Transcript Dietary Supplements: Kava

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
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 >40yo
Mean duration 20 years
Comorbidity:
• 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 GABAgated channel opening
 Benzodiazepine (Valium)
Potentiates GABA action
Increases frequencyof GABAgated 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 ingredients
15 compounds have been isolated
Extracts in US contain ~30% kavalactones
however, receptor targets and mechanisms of action are
unknown.
Effectiveness of Kava in
the treatment of anxiety.
Publications in peerreviewed 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 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
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)
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
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
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)
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)
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.
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)
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
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
Other published studies
 Kava-kava extract WS 1490 versus placebo in
anxiety disorders - a randomized placebocontrolled 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
Other published studies
 Effect of a special kava extract in patients with anxietytension 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
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.”
Problems with Kava?
 FDA issues Consumer Advisory
March 2002
 KAVA-CONTAINING DIETARY SUPPLEMENTS
MAY 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 movements
scaly, yellowed skin
kava dermopathy
potential 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 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
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?