- Mayo Clinic Proceedings

Cardiovascular Toxic Effects of Ma Huang
12
Mayo Clin Proc, January 2002, Vol 77
Original Article
Adverse Cardiovascular Events Temporally Associated With
Ma Huang, an Herbal Source of Ephedrine
DAVID SAMENUK, MD; MARK S. LINK, MD; MUNTHER K. HOMOUD, MD; ROBERT CONTRERAS, BS;
THEOHARIS C. THEOHARDES, MD; PAUL J. WANG, MD; AND N. A. MARK ESTES III, MD
• Objective: To evaluate possible cardiovascular toxic
effects associated with use of dietary supplements containing ma huang, an herbal source of ephedrine.
• Methods: We reviewed the comprehensive database
Adverse Reaction Monitoring System of the Food and
Drug Administration, which included clinical records, investigative reports, and autopsy reports related to ma
huang use. The main outcome measurements were stroke,
myocardial infarction, and sudden death.
• Results: From 1995 to 1997, 926 cases of possible ma
huang toxicity were reported to the Food and Drug Administration. In 37 patients (23 women and 14 men with a
mean ± SD age of 43±13 years), use of ma huang was
temporally related to stroke (in 16), myocardial infarction
(in 10), or sudden death (in 11). Autopsies performed in 7
of the 11 patients who experienced sudden death showed
a normal heart in 1, coronary atherosclerosis in 3, and cardiomyopathies in 3. In 36 of the 37 patients, use of ma
huang was reported to be within the manufacturers’ dosing guidelines.
• Conclusions: Analysis of the 37 patients indicates the
following findings: (1) ma huang use is temporally related
to stroke, myocardial infarction, and sudden death; (2)
underlying heart or vascular disease is not a prerequisite
for ma huang–related adverse events; and (3) the cardiovascular toxic effects associated with ma huang were not
limited to massive doses. Although the pathogenesis of the
cardiac toxic effects of ma huang remains incompletely
defined, available observational and circumstantial evidence indicates that use of the substance may be associated
with serious medical complications.
Mayo Clin Proc. 2002;77:12-16
ARMS = Adverse Reaction Monitoring System; FDA = Food
and Drug Administration
A
t present, herbal medicines are the most common
form of alternative therapy in health care.1 Retail sales
of dietary supplements, including herbal products, were
estimated at $3.6 billion in 1997.2 Ma huang, a popular
herb derived from the genus Ephedra, is used in many of
these nontraditional remedies. As a natural source of ephedrine, ma huang is taken most commonly for weight loss and
energy enhancement. The increasingly widespread use of
ma huang has been accompanied by the misconception that
this substance has no associated serious medical consequences. However, the potential cardiovascular toxic effects of ma huang have not been evaluated systematically.
According to the Dietary Supplement Health and Education Act of 1994, herbal remedies, including ma huang,
must be proved “unsafe” before they can be withdrawn
from the market. This law required that “the Food and Drug
Administration (FDA) bear the burden of proof that a mar-
keted dietary supplement presents a serious or unreasonable risk under the conditions of use on the label or as
commonly consumed.”3 This approach contrasts with that
for drugs in which rigorous standards of safety and efficacy
must be met through appropriately designed clinical trials
before the drug is available to the public. To monitor for
potential toxic effects of dietary supplements, the FDA
established an Adverse Reaction Monitoring System
(ARMS), which collects and systematically investigates
adverse and toxic effects reported with use of herbal medicines and dietary supplements. Because of the concerns
regarding the safety of ma huang, we systematically examined this database to evaluate possible adverse cardiovascular effects of this substance.
For editorial comment, see page 7.
METHODS
Via a Freedom of Information Act request, a copy of
Docket No. 95N-0304 was obtained from the Dockets
Management Branch of the FDA, US Department of
Health and Human Services. This docket includes Adverse
Event Reports associated with dietary supplements containing the ephedrine alkaloid ma huang. Adverse Event
Reports enter the FDA’s passive surveillance ARMS
through several means, including Drug Quality Reporting
From the Cardiac Arrhythmia Service, Division of Cardiology (D.S.,
M.S.L., M.K.H., R.C., P.J.W., N.A.M.E.), and Department of Pharmacology and Experimental Therapeutics (T.C.T.), New England Medical Center, Boston, Mass.
Address reprint requests and correspondence to N. A. Mark Estes
III, MD, Cardiac Arrhythmia Service, New England Medical Center,
750 Washington St, NEMCH Box 197, Boston, MA 02111 (e-mail:
[email protected]).
