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Harmless Energizers or Dangerous Drugs?

Photo: Barry Palevitz HELP OR HINDRANCE? Ephedra-containing products like those pictured above are coming under increased scrutiny. You've probably seen the ads in the supermarket checkout aisle, or on radio and TV. "I lost 63 pounds with Hydroxycut," screams the headline in Cosmopolitan, above pictures of a woman going from corpulent to bathing-beauty trim in 19 weeks. "Diet Fuel changes the shape of your life," claims another ad, this time sporting an ab-flashing model in boxing gloves

By | December 9, 2002

Photo: Barry Palevitz
 HELP OR HINDRANCE? Ephedra-containing products like those pictured above are coming under increased scrutiny.

You've probably seen the ads in the supermarket checkout aisle, or on radio and TV. "I lost 63 pounds with Hydroxycut," screams the headline in Cosmopolitan, above pictures of a woman going from corpulent to bathing-beauty trim in 19 weeks. "Diet Fuel changes the shape of your life," claims another ad, this time sporting an ab-flashing model in boxing gloves. Some may laugh, but to weight-conscious girls and women in a society that treasures thinness, reading "have you ever looked at your body and wanted to cry" hits home.

College student Lauren Mylacraine started hearing about the products in 10th grade. "They were pretty popular," she admits. Another student, speaking anonymously, claimed the pills were so tempting, "girls got hooked," some even taking them with their mothers. Morgan Pinkston used ephedra for another reason: energy on the soccer field. "You feel like you can run forever," she says.

Cramming for exams is another excuse. "I also took it to stay up at night for finals," adds Pinkston. She isn't alone--so do lots of her classmates at the University of Georgia in Athens. A gas station across the street from campus prominently displays "energizers" and diet pills next to the cash register.

It's not cocaine or speed that's pumping these kids up. The pills contain an herb called ephedra--in Chinese, ma huang. Unlike cocaine, though, the US government is ambivalent about how people should use it. The Food and Drug Administration (FDA) banned ephedrine--the active ingredient--in combination with caffeine for over-the-counter cold and allergy medications around 20 years ago (products like Sudafed and Actifed still contain pseudoephedrine.) But federal law, the Dietary Supplement Health Education Act of 1994, or DSHEA, allows producers of dietary supplements and energizers to concoct various mixes of ephedrine and caffeine unimpeded. Stephen Barrett, host of a consumer-oriented health Web site called Quackwatch, pulls no punches: "They're not supplements; they're drugs!"

Labels on products like Stacker 2, Black Beauty, Yellow Jacket, and Metabolife 356 say they're not for people under the age of 18, but kids buy them anyway, in supermarkets, convenience stores, mall kiosks, and drug chains. Manufacturers claim they sold more than 3 billion servings of ephedra supplements in 1999, but it's hard to know how many of those went to kids. Stores seem to cater to the cash and carry trade, selling pills in packets of three for as little as $1.50.



Graphics: Anne MacNamara

A LITTLE BOTANY Ephedrine and pseudoephedrine are the alkaloids produced by Ephedra sinica, an Asian plant grouped with conifers and cycads (palms) in the gymnosperms. According to David Giannasi, chemosystematist at the University of Georgia who teaches a course in medicinal plants, commercial preparations consist of ground stems from the Asian species. Giannasi says that several species indigenous to North America, like Ephedra nevadense, generally lack the drug, but he thinks "studies need to be redone on a larger scale" to be sure.

Giannasi sees more danger in supplements that contain purified ephedrine rather than true herbal preparations. "When we chromatograph the actual plant material, the amount of ephedrine is relatively low, in keeping with the concept of herbal remedies," he notes. Ephedrine is more potent in pure form because "it is in no way mediated by other components in the plant or by simple physical dilution."

Ephedrine is a close relative of amphetamine, sometimes called benzedrene. A little chemical tinkering creates the street drugs methamphetamine and Ecstasy. The whole class structurally mimics the neurotransmitters epinephrine (adrenaline) and norepinephrine and act to speed up heart rate, increase blood pressure, dilate airways, and stimulate other changes in the body. The transmitters bind to alpha- and beta- adrenergic receptors in nerves, muscle, blood vessels, and other tissues, which in turn activate secondary messengers like cyclic AMP.

The stimulus/response pathway is an evolutionary advantageous way of dealing with stress. Avoiding an imminent threat, like a hungry lion, means running fast, which requires elevated blood supply to muscles and greater intake of oxygen. Taking ephedrine to lose weight or stay awake all night was not in the human evolutionary equation, however, and therein lies the problem.

By 1997, the FDA had received hundreds of adverse event reports (AERs), indicating that ephedrine may cause debilitating or fatal heart attacks, strokes, seizures, and cardiac arrhythmias, even in young adults without other risk factors. According to Stephen Wolfe of the consumer group Public Citizen, which wants FDA to ban ephedrine-based supplements, AERs totaled almost 1,400 in 2001 and included 81 deaths. On Aug. 15 of this year, FDA asked the Justice Department to launch a criminal investigation of Metabolife International, the nation's leading manufacturer of ephedra products, to force the company to divulge more than 13,000 of its own AERs, which it has since done.

