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Article by Sidney Wolfe in Science magazine:

Ephedra Scientific Evidence Versus Money/Politics (HRG Publication
#1664)


Twenty-Year Chronology of of Events Concerning Ephedrine Alkaloids
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This article by Sidney Wolfe, M.D. appeared in the April 18, 2003
issue of Science magazine.

Does it make a difference, in terms of FDA regulation, that a drug is
natural, has been around for thousands of years and is dispensed as
"servings" rather than doses, if the drug has been known for decades
to cause increased blood pressure, increased pulse rate, and an
increased risk of cardiac arrhythmias? For dietary supplements
containing ephedra alkaloids[1], the answer is yes, it has made a
difference.

Because of dangers and abuse potential, in 1983 the FDA (Food and Drug
Administration) banned all over-the-counter (OTC) drugs that included
both synthetic ephedrine and caffeine, the combination used most in
dietary supplements containing ephedra alkaloids, and the agency is
now finalizing the ban on OTC drugs that contain ephedrine alone. At a
recent U.S. Senate Hearing on ephedra alkaloids, acting FDA
Commissioner Lester Crawford conceded that if these products were
drugs, not dietary supplements, they would be off the market. But he
also stated that unreasonable risk of harm at the recommended doses,
is sufficient for withdrawal under the 1994 Dietary Supplements Health
and Education Act (DSHEA), which allows marketing of naturally
occurring products without requirements for safety or efficacy studies
and is the legal standard for FDA withdrawal[2].

In a review of 140 cases of adverse reactions to ephedra reported to
the FDA by early 1999, hypertension was the most frequently named,
followed by palpitations, tachycardia (rapid heart rate), stroke, and
seizures. The adverse effects included 10 deaths, and 13 instances of
permanent disability[3]. Even one standard "serving" of a typical
ephedra alkaloid-containing dietary supplement can be dangerous: The
average increase in systolic blood pressure was 14 mmHg, 90 minutes
after subjects took two capsules with a total of 20 mg of ephedra and
200 mg of caffeine. Three of the eight people studied had evidence of
"mild clinical hypertension"[4].

Despite convincing evidence of heart attacks, arrhythmias, strokes,
and more than 100 reports to the FDA of death[5], these products are
still marketed in the United States. Notwithstanding FDA's reluctance
to take action, Army and Air Force commissaries and post exchanges
recently voluntarily removed all ephedra-containing dietary
supplements from their shelves[6]. The FDA has received do***entation
of about 30 deaths in active duty personnel who were using these
supplements, although no direct cause-and-effect relation has been
established[7]. The National Football League and the National
Collegiate Athletic Association had previously banned ephedra[8]. In
June 2001, the Canadian government warned Canadians not to use these
products, and in January 2002, it announced a recall of
"ephedra/ephedrine products with labelled or implied claims for
appetite suppression, weight loss promotion, metabolic enhancement,
increased exercise tolerance, body-building effects, euphoria,
increased energy or wakefulness, or other stimulant effects"[9].

Political Influence

According to the Washington Post, Metabolife, the nation's leading
seller of ephedra products, spent more than $4 million between 1998
and 2000 in Texas to lobby against state regulations. There have also
been accusations that Metabolife has attempted to exert influence in
Texas through political connections to members of the Bush
administration[10],[11]. According to Business Week, federal efforts
to remove ephedra have been hampered "by deep-pocketed industry
lobbying. Metabolife, has contributed . . . to national politicians
since 1999 . . . according to the Center for Responsive Politics"[12].
In California, Metabolife ranked fourth in the state for "soft money"
contributions, with $493,000 in 2000. Additional federal and state
influence-peddling has taken the form of soft money contributions to
political parties, whereby Metabolife gave $1,718,000 during the
1999-2000 and 2001-2002 election cycles[13].