Mayo Clin Proc. 2002;77:12-16
12
© 2002 Mayo Foundation for Medical Education and Research
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Mayo Clin Proc, January 2002, Vol 77
System, MedWatch program, US Pharmacopeia, FDA’s
field offices through the Office of Regulatory Affairs, Consumer Complaint System (FDA Form 2516), written and
electronic correspondence, and written documentation of
telephone conversations. Data were collected from January
1995 to January 1997. The clinical research and review
staff in the Office of Special Nutritionals is responsible
for the tracking and reviewing of Adverse Event Reports. Only Adverse Event Reports associated with an
illness or injury are included. Reports of product quality
or consumer dissatisfaction are not included. For the
current study, detailed information relevant to each Adverse Event Report file was reviewed, including medical
records, autopsy reports, affidavits from the Consumer/
Health Professional, Consumer Complaint Illness/Injury
Report (FDA Form 2516), Complaint/Injury Follow-up
(FDA Form 2516a), MedWatch report (FDA Form 3500),
Investigative Memoranda, Collection Report (FDA Form
464), Adverse Reaction Information Form A or Adverse
Reaction Questionnaire (Form A), Ephedrine Consumer
Hotline Questionnaire, correspondence related to the Adverse Event Report, Sample Summary (FDA Form 465),
and product labeling.4
Inclusion criteria for this study were adverse cardiovascular events defined as sudden death, myocardial infarction, or stroke in association with ma huang use reported to
the FDA through ARMS. Sudden death was defined as
death occurring within 1 hour of symptoms and/or
unwitnessed death.5 The diagnosis of myocardial infarction
was based on the World Health Organization definition and
included the presence of at least 2 of the following 3
criteria: (1) a clinical history of ischemic-type chest discomfort, (2) changes on serially obtained electrocardiographic tracings, and (3) abnormal serum cardiac enzymes.6 Stroke was characterized by a history of rapid
onset of localizing neurologic deficit and/or change in state
of consciousness with documentation by computed tomography that showed no definite signs of any disease process
or event causing focal brain deficit or coma other than
cerebral infarction or hemorrhage.6 Suspected cases of ma
huang toxicity with inadequate documentation were excluded as were cases in which the records indicated use of
any illicit substance.
RESULTS
Of the 926 cases of possible ma huang toxicity reported to
the FDA from 1995 to 1997, 37 involved serious cardiovascular events; 11 sudden deaths (1 resuscitation), 16 strokes
(including 3 deaths), and 10 myocardial infarctions were
temporally related to ma huang use (Table 1). The mean ±
SD age of the 23 women and 14 men was 43±13 years
(range, 20-69 years). Reasons for using ma huang were
Cardiovascular Toxic Effects of Ma Huang
13
Table 1. Adverse Cardiovascular Events Temporally Related
to Ma Huang Use
Adverse events
No. of patients
Mean ± SD
age (y)
Sudden death
Myocardial infarction
Stroke
7 M, 4 F
3 M, 7 F
4 M, 12 F
40±14
44±14
44±13
weight loss, energy enhancement, bodybuilding, and recreational. Prior cardiovascular disease was reported in only 1
of the 37 patients. A review of clinical records and investigative interviews indicates that 36 of the patients used ma
huang according to the manufacturers’ recommendations.
A 20-year-old man died suddenly after ingesting 2 times
the manufacturer’s recommended dosage. No patient had a
clinical history or toxicologic data to indicate use of any
other substance. Of the 37 patients, 33 (89%) used ma
huang for more than 1 week, and 27 (73%) used it for more
than 1 month.
Of the 11 patients who experienced sudden death, 7
were men, and 4 were women. The mean ± SD age of this
group was 40.4±14.4 years (range, 20-63 years). In these
11 patients, 7 autopsies demonstrated a normal heart in 1,
atherosclerosis (defined as ≥70% luminal stenosis) of a
major epicardial coronary artery in 3, and cardiomyopathies in 3 (Table 2).
Of the 10 patients with myocardial infarction, 7 (70%)
were women, and 3 (30%) were men; the mean ± SD age was
44.2±13.8 years (range, 23-67 years). Of these patients, 8
used ma huang for weight loss. Of the 10 patients with
myocardial infarctions, 8 underwent cardiac catheterization,
with normal findings in 3, obstructive coronary artery disease in 4, and a dissection of the circumflex artery in 1. The
mean ± SD creatine kinase level was 1509±914 U/L, and
mean ± SD creatine kinase–MB fraction was 85.6±40.6 U/L.
Of the 16 patients who suffered a stroke, 12 (75%) were
women, and 4 (25%) were men; the mean ± SD age was
43.6±13.0 years (range, 24-69 years). Eleven (69%) of
these patients used ma huang for weight loss. Of these 16
patients, 12 (75%) had an ischemic stroke, and 4 (25%) had
a hemorrhagic stroke.
