Ephedra
[Download PDF] [FDA Final Rule Banning Ephedra - HerbalGram 62, 2004]
Ephedra sinica Stapf
[Fam. Ephedraceae]
Overview
Editors’ note: In an attempt to clarify the
controversy surrounding the safety of ephedra, this monograph devotes
additional space to some of the safety, legal, and regulatory issues. Thus, the
“Overview” section is longer for ephedra than for other monographs in this
publication.
In Asian medicine, ephedra (known in Chinese as ma huang) is the primary herbal drug for
treatment of asthma and bronchitis. This herb is one of the oldest and most widely
used Chinese herbs, having been employed for thousands of years in traditional
Chinese medicine (TCM) as a primary component of multi-herb formulas prescribed
to treat bronchial asthma, cold and flu, cough and wheezing, fever, chills,
lack of perspiration, headache, and nasal congestion. Listed in the oldest
comprehensive materia medica, Shen Nong
Ben Cao Jing (ca. 100 C.E.),
among the “middle class” herbs, ephedra is used to induce perspiration, and as
an anti-allergy agent (Blumenthal and King, 1995; Bruneton, 1995; Der
Marderosian, 1999; Huang, 1999; Leung and Foster, 1996; Weiss, 1988).
Presently, ephedra is official in the national pharmacopeias of China, Germany, and Japan, while the isolated or synthesized alkaloids from the
plant, primarily ephedrine and pseudoephedrine, are official in most countries.
Ephedra-containing dietary supplements have become
increasingly popular in the past two decades as agents to help promote weight
loss and athletic performance. A recent survey has suggested that 7% of the
American adult population uses nonprescription drugs for weight loss, 2% using
phenylpropanolamine (PPA) (no longer sold over-the-counter), and 1% using
products containing ephedra (Blanck et
al., 2001). In a survey on herb use in the Minneapolis metro area, 230
people (61.2% of responders) said they had used herbs in the past 12 months;
with 13.6% responding that they had used herbs for weight loss. Forty-four
(12.0%) said they used ephedra for a variety of
reasons: 23 to boost energy; 20 for weight loss; 10 as a decongestant; 7 for
asthma. Over half rated the ephedra effective or very effective (Harnack et al., 2001).
Discussions of the safety and effectiveness of the herb
ephedra are usually based on scientific research conducted on the isolated (sometimes
synthesized) alkaloids in the herb (i.e., ephedrine and pseudoephedrine or
their related isomers; see Chemistry section below). Both are approved by the
U.S. Food and Drug Administration (FDA) as safe and effective over-the-counter
(OTC) drug ingredients. Most of the scientific literature to date focuses on
these alkaloids. Due to the popularity of the herb there is an increasing
number of clinical studies being conducted on the herb itself, often in
combination with other herbs. This review focuses on the herb itself, with
reference to research on ephedrine and pseudoephedrine in the Pharmacology and
Mechanisms sections, and others, as necessary.
The safety and the appropriate regulation of ephedra arose
as controversial issues in the U. S. during the 1980–90s when the herb began to
be used as a major ingredient in herbal dietary supplements intended to aid
weight loss and exercise. Some products that were subsequently determined to be
adulterated with synthetic ephedrine (e.g., Formula One®) or marketed
as purportedly legal substitutes for the illicit drug Ecstasy (e.g., Herbal Ecstacy® and
Ultimate Xphoria®) raised significant concerns among various state
health authorities, health professionals, and responsible members of the herb
and dietary supplement industry (Blumenthal and King, 1996). In 1994,
increasing concerns about potential risks associated with the use of ephedra
herbal products prompted the American Herbal Products Association (AHPA) and
the National Nutritional Foods Association (NNFA) to issue a labeling policy
for its member companies to set serving and daily intake limits as well as list
contraindications for the herb on labels of ephedra-containing products (see
Contraindications section below) (AHPA, 1994).
Health professionals also became increasingly concerned
about the public health implications of ephedra and ephedra alkaloid-containing
products, and several groups passed resolutions supporting the restriction of
ephedra alkaloid-containing products. In May 1995 the Texas Medical Association
(TMA) adopted a policy that ephedrine and ephedrine alkaloids should be
prohibited from non-prescription foods, dietary supplements, or other OTC
commercial products intended for public consumption, and that such products be
made available by prescription only. In November 1998, TMA also proposed that
such products be labeled to declare the amount of active ingredients of the
substances with pharmacologic properties and that the products have accurate
warning labels (TMA, n.d.). The American Medical Association (AMA) has adopted
a similar policy (AMA, 2002, 2000).
In 1996, the Ohio legislature passed a law, supported by
industry dietary supplement organizations, to appropriately regulate these
products. Since that time, laws regulating ephedra that incorporate the AHPA
and NNFA standards for formulation and labeling have been passed in Hawaii,
Michigan, Washington, Oklahoma, and Nebraska.
In June 1997, the FDA issued proposed regulations on
ephedra-containing dietary supplements that would limit the level of total
ephedra alkaloids in herbal preparations to no more than 8 mg per dose, with no
more than 24 mg per day (FDA, 1997). The proposal would have banned the
combination of ephedra with other stimulants like caffeine or caffeine-containing
herbs (including cola [Cola nitida],
guarana [Paullinia cupana var. sorbilis], maté [Ilex paraguariensis]) in herbal products; would have prohibited the
sale of ephedra products for use in weight loss or for athletic performance;
would have restricted use of ephedra-containing herbal products to no more than
seven days duration; and would have required warnings on all labels for
products containing ephedra. The proposal also called for the ban of so called
“street drug knockoffs” containing the herb ephedra or ephedrine alkaloids, to
be used as replacements for illicit drugs; such copies of drugs are illegal
under federal law. The proposed rule was based primarily on approximately 800
adverse event reports (AERs) submitted to FDA. Industry, scientific and medical
experts, and many consumers criticized the proposed rule, often noting that the
AERs were not a valid scientific basis for rulemaking, as was established by
the FDA’s own policies.
As a result of this criticism, Congress requested that the
U.S. General Accounting Office (GAO), the government agency that monitors
accountability of all federal agencies, conduct an audit of the scientific
basis for FDA’s proposed serving and daily intake limits, the proposed duration
of use limit (seven days), including the ban on claims for weight loss and
exercise, and FDA’s cost/benefit analysis for the proposed rule. In August
1999, the GAO issued a 68-page report,
Dietary Supplements: Uncertainties in Analyses Underlying FDA’s Proposed Rule
on Ephedrine Alkaloids (GAO, 1999). The report reveals deficiencies in the
FDA’s proposed rule on ephedra. GAO acknowledged that the AERs the FDA had
received for ephedra raised concerns that warranted examination. At the same
time, GAO questioned the reliability of many of the AERs and criticized the
apparent lack of science employed in formulating the proposed dosage limits of
alkaloids, the proposed duration limits, and ban on weight loss and exercise
claims. As a result of this and other significant deficiencies, including a
failure to establish that the proposed rule would have a public health benefit,
the GAO recommended that the FDA not finalize the proposed rule unless it could
develop a valid scientific basis and meet other requirements applicable to
federal rulemaking.
In March 2000, the FDA responded to the GAO by withdrawing
portions of its proposed rule on duration of use (including prohibitions
against marketing ephedra for weight loss and exercise) and dosage levels. FDA
simultaneously made public additional AERs on ephedra received since the
publication of the June 1997 proposed rule, as well as reviews of those AERs by
the FDA and outside consultants (FDA, 2000).
In August, the Office of Women’s Health (OWH) of the U.S.
Department of Health and Human Services (HHS) held a two-day public hearing on
the safety of ephedra in which testimony was presented by various scientific
and medical experts who had conducted extensive reviews of the scientific and
clinical literature on ephedra, as well as some who had conducted clinical
investigations into the safety and benefits of ephedra for weight loss. At the
OWH hearing, the Ephedra Education Council (EEC, an industry group) presented
the consensus views of a seven-member panel comprised of experts from various
medical and scientific disciplines who concluded, based on reviews of both the
published literature and the entire public record of more than 1,000 AERs
submitted to the FDA, that there was no evidence of an association between
ephedra and significant adverse events at the intake levels established by the
AHPA’s 1994 standards and subsequently adopted as law by several states. The
panel’s multi-disciplinary review of the AERs, which was subsequently submitted
to the FDA as public comment, was critical of reviews performed by FDA
consultants, one of which was subsequently published (Haller and Benowitz,
2000). One member of the EEC panel also conducted the first comparison of
incident rates of the adverse events at issue (e.g., stroke, heart attack, and
seizure) in the general population and incident rates of the same events in
ephedra consumers. His conclusion was that the analysis suggests that there was
no evidence of increased risk, even using the most conservative of assumptions
(Kimmel, 2000). In September 2000 the OWH issued a report recommending that
additional research be conducted (OWH, 2000).
