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Ephedra

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[FDA Final Rule Banning Ephedra - HerbalGram 62, 2004]

Ephedra sinica Stapf

[Fam. Ephedraceae]
Overview

Editors’ note: In an attempt to clarify thecontroversy surrounding the safety of ephedra, this monograph devotesadditional space to some of the safety, legal, and regulatory issues. Thus, the“Overview” section is longer for ephedra than for other monographs in thispublication.

In Asian medicine, ephedra (known in Chinese as ma huang) is the primary herbal drug fortreatment of asthma and bronchitis. This herb is one of the oldest and most widelyused Chinese herbs, having been employed for thousands of years in traditionalChinese medicine (TCM) as a primary component of multi-herb formulas prescribedto treat bronchial asthma, cold and flu, cough and wheezing, fever, chills,lack of perspiration, headache, and nasal congestion. Listed in the oldestcomprehensive materia medica, Shen NongBen Cao Jing (ca. 100 C.E.),among the “middle class” herbs, ephedra is used to induce perspiration, and asan anti-allergy agent (Blumenthal and King, 1995; Bruneton, 1995; DerMarderosian, 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 theplant, primarily ephedrine and pseudoephedrine, are official in most countries.

Ephedra-containing dietary supplements have becomeincreasingly popular in the past two decades as agents to help promote weightloss and athletic performance. A recent survey has suggested that 7% of theAmerican adult population uses nonprescription drugs for weight loss, 2% usingphenylpropanolamine (PPA) (no longer sold over-the-counter), and 1% usingproducts containing ephedra (Blanck etal., 2001). In a survey on herb use in the Minneapolis metro area, 230people (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 forasthma. Over half rated the ephedra effective or very effective (Harnack et al., 2001).

Discussions of the safety and effectiveness of the herbephedra are usually based on scientific research conducted on the isolated (sometimessynthesized) alkaloids in the herb (i.e., ephedrine and pseudoephedrine ortheir related isomers; see Chemistry section below). Both are approved by theU.S. Food and Drug Administration (FDA) as safe and effective over-the-counter(OTC) drug ingredients. Most of the scientific literature to date focuses onthese alkaloids. Due to the popularity of the herb there is an increasingnumber of clinical studies being conducted on the herb itself, often incombination with other herbs. This review focuses on the herb itself, withreference to research on ephedrine and pseudoephedrine in the Pharmacology andMechanisms sections, and others, as necessary.

The safety and the appropriate regulation of ephedra aroseas controversial issues in the U. S. during the 1980–90s when the herb began tobe used as a major ingredient in herbal dietary supplements intended to aidweight loss and exercise. Some products that were subsequently determined to beadulterated with synthetic ephedrine (e.g., Formula One®) or marketedas purportedly legal substitutes for the illicit drug Ecstasy (e.g., Herbal Ecstacy® andUltimate Xphoria®) raised significant concerns among various statehealth authorities, health professionals, and responsible members of the herband dietary supplement industry (Blumenthal and King, 1996). In 1994,increasing concerns about potential risks associated with the use of ephedraherbal products prompted the American Herbal Products Association (AHPA) andthe National Nutritional Foods Association (NNFA) to issue a labeling policyfor its member companies to set serving and daily intake limits as well as listcontraindications for the herb on labels of ephedra-containing products (seeContraindications section below) (AHPA, 1994).

Health professionals also became increasingly concernedabout the public health implications of ephedra and ephedra alkaloid-containingproducts, and several groups passed resolutions supporting the restriction ofephedra alkaloid-containing products. In May 1995 the Texas Medical Association(TMA) adopted a policy that ephedrine and ephedrine alkaloids should beprohibited from non-prescription foods, dietary supplements, or other OTCcommercial products intended for public consumption, and that such products bemade available by prescription only. In November 1998, TMA also proposed thatsuch products be labeled to declare the amount of active ingredients of thesubstances with pharmacologic properties and that the products have accuratewarning labels (TMA, n.d.). The American Medical Association (AMA) has adopteda similar policy (AMA, 2002, 2000).

In 1996, the Ohio legislature passed a law, supported byindustry dietary supplement organizations, to appropriately regulate theseproducts. Since that time, laws regulating ephedra that incorporate the AHPAand NNFA standards for formulation and labeling have been passed in Hawaii,Michigan, Washington, Oklahoma, and Nebraska.

