Ephedra

This article is about the use of species of Ephedra in medicine. For botanical information, see Ephedra (genus).

For the prescription medication ephedrine, see ephedrine.

Bottle of Ephedrine, an alkaloid found in Ephedra

Ephedra refers to the plant Ephedra sinica.^[1] E. sinica, known in Chinese as ma huang (麻黃; pinyin: má huáng), has been used in traditional Chinese medicine for 5,000 years for the treatment of asthma and hay fever, as well as for the common cold.^[2] Several additional species belonging to the genus Ephedra have traditionally been used for a variety of medicinal purposes, and are a possible candidate for the Soma plant of Indo-Iranian religion.^[3] Native Americans and Mormon pioneers drank a tea brewed from an Ephedra, called Mormon Tea.

Mormon Tea (Ephedra funerea) growing in the wild in the Fiery Furnace area of Arches National Park near Moab, Utah.

In recent years, the safety of ephedra-containing dietary supplements has been questioned by the United States Food and Drug Administration (FDA), the National Center for Complementary and Alternative Medicine, and the medical community as a result of a high rate of serious side effects and ephedra-related deaths.^{[4][5][6][7][8]} In response to accumulating evidence of adverse effects and deaths related to ephedra, the FDA banned the sale of ephedra-containing supplements on April 12, 2004.^[9] A suit by an ephedra manufacturer was upheld by a Federal District Court judge in Utah on April 14, 2005.^[10] The FDA appealed this ruling, and on August 17, 2006 the U.S. Court of Appeals for the Tenth Circuit upheld the FDA's ban of ephedra.^[11] The sale of ephedra-containing dietary supplements remains illegal in the United States due to evidence of adverse ephedra-related effects.

Ephedra biochemistry

The alkaloids ephedrine and pseudoephedrine are the active constituents of the plant. Pseudoephedrine is used in over-the-counter decongestants. Derivatives of ephedrine are used to treat low blood pressure, but alternatives with reduced cardiovascular risk have replaced it for treating asthma. Ephedrine is also considered a performance-enhancing drug and is prohibited in most competitive sports. Some species in the Ephedra genus have no alkaloid content and are therefore essentially inert; however, the most commonly used species, E. sinica, has a total alkaloid content of 1–3% by dry weight. Ephedrine constitutes 40–90% of the alkaloid content, with the remainder consisting of pseudoephedrine and the demethylated forms of each compound.^[12]

Effects and uses

Ephedra is both a stimulant and a thermogenic; its biological effects are due to its ephedrine and pseudoephedrine content.^[2] These compounds stimulate the brain, increase heart rate, constrict blood vessels (increasing blood pressure), and expand bronchial tubes (making breathing easier). Their thermogenic properties cause an increase in metabolism, evidenced by an increase in body heat.

In traditional Chinese herbology, E. sinica is included in many herbal formulas used to treat cold and flu such as 麻黃湯 ma huang tang (ephedra decoction) or 麻杏石甘湯 ma xing shi gan tang (ephedra, apricot kernel, gypsum, and licorice decoction). Ephedra is used therapeutically as a diaphoretic to help expel exterior pathogens and regulate the proper functioning of the lungs.^[13]

Ephedra is widely used by athletes,^[14] despite a lack of evidence that it enhances athletic performance.^[15][16] Ephedra may also be used as a precursor in the illicit manufacture of methamphetamine.^[17]

Ephedra has also been used for weight loss, sometimes in combination with aspirin and caffeine. Some studies have shown that ephedra, when taken in a regulated and supervised environment, is effective for marginal short-term weight loss (0.9kg/month more than the placebo), although it is unclear whether such weight loss is maintained.^[18] However, several reports have documented the large number of adverse events attributable to unregulated ephedra supplements.^[19]

Side effects of ephedra may include severe skin reactions, irritability, nervousness, dizziness, trembling, headache, insomnia, profuse perspiration, dehydration, itchy scalp and skin, vomiting, hyperthermia, irregular heartbeat, seizures, heart attack, stroke, or death.^[20]

