NUTR 547- Nutrition Update Kim McCorquodale Summer 2006 An Overview of Ephedra.

NUTR 547- Nutrition Update

Kim McCorquodale

Summer 2006

An Overview of EphedraAn Overview of Ephedra

Ephedra Ban Puts Market on Notice CBS News- 12/31/2003

The FDA’s Latest Scapegoat: Ephedra Idaho Observer -1/2004

FDA’s Ephedra Ban Takes Effect Web MD Medical News -4/12/2004

“We have a tremendous burden of proof in order to take supplements off of the market. We crossed the t’s and dotted the i’s so that the ephedra ban should stand up in court.” Human Services Secretary Tommy Thompson

In the News…In the News…

FDA Ban on Ephedra Overturned Seattle Times -4/15/2005

FDA Wants Ephedra Ban Restored CBS News -5/9/2006

Chinese Point Finger and Laugh at Stupid Americans

“We’ve had this stuff for like 5000 years. The Americans get it for a few decades and screw it all up. Morons.” Zhou Li Quing- spokesperson for the Chinese Herbal Safety Committee -12/03/2003

In the News…In the News…

EphedraEphedraEphedraceae sinicaEphedraceae sinica

An evergreen shrub native to central Asia

Predominant active alkaloid- ephedrine

Other active alkaloids include:

pseudoephedrine norephedrine norpseudoephedrine

Tea prepared from dried, comminuted branches

Used for ~5000 yrs. by practitioners of traditional Chinese medicine (TCM) to treat asthma, flu, and nasal congestion

Combined with other herbs to enhance or decrease effects

Traditional Uses of ephedra (ma huang)Traditional Uses of ephedra (ma huang)

History of Conventional Uses of EphedraHistory of Conventional Uses of Ephedra

1887- Ephedrine first isolated by Japanese chemist, N. Nagai

1920’s- Series of studies on ephedrine’s pharmacological properties leads to synthetic production

1927- Widely used as a nasal decongestant, central nervous system stimulant, and to treat bronchial asthma

1950’s- Many reports of side effects such as blood pressure and heart rate lead pharmaceutical companies to switch to pseudoephedrine

Physiological EffectsPhysiological Effects Strong stimulant- enhances the release of norepinephrine

(NE) from sympathetic nerve endings (see handout) Has 1 and 2 agonist activityrelaxes bronchial muscles

Has 1, 2, 1, and 2 adrenergic activityleads to less desirable effects such as blood pressure, heart rate, and nervousness

To compensate, the body releases adenosine and prostaglandin (PG) which inhibit the release of NE

Physiological EffectsPhysiological Effects Caffeine and aspirin may inhibit

and/or reduce the effects of adenosine and PG continued NE activation

“ECA” stack ephedrine alkaloids (ma huang) caffeine (Gaurana, Bissey Nut,

Kola) aspirin/salicin (Willow Bark

extract)

Reported BenefitsReported Benefits Increased weight loss due to thermogenic effect

Enhanced athletic performance

Increased energy

3 billion servings sold during 1999

12 million people using ephedra

Adverse EffectsAdverse Effects Dizziness, tremors, irregular heart rate myocardial

infarctions, strokes May induce psychological dependence 1993-2003- FDA documented 2,277 adverse event reports

(AER) concerning cardiovascular, neurological and psychiatric effects (~1% of total?)

Type ‘A’ AE- directly related to the pharmacological actions of the active ingredient

Type ‘B’ AE- rare and difficult to separate from pre-existing conditions; cause/effect hard to prove

Sound the Alarm!Sound the Alarm!