Act Now

The recent Rand report reviewing published literature on ephedra and
adverse reaction reports[14] takes away the last excuse given by the
government for not yet acting on our 5 September 2001 petition to ban
all dietary supplements containing ephedra alkaloids[15]. However, the
government is still equivocating and has announced, in a 7 March 2003
Federal Register Notice, that they want comments on any new
information on ephedra risks, public opinion as to whether the legal
standard for a ban can be met, and whether a proposed warning label
makes sense[16]. Much of this flurry of "activity" is in the wake of
the death of Baltimore Oriole pitcher, Steve Bechler, whose death has
been partially attributed to the use of ephedra dietary supplements.

"Regulation" is now coming from the marketplace, operating in the
vacuum created by FDA inaction. Several companies have announced that
they will stop selling ephedra-containing diet supplements[17],[18].
Even Metabolife has announced that the company launched an
ephedra-free "alternative"[19].

However, this alone is not an acceptable way to safeguard public
health, and product labeling is not enough. We call on the FDA as an
agency of the Public Health Service to fulfill their legal
responsibility and to stop the occurrence of further preventable
deaths and injuries by banning ephedra products.

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[1] Ephedrine, amphetamine, and the recently banned
phenylpropanolamine (PPA) are structurally similar. Because all of
these drugs are sympathomimetic, all can cause increased blood
pressure; amphetamine and ephedra can also cause increased pulse rate.

[2] Testimony by L. Crawford, D.V.M., Ph.D., Acting Commissioner, FDA;
8 October 2002; before Senate Governmental Affairs Committee,
Subcommittee on Oversight of Government Management.

[3] C.A. Haller, N.L. Benowitz, N. Engl. J. Med. 343, 1833 (2000).

[4] C.A. Haller, P. Jacob, N.L. Benowitz, Clin. Pharm. Ther. 71, 421
(2002).

[5] Associated Press. 15 August 2002.

[6] Announcement of recent Army/Air Force worldwide ban of sale of
ephedra-containing products in military exchanges. A similar memo was
sent concerning the ban of sales in commissaries. See
http://www.army.mil/usar/news/2002/08august/ephedra.html (accessed 7 October
2002).

[7] M. Heath, Senior Pharmacist, U.S. Army, Consultant for the U.S.
Army Surgeon General, Washington, DC, personal communication.

[8] See http://www.ncaa.org/news/2002/20020610/editorial/3912n46.html
(accessed 11/1/02).

[9] See http://www.hc-sc.gc.ca/english/protection/warnings/2002/2002_01e.htm

[10] D. Willman, Los Angeles Times, 6 September 2001, p. A1.

[11] M. Weisskopf, Time, 22 May 2000, p. XX.

[12] A. Weintraub, J. Carey, Business Week, 2 September, 2002, p. 40.

[13] See http://www.opensecrets.org/softmoney/softcomp1.asp?txtName=Metabolife

[14] See http://www.fda.gov/OHRMS/DOCKETS/98fr/95n-0304-bkg0003-ref-07-01-index.htm

[15] Petition to DHHS Secretary T. Thompson, available at
http://www.citizen.org/publications/release.cfm?ID=7053

[16] See http://www.fda.gov/OHRMS/DOCKETS/98fr/95n-0304-npr0003.pdf

[17] D. Evans, Bloomberg News, 11 April 2002.

[18] S. Roan, Los Angeles Times, 9 December 2002, p. F1.

[19] P. Crabtree, San Diego Union-Tribune, 23 January 2003, p. C1.


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Twenty-Year Chronology of of Events Concerning Ephedrine Alkaloids

1983: Because of dangers and abuse potential, the FDA bans all
over-the-counter (OTC) drugs that include both synthetic ephedrine and
caffeine, the combination found in most of the dietary supplements
containing ephedrine alkaloids (EADS).

July 1993: FDA issues its first public warning about possible safety
problems of dietary supplements containing ephedrine alkaloids.
Reports received by the FDA include hypertension, palpitation,
neuropathy (nerve damage), myopathy (muscle damage), psychosis, stroke
and memory loss.

February 1995: FDA warns consumers against a dietary supplement,
"Formula One," containing ephedra and caffeine.

February 1995: FDA working sub-group of Food Advisory Committee
composed of outside experts agrees that ephedrine alkaloids can cause
serious adverse events but cannot agree on specific dosage or warning
statement.

