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The Editor

Annals of Internal Medicine\
190 N. Independence Mall West\
Philadelphia, PA 19106-1572 June 27, 2002

April 7, 2003

**Comment to FDA regarding Docket: 95N-0304\
Dietary Supplements Containing Ephedrine Alkaloids**

To Whom It May Concern:

I am a neurologist and an epidemiologist at the University of
California, San Francisco, where I am director of the Stroke Service. I
do not believe that data are sufficient to justify prohibition of
distribution of ephedra alkaloids. This opinion is based on several
observations:

1.  Ephedra alkaloids are effective in supporting weight loss,
    particularly when combined with caffeine. A recent review of
    published randomized trials concluded that ephedra with caffeine
    results "...in weight loss that is approximately two pounds per
    month greater than that with placebo, for up to four to six
    months."^1^ A more recent trial not included in this review found
    that ephedra plus caffeine was effective at maintaining weight loss
    through 11 months of use.^2^ Although all randomized trials
    performed have weaknesses, the bulk of current studies suggest that
    ephedra/caffeine promotes weight loss.

2.  Use of ephedra/caffeine is associated with side effects but these
    are generally minor and self-limited, and do not appear to be
    associated with any unreasonable risk of harm. An independent study
    funded by the Agency for Healthcare Research and Quality (AHRQ),
    after reviewing over 20,000 reports of side effects, found only 33
    serious events (deaths, myocardial infarctions, strokes, seizures,
    and psychiatric cases) that could reasonably have been associated
    with ephedra or ephedrine.^1^ The study of Bent et al evaluated all
    adverse event reports, which would have included only a very small
    number with serious events and thus is not informative about
    important consequences of ephedra.^3^

3.  Trials have not demonstrated a unreasonable risk of serious adverse
    events, although the total number of patients in trials has been
    small. Furthermore, case reports have not provided convincing
    evidence of an association. The extensive review sponsored by AHRQ,
    which incorporated prior published series,^4,\ 5^ states, "For rare
    outcomes, we reviewed case reports, but a causal relationship
    between ephedra or ephedrine use and these events cannot be assumed
    or proven... The majority of case reports are insufficiently
    documented to make an informed judgment about a relationship between
    the use of ephedrine or ephedra-containing dietary supplements and
    the adverse event in question."^1^

4.  In terms of stroke risk, use of ephedra/caffeine is associated with
    an initial increase in blood pressure.^6^ Hypertension is a risk
    factor for ischemic and hemorrhagic stroke. However, the effect of
    ephedra/caffeine on blood pressure is modest and generally subsides
    over the first few days to weeks^7^, and is extremely unlikely to
    pose any reasonable risk of stroke in this period of time. In
    trials, blood pressure is often lower after the first month of
    use,^8^ probably because of weight loss. Thus, the long-term benefit
    of ephedra/caffeine in terms of weight loss may overwhelm any
    short-term risk associated with blood pressure elevation.

5.  Existing data are inadequate to implicate use of ephedra/caffeine as
    a cause of stroke, either ischemic or hemorrhagic. The proven effect
    on weight loss may be associated with a decreased risk of stroke.
    Results from a large-scale randomized trial are required before one
    of the few effective weight-loss agents is discarded.

The scientific opinions expressed above are my own, based on my review
of the literature and on my training as a neurologist and an
epidemiologist. However, I have been asked by the lawyers of Metabolife
to share these opinions, and I was paid to compose this letter. I am
happy to provide additional information.

Sincerely,

S. Claiborne Johnston, MD, PhD

[References]{.underline}

1\. Shekelle PG, Morton S, Maglione M, al. e. Ephedra and Ephedrine for
Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and
Side Effects. Evidence Report/Technology Assessment No. 76 (Prepared by
Southern California Evidence-based Practice Center, RAND, under Contract
No 290-97-0001, Task Order No. 9). AHRQ Publication No. 03-E022. Agence
for Healthcare Research and Quality. 2003

2\. Filozof C, Gonzalez C, Hofman E. The effect of ephedrine plus
caffeine after a 4-week portion controlled diet. International
Conference on Obesity. Sao Paulo, Brazil, 2002

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

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

5\. 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.

6\. Haller CA, Jacob P, 3rd, Benowitz NL. Pharmacology of ephedra
alkaloids and caffeine after single-dose dietary supplement use. Clin
Pharmacol Ther. 2002;71:421-432

7\. Boozer CN, Daly PA, Homel P et al. Herbal ephedra/caffeine for
weight loss: a 6-month randomized safety and efficacy trial. Int J Obes
Relat Metab Disord. 2002;26:593-604.

8\. 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. A double blind trial.
Int J Obes Relat Metab Disord. 1992;16:269-277