Cardiovascular Effects of Ephedra
Alkaloids: A Comprehensive Review
Richard Andraws, Preety Chawla, and David L. Brown
The Ephedra alkaloids have received much press
lately secondary to reported adverse events in
those using whole extracts as dietary supple-
ments for weight loss or athletic performance en-
hancement. These reports are troubling given the
increasing use of these supplements by the general
public. We reviewed the available literature as well
as online material on these compounds, including
information on their pharmacology, regulation, ef-
fects on weight loss and athletic performance, and
adverse events. Extracts of Ephedra shrubs con-
tain highly active !- and "-adrenergic agonists that
have profound effects on the heart and vasculature.
Evidence for their effectiveness is limited. Adverse
cardiovascular and cerebrovascular effects, includ-
ing stroke, myocardial infarction, and sudden
death, temporally related to their use are well de-
scribed. The recent Food and Drug Administration
ban on these compounds is not broad enough.
Ephedra supplements contain a highly bioactive
class of compounds that pose a significant risk to
the public under the current regulatory framework.
More stringent oversight by regulatory authorities is
required to minimize the incidence of adverse
events.
2005 Elsevier Inc. All rights reserved.
E phedra or the Ephedra alkaloids are a group of
sympathomimetic compounds derived from
shrubs of the genus Ephedra. Some 40 species are
scattered throughout the temperate and subtropi-
cal regions of Asia, Europe, and the Americas. The
Asian species (E. sinica, E. intermedia, and E. equi-
setina) have the highest alkaloid content.1 The
Ephedra alkaloids have a long history as tradi-
tional folk remedies, particularly among the Chi-
nese. The principle alkaloid, known as ephedrine,
was first isolated in 1885,2 and in its purest form
has found use in modern medicine as a broncho-
dilator, decongestant, and vasopressor.3 In recent
years, various companies have begun marketing
Progress in Cardiovascular Diseases, Vol. 47, No. 4, (January/February) 2005: pp 217-225
extracts of Ephedra shrubs for such purposes as
weight loss and enhancement of athletic perfor-
mance. Herbalists also market them as alterna-
tive medicines for cold and cough relief. It has
been estimated that nearly one third of young,
obese women have used a weight-loss supplement
containing Ephedra.4 In 1999 alone, 12 million
individuals in the United States used 3 billion
doses of Ephedra alkaloids.5 Given the frequency
of reports of adverse cardiovascular and cerebro-
vascular complications, the U.S. Food and Drug
Administration (FDA) recently moved to prohibit
the sale of these supplements. However, it is likely
these agents will remain available to the public
through illicit channels and related compounds
will be sold through legitimate vendors. Thus, the
purpose of this review is to examine the pharma-
cology of Ephedra alkaloids, the regulation of di-
etary supplements in the United States, the effects
of Ephedra and related alkaloids on weight loss and
athletic performance, and the available evidence re-
garding adverse events caused by these agents.
Structure and Pharmacology
Ephedra is a generic term for several sympatho-
mimetic agents including ephedrine, pseudo-
ephedrine, norpseudoephedrine, norephedrine,
methylephedrine, methylpseudoephedrine, and
phenylpropanolamine (a synthetic, racemic mix-
ture of the stereoisomers of norephedrine). Their
From the Department of Medicine, Beth Israel Medical
Center and the Division of Cardiology, Beth Israel Medical
Center, New York, NY.
Address reprint request to David L. Brown, MD, Division
of Cardiology, State University of New York-Stony Brook
School of Medicine, Stony Brook, NY 11794. dabrown@
chpnet.org
0033-0620/$ - see front matter
2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcad.2004.07.006
217
218
molecular structures are isomers of one another or
are closely related, substituted molecules that
demonstrate significant similarity with amphet-
amines and other catecholamines (Fig 1). It is not
surprising, then, that these molecules possess sig-
nificant !- and "-adrenergic agonist activity. In
addition, they enhance the release of endogenous
catecholamines. This latter effect, through deple-
tion of endogenous catecholamine stores, is
thought to explain the tachyphylaxis noted with
repeated dosing.5 The principle cardiovascular ef-
fects of Ephedra alkaloids include increases in sys-
tolic and diastolic blood pressure, heart rate and
indices of cardiac performance3,6,7 (Fig 2).
In species of Ephedra that contain appreciable
quantities of alkaloids, the greatest amount is
found in the branches, the remainder of the shrub
being devoid of the compounds.1 The dried
branches of the Asian species are known as ma
huang in Chinese, meaning yellow astringent,
perhaps due to the plants color and sharp taste
(Fig. 3). The name is frequently used commer-
cially in the United States and is synonymous with
Ephedra. Extracts of the branches contain varying
amounts of the different alkaloids and each alka-
loid differs somewhat in its pharmacodynamic
properties. From 40% to 90% of the alkaloid con-
tent consists of ephedrine with the other agents
Fig 1. Chemical structures of the Ephedra alkaloids (left). The structures of epinephrine, amphetamine, and
dobutamine (right) are shown for comparison. Ephedra alkaloid structures adapted from The Cantox Report.2
ANDRAWS, CHAWLA, AND BROWN
comprising the remainder in relatively smaller
quantities.2
Absorption of ephedrine from the gastrointesti-
nal tract is avid, approximating 100%.2 Time to
peak serum levels varies between 2 and 4 hours.
The pure alkaloid is absorbed most quickly;
herbal alkaloid mixtures may retard the rate of
absorption. The rate of absorption of ephedrine
may be increased with heat stress.8 Additionally,
elevations in blood pressure are significantly
greater when ephedrine is taken during heat
stress. The importance of this finding lays in the
fact that Ephedra extracts have been marketed as
enhancers of athletic performance and are often
taken prior to exercise in a warm environment.
Thus, they may add to the cardiovascular stress
already being experienced during physical activity.
Once absorbed, ephedrine has a large volume of
distribution and is not bound to plasma proteins.2
Ephedrine and related alkaloids are lipophilic and
cross the blood brain barrier. It is this physical
property that accounts for their effects on the central
nervous system, which include appetite suppres-
sion, anxiety, and changes in gastric motility.9-14 The
effects of ephedrine last for approximately 1 hour,3
but the serum half-life ranges from 3 to 11 hours.2
Excretion occurs primarily through the kidneys over
24 hours, predominately as the unchanged drug.
EPHEDRA ALKALOIDS 219