The FDA’s review of 140 AERs, reportedly associated with the
ingestion of ephedra-containing dietary supplements, from the FDA’s MedWatch
program concluded that 43 (31%) of the AERs were “definitely” or “probably”
associated with ephedra use (Haller and Benowitz, 2000). In response to a
critical letter to the editor (Hutchins, 2001) the authors cautioned that their
report “does not prove causation, nor does it provide quantitative information
with regard to risk” (Hutchins, 2001). A subsequent evaluation concluded:
“These reports, while possibly associating the use of herbal dietary
supplements containing ephedra with side effects, do not in any way prove a
causative relationship between herbal use and these problems. On the other
hand, controlled studies of supplements containing ephedra provide considerable
evidence of efficacy in weight loss and weight maintenance.” (Heber and
Greenway, 2002).
There have been several attempts to
put the number of ephedra-related AERs and ephedra-using consumers into
perspective, but there are no accurate or reliable data on how many consumers
are using ephedra, how many doses have been consumed, or how many AERs are
directly related to ephedra consumption. According to a survey by AHPA of 14
companies that manufactured and marketed ephedra-containing supplements there
was a 700% increase in sales in ephedra-containing supplements in five years
from 1995 to 1999, representing 425 million “servings” sold in 1995 rising to
an estimated 3 billion servings in 1999, with total estimated sales of ephedra
supplements equaling 6.8 billion servings (McGuffin, 2000). (Technically,
dietary supplements are considered foods, not drugs, under federal law, and
thus what would normally be considered a “unit dose” by a pharmacist or
physician must be referred to in food language by members of the herb and supplement
industries, hence the term “serving.”) A total of 66 serious adverse events
were reported to these 14 responding companies over the 5-year period from 1995
to 1999. Based on the estimate of more
than 6.8 billion servings sold in the same 5-year period, these AERs represent
a reporting rate of less than 10 such reports per billion servings sold.
According to the survey, these sales statistics, based on a large but not total
segment of ephedra manufacturers, show that although the reported sales of supplements
containing ephedrine alkaloids has increased more than seven-fold in the past 5
years, there has been no commensurate increase of adverse events gathered by
FDA (McGuffin, 2000).
In October 2000, a group of industry trade associations
petitioned the FDA to accept proposed limits of 100 mg ephedra alkaloids per
day and a proposed warning label (AHPA et
al., 2000). In December 2000, Cantox Health Sciences International (CHSI),
an independent Canadian research organization, concluded, on the basis of a
quantitative method developed by the National Academy of Sciences, that 90 mg
per day is a safe upper limit for the ingestion of ephedra alkaloids in normal,
healthy individuals and that the lowest observed adverse effect level (LOAEL)
is 150 mg per day (CHSI, 2000; Hathcock, 2001). The safety assessment was based
on a review of all available clinical studies on the alkaloid ephedrine and the
herb ephedra, plus pharmacological and other relevant studies. CHSI also
reviewed the FDA’s AER database but concluded that due to insufficient and
inconsistent clinical data, these reports were not useful for assessing product
safety. (The Council for Responsible Nutrition, a Washington, D.C.-based trade
association of dietary supplement manufacturers and suppliers, commissioned the
review.)
Some experts have suggested that the relative safety and
potential benefits of ephedra-containing dietary supplements should be viewed
within the broader public health context of the prevalence of obesity in
America. In December 2001, the U.S. Surgeon General David Satcher, M.D.
estimated that 300,000 Americans die each year from illnesses caused or
exacerbated by obesity (Anon., 2001b). Satcher said that 62% of Americans are
either overweight or obese, compared to 48% in 1980 (Anon., 2001a). A
comprehensive review article of the scientific and medical literature of
caffeine and ephedrine combinations in the treatment of obesity (Greenway,
2001) summed up the situation:
Overweight and obesity are common
problems affecting more than half the population, yet obesity is stigmatized by
society. Therefore, it is not surprising that an effective weight loss product
containing compounds with a long history of safe non-prescription use would be
embraced enthusiastically by the public. When large numbers of the public are
using any product, adverse events will inevitably occur, but the cause and
effect relationship of these adverse events to the product use are usually
unclear. Obesity is a disease that predisposes to diabetes, hypertension, and
cardiovascular disease. These increased risks are reversed with weight loss.
The peer-reviewed scientific literature suggests that the risks of caffeine and
ephedrine are outweighed by the benefits of achieving and maintaining a healthy
weight. Confirmation of that conclusion for herbal products containing caffeine
and ephedrine awaits controlled clinical trials.
Recent clinical research, published after the Greenway
(2001) review, suggests that ephedra, in combination with other herbs, produces
significant weight loss with no clinically significant adverse effects in the
study participants, and with small impact on blood pressure or heart rate
(Boozer et al., 2002; de Jonge et al., 2001) and safety (Belfie et al., 2001). Based on these findings,
additional research into the use of ephedra as a weight loss aid appears to be
warranted. In June 2002, the Secretary of HHS called for more research on
ephedra to determine its safety and efficacy (HHS, 2002). Supporters and some
prominent critics of ephedra agree that scientific reviews of the cases of the
AERs on ephedra do not establish causality, thereby making additional clinical
research the key to developing regulatory policy.
Description
Ephedra consists of the dried, young branchlets, harvested
in the fall, of Ephedra sinica Stapf
[Fam. Ephedraceae] or other
equivalent Ephedra species
(Blumenthal et al., 1998; DAB, 1999),
including E. intermedia Schrenk
ex C.A. Mey. and E. equisetina Bunge
(syn. E. shennungiana Tang)
(PPRC, 1997). The Japanese Pharmacopeia requires that it contain not less than
0.6% total alkaloids, calculated as ephedrine (JSHM, 1993). The Pharmacopoeia of the People’s Republic of
China requires not less than 0.8% (PPRC, 1997), and the German
Pharmacopoeia requires not less than 1% (DAB, 1999).
Primary Uses
Respiratory System
Mild bronchospasms in adults and children
over the age of six (Blumenthal et al.,1998)
Bronchodilator in treatment of bronchial
asthma (WHO, 1999)
Ear Nose and Throat
Nasal congestion due to hay fever, allergic rhinitis,
acute coryza (rhinitis), common cold, sinusitis (WHO, 1999)
Obesity/Weight Management
Increased weight loss and thermogenesis (Boozer et al., 2002, 2001;
Belfie et al., 2001; de Jonge et al., 2001; Greenway, 2001; Liu et al., 1995; Astrup et al., 1986; Pasquali et al., 1985)
Other Potential Uses
Uses in Traditional Chinese Medicine (TCM)
include common cold marked by chilliness and mild fever, headache, stuffed and
running nose, general aching, but no sweating; edema in acute nephritis;
bronchial asthma (PPRC, 1997).
Ephedra dietary supplements are frequently
used by athletes as performance enhancing agents (This use is highly
controversial and has been the subject of numerous athletic groups’ attempts to
ban or restrict dietary supplements containing ephedra for this application.)
(IOC, 2001; Anon., 2001c; NCAA, 2001)
Dosage
Internal
Crude Preparations
Note:
According to U.S. herb industry labeling policy, the maximum adult daily dose
for ephedra and ephedra-containing products is 100 mg total alkaloids (AHPA,
2002).
Decoction:
1–6 g dried herb daily (WHO, 1999), 1.5–9 g dried herb daily (PPRC, 1997). Note: The yield of alkaloids is higher with
hot water decoction than with extraction with ethanol and/or methanol (Noguchi et al., 1978). In a decoction made with
ephedra containing a range of a minimum of 0.8% alkaloids (according to the Pharmacopoeia of the People’s Republic of
China, PPRC) to 1.0% (according to the German
Pharmacopoeia), the estimated range of alkaloids based on the WHO daily
dosage range would be 8–60 mg and the range based on the PPRC dosage would be
12–90 mg.