In June 1997, the FDA issued proposed regulations onephedra-containing dietary supplements that would limit the level of totalephedra alkaloids in herbal preparations to no more than 8 mg per dose, with nomore than 24 mg per day (FDA, 1997). The proposal would have banned thecombination of ephedra with other stimulants like caffeine or caffeine-containingherbs (including cola [Cola nitida],guarana [Paullinia cupana var. sorbilis], maté [Ilex paraguariensis]) in herbal products; would have prohibited thesale of ephedra products for use in weight loss or for athletic performance;would have restricted use of ephedra-containing herbal products to no more thanseven days duration; and would have required warnings on all labels forproducts containing ephedra. The proposal also called for the ban of so called“street drug knockoffs” containing the herb ephedra or ephedrine alkaloids, tobe used as replacements for illicit drugs; such copies of drugs are illegalunder federal law. The proposed rule was based primarily on approximately 800adverse event reports (AERs) submitted to FDA. Industry, scientific and medicalexperts, and many consumers criticized the proposed rule, often noting that theAERs were not a valid scientific basis for rulemaking, as was established bythe FDA’s own policies.

As a result of this criticism, Congress requested that theU.S. General Accounting Office (GAO), the government agency that monitorsaccountability of all federal agencies, conduct an audit of the scientificbasis for FDA’s proposed serving and daily intake limits, the proposed durationof use limit (seven days), including the ban on claims for weight loss andexercise, and FDA’s cost/benefit analysis for the proposed rule. In August1999, the GAO issued a 68-page report,Dietary Supplements: Uncertainties in Analyses Underlying FDA’s Proposed Ruleon Ephedrine Alkaloids (GAO, 1999). The report reveals deficiencies in theFDA’s proposed rule on ephedra. GAO acknowledged that the AERs the FDA hadreceived for ephedra raised concerns that warranted examination. At the sametime, GAO questioned the reliability of many of the AERs and criticized theapparent lack of science employed in formulating the proposed dosage limits ofalkaloids, the proposed duration limits, and ban on weight loss and exerciseclaims. As a result of this and other significant deficiencies, including afailure 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 coulddevelop a valid scientific basis and meet other requirements applicable tofederal rulemaking.

In March 2000, the FDA responded to the GAO by withdrawingportions of its proposed rule on duration of use (including prohibitionsagainst marketing ephedra for weight loss and exercise) and dosage levels. FDAsimultaneously made public additional AERs on ephedra received since thepublication of the June 1997 proposed rule, as well as reviews of those AERs bythe 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 onthe safety of ephedra in which testimony was presented by various scientificand medical experts who had conducted extensive reviews of the scientific andclinical literature on ephedra, as well as some who had conducted clinicalinvestigations into the safety and benefits of ephedra for weight loss. At theOWH hearing, the Ephedra Education Council (EEC, an industry group) presentedthe consensus views of a seven-member panel comprised of experts from variousmedical and scientific disciplines who concluded, based on reviews of both thepublished literature and the entire public record of more than 1,000 AERssubmitted to the FDA, that there was no evidence of an association betweenephedra and significant adverse events at the intake levels established by theAHPA’s 1994 standards and subsequently adopted as law by several states. Thepanel’s multi-disciplinary review of the AERs, which was subsequently submittedto the FDA as public comment, was critical of reviews performed by FDAconsultants, one of which was subsequently published (Haller and Benowitz,2000). One member of the EEC panel also conducted the first comparison ofincident rates of the adverse events at issue (e.g., stroke, heart attack, andseizure) in the general population and incident rates of the same events inephedra consumers. His conclusion was that the analysis suggests that there wasno evidence of increased risk, even using the most conservative of assumptions(Kimmel, 2000). In September 2000 the OWH issued a report recommending thatadditional research be conducted (OWH, 2000).

The FDA’s review of 140 AERs, reportedly associated with theingestion of ephedra-containing dietary supplements, from the FDA’s MedWatchprogram concluded that 43 (31%) of the AERs were “definitely” or “probably”associated with ephedra use (Haller and Benowitz, 2000). In response to acritical letter to the editor (Hutchins, 2001) the authors cautioned that theirreport “does not prove causation, nor does it provide quantitative informationwith regard to risk” (Hutchins, 2001). A subsequent evaluation concluded:“These reports, while possibly associating the use of herbal dietarysupplements containing ephedra with side effects, do not in any way prove acausative relationship between herbal use and these problems. On the otherhand, controlled studies of supplements containing ephedra provide considerableevidence of efficacy in weight loss and weight maintenance.” (Heber andGreenway, 2002).