April 1996: FDA warns consumers not to buy or use ephedrine dietary
supplements with labels portraying products as alternatives to illegal
street drugs, since they pose significant health risks.

August 1996: Half of FDA Food Advisory Committee states that no safe
levels of ephedrine alkaloids in dietary supplements exist.

June 1997: FDA proposes to ban ephedrine dietary supplements with more
than 8 mg of ephedra per "serving" and to include warning labels.

July 1999: General Accounting Office (GAO) report finds that FDA did
not have an adequate basis for concluding that doses of more than 8 mg
are dangerous and 8 mg or less are safe.

April 2000: FDA withdraws June 1997 proposed regulation pending
further data collection and ****ysis.

August 2000: Office of Women's Health, HHS, convenes meeting on safety
of dietary supplements containing ephedrine alkaloids.

The conclusion is: "Despite the established limitations of AERs
(adverse event reports), many of the adverse effects are biologically
plausible based on the known pharmacologic effects of ephedrine
alkaloids. The pharmacology of ephedrine is supported by a rich
database, in contrast to the paucity of evidence on the benefits or
risks of EADS in humans. The level of concern for continued use of
EADS must be based on the totality of information available on ephedra
and ephedrine alkaloids, including the AERs, results of human and
animal studies, as well as what is known about the pharmacology and
chemistry of these compounds."

March 2000: FDA announces ****ysis of 140 adverse reaction reports
concerning ephedrine alkaloids: In 22 cases, the adverse reaction is
attributable to ephedrine alkaloids; in another 38 cases, the evidence
is supportive of being drug-induced; and in another 72 cases, there
are insufficent data for an evaluation to be made.

December 2000: Haller and Benowitz publish New England Journal of
Medicine article finding that among the adverse events reported to the
FDA deemed definitely, probably or possibly related to the use of
supplements containing ephedrine alkaloids, 47 percent involve the
cardiovascular system and 18 percent involve the central nervous
system. Hypertension is the single most frequent adverse effect (17
reports), followed by palpitations, tachycardia (rapid heart rate) or
both (13); stroke (10); and seizures (7). Ten events resulted in
death, and 13 events produced permanent disability, representing 26
percent of the definite, probable and possible cases.

June 2001: The Canadian government warns Canadians not to use these
products.

September 2001: Public Citizen's Health Research Group (PCHRG) and Dr.
Ray Woosley petition the FDA to ban all dietary supplements containing
ephedrine alkaloids. The petition includes results of an FDA memo
finding that there are more reports of deaths, heart arrhythmias,
strokes, heart attacks, hypertension and seizures for ephedrine
alkaloids than for all other dietary supplements combined.

January 2002: The Canadian government asks all manufacturers to recall
these products if they are being sold for weight reduction,
performance enhancement or body-building, the main uses for which they
are promoted.

June 2002: FDA announces plan to study ephedrine alkaloids (Rand
Corporation review) but defers decision on Public Citizen's petition
to ban.

August 2002: Army and Air Force commissaries and PXs ban the sale of
ephedrine alkaloid dietary supplements following reports of more than
30 deaths in active duty military personnel (previous bans had
occurred on Navy and Marine bases). The FDA has reports of more than
100 deaths in people using ephedrine dietary supplements.

October 2002: During a Senate Hearing chaired by U.S. Sen. Richard
Durbin (D-Ill.), acting FDA commissioner Dr. Lester Crawford admits
that even under the provisions of the Dietary Supplement Health and
Education Act (DSHEA), the FDA has the authority to ban ephedrine
alkaloids, implying that the legal standard for FDA withdrawal –
unreasonable risk of harm at the recommended doses – could be met. HHS
Secretary Thompson urges strong warning labels.

December 2002: Nationwide Harris Poll of adults finds that most people
are misinformed about the extent of government regulation of vitamins,
minerals and food supplements. They incorrectly believe that
supplements must be approved by a government agency such as the FDA
and that the manufacturers are not allowed to make claims for their
safety and effectiveness unless there is solid scientific evidence to
support them.