Dried comminuted herb
(According to the German Commission E for approved bronchial indications): the
adult single dose corresponds to 15–30 mg total alkaloid, calculated as
ephedrine. The adult maximum daily dose corresponds to 300 mg total alkaloid
calculated as ephedrine. For a child (over age 6) a single dose corresponds to
0.5 mg total alkaloid per kg of body weight. A child’s maximum daily dose is 2
mg total alkaloid per kg of body weight (Blumenthal et al., 1998). [Note:
This children’s dosage is based on the recommendation for licensed preparations
for the approved bronchial indication in Germany only. Ephedra supplements in the U.S. are not
recommended for children under the age of 18, according to industry labeling
policy.]
Fluid extract:
1:1 (g/ml), 45% alcohol, 1–3 ml daily
(WHO, 1999).
Tincture:
1:4 (g/ml), 45% alcohol, 6–8 ml daily
(WHO, 1999). Maximum weekly dose: 48 ml (Denham, 1998).
No Observed Adverse Effect Level Based
on the Cantox Toxicological Review: ephedra preparations equivalent to 30
mg total alkaloids per dose; 90 mg per day (CHSI, 2000).
Purified Ephedra Derivatives (i.e., OTC drugs):
For bronchodilation the maximum adult daily dose of
ephedrine (or usually its salt form, ephedrine hydrochloride) is 150 mg per day
(21 CFRa), and the maximum adult daily dose of pseudoephedrine (or its salt
form pseudoephedrine hydrocholoride) is 240mg per day (21 CFRb). [Note: for comparison purposes, the maximum
daily nonprescription oral dose of caffeine is 1,600 mg (Heber and Greenway,
2002).]
Duration of Administration
The Commission E monograph, published in 1991, recommended
that ephedra preparations should be used only short-term because of
tachyphylaxis and potential addiction. Note: A
more recent analysis of the available U.S. health and safety data compiled by
Edgar H. Adams, M.S., Sc.D., former director of the Division of Epidemiology
and Statistical Analysis at the U.S. National Institute on Drug Abuse,
indicates that there is no evidence of significant abuse of, or addiction to,
ephedra despite decades of widespread use, concluding that any potential for
addiction is low and does not rise to the level of regulatory concern that
warrants scheduling (as is done with addictive narcotic drugs) (Adams, 2000).
Nevertheless, as with other stimulant products that enhance athletic
performance, products containing ephedra alkaloids are still banned by the International
Olympic Committee for use by athletes competing in the Olympic games (IOC,
2001).
Chemistry
The herb ephedra contains approximately 1.3% alkaloids
composed mainly of ephedrine (up to 90%), pseudoephedrine, norephedrine,
nor-pseudoephedrine, methylephedrine, and methylpseudoephedrine (Huang, 1999;
Tang and Eisenbrand, 1992). These alkaloids are the primary active
constituents. Other components include flavonoid glycosides; glycans
(ephedrans); citric, malic, and oxalic acids; proanthocyanidins (condensed
tannins); tannins and volatile oils (l-a-terpineol,
limonene, and linalool) (Bruneton, 1995) but these compounds are not believed
to exert much influence on the well established pharmacological effects of this
herb.
Pharmacological Actions
The pharmacological data cited below pertain to research
conducted on the whole ephedra herb or its extracts, as well as to the isolated
alkaloids ephedrine and pseudoephedrine, plus (as noted below) combinations of
ephedrine and caffeine, or ephedrine and aspirin. Extensive clinical and
pharmacological research has been conducted on ephedrine, usually its salt
form, e.g. ephedrine hydrochloride (Astrup et
al., 1986; Tang and Eisenbrand, 1992), ephedrine and caffeine (Astrup et al., 1991; Astrup et al., 1992; Astrup and Toubro, 1993),
and an ephedrine-caffeine-aspirin combination (Daly et al., 1993). These results are probably directly relevant to the
actions of the herb ephedra or its combinations with caffeine-containing herbs.
One review on thermogenic agents states that the effects of ephedra and
ephedrine are the same, except that ephedra is gentler and less likely to cause
adverse effects, with the large body of scientific data on ephedrine being
applicable to ephedra (Jones, 2001). A small clinical trial suggests similar
pharmacokinetics between the ephedrine in ephedra and synthetic ephedrine
(Gurley et al., 1998). Research shows
that ephedra alkaloids (e.g., ephedrine) from supplements containing ephedra extracts are absorbed more quickly than
the alkaloids from preparations containing powdered ephedra herb, and thus
products containing extracts probably exhibit absorption and disposition
characteristics indistinguishable from those products containing isolated
ephedra alkaloids (e.g., OTC drugs) (Gurley, 2000). For a detailed review of
the clinical pharmacology of ephedrine, see Tang and Eisenbrand (1992), and for
ephedrine combined with caffeine and/or aspirin, see Heber and Greenway (2002).
Human
Ephedrine and related alkaloids produce
sympathomimetic effects, including vasoconstriction, increased heart rate, and
stimulation of central nervous system (Weiner, 1985).
Ephedra herb preparations are shown to
produce dilated bronchi (WHO, 1999), and induce perspiration (diaphoretic), and
diuresis (diuretic) (PPRC, 1997).
Increased thermogenesis and weight loss in
obese patients (ephedra-caffeine herb combination) (Boozer et al., 2002, 2001).
Ephedrine stimulates brown adipose tissue
(BAT) in rodents, but since humans possess relatively little BAT, ephedrine-induced
thermogenesis happens mainly in skeletal muscle (Astrup, 1986).
Ephedrine decreases gastric emptying,
possibly contributing to reduction of food intake (Jonderko and Kucio,
1991).
An ephedrine-caffeine combination was found safe and
effective in a pilot study on 32 obese adolescents, reducing weight more than
5% in 81% of the treatment group, compared to 31% in the placebo group (Molnar et al., 2000).
An acute dose of a combination of ephedrine (30 mg) and
aspirin (300 mg) produced greater post-prandial thermogenesis in 10 obese women
for 160 minutes following a liquid meal than an acute dose of ephedrine (30 mg)
alone. Aspirin alone did not produce this additional effect on thermogenesis in
10 lean women (Horton and Geissler, 1991) while ephedrine and aspirin
normalized the post-prandial thermogenesis in obese women to levels equal to
the lean (Geissler, 1993).
Stimulation of central nervous system and
cardiovascular parameters (i.e., increases in pulse rate, blood pressure, and
serum glucose levels) have been documented when ephedrine and/or caffeine are
given acutely either separately or together. According to a recent review of
the peer reviewed literature, these side effects disappear with chronic use and
are no longer present after 4 to 12 weeks, depending on the trial (Heber and
Greenway, 2002).
There has been concern about the potential hypertensive
effects of ephedra and its alkaloids. However, in one trial a proprietary
ephedrine (20 mg) and caffeine (200 mg) preparation tested for its weight loss
effects on 136 overweight normotensive or drug-controlled subjects with
controlled hypertension, three doses of the product showed blood pressure-lowering
effects over 6 weeks (Svendsen et al.,
1998). Systolic blood pressure was reduced 5.5 mm HG more in the controlled
hypertensive subjects treated with the preparation than placebo in subjects
treated with medication other than beta-blockers. The anti-hypertensive effect
of the beta-blocker drug was not reduced by the caffeine-ephedrine combination.
The normotensive patients treated with caffeine and ephedrine had a 4.4/3.9 mm
HG greater drop in blood pressure than those treated with placebo. The mean
loss of weight of 4 kg (8.8 lbs.) was significant for all groups.
A recent review of ephedrine cites literature
proposing it as an adjunct to cognitive restructuring and notes that ephedrine
has been considered in reviews about non-prescription weight loss supplements,
obesity management, energy balance, and obesity treatment (Heber and Greenway,
2002).
