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CDC Morbidity and Mortality Weekly Report
August 16, 1996 / Vol. 45 / No. 32


Adverse Events Associated with Ephedrine-Containing Products --
Texas, December 1993-September 1995

During December 1993-September 1995, the Bureau of Food and Drug Safety,
Texas Department of Health (TDH), received approximately 500 reports of
adverse events in persons who consumed dietary supplement products
containing ephedrine and associated alkaloids (pseudoephedrine,
norephedrine, and N-methyl ephedrine). This total included reports by
individuals and reports identified by the Bureau of Epidemiology, TDH, in
a review of records from the six centers of the Texas Poison Center
Network. Reported adverse events ranged in severity from tremor and
headache to death in eight ephedrine users and included reports of stroke,
myocardial infarction, chest pain, seizures, insomnia, nausea and
vomiting, fatigue, and dizziness. Seven of the eight reported fatalities
were attributed to myocardial infarction or cerebrovascular accident. This
report describes three patients in which the recommended dosage for the
dietary supplements reportedly was not exceeded, summarizes results from
ongoing investigations, and underscores the potential health risks
associated with the use of products containing ephedrine. 

Case Reports

Patient 1. In December 1993, a 44-year-old man died from acute coronary
artery thrombosis approximately 3 weeks after beginning daily use of a
dietary supplement containing ephedrine. He was an active swimmer and
tennis player with no k nown cardiovascular risk factors. He received the
dietary supplement from his family physician during a routine physical
examination when he requested a substitute for his daily coffee and cocoa.
He used the product as directed and eliminated his coffee and cocoa use.
On December 18, 1993, after playing tennis and returning home, he
sustained a cardiorespiratory arrest. An a utopsy revealed an acute
thrombus in the left anterior descending coronary artery. All other
coronary lumina were patent, although calcified with focal narrowing to
approximately 50%. 

Patient 2. In May 1995, a 35-year-old woman who was taking no other
prescription or over-the-counter (OTC) medications began use of a dietary
supplement containing ephedrine for weight loss. She used the supplement
within the dosage recommended on the label for approximately 30 days,
discontinued use of the supplement while on a 1-week vacation, then
resumed the usual dosage when she returned on June 24, 1995. On June 25,
while sleeping, she had acute onset of symptoms including anterior chest
pain that radiated to her left shoulder and arm, numbness of the left arm
and hand, diaphoresis, and shortness of breath. She was taken to the
hospital and her pain remitted after she was treated with nitroglycerin
and morphine. Although an electro cardiogram and car diac enzymes
indicated an acute myocardial infarct, cardiac catheterization indicated
normal cardiac function and normal coronary arteries. She had no history
of cardiovascular risk factors. She was discharged with a di agnosis of
acute myocardial infarction secondary to cardiac spasm and was advised to
discontinue use of the dietary supplement that contained ephedrine. Since
discontinuing use of the product, she has had no additional
cardiac-related symptoms. 

Patient 3.  On August 17, 1995, a 38-year-old woman with no history of
seizures experienced two petit mal seizures beginning at 11 p.m. She
experienced two additional petit mal seizures the following morning, and
that after noon had onset of a generalized tonic-clonic seizure lasting
approximately 2 minutes, during which she required respiratory assistance. 
On August 17, she had t aken two tablets of an ephedrine-containing
dietary supplement at 10 a.m. and two more 5 hours later as directed on
the product label. She denied use of other drugs except oral
contraceptives. During August 19-22, she experienced five additional
episodes of unresponsiveness while sit ting or standing; while waiting in
the office of a neurologi st, she sustained an additional generalized
seizure witnessed by the neurologist and staff. She was hospitalized for
monitoring, treated with antiseizure medication, and diagnosed with new
onset of tonic-clonic seizures with complex partial seizures. Other
possible causes of seizures were excluded. She was discharged and was
advised to avoid any medications or products that contained ephedrine,
pseudoephedrine, or related drugs. Since discontinuing use of the product,
she has had no additional seizures. 

