Ephedrine alkaloid dietary supplements - National Toxicology

41 Pages·2002·0.25 MB·English

SUMMARY OF DATA FOR CHEMICAL SELECTION
Dietary Supplements Containing Ephedrine Alkaloids
BASIS OF NOMINATION
Dietary supplements containing ephedrine alkaloids from herbal sources (ephedra) are brought to
the attention of the CSWG as part of an ongoing National Institutes of Health (NIH) Office of
Dietary Supplements (ODS) research initiative on the safety and efficacy of these products. This
initiative was recommended by the Senate Committee on Appropriations in fiscal year (FY) 2001.
In its Report making FY 2002 appropriations for the Department of Health and Human Services,
the Committee expressed pleasure that the ODS followed through on its FY 2001 recommendation
and urged the ODS to continue and expand this important effort. The nomination of ephedra­
containing supplements to the National Toxicology Program (NTP) is part of the expanded effort
by the ODS.

As the Senate Committee noted, the number of Americans taking dietary supplements containing
ephedra has risen dramatically. Dietary supplements containing herbal ephedra (chiefly Ephedra
sinica Stapf.) are widely used as diet aids and athletic performance enhancers, with over 3 billion
servings1 sold each year for weight loss alone. The active ingredients in these supplements are
primarily ephedrine and pseudoephedrine with small amounts of other ephedrine alkaloids usually
present. Ephedra-based diet aids often contain other stimulants, such as caffeine (guarana), as well
as salicin, diuretics, and cathartics. Ephedra-containing performance enhancers often contain
caffeine and other ingredients, such as chromium picolinate or l-carnitine, and may be consumed
with other performance enhancers, such as androstenedione and creatine monohydrate.

The ephedrine alkaloids are sympathomimetic amines, a class of compounds with fairly well
characterized short to medium term biological activities. Specific combinations of synthetic
ephedrine and caffeine have been used as prescription drugs in Europe, and were formerly available
in the US until they were withdrawn by the FDA in 1992 for reasons of safety. Very little is known
1Dose or portion, in this case, is referred to as a “serving” because diet aids are defined as foods.
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about the possible interactions between herbal ephedra and biologically active compounds in the
other plant species that are constituents of many dietary supplements. Some agents, often
components of herbal preparations at far greater concentrations than the ephedrine alkaloids, may
profoundly influence the toxicity attributed to ephedra supplements.
Limited information suggests that ephedrine may cause fetal heart defects, a matter that needs
further examination since dietary supplements containing ephedrine alkaloids are readily available
even though the manufacturers caution against their use during pregnancy.
Ephedrine sulfate and caffeine, tested separately, were both negative for carcinogenic activity. The
National Cancer Institute (NCI), through the Chemical Selection Working Group (CSWG), recently
submitted several other ingredients commonly found in combination with ephedrine alkaloid sports
supplements to the National Toxicology Program for toxicological testing. These include chromium
picolinate, androstenedione, and yohimbe bark extract.
INPUT FROM GOVERNMENT AGENCIES/INDUSTRY:
Dr. Paul Coates, Director of the NIH Office of Dietary Supplements, provided information on
existing studies of ephedra.
SELECTION STATUS:
Action By CSWG: 12/11/01
Studies requested:
- Reproductive and developmental toxicity studies
- Comparative toxicological evaluation using ephedra, ephedra and natural caffeine products,
and other combinations of ephedra/herbal remedies with an emphasis on the heart and central
nervous system
Priority: High
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Rationale/Remarks:
- Herbal ephedrine alkaloids (ma huang) combined with other herbal products are widely used
as diet aids and for performance enhancement.
- Concern that naturally occurring non-ephedrine alkaloid constituents of Ephedra spp. may
have toxicologic significance.
- Concern that the herbal combinations used as dietary supplements may possess toxicity not
seen from administration of synthetic ephedrine/caffeine combinations.
- Emphasize testing of products/combinations actually marketed to consumers as dietary
supplements.
- Priority for testing should be given to combinations of herbals used as diet aids.
- Involve the NIH Office of Dietary Supplements and the FDA in study design of to ensure
that the testing performed addresses their concerns.
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Ephedrine alkaloids
CHEMICAL IDENTIFICATION
CAS Registry Number: Ephedrine alkaloids: none
l-Ephedrine; (-)-ephedrine: 299-42-3
d-Pseudoephedrine; (+)-pseudoephedrine: 90-82-4
CAS Name: None
Synonyms and Trade Names: Chinese Ephedra, Chinese Jointfir, herbal ephedra, ma
huang
Structural Class: Botanical mixture
Structure, Molecular Formula and Molecular Weight:

This information is provided for the main active ingredients in ephedrine alkaloid supplements.