February 2003: Steve Bechler, Baltimore Orioles pitcher, dies. His
death is partially attributed to the use of ephedrine alkaloid dietary
supplements.

February 2003: HHS summarizes the results of the Rand Corporation
review, stating that "dietary supplements containing ephedra may
present significant or unreasonable risks as currently marketed…." A
Federal Register notice seeks comments on whether there is new
information about the risks of these products, whether the public
thinks that the legal standard for a ban – unreasonable risk of harm
at the recommended doses – can be met and whether the public agrees
with proposed warnings such as not to use more than the recommended
dosage and not to engage in "strenuous" exercise while using these
products.

April 2003: Ad on Web site of a large Internet seller of dietary
supplements (http://www.milehighmuscle.com—accessed 4/16/03) in section on
ephedra dietary supplements:

"HURRY, before they're gone! Manufacturers are discontinuing Ephedra
products faster than you realize. As of 03/17/03, we had to pull a
large list of products containing ephedra from our shelves because the
manufacturers do not have the liability insurance for these products."

On part of the site directed at active duty military personnel, now
unable to purchase ephedra products in commissaries or PXs because of
the military's ban, ephedrine alkaloids and other dietary supplements
are shamelessly promoted with a discount for active duty military
personnel:

You serve and protect the United States, you're stateside or overseas.
We, at Mile High Muscle appreciate your efforts and to thank you, we
have created a section just for you!

Exclusive Military Offers!

As a military customer, you will be able to receive exclusive offers.
You automatically get $5 off every order. Please use coupon code:
military5 on our checkout page in the coupon code field.

The site does include the following disclaimer:

"Ephedra Products Disclaimer: Please use extra consideration when
making the choice to use these products. Those of you in the Middle
East and similar warm climates, please be advised that your heavy
equipment and uniforms compounded with the heat and potential exposure
to chemical agents, may be at risk for elevated blood pressure, heart
rate, etc. and could experience effects beyond normal use."

Go To: Articles Press Releases Publications


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Related Topics Articles: (7/2/02) supplements index

Press Releases: (4/17/03) Public Citizen Cites Military Study of
Heat-Related Injuries at California Military Base to Underscore
Dangers of Ephedra
(2/28/03) Statement by Sidney M. Wolfe, M.D., Director, Public
Citizen's Health Research Group, Concerning FDA's Failure to Ban
Ephedra
(10/8/02) 33 Deaths Among Military Prompted Ephedra Ban; FDA Should
Follow Suit

Publications: (10/8/02) Testimony Before Senate Governmental Affairs
Committee Hearing on Dangers of Ephedra (HRG Publication #1642)
(6/17/02) Statement on HHS Failure to Ban Ephedra or Issue Adequate
Warnings (HRG Publication #1624)
(1/17/02) Letter to American Medical Association urging their support
of HRG petition to the FDA to ban dietary supplements containing
ephedrine alkaloids (HRG Publication #1604)
(10/11/01) Statement before the National Academy of Sciences on the
Framework for Evaluating the Safety of Dietary Supplements (HRG
Publication #1594)
(3/20/01) Testimony before the House of Representatives Committee on
Government Reform Hearing on Dietary Supplements. (HRG Publication
#1560)
(4/24/00) Comments on the Department of Health and Human Services'
Inspector General's Study of Adverse Event Reporting for Dietary
Supplements. (HRG Publication #1568)
(3/30/00) Testimony regarding the FDA's categorization of "morning
sickness" and "leg edema" during pregnancy as conditions not diseases
which allows dietary supplement manufacturers to promote for these
symptoms (HRG Publication #1517)
(3/2/00) Letter to the FDA concerning the United Kingdom's Committee
on Safety of Medicine's recent warning about potentially serious drug
interactions between St. John's Wort and a large number of other
drugs. (HRG Publication #1513)
(2/3/00) Letter to the Food and Drug Administration regarding their
final regulations on dietary supplements and their definition of
adverse effects of pregnancy. (HRG Publication #1507)


http://www.citizen.org/publications/release.cfm?ID=7241