There has been recent concern about the use of dietary
supplements containing the herb ephedra when used as performance enhancers in
athletic activities. Although no studies are available on the herb ephedra in
athletic performance, numerous clinical trials conducted at the Canadian
Defence and Civil Institute of Environmental Medicine have measured the effects
of ephedrine and caffeine combinations on exercise and related performance
activities. These pilot studies have concluded that the combination of
ephedrine (E) and caffeine (C), or ephedrine alone, produces the following
effects in athletes or soldiers: (1) an improvement in anaerobic exercise
performance is likely a result of both stimulation of the CNS by E and skeletal
muscle by C (Bell et al. 2001); (2)
although the metabolic rate in subjects was slightly increased with C+E
treatment, it was sufficiently offset by increased heat loss mechanisms so that
internal body temperature was not increased during moderate exercise in a hot,
dry environment (Bell et al., 1999a);
(3) C+E improved performance of the Canadian Forces Warrior Test, a 3.2 km run
wearing about 11 kg of battlefield uniform and equipment (Bell, Jacobs, 1999b);
(4) C+E significantly prolonged exercise time to exhaustion compared to placebo,
while neither C nor E treatments alone significantly changed time to
exhaustion, the improved performance being attributed to increased CNS
stimulation (Bell et al., 1998); (5)
the previously observed additive effects of C+E was not evident, with the
primary ergogenic effect being attributed to E (Bell et al., 2002); and (6) a lower dose (approx. 20% lower) of C+E than
used previously resulted in an ergogenic effect similar in magnitude to that
reported previously with a higher dose, and with a reduced incidence of
negative side effects (vomiting and nausea) (Bell et al., 2000).
Animal
Ephedra herb prevents or relieves coughing
and inhibits growth of bacteria in animal experiments, according to the
Commission E (Blumenthal et al.,
1998);
Ephedra
stimulates the sympathetic nervous system in dogs (Huang, 1999), analogues of
feruloyl-histamine, an alkaloid in ephedra roots,
inhibit hypotension and histidine decarboxylase, is anti-ulcerous and
anti-hepatoxic (Hikino et al., 1984);
Ephenadrines block ganglions (Hikino et al., 1983);
Pseudoephedrine relieves inflammation (Hikino et
al., 1980).
Mechanism of Action
All mechanistic data cited below pertain to isolated ephedra
alkaloids.
Ephedrine indirectly stimulates the
sympathomimetic and central nervous systems (Blumenthal et al., 1998). It has been shown to produce sympathomimetic effects
(e.g., vasoconstriction and cardiac stimulation) by combining with a-
and b-adrenergic receptors (WHO, 1999; Hardman et al., 1996; Chang and But, 1986);
The chemical structure of ephedrine
resembles epinephrine (adrenaline) (Chang and But, 1986), though unlike epinephrine,
it is completely absorbed from the intestine and has a much longer duration of
action (Huang, 1999);
Ephedrine triggers the release of
endogenous catecholamines from post-ganglionic sympathetic fibers (Bruneton,
1995);
Ephedrine relaxes bronchial muscles and
acts as a bronchodilator by activating the b-adrenoceptors in the lungs (Weiner,
1985; Hardman et al., 1996);
Both ephedrine and pseudoephedrine inhibit
norepinephrine uptake by nervous and nonnervous tissues (Chang and But, 1986);
Ephedrine (i.v.) stimulates beta-1 receptors
(stimulating heart rate), beta-2, and beta-3 receptors (stimulating glucose and
oxygen consumption), insulin, and c-peptide (Jaedig and Henningsen, 1991).
Contraindications
The Commission E noted the following contraindications: anxiety
and restlessness, hypertension, glaucoma, impaired circulation of the cerebrum,
adenoma of the prostate with residual urine accumulation, pheochromocytoma, and
thyrotoxicosis (Blumenthal et al.,
1998). Additional contraindications include pregnancy, anorexia, diabetes,
heart disease, insomnia, stomach ulcers, renal failure, and in children
(Brinker, 2001).
The industry label warning for ephedra, currently being
suggested as an official national standard by a group of dietary supplement
industry trade organizations in a petition to the FDA, is as follows: “WARNING:
Not intended for use by anyone under the age of 18. Do not use this product if
you are pregnant or nursing. Consult a health care professional before using
this product if you have heart disease, thyroid disease, diabetes, high blood
pressure, depression or other psychiatric condition, glaucoma, difficulty in
urinating, prostate enlargement, or seizure disorder, if you are using a
monoamine oxidase inhibitor (MAO), or any other prescription drug, or you are
using an over-the-counter drug containing ephedrine, pseudoephedrine or
phenylpropanolamine (PPA) (ingredients found in certain allergy, asthma,
cough/cold and weight control products).
[PPA has been removed from the OTC market, but consumers might still
possess older PPA-containing drug products.] Exceeding recommended serving will
not improve results and may cause serious adverse health effects. Discontinue
use and call a health care professional immediately if you experience rapid
heartbeat, dizziness, severe headache, shortness of breath, or other similar
symptoms.” (AHPA et al., 2000).
Pregnancy and Lactation: Not
recommended for use during pregnancy or lactation (Brinker, 2001; McGuffin et al., 1997).
Adverse Effects
According to the Commission E, the adverse effects of the
herb ephedra include insomnia, motor restlessness, irritability, headaches,
nausea, vomiting, disturbances of urination, and tachycardia. The commission
also noted that higher dosages (presumably higher than the Commission E’s
recommended daily limit, equivalent to 300 mg ephedra alkaloids) may produce a
drastic increase in blood pressure, cardiac arrhythmia, and development of
dependency (Blumenthal et al., 1998).
(See “Note” about dependency in “Duration of Administration” above.)
There have been isolated reports of adverse events, some
serious, including stroke and death, in the published literature. Some are
related to overdosing; others (e.g., possible myocarditis in a few case
reports) are attributed to the consumption of relatively normal levels (Leikin
and Klein, 2000; Zaacks et al.,
1999).
In a recent review of FDA’s AERs (926 cases reported to FDA
between 1995 to 1997) focusing on 37 patients, ephedra use was temporarily
related to stroke (16 patients, 3 deaths), myocardial infarction (10), or
sudden death (11), noting that cardiovascular adverse effects were not limited
to large doses (Samenuk et al.,
2002). (This review relied on the same FDA database of AERs that had been
previously analyzed and questioned for accuracy by the GAO.)
One highly publicized review of selected events reported to
the FDA concluded that the AERs do not establish causality and cannot be used
to quantify risk (Haller and Benowitz, 2000). This paper reviewed 140 reports
of adverse events associated with the use of dietary supplements containing
ephedra alkaloids submitted to the FDA between June 1, 1997, and March 31,
1999. The authors employed a standardized rating system for evaluating
causation. They concluded that 43 (31%) cases were definitely or probably
related to the use of ephedra-containing supplements, 44 cases (31%) deemed possibly related to the use of ephedra
supplements, and 24 cases (17%) were considered unrelated. Of the adverse
events that were assessed to be definitely, probably, or possibly related to
the use of ephedra supplements, 47% involved cardiovascular symptoms and 18%
involved the central nervous system. The most frequently reported adverse event
was hypertension (17 reports), followed by palpitations, tachycardia, or both
(13); stroke (10); and seizures (7). Ten events were associated with deaths,
and 13 associated events resulted in permanent disability; these represent 26%
of the definite, probable, and possible cases. In response to a critical letter
to the editor (Hutchins, 2001) the authors cautioned that their report “does
not prove causation, nor does it provide quantitative information with regard
to risk” (Hutchins, 2001). A recent review concluded, “These reports, while
possibly associating the use of herbal dietary supplements containing ephedra
with side effects, do not in any way prove a causative relationship between
herbal use and these problems.” (Heber and Greenway, 2002).
More extensive evaluations of the entire FDA database of
AERs have been submitted to the FDA, suggesting no association between
clinically significant adverse events at doses of up to 100 mg per day (EEC,
2000; CHSI, 2000).
The AERs associated with ephedra have been analyzed from an
epidemiological perspective suggesting no greater incidence of seizures,
strokes, and myocardial infarctions (MIs) in persons consuming dietary supplements
containing ephedrine alkaloids than that expected in the general U.S.
population (Kimmel, 2000).
The Secretary of HHS, in a press release announcing plans to
study ephedra, stated as follows:
Adverse event reports regarding the use
of dietary supplements containing ephedrine alkaloids have been received by the
Food and Drug Administration (FDA) and have raised questions regarding the
safety of these products. However, the FDA has advised that adverse event
reports alone regarding dietary supplements containing ephedrine alkaloids do
not provide a scientific basis for assessing the safety of these products and
that there is need for further scientific research. (HHS, 2002).
