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Ephedra: A Dangerous Supplement

Author: Stan Reents, PharmD
Original Posting: 05/06/2007 08:51 AM
Last Revision: 01/15/2016 07:55 AM

On February 17, 2003, Baltimore Orioles pitcher Steve Bechler died of heat stroke while practicing in Florida. At the time of his death, his body temperature was reported to be 108 degrees F. The use of the herbal supplement ephedra was implicated.

On January 5, 2004, the Food and Drug Administration (FDA) banned the sale of all dietary supplements containing ephedra. This ruling went into effect on April 12, 2004.

In this article, I will summarize ephedra, and, some of the FDA actions regarding its regulation in the US.

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.

DESCRIPTION

Readers should not confuse ephedra, ephedrine, and pseudoephedrine. "Ephedra" refers to the plant source or herbal products in their raw form. "Ephedrine" is a specific chemical ingredient obtained from ephedra plants (see below). 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 an herbal supplement. 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 (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.

FDA ACTIONS REGARDING EPHEDRA SUPPLEMENTS

Prior to the death of Steve Bechler in 2003, the FDA had been trying to ban the sale of this substance for years. In the US, dietary supplements are regulated under the DSHEA law, which was passed in 1994. DSHEA puts the burden of proving that something is unsafe on the shoulders of the FDA, not the manufacturer, as is required before traditional pharmaceutical drugs are approved. This means that supplements can be marketed before safety issues are investigated.

• June 4, 1997: FDA proposes limiting 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. This generated an outcry from lawmakers and industry groups. They claimed that FDA did not have enough evidence to support these restrictions. (see below for a summary of adverse reaction reports).

• October 1, 1998: Anne Marie Capati, 37, a known hypertensive, suffers a stroke and dies after working out while taking Thermadrene, which contains ephedra. Family files a $320 million lawsuit (source: NY Times, June 29, 1999).

• August 4, 1999: A GAO report states that the FDA did not have enough evidence to justify their proposal to limit individual and daily doses of ephedra.

• February 25, 2000: FDA informs Congress of its intent to withdraw its proposed restrictions. On March 31, 2000, the FDA reluctantly withdraws them.

• December 21, 2000: The New England Journal of Medicine publishes 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.

• September 5, 2001: Public Citizen files a petition to FDA requesting a ban on the manufacture and sale of all ephedra-containing dietary supplements.

• January 2002: Health Canada bans the sale of ephedra supplements in Canada.

• September 3, 2002: 16-yr old Sean Riggins, a football player in Lincoln, IL suffers a seizure and dies after taking Yellow Jackets, an OTC supplement containing ephedra and kola nut.

• October 8, 2002: The American Medical Association and Sidney Wolfe, MD of Public Citizen testify at a House Committee on Government Reform in favor of banning the sale of ephedra. HHS Secretary Tommy Thompson asks the FDA to evaluate the scientific evidence available and recommend the "strongest possible mandatory warning label possible for ephedra products."

• February 17, 2003: Baltimore Orioles pitcher Steve Bechler dies of heat stroke during practice in Florida. He was taking Xenadrine-RFA-1.

• March 2003: FDA again proposes 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.

• December 30, 2003: The FDA succeeds in categorizing ephedra products as "adulterated" under the FD&C act due to their unreasonable risk of adverse reactions.

• January 5, 2004: FDA issues ban on sale of ephedra supplements.

• February 5, 2004: FDA seizes nearly 1000 bottles of ephedra-containing supplements from MuscleMaster.com (NOTE: this web site has since been shut down) based on erroneous claims of enhanced athletic and muscular performance.

• April 12, 2004: Effective date for the January 5, 2004 ban.

• April 13, 2005: In response to a protest filed by a Park City, UT corporation (Nutraceutical Corp.), Judge Tena Campbell strikes down the FDA ban stating that FDA did not prove that ephedra was unsafe at low doses.

• June 13, 2005: FDA informs the court of its intent to appeal this decision.

• August 2005: Utah District Court (Judge Tena Campbell) decision is reversed.

• May 14, 2007: In response to another protest filed by Nutraceutical Corp. (Park City, UT), the appellate court rejected the protest outright. This appears to be the end of the road for ephedra supplements in the US marketplace.

EXTENSIVE DOCUMENTATION OF SIDE EFFECTS

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).

DSHEA vs. GMP

Another problem that DSHEA created when it was passed in 1994 is that supplement manufacturers were not held to the same production standards that manufacturers of traditional pharmaceutical drugs are held to. In other words, 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. Prior to 2007, producers of dietary supplements did 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 were 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 BJ, 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.

GUIDELINES

As mentioned above, the FDA banned the sale of supplements containing ephedra in 2004. Nevertheless, it's possible that ephedra supplements could still 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).

Readers may also be interested in these topics:

EXPERT HEALTH and FITNESS COACHING

Stan Reents, PharmD, is available to speak on this and many other exercise-related topics. (Here is a downloadable recording of one of his Health Talks.) He also provides a one-on-one Health Coaching Service. Contact him through the Contact Us page.

