had been used in the Pacific regions of Polynesia, Melanesia, and Micronesia as a beverage to induce relaxation and thus promote discussion and interaction. It was prepared by chewing the root, which became fermented in saliva, leaving a bitter, hot, numbing taste. Other preparations included pounding the root or grating it into a powder and using hot water to extract die kava. Currently, kava kava also known more simply as kava is prepared commercially by either ethanol or acetone, which yields 30-70% kava lactones, respectively. The active components of kava are referred to as kavapyrones and consist of kavain, dihydrokavain, methysticin, dihydrornethysticin, yangonin, and desmethoxyyangonin.
Although only the anxiolytic properties of kava have been studied in humans to date, empirical data suggest usefulness in several other areas. In response to a report about alleged hepatotoxic reactions to kava use, worldwide controversy sprang up (FDA/CFSAN Consumer Advisory, 2002). As a result, kava was banned in many countries, and Merck, the manufacturer of two kava supplements, withdrew the supplements from the market (Abt and Hammerly, 2003; DerMarderosian, 2003).
The pharmacologic mechanism of action of kava is largely attributed to the kavapyrones kavain, dihydrokavain, methysticin, dihydromethys-ticin, and yangonin. Preliminary evidence indicates kava can inhibit the cytochrome P4503A4 enzyme and possibly others. In vitro, kava extract and kavapyrones, desmethoxyyangonin, and methysticin have been shown to be reversible inhibitors of monoamine oxidase B through competitive inhibition. In vitro, two kavapyrones have been shown to inhibit the uptake of noradrenaline in the cerebral cortex, suggesting antidepressant activity. The sedative effects of kava may be the result of an increased numbers of y-amino butyric acid (CABA)-binding sites or dopamine antagonism. The psychotropic actions of kava are thought to stem from the kavapyrones (+)-methysticin, and (+)-kavain, by noradrenaline uptake inhibition. Kava is also thought to inhibit inflammation by inhibiting COX-1 and COX-2.
Reports Unking liver toxicity to kava use have been widely debated, and their validity is still controversial. A systematic review of clinical trials and short-term post marketing surveillance studies found that the adverse effects associated with kava use are rare, mild, and reversible. Although the data for short-term use of kava have found it to be safe, with only mild side effects, more studies on the side effects of long-term use would benefit our understanding of its use for longer periods (Stevinson et ah, 2002).
A meta-analysis of randomized, double-blind, placebo-controlled studies of kava found that 11 trials with a total of 645 participants met die criteria for the analysis. The analysis of six of die trials found the Hamilton Anxiety Scale (KAMA) total score to show a significant improvement in symptoms, with few adverse effects (Pittler and Ernst, 2003).
An earlier meta-analysis by Pittler and Ernst (2000) found seven trials met the inclusion criteria. All seven trials suggested that kava extract was better than a placebo for anxiety; the m eta-analysis of three of the trials suggested a significant lowering in the HAMA total score for anxiety for the use of kava over a placebo.
Lehrl (2004) tested the clinical effects of a kava extract (WS 1490) in sleep disturbances associated with anxiety disorders. In the multicenter, randomized, double-blind study, 61 patients received 200 mg of the extract or a placebo for 4 weeks. A significant increase in the quality of sleep and the recuperative effect after sleep was found for the group taking the kava extract. The HAMA also showed superior effects for kava, and significant effects were found in the self-ratings of well-being.
A double-blind, placebo-controlled study was conducted to obtain dosage range information on kava (WS 1490) in patients with nonpsy-chotic anxiety. The drug was well tolerated and had a safety profile with no drug-related adverse events or post-study withdrawal symptoms. The authors found that 150 mg of WS 1490 was an effective treatment for nonpsychotic anxiety syndromes (Geier and Konstantinowicz, 2004).