There have been several attempts toput the number of ephedra-related AERs and ephedra-using consumers intoperspective, but there are no accurate or reliable data on how many consumersare using ephedra, how many doses have been consumed, or how many AERs aredirectly related to ephedra consumption. According to a survey by AHPA of 14companies that manufactured and marketed ephedra-containing supplements therewas a 700% increase in sales in ephedra-containing supplements in five yearsfrom 1995 to 1999, representing 425 million “servings” sold in 1995 rising toan estimated 3 billion servings in 1999, with total estimated sales of ephedrasupplements equaling 6.8 billion servings (McGuffin, 2000). (Technically,dietary supplements are considered foods, not drugs, under federal law, andthus what would normally be considered a “unit dose” by a pharmacist orphysician must be referred to in food language by members of the herb and supplementindustries, hence the term “serving.”) A total of 66 serious adverse eventswere reported to these 14 responding companies over the 5-year period from 1995to 1999. Based on the estimate of morethan 6.8 billion servings sold in the same 5-year period, these AERs representa 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 totalsegment of ephedra manufacturers, show that although the reported sales of supplementscontaining ephedrine alkaloids has increased more than seven-fold in the past 5years, there has been no commensurate increase of adverse events gathered byFDA (McGuffin, 2000).

In October 2000, a group of industry trade associationspetitioned the FDA to accept proposed limits of 100 mg ephedra alkaloids perday and a proposed warning label (AHPA etal., 2000). In December 2000, Cantox Health Sciences International (CHSI),an independent Canadian research organization, concluded, on the basis of aquantitative method developed by the National Academy of Sciences, that 90 mgper 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 basedon a review of all available clinical studies on the alkaloid ephedrine and theherb ephedra, plus pharmacological and other relevant studies. CHSI alsoreviewed the FDA’s AER database but concluded that due to insufficient andinconsistent clinical data, these reports were not useful for assessing productsafety. (The Council for Responsible Nutrition, a Washington, D.C.-based tradeassociation of dietary supplement manufacturers and suppliers, commissioned thereview.)

Some experts have suggested that the relative safety andpotential benefits of ephedra-containing dietary supplements should be viewedwithin the broader public health context of the prevalence of obesity inAmerica. In December 2001, the U.S. Surgeon General David Satcher, M.D.estimated that 300,000 Americans die each year from illnesses caused orexacerbated by obesity (Anon., 2001b). Satcher said that 62% of Americans areeither overweight or obese, compared to 48% in 1980 (Anon., 2001a). Acomprehensive review article of the scientific and medical literature ofcaffeine and ephedrine combinations in the treatment of obesity (Greenway,2001) summed up the situation:

Overweight and obesity are commonproblems affecting more than half the population, yet obesity is stigmatized bysociety. Therefore, it is not surprising that an effective weight loss productcontaining compounds with a long history of safe non-prescription use would beembraced enthusiastically by the public. When large numbers of the public areusing any product, adverse events will inevitably occur, but the cause andeffect relationship of these adverse events to the product use are usuallyunclear. Obesity is a disease that predisposes to diabetes, hypertension, andcardiovascular disease. These increased risks are reversed with weight loss.The peer-reviewed scientific literature suggests that the risks of caffeine andephedrine are outweighed by the benefits of achieving and maintaining a healthyweight. Confirmation of that conclusion for herbal products containing caffeineand ephedrine awaits controlled clinical trials.

Recent clinical research, published after the Greenway(2001) review, suggests that ephedra, in combination with other herbs, producessignificant weight loss with no clinically significant adverse effects in thestudy 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 bewarranted. In June 2002, the Secretary of HHS called for more research onephedra to determine its safety and efficacy (HHS, 2002). Supporters and someprominent critics of ephedra agree that scientific reviews of the cases of theAERs on ephedra do not establish causality, thereby making additional clinicalresearch the key to developing regulatory policy.

Description

Ephedra consists of the dried, young branchlets, harvestedin the fall, of Ephedra sinica Stapf[Fam. Ephedraceae] or otherequivalent Ephedra species(Blumenthal et al., 1998; DAB, 1999),including E. intermedia Schrenkex C.A. Mey. and E. equisetina Bunge(syn. E. shennungiana Tang)(PPRC, 1997). The Japanese Pharmacopeia requires that it contain not less than0.6% total alkaloids, calculated as ephedrine (JSHM, 1993). The Pharmacopoeia of the People’s Republic ofChina requires not less than 0.8% (PPRC, 1997), and the GermanPharmacopoeia requires not less than 1% (DAB, 1999).

Primary Uses

Respiratory System

Mild bronchospasms in adults and childrenover the age of six (Blumenthal et al.,1998)

Bronchodilator in treatment of bronchialasthma (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 andrunning nose, general aching, but no sweating; edema in acute nephritis;bronchial asthma (PPRC, 1997).

