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Dietary Supplements: Kava: a case study

Dietary Supplements: Kava: a case study. NUTR 547 - Nutrition Update David L. Gee, PhD Summer 2006. Learning Objectives. Identify health claims associated with kava use. Define generalized anxiety disorder and describe its prevalence. Describe the biology and therapeutic control of anxiety.

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Dietary Supplements: Kava: a case study

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  1. Dietary Supplements:Kava: a case study NUTR 547 - Nutrition Update David L. Gee, PhD Summer 2006

  2. Learning Objectives • Identify health claims associated with kava use. • Define generalized anxiety disorder and describe its prevalence. • Describe the biology and therapeutic control of anxiety

  3. Learning Objectives • Name the active chemical in kava • Describe the effect of kava on anxiety compared to placebo and pharmacologic agents in RCT’s. • Describe the current status of kava availability in Europe, Canada, and the US.

  4. Learning Objectives • Describe the health concerns related to kava use. • Describe the rationale behind the criticism of the evidence used in the restriction of kava availability.

  5. Kava (Kava-Kava)Piper methysticum • Claims: • Relieve stress and anxiety • Muscle relaxant, pain reliever, diuretic, and remedy for insomnia.

  6. Traditional Uses of Kava • Perennial shrub native to Pacific Islands • Tea prepared from dried ground, pounded, grated, (chewed) • Traditionally used in ceremonies valued for its tranquilizing and relaxant effects • weddings, births, funerals, official ceremonies

  7. Anxiety and Sleep Disorders • Anxiety (General Anxiety Disorder) • Apprehension, tension, uneasiness • Normal unless it becomes disruptive/affects normal function • Estimated lifetime prevalence of ~5% (NIMH, 2006) • May be 2X higher in women >40yo • Mean duration 20 years • Comorbidity: • insomnia • Other anxiety disorders (~18%) • panic, obsessive-compulsive, post-traumatic stress, phobias

  8. The biology of controlling anxiety • Gamma-amino benzoic acid (GABA) • Major inhibitory neurotransmitter of CNS • GABA receptor–chloride ion channel macromolecular complex • Binding of GABA increases flow of Cl- into neuron and decreases firing rate

  9. Therapeutic treatment of anxiety • Barbituates • Potentiates GABA action • Increase duration of GABA-gated channel opening • Benzodiazepine (Valium) • Potentiates GABA action • Increases frequencyof GABA-gated channel opening • Both drugs involve risk of overdose, tolerance, habituation, and addiction

  10. Chemical composition of Kava • Dried root • Starch (43%), fiber (20%), sugar (3%), protein (3.5%), minerals (3%), kavalactones (15%) • Kavalactones (Kava pyrones) are pharmacologic active ingredients • 15 compounds have been isolated • Extracts in US contain ~30% kavalactones • however, receptor targets and mechanisms of action are unknown.

  11. Effectiveness of Kava in the treatment of anxiety. Publications in peer-reviewed scientific journals

  12. Treatment of anxiety, tension and restlessness states with Kava special extract WS.1490 in general practice: A randomized placebo-controlled double-blind multicenter trial.Phytomedicine (2003) 10:631 • Specific aim • investigate the efficacy and tolerability of 150mg of a special monoextract of Kava (70% kavalactones, 105 mg/d kavalactones) in patients with anxiety, tension, and restlessness states. • Study design • randomized, double blind, placebo-controlled, multicenter trial • Subjects • 141 patients with generalized anxiety disorder (>18 on Hamilton anxiety Scale) • 74% female, mean age = 48.8 yo

  13. Treatment of anxiety, tension and restlessness states with Kava special extract WS.1490 in general practice: A randomized placebo-controlled double-blind multicenter trial.Phytomedicine (2003) 10:631 • Treatment • 3 x 50 mg/day WS.1490 or placebo • 4 weeks • Outcome measure • Anxiety Status Inventory score • observer rating score

  14. Treatment of anxiety, tension and restlessness states with Kava special extract WS.1490 in general practice: A randomized placebo-controlled double-blind multicenter trial.Phytomedicine (2003) 10:631 • Anxiety status inventory score decreased in both Kava and placebo group • NS between treatments based on final ASI score • Kava group change from baseline significantly greater (p<.001)

  15. Treatment of anxiety, tension and restlessness states with Kava special extract WS.1490 in general practice: A randomized placebo-controlled double-blind multicenter trial.Phytomedicine (2003) 10:631 • % of patients with ASI improvement of >5 points was 12% greater in Kava extract group than placebo

  16. Treatment of anxiety, tension and restlessness states with Kava special extract WS.1490 in general practice: A randomized placebo-controlled double-blind multicenter trial.Phytomedicine (2003) 10:631 • Liver function tests showed no significant change in either Kava extract or placebo group • 10% of subjects did not complete experiment; none deemed related to adverse drug effects

  17. Treatment of anxiety, tension and restlessness states with Kava special extract WS.1490 in general practice: A randomized placebo-controlled double-blind multicenter trial.Phytomedicine (2003) 10:631 • Conclusions • Kava extract was effective in reducing severity of symptoms associated with anxiety. • Not as effective as earlier studies using 300mg/d • 300 mg/d dosage commonly used • 150 mg/d dosage recommended by German regulatory agency (Commission E). • Noted by Gee • variation in AIS scores between subjects so large, such that final AIS score not different between treatments. • Difference between Kava extract and placebo not great. • “beneficial effect…in patient’s self-assessment…” (These results not reported)

  18. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalized Anxiety disorder: an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.Phytomedicine (2003) 10:38. • Specific aim • investigate the efficacy of a Kava extract 400 mg/d (120 mg/d kavapyrones) in the treatment of GAD compared to two commonly used drugs. • Opipramol: German drug, tricyclic antidepressant • Buspirone: US drug, 5-HT receptor agonist • Study design • 84% female • Outcome measures • Hamilton Anxiety Scale (HAMA) • Boerner Anxiety Scale (BOEAS)

  19. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalized Anxiety disorder: an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.Phytomedicine (2003) 10:38. • Mean HAMA scores decreased from 23 to 8 after 8 weeks of treatment. • No significant difference in HAMA scores between treatments.

