Revisiting Ephedra

Revisiting Ephedra

by Peter Huck

Just more thanthree years ago, 20-year Peter Schlendorf, a Long Island, N.Y. student on Spring Break inPanama City, died in March, 1996, after apparently taking eight tablets of anephedra-based dietary supplement called "Ultimate Xphoria." In the media frenzythat followed, New York Newsday, Newsweek, The New York Times, PrimeTimeLive and CNN Headline News were among the news outlets that reported on theincident. In Newsweek's coverage alone, Schlendorf's death prompted the magazine towrite a cover story titled "The Natural Drug Culture," as well as such sidebararticles as "Herbal Warning" and "Herbs to Handle with Care." The Foodand Drug Administration (FDA) also quickly weighed in, issuing an April 10, 1996 warningabout "herbal ecstasy" supplements containing ephedra (also called ma huang). Ittook more than a year for the heated controversy over ephedra supplements to abate.

The Schlendorf death wasn't the first time that ephedra supplements were under fire. InMay 1994, ephedra made headline news after a woman in her early forties died while playingtennis. She allegedly had been using a product called Formula One, consisting of ephedraand kola nut (an herb that contains caffeine). The woman's death led a few states to begintaking regulatory steps to restrict the sale of ephedra supplements. However, to date moststates and FDA have not banned nor heavily restricted dietary supplements containingephedra. Although the debate surrounding ephedra supplements has quieted in the last twoyears, very little has been resolved. Currently, supplements containing ephedra remain inmost markets and continue to be popular not just as decongestants, but even more so forboosting energy and/or weight loss. With continuing questions about the safety andappropriateness of some ephedra products, as well as an uncertain regulatory status, thetime has come to revisit ephedra.

In the wake of numerous adverse reactions, not to mention deaths, being attributed tothe use of ephedra supplements, it is no small miracle that ephedra supplements remainedon the market in most regions of the country. Some states did take regulatory action inresponse to safety concerns about ephedra supplements. Nebraska currently bans all ephedrasupplements, and Texas time and again has proposed strict ephedra regulations. Although inthe past calling for a ban on ephedra products, the Texas Department of Health recentlyreached a compromise with industry representatives and passed regulations this Januarythat require a warning label on ephedra supplements, including an advisement that theproducts are not for use by those under the age of 18. Ohio passed regulations that allowthe sale of an ephedra supplement if it, among other things, is packaged with labelingthat states the amount of ephedrine per dose and has a recommended daily dosage of notmore than 100 mg ephedrine alkaloids for more than 12 weeks.

Ephedrine (the main active component in ephedra) also has been the subject of proposedregulations by international health organizations. The World Health Organization (WHO) hasrecommended to the United Nations' Convention on Narcotic Drugs (CND) that it viewephedrine as a psychotropic substance to be classified as Schedule IV in accordance withU.N. convention on psychotropic substances. If that occurs, signatories to the CND,including the United States, would be required to treat ephedrine as prescription-onlyunless granted specific exemptions. The WHO proposal alludes to issues concerning ephedra,but it is unclear if it would apply. At an FDA public meeting held on Feb. 19, the agencywas described by attendee Marc Ullman of the law firm of Ullman, Shapiro & Ullman asnon-committal at best on whether the WHO proposal would apply to ephedra products. Ullmanadded, however, that the agency may have tipped its hand when it supplied WHO with the FDAproposed rules on ephedra (which are widely regarded as overly restrictive) in response toa request for information on the herb. (At HSR press time, CND had not yet met toconsider the ephedrine proposal.)

As CND considers how to classify ephedrine and after some states have previously passedrules for the manufacture and marketing of ephedra products, a glaring omission in theregulatory picture is a lack of implemented regulations on ephedra from FDA. True, FDA hasoccasionally issued statements or warnings about specific types of ephedra products, suchas products with street drug knockoff names or so-called "herbal fen-phen"supplements. However, with no encompassing FDA rules on ephedra products in effect, thesupplements have existed in a regulatory vacuum at the federal level.

