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4/12/2004

Ephedrine Alkaloids Banned From Dietary Supplements

Cheryl A. Thompson

Barring last-minute intervention by a federal court, FDA has won its uphill battle to stop sales of dietary supplements containing ephedrine or related alkaloids.

As of April 12, it is illegal for companies to sell dietary supplements containing ephedrine alkaloids because these products, in FDA's determination, are adulterated by virtue of their unreasonable health risks to consumers.

"Dietary supplements containing ephedrine alkaloids pose a risk of serious adverse events, including heart attack, stroke, and death," the agency stated in the regulation issued February 11.1 "These risks are unreasonable in light of any benefits that may result from the use of these products under their labeled conditions of use, or under ordinary conditions of use if the labeling is silent."

FDA's action marks the first time a dietary supplement has been banned from commerce since the Dietary Supplements Health and Education Act of 1994 (DSHEA) eased the marketing of this type of product and placed restrictions on the agency's ability to regulate dietary ingredients.

Nearly a nine-year effort. One year after DSHEA's enactment, FDA asked an advisory committee working group to consider the importance and extent of serious adverse events that had been linked to food products containing any of the ephedrine alkaloids from Ephedra species and other botanical sources.

Food products containing ephedrine alkaloids had, with the enactment of DSHEA, become known as dietary supplements. Any dietary ingredient on the market in 1994 could be sold in a dietary supplement until FDA proved the ingredient unsafe.

Marketed as aids for weight loss, energy, and increased athletic performance, sales of ephedrine-alkaloid-containing products increased.

By the time FDA first sought assistance, the agency had amassed over 300 voluntarily submitted reports of adverse events in persons who had ingested food products declaring ephedrine alkaloids as an ingredient.

According to the minutes of the working group's meeting, FDA's laboratory analysis of products labeled as containing botanical sources of ephedrine alkaloids revealed alkaloid content ranging from undetectable amounts to as much as 110 mg per recommended serving.

The working group recommended that FDA establish single-serving and daily-total-use limits for ephedrine and total ephedrine alkaloids, require warning or cautionary statements on the labels of these products, and establish good-manufacturing-practice requirements, including proper botanical identification and standardization of the ephedrine alkaloid and ephedrine content in concentrated extracts.

In the ensuing six months, FDA received about 300 additional reports of adverse events related to dietary supplements claiming to contain ephedrine alkaloids. The agency also received information on the deaths of two young men "in which the medical examiners specifically attributed the cause of death to use of ephedrine alkaloid-containing dietary supplements": a 20-year-old college student who consumed eight tablets of Ultimate Xphoria instead of the four recommended in the labeling and a 23-year-old college student who had been using various dietary supplements, including Ripped Fuel (with 20 mg of ephedrine alkaloids per two-capsule recommended serving size), daily for at least one year.

At the August 1996 meeting of the advisory committee and its working group, more than half of the committee members said they could not identify a safe amount of ephedrine alkaloids for inclusion in dietary supplements. But the committee did not reach a consensus on what FDA should do to protect the public.

After considering the adverse-event reports and input from advisers and the public, FDA in June 1997 proposed (1) setting a limit on the amount of ephedrine alkaloids in any dietary supplement, (2) requiring products' labeling to include information about maximum duration of use and dosage and warn against use by consumers with certain health conditions or medication regimens, and (3) banning the combination of ephedrine alkaloids with any other stimulant in a dietary supplement.

Not as easy a change as expected. What ensued in the months and years following issuance of the proposal led FDA to reassess its strategy.

  • Nearly 15,000 comments on the proposal poured in from consumers, dietary supplement distributors, industry groups, health care professionals and their organizations, and the Small Business Administration's Office of Advocacy.
  • The DSHEA-mandated Commission on Dietary Supplement Labels, in a report to the Clinton administration, urged FDA "to use its authority under DSHEA to take swift enforcement action to address potential safety issues such as those posed recently by products containing ephedrine alkaloids."
  • The General Accounting Office, in a report requested by a House of Representatives committee, recommended that "FDA obtain additional information to support the proposed dosing levels and duration of use limits and improve the transparency of its cost-benefit analysis before proceeding to final rulemaking."

In April 2000, FDA decided to drop its pursuit of a limit on ephedrine alkaloid content, dosage, and duration of use but continued monitoring the adverse effects of dietary supplements containing ephedrine alkaloids.

To stem the use or misuse of such products as Ultimate Xphoria and Ripped Fuel, FDA told the dietary supplement industry and public that the agency "considers any product that is promoted as a street drug alternative to be an unapproved new drug and a misbranded drug."

FDA continued its work and returned in March 2003 better prepared to back its stance on regulating dietary supplements.

The Rand Corporation, a California-based think tank, had recently completed a government-funded review of the clinical efficacy and adverse effects of ephedrine-alkaloid-containing dietary supplements when used for weight loss or athletic performance enhancement. In general, the research group found that the products' risks to consumers' health outweighed the benefits. Additionally, FDA had collected about 17,000 reports of adverse events linked to ephedrine alkaloids.

