Cardiovascular Effects of Ephedra Alkaloids: A Comprehensive Review

Cardiovascular Effects of Ephedra Alkaloids: A Comprehensive Review Richard Andraws, Preety Chawla, and David L. Brown

The Ephedra alkaloids have received much press lately secondary to reported adverse events in those using whole extracts as “dietary supplements” for weight loss or athletic performance enhancement. These reports are troubling given the increasing use of these supplements by the general public. We reviewed the available literature as well as online material on these compounds, including information on their pharmacology, regulation, effects on weight loss and athletic performance, and adverse events. Extracts of Ephedra shrubs contain highly active ␣- and ␤-adrenergic agonists that have profound effects on the heart and vasculature. Evidence for their effectiveness is limited. Adverse cardiovascular and cerebrovascular effects, including stroke, myocardial infarction, and sudden death, temporally related to their use are well described. The recent Food and Drug Administration ban on these compounds is not broad enough. Ephedra supplements contain a highly bioactive class of compounds that pose a significant risk to the public under the current regulatory framework. More stringent oversight by regulatory authorities is required to minimize the incidence of adverse events. © 2005 Elsevier Inc. All rights reserved.

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phedra or the Ephedra alkaloids are a group of sympathomimetic compounds derived from shrubs of the genus Ephedra. Some 40 species are scattered throughout the temperate and subtropical regions of Asia, Europe, and the Americas. The Asian species (E. sinica, E. intermedia, and E. equisetina) have the highest alkaloid content.1 The Ephedra alkaloids have a long history as traditional folk remedies, particularly among the Chinese. The principle alkaloid, known as ephedrine, was first isolated in 1885,2 and in its purest form has found use in modern medicine as a bronchodilator, decongestant, and vasopressor.3 In recent years, various companies have begun marketing

extracts of Ephedra shrubs for such purposes as weight loss and enhancement of athletic performance. Herbalists also market them as “alternative medicines” for cold and cough relief. It has been estimated that nearly one third of young, obese women have used a weight-loss supplement containing Ephedra.4 In 1999 alone, 12 million individuals in the United States used 3 billion doses of Ephedra alkaloids.5 Given the frequency of reports of adverse cardiovascular and cerebrovascular complications, the U.S. Food and Drug Administration (FDA) recently moved to prohibit the sale of these supplements. However, it is likely these agents will remain available to the public through illicit channels and related compounds will be sold through legitimate vendors. Thus, the purpose of this review is to examine the pharmacology of Ephedra alkaloids, the regulation of dietary supplements in the United States, the effects of Ephedra and related alkaloids on weight loss and athletic performance, and the available evidence regarding adverse events caused by these agents.

Structure and Pharmacology Ephedra is a generic term for several sympathomimetic agents including ephedrine, pseudoephedrine, norpseudoephedrine, norephedrine, methylephedrine, methylpseudoephedrine, and phenylpropanolamine (a synthetic, racemic mixture of the stereoisomers of norephedrine). Their From the Department of Medicine, Beth Israel Medical Center and the Division of Cardiology, Beth Israel Medical Center, New York, NY. Address reprint request to David L. Brown, MD, Division of Cardiology, State University of New York-Stony Brook School of Medicine, Stony Brook, NY 11794. dabrown@ chpnet.org 0033-0620/$ - see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2004.07.006

Progress in Cardiovascular Diseases, Vol. 47, No. 4, (January/February) 2005: pp 217-225

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218 molecular structures are isomers of one another or are closely related, substituted molecules that demonstrate significant similarity with amphetamines and other catecholamines (Fig 1). It is not surprising, then, that these molecules possess significant ␣- and ␤-adrenergic agonist activity. In addition, they enhance the release of endogenous catecholamines. This latter effect, through depletion of endogenous catecholamine stores, is thought to explain the tachyphylaxis noted with repeated dosing.5 The principle cardiovascular effects of Ephedra alkaloids include increases in systolic and diastolic blood pressure, heart rate and indices of cardiac performance3,6,7 (Fig 2). In species of Ephedra that contain appreciable quantities of alkaloids, the greatest amount is found in the branches, the remainder of the shrub being devoid of the compounds.1 The dried branches of the Asian species are known as ma huang in Chinese, meaning “yellow astringent,” perhaps due to the plant’s color and sharp taste (Fig. 3). The name is frequently used commercially in the United States and is synonymous with Ephedra. Extracts of the branches contain varying amounts of the different alkaloids and each alkaloid differs somewhat in its pharmacodynamic properties. From 40% to 90% of the alkaloid content consists of ephedrine with the other agents