After the deaths that reportedly resulted from ephedra use, FDA approached safetyconcerns during 1995 and 1996 with what seemed like a surprising level of restraint. In anattempt to develop the correct regulatory policy for ephedra supplements, FDA convened anexpert advisory subcommittee formally known as the "Special Working Group ConcerningFood Products Containing a Source of Ephedrine Alkaloids." The subcommittee, whichfirst met Oct. 11-12, 1995, consisted of herbal experts from academic institutions, aswell as leading industry representatives.

The expert advisory group met again at FDA's behest on Aug. 27-28, 1996. Prior to thismeeting, four industry trade groups--the American Herbal Products Association (AHPA),Council for Responsible Nutrition (CRN), Utah Natural Products Alliance (UNPA) andNational Nutritional Foods Association (NNFA)--took a proactive approach by proposingstrict dosage limits of 12 or 15 mg ephedrine alkaloids per dose four times per day (mostof the industry has since backed away from this recommendation; for example, AHPA nowrecommends members' products not contain in excess of 30 mg ephedrine alkaloids with adaily consumption of not more than 120 mg). Much of the discussion at the August meetingof the advisory group concerned how to interpret the more than 800 adverse event reports(AERs) from using ephedra-containing products. NNFA retained a consultant, MichaelDavidson, M.D., medical director of the Chicago Center for Clinical Research, tothoroughly review 191 of the full case reports of adverse effect events associated withephedra use. He found that 29 of the serious cases were possibly or probably related tothe effects of ephedra. Although this number is substantial and warranted concern,Davidson's review also clearly showed that the reported number of AERs was grosslyinaccurate and thus misleading.

What came out of the advisory group's recommendations to FDA? Judging from FDA'sproposed rules for regulating ephedra supplements, which appeared in the June 4, 1997 FederalRegister, the agency appeared to have mostly disregarded suggestions from experts andindustry representatives (one notable exception is Dr. Edward Croom of the University ofMississippi, whose recommendations were similar to FDA's proposed rules). Said DianeMcEnroe of the law firm of Sidley & Austin, general council for NNFA, "Therecommendations died, even though a lot of work went into them and a lot of respectedpeople worked on them. They were presented to FDA and then FDA came out with proposedrules that are basically inoperable."

Among the FDA proposed rules: prohibit the marketing of dietary supplements containing8 mg or more of ephedrine alkaloids per serving with a maximum daily dosage of 25 mg;require label statements instructing consumers not to use the product for more than 7days; prohibit the use of ephedrine alkaloids with caffeine or herbs containing caffeine;prohibit labeling claims that require long-term intake to achieve the purported effect;and require a statement in conjunction with claims that encourage short-term excessiveintake to enhance the purported effect that "taking more than the recommended servingmay result in heart attack, stroke, seizure or death."

Any consumer or retailer familiar with ephedra products currently on the marketimmediately realizes that these proposed rules are not in effect. An FDA spokesperson saidthat the rules remain in the proposed state but was unspecific as to the reasons for thedelay. "The proposed rules for ephedra go through a lot of different hands as part ofa clearance policy after it leaves FDA," explained the spokesperson. "Myunderstanding is that it is currently in the Office of Management and Budget. The rulesare still in the works, but there is no way to know when the proposed rules will takeeffect. This is something beyond our agency's control."