OH
OH
H
H
N
N
CH
CH 3
3
CH
CH 3
3
l-Ephedrine d-Pseudoephedrine
C H NO Mol. wt.: 165.23
10 15
Chemical and Physical Properties: The information provided in Table 1 includes the main active
ingredients in ephedrine alkaloid supplements and some of their common salts.
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Ephedrine alkaloids
Table 1. Chemical & Physical Properties of Some Ephedrine Alkaloids.
d,l-Ephedrine Crystals; mp 79EC; sol in water, alcohol, ether, chloroform, oils
l-Ephedrine Waxy solid, crystals, or granules; soapy feel; mp 34EC (absorption of water
raises mp to 40EC; sol in water, alcohol, ether, chloroform, oils
d,l-Ephedrine hydrochloride Crystals; mp 187-188EC; sol in water, alcohol, insol in ether
l-Ephedrine hydrochloride Orthorhombic needles; affected by light; mp 216-220EC; sol in water, alcohol,
insol in ether or chloroform
d,l-Pseudoephedrine Crystals, mp 118EC
(+)-Pseudoephedrine Rhombic tablets from ether; mp 119EC; sparingly sol in water, sol in alcohol or
ether
(+)-Pseudoephedrine Needles; mp 181-182EC; sol in water, alcohol, chloroform
hydrochloride
Source: Merck, 2000
Technical Products and Impurities: In the United States, ephedrine alkaloid dietary supplements
contain herbal ephedra extracts, not synthetic ephedrine even though ephedrine is the principal
active ingredient. Pure or synthetic ephedrine is considered to be a drug, not a dietary
supplement; in fact, a company was recently fined, and all of its product seized, for “spiking”
its ma huang-containing extracts with synthetic ephedrine (Coates, 2001).
The most commonly used herbal ephedra, ma huang contains total ephedrine alkaloids at 0.5­
2.5% by weight; ephedrine accounts for 30-90% of these alkaloids (Lee et al., 2000). Because
of the variation in content, ma huang is mostly used as an extract, concentrated to about 6%
alkaloids (American Herbal Products Association, 1999). The alkaloid pattern can often lead
to identification of the species, the geographical area where it grew and the climatic conditions,
while atypical patterns can suggest that a ma huang sample is “fake”, made from
pharmaceutical raw materials (American Herbal Products Association, 1999).
Twenty commercially available diet aids containing ephedrine alkaloids were tested by HPLC
procedures. Ephedrine and pseudoephedrine in a 2:1 ratio accounted for 96-98% of the
ephedrine alkaloid content. Norephedrine (phenylpropanolamine) content was less than 2%
of the total ephedrine alkaloid content. Additional ephedrine alkaloids, (+)-norpseudoephedrine
(cathine), a Schedule IV controlled substance, and methylephedrine have been identified in
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Ephedrine alkaloids
small amounts in ma huang and in extracts prepared from ma huang (CANTOX, 2000; Gurley
et al., 2000; Kalix, 1991; Lwanami et al., 1985).
Among the 20 dietary supplements examined, ephedrine alkaloid content varied considerably
suggesting that industry standards are often not met by individual supplements. Total alkaloid
content ranged from 0.0 to 18.5 mg per dosage unit. Ranges for (-)-ephedrine and (+)­
pseudoephedrine were 1.1-15.3 mg and 0.2-9.5 mg, respectively. Significant lot-to-lot
variations in alkaloid content, from 44 to 260% of label claim, were also observed. Half the
products exhibited discrepancies between the label claim for ephedrine alkaloid content and
actual alkaloid content in excess of 20% (CANTOX, 2000; Gurley et al., 2000).
Most ephedra product labels indicate the amount of ephedra herb or extract contained in each
dosage form; however, not all make a claim of ephedrine alkaloid content (CANTOX, 2000).
Dietary supplements containing ephedrine alkaloids generally contain a host of other botanical
ingredients. Kola nut and guarana are used as natural caffeine sources; St. John’s Wort, white
willow bark (salicin), diuretics, or cathartics are also often included (CANTOX, 2000).
Performance enhancers may include chromium picolinate or l-carnitine (Karch, 2000).
Yohimbine is sometimes added (Bucci, 2000).
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Prepared for NCI by Technical Resources International, Inc. to support chemical nominations under contract no. N02-CB-07007 (10/01)
Ephedrine alkaloids
EXPOSURE INFORMATION
Production and Producers: Dietary supplements containing botanical sources of ephedrine
alkaloids are marketed for weight loss and increased energy. These products are available
in a variety of forms, including pills, powders, liquid drops, and teas (GAO, 1999).
Herbal ephedra products are sold via traditional retail chains (drug stores, health food
stores, etc.), mail-order catalogs, and direct sales distribution networks. Industry sources
estimate that there are over 500,000-750,000 independent distributors of dietary
supplements that contain herbal ephedra (Pape et al., 1999).
Most companies marketing herbal ephedra are privately held and do not report sales and
earnings figures to the public. Nevertheless, retail sales of these dietary supplement
products are conservatively estimated to exceed $1.5 - $2 billion per year (Pape et al.,
1999).