Ongoing Investigations

TDH also has received reports of persons who had acute onset of
palpitations and fainting after using ephedrine-containing products
marketed as "beyond smart drugs"  for "euphoric stimulation, highly
increased energy levels, tingly skin sensations, enhanced sensory
processing, increased sexual sensations, and mood elevations." Although
these sub stances have been sold without warnings or contraindications on
the information labels, one label indicated that the product "acts on the
same basis as MDMA (3,4-methylenedioxy-methamphetamine, "ecstasy" )
triggering similar but not identical physical reactions in the body."  TDH
investigators purchased a product labeled "no side effects"  that also
listed wild Chinese ginseng as the only ingredient. Laboratory analysis
indicated that a single tablet contained 45 mg ephedrine and 20 mg
caffeine; the label on this product instructed users to take five tablets,
representing a total ephedrine dosage of approximately 11 times the usual
recommended OTC dosage of bronchodilator products, which contain 12.5
mg-25.0 mg of ephedrine per dose. 

Ephedrine-containing products usually are marketed and labeled for weight
loss, energy, "pep,"  performance enhancement, or body building or as a
substitute for illicit drugs such as MDMA. They are commonly labeled as
"natural"  or "herbal"  and use common names for herbs as the source of
active ingredients (ma huang, Chinese ephedra, and Sida
cordifolia--another plant source with small amounts of ephedrine
alkaloids). An additional 400 reports of adverse events involved OTC drug
products containing ephedrine that were labeled as required for use as
bronchodilators but marketed in a manner to imply their effectiveness for
weight loss and as stimulants. 

Since September 1995, the Texas Poison Control Network has received
approximately 300 additional reports of adverse events in persons
consuming products containing ephedrine. These reports are being
investigated by TDH. 

Reported by: DM Perrotta, PhD, Bur of Epidemiology; G C oody, C Culmo, Bur
of Food and DrugSafety; Texas Poison Center Network, Texas Dept of Health.
Clinical Research and Review Staff, Center for Food Safety and Applied
Nutrition, Food and Drug Administration. Environmental Hazards Epidemiology
Section, Health Studies Br, Div of Environmental Hazards  and Health Effects,
National Center for Environmental Health, CDC.


Editorial Note: The three reports presented here and the approximately 500
reports of adverse events received by TDH underscore that use of dietary
supplements containing ephedrine and related alkaloids can be associated
with a spectrum of adverse health events. Although a cause-and-effect
relation cannot be established for the three patients presented here, no
other cause was found to explain their medical conditions, all of which
are compati ble with d ocumented effects of ephedrine con sumption.
Ephedrine and associated alkaloids are structurally similar to the
amphetamines ( 1 ) and, by stimulating adrenergic receptors, can increase
arterial blood pressure through both peripheral vasoconstriction and
cardiac stimulation. Adverse effects from ephedrine can be variable, and
do not always depend on the dose consumed. Serious adverse effects of
ephedrine and related alkaloids, such as acute cardiovascular and central
nervous system stimulant effects, can occur in susceptible persons with
use of low dosages. Other adverse effects associated with the use of
ephedrine include palpitations, tachycardia, hypertension, coronary spasm,
paranoid psychoses, convulsions, respiratory depression, coma, and d eath
( 2 ).  Particularly when used in combinations with phenylpropanolamine
(PPA) and caffeine, ephedrine has been associated with stroke secondary to
intracranial hemorrhage, seizures, mania, and psychosis (3,4 ).
Combinations of ephedrine and caffeine have been documented to have side
effects substantially greater than those from the consumption of either
compound alone or of a placebo (5-8 ). 

In the United States, ephedrine, pseudoephedrine, and PPA have been
marketed extensively for some OTC uses. For example, preparations
containing ephedrine are marketed for oral use as a short-term, OTC
bronchodilator for persons with mild asthma. The Food and Drug
Administration (FDA)  has proposed to remove oral ephedrine drug products
from the OTC market based on their use in the production of illicit drugs
and on their misuse and abuse as stim ulants and for weight loss.*
Pseudoephedrine, an ephedrine alkaloid contained in many OTC decongestant,
cold, and allergy products, is associated with fewer cardiovascular and
central nervous system stimulant effects than ephedrine. PPA, another
ephedrine alkaloid, also is contained in OTC decongestant, cold, and
allergy preparations and is marketed for use in the United States as a
weight-control agent. 