Ephedra dietary supplements are frequentlyused by athletes as performance enhancing agents (This use is highlycontroversial and has been the subject of numerous athletic groups’ attempts toban 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 dosefor 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 withhot water decoction than with extraction with ethanol and/or methanol (Noguchi et al., 1978). In a decoction made withephedra containing a range of a minimum of 0.8% alkaloids (according to the Pharmacopoeia of the People’s Republic ofChina, PPRC) to 1.0% (according to the GermanPharmacopoeia), the estimated range of alkaloids based on the WHO dailydosage range would be 8–60 mg and the range based on the PPRC dosage would be12–90 mg.

Dried comminuted herb(According to the German Commission E for approved bronchial indications): theadult single dose corresponds to 15–30 mg total alkaloid, calculated asephedrine. The adult maximum daily dose corresponds to 300 mg total alkaloidcalculated as ephedrine. For a child (over age 6) a single dose corresponds to0.5 mg total alkaloid per kg of body weight. A child’s maximum daily dose is 2mg total alkaloid per kg of body weight (Blumenthal et al., 1998). [Note:This children’s dosage is based on the recommendation for licensed preparationsfor the approved bronchial indication in Germany only. Ephedra supplements in the U.S. are notrecommended for children under the age of 18, according to industry labelingpolicy.]

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 Basedon the Cantox Toxicological Review: ephedra preparations equivalent to 30mg total alkaloids per dose; 90 mg per day (CHSI, 2000).

Purified Ephedra Derivatives (i.e., OTC drugs):

For bronchodilation the maximum adult daily dose ofephedrine (or usually its salt form, ephedrine hydrochloride) is 150 mg per day(21 CFRa), and the maximum adult daily dose of pseudoephedrine (or its saltform pseudoephedrine hydrocholoride) is 240mg per day (21 CFRb). [Note: for comparison purposes, the maximumdaily nonprescription oral dose of caffeine is 1,600 mg (Heber and Greenway,2002).]

Duration of Administration

The Commission E monograph, published in 1991, recommendedthat ephedra preparations should be used only short-term because oftachyphylaxis and potential addiction. Note: Amore recent analysis of the available U.S. health and safety data compiled byEdgar H. Adams, M.S., Sc.D., former director of the Division of Epidemiologyand 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 foraddiction is low and does not rise to the level of regulatory concern thatwarrants scheduling (as is done with addictive narcotic drugs) (Adams, 2000).Nevertheless, as with other stimulant products that enhance athleticperformance, products containing ephedra alkaloids are still banned by the InternationalOlympic Committee for use by athletes competing in the Olympic games (IOC,2001).

Chemistry

The herb ephedra contains approximately 1.3% alkaloidscomposed mainly of ephedrine (up to 90%), pseudoephedrine, norephedrine,nor-pseudoephedrine, methylephedrine, and methylpseudoephedrine (Huang, 1999;Tang and Eisenbrand, 1992). These alkaloids are the primary activeconstituents. Other components include flavonoid glycosides; glycans(ephedrans); citric, malic, and oxalic acids; proanthocyanidins (condensedtannins); tannins and volatile oils (l-a-terpineol,limonene, and linalool) (Bruneton, 1995) but these compounds are not believedto exert much influence on the well established pharmacological effects of thisherb.

Pharmacological Actions

The pharmacological data cited below pertain to researchconducted on the whole ephedra herb or its extracts, as well as to the isolatedalkaloids ephedrine and pseudoephedrine, plus (as noted below) combinations ofephedrine and caffeine, or ephedrine and aspirin. Extensive clinical andpharmacological research has been conducted on ephedrine, usually its saltform, e.g. ephedrine hydrochloride (Astrup etal., 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 theactions of the herb ephedra or its combinations with caffeine-containing herbs.One review on thermogenic agents states that the effects of ephedra andephedrine are the same, except that ephedra is gentler and less likely to causeadverse effects, with the large body of scientific data on ephedrine beingapplicable to ephedra (Jones, 2001). A small clinical trial suggests similarpharmacokinetics between the ephedrine in ephedra and synthetic ephedrine(Gurley et al., 1998). Research showsthat ephedra alkaloids (e.g., ephedrine) from supplements containing ephedra extracts are absorbed more quickly thanthe alkaloids from preparations containing powdered ephedra herb, and thusproducts containing extracts probably exhibit absorption and dispositioncharacteristics indistinguishable from those products containing isolatedephedra alkaloids (e.g., OTC drugs) (Gurley, 2000). For a detailed review ofthe clinical pharmacology of ephedrine, see Tang and Eisenbrand (1992), and forephedrine combined with caffeine and/or aspirin, see Heber and Greenway (2002).