Isolated ephedrine has been reported to cause urinary
difficulty in men with benign prostatic hyperplasia and is believed to
exacerbate angle-closure glaucoma (Dvorak et
al., 1997), forming the basis for the contraindications for these
conditions noted above. Other adverse effects documented for ephedrine in
controlled conditions include agitation, insomnia, headache, weakness,
palpitations, giddiness, tremors, and constipation; these effects were noted
only with 50 mg dose given three times daily (total 150 mg per day), with
amelioration during the duration of use, with no significant changes in pulse
rate or blood pressure (Pasquali and Casimirri, 1993). The German phytomedicine
authority R.F. Weiss, claims that the natural ephedrine found in ephedra is
“better tolerated, causing fewer heart symptoms such as palpitation” than
synthetic ephedrine (Weiss, 1988), although a revision of his book by another
author suggests that patients use synthetic beta-sympathomimetics for bronchodilation
due to the potential toxicity of ephedra (Weiss and Fintelmann, 2000).
Drug Interactions
The following are actual or potential interactions of orally
ingested ephedrine alkaloids (mainly ephedrine and/or pseudoephedrine, not
necessarily the herb ephedra itself), with other substances. Documented
interactions are derived mainly from human case studies or clinical trials,
based on the alkaloid intake at various dosages.
Antihypertensives, including ACE
inhibitors and beta-blockers: May be antagonized with resulting
severe hyper-tension (speculative) (Brinker, 2001).
Bromocriptine: Dopaminergic
activity may become increas-ingly toxic due to ephedra’s sympathomimetic
actions (speculative) (Brinker, 2001).
Cardiac glycosides or halothane: Can
cause arrhythmia (Brinker, 2001).
Corticosteroids:
Increases the clearance of dexamethasone, decreasing its activity (Brinker,
2001; Jubiz and Meikle, 1979).
Guanethidine:
Antagonizes the hypotensive effect (Brinker, 2001).
MAO-inhibitors
(including tranylcypromine, pargyline, procarbazine, selegiline, phenelzine,
and moclobemide) Significantly raise the sympathomimetic action of ephedrine
(Brinker, 2001).
Methyl xanthines (e.g.,
caffeine, theophylline):
Increase thermogenesis and weight loss with reduction in body fat when
ephedrine is combined with xanthines, plus excessive nervous stimulation (noted
in some case reports) (Brinker, 2001).
Caffeine: The
alkaloids in ephedra combined with methylxanthines have been demonstrated to be
synergistic on oxygen consumption in animals. A recent review noted both the
caffeine and the catechins in various types of tea (Camellia sinensis), e.g., oolong tea, may interact with respect to
respiration of brown adipose tissue, based on in vitro evidence. Catechins in green tea are synergistic with
respect to oxygen consumption with caffeine, ephedrine, and the combination of
caffeine and ephedrine; catechins inhibit catechol-O-methyl transferase, the enzyme that breaks down norepinephrine
(Heber and Greenway, 2002).
Secale alkaloid derivatives or
oxytocin: Develop hyper-tension (listed by German Commission E)
(Blumenthal et al., 1998).
Sympathomimetics: May
be potentiated when used with ephedra or ephedra alkaloids (speculative)
(Brinker, 2001).
Urinary alkalizers e.g., acetazolamide
(Wilkinson and Beckett, 1968);
sodium bicarbonate: Excrete more slowly than with urinary
acidifiers (e.g., ammonium chloride), due to effects of reabsorption from
tubules in the kidneys (Brinker, 2001).
American Herbal Products Association (AHPA) Safety Rating
Class 2b: Not
for use during pregnancy.
Class 2c: Not
for use during nursing.
Class 2d: Contraindicated
with anorexia, bulimia, and glaucoma; thyroid stimulant; not recommended for
excessive or long-term use; may potentiate pharmaceutical MAO-inhibitors
(McGuffin et al.,1997).
Regulatory Status
Australia: Ephedra, and products
containing ephedra, are controlled substances listed in the Customs Prohibited
Imports Regulations. Import permit required (TGA, 2001).
Canada: Included
in Drugs Directorate “List of Herbs Unacceptable as Non-medicinal Ingredients
in Oral Use Products” (Health Canada, 1995). Ephedra Labeling Standard:
Approved Schedule OTC drug with specific indications: (1) Traditional Herbal
Medicine (THM) for relief of nasal congestion (cold, hayfever); (2) Traditional
Herbal Nasal Decongestant. Dried young stem contains no less than 1.25% total
alkaloids calculated as l-ephedrine (Health Canada, 1996). Also, permitted as a
homeopathic drug. In either case requires premarket authorization and
assignment of a Drug Identification Number (DIN) (Health Canada, 2001). In
January, 2002 Health Canada issued a “voluntary recall” for ephedra- and
ephedrine-containing products that are marketed for unapproved uses, e.g.,
appetite suppression, promoting weight loss, or increasing energy; or that
contain over 8 mg ephedrine or a total dose of ephedrine alkaloids exceeding 32
mg per day (Lawlor, 2002).
China: Dried
herbaceous stem containing no less than 0.80% total alkaloids, calculated as
ephedrine, official drug of the Pharmacopoeia
of the People’s Republic of China (PPRC, 1997).
France: Ephedra
removed from French Pharmacopoeia.
Isolated ephedrine is official (Bruneton, 1995).
Germany:
Dried young whole or cut branchlet collected in autumn containing no less than
1.0% total alkaloids (as ephedrine) official in German Pharmacopoeia (DAB, 1999). Dried young branchlet is approved
drug of the German Commission E (Blumenthal et
al., 1998).
Japan: Traditional Kampo
medicine (Tsumura, 1996). Dried terrestrial stem containing no less than 0.15%
total alkaloids (as ephedrine) official in Japanese
Pharmacopoeia (JSHM, 1993).
Sweden: No products containing
ephedra are presently registered in the Medical Products Agency’s (MPA)
“Authorized Natural Remedies,” “Homeopathic Remedies” or “Drugs” listings (MPA,
2001a and 2001b).
Switzerland: No
monograph in the Swiss pharmacopeia.
No ephedra-containing products are listed in the Swiss Codex 2000/01 (Ruppanner and Schaefer, 2000). Since 1992,
traditional Chinese medicine (TCM) has been made available as a primary health
care option in the national HMO. Patients who choose TCM for their primary
health care plan may receive traditional Chinese herbal medicines (which may
contain ephedra) by prescription (Grüninger, 1992).
U.K.: Schedule
III herb recommended to be limited for use by medical herbalists only (Denham,
1998).
U.S.: Dietary
supplement (USC, 1994) and approved OTC drug ingredient, for bronchodilation
(25 mg/dose orally up to 6 times per day, no limit on duration of use) and as a
nasal decongestant (nasal spray) (21 CFR a-d).
Clinical Review
Seven studies conducted on the herb ephedra (327 total
participants) are summarized in the Table of Clinical Studies on Ephedra. One
study on a preparation containing only powdered ephedra measured cardiovascular
effects and pharmacokinetics (White et al., 1997). However, few clinical trials are
based on ephedra as a single ingredient. Most ephedra trials tested
multi-ingredient formulations that include a caffeine-containing herb like cola
nut (Cola nitida) (Boozer et al., 2002; DeJong et al., 2001; Greenway et al., 2000) or guarana (Paullinia cupana) (Belfie et al.¸2001; Boozer et al. 2001). The Boozer et
al., 2002 and 2001 trials focused on weight loss and safety. One small
randomized, crossover trial concluded that the pharmacokinetic properties of
ephedrine in ephedra in dietary supplements were similar to those of synthetic
ephedrine hydrochloride (Gurley et al.,
1998). At least three clinical studies have been conducted on the isolated
alkaloid ephedrine for its use in weight loss (Liu et al., 1995; Astrup et al.,
1986; Pasquali et al., 1985), as
summarized in the Table of Clinical Studies on Ephedra.
[Editors’ note: the
following studies are not listed in the Table of Clinical Studies on Ephedra or
the Table of Clinical Studies on Ephedrine.] Several unpublished trials
employed four different ephedra products (ephedra only, not combinations) on
300 subjects over a period of six weeks and six months, to monitor weight loss
and adverse effects respectively. The studies concluded that ephedra appears to
be safe, effective, and cost-effective; and compares favorably with
pharmaceutical weight loss agents, with a relatively low side effect profile
(Huber, 2001). Clinical trials have been successfully conducted for weight loss
using ephedrine and caffeine combinations (Astrup and Toubro, 1993; Astrup et al., 1992, 1991) and a
much-publicized Danish formula of ephedrine in combination with caffeine and
aspirin demonstrated the relative safety and efficacy of this combination for
weight loss (Daly et al., 1993).
