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.

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