REFERENCES

Astrup A, Breum L, Toubro S, et al. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. Int J Obes Relat Metab Disord 1992;16:269-277.  Abstract

Astrup A, Toubro S. Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. Int J Obes Relat Metab Disord 1993;17 suppl 1:S41-S43.  Abstract

Barlow CE, Kohl HW, Gibbons LW, et al. Physical fitness, mortality and obesity. Int J Obes Rel Metab Disord 1995;19(suppl 2):S41-S44.  Abstract

Bent S, Tiedt TN, Odden MC, et al. The relative safety of ephedra compared with other herbal products. Ann Intern Med 2003;138:468-471.  Abstract

Bright TP, Sandage BW, Fletcher HP. Selected cardiac and metabolic responses to pseudoephedrine with exercise. J Clin Pharmacol 1981;21:488-492.  Abstract

Centers for Disease Control and Prevention. Adverse events associated with ephedrine-containing products: Texas, December 1993 - September 1995. MMWR 1996;45:689-692.  Abstract

Chait LD. Factors influencing the reinforcing and subjective effects of ephedrine in humans. Psychopharmacol (Berl) 1994;113:381-387.  Abstract

Clemons JM, Crosby SL. Cardiopulmonary and subjective effects of a 60 mg dose of pseudoephedrine on graded treadmill exercise. J Sports Med Phys Fit 1993;33:405-412.  Abstract

DeMeersman R, Getty D, Schaefer DC. Sympathomimetics and exercise enhancement: all in the mind? Pharmacol Biochem Behav 1987;28:361-365.  Abstract

Fontanarosa PB, Drummond R, DeAngelis CD. The need for regulation of dietary supplements - lessons from ephedra. JAMA 2003;289:1568-1570.  Abstract

Gruber AJ, Pope HG. Ephedrine abuse among 36 female weightlifters. Am J Addict 1998;7:256-261.  Abstract

Gurley BJ, Gardner SF, Hubbard MA. Content versus label claims in ephedra-containing dietary supplements. Am J Health-Syst Pharm 2000;57:963-969.  Abstract

Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833-1838.  Abstract

Haller CA, Benowitz NL, Jacob P. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med 2005;118:998-1003.  Abstract

Haller CA, Duan M, Benowitz NL, et al. Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements. J Anal Toxicol 2004;28:145-151.  Abstract

Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826-1832.  Abstract

Krome CN, Tucker AM. Cardiac arrhythmia in a professional football player. Was ephedrine to blame? Phys Sportsmed 2003;31:21-29.  (no abstract)

Lee CD, Blair SN, Jackson AS. Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men. Am J Clin Nutr 1999;69:373-380.  Abstract

Lentz TL, Hamilton WR. Supplemental products used for weight loss. J Am Pharm Assoc 2004;44:59-68.  (no abstract)

MacDougall JD, Tuxen D, Sale DG, et al. Arterial blood pressure response to heavy resistance exercise. J Appl Physiol 1985;58:785-790.  Abstract

New drug status of OTC combination drug products containing caffeine, phenylpropanolamine, and ephedrine. Fed Reg 1982;47:35344-35345.  (no abstract)

Ooms TG, Khan SA, Means C. Suspected caffeine and ephedrine toxicosis resulting from ingestion of an herbal supplement containing guarana and ma huang in dogs: 47 cases (1997-1999). J Am Vet Med Assoc 2001;218:225-229.  Abstract

Perrotta DM. Adverse events associated with ephedrine-containing products: Texas, December 1993 - September 1995. JAMA 1996;276:1711-1712.  Abstract

Samenuk D, Link MS, Homoud MK, et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clinic Proc 2002;77:12-16.  Abstract

Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 2003;289:1537-1545.  Abstract

Toubro S, Astrup AV, Breum L, et al. Safety and efficacy of long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture. Int J Obes Relat Metab Disord 1993;17 suppl 1:S69-S72.  Abstract

Traub SJ, Hoyek W, Hoffman RS. Dietary supplements containing ephedra alkaloids. N Engl J Med 2001;344:1096.  Abstract

Vahedi K, Domigo V, Amarenco P, et al. Ischaemic stroke in a sportsman who consumed Ma Huang extract and creatine monohydrate for body building. J Neurol Neurosurg Psychiatry 2000;68:112-113.  Abstract

White LM, Gardner SF, Gurley BJ, et al. Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol 1997;37:116-122.  Abstract

ABOUT THE AUTHOR



Stan Reents, PharmD, is a former healthcare professional. He is a member of the American College of Sports Medicine (ACSM) and holds current certifications from ACSM (Health & Fitness Specialist), ACE (Health Coach) and has been certified as a tennis coach by USTA. He is the author of Sport and Exercise Pharmacology (published by Human Kinetics) and has written for Runner's World magazine, Training and Conditioning, Club Solutions, and other fitness publications.




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