In an earlier randomized, placebo-controlled, double-blind study, kava was studied for its effect on climacteric-related symptomology. Patients received 300 mg of kava (WS 1490) 3 times daily or a placebo for S weeks. After only 1 week of treatment, the target variable anxiety as measured by the HAMA showed significant improvement. Over the study period, kava showed a high level of efficaq’ for neurovegetative and psychosomatic dysfunctions in the climacteric woman (War-necke, 1991).
In a randomized, double-blind placebo-controlled study, kava was tested for its effect on anxiety syndrome. Kava (WS 1490, or Laitan) was given at the rate of 100 mg 3 times daily for 4 weeks, or a placebo was administered. After 4 weeks, the HAMA score was significantly improved, as was the Adjectives List Scale and the Clinical Global Impression Scale. No adverse effects were found (Kinzler et al., 1991).
In an S-week, randomized, multicenter, double-blind, controlled study, 400 mg of kava (LI) was studied for generalized anxiety disorder. Kava or one of two reference drugs, buspirone (10 mg) or opipramol (100 mg) was given to 129 outpatients. Kava was found lo be as effective as the reference drugs and well tolerated in the acute treatment of people suffering from generalized anxiety disorder (Boerner et al., 2003).
In a 5-week, randomized, placebo-controlled, double-blind study, kava was investigated for its use for treating nonpsychotic nervous anxiety, tension, and restlessness. Kava (WS 1490) was administered at the dosage of 50 mg/day, increasing to 300 mg/day in the first week as the pretreatment of benzodiazepines was tapered off over 2 weeks. The kava extract was found to be superior to the placebo according to the H/VMA and a subjective well-being scale. The tolerance to kava was the same as to the placebo. The authors concluded that further symptom reduction is possible after a changeover from benzodiazepine treatment (Malsch and Keiser, 2001).
De Leo et al. (2001) studied the use of kava in combination with hormone replacement therapy in the treatment of menopausal anxiety. A significant reduction in the HAMA score was observed in four groups receiving hormone replacement therapy, with or without progestogens and with kava extract or placebo for 6 months. The groups with kava treatment had the more significant reductions in HAMA scores, and the authors concluded that kava accelerated the betterment of psychological symptoms with hormone therapy. An earlier study also investigated the use of kava wth hormone replacement therapy and found significantly lower HAMA scores after 3 and 6 months of treatment in all four groups studied, although the groups treated with kava in combination with the hormone replacement showed the best improvements (De Leo et al., 2000).
In a study on anxiety of nonpsychotic origin (criteria of ihe, Diagnostic and Statistical Manual of Mental Disorders [DSM-IH-R: agoraphobia, specific phobia, generalized anxiety disorder, and adjustment disorder with anxiety), kava (YVS 1490) was tested in a multicenter, randomized, placebo-controlled, double-blind test design. Starting at week 8, the kava treatment group resulted in significant improvement in HAMA scores as well as other secondary outcomes. The authors concluded that this supported using WS 1490 instead of tricyclic antidepressants and benzo-diazepines in anxiety disorders, with none of the side effects of conventional treatment (Volz and Kieser, 1997).
In a placebo-controlled, double-blind trial with 84 subjects, kavain improved memory and reaction time. In a similar study with 38 subjects, kavain showed equivalent activity to oxazepam (Lindenberg and Pitule-Schodel, 1990).
For typical anxiolytic uses, 70% kava lactones (kavapyroties) is recommended. In capsule form, the recommended dosage is 300 mg (70 mg kava lactone) daily for 1 to 8 weeks. As a tincture, 30 drops with water 3 times daily is recommended. Dosage varies depending on the kava lactones present in the source. For the typical tea preparation, 2-4 g of kava root should be simmered in 150 mL of boiling water for 5-10 minutes and then strained (Abt and Hammerly, 2003; Blinker, 2002; Cupp, 2000).