Human

Ephedrine and related alkaloids producesympathomimetic effects, including vasoconstriction, increased heart rate, andstimulation of central nervous system (Weiner, 1985).

Ephedra herb preparations are shown toproduce dilated bronchi (WHO, 1999), and induce perspiration (diaphoretic), anddiuresis (diuretic) (PPRC, 1997).

Increased thermogenesis and weight loss inobese 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-inducedthermogenesis 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 andeffective in a pilot study on 32 obese adolescents, reducing weight more than5% 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) andaspirin (300 mg) produced greater post-prandial thermogenesis in 10 obese womenfor 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 in10 lean women (Horton and Geissler, 1991) while ephedrine and aspirinnormalized the post-prandial thermogenesis in obese women to levels equal tothe lean (Geissler, 1993).

Stimulation of central nervous system andcardiovascular parameters (i.e., increases in pulse rate, blood pressure, andserum glucose levels) have been documented when ephedrine and/or caffeine aregiven acutely either separately or together. According to a recent review ofthe peer reviewed literature, these side effects disappear with chronic use andare no longer present after 4 to 12 weeks, depending on the trial (Heber andGreenway, 2002).

There has been concern about the potential hypertensiveeffects of ephedra and its alkaloids. However, in one trial a proprietaryephedrine (20 mg) and caffeine (200 mg) preparation tested for its weight losseffects on 136 overweight normotensive or drug-controlled subjects withcontrolled hypertension, three doses of the product showed blood pressure-loweringeffects over 6 weeks (Svendsen et al.,1998). Systolic blood pressure was reduced 5.5 mm HG more in the controlledhypertensive subjects treated with the preparation than placebo in subjectstreated with medication other than beta-blockers. The anti-hypertensive effectof 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 mmHG greater drop in blood pressure than those treated with placebo. The meanloss of weight of 4 kg (8.8 lbs.) was significant for all groups.

A recent review of ephedrine cites literatureproposing it as an adjunct to cognitive restructuring and notes that ephedrinehas 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 dietarysupplements containing the herb ephedra when used as performance enhancers inathletic activities. Although no studies are available on the herb ephedra inathletic performance, numerous clinical trials conducted at the CanadianDefence and Civil Institute of Environmental Medicine have measured the effectsof ephedrine and caffeine combinations on exercise and related performanceactivities. These pilot studies have concluded that the combination ofephedrine (E) and caffeine (C), or ephedrine alone, produces the followingeffects in athletes or soldiers: (1) an improvement in anaerobic exerciseperformance is likely a result of both stimulation of the CNS by E and skeletalmuscle by C (Bell et al. 2001); (2)although the metabolic rate in subjects was slightly increased with C+Etreatment, it was sufficiently offset by increased heat loss mechanisms so thatinternal 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 runwearing 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 toexhaustion, the improved performance being attributed to increased CNSstimulation (Bell et al., 1998); (5)the previously observed additive effects of C+E was not evident, with theprimary ergogenic effect being attributed to E (Bell et al., 2002); and (6) a lower dose (approx. 20% lower) of C+E thanused previously resulted in an ergogenic effect similar in magnitude to thatreported previously with a higher dose, and with a reduced incidence ofnegative side effects (vomiting and nausea) (Bell et al., 2000).

Animal

Ephedra herb prevents or relieves coughingand inhibits growth of bacteria in animal experiments, according to theCommission E (Blumenthal et al.,1998);

Ephedrastimulates the sympathetic nervous system in dogs (Huang, 1999), analogues offeruloyl-histamine, an alkaloid in ephedra roots,inhibit hypotension and histidine decarboxylase, is anti-ulcerous andanti-hepatoxic (Hikino et al., 1984);

Ephenadrines block ganglions (Hikino et al., 1983);

Pseudoephedrine relieves inflammation (Hikino etal., 1980).

Mechanism of Action

All mechanistic data cited below pertain to isolated ephedraalkaloids.

Ephedrine indirectly stimulates thesympathomimetic 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 ephedrineresembles epinephrine (adrenaline) (Chang and But, 1986), though unlike epinephrine,it is completely absorbed from the intestine and has a much longer duration ofaction (Huang, 1999); 

Ephedrine triggers the release ofendogenous catecholamines from post-ganglionic sympathetic fibers (Bruneton,1995);

Ephedrine relaxes bronchial muscles andacts as a bronchodilator by activating the b-adrenoceptors in the lungs (Weiner,1985; Hardman et al., 1996);

Both ephedrine and pseudoephedrine inhibitnorepinephrine 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 andoxygen consumption), insulin, and c-peptide (Jaedig and Henningsen, 1991).

