On April 12, 2004, the Food and Drug Administration (FDA) officially banned the sale of all dietary supplements containing ephedra. One year later, on April 14, 2005, a district court in Utah overturned this decision.

Judge Tena Campbell of the US District Court for the Central District of Utah issued the ruling. While Campbell agreed that the FDA did prove that some ephedra supplements were harmful, she also said that there was no evidence to ban supplements containing low amounts of ephedra. Campbell ordered that supplements containing 10 mg or less of ephedra be allowed to return to the market. The FDA ban on products with higher amounts of ephedra should remain, she said.

This latest ruling opens the door for ephedra supplements to once again be sold in the US. This is worrisome. It is important that athletes, dieters, and everyone else understand how risky ephedra supplements can be. In this article, I will summarize ephedra and attempt to explain why I think that the sale of herbal ephedra supplements is a bad idea. First, some background information....

HISTORY OF EPHEDRA

Ephedra, also called "Ma huang", is one of the oldest and best known herbs in Chinese medicine. It is mentioned in the book Shen Nong Ben Cao Jing which dates to around 100 AD. Some sources claim that ephedra has been used for more than 5000 years.

Readers should not confuse ephedra, ephedrine, and pseudoephedrine. These terms are discussed below.

DESCRIPTION

It is important to make a distinction between "ephedra" and "ephedrine". "Ephedra" refers to the plant source or herbal products in their raw form. "Ephedrine" is a specific chemical ingredient obtained from ephedra plants. An analogy is nicotine and tobacco: nicotine is one of many chemicals obtained from the tobacco plant. Further, note that ephedrine is marketed as a legitimate pharmaceutical drug while ephedra is marketed as a dietary supplement in the US. Thus, the names "ephedra" and "ephedrine" should not be used interchangeably.

There are approximately 40 different species of ephedra plants. Biological names for two of the more commonly used plants are Ephedra sinica and Ephedra intermedia.

Ephedra plants yield at least 6 chemicals: the first 2 below are major, while the other 4 are minor:

• ephedrine
• pseudoephedrine (more commonly known by the brand name "Sudafed®")
• norephedrine (a component of phenylpropanolamine, PPA)
• norpseudoephedrine (a controlled substance in the US; also known as "cathine")
• methylephedrine
• methylpseudoephedrine

Of these 6 chemicals, ephedrine and pseudoephedrine represent about 90% of the total alkaloid content in ephedra plants, with Ephedra sinica being a slightly better source than Ephedra intermedia.

PHARMACOLOGY

While it is useful to know the chemical make-up of herbal ephedra, it is even more important to realize that its ingredients -- ephedrine, pseudoephedrine, etc. -- are related to amphetamine; the chemical structures of all these drugs are almost identical. Thus, it should not be surprising that the effects of herbal ephedra are similar to those of amphetamine. Fortunately, it appears that ephedra is not as prone to addiction as amphetamines are. Nevertheless, in high doses, ephedrine has been shown to cause psychosis (see below).

Ephedra's actions are mostly seen on the cardiovascular system. The alkaloids in ephedra cause a release of adrenalin (aka: epinephrine). This leads to an increase in heart rate and blood pressure. In controlled settings like an operating room, and with precise dosing, IV ephedrine is used therapeutically to increase low blood pressure and low heart rate during surgery. But, this mechanism is also the most likely explanation for why ephedra supplements have been associated with severe cases of cardiovascular and cerebrovascular toxicity.

USES OF EPHEDRA AND EPHEDRINE

Use in Weight Loss: Ephedrine has been shown to be effective for weight-loss in obese subjects, however it appears that it does so only when administered either in high doses (Shekelle PG, et al. 2003), or in combination with caffeine (Astrup A, et al. 1992) (Lenz TL, et al. 2004). Unfortunately, combining ephedra (or ephedrine) with caffeine leads to more side effects (see below).

Use in Sports:

The February 2, 1998 issue of Sports Illustrated carried a story about the use (abuse) of pseudoephedrine (commonly known by the brand name Sudafed®) in the NHL. The article stated that, as players were being warned of the risks of pseudoephedrine, many were switching to ephedra supplements to provide the same boost.

COMBINING EPHEDRA WITH CAFFEINE

The risks of ephedra increase when combined with caffeine. This combination is not only dangerous, but potentially deadly. Caffeine increases body temperature while several alkaloids in ephedra cause vasoconstriction, which inhibits heat loss. These 2 actions aren't a good combination for the cardiovascular system. When dogs were given high doses of guarana (an herbal source of caffeine) with ephedra, 17% died or had to be euthanized (Ooms TG, et al. 2001).