Although the FDA spokesperson suggests that the agency's job is essentially done inregard to the proposed rules for ephedra, a Washington lobbyist whose firm represents thesupplement industry disputed the statement that the proposed rules have left FDA and goneon to another arm of the federal government. To further complicate the situation, astaffer for Rep. Dan Burton (R-Ind.) confirmed that the Congressmen and others in both theHouse and Senate have concerns about the FDA proposed rules on ephedra, as well as the WHOrecommendations to the U.N. CND. Hearings by the Government Reform Committee, of whichRep. Burton is chairman, were scheduled to be held March 25 to address dietary supplementsand FDA's interpretation of the Dietary Supplement Health and Education Act (DSHEA).Consideration also was being given to future hearings solely on ephedra and FDA's systemof reporting adverse events. Spearheaded by such friends of the industry as Rep. Burtonand Sen. Orrin Hatch (R-Utah), who serves on the Senate Subcommittee on Health Care, thesehearings will exert intense pressure on FDA to significantly modify its proposed ephedrarules.

While the watchful eye of Congress may cause FDA to be reluctant to implement rules sovehemently opposed by industry representatives, some have speculated that the agency'sdelay in implementing the rules had larger political motivations. Said McEnroe,"There are many who feel that FDA wanted some kind of scapegoat for the industry andused ephedra as an example of an unsafe, unregulated dietary supplement, and then made itsgeneral argument through this one product."

In the February 1997 issue of Health Foods Business, a trade publication, RobertUllman and Marc Ullman of Ullman, Shapiro & Ullman wrote an editorial analysis inwhich they suggested that FDA used safety concerns over ephedra to mount a media campaignannouncing that the agency was hamstrung by DSHEA to remove potentially dangeroussupplements from the market. However, Ullman and Ullman noted that DSHEA makes it possiblefor the Secretary of Health & Human Services to order the immediate removal of anysupplement that is found to pose an "an imminent hazard."

Since FDA has this ability to get a product taken off retail shelves, Ullman and Ullmanpondered why FDA continually stated that it does not have the authority to act. A possiblereason, according to the two lawyers: "A direct and candid answer would likely revealeither that the agency simply does not want to act and is more interested in attackingDSHEA than removing a potentially dangerous product from the market, or that that maybethe danger from ma huang (ephedra) isn't exactly what FDA claims it to be, but is merelybeing used as an excuse to attack DSHEA."

Whether the FDA proposed rules will ever go into effect is yet to be seen. What isclear is that if the rules are implemented in the proposed form, the majority of ephedraproducts on the market will have to be reformulated and relabeled. Or these products willsimply cease to be. Although the majority of ephedra supplements only list ephedra contentand not the specific ephedrine content (excluding products in Ohio, where this informationis required), one still can deduce from the products' ephedra content that the greatmajority of them contain ephedrine contents higher than 7 mg per dose, which the FDAproposed rules would prohibit. The proposed rules to prohibit use for more than 7 days andprohibit label claims that require long-term intake are thinly veiled attempts to banephedra supplements marketed for weight loss. Finally, the proposal to not allow caffeineand ephedra in the same supplement formulation would affect scores of  products forenergy, in addition to those for weight loss.

The implementation of the FDA proposed rules undoubtedly would have drasticconsequences for the ephedra supplement category. According to an FDA market study ofephedra products conducted in 1996, 68 made energy claims, 33 made body building claims,47 were marketed for weight loss, nine claimed to produce euphoria, and four were sold torelieve asthma or allergy. Excluding products for allergy/asthma with low ephedrinecontent, the rest of the ephedra products would be in danger of being in violation of theFDA proposed rules.

Needless to say, companies that manufacture and market ephedra products are stronglyopposed to the proposed rules, and they defend ephedra as a safe herb. "A properlyformulated, well-balanced ephedra products is certainly safe to use, when taken asdirected," said Scott Smith, vice president of corporate development at NaturalBalance. "In fact, it's no more dangerous, for example, than drinking a few cups ofcoffee every day; however, if a person drinks an excessive amount, say six or eight cups aday, he or she is much more likely to experience some ill effects. Likewise, people whoabuse ephedra products can experience some ill effects as a result, not unlike thoseassociated with high caffeine consumption. Most people can enjoy the benefits of ephedrawithout problems, if they follow directions and do not exceed the recommended use."