Contraindications

The Commission E noted the following contraindications: anxietyand restlessness, hypertension, glaucoma, impaired circulation of the cerebrum,adenoma of the prostate with residual urine accumulation, pheochromocytoma, andthyrotoxicosis (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 beingsuggested as an official national standard by a group of dietary supplementindustry 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 ifyou are pregnant or nursing. Consult a health care professional before usingthis product if you have heart disease, thyroid disease, diabetes, high bloodpressure, depression or other psychiatric condition, glaucoma, difficulty inurinating, prostate enlargement, or seizure disorder, if you are using amonoamine oxidase inhibitor (MAO), or any other prescription drug, or you areusing an over-the-counter drug containing ephedrine, pseudoephedrine orphenylpropanolamine (PPA) (ingredients found in certain allergy, asthma,cough/cold and weight control products). [PPA has been removed from the OTC market, but consumers might stillpossess older PPA-containing drug products.] Exceeding recommended serving willnot improve results and may cause serious adverse health effects. Discontinueuse and call a health care professional immediately if you experience rapidheartbeat, dizziness, severe headache, shortness of breath, or other similarsymptoms.” (AHPA et al., 2000).

Pregnancy and Lactation: Notrecommended for use during pregnancy or lactation (Brinker, 2001; McGuffin et al., 1997).

Adverse Effects

According to the Commission E, the adverse effects of theherb ephedra include insomnia, motor restlessness, irritability, headaches,nausea, vomiting, disturbances of urination, and tachycardia. The commissionalso noted that higher dosages (presumably higher than the Commission E’srecommended daily limit, equivalent to 300 mg ephedra alkaloids) may produce adrastic increase in blood pressure, cardiac arrhythmia, and development ofdependency (Blumenthal et al., 1998).(See “Note” about dependency in “Duration of Administration” above.)

There have been isolated reports of adverse events, someserious, including stroke and death, in the published literature. Some arerelated to overdosing; others (e.g., possible myocarditis in a few casereports) are attributed to the consumption of relatively normal levels (Leikinand Klein, 2000; Zaacks et al.,1999).

In a recent review of FDA’s AERs (926 cases reported to FDAbetween 1995 to 1997) focusing on 37 patients, ephedra use was temporarilyrelated to stroke (16 patients, 3 deaths), myocardial infarction (10), orsudden death (11), noting that cardiovascular adverse effects were not limitedto large doses (Samenuk et al.,2002). (This review relied on the same FDA database of AERs that had beenpreviously analyzed and questioned for accuracy by the GAO.)

One highly publicized review of selected events reported tothe FDA concluded that the AERs do not establish causality and cannot be usedto quantify risk (Haller and Benowitz, 2000). This paper reviewed 140 reportsof adverse events associated with the use of dietary supplements containingephedra alkaloids submitted to the FDA between June 1, 1997, and March 31,1999. The authors employed a standardized rating system for evaluatingcausation. They concluded that 43 (31%) cases were definitely or probablyrelated to the use of ephedra-containing supplements, 44 cases (31%) deemed possibly related to the use of ephedrasupplements, and 24 cases (17%) were considered unrelated. Of the adverseevents that were assessed to be definitely, probably, or possibly related tothe use of ephedra supplements, 47% involved cardiovascular symptoms and 18%involved the central nervous system. The most frequently reported adverse eventwas 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 letterto the editor (Hutchins, 2001) the authors cautioned that their report “doesnot prove causation, nor does it provide quantitative information with regardto risk” (Hutchins, 2001). A recent review concluded, “These reports, whilepossibly associating the use of herbal dietary supplements containing ephedrawith side effects, do not in any way prove a causative relationship betweenherbal use and these problems.” (Heber and Greenway, 2002). 

More extensive evaluations of the entire FDA database ofAERs have been submitted to the FDA, suggesting no association betweenclinically 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 anepidemiological perspective suggesting no greater incidence of seizures,strokes, and myocardial infarctions (MIs) in persons consuming dietary supplementscontaining ephedrine alkaloids than that expected in the general U.S.population (Kimmel, 2000).

The Secretary of HHS, in a press release announcing plans tostudy ephedra, stated as follows:

Adverse event reports regarding the useof dietary supplements containing ephedrine alkaloids have been received by theFood and Drug Administration (FDA) and have raised questions regarding thesafety of these products. However, the FDA has advised that adverse eventreports alone regarding dietary supplements containing ephedrine alkaloids donot provide a scientific basis for assessing the safety of these products andthat there is need for further scientific research. (HHS, 2002).