Nevertheless, some researchers argue that caffeine and ephedrine have been used together successfully as a weight loss aid in obese subjects without problems. Several studies from Copenhagen show that chronic administration of caffeine and ephedrine together does not produce severe side effects. And the doses used in these studies were large: caffeine 600 mg/day and ephedrine 60 mg/day (Astrup A, et al. 1992) (Astrup A, et al. 1993) (Toubro S, et al. 1993).

Yet, an equally compelling argument can be made against the use of caffeine+ephedra:

• In 2000, a report appeared in the New England Journal of Medicine describing a 19 year-old body-builder who developed severe chest pain resulting in an MI minutes after ingesting 24 mg of ephedra with 10 mg of caffeine (Traub SJ, et al. 2001).
• Another report, appearing also in 2000, describes a 33 year-old body-builder who suffered a stroke after using ephedra and caffeine daily for 6 weeks (Vahedi K, et al. 2000).

Unfortunately, this information was either not passed on to Baltimore Orioles pitcher Steve Bechler or he chose to ignore it. During spring training in February 2003, Bechler died after using ephedra supplements. At the time of his death, his body temperature was 108 degrees.

WHY ISN'T THE FDA DOING SOMETHING ABOUT EPHEDRA SUPPLEMENTS?

Actually, the FDA has been trying to ban the sale of this substance for years. In 1997, the FDA proposed capping the amount of ephedra in dietary supplements. At that time, they had received more than 800 reports of adverse events in people taking this supplement. The restrictions would have limited use to no more than 8 mg in a 6-hr period, or, 24 mg in a 24-hr period. FDA also proposed putting warning labels on containers.

But this generated an outcry from lawmakers and industry groups. They claimed that FDA did not have enough evidence to support these restrictions. Thus, on March 31, 2000, the FDA reluctantly withdrew them.

Several months later, the December 21, 2000 issue of the New England Journal of Medicine published a summary of 140 adverse reactions to ephedra (Haller CA, et al. 2000). Though not intentional, this article seemed to vindicate and validate the efforts of the FDA.

On October 8, 2002, HHS Secretary Tommy Thompson asked the FDA to evaluate the scientific evidence available and recommend the "strongest possible mandatory warning label possible for ephedra products". Perhaps this was a reaction to a September 2002 petition from Public Citizen threatening a lawsuit against the FDA and HHS to force a ban. Also on this date, the American Medical Association testified at a House Committee on Government Reform in favor of banning the sale of ephedra.

Then, in February 2003, Baltimore Orioles pitcher Steve Bechler died of heat stroke. Ephedra was implicated in his death. In March 2003, the FDA again proposed putting warning labels on ephedra. At that time, the FDA was aware of at least 100 reports of deaths linked to ephedra and a report, co-authored by representative Henry Waxman documenting 13,000 adverse reactions to ephedra was ready.

Finally, on December 30, 2003, the FDA succeeded in categorizing ephedra products as "adulterated" under the FD&C act due to their unreasonable risk of adverse reactions. These products were officially pulled from the market on April 12, 2004.

FDA vs. DSHEA

On February 5, 2004, the FDA seized nearly 1000 bottles of ephedra-containing supplements from MuscleMaster.com based on erroneous claims of enhanced athletic and muscular performance. So, it appears that the FDA finally has the legal basis to act, right?

Now, FDA is again being challenged, this time, on the basis that ephedra is safe at "lower doses". Dietary supplements are regulated under DSHEA 1994 and that means that the FDA must prove that something is not safe before it can pull it from the market. However, if they can't PROVE ephedra is unsafe at lower doses, then, reluctantly, they must back off.

EXTENSIVE DOCUMENTATION OF SIDE EFFECTS

It is hard to understand why we would continue to let ephedra supplements be marketed in the face of such an extensive number of reports of adverse events. Consider the following:

Between December 1993 and September 1995, the Texas Department of Health received approximately 500 reports of adverse events in persons who consumed dietary supplements containing ephedra. The reports described stroke, myocardial infarction, seizures, insomnia, dizziness, and 8 fatalities (MMWR 8/16/96). Since then, at least 4 extensive evaluations of side effects to ephedra supplements have been published:

1) An analysis of 926 reports of possible ephedra toxicity received by the FDA between 1995 and 1997 revealed that 4% involved serious cardiovascular events: 11 sudden deaths, 16 strokes (3 deaths), and 10 myocardial infarctions (Samenuk D, et al. 2002).

2) In 2000, Haller and Benowitz reviewed 140 reports of adverse events involving ephedra supplements that were submitted to the FDA between June 1, 1997 and March 31, 1999. Hypertension and cardiac arrhythmias were common in these reports including ten deaths and 13 cases of permanent disability. They concluded that 31% were "definitely" or "probably" related to ephedra, and another 31% were "possibly" related (Haller CA, et al. 2000).