Branded Products
DietMax®: NaturalMax Co./ Kal Inc., Div.
Nutraceutical Corp., 1400 Kearns Blvd. / Park City, Utah 84060 / U.S.A. / Tel:
(800) 669-8877 / www.nutraceutical.com. Each tablet contains 110 mg extract
standardized to 8% ephedra alkaloids, equivalent to 5 mg ephedrine, 50 mg
standardized kola nut extract (equivalent to 10 mg caffeine), 50 mg mustard
seed powder, 50 mg spirulina, 50 mg ascorbic acid (vitamin C), potassium
citrate 25 mg, magnesium aspartate 25 mg.
Escalation™: Enzymatic Therapy / 825 Challenger Drive /
Green Bay, WI 54311 / U.S.A. / Tel:
920-469-1313 / www.enzy.com. Each capsule contains 250 mg cola (Cola nitida) nut extract containing 35
mg of caffeine alkaloids; 250 mg ephedra aerial part extract containing 15mg
concentrated ephedrine group alkaloids in the form of herbal extracts; and 110
mg green tea (Camellia sinensis) leaf
extract containing 15 mg of caffeine alkaloids.
Excel: Excel Corporation / Salt Lake City, UT: no
information available.
Metabolife 356®: Metabolife International, 5070
Santa Fe Street / San Diego, CA 92109 / U.S.A. / Tel: (858) 490-5222 /
www.metabolife.com. Each tablet contains 12 mg of ephedrine group alkaloids and
40 mg of caffeine alkaloids, combined with the following ingredients: Ma huang,
Siberian ginseng (Eleuthero), lecithin, ginger root, damiana, sarsaparilla
root, goldenseal, gotu kola, spirulina, algae, bee pollen, nettle leaf, royal
jelly, bovine complex, 6 I.U. vitamin E, 75 mg magnesium chelate, 5 mg zinc
chelate, and 75 mcg chromium picolinate.
Solaray® Ephedra: Nutraceutical Corp. Each
capsule contains 375 mg powdered ephedra herb calculated at 4.8 mg ephedrine,
1.2 mg pseudoephedrine, 0.3 mg methyl-ephedrine per capsule.
Up Your Gas: National Health Products / 731 South Kirkman
Road / Orlando, FL 32811 / U.S.A. / Tel:
(407) 297-7671. Each capsule contains: 30 IU Vitamin E (as dl-alpha-tocopherol
acetate); 255 mg calcium (as dicalcium phosphate and calcium carbonate); 4.5 mg
magnesium (as magnesium carbonate); 5 mg potassium (as potassium bicarbonate);
and 695 mg Up Your Gas Blend consisting of: guarana concentrate (seed), mahuang
extract (Ephedra sinica) (stem) (285
mg of 6% alkaloid extract), ginseng extract (root), bee pollen, spirulina blue
green algae, gotu kola (leaf), inosine monophosphate,
pyridoxal-alpha-ketoglutarate, wheat grass, cayenne pepper (fruit), lipoic
acid, co-enzyme Q-10, and octacosanol.
References
21 CFRa [Code of Federal Regulations] Sect. 341.76 Food and Drug
Administration, Department of Health and Human Services. Labeling of
Bronchodilator Drug Products.
21 CFRb [Code of Federal Regulations]
Sect. 341.80. Food and Drug Administration, Department of Health and Human
Services. Labeling of Nasal Decongestant Drug Products.
21 CFRc [Code of Federal Regulations] Sect. 341.16 Food and Drug
Administration, Department of Health and Human Services. Bronchodilator Active
Ingredients.
21 CFRd [Code of Federal Regulations]
Sect. 341.20. Food and Drug Administration, Department of Health and Human
Services. Nasal Decongestant Active Ingredients.
Adams E. Statement of Edgar H. Adams, M.S., Sc.D. Submitted to FDA; Docket
No. 98N–0148, cmt. 28, tab A: February
10, 1999.
AHPA. See: American Herbal Products Association.
American Herbal Products Association (AHPA). Policy Statement on Ephedra sinica (Ma huang). Austin, TX,
1994 Mar. 30.
American Herbal Products Association (AHPA), Consumer Healthcare Products
Association, National Nutritional Foods Association, and Utah Natural Products
Alliance. Citizens Petition to FDA on Ephedra Labeling. Oct. 25, 2000.
American Herbal Products Association (AHPA). Code of Ethics and Business Conduct. Silver
Spring (MD): AHPA; 2002 Jul [cited 2002 Nov 13]. Available at: URL:
http://www.ahpa.org/CodeJuly02.pdf.
Anonymous. NFL bans ephedrine, other stimulants. NFL News 2001c Sept 27.
Available from:URL: http://www.nfl.com/news/2001/ephedrine092701.html.
Anonymous. Obesity becoming top threat to health. Los Angeles Times article published in Austin American-Statesman, Dec. 14, 2001a.
Anonymous. U.S. warning of death toll from obesity. Associated Press in New York Times. Dec. 14, 2001b.
Astrup A. Thermogenesis in human brown adipose tissue and skeletal muscle
induced by sympathomimetic stimulation.
Acta Endocrinol 1986(suppl.);278:1-32.
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 Obesity
1992;16:269–77.
Astrup A, Madsen J, Holst JJ, Christensen NJ. The effect of chronic
ephedrine treatment on substrate utilization, the sympathoadrenal activity, and
energy expenditure during glucose-induced thermogenesis in man. Metabolism 1986;35(3):260–5.
Astrup A, Toubro S. Thermogenic, metabolic, and cardiovascular responses to
ephedrine and caffeine in man. Int J
Obesity 1993;17 (suppl):S41–3.
Astrup A, Toubro S, Cannon S et al.
Thermogenic synergism between ephedrine and caffeine in healthy volunteers: A
double-blind, placebo-controlled study. Metabolism
1991;40(3):323–9.
BAnz. See: Bundesanzeiger.
Belfie L, Petrie H, Chown S et al.
Safety and effectiveness of an herbal dietary supplement containing ephedra (ma
huang) and caffeine (guarana extract) when used in combination with a
supervised diet and exercise intervention [presentation abstract]. Obesity Research 2001;9(S3):26.
Bell DG, McLellan TM, Sabiston CM. Effect of ingesting caffeine and
ephedrine on 10-km run performance. Med
Sci Sports Exerc 2002;34(2):344–9.
Bell DG, Jacobs I, Ellerington K. Effect of caffeine and ephedrine
ingestion on anaerobic exercise performance. Med Sci Sports Exerc 2001;33(8):1399–403.
Bell DG, Jacobs I, McLellan TM, Zamecnik J. Reducing the dose of combined
caffeine and ephedrine preserves the ergogenic effect. Aviat Space Environ Med 2000;71(4):415–9.
Bell DG, Jacobs I, McLellan TM, Miyazaki M, Sabiston CM. Thermal regulation
in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med
1999a;70(6):583–8.
Bell DG, Jacobs I. Combined caffeine and ephedrine ingestion improves run
times of Canadian forces warrior test. Aviat
Space Environ Med 1999b Apr;70(4):325-9.
Bell DG, Jacobs I, Zamecnik J. Effects of caffeine, ephedrine and their
combination on time exhaustion during high intensity exercise, Eur J Appl Physiol 1998:77:427-33.
Bensky D, Gamble A. Chinese Herbal
Medicine Materia Medica. Revised (ed.). Seattle, WA: Eastland Press;1993.
Blanck HM, Khan LK, Serdula MK. Use of nonprescription weight loss products:
results from a multistate survey. JAMA 2001;286(8):930-5.
Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, Rister
RS (eds.). Klein S, Rister RS (trans.). The
Complete German Commission E
Monographs—Therapeutic Guide to Herbal Medicines. Austin, TX: American
Botanical Council; Boston: Integrative Medicine Communication; 1998.
Blumenthal M, Goldberg A, Brinckmann J. Herbal
Medicine—Expanded Commission E
Monographs. Austin: American Botanical Council; Boston, MA: Integrative
Medicine Communication; 2000.
Blumenthal M, King P. The agony of the ecstasy: Herbal high products get
media attention. HerbalGram 1996;
37:20-24,32,49.
Blumenthal M, King P. Ma Huang: Ancient herb, modern medicine, regulatory
dilemma. HerbalGram 1995;34:22–27,42–3,56–7.
Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Sanner JA, et al. Herbal ephedra/caffeine for
weight loss: a 6-month randomized safety and efficacy trial. Int J Obes 2002;26:593-604.
