The Safety of Ephedra
and Related Alkaloids

Volume VI, Number 2 | March/April 2003
Amy Dickson, Pharm.D., BCPS

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The death of a 23-year-old Baltimore Orioles pitcher has many consumers and health professionals concerned about the safety of ephedra. Steve Bechler fatally collapsed from heat stroke on February 16, 2003 after using supplements containing ephedra. The postmortem toxicology report stated that a considerable amount of ephedrine (active ingredient in ephedra) was present in his blood when he collapsed and died. Ephedra, a dietary supplement found in many weight loss and performance enhancement products, has recently been examined for its safety.

This update will review the pharmacology of ephedra and discuss the issues surrounding the safety profile of this supplement.

Ephedra has been known in China for more than 5,000 years and utilized in Traditional Chinese Medicine and its Japanese counterpart, Kampo medicine. All ephedra plant species have a distinct pine odor and astringent taste, but not all produce alkaloids (i.e., active ephedra constituents). Alkaloid-containing species are found in temperate and subtropical regions of Europe and Asia, but North and Central American types appear to be alkaloid free. Ma Huang, Chinese Ephedra, and epitonin are common names used for ephedra; Miner's Tea, Yellow Astringent, and Sea Grape are examples of ephedra's less common names. There are many products that contain ephedra, and some well-known brands include Metabolife 356®, Xenadrine®, and Metab-O-Lite®.

When an ephedra-containing product is purchased, a consumer may not realize what ephedra actually consists of. The ephedra plant contains six active alkaloids. These alkaloids include ephedrine, pseudoephedrine, norephedrine [or phenylpropanolamine (PPA)], methylephedrine, norpseudoephedrine, and methyl-pseudoephedrine. Exact amounts of each alkaloid can vary between species, however, ephedrine is the predominant alkaloid, followed by pseudoephedrine.

Many non-prescription, FDA-regulated products contain ephedrine, pseudoephedrine, or norephedrine (PPA). However, no conventional drug product in the U.S. contains methylephedrine or norpseudoephedrine; in fact, norpseudoephedrine is classified as a Schedule IV Controlled Substance by the Food and Drug Administration (FDA).

The effects of ephedra can be explained by its constituent alkaloids, specifically ephedrine. Ephedrine increases the availability of naturally released catecholamines at synaptic areas in the brain and heart; in addition, ephedrine also stimulates catecholamine receptors directly on its own, acting as a direct sympathomimetic agent. The effects of ephedrine on each body system are listed in Table 1, many of which can be explained by activation of the sympathetic nervous system (e.g., cardiovascular stimulation, bronchodilation, central nervous system stimulation, relaxation of smooth muscle in the gastrointestinal tract, etc.).

 Table 1. Action, Use, and Effectiveness of Ephedra

CV = Cardiovascular; Resp = Respiratory
CNS = Central Nervous System
Endo = Endocrine
Gent = Genital
GI = Gastrointestinal

The known actions of ephedra drive many of its uses (See Table 1). Ephedra is used for bronchodilation, cardiovascular stimulation, central nervous system stimulation, appetite suppression, weight loss, performance enhancement, and energy. Unfortunately, the effectiveness of ephedra for many of its uses has yet to be proven (See Table 1). The only area of convincing effectiveness is in the short-term treatment of diseases of the respiratory tract, including asthma, bronchitis and bronchospasm; however, doses recommended for these indications often exceed the safe limit.

The recommended doses for ephedra can vary between sources. The FDA recommends that ephedra products not be used for longer than 7 days and doses should not be more than 8 mg of ephedrine every 6 hours, or 24 mg/day. Other sources state that the adult dose is 15 to 30 mg/dose, while some list the maximum dose as 300 mg/day.

With any dose of ephedra, there is the potential for interaction with drugs, lab tests, and disease states or conditions (See Table 2). In general, other stimulants should be avoided due to additive effects with ephedra. Interactions with lab tests can also be problematic. Norpseudoephedrine (Schedule IV substance) may be found in urine screens, and ephedra may cause false-positive test results in amphetamine and methamphetamine urine tests. Ephedra can also raise blood glucose levels, causing poor control in diabetic patients.

There are additional disease states and conditions where the use of ephedra should also be avoided. Most of these disease state-ephedra interactions can be predicted by knowing the actions of ephedrine. For example, any cardiovascular disease should be considered a potential contraindication to ephedra. Also, anorexia and bulimia are contraindicated due to the appetite suppressing effects of ephedra. Even conditions such as narrow-angle glaucoma can be exacerbated due to sympathetic nervous system activation and resultant mydriasis.

Ephedra can also cause adverse events independent of disease state interactions. These side effects are still consistent with the adverse effects of sympathomimetic agents and are listed in Table 3. Many manufacturers add other substances to ephedra products that may increase the risk for side effects (See Table 4). For example, some herbs are included for an additive stimulant effect, such as the caffeine-containing herbs kola nut and guarana, as well as C. aurantium, which contains adrenergic agonists. Finally, other substances may be added to increase blood levels of ephedrine, such as willowbark, amino acids, Uva Ursi, senna, and cascara.

 Table 3. Ephedra Adverse Reactions

CV = Cardiovascular
Resp = Respiratory
CNS = Central Nervous System
GI = Gastrointestinal
Ext = Extremities

The combination of erratic dosage recommendations, potential adverse reactions (which include sudden death), and co-administration of additive herbal substances, present a safety issue with ephedra use. Unfortunately, these are not the only issues surrounding the safety of ephedra. In a study by Gurley and colleagues, quality control in manufacturing was investigated, and the ephedra alkaloid content of 20 ephedra-containing supplements was determined. The authors found that total alkaloid content could vary from as little as 0% up to 154% of the label claim. The FDA-recommended dosing schedule become difficult to follow considering this finding. To complicate the matter, there was excessive lot-to-lot variability found within the same product. In addition, no two ephedra supplements were the same, even though label claims for ephedra content were identical. Lastly, some of the supplements contained substantial quantities of norpseudoephedrine (Schedule IV substance).