Fig 2. Change in systolic blood pressure and heart rate with time from ephedrine ingestion (A,B) and with serum
concentration (C,D). Adapted from Haller, Jacob, and Benowitz.3

From 8% to 20% is excreted after demethylation and
delamination.2 Excretion is pH dependent because
of an ionizable amino group on the molecule. Acidic
urine promotes excretion because the amino group
is then positively charged and not readily reab-
sorbed; an alkaline urine has the opposite effect.6,15
In addition to renal excretion, ephedrine is also
found to be excreted in breast milk and crosses the
placenta, which poses concerns for younger women
who may be using extracts for weight loss purposes
while pregnant or after delivery.
Marketing and Regulation
Ephedrine and related compounds are marketed in 2
ways in the United States. The pure alkaloids are

Fig 3. A. Ephedra sinica. B. The dried branches of the plant (known in Chinese as ma huang).
220
marketed as pharmaceuticals and are used as bron-
chodilators, vasopressors, and constituents in vari-
ous over-the-counter decongestants.3,16-19 The other
marketed form is as an herbal or dietary supplement.
The 1994 Dietary Supplement Health and Education
Act (DSHEA) defines a dietary supplement as any
product which contains one or more dietary ingre-
dients such as vitamins, minerals, herbs or other
botanicals, amino acids or other ingredients used to
supplement the diet.20 Dietary supplement ingredi-
ents may not be regulated as food additives.20 The
DSHEA was passed after a major lobbying effort,21
and the result was intended to be a new regulatory
framework for supplements, ensuring continued ac-
cess to safe products that are manufactured to qual-
ity standards. It was also supposed to result in in-
creased dissemination of information about the
health benefits of these products.20
In practice, the DSHEA led to deregulation of
these products.21,22 The rigorous oversight that
the FDA exercises over pharmaceuticals does not
extend to supplements. Quality control and regu-
lations regarding product labeling are lax. Gurley,
Gardner, and Hubbard23 examined 20 brands of
dietary supplements containing Ephedra alka-
loids in an attempt to correlate claims of content
on product labels with laboratory analysis of the
content. There was poor correlation between
claims and actual content. Several brands did not
even note chemical constituents on their labels,
which is mandated by the DSHEA as well as the
Federal Food, Drug, and Cosmetic (FD&C) Act.
Perhaps more disturbing was the finding of signif-
icant content variability within several brands.
The status of supplements under the DSHEA
presents particular problems for the FDA in terms
of safety concerns. Supplements may come to
market without FDA approval. This is very differ-
ent from the case of pharmaceuticals, where man-
ufacturers are compelled to prove both the safety
and efficacy of their products through well-de-
signed clinical trials before being allowed to bring
them to market. Neither burden is imposed on
makers of herbal or dietary supplements. Yet these
products contain compounds, such as ephedrine,
which have significant biological effects and have
interactions with many common medications,
making them similar to drugs.22,24 The Ephedra
alkaloids are thus a fascinating example of a trou-
bling paradox: the whole extract is considered a
ANDRAWS, CHAWLA, AND BROWN
supplement, whereas the purified or synthesized
constituents are considered pharmaceuticals.
Proving efficacy is less of a priority for manufac-
turers of dietary supplements because under the
terms of the DSHEA, they cannot make claims of
efficacy regarding a specific condition. They can,
however, make vague or suggestive claims that may
or may not be substantiated in clinical studies.21
Additionally, the burden of proving safety is shifted
to the FDA. Under the DSHEA, the FDA must prove
that a supplement is unsafe before it can move to
regulate or ban it. Such proof is drawn from case
reports of adverse reactions, which are compiled by
the FDA, other regulatory organizations, and manu-
facturers, and published in medical literature. How-
ever, these reports are not the best form of evidence;
reporting is voluntary, information may be incom-
plete, or there may be confounding factors that make
proving that an adverse event was directly linked to
ephedrine or related compounds difficult. For exam-
ple, Haller and Benowitz5 reviewed 140 cases of ad-
verse cardiovascular and central nervous system ef-
fects linked to Ephedra alkaloids and reported to
FDA MedWatch between June 1997 and March
1999. Of the cases reported, only 43 (31%) were
classified as definitely or probably related to in-
take of these products, and even these were the sub-
ject of some controversy.25 Another problem noted
by Haller and Benowitz is that adverse events are
often underreported, and so the true magnitude of
risk to the public health may seem less than it actu-
ally is. Thus, when it comes to regulating the safety
of dietary supplements, the FDA is at a distinct dis-
advantage.
Effects on Weight Loss and Athletic
Performance
The Ephedra alkaloids are marketed as supplements
primarily for weight loss and enhancement of ath-
letic performance. Several studies on these com-