Isolated ephedrine has been reported to cause urinarydifficulty in men with benign prostatic hyperplasia and is believed toexacerbate angle-closure glaucoma (Dvorak etal., 1997), forming the basis for the contraindications for theseconditions noted above. Other adverse effects documented for ephedrine incontrolled conditions include agitation, insomnia, headache, weakness,palpitations, giddiness, tremors, and constipation; these effects were notedonly with 50 mg dose given three times daily (total 150 mg per day), withamelioration during the duration of use, with no significant changes in pulserate or blood pressure (Pasquali and Casimirri, 1993). The German phytomedicineauthority R.F. Weiss, claims that the natural ephedrine found in ephedra is“better tolerated, causing fewer heart symptoms such as palpitation” thansynthetic ephedrine (Weiss, 1988), although a revision of his book by anotherauthor suggests that patients use synthetic beta-sympathomimetics for bronchodilationdue to the potential toxicity of ephedra (Weiss and Fintelmann, 2000).

Drug Interactions

The following are actual or potential interactions of orallyingested ephedrine alkaloids (mainly ephedrine and/or pseudoephedrine, notnecessarily the herb ephedra itself), with other substances. Documentedinteractions are derived mainly from human case studies or clinical trials,based on the alkaloid intake at various dosages.

Antihypertensives, including ACEinhibitors and beta-blockers: May be antagonized with resultingsevere hyper-tension (speculative) (Brinker, 2001).

Bromocriptine: Dopaminergicactivity may become increas-ingly toxic due to ephedra’s sympathomimeticactions (speculative) (Brinker, 2001).

Cardiac glycosides or halothane: Cancause 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 whenephedrine is combined with xanthines, plus excessive nervous stimulation (notedin some case reports) (Brinker, 2001).

Caffeine: Thealkaloids in ephedra combined with methylxanthines have been demonstrated to besynergistic on oxygen consumption in animals. A recent review noted both thecaffeine and the catechins in various types of tea (Camellia sinensis), e.g., oolong tea, may interact with respect torespiration of brown adipose tissue, based on in vitro evidence. Catechins in green tea are synergistic withrespect to oxygen consumption with caffeine, ephedrine, and the combination ofcaffeine and ephedrine; catechins inhibit catechol-O-methyl transferase, the enzyme that breaks down norepinephrine(Heber and Greenway, 2002). 

Secale alkaloid derivatives oroxytocin: Develop hyper-tension (listed by German Commission E)(Blumenthal et al., 1998).

Sympathomimetics: Maybe 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 urinaryacidifiers (e.g., ammonium chloride), due to effects of reabsorption fromtubules in the kidneys (Brinker, 2001).

American Herbal Products Association (AHPA) Safety Rating

Class 2b: Notfor use during pregnancy.

Class 2c: Notfor use during nursing.

Class 2d: Contraindicatedwith anorexia, bulimia, and glaucoma; thyroid stimulant; not recommended forexcessive or long-term use; may potentiate pharmaceutical MAO-inhibitors(McGuffin et al.,1997).

Regulatory Status

Australia: Ephedra, and productscontaining ephedra, are controlled substances listed in the Customs ProhibitedImports Regulations. Import permit required (TGA, 2001).

Canada: Includedin Drugs Directorate “List of Herbs Unacceptable as Non-medicinal Ingredientsin Oral Use Products” (Health Canada, 1995). Ephedra Labeling Standard:Approved Schedule OTC drug with specific indications: (1) Traditional HerbalMedicine (THM) for relief of nasal congestion (cold, hayfever); (2) TraditionalHerbal Nasal Decongestant. Dried young stem contains no less than 1.25% totalalkaloids calculated as l-ephedrine (Health Canada, 1996). Also, permitted as ahomeopathic drug. In either case requires premarket authorization andassignment of a Drug Identification Number (DIN) (Health Canada, 2001). InJanuary, 2002 Health Canada issued a “voluntary recall” for ephedra- andephedrine-containing products that are marketed for unapproved uses, e.g.,appetite suppression, promoting weight loss, or increasing energy; or thatcontain over 8 mg ephedrine or a total dose of ephedrine alkaloids exceeding 32mg per day (Lawlor, 2002).

China: Driedherbaceous stem containing no less than 0.80% total alkaloids, calculated asephedrine, official drug of the Pharmacopoeiaof the People’s Republic of China (PPRC, 1997).

France: Ephedraremoved from French Pharmacopoeia.Isolated ephedrine is official (Bruneton, 1995).

Germany:Dried young whole or cut branchlet collected in autumn containing no less than1.0% total alkaloids (as ephedrine) official in German Pharmacopoeia (DAB, 1999). Dried young branchlet is approveddrug of the German Commission E (Blumenthal etal., 1998).