With that evidence in hand, FDA proposed adding a warning statement and precautionary information to the outside container label of dietary supplements containing ephedrine alkaloids.

FDA also sought the public's opinion on whether the agency should declare that dietary supplements containing ephedrine alkaloids pose a "significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use."

The American Society of Health-System Pharmacists, in one of its actions to safeguard patients, formally asked FDA to ban the manufacture and sale of dietary supplements containing ephedrine alkaloids (see box at end of article).

Ephedrine alkaloids in other products. In declaring the ban, FDA stated that traditional Asian medicines containing ephedrine alkaloids may continue to be sold in the United States because those products are not marketed as dietary supplements.

Practitioners of traditional Chinese medicine, said Cathi Dennehy, an associate clinical professor at the University of California —San Francisco School of Pharmacy, use ephedra-containing herbal mixtures to open the airways in persons with bronchial disorders, much in the same way that ephedrine-containing nonprescription products were used. Neither type of product is used as long-term therapy, she said.

Dennehy teaches an elective course on herbals and provides evidence-based information on plant-derived dietary supplements.

Acupuncturists include botanical sources of ephedrine alkaloids in herbal remedies "usually as a small part of the entire mixture," she said. "They're using other herbs to counterbalance the stimulatory effects of the [ephedrine alkaloids]. . . . They're using the whole herb or an extract of the whole herb versus just isolating out the ephedra alkaloids and using those by themselves."

In addition to Ephedra species, Dennehy said FDA's ban applies to dietary supplements containing ephedrine alkaloids from Sida cordifolia L. (also known as country mallow or bala) and Pinellia ternata (also known as ban xia). American species of Ephedra, including the source of Mormon tea, do not contain ephedrine alkaloids and thus are unaffected by FDA's ban, she said.

Alternatives to ephedrine alkaloids. Once supplies run out, users of ephedrine-alkaloid-containing dietary supplements may seek alternatives for weight loss—perhaps one of the reformulated products now labeled "ephedra free" or containing ingredients other than ephedrine alkaloids.

C. Michael White, codirector of the Arrhythmia and Cardiac Pharmacology Research Group at Connecticut's Hartford Hospital and director of the Cardiovascular Pharmacology Service, said that, despite FDA's recent action, some consumers still face large risks if they use a dietary supplement to lose weight.

"If you look at ephedra-free Metabolife and you ask me how many milligrams of caffeine is in the product, I'll tell you I don't know," he said.

The weight-loss product contains caffeine itself but also unspecified amounts of guarana seed extract, green tea extract, and mate extract—all of which have caffeine, he said.

Manufacturers of dietary supplements typically describe their products as "a proprietary blend," White said. "They tell you what the total number of milligrams is, and then they tell you what [the] seven ingredients are that make up that total number of milligrams. So you don't know for any specific product exactly how many milligrams of this ingredient, exactly how many milligrams of that ingredient exist in the product."

With regard to Ephedra alternatives for weight loss, White advised forgoing dietary supplements until more is known about the amounts and activities of the individual ingredients, particularly their effects on heart activity and blood pressure.

White's research group recently reported that a single dose of ephedra- and caffeine-containing Metabolife 356 prolonged the corrected QT (QTc) interval by an average of 27 ms and increased the systolic blood pressure of 15 healthy volunteers.2

Overweight people with hypertension who use a dietary supplement to lose weight are "already starting off higher at risk for stroke and the development of coronary artery disease and heart failure," White said. "If they then take a product that's going to raise their blood pressure, they might have an increased risk" on top of where they started.

But that increased risk has to be weighed against the potential benefit of an overweight person with hypertension losing weight and thus lowering their blood pressure.

Said White: "If they were able to lose weight very well and . . . able to maintain that weight loss when they came off the products, maybe the cardiovascular risks over the course of a couple of years would end up balancing itself out."

But, he said, this was not the case with dietary supplements containing ephedrine alkaloids, which FDA concluded led to modest weight loss that users could not sustain once they stopped treatment.

Even though people without hypertension and QTc-interval prolongation may have a very low risk of problems with dietary supplements used for weight loss, he said, "you still won't know about the drug interaction risk" and the effect of the ingredients on blood coagulation, for example.

Effort to stop the ban. NVE Pharmaceuticals, maker of Stacker 2, a dietary supplement containing ephedrine alkaloids, reportedly filed a lawsuit in a New Jersey federal court to stop FDA's ban from going into effect.

According to Forbes.com, the March 9 lawsuit says FDA violated DSHEA in declaring ephedrine-alkaloid-containing dietary supplements adulterated and NVE has lost millions of dollars since the agency moved to ban the products.

So far, NVE stands alone in filing legal action against FDA.

