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December 1, 2000
Industry Responds To NEJM Ephedra Study
SAN FRANCISCO--Citing "potential health implications," the NewEngland Journal of Medicine in November elected to pre-release two studiesscheduled to appear in its Dec. 21 issue. The first was a four-and-a-half yearstudy on an association between use of phenylpropanolamine (PPA), a syntheticcompound, and hemorrhagic stroke; the pre-publication was quickly followed by apublic health warning from the Food and Drug Administration (FDA) about thesehealth risks and many retailers pulling the products from their shelves. Thesecond was a slight revision to an analysis submitted in April to FDA about"Adverse Cardiovascular and Central Nervous System Events Associated withDietary Supplements Containing Ephedra Alkaloids."
Both reports were picked up by the popular media, and much concern was madeover the dangerous compounds on the market. However, as of Dec. 1, there hasstill been no FDA comment about the ephedra paper, nor any movement on theindustry petition filed Oct. 25 asking FDA to move forward on standards for theformulation, labeling and marketing of ephedra products.
In the NEJM ephedra paper, researchers at the University of Californiaand the California Poison Control System, both based here, reviewed 140 adverseevent reports (AERs) related to the use of dietary supplements containingephedra alkaloids that were submitted to the FDA between June 1, 1997, and March31, 1999. (The study does not mention that 2/3 of the AERs were self-reported byconsumers and 1/3 submitted by medical practitioners.) Researchers ChristineHaller and Neal Benowitz found that 31 percent of the cases were"definitely" or "probably" related to the ephedrasupplements and an additional 31 percent were "possibly" related. Ofthat 62 percent, cardiovascular (hypertension, tachycardia) and central nervoussystem problems were most common. They concluded that "the risks of takingephedra alkaloids as a dietary supplement ... are difficult to justify becausethe alkaloids have no demonstrated benefit."
Industry members expressed concern over the timing of the release, the needfor reprinting existing study data, and some errors in the report. "Thisreview has blatant errors of fact," said Michael McGuffin, president of theAmerican Herbal Products Association (AHPA). Two patient records in particularwere of concern. When contacted about the two errors, Gregory Curfman, M.D.,with NEJM noted that changes were made Nov. 30 to the Web site and willbe made in the print version.
The first error was with Patient 1, whose record noted that "a urinetoxicology screen was positive for amphetamine, a known metabolite ofephedrine," which McGuffin noted is an absolute error. The record has nowbeen changed to "a urine toxicology screen was positive for amphetamine, aresult presumed to reflect a cross-reaction with the ephedrine and therefore tobe false positive." The second error was with Patient 7, a 38-year-old man,who was described as "healthy," though after his fatal heart attack itwas found that he suffered coronary artery disease, with narrowing of 50 to 75percent in four vessels. His record has been changed to state he was an"apparently healthy" man.
Industry members said the "apparently healthy" issue was not asserious as the amphetamine error, which was widely reported in the mass media."Given the wide circulation of this error, the Journal should publish acorrection promptly," said Joseph Betz, Ph.D., vice president of scientificaffairs for AHPA. When Curfman was asked whether there were plans to make apublic correction or statement about the error, he would not give a definiteanswer, stating that the error would be corrected online and in the hard copy.
Other industry members questioned why the paper was released early."This is basically the same thing previously reported in the FederalRegister, with minor editorial changes put into a journal articleformat," said John Hathcock, Ph.D., vice president of nutrition andregulatory sciences at the Council for Responsible Nutrition (CRN). According toCurfman, the NEJM editors made the decision to pre-release the study onthe Web site in part because they were pre-releasing the PPA report. "If wehad the Benowitz paper alone without the PPA issue, we might not have put itup," Curfman said. "But tied in to the PPA story, since ephedra isnearly unregulated in the dietary supplement market, it provided an additionaldimension to the whole issue."
Unfortunately, it has also clouded some issues, as AHPA's member updatednoted: "The unfortunate ability of the media to keep these stories separatehas led to some consumer confusion about the relationship of PPA and ephedra."In fact, the ephedra study drew a specific parallel between the effects ofphenylpropanolamine (PPA) with caffeine (a combination banned in 1983) andephedra and caffeine. "PPA is a synthetic mixture of isomers," saidJim Kababick with Flora Research. "While there is a naturally occurring D30form as norpseudoephedrine, the planes of the molecules are different and itdoesn't necessarily have the same activity."
One additional concern has been that several AERs were in persons not takingephedra as recommended on the label. About 10 of the AERs were in persons under18, while others (such as Patient 7) had pre-existing health conditions."What is the essential finding of the NEJM article," askedDaniel Mowrey, president of the American Phytotherapy Research Laboratory."That when you abuse stimulants, when you use ephedra improperly and not inaccordance with label directions, it is potentially dangerous." Since 1994and as recently as just a month ago, industry associations and companiesproposed warning labels detailing users should be over 18 and with a maximumdosage of 25 mg/dose and 100 mg/day ephedra alkaloids. The industry proposal andcurrent labels also advise consumers not to use the products if they have aheart condition.
"We have a cautionary label statement on ephedra products that say don'tuse this if you have hypertension or heart disease," McGuffin said."If consumers don't know, they should go find out. They need to read [thewarnings], believe it and act like it's true."
Cautionary statements on labels have been one step taken by the industry toresponsibly market dietary supplements. In fact, most industry members agreedwith the NEJM authors' statement that "the use of dietarysupplements that contain ephedra alkaloids may pose a health risk to somepersons." "There's no use in defending that ephedra doesn't have sideeffects, because it does," said Roy Upton, executive director of theAmerican Herbal Pharmacopoeia (AHP). He added that consumers should have accessto the products as long as they are warned of potential side effects so they canmeasure the risks vs. benefits of a product. "Consumers should decide whereephedra lies on the spectrum of weight loss therapies," he said,particularly when faced with the consequences of obesity and other weight losstherapies.
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