Dietary supplements can be marketed with no premarket safety evaluation by
FDA. For dietary supplements that include an ingredient marketed in the
United States before October 15, 1994--such as products containing sources
of ephedrine alkaloids-- no FDA review is required. For dietary
supplements that include an ingredient that was not marketed before
October 15, 1994, manufacturers or distributors must submit a notice to
FDA 75 days before marketing; however, the notice is not required to
include objective evidence of safety, only an explanation of why there is
a reasonable expectation that use of the supplement will be safe. 

* 60 FR 38,643.

Because many of these products are marketed as " natural"  or promoted as
foods, consumers may assume incorrectly that the products are safe and
without side effects. For example, the TDH investig ation determined that,
during medical evaluations, some patients did not report taking
ephedrine-containing dietary supplements because they did not initially
believe that a " natural"  or "herbal"  food supplement could be related
to their illness. In addition, health-care providers or consumers may not
have realized that ephedrine alkaloids and other stimulants were in the
product because they were not included in the ingredient listing or
because an unfamiliar name for the compound was used. 

Because of misuse of and adverse reactions to products containing
ephedrine, approximately 21 sta tes have passed r egulations stricter than
federal regulations, including requiring that ephedrine drug and food
products be made available by prescription only; moving ephedrine p
roducts to the schedules of controlled substances; and prohibiting weight
loss, appetite control, or stimulant claims on the labels. B ecause of
concerns ab out the safety of dietary supplements that contain sources of
ephedrine alkaloids, a working group convened by FDA in October 1995 made
several recommendations about potency limits and label warnings to promote
safer use of these products. FDA has been evaluating these recommendations
and, because of continuing concerns about the safety of these products, is
co nvening a meeting of the Food Advisory Committee and the s pecial
working group on August 27-28, 1996, in Washington, D.C. 

The findings in this report underscore the need for the general public and
for health-care providers to be aware of potential health hazards
associated with use of dietary supplements containing ephedrine and
associated alkaloids. Health-care providers should question patients about
their use of dietary supplements and herbal medications and report any
adverse effects to dietary supplements, including those containing
ephedrine and associated alkaloids, to FDA's MedWatch Program, telephone
(800) 322-1088 ([800] FDA-1088). Consumers can report adverse events to
the FDA Consumer Hotline, (800) 322-4010 ([800] FDA-4010). 

References

1. Dollery C, ed. Ephedrine (hydrochloride). In: Therapeutic drugs. Vol 1. 
New York: Churchill Livingstone, 1991:E26-E29. 

2. Pentel P. Toxicity of over-the-counter stimulants. JAMA
1984;252:1898-903. 

3. Loizou LA, Hamilton JG, Tsementzis SA. Intracranial haemor rhage in
association with pseudoephedrine overdose. J Neurol Neurosurg Psychiatry
1982;45:471-2. 

4.  Lake CR, Gallant S, Masson E, Miller P. Adverse drug effects
attributed to phenylpropanolamine:  a review of 142 case reports.  Am J
Med 1990;89:195-208. 

5. Breum L, Pedersen JK, Ahlstrom F, Frimodt-Mo ller J.  Comparison of an
ephedrine/caffeine combination and dexfenfluramine in the treatment of
obesity: a double-blind, multi-centre trial in general practice. 
International Journal of Obesity and Related Metabolic Disorders
1994;18:99-103. 

6. Astrup A, Lundsgaard C, Madsen J, Christensen NJ.  Enhanced thermogenic
responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr
1985;42:83-94. 

7. Astrup A, Toubro S. Thermogenic, metabolic, and cardiovas cular
responses to ephedrine and caffeine in man. International Journal of
Obesity and Related Metabolic Disorders 1993;17 (suppl):S41-S43.  Astrup
A, Toubro S, Cannon S, Hein P, Breum L, Madsen J. Caffeine: a
double-blind, placebo-controlled study of its thermogenic, metabolic, and
cardiovascular effects in healthy volunteers. Am J Clin Nutr
1990;51:759-67.