Kava: Curing or Causing Anxiety?
Kava: Curing or Causing Anxiety?
By Melinda Ring, MD, and Marjorie Alschuler, PhD
Recent reports tying serious liver damage with the herbal sedative kava (Piper methysticum) have created anxiety for consumers, practitioners, and federal regulators. Although the possible connection was strong enough for the Food and Drug Administration (FDA) to issue an advisory, the proof of risk to American consumers was not sufficient for an enforced withdrawal of kava products.1 So the question becomes: Are these adverse reactions significant in light of thousands of years of kava ingestion?
Historical Perspective
The fascinating legends of kava’s use and discovery provide insight into how it became one of today’s most popular herbal remedies.
In the 18th century, Capt. James Cook reported to the Western world of an intoxicating substance encountered on his voyages to the South Seas. Islanders of Oceania (Micronesia, Melanesia, and Polynesia) imbibed a "magical drink" called kava for informal social occasions and ritualistic ceremonies.2 Tribal members prepared the drink first by chewing the root, and then spitting the macerated pieces into a bowl to be pressed and strained with coconut milk. The kava was drunk from the coconut shell, purportedly inducing feelings of harmony and sociability.
The kava ceremony still is performed in some Pacific islands, although more sanitary methods of preparation generally are employed.
Pharmacology
P. methysticum is a slow-growing perennial member of the pepper family.2 The plant may grow to heights of 9 feet or taller, and has sparse heart-shaped leaves. The active ingredients are located in the root/rhizome. The pharmacological activity of kava has been attributed to lipid-soluble compounds known as kavalactones, or kava alpha-pyrones. Of the 15 known kavalactones, kavain, methysticin, and dihydrokavain are considered major components. The root’s kavalactone content varies between 3% and 20%, depending on the plant lineage, age, and cultivation conditions.3
Plasma levels of kavalactones peak 1.8 hours after dosing, and the elimination half-life is nine hours.4 Kavalactones and their metabolites are excreted in urine and feces. Human and animal studies suggest that kavalactones given as part of a crude extract (i.e., with other naturally occurring substances in the root) are more rapidly absorbed, have greater bioavailability, and achieve higher brain concentrations than the isolated compounds.2
Bioactivity of Kavalactones
Although kava is most widely recognized for its psychoactive/anxiolytic effects, it also has sedative, analgesic, anticonvulsant, and neuroprotective properties.
Analgesic/anesthetic. Four of the kavalactones have exhibited analgesic effects in animal studies.5 Kavalactones, particularly kavain, also exert local anesthetic properties similar to cocaine when applied topically or by subcutaneous injection.
Anticonvulsant/neuroprotective. The infarct area from ischemia induced in rats was significantly reduced by kava extract and isolated methysticin and dihydromethysticum, comparable to that provided by the anticonvulsant memantine.6 Kava extracts also halted induced seizures in animal models.
Mechanism of Action
Anxiolytic. Several mechanisms of action for these CNS effects have been postulated, based on results of animal studies and in vitro assays.3,7 Reduced excitability of the limbic system, particularly the amygdala complex, appears responsible at least in part for emotion modulation by kavalactones. In contrast to most hypnotic-sedatives, such as benzodiazepines, kavalactones inconsistently bind GABA or benzodiazepine receptors. Potentiation of GABA neurotransmission could occur by other means such as altering receptor domains. Inhibition of monoamine oxidase and noradrenaline uptake also may contribute to kava’s psychoactivity.
Other effects. Analgesia does not appear to operate by opiate pathways, since opiate-receptor binding was not found, and naloxone is ineffective in reversing the effect.
The anticonvulsant and neuroprotective actions may result from inhibition of voltage-dependent sodium channels, similar to several traditional anti-epileptics. Antithrombotic effects may assist in cerebrovascular protection. COX-I and COX-II inhibition by six compounds from kava extract was demonstrated; the kavalactones dihydrokavain and yangonin were the most potent in this assay.8 Kavain also has been found to reduce platelet aggregation, presumably from reversible inhibition of cyclooxygenase, and thence thromboxane A2 production.9 Antioxidant activity of some kavalactones also was demonstrated in a free radical scavenging assay.8
Clinical Evidence of Efficacy in Anxiety
Ernst et al published a systematic literature review and meta-analysis of randomized controlled trials culled from MEDLINE, EMBASE, Biosis, AMED, CISCOM and the Cochrane Library.10,11 Only studies on kava as a singular extract, not as part of an herbal combination product, were included. The authors identified seven double-blind placebo-controlled studies, six of which met criteria for methodological quality. Three trials that used the Hamilton Rating Scale for Anxiety (HAM-A) as the main outcome measure (see Table 1), and employed the same dose kava extract WS1490, were suitable for inclusion in a meta-analysis (see Table 2).
The results of the meta-analysis showed a significant reduction in baseline HAM-A scores (9.69 out of possible total score of 56, 95% confidence interval 3.54-15.83) after treatment for 4-24 weeks. The number needed to treat ranged from six to 21. The remaining four studies also demonstrated superiority of kava extract over placebo using varied anxiety measurements and dosages of 60-240 mg kavalactones daily.