These findings support the bans that many organizations have placed on the use of ephedra supplements. Organizations that have banned the use of ephedra include the International Olympic Committee, the National Football League, the National Collegiate Athletic Association, minor league baseball, and the U.S. Armed Forces. Laws and policies regulating ephedra have also been passed in Texas, Ohio, Hawaii, Michigan, Washington, Oklahoma, and Nebraska.

With all of the restrictions placed on ephedra supplements by non-Federal Government entities, the issue of federal regulation needs to be taken into consideration. The Dietary Supplement Health and Education Act (DSHEA), enacted in 1994, allowed greater access to dietary supplements so that consumers could participate in improving their own health. The DSHEA distinguishes dietary supplements as their own entity, separate from drugs, which are regulated by the FDA (i.e., dietary supplements do not need approval from the FDA before they are marketed). Except in the case of a new dietary ingredient, where pre-market review for safety data and other information is required by law, a manufacturer does not have to provide the FDA with the evidence it relies on to substantiate safety or effectiveness before or after it markets its products. To complicate matters, the burden of proof lies with the FDA; the FDA must prove that a dietary supplement is unsafe before it can restrict a product's use.

As a result of the DSHEA, adverse event reporting is ultimately relied upon for safety surveillance of dietary supplements. However, unlike prescription drug manufacturers, manufacturers of supplements do not have any post-marketing reporting requirements. Adverse event reporting is strictly voluntary. The FDA established the Special Nutritionals Adverse Event Monitoring System (SN/AEMS) to collect adverse event reports from consumers, manufacturers and health professionals. The sources of adverse event reports for this database vary, and include systems such as MedWatch. Voluntary reporting is a major limitation of this system. In a recent report, the Department of Health and Human Services (HHS) Office of Inspector General concluded that less than 1% of supplement-related adverse events are reported to the FDA. Even after obtaining reports, proving causality from case reports and case series is difficult.

Recently, there have been several case reports that show a strong association between ephedra and certain unsafe adverse events, including death. One analysis of case reports concluded that underlying heart or vascular disease is not a prerequisite for ma huang adverse events.

The analysis also found that cardiovascular toxic effects were not limited to massive doses. In a single case report of the death of a 23-year-old healthy male, autopsy and microscopic examination reports included specific details of the cardiotoxic effect of ephedrine. The microscopic examination revealed that the myocyte necrosis differed from the typical damage seen with large vascular obstructions. That report specified that the findings "suggest multiple ongoing insults which could have resulted in vasoconstriction of small arterial vessels and myocyte toxicity. These pathologic features are reminiscent of experimental and clinical aspects of adrenergic/sympathomimetic agents." The official autopsy report and death certificate read "patchy myocardial necrosis associated with ephedrine toxicity from protein drink containing ma huang extract."

Myocardial necrosis is not the only mechanism by which ephedrine can cause death. Depending on where in the heart ephedrine-induced pathology develops, pacemaker centers may be "short-circuited" and lead to sudden fatal arrhythmias. Ephedrine can also predispose patients to both hemorrhagic and ischemic stroke. Subarachnoid hemorrhage is thought to be a result of the hypertensive action of ephedrine, or a result of cerebral vasculitis, which has been described in association with a variety of sympathomimetic drugs. Thrombotic stroke is presumably related to vasoconstriction of large cerebral arteries, which leads to local thrombosis as a result of stasis and sympathomimetic-induced platelet activation.

The RAND report, commissioned by the National Institutes of Health (NIH), was able to identify sentinel events related to ephedra and ephedrine consumption. For ephedra containing products, the following were identified as sentinel events: two deaths, three myocardial infarctions, nine cerebrovascular accidents, three seizures, and five psychiatric cases. For ephedrine consumption, sentinel events included: three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases. The symptoms described in the psychiatric cases included psychosis, hallucinations, delusions, homicidal intent, insomnia and paranoia. Between ephedra and ephedrine, 50 additional cases were identified as possible sentinel events. Another study, funded by the National Center for Complementary and Alternative Medicine (NCCAM), released preliminary results on the relative safety of ephedra compared with other herbal products. The study found that the relative risk for an adverse reaction from ephedra was more than 100 times greater compared with other herbs.

Based upon the recent case reports and studies, the HHS issued a press release on February 28, 2003 announcing a series of actions designed to protect consumers from products containing ephedra. Warning letters have been sent to dozens of manufacturers challenging them to remove unproven claims or substantiate those claims, particularly with regard to performance enhancement.

A black box warning label about the risk of adverse effects and death will also be mandated. Additionally, the FDA is seeking comments from health professionals, the supplement industry and the general public. Comments may include any additional data on ephedra's safety, as well as whether the evidence of significant safety concerns is sufficient for new restrictions on products regulated under the DSHEA. Once the 30-day comment period has ended, the FDA will analyze the comments and publish its conclusions. The NCCAM met on March 17, 2003, to assess the evidence on ephedra's safety and effectiveness in order to develop a research agenda on ephedra.

The recent concern towards the safety of ephedra-containing supplements is warranted due to an abundance of case reports and studies. This body of evidence may likely grow in response to the current NCCAM and FDA research efforts. The NCCAM advises consumers that safety should be the primary concern for all users of ephedra. As health care professionals, it is important to be aware of the adverse effects, including death, which may potentially occur with the use of ephedra. It is also important to advise patients of these adverse effects until the FDA gives further direction.

References Available Upon Request

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