Much of the industry's criticism of the proposed rules is directed to the fact that theFDA based its proposal on AERs that have were not carefully reviewed by the agency. Adocument put out by the Dietary Supplement Safety and Science Coalition (DSSSC), a groupconsisting of manufacturers of ephedra products, succinctly summarizes the opinion ofcritics of the FDA's AERs on ephedra. "A careful review of these reports has shownthat they present nothing more than anecdotal evidence, much of which has nothing to dowith ephedra. These AERs...are not a valid scientific basis for FDA's proposed rules. TheFDA is using scare tactics to improperly promote an overall restriction of ephedraproducts."

NNFA has also criticized the rules while reaffirming its support of responsiblymanufactured and marketed supplements containing ephedra. These products include ones forweight loss, exercise performance and boosting energy. "NNFA is trying to do whateverit can to support the legitimately marketed, labeled and formulated ephedra-based productswith weight loss and energy boosting claims," said McEnroe. "Historically, ithas been quite clear that NNFA has not been supportive of the more aggressively marketedephedra products that cross the line; those being street drug knockoffs marketed to elicita high. These products cast a negative light on the whole industry, and that is somethingNNFA would prefer not to happen."

Although industry groups generally defend the manufacture and marketing of ephedraproducts for multiple uses, no one denies that the herb should be used with caution, andthat consumers should pay close attention to warning labels. A look at how ephedrineaffects the body indicates that ephedra is a potent herb that has an immediatephysiological impact.

According to Pharmacognosy, Phytochemistry, Medicinal Plants by Dr. Jean Brune,ephedrine historically has been widely used to treat acute attack of asthma. However,because of numerous contraindications and drug interactions, the use of ephedrine as abronchodilator and analeptic have been virtually abandoned. Similarly, ephedrine in OTCand prescribed decongestant drugs has also begun to fall out of favor, and pseudoephedrine(also in ephedra) is more commonly utilized in these medications.

Modern medicine was not the first to see the potential of ephedrine alkaloids as adecongestant. Ma huang, the dried stems of the ephedra plant, has been used in TraditionalChinese Medicine (TCM) for approximately 5,000 years to treat symptoms of asthma and upperrespiratory infections. No consulted sources list boosting energy, exercise performance orweight loss as traditional uses of  the herb.

Ephedra contains a total of between 0.5 percent to 2.5 percent of several alkaloids(standardized ephedra extracts can consist of a considerably higher alkaloid content). Theprimary alkaloid is ephedrine, which comprises anywhere between 30 and 90 percent of totalalkaloids, depending on the species. This variance in ephedrine content, as well asdiffering formulation techniques, can make it very difficult to judge total amount ofephedrine in a product based solely on ephedra content. The implication of this variancein ephedrine content is that two products, while both having the same amount of ephedralisted on their respective labels, can have significantly different potencies and, byextension, possible side effects.

The pharmacological effects of ephedrine alkaloids in ephedra are pronounced. Standardtexts on herbal medicines are closely uniform in their description of ephedra's action onthe human body, as well as its side effects. In the classic text Pharmacognosy(Tyler V., Brady L., Robbers J.), ephedrine is noted as "a potent sympathomimeticthat stimulates ... adrenergic receptors. It excites the sympathetic nervous system,causes vasoconstriction and cardiac stimulation, and produces effects similar to those ofepinephrine (adrenalin). It produces a rather lasting rise in blood pressure, causesmydriasis (dilation of the pupils) and diminishes hyperemia (excess of blood in a bodypart)."

The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicineslists side effects of ephedra as insomnia, motor restlessness, irritability, headaches,nausea, vomiting, disturbances of urination and tachycardia (abnormally rapid heartbeat).In higher dosages, the German Commission E Monographs cite dramatic increase inblood pressure, cardiac arrhythmia and development of dependency. The Guide alsostates that "ephedra preparations should be only used in short-term duration becauseof tachyphylaxis and danger of addiction." The Physicians' Desk Reference forHerbal Medicines also notes that "dependence upon the drug (ephedra) can developwith extended intake." Ephedra also adversely interacts with such drugs asMAO-inhibitors, cardiac glycosides or halothane and guanethidine. The herb is notrecommended for people with a history of high blood pressure or cardiovascular problems,thyroid disease, diabetes or prostate conditions.