Acceptance of these positive findings has been cautious due to criticisms about the small sample sizes, brief treatment duration, and ill-defined patient populations.12
|
Table 1 |
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|
Hamilton Rating Scale for Anxiety (HAM-A) |
||
| I. Symptoms | ||
| A. Anxious mood | F. Depressed mood | K. Gastrointestinal symptoms |
| 1. worries | 1. decreased interest in activities | 1. dysphagia |
| 2. anticipates worst | 2. anhedonia | 2. nausea or vomiting |
| B. Tension | 3. insomnia | 3. constipation |
| 1. startles | G. Somatic complaints: muscular | 4. weight loss |
| 2. cries easily | 1. muscle aches and pains | 5. abdominal fullness |
| 3. restless | 2. bruxism | L. Genitourinary symptoms |
| 4. trembling | H. Somatic complaints: sensory | 1. urinary frequency or urgency |
| C. Fears | 1. tinnitus | 2. dysmenorrhea |
| 1. fear of the dark | 2. blurred vision | 3. impotence |
| 2. fear of strangers | I. Cardiovascular symptoms | M. Autonomic symptoms |
| 3. fear of being alone | 1. tachycardia | 1. dry mouth |
| 4. fear of animals | 2. palpitations | 2. flushing |
| D. Insomnia | 3. chest pain | 3. pallor |
| 1. difficulty falling asleep or staying asleep | 4. sensation of feeling faint | 4. sweating |
| 2. difficulty with nightmares | J. Respiratory symptoms | N. Behavior at interview |
| E. Intellectual | 1. chest pressure | 1. fidgets |
| 1. poor concentration | 2. choking sensation | 2. tremor |
| 2. memory impairment | 3. shortness of breath | 3. shortness of breath |
| II. Interpretation | ||
| A. Symptoms above are graded on scale: | B. Criteria | |
| 1. 0 = Not present | 1. 18-24 = Mild anxiety | |
| 2. 4 = Very severe | 2. 25-29 = Moderate anxiety | |
| 3. 30+ = Severe anxiety | ||
| Table 2 | ||||
|
Trials included in the meta-analysis of kava extract WS1490 for treatment of anxiety |
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| Study | Patient Profile | Duration | HAM-A Score-Kava | HAM-A Score-Placebo |
| Baseline/final (reduction) | Baseline/final (reduction) | |||
| Kinzler et al | Outpatients with anxiety syndrome of non-psychotic origin; HAM-A > 19; n = 58 | 4 weeks | 25.3/12.6 (-12.7) | 24.3/21.0 (-3.3) |
| Warnecke et al | Postmenopausal female patients with anxiety syndrome; HAM-A > 19; n = 40 | 8 weeks | 31.1/5.5 (-25.6) | 30.2/22.5 (-7.7) |
| Volz et al | DSM-IIIr-diagnosed anxiety syndromes of non-psychotic origin;* HAM-A > 19; n = 101 | 24 weeks | 30.7/9.7 (-21.0) | 31.4/15.2 (-16.2) |
|
* Includes generalized anxiety disorder, adjustment disorder with anxiety, agoraphobia, and specific phobia. |
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Adapted from: Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: Systematic review and meta-analysis. J Clin Psychopharmacol 2000;20:84-89. |
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Preparation/Dosage
Commercial kava supplements usually are standardized to either 30% or 70% kavalactone content (e.g., 30 mg or 70 mg kavalactones per 100 mg total). These formulations are prepared by extraction from dried kava root with ethanol-water (30%) and acetone-water (70%) mixtures.
Many clinical studies involve 70 mg kavalactones given in three doses daily (known as WS1490). Recommended daily dosages for the treatment of anxiety disorders range from 120 mg to 225 mg kavalactones in divided doses, with maximum limits of 120 mg recommended by the German Commission E and 300 mg by an herbal product trade group.13
A tea prepared from 2-4 g of rootstock simmered for 5-10 minutes in 150 mL water also may be imbibed three times a day, although the kavalactone content will be more variable.
Safety: Drug and Disease Interactions
Hepatic. The greatest concern regarding adverse effects is whether kava causes liver toxicity. In Germany and Switzerland, 25 cases of serious conditions have been reported including hepatitis, cirrhosis, and liver failure.1 The sale of the kava extract associated with these problems has been prohibited in Switzerland, and German authorities have proposed a similar ban. One report of hepatotoxicity identified the patient as having decreased metabolism by cytochrome P450 secondary to CYP2D6 deficiency, and proposed this as a risk factor for liver damage.14 In susceptible patients, symptoms and abnormal labs suggestive of hepatotoxicity may appear as soon as one month after regular use.