SAFETY AN ISSUE Metabolife maintains its products are safe, a view shared by Judy Blatman, vice president of communications for the Council for Responsible Nutrition, a dietary supplement trade association. Metabolife CEO David Brown claimed in a written statement on Oct. 8 that the thousands of reports it turned over are just "anecdotal consumer call records that do not demonstrate causation. To our knowledge, there is not a single well-controlled clinical study that demonstrated that ephedra supplements are unsafe when taken as directed," but there are "over 30 reports and studies ... supporting safety and efficacy."

San Francisco attorney Christopher Grell disagrees. He represents a client suing Metabolife after suffering a stroke. "Metabolife's own study showed adverse effects," Grell maintains. As to the many negative reports to FDA on ephedra products, Grell adds, "we know from studies that the number of reported cases is a small fraction of adverse events. Most doctors are unaware of ephedrine's effects." Staffers for the House Committee on Governmental Reform also balked at Metabolife's take, claiming the company's AERs contain "significant adverse events and conflict with Metabolife's statements."

The American Medical Association and Health Canada are also concerned. AMA trustee Ron Davis told an Oct. 8 Senate hearing that the FDA should remove dietary supplements containing ephedra from the market because "they pose an unreasonable risk of illness or injury under conditions of recommended use in the labeling. These uses are of questionable benefit with little if any clinical data to support efficacy."

The Canadians went further, asking for a voluntary recall of ephedra products that recommend taking more than 32 mg a day or contain more than 8 mg per pill. Health Canada also nixed claims for weight loss, energy enhancement, bodybuilding, and alertness.

Ephedrine's critics often cite a study done by Christine Haller and Neal Benowitz of the University of California, San Francisco, and the California Poison Control System. The researchers reviewed 140 AERs submitted to FDA and concluded that "dietary supplements that contain ephedra alkaloids pose a serious health risk to some users." The paper also called for more research on individual susceptibility.1

Possible harm from ephedrine should come as no surprise. Besides banning ephedrine's over-the-counter use with caffeine 20 years ago, FDA asked companies in September 2000 to withdraw phenylpropanolamine--another close relative of ephedrine used as an appetite suppressant and nasal decongestant--from the marketplace because of health risks.

Industry guidelines tell people to consume no more than 100 mg of ephedrine a day, at 25 mg per pill, in the interest of safety. The problem is, potency of various ephedra plants varies, making it hard for consumers to know what they're taking. A study by the US General Accounting Office (GAO) found one product with 154% of the ephedrine level stated on the label. That's bad news for people who often don't pay attention to labels or think if some is good, more is better.

To complicate matters, dietary supplements and energizers often contain more than one stimulant, sometimes several. The label for Yellow Jacket, marketed by NVE Pharmaceuticals in Newton, NJ, lists ephedra extract plus 300 mg caffeine, sida cordifolia (another source of ephedrine), citrus aurantium--which contains the stimulant sinephrine--and ginseng, a source of ginsenoside stimulants. Ultra Energy Now uses three different ginsengs in addition to ephedra, ginkgo, and other herbs.

"The risk of adverse events may increase when ephedra is combined with other stimulants such as caffeine, ... and depending on the content of ephedra alkaloids, which varies from product to product and within different lots of the same product," concluded AMA's Davis in his Senate testimony.

POLITICS, POLITICS, POLITICS Since DSHEA went into effect, products like ephedra do not have to pass prior muster by FDA in the same way that prescription and over-the-counter drugs do. Instead, FDA can remove products post-marketing only if it can prove that they are dangerous. Quackwatch's Barrett says Congress bowed to political influence from industry in passing DSHEA. He wants to see Congress revisit the issue by giving FDA more power to levy stiff financial penalties and launch criminal proceedings against companies guilty of false or misleading claims. Attorney Grell goes further: "We need some sort of amendment to DSHEA so the public has access to vitamins, but treats other stuff that's pharmaceutically active differently. Companies should prove products are safe before marketing."

FDA proposed more rigid standards for ephedrine-containing supplements in 1997, including much lower dosages, but the agency backed down after the GAO criticized the science behind its action. FDA may finally be moving on ephedra, however. Health and Human Services (HHS) Secretary Tommy Thompson asked FDA on Oct. 8, concurrently with the Senate congressional inquiry that day, to recommend stronger warning labels on dietary supplements. FDA also finished work on guidelines to improve product quality.

The agency recently banned sale of ephedra-containing supplements like Yellow Jacket as substitutes for street drugs such as Ecstasy. That didn't satisfy Illinois Sen. Richard Durbin, who chaired the October Senate hearing. Durbin sparred with acting FDA commissioner Lester Crawford for not banning outright the same ingredients when marketed as dietary supplements. Said Durbin, "This really goes to half our concern, but to the heart of the problem."

Jenni Engbretsen, Durbin's press secretary, says the senator thinks modifying current definitions of dietary supplements is a good idea but is waiting to hear ideas from FDA and HHS. The Rand Corp. is also studying ephedra and should report to Uncle Sam by the end of the year. Karen Lightfoot, an aide to Rep. Henry Waxman of California, thinks legislative action may not be far off. "I definitely think there's a feeling it [DSHEA] needs to be fixed." While Congress is in recess, "people will take some time to figure out the best way to make something happen," she says.

Barry A. Palevitz (palevitz@dogwood.botany.uga.edu) is a contributing editor.

1. A. Haller, N.L. Benowitz, "Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids," New England Journal of Medicine, 343:1833-8, 2000.
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