Another potential danger of continued ephedra intake was discovered last year byresearchers from the Washington University School of Medicine, who reported in the AmericanJournal of Kidney Disease that they believe 200 patients developed kidney stones aftertaking ephedra supplements. Using gas chromatography mass spectrometry, the researchersidentified the kidney stones as containing ephedrine, norephedrine and pseudoephedrine.

It would be a mistake to believe that the dietary supplement industry is totallyunified in its position on ephedra. Because of its strong action as a stimulant, as wellas its side effects, contraindications and drug interactions, some herbal experts in theindustry believe that taking ephedra for boosting energy, enhancing exercise performanceand/or weight loss is inappropriate and unhealthy. "These uses are not the intendedpurpose of ephedra in Traditional Chinese Medicine," reiterated Kara Dinda, M.S.,education project coordinator at the American Botanical Council in Austin, Texas."The intended purpose was to help with upper respiratory problems. It is being usedfor these other reasons because it is a central nervous system stimulant."

Roy Upton, herbalist and executive director of the Santa Cruz, Calif.-based AmericanHerbal Pharmacopoeia, is blunt in his opinion of the common practice of utilizing ephedrain weight loss, sports nutrition or energy supplements. "The use of ephedra andcaffeine in weight loss and energy products represents perhaps the worst example ofherbalism in the health food industry," he said. "These products rob the systemof vital energy, drain the adrenals, frazzle the nervous system, create an uneasy mind,and, most specifically, put the body in a continual flight or fight state of stress. Theuse of ephedra for these reasons is directly counter to the basic tenets of the healthfood industry to promote physical and mental health and well-being. Use of ephedra inenergy and weight loss supplements has compromised the health of a considerable number ofpeople."

To reduce potential health risks to consumers taking ephedra and in a welcomed exampleof self regulation, many companies that manufacture and market ephedra supplements includea fairly extensive warning on labels that cite contraindications, side effects andrecommended use. Many of these companies' labels are approximations of a warning labeldeveloped by AHPA, based in Silver Spring, Md., which reads: "Seek advise of a healthcare practitioner prior to use if you are pregnant or nursing, or if you have high bloodpressure, heart or thyroid disease, diabetes, difficulty in urination due to prostateenlargement, or if taking an MAO inhibitor or any other prescription drug. Reduce ordiscontinue use if nervousness, tremor, sleeplessness, loss of appetite or nausea occur.Not intended for use by persons under the age of 18. KEEP OUT OF REACH OF CHILDREN."Companies also commonly recommend not taking the product for more than 12 weeks. Many inthe industry consider the presence of a significant warning as a helpful way for retailersto know if  an ephedra product is being responsibly marketed.

Although warning labels are intended to ensure that consumers are fully aware of whocan and cannot safely take ephedra supplements, there is concern that ephedra for weightloss or for boosting energy prior to exercise targets the very consumers who should nottake the herb. Further, these consumers are people who, hypothetically, have a greaterpropensity to abuse an ephedra supplement.

Rob McCaleb, president of the Boulder, Colo.-based Herb Research Foundation, pointedout that consumers using ephedra for weight loss may be the very people who are advisednot to take it. "The known contraindications for ephedra are often squarely in thedemographics of people who likely use the products." He further explained, "Forexample, in the community of people who might use a weight loss product, there are manywho may have obesity-associated problems like high blood pressure and other cardiovascularproblems, which are clearly contraindicated for ephedra."