Neurologic. There are several reports of extra-pyramidal-like dystonic reactions (oral/lingual dyskinesia, torticollis, oculogyric crisis, painful twisting movements of the trunk) as well as exacerbation of Parkinson’s disease.15
The use of kava with CNS depressants (e.g., sedatives, alcohol, and antipsychotics) is discouraged. One report attributed a coma, reversed after cessation of all medications, to kava-benzodiazepine drug interaction.16 Current recommendations suggest cessation of kava use at least 24 hours before surgery to avoid potentiation of the sedative effects of anesthetics.4 A double-blind crossover study of oxazepam and kava extract showed that, unlike benzodiazepines, kava did not impair cognitive performance and vigilance.17
Dermatologic. Kava dermopathy is a well-defined entity associated with prolonged intake of high-doses (> 400 mg kavalactones daily), although there have been several reports of onset after only 2-3 weeks at recommended doses. It manifests as dry, scaling areas with yellow pigmentation most prominent on the palms, soles, forearms, shins, and torso.18 Dermopathy usually reverses after cessation of kava use.
Addiction. Abuse potential does exist; however, issues such as whether it can result in withdrawal syndromes, addiction, and tolerance still need clarification. In the seven clinical trials analyzed by Ernst, no reports of withdrawal after cessation of the extract were reported.
Other. Use of kava with antiplatelet agents is discouraged to prevent bleeding complications due to COX inhibition. Avoidance is recommended in pregnancy/lactation. Chronic heavy use (mean 440 g/wk) among Pacific Islanders was found to result in elevated liver enzymes, hematuria, macrocytic anemia, lymphopenia, increased patellar reflexes, significant weight loss, hypoalbuminemia, rash, and social problems similar to alcoholism.19,20
Conclusion
Despite some problems with methodology, the recent meta-analysis and literature review support the efficacy of kava in treating a variety of anxiety disorders. Insufficient proof exists for the use of kava for other indications. Unfortunately, the escalating reports of serious hepatotoxicity abroad warrant close examination of whether the evidence for benefit is strong enough to outweigh potential risks.
Recommendation
The FDA is investigating whether U.S. formulations carry the same risks of liver damage as their European counterparts. Until this question is answered, or predictive risk factors for susceptibility are identified, it would be prudent to suggest that patients avoid products containing kava extracts. Patients should be warned to check the labels of combination products, such as "Herbal Ecstacy," which often contain kava. For those patients who choose to use kava, emphasize the need to limit use to one month, since most hepatic damage does not occur before that time. Avoid herb-drug interactions and monitor closely for problems.
Dr. Alschuler is Medical Education Specialist, and Dr. Ring is Clinical Training Attending Physician and Coordinator, CAM Curriculum, Internal Medicine Residency Training Program, St. Joseph Hospital, Chicago, IL.
References
1. Food and Drug Administration letter to health care professionals, Dec. 19, 2001. Available at: www.fda.gov/medwatch/safety/2001/kava.htm. Accessed June 10, 2002.
2. Piper methysticum (kava). In: Pizzorno JE, Murray MT, eds. Textbook of Natural Medicine. 2nd. ed. Philadelphia, PA: Churchill Livingstone, Inc.; 1999.
3. Pepping J. Kava: Piper methysticum. Am J Health Syst Pharm 1999;56:957-960.
4. Ang-Lee M, et al. Herbal medicine and perioperative care. JAMA 2001;286:208-216.
5. Jamieson DD, Duffield PH. The antinociceptive actions of kava components in mice. Clin Exp Pharmacol Physiol 1990;17:495-507.
6. Backhauss C, Krieglstein J. Extract of kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol 1992;215:265-269.
7. Beaubrun G, Gray GE. A review of herbal medicines for psychiatric disorders. Psychiatr Serv 2000;51: 1130-1134.
8. Wu D, et al. Cyclooxygenase enzyme inhibitory compounds with antioxidant activities from Piper methysticum (kava kava) roots. Phytomedicine 2002;9:41-47.
9. Gleitz J, et al. Antithrombotic action of the kava pyrone (+)-kavain prepared from Piper methysticum on human platelets. Planta Med 1997;63:27-30.
10. Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: Systematic review and meta-analysis. J Clin Psychopharmacol 2000;20:84-89.
11. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 2002:CD003383.
12. Abadi S, et al. Is kava effective for treating anxiety? Can Fam Physician 2001;47:1745-1747.
13. Ronan A, deLeon D. Kava for the treatment of anxiety. Altern Med Alert 1998;1:85-88.
14. Russmann S, et al. Kava hepatotoxicity. Ann Intern Med 2001;135:68.
15. Meseguer E, et al. Life-threatening parkinsonism induced by kava-kava. Mov Disord 2002;17:195-196.
16. Almeida JC, Grimsley EW. Coma from the health food store: Interaction between kava and alprazolam. Ann Intern Med 1996;125:940-941.
17. Munte TF, et al. Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word recognition task. Neuropsychobiology 1993;27:46-53.
18. Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000;143:923-929.
19. Kava R. The adverse effects of kava. Pac Health Dialog 2001;8:115-118.
20. Mathews JD, et al. Effects of the heavy usage of kava on physical health: Summary of a pilot survey in an aboriginal community. Med J Aust 1988;148:548-555.
Ring M, Alschuler M. Kava: Curing or causing anxiety? Altern Med Alert 2002;5:89-93.Subscribe Now for Access
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