ANDRAWS, CHAWLA, AND BROWN

comprising the remainder in relatively smaller quantities.2 Absorption of ephedrine from the gastrointestinal tract is avid, approximating 100%.2 Time to peak serum levels varies between 2 and 4 hours. The pure alkaloid is absorbed most quickly; herbal alkaloid mixtures may retard the rate of absorption. The rate of absorption of ephedrine may be increased with heat stress.8 Additionally, elevations in blood pressure are significantly greater when ephedrine is taken during heat stress. The importance of this finding lays in the fact that Ephedra extracts have been marketed as enhancers of athletic performance and are often taken prior to exercise in a warm environment. Thus, they may add to the cardiovascular stress already being experienced during physical activity. Once absorbed, ephedrine has a large volume of distribution and is not bound to plasma proteins.2 Ephedrine and related alkaloids are lipophilic and cross the blood– brain barrier. It is this physical property that accounts for their effects on the central nervous system, which include appetite suppression, anxiety, and changes in gastric motility.9-14 The effects of ephedrine last for approximately 1 hour,3 but the serum half-life ranges from 3 to 11 hours.2 Excretion occurs primarily through the kidneys over 24 hours, predominately as the unchanged drug.

Fig 1. Chemical structures of the Ephedra alkaloids (left). The structures of epinephrine, amphetamine, and dobutamine (right) are shown for comparison. Ephedra alkaloid structures adapted from The Cantox Report.2

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Fig 2. Change in systolic blood pressure and heart rate with time from ephedrine ingestion (A,B) and with serum concentration (C,D). Adapted from Haller, Jacob, and Benowitz.3

From 8% to 20% is excreted after demethylation and delamination.2 Excretion is pH dependent because of an ionizable amino group on the molecule. Acidic urine promotes excretion because the amino group is then positively charged and not readily reabsorbed; an alkaline urine has the opposite effect.6,15 In addition to renal excretion, ephedrine is also found to be excreted in breast milk and crosses the

placenta, which poses concerns for younger women who may be using extracts for weight loss purposes while pregnant or after delivery.

Marketing and Regulation Ephedrine and related compounds are marketed in 2 ways in the United States. The pure alkaloids are

Fig 3. A. Ephedra sinica. B. The dried branches of the plant (known in Chinese as ma huang).

220 marketed as pharmaceuticals and are used as bronchodilators, vasopressors, and constituents in various over-the-counter decongestants.3,16-19 The other marketed form is as an herbal or dietary supplement. The 1994 Dietary Supplement Health and Education Act (DSHEA) defines a dietary supplement as “any product which contains one or more dietary ingredients such as vitamins, minerals, herbs or other botanicals, amino acids or other ingredients used to supplement the diet.”20 Dietary supplement ingredients may not be regulated as food additives.20 The DSHEA was passed after a major lobbying effort,21 and the result was intended to be a new regulatory framework for supplements, ensuring continued access to safe products that are manufactured to quality standards. It was also supposed to result in increased dissemination of information about the health benefits of these products.20 In practice, the DSHEA led to deregulation of these products.21,22 The rigorous oversight that the FDA exercises over pharmaceuticals does not extend to supplements. Quality control and regulations regarding product labeling are lax. Gurley, Gardner, and Hubbard23 examined 20 brands of dietary supplements containing Ephedra alkaloids in an attempt to correlate claims of content on product labels with laboratory analysis of the content. There was poor correlation between claims and actual content. Several brands did not even note chemical constituents on their labels, which is mandated by the DSHEA as well as the Federal Food, Drug, and Cosmetic (FD&C) Act. Perhaps more disturbing was the finding of significant content variability within several brands. The status of supplements under the DSHEA presents particular problems for the FDA in terms of safety concerns. Supplements may come to market without FDA approval. This is very different from the case of pharmaceuticals, where manufacturers are compelled to prove both the safety and efficacy of their products through well-designed clinical trials before being allowed to bring them to market. Neither burden is imposed on makers of herbal or dietary supplements. Yet these products contain compounds, such as ephedrine, which have significant biological effects and have interactions with many common medications, making them similar to drugs.22,24 The Ephedra alkaloids are thus a fascinating example of a troubling paradox: the whole extract is considered a