Boozer C, Nasser J, Heymsfield S, Wang V, Chen G, Solomon J. An herbal
supplement containing ma huang-guarana for weight loss: a randomized,
double-blind trial. Intl J Obesity 2001
Mar;25(3):316–24.
Brinker F. Herb Contraindications and
Drug Interactions, 3d ed. Sandy, OR: Eclectic Medical Publications; 2001:87–90.
Bruneton J. Pharmacognosy,
Phytochemistry, Medicinal Plants. Paris, France: Lavoisier Publishing;
1995;711–4.
Bundesanzeiger (BAnz). Monographien der Kommission E
(Zulassungs- und Aufbereitungskommission am BGA für den humanmed. Bereich,
phytotherapeutische Therapierichtung und Stoffgruppe). Köln:
Bundesgesundheitsamt (BGA); 1998.
Cantox Health Sciences International (CHSI). Safety assessment and
determination of a tolerable upper limit for ephedra. December 2000.
http://www.crnusa.org/ CRNCantoxreportindex.html.
Chang H, But P (eds.). Pharmacology
and Applications of Chinese Materia Medica, Vol. 1. Philadelphia, PA: World
Scientific;1986:1119–24.
CHSI. See: Cantox Health Sciences International.
Code of Federal Regulations. See: 21 CFR.
DAB. See: Deutsches Arzneibuch.
Daly PA, Krieger DR, Dulloo AG et al.
Ephedrine, caffeine, and aspirin: safety and efficacy for treatment of human
obesity. Int J Obesity 1993;17
(suppl):S73–8.
De Jonge L, Frisard M, Blanchard D, Greenway F. Safety and efficacy of an
herbal dietary supplement containing caffeine and ephedra for obesity
treatment. Obesity Research
2001;9(S3):20.
Denham A. The 1968 Medicines Act ~ Schedule 3 herbs, and their use by
practitioners. Eur J Herbal Med
1998;4(3):19–28.
Der Marderosian A (ed.). The Review
of Natural Products. St. Louis: Facts and Comparisons; 1999.
Deutsches Arzneibuch (DAB 1999).
Stuttgart, Germany: Deutscher Apotheker Verlag;1999.
Dvorak R, Starling RD, Calles-Escandon J et al. Drug therapy for obesity in the elderly. Drugs Aging 1997;11:338-51.
EEC. See: Ephedra Education Council.
Ephedra Education Council (EEC). Comments of the Expert Panel of the
Ephedra Education Council on the Safety of Dietary Supplements Containing
Ephedrine Alkaloids and on the Adverse Event Reports (AERs) and Health
Assessments Released by the Food and Drug Administration (FDA) on April 3,
2000. Submitted to FDA; Docket No. 00N-1200: September 29, 2000.
FDA. See: Food and Drug Administration.
Fleming T. PDR for Herbal Medicines.
Montvale, NJ: Medical Economics Co.; 1998.
Food and Drug Administration (FDA). Dietary Supplements Containing
Ephedrine Alkaloids: Proposed Rule. Federal
Register 1997;62(107):30678–717.
Food and Drug Administration (FDA).
FDA announces the availability of new ephedrine and “street drug
alternative” documents. FDA Talk Paper; 2000 Mar 31 [cited 2002
Jul 3]. Available from: URL:
http://www.cfsan.fda.gov/~lrd/ tpephedr.html.
GAO. See: General Accounting Office.
Geissler CA. Effects of weight loss, ephedrine and aspirin on energy expenditure
in obese women. Int J Obes Relat Metab
Disord 1993;17 (suppl. 1):S45-8.
General Accounting Office (GAO). Dietary Supplements: Uncertainties in
Analyses Underlying FDA’s Proposed Rule on Ephedrine Alkaloids. Washington, DC:
United States General Accounting Office; 1999 July.
Greenway F. The safety and efficacy of pharmaceutical and herbal caffeine
and ephedrine use as a weight loss agent. Obesity
Rev 2001;2:199-211.
Greenway F, Raum W, DeLany J. The effect of an herbal dietary supplement
containing ephedrine and caffeine on oxygen consumption in human. J Alt Compl Med 2000;6(6):553–5.
Grüninger T. Traditional Chinese Medicine in ENT. [in German]. HMO Aktuell 1992;3:3.
Gurley B. Extract versus herb: effect of formulation on the absorption rate
of botanical ephedrine from dietary supplements containing Ephedra (ma huang). Ther Drug Monitoring 2000;22(4):497.
Gurley B, Gardner S, White L, Wang P. Ephedrine pharmacokinetics after the
ingestion of nutritional supplements containing Ephedra sinica (ma huang). Ther
Drug Monit 1998 Aug;20(4):439–45.
Haller C, Benowitz N. Adverse cardiovascular and central nervous system
events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000 Dec 21;343(25):1833–8.
Hardman J, Limbird L, Molinoff P, Ruddon R, Gilman A (eds.). Goodman and Gilman’s The Pharmacological
Basis of Therapeutics, 9th ed. New York: MacMillan Publishing;1996:221.
Harnack LJ, Rydell SA, Stang J. Prevalence of use of herbal products by
adults in the Minneapolis/St. Paul, Minn, metropolitan area. Mayo Clin Proc 2001;76(7):688–94.
Hathcock JN. CRN’s Cantox Report on the Quantitative Risk Assessment of
Ephedra. HerbalGram 2001;53:31–3.
Health & Human Services (HHS).
HHS announces plans to study ephedra: steps up enforcement of illegal
ephedrine marketing [press release].
HHS; 2002 Jun 14 [cited 2002 Jul 3].
Available from: URL: http://www.hhs.gov/news/press/
2002pres/20020614.html.
Health Canada. Ephedra. In: Drug
Product Database (DPD). Ottawa, Ontario: Health Canada Therapeutic Products
Programme; 2001.
Health Canada. Ephedra. In: Herbs
Used as Non-medicinal Ingredients in Non-prescription Drugs for Human Use.
Appendix II: List of Herbs Unacceptable as Non-medicinal Ingredients in Oral
Use Products Subject to Part B. Ottawa, Ontario: Health Canada Therapeutic
Products Programme; 1995 Sept 22:6–15.
Health Canada. Labelling Standard:
Ephedra. Ottawa, Canada: Health Canada Drugs Directorate; 1996:1–4.
Heber D, Greenway F. Herbal and Alternative Approaches to Obesity. In: Bray
GA, Bouchard C (eds.). Handbook of
Obesity 2d ed. New York: Marcel Dekker, 2002. (in press).
HHS. See: Health & Human Services.
Hikino H, Kiso Y, Ogata M, Konno C, et
al. Pharmacological actions of analogues of feruloyl-histamine, an
imidazole alkaloid of ephedra roots. Planta
Med 1984;50(6):478–80.
Hikino H, Ogata K, Konno C, Sato S. Hypotensive actions of ephenadrines,
macrocyclic spermine alkaloids of ephedra roots. J Med Plant Res 1983;48:290–3.
Hikino H, Konno C, Takata H, Tamada M. Anti-inflammatory principle of
ephedra herbs. Chem Pharm Bull 1980;28:2900–4.
Horton TJ, Geissler CA. Aspirin potentiates the effect of ephedrine on the
thermogenic response to a meal in obese but not lean women. Int J Obes 1991;15:359-66.
Hsu H. Oriental Materia Medica.
Oriental Healing Arts Institute; 1986.
Huang K. The Pharmacology of Chinese
Herbs, 2nd edition. Boca Raton, FL: CRC Press LLC; 1999:291–300.
Huber G. Preliminary results from clinical trials on ephedra dietary
supplements (unpublished). Personal communication to M Blumenthal, Dec 18,
2001.
Hutchins GM. Dietary supplements containing ephedra alkaloids [letter]. N Engl J Med 2001 Apr
5;344(14):1095–6;discussion 1096–7.
Indian Pharmacopoeia (IP, 1996),
Vol. I (A-O). Delhi, India: Controller of Publications Government of India
Ministry of Health & Family Welfare; 1996:282–5.
International Olympic Committee (IOC). Prohibited classes of substances and
prohibited methods 2001–2002. September, 2001. Available from: URL:
http://www.wada-ama.org/asiakas/003/wada_english.nsf/Home?/OpenPage.
IOC. See: International Olympic Committee
IP. See: Indian Pharmacopoeia.