Kava can adversely affect the liver, possibly leading to hepatitis, cirrhosis, and liver failure requiring a transplant. The use of kava for as little as 1-3 months has resulted in the need for liver transplants, and even death. Symptoms may resolve following discontinuation. Other adverse effects include gastrointestinal distress, headache, dizziness, drowsiness, enlarged pupils, disturbances of oculomotor equilibrium and accommodation, dry mouth, allergic skin reaction (rare), and extrapyramidal supplements). With chronic use at high doses (greater than 400 mg/day), endocrine and metabolic effects can result, including weight loss, reduced protein levels, puffy face, hematuna, increased red blood cell volume, decreased platelets and lymphocytes, and possible pulmonary hypertension. Chronic use of kava has also been associated with dermopathy (reddened eyes; dry, scaly, flak)’ skin; temporary yellow discoloration of the skin, hair, and nails). These effects usually resolve with discontinuation (Abt and Hammerly, 2003; Brinker, 2002; Cupp, 2000).
Many concerns have been expressed about the use of kava with alcohol. In reality, this effect varies with the type of extract. For example, 200 mg/kg of kava lipid-soluble extract (resin administered orally in mice) increased the hypnotic effect of ethanol, whereas kava extract (WS 1490, administered orally in humans) showed no negative additive effects (Lehrl, 2004). The risk of drowsiness and motor reflex depression is increased because of depression of the central nervous system. Py rones in kava with pentobarbital increased sleeping time in mice (Abt and Hammerly, 2003; Brinker, 2002; Cupp, 2000).
Possible drug interactions include the following:
Levodopa:Thekavapyroneyangonin is a potent dopamlne antagon ist that decreases the efficacy of levodopa and worsens the symptoms of Parkinson disease.
Benzodiazepines: In vitro, kavapyrones may indirectly increase the affinity of GABAA-receptor binding sites with the use of alprazolam and may increase the number of GABA binding sites. Other studies report the possible interaction because ofkava’s inhibition of cytochrome P450 enzymes.
Strychnine: Kavapyrones kavain, dihydrokavain, methysticin, and dihydromethysticin protect against strychnine poisoning more effectively than does mephenesin.
Warfarin: Because of its interaction with the cytochrome P450 sys tem, kava may increase warfarin’s effects.
Antiplatelets: May result in an increased risk of bleeding.
Monoamine oxidase inhibitors: Additive effects.
Hepatotoxic drugs: Include, but are not limited to, acarbose, amiodarone, atorvastatin, azalhioprine, carbamazepine, gemfibrozil, itraconazole, methotrexate, valproic acid, zileuton.
Hepatotoxic herbals: Include, but are not limited to, chaparral (Larrea tridenlate), Russian comfrey (Symphytitm x uplandicum], coltsfoot (Tussi/ago farfara], germander (Teiicmtm chamaedtys], Jin bu huan, pennyroyal [Mentha pitlegiitm, Hedeoma pulegoides], and petasites [Petasites japcmicits]. Additionally, androstenedione, coenzyme Q10 (in high doses), dehydroepiandrosterone, niacin, red yeast, skullcap, and valerian have been reported to adversely affect the liver with concomitant use.
Sedative herbals: Include, but are not limited to, 5-HTP, calamus, calendula, California poppy, catnip, capsicum, celery, couch grass, elecampane, German chamomile, goldenseal, gotu kola, hops, Jamaican dogwood, lemon balm, melatonin, sage, St, John’s wort, sassafras, skullcap, shepherd’s purse, Siberian ginseng, stinging neLde, valerian, carrot, wild lettuce, ashwangandha root, and yerba mansa; all may increase the risk of excessive drowsiness with concomitant use with kava (Abt and Hammerly, 2003; Kri nicer, 2002; Cupp, 2000).
Kava is not good in pregnancy because pyrones may result in the loss of uterine tone. Pyrones may also he carried in breast milk. Kava resin and the pyrones dihydrokawain and dihydromethysticin may contribute to suicidal tendencies. Kava is associated with elevated liver trans-aminases with or without concomitant hepatic damage. Patients with Parkinson disease should not use kava because of its dopamine antagonism (Abt and Hammerly, 2003; Drinker, 2002; Cupp, 2000).
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