1990s- Government and herbal agencies attempt to decrease intake (warning labels, dosage limits, prohibit combination with caffeine…)

2003- RAND report published April 12, 2004- FDA’s Final Rule effectivebanning

the sale of dietary supplements containing ephedra (didn’t apply to use in TCM)

April 2005- Ban overturned in Utah federal court for doses 10 mg; sent back to FDA to determine safe and dangerous levels

Efficacy and Safety of Ephedra and Ephedrine Efficacy and Safety of Ephedra and Ephedrine

for Weight Loss and Athletic Performance:for Weight Loss and Athletic Performance:

A Meta-analysisA Meta-analysis Performed by the Southern California Evidence-

based Practice Center-RAND

Published in Journal of American Medical Association on March 23, 2003

Objective:Objective: Assess the efficacy and safety of ephedra and ephedrine used for weight loss and enhanced athletic performance

Data SourcesData Sources:: Searched 9 databases (including unpublished trials

and non-English documents) for any related studies; adverse events (AE) reported to the FDA included

Study Selection:Study Selection: Controlled trials for weight loss (min. 8 week

follow-up) or athletic performance (no min. follow-up); case report for adverse events included if:

1)strong evidence ephedra taken within 24 hrs. prior to event 2)alternative explanations were ruled out

-of 530 screened articles, 52 controlled trials and 65 case reports included in AE analysis

-of > 18,000 other case reports screened, 284 reviewed in detail

Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A meta-analysis. JAMA(2003)289:12

Data ExtractionData Extraction:: Trials identified independently by 2 reviewers Case reports reviewed with explicit and implicit methods

Data Synthesis:Data Synthesis: No trials of ephedra and athletic performance found that met

criteria Safety data yielded estimates of 2.2- to 3.6-fold increases in

odds of psychiatric, autonomic, or GI symptoms, and heart palpitations

Insufficient data for conclusions about AE at a rate les than 1.0 per thousand

Majority of case reports insufficiently documented

Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A meta-analysis. JAMA(2003)289:12

Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A meta-analysis. JAMA(2003)289:12

CategorySample

size

Weight Loss

(kg/mo)95% CI

ephedrine1 5 0.6 0.2-1.0

ephedrine1 + caffeine 12 1.0 0.7-1.3

ephedra2 1 0.8 0.4-1.2

ephedra2 + herbs3 4 1.0 0.6-1.3

Weight Loss achieved using ephedra, ephedrine Weight Loss achieved using ephedra, ephedrine containing products greater than placebocontaining products greater than placebo

1derived from pharmaceutical sources 2derived from botanical sources 3caffeine containing herbs

Conclusions:Conclusions:Ephedrine and ephedra promote modest short-

term weight loss (~0.9 kg/mo > than placebo)

No data regarding long-term weight loss

Insufficient evidence to support use for athletic performance

Use with caffeine is associated with increased risk of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations

Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A meta-analysis. JAMA(2003)289:12

- - BJ Gurley, SF Gardner, and MA HubbardBJ Gurley, SF Gardner, and MA Hubbard

- American Journal of Health-System Pharmacy(2000) - American Journal of Health-System Pharmacy(2000) 57:57:1010

Content versus label claims Content versus label claims in ephedra-containing in ephedra-containing dietary supplementsdietary supplements

Specific Aim:Specific Aim: To determine the content of ephedra alkaloids in herbal dietary supplements containing ephedra (ma huang).

Study Design:Study Design: The contents of ephedrine, pseudoephedrine, methylephedrine, norephedrine, and norpseudoephedrine were measured in 20 ephedra-containing supplements using high-performance liquid chromatography

Content versus label claims in ephedra-containing dietary supplements (abstract). Am J of Health-System Pharmacy (2000) 57:10

Results:Results:

total alkaloid content varied considerably (0.0-18.5 mg/dosage unit)

Observed significant lot-to-lot variations in alkaloid content for 4 products

10 supplements exhibited discrepancies between the label claim for alkaloid content and the actual alkaloid content in excess of 20%

One product was devoid of ephedra alkaloids

Content versus label claims in ephedra-containing dietary supplements (abstract). Am J of Health-System Pharmacy (2000) 57:10

Conclusion:Conclusion: “Assay of 20 ephedra-containing dietary supplements

showed that alkaloid content often differed markedly from label claims and was inconsistent

between 2 lots of some products.”

Content versus label claims in ephedra-containing dietary supplements (abstract). Am J of Health-System Pharmacy (2000) 57:10

Summary and RecommendationsSummary and Recommendations

1) Slight short-term wt.loss

2) Athletic enhancement?

3) adverse events

4) Dosage level?

Thus…Thus… High cost/benefit ratio Official positions

SummarySummary

Market forces Conventional sales Internet Sales

Is it legal? TCM Still under appeal

The End…The End… not not