Purity and dosage

There are no formal requirements for standardization or quality control of dietary supplements in the United States, and the dosage of effective ingredients in supplements may vary widely from brand to brand or batch to batch.^[21][22][23] Studies of ephedra supplements have found significant discrepancies between the labeled dose and the actual amount of ephedra in the product. Significant variation in ephedrine alkaloid levels, by as much as 10-fold, was seen even from lot to lot within the same brand.^[24][25]

Safety and regulatory actions in the United States

Escalating concerns regarding the safety of ephedra supplements led the FDA to ban the sale of ephedra-containing supplements in the United States in 2004. This ban was challenged by supplement manufacturers and initially overturned, but ultimately upheld.

Initial concerns and supplement industry response

In 1997, in response to mounting concern over serious side effects of ephedra, the FDA proposed a ban on products containing 8 mg or more of ephedrine alkaloids and stricter labeling of low-dose ephedra supplements. The FDA also proposed that ephedra labels be required to disclose the health risks of ephedra, such as heart attack, stroke, or death.^[26]

In response, the supplement industry created a public relations group, the Ephedra Education Council, to oppose the changes, and commissioned a scientific review by a private consulting firm, which reported that ephedra was safe.^[27] The Ephedra Education Council also attempted to block publication of a study confirming wide discrepancies between the labeled potency of supplements and the actual amount of ephedra in the product.^[21]

During this time, Metabolife, makers of the best-selling brand of ephedra supplement, had received over 14,000 complaints of adverse events associated with its product; these reports were not provided to the FDA.^[27][28] Co-founder of Metabolife, Michael J. Ellis, has been sentenced to six months in Federal prison for his failure to report adverse effects from his company's products to the FDA.^[29] Senators Orrin Hatch and Tom Harkin, authors of the Dietary Supplements Health and Education Act, questioned the scientific basis for the FDA's proposed labeling changes and suggested that the number of problems reported were insufficient to warrant regulatory action. At the time, Hatch's son was working for a firm hired to lobby Congress and the FDA on behalf of ephedra manufacturers.^[30]

In addition to the activities of the Ephedra Education Council, Metabolife spent more than $4 million between 1998 and 2000 lobbying against state regulation of ephedra in Texas.^[31] Business Week reported that efforts to regulate ephedra and other potentially harmful supplements had been "beaten down by deep-pocketed industry lobbying."^[32]

Ultimately, in 2000, the FDA withdrew the proposed labeling changes and restrictions.^[33]

Additional evidence

A review of ephedra-related adverse reactions, published in the New England Journal of Medicine in 2000, found a number of cases of sudden cardiac death or severe disability resulting from ephedra use, many of which occurred in young adults using ephedra in the labeled dosages.^[4] Subsequently, in response to pressure from the consumer advocacy group Public Citizen,^[32] Metabolife was compelled by the Department of Justice in 2002 to turn over reports of over 15,000 ephedra-related adverse events, ranging from insomnia to death, which the company had previously withheld from the FDA.^[34][27] Use of ephedra was considered to have possibly contributed to the death of Minnesota Vikings offensive lineman Korey Stringer from heatstroke in 2001.^[35]

Death of Steve Bechler

Steve Bechler, a pitcher for the Baltimore Orioles, died of complications from heatstroke following a spring training workout on February 17, 2003. The medical examiner found that ephedra toxicity played a "significant role" in Bechler's sudden death.^[36] Following Bechler's death, the FDA re-opened its efforts to regulate ephedra use. According to Bruce Silverglade, legal director for the Center for Science in the Public Interest, "All of a sudden [after Bechler's death] Congress dropped objections to an ephedra ban and started demanding the FDA act."^[27]

Senator Orrin Hatch, who in 1999 had helped block the FDA's attempts to regulate ephedra, said in March 2003 that "...it has been obvious to even the most casual observer that problems exist," and called FDA action to regulate ephedra "long overdue."^[30] Given Hatch's prior defense of ephedra, Time described his statement as "a dazzling display of hypocrisy."^[37]