Ephedra supplements that are marketed for enhancing physical performance usually directusers to take the products before a workout, which may be problematic since exerciseraises a person's heart rate beyond normal whether that person has taken stimulants ornot. John Cardellina, Ph.D., vice president of botanical science and regulatory affairs atCRN, said that people using ephedra for weight loss or an energy boost before exercisealready are stressing their bodies through exercise and rigorous diet. "While thereare people who feel, or can even document, that ephedra helps them exercise longer or loseweight, ephedrine alkaloids have a very powerful effect on the body's central nervous andcardiovascular systems," he said. "If people are dieting, that means they aretrying to reduce caloric intake, and a lot of people push themselves on this front. Ifpeople are also exercising, the body clearly is stressed. The problem with ephedra is thatit acts on both the alpha and beta receptors. What this means in simplistic terms is thatephedra stimulates the central nervous system but also drives the cardiovascular system toperform harder. While that sounds good for athletic performance, it threatens to bring anyknown existing weaknesses or unknown latent weaknesses in the cardiovascular system to thesurface."

Upton also warned against taking ephedra before exercising. "I do not believeephedra should ever be used before a workout as it taxes the heart," he said."It makes it race faster than it should. The purpose of working out is to improvecardiovascular efficiency. The ability of the heart to recover its normal rhythm afterexertion is the true sign of physical conditioning. Proper exercise facilitates thisconditioning. Ephedra does the exact opposite."

Luke Bucci, vice president of research at Weider Nutrition, which offers suchephedra-containing supplements as Metadrene, Metacuts and Metaform Heat through itsMetaform line, said that research has indicated that ephedra is not only effective forweight loss and exercise performance, but also safe.

"We need to go with the scientific literature, and there are long-term studieslasting up to six months of continual ephedrine use," Bucci said. "Further, thelonger a person takes ephedra products, the less the mental side effects occur; however,the positive metabolic effects are still there. So we disagree with proposals that ephedrashould not be taken for more than a week. If used in a lower dosage, ephedra can be usedindefinitely in a manner much like the way caffeine has been used over thecenturies."

Weider has human studies on file that investigated the effect and safety ofephedrine/caffeine mixtures on energy expenditure and glucose metabolism in human. Thestudies were conducted by the same group of Danish researchers (a search of the Medlinedatabase found an additional five studies investigating the use of ephedrine for weightloss). The studies by the Dutch researchers concluded that an ephedrine/caffeinecombination is safe and effective in long-term treatment of up to six months in improvingand maintaining weight loss (the ephedra/caffeine combinations were taken before meals asopposed to before exercising). The researchers found that reported side effects were minorand transient and no clinically relevant withdrawal symptoms were observed. However,determining if side effects are serious or not is subject to interpretation."Minor" and "transient" side effects reported by the researchersincluded tremor, agitation, insomnia, increased sweating, nervousness, heart palpitationsand tachycardia.

No one can deny that Americans love taking stimulants to get an energy boost; justconsider yearly sales for both coffee and soda. Caffeine, especially if used excessively,can have such side effects as tachycardia, jitteriness and increased blood pressure.Further, a study sponsored by the National Institutes on Drug Abuse confirmed what coffeedrinkers have always known--caffeine is mildly addictive. Nevertheless, FDA has statedthat, except for pregnant women, caffeine is perfectly safe when taken in moderation. Somemay wonder if there is a double standard in which caffeine is acceptable while ephedra isvilified.

This may be a problematic line of argument for the supplement industry to pursue,however. Although a cup or two of coffee a day usually is not harmful, it also is nothealthy. People know and accept this; after all, they're not drinking coffee or soda fortheir health. However, dietary supplements, by definition, are supposed to be good for thebody.

Yes, ephedra does effectively boost energy levels. It also promotes weight loss, atleast in the short-term. Further, safety concerns about ephedra based on AERs have beenoverstated and manipulated by FDA. Nevertheless, there is still the issue of whetherephedra for boosting energy or for weight loss is health-enhancing. As long as thisquestion lingers, ephedra supplements are likely to remain mired in controversy anduncertainty.