NUTR 547- Nutrition Update Kim McCorquodale Summer 2006 An 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…

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…

Ephedra Ephedraceae 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)

History of Conventional Uses of Ephedra Ephedrine first isolated by Japanese chemist, N. Nagai 1920’s- Series of studies on ephedrine’s pharmacological properties leads to synthetic production 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 Effects Strong stimulant- enhances the release of norepinephrine (NE) from sympathetic nerve endings (see handout) Has  1 and  2 agonist activity  relaxes bronchial muscles Has  1,  2,  1, and  2 adrenergic activity  leads 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 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 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 Effects Dizziness, tremors, irregular heart rate  myocardial infarctions, strokes May induce psychological dependence 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! 1990s- Government and herbal agencies attempt to decrease intake (warning labels, dosage limits, prohibit combination with caffeine…) RAND report published April 12, FDA’s Final Rule effective  banning the sale of dietary supplements containing ephedra (didn’t apply to use in TCM) April 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 for Weight Loss and Athletic Performance: A 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: A ssess the efficacy and safety of ephedra and ephedrine used for weight loss and enhanced athletic performance Data Sources: Data Sources: S earched 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: C ontrolled 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 Extraction: Data 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

Category Sample size Weight Loss (kg/mo) 95% CI ephedrine ephedrine 1 + caffeine ephedra ephedra 2 + herbs Weight Loss achieved using ephedra, ephedrine containing products greater than placebo 1 derived from pharmaceutical sources 2 derived from botanical sources 3 caffeine 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 Hubbard - American Journal of Health-System Pharmacy(2000) 57:10 Content versus label claims in ephedra-containing dietary 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 ( 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 Recommendations 1) Slight  short-term wt.loss 2) Athletic enhancement? 3)  adverse events 4) Dosage level? Thus…  High cost/benefit ratio  Official positions

Summary Market forces Conventional sales Internet Sales Is it legal? TCM Still under appeal

The End… not