Ephedra banned

In response to renewed calls for the regulation of ephedra, the FDA commissioned a large meta-analysis of ephedra's safety and efficacy by the RAND Corporation. This study found that while ephedra promoted modest short-term weight loss, there was no evidence that it was effective for long-term weight loss or performance enhancement. The use of ephedra in this study was associated with significant gastrointestinal, psychiatric, and autonomic side effects.^[38] Almost simultaneously, a study in Annals of Internal Medicine found that ephedra was 100 to 700 times more likely to cause a significant adverse reaction than other commonly used supplements such as kava or Ginkgo biloba.^[5]

On December 30, 2003, the FDA issued a press release recommending that consumers stop buying and using ephedra, and indicating its intention to ban the sale of ephedra-containing supplements.^[39] Subsequently, on April 12, 2004, the FDA issued a final rule banning the sale of ephedra-containing dietary supplements. Tommy Thompson, the Secretary of Health and Human Services, stated that "...These products pose unacceptable health risks, and any consumers who are still using them should stop immediately."^[9]

Legal challenges

Nutraceutical Corporation, a supplement manufacturer based in Park City, Utah, challenged the legality of the FDA's ban of ephedra as exceeding the authority given the agency by the Dietary Health Supplements and Education Act. Nutraceutical Corporation stated that they did not intend to start marketing ephedra, but were concerned about the scope of the FDA's regulatory action. Judge Tena Campbell of the Utah Federal District Court ruled that the FDA had not proven that low doses of ephedra were unsafe, although she also noted that studies to address the safety of low-dose ephedra would be unethical. Nevertheless, her ruling overturned the ban on the sale of ephedra in the state of Utah, and called into question whether the ban could be enforced anywhere in the United States.^[40]

The ruling was appealed to the U.S. Court of Appeals for the Tenth Circuit in Denver, Colorado. On August 17, 2006, the Appeals Court upheld the FDA's ban of ephedra, finding that the 133,000 page administrative record compiled by the FDA supported the agency's finding that ephedra posed an unreasonable risk to consumers.^[11] Nutraceutical Corp. filed a petition for a writ of certiorari seeking a rehearing on the ban of ephedra; however, on May 14, 2007 the United States Supreme Court declined to hear this petition. The sale of ephedra-containing dietary supplements remains illegal in the United States.^[7]

Use in sports

Ephedrine is listed as a banned substance by both the International Olympic Committee and the World Anti-Doping Agency.^[41] The U.S. National Football League banned players from using ephedra as a dietary supplement in 2001 after the death of Minnesota Vikings offensive tackle Korey Stringer; ephedra was found in Stringer's locker and lawyers for the team contend that it contributed to his death.^[35][42] The substance is also banned by the National Basketball Association.^[40] Nonetheless, ephedra remains widely used by athletes; a 2006 survey of collegiate hockey players found that nearly half had used ephedra in the belief it would enhance athletic performance.^[14]

Prominent cases of ephedra use

In the 1994 FIFA World Cup, the Argentine footballer Diego Armando Maradona tested positive for ephedrine.^[43] The Japanese motorcycle racer Noriyuki Haga tested positive for it in 2000, being disqualified from two races and banned from two more as a result.^[44] NFL punter Todd Sauerbrun of the Denver Broncos was suspended for the first month of the 2006 season after testing positive for ephedra.^[42]