3) In an attempt to compare the rates of adverse reactions from ephedra supplements against other types of herbal supplements, investigators at UCSF analyzed adverse reactions to herbal products reported to the American Association of Poison Control Centers during 2001. They found that products containing ephedra accounted for 64% of the reports even though ephedra products represented less than 1% of total herbal sales (Bent S, et al. 2003).

4) In the most thorough analysis to date, the RAND Corporation, at the request of the US Department of Health and Human Services, performed a comprehensive search and review of published reports on ephedra. The investigators concluded that ephedrine and ephedra are associated with 2-3 times the risk of heart palpitations, autonomic symptoms, and psychiatric symptoms (Shekelle PG, et al. 2003).

EPHEDRA NOT SAFE AT ANY DOSE?

As stated above, the April 2005 ruling in the Utah district court proposes to allow ephedra use at lower doses.

But "safe at lower doses" presupposes one critical detail: that all ephedra products yield a dependable, reliable quantity of active ingredient in each and every dose. For example, when you buy a bottle of Tylenol® or Motrin®, you don't worry that the tablet might contain too much active ingredient.

Yet this is exactly the risk you have with dietary supplements. Producers of dietary supplements do not always adhere to the Good Manufacturing Practice (GMP) standards that are required for the production of pharmaceutical drugs (Fontanarosa PB, et al. 2003). Not following GMP standards can lead to quality-control problems.

And quality-control issues have been demonstrated for ephedra supplements: In 2000, researchers at the University of Arkansas analyzed two separate lots of 10 commercially available ephedra supplements (Gurley BJ, et al. 2000.). Brands such as Metabolife, Ripped Fuel, and Xenadrine, to name a few, were included. Nineteen of 20 products contained measurable amounts of ephedrine, the major alkaloid found in herbal ephedra. But the amount of ephedrine ranged from 1.09 to 15.33 mg/capsule. Pseudoephedrine was identified in 16 of these 20 products; quantities ranged from 0.16 to 9.45 mg per capsule.

When 2 brands that each claimed 150 mg of ephedra per capsule were compared, one contained only 3.0 mg ephedrine while the other contained 14.2 mg ephedrine. This does not suggest these products were mislabeled. Rather, it is simply an example of how much a specific ingredient in an herbal substance can vary. Different manufacturers will obtain their raw material from different suppliers. In this case, even though both products used the same amount of raw material (150 mg), the amount of active ingredient (ephedrine) varied by nearly 5-fold. In another report, researchers from UCSF revealed that 31% of the products they tested contained more than 110% of the amount stated on the product's label (Haller CA, et al. 2004).

Even more worrisome is a lack of consistency between 2 lots of the same brand:

When the University of Arkansas researchers compared different lots of the same brand, variations in ephedrine content ranged as high as 260% (Gurley, et al. 2000). Again, this can be explained by normal variation in the amount of active ingredient in an herbal substance, or, by the manufacturer changing the source of their raw material. Thus, consumers are unknowingly subjected to wide variations in the amount of substances they ingest, even if they purchase the same identical brand each time.

Some athletes abuse ephedrine (Gruber AJ, et al. 1998). This behavior is serious enough when the amount of active ingredient per dosage unit is known and consistent from batch to batch. However, when the amount of active ingredient varies from batch to batch, or, worse, is higher than what is stated on the label, serious side effects are possible. Even "normal" doses of pseudoephedrine have been associated with cardiac arrhythmias (Bright TP, et al. 1981).

This is the side of the story that consumers need to be aware of. Ephedra is a potentially dangerous herb; even more so when you can't be certain what amount you are actually ingesting.

WHERE DO WE GO FROM HERE?

The April 14, 2005 ruling from the Utah district court does not automatically mean that ephedra supplements will be widely available again. Consider the following:

1) The FDA will likely appeal this decision. Thus, it may be years before this issue is truly settled.

2) Some feel that the ruling may only be applicable in Utah. Several states (eg., California, Illinois, New York) had already passed laws banning the sale of ephedra products before the April 2004 ban by the FDA; the Utah ruling would not overturn regulations in other states.

3) Many retailers -- including GNC, 7-Eleven, CVS, Walgreens -- have voluntarily chosen to stop selling ephedra supplements.

4) Many groups oppose the sale of ephedra supplements: American College of Sports Medicine, American Heart Association, American Medical Association, Consumers Union (publisher of Consumer Reports), Public Citizen, and others. It is important to keep in mind that the Utah case was initiated by a supplement manufacturer.

GUIDELINES

Nevertheless, ephedra supplements can be purchased via the Internet. If that occurs, then athletes, dieters, and other consumers are urged to consider the following:

Guidelines for Athletes:

Athletes should avoid ephedra for the following reasons:

• Ephedra is a stimulant; stimulants are banned from sports competition. Olympic athletes Rick DeMont (swimming, 1972) and Andreea Raducan (gymnastics, 2000) lost gold medals due to consuming prescription drugs that contained ephedrine and pseudoephedrine. The herb ephedra also contains those ingredients.

