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**April 4, 2003**

**Documents Management Branch (HFA-305)**

**Food and Drug Administration**

**5630 Fishers Lane, Room 1061**

**Rockville, MD 20852**

**Re: Dietary Supplements Containing Ephedrine (Docket No. 95-N-0304)**

The Massachusetts Medical Society (MMS) welcomes the opportunity to
comment on the health risks associated with dietary supplements
containing ephedrine (ephedra) and commends the Commissioner of Food and
Drug Administration for reopening the comment period on this issue.
(Federal Register: 2003; 68(43): 10417-10420). Recent and compelling
evidence about the harms of this supplement warrant aggressive
regulation by the federal government including a total ban on ephedrine
use in dietary supplements.

The Massachusetts Medical Society, which represents over 18,000
physicians and students, is dedicated to educating and advocating for
the physicians and patients of Massachusetts. Founded in 1781, the MMS
is the oldest continuously operating medical society in the country. The
Society owns and publishes *The New England Journal of Medicine, Journal
Watch and AIDS Clinical Care* among other publications.

**Massachusetts Medical Society Efforts to Ban Ephedrine**

The MMS has been concerned about the harmful affects of ephedrine since
its introduction to the consumer market in dietary supplements. In 1998
the MMS passed a compelling policy statement calling upon the society to
take all appropriate action to limit the distribution of dietary
supplements. At that time we advocated for legislation at the state
level to allow the Department of Public Health to address the use of
dietary supplements in Massachusetts. In every session since 1998, we
have continued our efforts to focus attention on the risks of dietary
supplements. In 2002, we prevailed in our efforts to persuade Governor
Jane Swift to veto legislation mandating warning labels with high
suggested doses for ephedrine products. Following the veto, we worked
with the Department of Public Health to determine appropriate dosage
levels if any, for ephedrine products. Our testimony at that hearing was
that the appropriate level of ephedrine in a dietary supplement is zero.
As physicians we were and continue to be convinced that the minimal so
called benefits from ephedrine are far outweighed by the potentially
debilitating and life threatening risks of this dietary supplement.

During the 2002 legislative session, the MMS worked closely with the
Department of Public Health and Senator Richard Moore, Senate chair of
the MA Health Care Committee and a champion for health care issues, to
persuade then Governor Jane Swift to veto the labeling legislation
mentioned above. Our position was based on the belief that the proposed
legislation would have served more to protect manufacturers and to
advertise their products than to establish any meaningful public
protections. In March of this year, the MMS testified in support of new
legislation S 1961, filed by Senator Moore, that will ban the use of
ephedrine in dietary supplements.

In 1998 the MMS also passed a policy encouraging the American Medical
Association to seek federal standards for quality control of
manufacturing and accurate labeling of herbal remedies and dietary
supplements. In addition, the MMS called upon the AMA to seek federal
standards for documented evidence of the efficacy of herbal remedies and
dietary supplements prior to marketing. We continue to believe that
regulation of this and other potentially harmful supplements is the
responsibility of the FDA. Given our experience at the state level, we
believe it is unlikely that our concerns as physicians and the interest
of the public health will prevail uniformly over the powerful and
influential lobby of those producing these supplements.

**Scientific Evidence is Clear: Ephedrine Alkaloids present an
"unreasonable risk of illness or injury"**

The body of scientific evidence establishing the serious risks of
ephedrine is clear and growing.

The Center for Disease Control (CDC), in its Morbidity and Mortality
Weekly Report of August 16, 1996 published reports that the Texas
Department of Health received approximately 500 reports of adverse
events by persons who had consumed dietary supplements containing
ephedrine and associated alkaloids. These reports were generated from
December 1993 to September 1995. A case report in this article describes
the death from acute coronary artery thrombosis of a 44-year-old man
after three weeks use of a dietary supplement containing ephedrine.

The Federal Register of June 4, 1997 includes an extensive entry on
ephedrine which includes data on over 600 adverse event reports
associated with the use of dietary supplement products containing
ephedrine alkaloid. According to the FDA, approximately 15 % of the
reports described serious cardiovascular effects, including abnormal
heart rhythms, stroke, heart attack, and cardiomyopathy. 16% of the
reports mentioned serious nervous system effects. Liver damage, muscular
disease and other serious complications were also reported.