pounds (particularly ephedrine) have been under-
taken to assess their efficacy and safety in humans
for the treatment of obesity.12,26-35 Doses of ephed-
rine and related compounds ranged from 60 to 150
mg/d. Overall, studies have found statistically signif-
icant reductions in weight in obese patients treated
with Ephedra alkaloids versus those treated with
placebo. This finding was corroborated by the recent
Rand Report36 and a review by Shekelle et al14 Treat-
ment with these carefully controlled doses resulted
EPHEDRA ALKALOIDS
in a modest incidence of cardiovascular side effects,
including increases in blood pressure (both systolic
and diastolic), heart rate, and palpitations that were
often mild and transient. No clinical trial has re-
ported major adverse cardiovascular events (stroke,
myocardial infarction, or malignant arrhythmias)
associated with the use of Ephedra alkaloids for
weight loss.
However, several caveats must be noted. The
studies to date have examined small cohorts for
relatively short periods of time, usually 6 months
or less.14,36 They have also suffered from high at-
trition rates. In addition, most studies have looked
at ephedrine in combination with caffeine and, in
several cases, aspirin. (The rationale for this com-
bination is that it better stimulates increases in fat
metabolism and energy expenditure.37-48) Per-
haps the most sobering finding is that weight loss,
although statistically significant, may not be clin-
ically significant (!1 kg)14 with anywhere from a
2- to 4-fold increase in side effects compared to
placebo. Moreover, side effect profiles may be
quite different in cohorts with preexisting cardio-
vascular disease. Thus, it is difficult to generalize
these results to the various Ephedra products on
the market that contain variable amounts of active
compound and are sold to a variety of consumers
with different risk factors who may consume
higher doses than those studied.
Evidence for enhancement of athletic perfor-
mance is less robust. Ephedra products are mar-
keted as energy enhancers, which may reflect
stimulation of the central nervous system through
adrenergic pathways similar to amphetamines
given that these molecules share important struc-
tural and pharmacodynamic properties. Numer-
ous studies fail to show an improvement in vari-
ous exercise parameters (e.g., oxygen
consumption, time to exhaustion) with Ephedra
alkaloids alone. The results of studies on Ephedra
in combination with caffeine are mixed.48-51
Pseudoephedrine significantly prolongs time to
heart rate recovery following exercise, and other
studies have found a significant increase in heart
rate and blood pressure over controls. Again,
studies tend to be small and contain young
healthy individuals who may not reflect the gen-
eral population. Thus, once more, the limited
available safety assessments are difficult to extrap-
olate to the general population.
221
Adverse Events
Adverse reactions related to the use of Ephedra
alkaloids have received much attention recently,
especially with the death of a professional baseball
player who used a formulation during training
camp.52 The bulk of evidence regarding adverse
reactions comes from case reports. Larger studies
that appear to demonstrate safety are difficult to
extrapolate to supplements because they often
look at pure, minor constituents (such as pseudo-
ephedrine), which are used under controlled con-
ditions.53 Although Ephedra products make up a
modest amount of overall supplement sales
(0.82%), they account for an inordinately large
number of reported adverse events (64%).54
Insight into the potential toxicity of these
agents may be obtained by considering their phar-
macologic properties. Ephedra alkaloids are !-
and "-adrenergic agonists that stimulate the re-
lease of endogenous catecholamines. The physio-
logic effects of compounds with these properties
have been known for decades. In addition to ef-
fects on blood pressure (which can lead to hyper-
tensive urgencies/emergencies)55 and cardiac per-
formance, they cause vasoconstriction and
vasospasm, including coronary vasospasm. The
latter effect may be more pronounced in individ-
uals with higher vagal tone,56 a group which in-
cludes well-conditioned, athletic individuals.
Moreover, there is some evidence that, along with
spasm, Ephedra alkaloids may induce hypercoag-
ulable states, low flow, and oxygen supply
demand imbalance within the coronary circula-
tion.57 This could account for reported cases of
myocardial infarction in otherwise healthy young
people without significant underlying coronary
artery disease.17,58-61 Myocardial ischemia has also
been reported when Ephedra alkaloids are com-
bined with other medications that cause increased
adrenergic tone, such as bupropion17 or mono-
amine oxidase inhibitors.62,63 Catecholamines
also decrease myocardial refractoriness, which
can predispose the heart to arrhythmias, and in-
deed ventricular arrhythmias have been reported
in pregnant women using over-the-counter de-
congestants19 as well as in others using Ephedra
alkaloids recreationally.55 Table 1 summarizes ad-
verse cardiovascular events noted in the literature.
Cerebrovascular events associated with Ephedra
use are another area of concern. Cases of stroke in
222 ANDRAWS, CHAWLA, AND BROWN