Jaedig S, Henningsen NC. Increased metabolic rate in obese women after
ingestion of potassium, magnesium- and phosphate-enriched orange juice or
injection of ephedrine. Int J Obes
1991;15:429-36.
Japanese Pharmacopoeia (JP XII).
Tokyo, Japan: The Society of Japanese Pharmacopoeia; 1991.
Japanese Standards for Herbal
Medicines (JSHM). Tokyo, Japan: Yakuji Nippo, Ltd.; 1993:107–8.
Jonderko K, Kucio C. Effect of anti-obesity drugs promoting energy
expenditure, yohimbine and ephedrine, on gastric emptying in obese patients. Aliment Pharmacol Ther 1991;5:413-8.
Jones D. Thermogenesis: Theoretical and practical implications of
thermogenic agents as aids to weight loss. Unpublished, 2001.
JP. See: Japanese Pharmacopoeia.
JSHM. See: Japanese Standards for Herbal Medicines.
Jubiz W, Meikle A. Alterations of glucocorticoid actions by other drugs and
disease states. Drugs 1979;18:113–21.
Kimmel S. Summary of incidence of
seizures, strokes, and myocardial infarctions in the population and estimations
of risk in the population from ephedra products. Submitted to FDA; 2000 Aug [cited 2002 Jul
3]. Available from: URL:
http://ephedrafacts.com/2.html.
Lawlor A. Health Canada recalls certain Ephedra products. Globe and Mail, Jan. 9, 2002.
Leikin J, Klein L . Ephedra causes myocarditis. J Toxicol Clin Toxicol 2000;38 (3):353–4
Leung A. Personal communication to M. Blumenthal. 1999, July 7th.
Leung A, Foster S. Encyclopedia of
Common Natural Ingredients Used in Food, Drugs and Cosmetics, 2nd ed. New
York, NY: John Wiley & Sons, Inc.; 1996.
Ling M, Piddlesden SJ, Morgan BP. A component of the medicinal herb ephedra
blocks activation in the classical and alternative pathways of complement. Clin Exp Immunol 1995 Dec;102(3):582–8.
Liu Y, Toubro S, Astrup A, Stock M. Contribution of Beta-3-adrenoceptor
activation to ephedrine-induced thermogenesis in humans. Intl J Obesity 1995;19:678–85.
McGuffin M. Statement before Department of Health & Human Services
Office of Public Health & Sciences, Public Meeting on the Safety of Dietary
Supplements Containing Ephedrine Alkaloids; 2000 Aug 8; Washington DC.
McGuffin M, Hobbs C, Upton R, Goldberg A. (eds.). American Herbal Products Association’s Botanical Safety Handbook
Boca Raton, FL: CRC Press; 1997.
Medical Products Agency (MPA). Läkemedel:
Läkemedelsnära Produkter (registrerade homeopatiska produkter). Uppsala,
Sweden: Medical Products Agency; 2001b.
Medical Products Agency (MPA). Naturläkemedel:
Authorised Natural Remedies (as of January 24, 2001). Uppsala, Sweden:
Medical Products Agency; 2001a.
Molnar D, Torok K, Erhardt E, Jeges S. Safety and efficacy of treatment
with an ephedrine/caffeine mixture. The first double-blind placebo-controlled
pilot study in adolescents. In J Obes
Relat Metab Disord 2000;24(12):1573-8.
Morton J. Major Medicinal Plants:
Botany, Culture and Uses. Springfield, IL: Charles C. Thomas; 1977.
MPA. See: Medical Products Agency.
Nasser J, et al. Efficacy trial
for weight loss of an herbal supplement of ma huang and guarana. FASEB J 1999;13(5).
National Collegiate Athletic Association (NCAA) 2001–2002 NCAA banned-drug
classes. Updated 2001 Aug 9. Available from: URL: http://www.ncaa.org/
sports_sciences/drugtesting/banned_list.html.
NCAA. See: National Collegiate Athletic Association.
Noguchi M, Kubo M, Naka Y. Studies on the pharmaceutical quality evaluation
of crude drug preparations used in the Oriental Medicine “Kampo”. IV. Behavior
of alkaloids in ephedra herb mixed with other crude drugs under decoction
processes. [in Japanese]. Yakugaku Zasshi
1978;98(7):923–8.
Office on Women’s Health. Safety of dietary supplements containing
ephedrine alkaloids [report on public meeting of 8-9 Aug 2000]. The National
Women’s Health Information Center; 2000 Sep [cited 14 Nov 2002]. Available at:
http://www.4woman.gov/owh/public/report.htm.
OWH. See: Office on Women’s Health.
Pasquali R, Casimirri F. Clinical aspects of ephedrine in the treatment of
obesity. Int J Obes Relat Metab Disord
1993;17 (suppl 1):S65-8.
Pasquali R, Baraldi G, Cesari M et
al. A controlled study using ephedrine in the treatment of obesity. Intl J Obesity 1985;9(2):93–8.
Pharmacopoeia of the People’s Republic of China (PPRC
1997 English Edition). Beijing, China: Chemical Industry Press. 1997;92–93.
PPRC. See: Pharmacopoeia of the
People’s Republic of China.
Robbers J, Tyler V. Tyler’s Herbs of
Choice: The Therapeutic Use of Phytomedicinals. New York: Haworth Herbal
Press; 1999;112–6.
Ruppanner H, Schaefer U (eds.). Codex
2000/01 — Die Schweizer Arzneimittel in einem Griff. Basel, Switzerland:
Documed AG; 2000.
Samenuk D, Link MS, Homoud MK et al.
Adverse cardiovascular events temporarily associated with ma huang, an herbal
source of ephedrine. Mayo Clin Proc 2002;77:12-6.
Svendsen TL, Ingerslev J, Mork A. Is Letigen contraindicated in
hypertension? A double-blind, placebo controlled multipractice study of Letigen
administered to normotensive and adequately treated patients with
hypersensitivity. Ugeskr Laeger
1998;160:4073-5, cited in Heber D, Greenway F. Herbal and Alternative
Approaches to Obesity. In: Bray GA, Bouchard C (eds.) Handbook of Obesity 2d ed. NewYork: Marcel Dekker, 2002. (in
press).
Tang W, Eisenbrand G. Chinese Drugs
of Plant Origin. New York: Springer-Verlag; 1992;481–90.
Texas Medical Association. TMA Policy Compendium 260.057 Regulation of
Ephedrine Products; 260.058 Labeling of Ephedrine Products. Austin, TX.
TGA. See: Therapeutic Goods Administration.
TMA. See: Texas Medical Association.
Therapeutic Goods Administration (TGA). Commonly
Asked Questions: Why are some substances available without a prescription
overseas but are controlled substances in Australia? Woden, Australia: TGA;
2001.
Tsumura Co., Ltd. Science and expert know how join forces to maintain the
quality of raw herbs. Kampo Today
1996;1(3):1–2.
United States Congress (USC). Public Law 103–417: Dietary Supplement Health and Education Act of 1994. Washington,
DC: 103rd Congress of the United States; 1994.
USC. See: United States Congress.
Weiner N. Norepinephrine, Epinephrine and the Sympathomimetic Amines. In:
Goodman A et al. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8th
edition. New York, NY: MacMillan; 1985;169–70.
Weiss R. Herbal Medicine.
Beaconsfield, England: Beaconsfield Publishers; 1988.
Weiss R, Fintelmann V. Herbal
Medicine 2nd ed. New York: Thieme; 2000:209.
White L,M, Gardner SF, Gurley BJ et
al. Pharmacokinetics and cardiovascular effects of ma huang (Ephedra sinica) in normotensive adults.
J Clin Pharmacol 1997;37:116–22.
WHO. See: World Health Organization.
Wilkinson GR, Beckett AH. Absorption, metabolism and excretion of the
epinedrines in man. II. Pharmacokinetics. J
Pharm Sci 1968 Nov;57(11):1933–8.
World Health Organization (WHO). Herba Ephedrae. In: WHO Monographs on Selected Medicinal Plants, Vol. 1. Geneva: World
Health Organization; 1999:145–53.
Zaacks S, Klein L, Tan C, Rodriguez E, Leikin J. Hypersensitivity
myocarditis associated with ephedra use.
J Toxicol Clin Toxicol 1999;37(4):485–9.
Zhu Y. Chinese Materia Medica.
Australia: Harwood Academic Publishers; 1998.