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

Dietary Supplements:Kava: a case study

NUTR 547 - Nutrition UpdateDavid 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

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.

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.

Kava (Kava-Kava)Piper methysticum

Claims: Relieve stress and

anxiety Muscle relaxant, pain

reliever, diuretic, and remedy for insomnia.

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

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 >40yoMean duration 20 yearsComorbidity:

• insomnia

Other anxiety disorders (~18%) panic, obsessive-compulsive, post-traumatic stress,

phobias

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

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

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 ingredients15 compounds have been isolatedExtracts in US contain ~30% kavalactoneshowever, receptor targets and mechanisms of action

are unknown.

Effectiveness of Kava in the treatment of anxiety.

Publications in peer-reviewed scientific journals

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



Treatment 3 x 50 mg/day WS.1490 or placebo 4 weeks

Outcome measure Anxiety Status Inventory score

observer rating score



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)



% of patients with ASI improvement of >5 points was 12% greater in Kava extract group than placebo



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



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)

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 antidepressantBuspirone: US drug, 5-HT receptor agonist

Study design 84% female

Outcome measures Hamilton Anxiety Scale (HAMA) Boerner Anxiety Scale (BOEAS)

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.



~75% of patients responded well to treatments ~ 2/3rd patients fully remitted (non-significant trend in favor of Opipramol)

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 tolerabilityKava: 86%, Busprione: 95%, Opipramol: 98%

elevated liver enzymesKava: 2, Busprione: 3, Opipramol: 2 patientsno significant heptotoxic reactions



Conclusion: “patients suffering from GAD may

benefit from an acute treatment with Kava.”

Comments (Gee) no placebo group

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 measuresHAMA subscoresclinical global impressionself-report symptom inventoryadjective mood scale


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


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.”

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)

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

Other reported effects of Kava

Dystonia Abnormal muscle spasms or involuntary

muscle movementsscaly, yellowed skin

kava dermopathypotential interaction with other drugs

anti-Parkinson’s medications less effective additive sedative effect with Xanax

(bensodiazepine)

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 drugNoted 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

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

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?

Documents

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