In testimony to the Office on Women’s Health, industry sources estimated that 3 billion
doses of ephedra-containing products are sold in the United States annually. This figure
appears to be low. The American Herbal Products Association contacted 42 companies
known to distribute dietary supplements containing ephedrine alkaloids. The 13
companies that responded reported aggregate figures of 3,086,041,072 servings sold in
1999. Metabolife International reported that projected sales of one ephedrine alkaloid
weight-loss product, Metabolife 356®, were nearly 2 billion caplets in that same year
(Anon., 1999; CANTOX, 2000; Office on Women’s Health, 2000).
Use Pattern: Ma huang is derived from Ephedra sinica Stapf, E. intermedia Schrenk et C.A.
Mey, and E. equisetina Bunge (Ephedraceae). North American and Central American
types are alkaloid free (American Herbal Products Association, 1999).
A traditional Chinese medicine, it has been used for about 5000 years to treat asthma,
nose and lung congestion, and fever with anhidrosis. Ma huang’s traditional use to treat
cough and respiratory infections may be related to 4-quinolone-2-carboxylic acid
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Ephedrine alkaloids
(transtorine) which inhibits the growth of several common bacteria. Large quantities of
ma huang are now used as a source of ephedrine in dietary supplements formulated to
promote weight loss. Ma huang products sold for weight control often contain other
stimulants, such as caffeine, which may have synergistic effects and increase the potential
for adverse effects (American Herbal Products Association, 1999; Botanical Dermatology
Database, 2001; FDA, 1993; Office on Women’s Health, 2000; Karch, 2000; Lee et al.,
2000).
The best selling herbal weight-loss product is Metabolife 356® (Anon., 1999). According
to its manufacturer, Metabolife 356® contains vitamin E, magnesium chelate, zinc
chelate, chromium picolinate, guarana (seed), ma huang extract, bee pollen, Siberian
ginseng (root), ginger root, lecithin, bovine complex, damiana (leaf), sarsaparilla root,
goldenseal, nettle leaf, gotu kola, spirulina, Royal jelly, citric acid, glycine, caffeine,
croscarmellose sodium, protein hydrolysate, silica, modified cellulose, magnesium
stearate, dextrin, dextrose, sodium carboxymethylcellulose, sodium citrate, and ascorbic
acid (Metabolife, 2001). The exact amounts of each ingredient are proprietary, but each
tablet contains 12 mg of ephedrine alkaloids and 40 mg of caffeine alkaloids (Metabolife,
2001).
Ephedrine alkaloid/caffeine products are used by some athletes to enhance physical
performance, especially bodybuilders who want to maximize body fat loss while
maintaining muscle mass (Bucci, 2000). Ephedra is often taken along with other sports
nutrition supplements, especially androstenedione and creatine monohydrate (Consumers
Union, 2001).
l-Ephedrine sulfate has FDA approval as an over-the-counter (OTC) medication for use
in asthma patients. An α + β adrenergic agonist, ephedrine functions as a bronchodilator.
Isolated and synthesized in 1885, ephedrine became a first-line drug against asthma in the
1930s, although this no longer appears to be an important use of ephedrine. Unlike the
other alkaloid drugs, ephedrine is also a potent central nervous system (CNS) stimulant
that has been used as a drug of abuse, much like methamphetamine (McEvoy, 2000;
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Prepared for NCI by Technical Resources International, Inc. to support chemical nominations under contract no. N02-CB-07007 (10/01)
Ephedrine alkaloids
Karch, 2000; Office on Women’s Health, 2000).
In the past, ephedrine was used to treat Stokes-Adams attacks with complete heart block
and as a CNS stimulant in narcolepsy and depressive states. Ephedrine has been used to
treat the hypotension that may occur with spinal anesthesia (McEvoy, 2000).
As an alternative for the structurally related illegal drug, Ecstasy (4-methyl-2-dimethoxy­