Table 1. Adverse Cardiac Events

Source Study Type No. of Subjects Reported Events (No. of subjects)
Haller and Benowitz 5 Case review 46* Hypertension (17), palpitations/tachycardia/
arrhythmias (19), myocardial infarction
(2), cardiac sudden death (8)
Shekelle et al14 Meta-analyis/case review 98 Palpitations (51), hypertension (7),
tachycardia (6), myocardial infarction
(11), cardiac sudden death (15), near
sudden death (3), cardiomyopathy (4),
ventricular tachycardia (1)
Pederson et al7 Case report 1 Myocardial infarction
Zahn et al55 Case report 1 Hypertension, ventricular tachycardia
Wahl et al56 Case report 2 Coronary vasospasm and nonQ-wave
myocardial infarction (2)
Rezkalla et al57 Case report 1 Myocardial infarction
Derreza et al58 Case report 1 Coronary vasospasm, ST-elevation
myocardial infarction
Weiner et al59 Case report 1 Coronary vasospasm, ST-segment
elevation myocardial infarction
Samenuk et al60 Case review 21 Myocardial infarction (10), cardiac sudden
death (11)
Cockings and Brown61 Case report 1 Myocardial infarction
Lefebvre et al63 Case report 1 Hypertension

*Total N # 140, of which 46 were cardiac and considered definitely, probably, or possibly related to ephedra use.
Pooled adverse cardiac effects from clinical trials reviewed and case reports (exclusive of the others mentioned).