See also

• Chinese medicine
• Sida cordifolia
• Pinellia
• Synephrine

References

1. ^ Gurley B, Wang P, Gardner S (1998). "Ephedrine-type alkaloid content of nutritional supplements containing Ephedra sinica (Ma-huang) as determined by high performance liquid chromatography". J Pharm Sci 87 (12): 1547–53. doi:10.1021/js9801844. PMID 10189265. 
2. ^ ^{a b} Abourashed E, El-Alfy A, Khan I, Walker L (2003). "Ephedra in perspective--a current review". Phytother Res 17 (7): 703–12. doi:10.1002/ptr.1337. PMID 12916063. 
3. ^ Botany of Haoma, from Encyclopedia Iranica. Accessed March 15, 2007.
4. ^ ^{a b} Haller C, Benowitz N (2000). "Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids". N Engl J Med 343 (25): 1833–8. doi:10.1056/NEJM200012213432502. PMID 11117974. 
5. ^ ^{a b} Bent S, Tiedt T, Odden M, Shlipak M (2003). "The relative safety of ephedra compared with other herbal products". Ann Intern Med 138 (6): 468–71. PMID 12639079. 
6. ^ "National Center for Complementary and Alternative Medicine Consumer Advisory on ephedra". 2004-10-01. http://nccam.nih.gov/health/alerts/ephedra/consumeradvisory.htm. Retrieved 2007-02-13.  ]
7. ^ ^{a b} "Food and Drug Administration summary of actions regarding sale of ephedra supplements". http://www.fda.gov/oc/initiatives/ephedra/february2004/. Retrieved 2007-02-13. 
8. ^ WebMD page on ephedra supplements. Accessed 7 Feb 2007.
9. ^ ^{a b} FDA Final Rule Banning Dietary Supplements With Ephedrine Alkaloids Becomes Effective. Accessed from FDA website 7 Feb 2007.
10. ^ "Ephedra", from MayoClinic.com. Accessed 7 Feb 2007.
11. ^ ^{a b} FDA Statement on 10th Circuit Court's ruling to uphold ban of ephedra
12. ^ Adverse Effects of Botanical and Non-Botanical Ephedrine Products, from the Harvard School of Public Health. Published 1997. Accessed 7 Feb 2007.
13. ^ Ephedra, Mahuang, Ma Huang, desert tea, Mormon tea, American ephedra, Chinese ephedra, European ephedra, Pakistani ephedra, Ephedra sinica, Ephedra intermedia, Ephedra equisetina, Ephedra distacha, Ephedra trifurca
14. ^ ^{a b} Bents R, Marsh E (2006). "Patterns of ephedra and other stimulant use in collegiate hockey athletes". Int J Sport Nutr Exerc Metab 16 (6): 636–43. PMID 17342884. 
15. ^ Bohn A, Khodaee M, Schwenk T (2003). "Ephedrine and other stimulants as ergogenic aids". Curr Sports Med Rep 2 (4): 220–5. doi:10.1007/s11932-003-0009-2. PMID 12834578. 
16. ^ Calfee R, Fadale P (2006). "Popular ergogenic drugs and supplements in young athletes". Pediatrics 117 (3): e577–89. doi:10.1542/peds.2005-1429. PMID 16510635. 
17. ^ Barker W, Antia U (2007). "A study of the use of Ephedra in the manufacture of methamphetamine". Forensic Sci Int 166 (2–3): 102–9. doi:10.1016/j.forsciint.2006.04.005. PMID 16707238. 
18. ^ Boozer C, Daly P, Homel P, Solomon J, Blanchard D, Nasser J, Strauss R, Meredith T (2002). "Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial". Int J Obes Relat Metab Disord 26 (5): 593–604. doi:10.1038/sj.ijo.0802023. PMID 12032741. 
19. ^ Woolf A, Watson W, Smolinske S, Litovitz T (2005). "The severity of toxic reactions to ephedra: comparisons to other botanical products and national trends from 1993-2002". Clin Toxicol (Phila) 43 (5): 347–55. doi:10.1081/CLT-200066075. PMID 16235509. 
20. ^ Ephedra information from Memorial Sloan-Kettering Cancer Center. Accessed April 11, 2007.
21. ^ ^{a b} "Swallowing Ephedra", by Sharon Brownlee. Published online at Salon.com on June 7, 2000. Accessed 8 Feb 2007.
