Ephedra – Scientific Evidence Versus Money/Politics

Twenty-Year Chronology of of Events Concerning Ephedrine Alkaloids

This article by Sidney Wolfe, M.D. appeared in the April 18, 2003 issue of Science magazine.

Does it make a difference, in terms of FDA regulation, that a drug is natural, has been around for thousands of years and is dispensed as “servings” rather than doses, if the drug has been known for decades to cause increased blood pressure, increased pulse rate, and an increased risk of cardiac arrhythmias? For dietary supplements containing ephedra alkaloids[1], the answer is yes, it has made a difference.

Because of dangers and abuse potential, in 1983 the FDA (Food and Drug Administration) banned all over-the-counter (OTC) drugs that included both synthetic ephedrine and caffeine, the combination used most in dietary supplements containing ephedra alkaloids, and the agency is now finalizing the ban on OTC drugs that contain ephedrine alone. At a recent U.S. Senate Hearing on ephedra alkaloids, acting FDA Commissioner Lester Crawford conceded that if these products were drugs, not dietary supplements, they would be off the market. But he also stated that unreasonable risk of harm at the recommended doses, is sufficient for withdrawal under the 1994 Dietary Supplements Health and Education Act (DSHEA), which allows marketing of naturally occurring products without requirements for safety or efficacy studies and is the legal standard for FDA withdrawal[2].

In a review of 140 cases of adverse reactions to ephedra reported to the FDA by early 1999, hypertension was the most frequently named, followed by palpitations, tachycardia (rapid heart rate), stroke, and seizures. The adverse effects included 10 deaths, and 13 instances of permanent disability[3]. Even one standard “serving” of a typical ephedra alkaloid-containing dietary supplement can be dangerous: The average increase in systolic blood pressure was 14 mmHg, 90 minutes after subjects took two capsules with a total of 20 mg of ephedra and 200 mg of caffeine. Three of the eight people studied had evidence of “mild clinical hypertension”[4].

Despite convincing evidence of heart attacks, arrhythmias, strokes, and more than 100 reports to the FDA of death[5], these products are still marketed in the United States. Notwithstanding FDA’s reluctance to take action, Army and Air Force commissaries and post exchanges recently voluntarily removed all ephedra-containing dietary supplements from their shelves[6]. The FDA has received documentation of about 30 deaths in active duty personnel who were using these supplements, although no direct cause-and-effect relation has been established[7]. The National Football League and the National Collegiate Athletic Association had previously banned ephedra[8]. In June 2001, the Canadian government warned Canadians not to use these products, and in January 2002, it announced a recall of “ephedra/ephedrine products with labelled or implied claims for appetite suppression, weight loss promotion, metabolic enhancement, increased exercise tolerance, body-building effects, euphoria, increased energy or wakefulness, or other stimulant effects”[9].

Political Influence

According to the Washington Post, Metabolife, the nation’s leading seller of ephedra products, spent more than $4 million between 1998 and 2000 in Texas to lobby against state regulations. There have also been accusations that Metabolife has attempted to exert influence in Texas through political connections to members of the Bush administration[10],[11]. According to Business Week, federal efforts to remove ephedra have been hampered “by deep-pocketed industry lobbying. Metabolife, has contributed . . . to national politicians since 1999 . . . according to the Center for Responsive Politics”[12]. In California, Metabolife ranked fourth in the state for “soft money” contributions, with $493,000 in 2000. Additional federal and state influence-peddling has taken the form of soft money contributions to political parties, whereby Metabolife gave $1,718,000 during the 1999-2000 and 2001-2002 election cycles[13].