amphetamine, MDMA), ephedra supplements are sometimes sold outside usual channels
of commerce and marketed specifically to young adults to achieve a legal high (FDA,
2000). These products may be spiked with synthetic ephedrine alkaloids and combined
with other stimulants such as caffeine (Bucci, 2000). One of these products, Cloud 9, was
labeled as containing 650 mg of Indonesian ma huang extract per capsule with a
recommended dose of 1-2 capsules 30-35 minutes before activity (Blumenthal & King,
1996).
The FDA considers Herbal Ecstasy to be a street drug alternative, not a dietary
supplement. Since street drug alternatives have a potential for abuse, FDA considers
them to be unapproved new drugs and misbranded drugs under sections 505 and 502of
the Federal Food, Drug, and Cosmetic Act (FDA, 2000; US Department of Health and
Human Services, 1996).
Human Exposure: The two main groups that use ephedra products are young to middle age,
overweight individuals, and young individuals engaged in exercise programs (Office on
Women’s Health, 2000).
Results of the National Health and Nutrition Examination Survey (NHANES) in 1999
indicate that an estimated 61% of US adults are either overweight or obese. In adults
aged 20-74 years, obesity has nearly doubled from approximately 15% in 1980 to 27%
in 1999 (CDC, 2001). According to industry sources, Americans spend more than $30
billion a year on diet-related products and services related to obesity treatment (Office
on Women’s Health, 2000).
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Ephedrine alkaloids
Ephedra supplement labels warn customers not to use herbal ephedra for more than 12
weeks. An industry spokesperson testified before the Office on Women’s Health that
this warning label is needed to comply with state laws and is not regarded by the industry
as scientifically based (Office of Women’s Health, 2000). On the other hand, there have
been no published studies in which subjects have been given ephedra for longer than 12
weeks (Coates, 2001). Metabolife International advertises a “preferred customer”
program that ships Metabolife 356® automatically every month without a specified time
limit (Metabolife, 2001).
A typical ephedra supplement for weight loss contains approximately 12 mg of ephedrine
alkaloids per oral serving with a maximum daily intake of 96 mg recommended. Some
products include as much as 20 mg of ephedra per dose, but those products recommend
consumption of no more than 100 mg/day (Office on Women’s Health, 2000).
No information was found in the available literature on the number of persons taking
ephedrine alkaloid diet aids. If 3 billion servings are taken at a rate of 8 per day for 12
weeks in the course of one year, then over 370,000 persons would be exposed annually
for purposes of weight loss alone.
According to Nutrition Business Journal, 4% of American adults have taken a sports
supplement at least once and 1.2 million use them regularly. According to a 1999 survey
by Blue Cross/Blue Shield, 6% of youths 15-16 and 8% of those 17-18 have taken sports
supplements; the vast majority of users were male. Although ephedra was mentioned as
one of the most popular supplements, estimates of the actual number of persons taking
ephedra supplements for performance enhancement were not provided. Ephedra is often
taken along with other sports nutrition supplements, e.g., androstenedione and creatine
monohydrate (Consumers Union, 2001; Council for Responsible Nutrition, 2001).
Ripped Fuel by Twin Labs is a popular supplement used by bodybuilders that contains
ma huang, guarana, l-carnitine, and chromium picolinate. Another popular product is
AST Research’s EPH 833, composed mainly of ma huang. The ephedrine content of this
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Prepared for NCI by Technical Resources International, Inc. to support chemical nominations under contract no. N02-CB-07007 (10/01)