  20. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalized Anxiety disorder: an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.Phytomedicine (2003) 10:38. • ~75% of patients responded well to treatments • ~ 2/3rd patients fully remitted (non-significant trend in favor of Opipramol)

  21. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalized Anxiety disorder: an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.Phytomedicine (2003) 10:38. • Safety • total 57 adverse events reported • trend towards more events under Kava medication • Kava: 27, Busprione: 16, Opipramol: 14 • no systematic differences between treatments noted • investigator rated tolerability (“good or very good” • Kava: 86%, Busprione: 98%, Opipramol: 98% • subject rated tolerability • Kava: 86%, Busprione: 95%, Opipramol: 98% • elevated liver enzymes • Kava: 2, Busprione: 3, Opipramol: 2 patients • no significant heptotoxic reactions

  22. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalized Anxiety disorder: an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.Phytomedicine (2003) 10:38. • Conclusion: • “patients suffering from GAD may benefit from an acute treatment with Kava.” • Comments (Gee) • no placebo group

  23. Other published studies • Kava-kava extract WS 1490 versus placebo in anxiety disorders - a randomized placebo-controlled 25 week outpatient trial. • Pharmacopsychiatry. (1997) 30:1-5 • HAMA scores showed pronounced decrease in both groups • Kava group (210 mg/d kavalactones)significantly better from week 8 to end of study • Kava group more effective in other outcome measures • HAMA subscores • clinical global impression • self-report symptom inventory • adjective mood scale

  24. Other published studies • Effect of a special kava extract in patients with anxiety-tension and excitation states of nonpsychotic genesis. Double blind study with placebos over 4 weeks. • Arzneimittelforschung. (1991)41:584-588. • 58 patients, Kava extract WS 1490, • patients taking kava extract had a significant reduction in anxiety (HAMA) • magnitude of anxiety reduction increased with time

  25. Other published studies • Efficacy of kava extracts for treating anxiety: systematic review and meta-analysis. • J. Clin. Psychopharm. (2000) 20:84-89. • Systematic review and meta-analysis • superiority of kava extract over placebo in all seven reviewed trials • meta-analysis using HAMA show significant effect of kava extract over placebo • “Therefore, kava extract is an herbal treatment option for anxiety that is worthy of consideration.”

  26. Problems with Kava? • FDA issues Consumer Advisory • March 2002 • KAVA-CONTAINING DIETARY SUPPLEMENTSMAY BE ASSOCIATED WITH SEVERE LIVER INJURY • “...advising consumers of the potential risk of severe liver injury associated with the use of kava-containing dietary supplements.” • Based on • 25 reports of adverse effects (liver related injuries) in other countries • four patients requiring liver transplants • Actions of regulatory agencies in Germany, UK, Switzerland, France • consumer warnings • removal of products (Germany and UK)

  27. Problems with Kava? • CDC - MMWR • Nov. 2002 • Hepatic Toxicity Possibly Associated with Kava-Containing Products --- United States, Germany, and Switzerland, 1999--2002 • 11 patients with liver failure and underwent liver transplantation after using Kava supplements • described two patients in US • Council for Responsible Nutrition • supports FDA Consumer Advisory • recommends warning label on Kava supplements

  28. Other reported effects of Kava • Dystonia • Abnormal muscle spasms or involuntary muscle movements • scaly, yellowed skin • kava dermopathy • potential interaction with other drugs • anti-Parkinson’s medications less effective • additive sedative effect with Xanax (bensodiazepine)

  29. Problems with Kava? • Kava: a test case for Canada’s new approach to natural health products. • Can. Med. Assoc. J. (2003) 169:1163. • Canada reclassifies Kava as a conventional drug • Noted weaknesses in case against kava • all were case reports • some patients taking other potentially hepatotoxic drugs • concurrent alcohol use not always noted • duration of kava use not always noted • different types of kava extracts were used

  30. Impact on Kava use • Kava Use • banned in major European countries and Australia • prescription drug in Canada • warnings in US • use and production of kava greatly reduced • US companies advised to suspend sales to avoid potential lawsuits • research studies on hold due to ethical issues

  31. Summary and Recommendations (Gee) • Kava appears to be more effective than placebo in reducing anxiety • Kava appears to be as effective as current prescription drugs without addictive/tolerance effects • Hepatotoxic effects of kava are relatively rare (and perhaps unproven) • Recommend: kava use should be supervised by physicians • German Commission. E had approved kava for GAD at 70 mg/d kavalactones and 180-210 mg/d kavalactones as a sleep aid. • Is Kava a food (dietary supplement)? • Or is it a drug?

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