Act Now

The recent Rand report reviewing published literature on ephedra and adverse reaction reports[14] takes away the last excuse given by the government for not yet acting on our 5 September 2001 petition to ban all dietary supplements containing ephedra alkaloids[15]. However, the government is still equivocating and has announced, in a 7 March 2003 Federal Register Notice, that they want comments on any new information on ephedra risks, public opinion as to whether the legal standard for a ban can be met, and whether a proposed warning label makes sense[16]. Much of this flurry of “activity” is in the wake of the death of Baltimore Oriole pitcher, Steve Bechler, whose death has been partially attributed to the use of ephedra dietary supplements.

“Regulation” is now coming from the marketplace, operating in the vacuum created by FDA inaction.  Several companies have announced that they will stop selling ephedra-containing diet supplements[17],[18]. Even Metabolife has announced that the company launched an ephedra-free “alternative”[19].

However, this alone is not an acceptable way to safeguard public health, and product labeling is not enough. We call on the FDA as an agency of the Public Health Service to fulfill their legal responsibility and to stop the occurrence of further preventable deaths and injuries by banning ephedra products.

REFERENCES

[1] Ephedrine, amphetamine, and the recently banned phenylpropanolamine (PPA) are structurally similar. Because all of these drugs are sympathomimetic, all can cause increased blood pressure; amphetamine and ephedra can also cause increased pulse rate.

[19] P. Crabtree, San Diego Union-Tribune, 23 January 2003, p. C1.

Twenty-Year Chronology of of Events Concerning Ephedrine Alkaloids

1983: Because of dangers and abuse potential, the FDA bans all over-the-counter (OTC) drugs that include both synthetic ephedrine and caffeine, the combination found in most of the dietary supplements containing ephedrine alkaloids (EADS).

July 1993: FDA issues its first public warning about possible safety problems of dietary supplements containing ephedrine alkaloids. Reports received by the FDA include hypertension, palpitation, neuropathy (nerve damage), myopathy (muscle damage), psychosis, stroke and memory loss.

February 1995: FDA warns consumers against a dietary supplement, “Formula One,” containing ephedra and caffeine.

February 1995: FDA working sub-group of Food Advisory Committee composed of outside experts agrees that ephedrine alkaloids can cause serious adverse events but cannot agree on specific dosage or warning statement.

April 1996: FDA warns consumers not to buy or use ephedrine dietary supplements with labels portraying products as alternatives to illegal street drugs, since they pose significant health risks.

August 1996: Half of FDA Food Advisory Committee states that no safe levels of ephedrine alkaloids in dietary supplements exist.

June 1997: FDA proposes to ban ephedrine dietary supplements with more than 8 mg of ephedra per “serving” and to include warning labels.

July 1999: General Accounting Office (GAO) report finds that FDA did not have an adequate basis for concluding that doses of more than 8 mg are dangerous and 8 mg or less are safe.

April 2000: FDA withdraws June 1997 proposed regulation pending further data collection and analysis.

August 2000: Office of Women’s Health, HHS, convenes meeting on safety of dietary supplements containing ephedrine alkaloids.

The conclusion is: “Despite the established limitations of AERs (adverse event reports), many of the adverse effects are biologically plausible based on the known pharmacologic effects of ephedrine alkaloids. The pharmacology of ephedrine is supported by a rich database, in contrast to the paucity of evidence on the benefits or risks of EADS in humans. The level of concern for continued use of EADS must be based on the totality of information available on ephedra and ephedrine alkaloids, including the AERs, results of human and animal studies, as well as what is known about the pharmacology and chemistry of these compounds.”

March 2000: FDA announces analysis of 140 adverse reaction reports concerning ephedrine alkaloids: In 22 cases, the adverse reaction is attributable to ephedrine alkaloids; in another 38 cases, the evidence is supportive of being drug-induced; and in another 72 cases, there are insufficent data for an evaluation to be made.

December 2000: Haller and Benowitz publish New England Journal of Medicine article finding that among the adverse events reported to the FDA deemed definitely, probably or possibly related to the use of supplements containing ephedrine alkaloids, 47 percent involve the cardiovascular system and 18 percent involve the central nervous system. Hypertension is the single most frequent adverse effect (17 reports), followed by palpitations, tachycardia (rapid heart rate) or both (13); stroke (10); and seizures (7). Ten events resulted in death, and 13 events produced permanent disability, representing 26 percent of the definite, probable and possible cases.