• Ephedra can produce serious side effects, which are somewhat unpredictable: Even though some research shows that ephedra alkaloids don't increase HR or BP during aerobic exercise very much, don't be misled by this. It is risky to consume herbs with the potential for increasing blood pressure prior to, or during strenuous exercise. This would be especially true for weight-lifting, which can produce enormous, though brief, increases in blood pressure. In one study, the blood pressure in a body-builder performing leg press reached an astounding 480/350 mmHg (MacDougall J, et al. 1985).

Ephedra can also interfere with heat loss, as in the case of Steve Bechler.

• Lack of performance-enhancing effects. It's hard to understand why athletes use (abuse) ephedra in the first place. It appears that the performance-enhancing effects are minimal, if they exist at all:

Pseudoephedrine demonstrated no performance-enhancing effects during cycling (Gillies H, et al. 1996) or treadmill running (Clemons JM, et al. 1993) and oral ephedrine had no effect on performance during cycling (DeMeersman R, et al. 1987), or on muscle strength, endurance, reaction time, or hand-eye coordination (Sidney KH, et al. 1977). Because ephedrine and pseudoephedrine are the main alkaloids in herbal ephedra, these studies cast serious doubt on the performance-enhancing capabilities of herbal ephedra.

Guidelines for Dieters:

Resorting to the use of stimulants for weight-loss is a poor choice. Many different stimulants have been used over the past several decades in an attempt to facilitate weight loss. Generally, this doesn't work long-term. Stimulants exert their effects by decreasing appetite, not by burning more calories. Further, attempting to lose weight by taking drugs or supplements does not achieve the other health benefits that exercise provides, namely, a stronger heart, lower blood pressure, increased bone density, and a lower risk of cardiovascular disease. Exercise is a better choice. In fact, exercise lowers blood pressure and lowers the risk of cardiovascular disease in obese people even if they remain obese (Barlow CE, et al. 1995) (Lee CD, et al. 1999).

SUMMARY: WHY THE SALE OF HERBAL EPHEDRA SHOULD BE PROHIBITED

• Lack of quality-control: "Natural" does not mean "safe". The alkaloids found in the herb ephedra produce powerful effects on the circulatory system. Combined with the issue of too much uncertainty regarding the amounts of these ingredients in different batches and different brands of ephedra supplements..... Thus, even if a person takes the dose recommended on the label, he/she cannot be certain that they will actually receive that amount.

• Interaction with caffeine: Caffeine increases the toxicity of ephedra. A large majority of the population drinks caffeinated beverages regularly. Thus, it seems inevitable that use of herbal ephedra by large populations increases the likelihood of adverse reactions. The FDA was concerned enough by this drug interaction in 1982 to ban drug products that combined caffeine with ephedrine and PPA.

• Herbal ephedra contains ingredients that the FDA has already banned: In August 1982, FDA banned drug products containing the triple combination of caffeine-ephedrine-phenylpropanolamine stating that the combination was irrational and presented a potential health hazard (Federal Register, 1982). In addition, the decongestant phenylpropanolamine (PPA) was removed from US and Canadian markets in 2000 due to the risk of stroke. Australia removed PPA products in 2001. Norephedrine is found in phenylpropanolamine (PPA) and the herb ephedra. If PPA is so risky, and, if ephedra contains a compound similar to PPA, why would we ban PPA but not herbal ephedra?

• The risks far exceed its potential benefits: Even though it is true that ephedra and ephedrine assist in promoting weight-loss, the impact is minimal. In 2003, JAMA published an extensive review of the scientific literature on ephedra and ephedrine conducted by the RAND group. They found that, by itself, ephedrine increased the rate of weight-loss by only 0.6 kg/month; when ephedrine or ephedra was combined with caffeine, the rate was still only 1.0 kg/month better than placebo (Shekelle PG, et al. 2003).

FOR MORE INFORMATION

Consumers Union, publisher of the magazine Consumer Reports, provides a fact sheet on ephedra on their web site: www.ConsumersUnion.org. Their January 2004 issue contains a review of ephedra.

The best source of scientific information on herbal ephedra can be found at Natural Standard (www.NaturalStandard.com). Another site offering a monograph on ephedra is Supplement Watch (www.SupplementWatch.com).

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REFERENCES

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ABOUT THE AUTHOR

Stan Reents, PharmD, is a former healthcare professional. He holds Personal Trainer and Lifestyle Counselor certifications from the American Council on Exercise and has been certified as a tennis coach by USTA. He is the author of Sport and Exercise Pharmacology (published by Human Kinetics).  He can be reached at: Editor@athleteinme.com.