22. ^ Dietary Supplements: Background Information. From the Office of Dietary Supplements at the National Institutes of Health. Accessed 7 Feb 2007.
23. ^ Herbal Rx: the promise and pitfalls. Consumer Reports, 1999, pp 44–48.
24. ^ Haller C, Duan M, Benowitz N, Jacob P (2004). "Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements". J Anal Toxicol 28 (3): 145–51. PMID 15107143. 
25. ^ Gurley B, Gardner S, Hubbard M (2000). "Content versus label claims in ephedra-containing dietary supplements". Am J Health Syst Pharm 57 (10): 963–9. PMID 10832496. 
26. ^ "Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule", from the Federal Register, June 4 1997. Accessed 7 Feb 2007.
27. ^ ^{a b c d} "Dangerous supplements: Still at large", from Consumer Reports magazine. Published May 2004, accessed 7 Feb 2007.
28. ^ Criminal investigation sought for diet supplement seller, published in USA Today on August 15, 2002. Accessed April 10, 2007.
29. ^ Metabolife Founder Sentenced For Lying To FDA
30. ^ ^{a b} "Senator, His Son Get Boosts From Makers of Ephedra", published in the Los Angeles Times on March 5, 2003. Purchase required to view full text. Accessed 7 Feb 2007.
31. ^ Wolfe S (2003). "Medicine. Ephedra--scientific evidence versus money/politics". Science 300 (5618): 437. doi:10.1126/science.1081910. PMID 12702860. 
32. ^ ^{a b} "Diet Pills and Pols: A Dangerous Mix", by Arlene Weintraub and John Carey. Published in Business Week on September 2, 2002. Accessed March 31, 2007.
33. ^ "Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part", from the Federal Register, April 3, 2000. Accessed 7 Feb 2007.
34. ^ "The Secret of Ephedra's Questionable Success". A report on "All Things Considered", National Public Radio, November 22, 2002. Accessed 7 Feb 2007.
35. ^ ^{a b} Vikings: Stringer's use of ephedra contributed to death, published online by Sports Illustrated on February 25, 2003. Accessed March 15, 2007.
36. ^ "Medical examiner: Ephedra a factor in Bechler death", from USA Today, published March 13, 2003. Accessed 7 Feb 2007.
37. ^ "It's Time To Rethink Ephedra Regulation", by Leon Jaroff. Published in Time on March 5, 2003. Accessed March 31, 2007.
38. ^ Shekelle P, Hardy M, Morton S, Maglione M, Mojica W, Suttorp M, Rhodes S, Jungvig L, Gagné J (2003). "Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis". JAMA 289 (12): 1537–45. doi:10.1001/jama.289.12.1537. PMID 12672771. 
39. ^ "FDA Announces Plans to Prohibit Sales of Dietary Supplements Containing Ephedra": Press release from the FDA website, issued December 30, 2003, accessed 7 Feb 2007.
40. ^ ^{a b} "Judge's Decision Lifts Ban On Sale of Ephedra in Utah", from the New York Times, published April 15, 2005. Accessed 7 Feb 2007.
41. ^ World Anti-Doping Agency Prohibited List, 2006.PDF (1.50 MiB) Accessed March 15, 2007.
42. ^ ^{a b} Sauerbrun fails test: Broncos punter faces suspension for use of ephedra, by Bill Williamson. Published in the Denver Post on July 6, 2006. Accessed March 15, 2007.
43. ^ "Maradona's fall from grace", by John May. From the BBC, published April 19, 2004. Accessed March 15, 2007.
44. ^ "Haga Saga", by Dirck Edge. From motorcycledaily.com, May 24, 2000. Accessed March 15, 2007.

External links

• United States FDA links to actions
• FDA Rule
• United States NIH Factsheet regarding weight loss and athletic performance
• Dietary Supplements: Balancing Consumer Choice and Safety. A report of the New York State Task Force on Life & the Law.
• The history of Ephedra (ma-huang).