June 2001: The Canadian government warns Canadians not to use these products.

September 2001: Public Citizen’s Health Research Group (PCHRG) and Dr. Ray Woosley petition the FDA to ban all dietary supplements containing ephedrine alkaloids. The petition includes results of an FDA memo finding that there are more reports of deaths, heart arrhythmias, strokes, heart attacks, hypertension and seizures for ephedrine alkaloids than for all other dietary supplements combined.

January 2002: The Canadian government asks all manufacturers to recall these products if they are being sold for weight reduction, performance enhancement or body-building, the main uses for which they are promoted.

June 2002: FDA announces plan to study ephedrine alkaloids (Rand Corporation review) but defers decision on Public Citizen’s petition to ban.

August 2002: Army and Air Force commissaries and PXs ban the sale of ephedrine alkaloid dietary supplements following reports of more than 30 deaths in active duty military personnel (previous bans had occurred on Navy and Marine bases). The FDA has reports of more than 100 deaths in people using ephedrine dietary supplements.

October 2002: During a Senate Hearing chaired by U.S. Sen. Richard Durbin (D-Ill.), acting FDA commissioner Dr. Lester Crawford admits that even under the provisions of the Dietary Supplement Health and Education Act (DSHEA), the FDA has the authority to ban ephedrine alkaloids, implying that the legal standard for FDA withdrawal – unreasonable risk of harm at the recommended doses – could be met. HHS Secretary Thompson urges strong warning labels.

December 2002: Nationwide Harris Poll of adults finds that most people are misinformed about the extent of government regulation of vitamins, minerals and food supplements. They incorrectly believe that supplements must be approved by a government agency such as the FDA and that the manufacturers are not allowed to make claims for their safety and effectiveness unless there is solid scientific evidence to support them.

February 2003: Steve Bechler, Baltimore Orioles pitcher, dies. His death is partially attributed to the use of ephedrine alkaloid dietary supplements.

February 2003: HHS summarizes the results of the Rand Corporation review, stating that “dietary supplements containing ephedra may present significant or unreasonable risks as currently marketed….” A Federal Register notice seeks comments on whether there is new information about the risks of these products, whether the public thinks that the legal standard for a ban – unreasonable risk of harm at the recommended doses – can be met and whether the public agrees with proposed warnings such as not to use more than the recommended dosage and not to engage in “strenuous” exercise while using these products.

April 2003: Ad on Web site of a large Internet seller of dietary supplements (www.milehighmuscle.com – accessed 4/16/03) in section on ephedra dietary supplements:

“HURRY, before they’re gone! Manufacturers are discontinuing Ephedra products faster than you realize. As of 03/17/03, we had to pull a large list of products containing ephedra from our shelves because the manufacturers do not have the liability insurance for these products.”
 

On part of the site directed at active duty military personnel, now unable to purchase ephedra products in commissaries or PXs because of the military’s ban, ephedrine alkaloids and other dietary supplements are shamelessly promoted with a discount for active duty military personnel:

You serve and protect the United States, you’re stateside or overseas. We, at Mile High Muscle appreciate your efforts and to thank you, we have created a section just for you!

Exclusive Military Offers!

As a military customer, you will be able to receive exclusive offers. You automatically get $5 off every order. Please use coupon code: military5 on our checkout page in the coupon code field.

The site does include the following disclaimer:

“Ephedra Products Disclaimer: Please use extra consideration when making the choice to use these products. Those of you in the Middle East and similar warm climates, please be advised that your heavy equipment and uniforms compounded with the heat and potential exposure to chemical agents, may be at risk for elevated blood pressure, heart rate, etc. and could experience effects beyond normal use.”