More recently the December 21, 2000 issue of the New England Journal of
Medicine, published by the MMS, contains an article entitled, *Adverse
Cardiovascular And Central Nervous System Events Associated With Dietary
Supplements Containing Ephedra Alkaloids.* Doctors Haller and Benowitz,
the authors of this study, reviewed 140 reports of adverse events
related to the use of dietary supplements containing ephedra alkaloids
that were submitted to the Food and Drug Administration (FDA) between
June 1997 and March 1999. The study found that 31% of the reported cases
were definitely or probably related to ephedra use, and a further 31%
were deemed to be possibly related. Among these cases, 47% involved
cardiovascular symptoms and 18% involved the central nervous system. Ten
events resulted in death and 13 events produced permanent disability,
representing 26 % of the definite, probable and possible cases.[^1]

It is also significant that the authors note that "Although the labels
on most such products state that they are not intended for use by
persons less than 18 years of age, adverse events were recorded in at
least 10 persons under this age."

Haller and Berkowitz also acknowledge the limitations of the study -
that is it is difficult to get an accurate calculation of the number of
people who actually have taken ephedrine vs. the number who experienced
problems, and the fact that adverse effects are significantly
underreported.

Nevertheless they conclude: "Because of the severity of the adverse
events that we reviewed and, in particular, the occurrence of events
that cause permanent disability and death, we conclude that dietary
supplements that contain ephedrine alkaloids pose a serious health risk
to some users"

We agree.

An editorial in the same issue of the New England Journal of Medicine,
commenting on the study above states:" The report by Haller and Benowitz
reminds us to behold the loophole that was created by Congress with the
passage of the Dietary Supplement and Education Act. This act allows
inadequately tested drugs to be marketed as "dietary supplements" \-\--
an innocuous and even holistic-sounding term. There are legitimate
dietary supplements, and they should be available to consumers without
restriction. A compound containing ephedra alkaloids should not be
called a dietary supplement; it is a drug. Abuse of this and other drugs
marketed as dietary supplements would be reduced if we simply stopped
calling them dietary supplements and instead regulated their use in the
same way as we do over-the-counter drugs and foods containing
drugs.....It is time for Congress to legislate a holistic approach to
drug regulation and to amend the Dietary Supplement and Education Act to
close the loophole."[^2]

In December 2002, the NEJM published a Sounding Board piece entitled,
*Botanical Medicine -- The Need for Regulation,* authored by Marcus and
Grollman,MD. The authors state " More than 1,200 serious reactions
related to ephedrine have been reported to the FDA, although the actual
number of events its is undoubtedly far greater. An estimated 12 million
people in the United States take Metabolife 356, a product containing
ephedrine, caffeine and several herbs. It was recently revealed that
13,000 complaints have been registered with the manufacturer. Included
were reports of several hundred people who required hospitalization, and
80 incidents of serious injury or death." The authors conclude " The
numerous reports of adverse effects and deaths associated with botanical
health products, the distribution and widespread sale of adulterated
products, and the marked increase in misleading promotional claims on
the Internet demand prompt action to protect the public health."

**FDA should aggressively regulate dietary supplements and ban dietary
supplements containing ephedra alkaloids**

From a medical and public health perspective, there is no question in
our minds that the risks posed by supplements containing ephedra are
real. This conclusion is unavoidable whether you employ the DSHEA
criteria of "unreasonable risk of illness or injury" or
"harm-outweighing risk"."

The MMS will continue to work with the AMA and other organizations to
advocate for Congressional reforms which will , more clearly empower the
FDA to establish federal standards for quality control of manufacturing
and accurate labeling of herbal remedies and dietary supplements; to
seek federal standards for documented evidence of the efficacy of herbal
remedies and dietary supplements prior to marketing and to implement and
enforce standards established by the United States Pharmacopoeia, among
other reforms.

Until Congress acts, the FDA must aggressively regulate dietary
supplements containing ephedrine to the fullest extent possible to
fulfill its obligation to protect the health of the American public.
Even at this juncture we as physicians find that there is sufficient and
compelling data to require the FDA to remove ephedrine from the US
market.

Sincerely,

![](media/image2.png){width="2.2041666666666666in"
height="0.41597222222222224in"}

Charles A. Welch, M.D.

President

[^1]: Haller CA, Benowitz NL, *Adverse Cardiovascular And Central
    Nervous System Events Associated With Dietary Supplements Containing
    Ephedra Alkaloids.* New England Journal of Medicine, 2000;
    343:1833-8. December 21, 2000.

[^2]: Fleming, GA, *Editorial, The FDA, Regulation, and the Risk of
    Stroke.* New England Journal of Medicine, 2000; 343:1886-7. December
    21, 2000.