DISCUSSION
Our study findings provide evidence that ma huang may
precipitate life-threatening cardiovascular events, and they
expand on observations from other reports.8-11 Because of
the absence of appropriately designed toxicity trials and
absence of rechallenges in any of the surviving patients, the
cases presented in this report must be interpreted as demonstrating only a temporal, not causal, relationship between
ma huang and adverse cardiovascular events.
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14
Cardiovascular Toxic Effects of Ma Huang
Table 2. Autopsy Findings in 7 Patients Who
Experienced Sudden Death*
Age (y)/
sex
Cardiac pathology
20/M
Normal
23/M
Multifocal and confluent myocyte necrosis with
healing of approximately 1 to 2 weeks; mild
perivascular, focal endocardial, and local
epicardial fibrosis; and moderate myocyte
hypertrophy and vascular congestion. No evidence
of myocarditis. Myocyte necrosis findings are
nonspecific and could be due to primary myocyte
toxicity or secondary to ischemia. The peculiar
distribution of the necrosis as a band in the
subepicardial one third of the myocardium
contrasts with the typical subendocardial
distribution of myocardial damage associated with
large coronary vascular obstructions. This finding,
the myocardial hemorrhage, and the observed
single, few cell necrotic areas certainly are
consistent with effects of factors that collectively
could be responsible for vascular damage, vasoconstriction of small arterial vessels, and myocyte
toxicity. Variable duration of lesions suggests
multiple/ongoing insults. These pathologic
features are reminiscent of experimental and
clinical aspects of adrenergic/sympathomimetic
agents†
29/F
Greater than or equal to 90% stenosis of left main,
left circumflex, left anterior descending, and right
coronary arteries
32/M
Mild chronic inflammation and focal fibrosis of the
epicardium. Widespread, focally severe
necrotizing interstitial myocarditis involving the
intraventricular septum and all sections of the left
ventricle, sparing the right ventricle. Infiltration of
these areas is composed of neutrophils and
macrophages, with rare eosinophils. Monocytes
and nuclei show moderate hypertrophy, and intramural arteries show moderate and focally severe
thickening of the walls. Heart weight, 600 g
37/M
Myocardial hypertrophy, focal interstitial fibrosis,
mild focal disarray of myocardial fibers, and mild
medial hypertrophy of the intramyocardial small
arteries
38/M
Greater than 75% stenosis of the obtuse marginal,
50% of the left anterior descending, 75% of the
proximal right coronary artery, and 75% of the
proximal left circumflex coronary artery.
Cardiomegaly (heart weight, 490 g)
45/M
Approximately 50% stenosis of the proximal left
anterior descending coronary artery with acute
intracoronary thrombus
*Data from Adverse Reaction Monitoring System database.
†Autopsy report from Backer et al.7
Mayo Clin Proc, January 2002, Vol 77
Another analysis of FDA adverse events during a different period (June 1997-March 1999)10 similarly concluded
that dietary supplements containing ephedra alkaloids may
pose a health risk.8 Among 140 reported adverse effects
related to the use of dietary supplements containing ma
huang, 47% involved the cardiovascular system and 18%
the central nervous system.8
The pathogenesis of ma huang toxicity remains incompletely defined. Ma huang (Ephedra) has been used in
traditional Chinese medicine for more than 5 millennia.12
The approximately 40 species of herbs in the genus Ephedra are divided into several geographic types and vary
qualitatively and quantitatively in their alkaloid content.12
Commercially available ma huang varies considerably in
ephedrine alkaloid content.12,13 Many products do not list
ephedrine content on the label.13,14 A recent determination
of the content of alkaloids in 20 herbal dietary supplements
containing ma huang showed that alkaloid content often
differed markedly from label claims and was inconsistent
between 2 lots of the same products. Total alkaloid content
ranged from 0.0 to 18.5 mg per dosage unit.13,14 Ranges for
ephedrine and pseudoephedrine were 1.1 to 15.3 mg and
0.2 to 9.5 mg per unit dose, respectively. Norpseudoephedrine, a schedule 4 controlled substance, was often
present.14 Substantial lot-to-lot variations in alkaloid content were observed for multiple products. This included lotto-lot variation of ephedrine, pseudoephedrine, and
methylephedrine that exceeded 180%, 250%, and 100%,
respectively. Analysis of 1 product showed no detectable
ephedra alkaloid. Similar analysis of other nutraceuticals,
including melatonin, dehydroepiandrosterone, ginseng, feverfew, and kava, documented substantial deviations in
content from the product label.13,14 Botanical supplements
have been contaminated with harmful herbs, undeclared
conventional pharmaceuticals, or heavy metals.3,14 These
observations raise questions regarding the adequacy of
self-regulation for product quality, consistency, potency,
and purity within the nutraceutical industry.