Japan: Traditional Kampomedicine (Tsumura, 1996). Dried terrestrial stem containing no less than 0.15%total alkaloids (as ephedrine) official in JapanesePharmacopoeia (JSHM, 1993).

Sweden: No products containingephedra are presently registered in the Medical Products Agency’s (MPA)“Authorized Natural Remedies,” “Homeopathic Remedies” or “Drugs” listings (MPA,2001a and 2001b).

Switzerland: Nomonograph 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 healthcare option in the national HMO. Patients who choose TCM for their primaryhealth care plan may receive traditional Chinese herbal medicines (which maycontain ephedra) by prescription (Grüninger, 1992).

U.K.: ScheduleIII herb recommended to be limited for use by medical herbalists only (Denham,1998).

U.S.: Dietarysupplement (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 anasal decongestant (nasal spray) (21 CFR a-d).

Clinical Review

Seven studies conducted on the herb ephedra (327 totalparticipants) are summarized in the Table of Clinical Studies on Ephedra. Onestudy on a preparation containing only powdered ephedra measured cardiovasculareffects and pharmacokinetics (White et al., 1997). However, few clinical trials arebased on ephedra as a single ingredient. Most ephedra trials testedmulti-ingredient formulations that include a caffeine-containing herb like colanut (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 etal., 2002 and 2001 trials focused on weight loss and safety. One smallrandomized, crossover trial concluded that the pharmacokinetic properties ofephedrine in ephedra in dietary supplements were similar to those of syntheticephedrine hydrochloride (Gurley et al.,1998). At least three clinical studies have been conducted on the isolatedalkaloid ephedrine for its use in weight loss (Liu et al., 1995; Astrup et al.,1986; Pasquali et al., 1985), assummarized in the Table of Clinical Studies on Ephedra.

[Editors’ note: thefollowing studies are not listed in the Table of Clinical Studies on Ephedra orthe Table of Clinical Studies on Ephedrine.] Several unpublished trialsemployed four different ephedra products (ephedra only, not combinations) on300 subjects over a period of six weeks and six months, to monitor weight lossand adverse effects respectively. The studies concluded that ephedra appears tobe safe, effective, and cost-effective; and compares favorably withpharmaceutical weight loss agents, with a relatively low side effect profile(Huber, 2001). Clinical trials have been successfully conducted for weight lossusing ephedrine and caffeine combinations (Astrup and Toubro, 1993; Astrup et al., 1992, 1991) and amuch-publicized Danish formula of ephedrine in combination with caffeine andaspirin demonstrated the relative safety and efficacy of this combination forweight 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 extractstandardized to 8% ephedra alkaloids, equivalent to 5 mg ephedrine, 50 mgstandardized kola nut extract (equivalent to 10 mg caffeine), 50 mg mustardseed powder, 50 mg spirulina, 50 mg ascorbic acid (vitamin C), potassiumcitrate 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 35mg of caffeine alkaloids; 250 mg ephedra aerial part extract containing 15mgconcentrated ephedrine group alkaloids in the form of herbal extracts; and 110mg green tea (Camellia sinensis) leafextract containing 15 mg of caffeine alkaloids.

Excel: Excel Corporation / Salt Lake City, UT: noinformation available.

Metabolife 356®: Metabolife International, 5070Santa 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 and40 mg of caffeine alkaloids, combined with the following ingredients: Ma huang,Siberian ginseng (Eleuthero), lecithin, ginger root, damiana, sarsaparillaroot, goldenseal, gotu kola, spirulina, algae, bee pollen, nettle leaf, royaljelly, bovine complex, 6 I.U. vitamin E, 75 mg magnesium chelate, 5 mg zincchelate, and 75 mcg chromium picolinate.

Solaray® Ephedra: Nutraceutical Corp. Eachcapsule 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 KirkmanRoad / Orlando, FL 32811 / U.S.A. / Tel:(407) 297-7671. Each capsule contains: 30 IU Vitamin E (as dl-alpha-tocopherolacetate); 255 mg calcium (as dicalcium phosphate and calcium carbonate); 4.5 mgmagnesium (as magnesium carbonate); 5 mg potassium (as potassium bicarbonate);and 695 mg Up Your Gas Blend consisting of: guarana concentrate (seed), mahuangextract (Ephedra sinica) (stem) (285mg of 6% alkaloid extract), ginseng extract (root), bee pollen, spirulina bluegreen algae, gotu kola (leaf), inosine monophosphate,pyridoxal-alpha-ketoglutarate, wheat grass, cayenne pepper (fruit), lipoicacid, co-enzyme Q-10, and octacosanol.

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