connection with the use of ephedrine and related
compounds have been reported.60,64-68 Morgenstern
et al69 recently published a case-control study exam-
ining the risk of hemorrhagic stroke associated with
these compounds. Overall, they found a trend to-
ward increased risk at doses "32 mg/d. These doses
are much lower than those used in studies examin-
ing safety and those examining Ephedra compounds
as pharmacotherapy for weight loss, in which doses
ranged from 90 to 150 mg/d. A similar study of
phenylpropanolamine, an alkaloid commonly
found in appetite suppressants and cold remedies,
found a significant increase in hemorrhagic stroke
among women.16 This latter report prompted the
FDA to request that drug companies manufacturing
products that contain phenylpropanolamine discon-
tinue them or reformulate them so as to exclude the
alkaloid.70 Table 2 summarizes adverse cerebrovas-
cular events associated with Ephedra alkaloids in the
literature.
Toxicity may not be limited to the pharmaco-
logic effects of the alkaloids themselves. Lee et al71
found toxicity to a line of cultured neurons when
they were exposed to various ma-huang prepara-

Table 2. Adverse Cerebrovascular Events

Source Study Type No. of Subjects Reported Events (No. of subjects)
Haller and Benowitz 5 Case review 11* Stroke (10), transient ischemic attack (1)
Shekelle et al14 Meta-analysis/case review 25 Stroke (22), transient ischemic attack
(1), sudden death related to
intracerebral hemorrhage (2)
Samenuk et al60 Case review 16 Stroke (16)
Vahedi et al64 Case report 1 Stroke
Mourand et al65 Case report 1 Intracranial hypertension/stroke
Yin66 Case report 1 Intracerebral hemorrhage/vasculitis
Stossel et al67 Case report 2 Intracerebral hemorrhage
Kaberi-Otarod et al68 Case report 1 Stroke

*Total N # 140, of which 11 were cerebrovascular and considered definitely, probably, or possibly related to
ephedra use.
Pooled adverse cerebrovascular events from clinical trials and case reports (exclusive of the others mentioned).
EPHEDRA ALKALOIDS
tions. The authors note that methods of extraction
of the alkaloids and grinding of the plant may lead
to unrecognized adulterants finding their way into
the final product.
Regulation Revisited
Based on the evidence of adverse outcomes, pro-
fessional sports leagues, college athletics associa-
tions, and the military were among the first to
prohibit the use of these supplements among its
members. Several states passed legislation ban-
ning the sale of Ephedra. The FDA was slower in
announcing a national ban, likely because the
DSHEA demanded such a high burden of proof.
However, in testimony before the House Subcom-
mittee on Commerce, Trade, and Consumer Pro-
tection72 in July 2003, FDA Commissioner Mark
McClellan noted that there was now reasonable
evidence that Ephedra-containing compounds
pose a threat to the public health and have not
been proven to offer the benefits often claimed by
manufacturers. He went on to mention that
though the FDA had not yet issued a formal ban, it
was in the midst of implementing more stringent
labeling and manufacturing requirements on
these supplements and was launching investiga-
tions into manufacturers who make inaccurate or
misleading claims. A formal ban was finally an-
nounced in December 2003 with implementation
set for April 2004.
Yet, even after this long and winding road towards
regulation, the threat from Ephedra still exists. Re-
cent commentaries73,74 have noted that the national
ban has several loopholes. Extracts sold as dietary
supplements and athletic enhancers are prohibited,
but those marketed as herbal remedies are not.
Moreover, compounds similar to Ephedra that tech-
nically do not fall into the Ephedra family of alka-
loids are not covered by the ban. Synephrine, also
known as bitter orange, is a prime example. This
agent is derived from the fruit Citrus aurantium, an
orange with a thick rind and very sour juice that is
indigenous to Southeast Asia but has since been cul-
tivated worldwide. Synephrine shares structural
similarity with Ephedra alkaloids and other cathe-
cholamines and has !-adrenergic properties. It may
thus pose the same risks to consumers as its banned
cousins, although supplements containing syneph-
rine are often sold under the misleading phrase
Ephedra free.
223
Conclusion
The use of Ephedra alkaloids is associated with
significant health risk and no significant health
benefit. Despite a recently implemented FDA ban,
they as well as related supplements remain on the
market. Because of the widespread availability and
deceptive advertising for these agents, physicians
should question patients about use and discour-
age patients from taking them. Furthermore, phy-
sicians should actively encourage state and federal
agencies to implement more comprehensive reg-
ulation of these potentially deadly substances.
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