Although the association of ma huang use and cardiovascular toxic effects in our study is circumstantial, a considerable body of knowledge is available on the potential
and similar toxic effects of ephedrine, the active alkaloid in
ma huang. Ma huang increases the availability of naturally
released catecholamines at synaptic areas in the brain and
in the heart and directly stimulates α- and β-adrenergic
receptors.15 As a result, ma huang increases blood pressure
secondary to elevations in heart rate, cardiac output, and
peripheral resistance.16 Ephedrine is well absorbed after
oral administration and is excreted primarily unchanged in
the urine, with a serum half-life of 2.7 to 3.6 hours.17 The
therapeutic index for ephedrine is low, with toxic effects
reported with both short-term and long-term use.17 Ephed-
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, January 2002, Vol 77
rine has been previously reported to be associated with
both ischemic and hemorrhagic stroke.18 In addition, combinations with other common stimulants, such as caffeine,
have been associated with cardiac arrhythmias including
ventricular tachycardia.19 Coronary artery vasospasm has
been documented with ephedrine administration during
spinal anesthesia.20,21 Intravenous ephedrine has been
linked to acute myocardial infarction.22 Sudden death resulting from an ephedrine overdose has been reported.7
Long-term ephedrine use may lead to a cardiomyopathy
typically seen with catecholamine excess.23,24
The serious adverse reactions associated with ma huang
ingestion documented in the current study are consistent
with those previously reported with ephedrine toxicity.
Cases in which a reasonable alternative explanation was
possible for the cardiovascular events were excluded from
our study. The pathophysiology for such devastating complications may be related to intense vasoconstriction in
both cerebral and coronary arteries, similar to that seen
with ephedrine and also with cocaine.25 Toxic effects of
ephedrine may be related to ischemia secondary to sudden
increases in myocardial oxygen requirements. Long-term
ephedrine use may lead to conditions seen with prolonged
catecholamine excess resulting in fibrosis and even death.26
In the current study, ma huang was associated with
sudden death even in the absence of structural heart disease. In addition, a substantial proportion of patients were
young and had no other risk factors for cardiovascular
disease, such as diabetes, hypertension, smoking, or family
history of cardiovascular diseases. The mean age of patients who experienced these adverse events was young
compared to those who typically experience stroke, myocardial infarction, or sudden death. This observation may
be related to the greater proportion of younger people
choosing alternative therapies27 and the marketing of these
agents for younger people. Importantly, in 36 of the 37
patients in this report, use of ma huang was reported to be
within the manufacturers’ recommended dosing.
The exact number of people in the United States who
use ma huang is unknown. An estimated 12 million persons
in the United States consumed products containing ma
huang in 1999.8 Adverse effects of drugs are underreported,
with reporting rates lower than 15%.8 The reporting rate for
adverse reactions to nutraceuticals is believed to be even
lower.8 Accordingly, it is not possible to know precisely the
proportion of people taking ma huang who are at risk.
Despite this limitation, the adverse effects of ma huang
documented in this report and others raise several issues
regarding the risk of this agent, which has no scientifically
proven benefit.8 The cases presented herein cannot be used
to establish the frequency of adverse reactions because of
almost certain underreporting of adverse events. However,
Cardiovascular Toxic Effects of Ma Huang
15
these cases can serve as a reminder of the potential toxic
effects of ma huang to both the medical community and to
the people who consume ma huang.
Our report has the limitation of being an observational
study and as such does not definitively establish the relationship between ma huang use and the risk of adverse
cardiovascular events. In August 1997, a small observational study reported on the association of fenfluramine and
phentermine use and cardiac valvular regurgitation.28 That
report had limitations similar to our observations regarding potential ma huang toxicity.28 In the year preceding
the report on valvular abnormalities in association with
anorectic agents, the number of prescriptions written for
these agents in the United States exceeded 18 million.
Although not approved by the FDA for combination use,
these drugs were commonly used together. Within 3 weeks
of the publication by Connolly et al28 before more definitive investigations were conducted, fenfluramine and
dexfenfluramine were withdrawn from the market at the
request of the FDA. Population-based follow-up studies,
case-control investigations, and analyses of a double-blind,
placebo-controlled study were performed to assess the incidence and prevalence of these cardiac valvular findings.29-31
The subsequent studies ultimately concluded that these
anorectic agents are associated with an increased risk of
newly diagnosed cardiac valve disorders.29-31 Neither the
small observational study by Connolly et al28 nor our report on ma huang use definitively establishes a causal
relationship between the respective agents and the observed adverse cardiovascular events. Additionally, these
reports provide no insight on the potential biologic mechanisms of the adverse effects of ma huang or the combined
anorectic agents. However, like the cases of fenfluraminephentermine, our observations raise important public
health issues that warrant further research. Persons using
or considering using ma huang should be informed of
the possibility of associated serious adverse cardiovascular
effects.
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