Three dietary-supplement trade groups—the Council for Responsible Nutrition, the National Nutritional Foods Association, and the Utah Natural Products Alliance—jointly stated in mid-February that they believe FDA "presented a balanced rationale" but disagree with some of the individual points in the agency's justification.

A new battle. A stopgap action by FDA on March 11 aims to curtail the manufacture, distribution, and sale of dietary supplements containing androstenedione, also known as "andro."

Citing androstenedione as a substance not in chemically unaltered foods and not recognized as a dietary ingredient before enactment of DSHEA, the agency sent "warning" letters to 23 firms telling them to stop distributing dietary supplements containing the ingredient because they are adulterated.

That same day, the Anabolic Steroid Control Act of 2004 was introduced in the Senate, 10 days after the same legislation was presented in the House of Representatives.

The legislation seeks to classify as a controlled substance any product containing androstenedione or another anabolic drug or hormonal substance related to testosterone.

ASHP Acts to Inform Pharmacists, Protect Consumers

January 1995

AHFS DI adds section on misuse and abuse to Ephedrine monograph to address escalating concerns about the issue, including those of the Drug Enforcement Administration (DEA); prepublication review of this information included key staff at Department of Justice.

January 1996

AHFS DI updates Ephedrine monograph to reflect FDA's determination that the drug should no longer be considered safe and effective for nonprescription use as a bronchodilator because of the potential for misuse and abuse.

January 1997

AHFS DI updates Ephedrine monograph to reflect new restrictions placed by DEA on nonprescription availability of the drug because of heightened concerns about misuse and abuse.

January 1998

AHFS DI revises Ephedrine monograph's section on misuse and abuse to draw greater attention to risks associated with ephedra-containing dietary supplements (i.e., risks of death and severe adverse effects such as cardiovascular and nervous system toxicity), to increased misuse and abuse of these supplements as so-called natural substitutes for the recently withdrawn fenfluramine-phentermine ("fen-phen") regimen, which was cardiotoxic, and to FDA's concerns about the increasingly prevalent promotion of these supplements for uses other than weight loss (e.g., performance and energy enhancement, bodybuilding, increased mental concentration, sexual performance enhancement).

January 1999

AHFS DI adds to Ephedrine monograph information on oral bioavailability of ephedrine alkaloids from several ephedra-containing dietary supplements.

May 2000

AJHP publishes article on research showing potentially dangerous inconsistencies in ephedrine alkaloid content in ephedra-containing dietary supplements. ASHP alerts media to AJHP article (released early on www.ashp.org), resulting in coverage by Associated Press, USA Today, Fox News, Los Angeles Times, Washington Post, WRC-TV, ABCNews.com, Yahoo!News, Excite.com, InteliHealth.com, and Quad-City Times.

June-November 2000

AHFS DI revises Ephedrine monograph to address recent AJHP article on inconsistent ephedrine alkaloid content of ephedra-containing dietary supplements and FDA's advisory to health professionals about risks of ephedra-containing dietary supplements.

Key FDA staff members review AHFS DI revision of Ephedrine monograph, leading to a prolonged meeting between FDA and AHFS DI staffs, which resulted in heightened cautionary language in the monograph.

January 2001

AHFS DI publishes revised Ephedrine monograph.

January 2003

AHFS DI revises Ephedrine monograph to include information on additional DEA controls that had recently become effective.

March 2003

ASHP Committee on Therapeutics (COT) approves professional policy statement "Sale and Manufacture of Dietary Supplements Containing Ephedrine Alkaloids," which recommends that the Society support a ban on the manufacture and sale of dietary supplements containing ephedrine alkaloids.

April 2003

ASHP Board of Directors approves professional policy statement developed by COT.

ASHP Board of Directors approves interim professional policy statement "Regulation of Dietary Supplements," which in part calls on ASHP to advocate a change in the Dietary Supplement Health and Education Act of 1994 so that dietary supplements must meet the same legal requirements as nonprescription drugs.

ASHP asks FDA to ban the manufacture and sale of dietary supplements containing ephedrine alkaloids.

June 2003

ASHP House of Delegates approves professional policy supporting a ban on manufacturing and sale of dietary supplements containing ephedrine alkaloids.

January 2004

AHFS DI extensively revises Ephedrine monograph to address ongoing concerns about use of the drug in obesity treatment, additional findings by Rand Corporation about risks of ephedra-containing dietary supplements for athletic performance enhancement, and FDA's announcement to ban U.S. sales of ephedra-containing dietary supplements.

April 2004

ASHP Board of Directors approves ASHP Statement on the Use of Dietary Supplements, which includes ephedra among the dietary supplements that are inherently unsafe when ingested orally.

June 2004

ASHP House of Delegates to vote on ASHP Statement on the Use of Dietary Supplements.

  1. Food and Drug Administration. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. Fed Regist. 2004; 69:6787-854.
  2. McBride BF, Karapanos AK, Krudysz A et al. Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: a randomized controlled trial. JAMA. 2004; 291:216-21.