ANDRAWS, CHAWLA, AND BROWN

supplement, whereas the purified or synthesized constituents are considered pharmaceuticals. Proving efficacy is less of a priority for manufacturers of dietary supplements because under the terms of the DSHEA, they cannot make claims of efficacy regarding a specific condition. They can, however, make vague or suggestive claims that may or may not be substantiated in clinical studies.21 Additionally, the burden of proving safety is shifted to the FDA. Under the DSHEA, the FDA must prove that a supplement is unsafe before it can move to regulate or ban it. Such proof is drawn from case reports of adverse reactions, which are compiled by the FDA, other regulatory organizations, and manufacturers, and published in medical literature. However, these reports are not the best form of evidence; reporting is voluntary, information may be incomplete, or there may be confounding factors that make proving that an adverse event was directly linked to ephedrine or related compounds difficult. For example, Haller and Benowitz5 reviewed 140 cases of adverse cardiovascular and central nervous system effects linked to Ephedra alkaloids and reported to FDA MedWatch between June 1997 and March 1999. Of the cases reported, only 43 (31%) were classified as “definitely” or “probably” related to intake of these products, and even these were the subject of some controversy.25 Another problem noted by Haller and Benowitz is that adverse events are often underreported, and so the true magnitude of risk to the public health may seem less than it actually is. Thus, when it comes to regulating the safety of dietary supplements, the FDA is at a distinct disadvantage.

Effects on Weight Loss and Athletic Performance The Ephedra alkaloids are marketed as supplements primarily for weight loss and enhancement of athletic performance. Several studies on these compounds (particularly ephedrine) have been undertaken to assess their efficacy and safety in humans for the treatment of obesity.12,26-35 Doses of ephedrine and related compounds ranged from 60 to 150 mg/d. Overall, studies have found statistically significant reductions in weight in obese patients treated with Ephedra alkaloids versus those treated with placebo. This finding was corroborated by the recent Rand Report36 and a review by Shekelle et al14 Treatment with these carefully controlled doses resulted

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in a modest incidence of cardiovascular side effects, including increases in blood pressure (both systolic and diastolic), heart rate, and palpitations that were often mild and transient. No clinical trial has reported major adverse cardiovascular events (stroke, myocardial infarction, or malignant arrhythmias) associated with the use of Ephedra alkaloids for weight loss. However, several caveats must be noted. The studies to date have examined small cohorts for relatively short periods of time, usually 6 months or less.14,36 They have also suffered from high attrition rates. In addition, most studies have looked at ephedrine in combination with caffeine and, in several cases, aspirin. (The rationale for this combination is that it better stimulates increases in fat metabolism and energy expenditure.37-48) Perhaps the most sobering finding is that weight loss, although statistically significant, may not be clinically significant (⬍1 kg)14 with anywhere from a 2- to 4-fold increase in side effects compared to placebo. Moreover, side effect profiles may be quite different in cohorts with preexisting cardiovascular disease. Thus, it is difficult to generalize these results to the various Ephedra products on the market that contain variable amounts of active compound and are sold to a variety of consumers with different risk factors who may consume higher doses than those studied. Evidence for enhancement of athletic performance is less robust. Ephedra products are marketed as “energy enhancers,” which may reflect stimulation of the central nervous system through adrenergic pathways similar to amphetamines given that these molecules share important structural and pharmacodynamic properties. Numerous studies fail to show an improvement in various exercise parameters (e.g., oxygen consumption, time to exhaustion) with Ephedra alkaloids alone. The results of studies on Ephedra in combination with caffeine are mixed.48-51 Pseudoephedrine significantly prolongs time to heart rate recovery following exercise, and other studies have found a significant increase in heart rate and blood pressure over controls. Again, studies tend to be small and contain young healthy individuals who may not reflect the general population. Thus, once more, the limited available safety assessments are difficult to extrapolate to the general population.

Adverse Events Adverse reactions related to the use of Ephedra alkaloids have received much attention recently, especially with the death of a professional baseball player who used a formulation during training camp.52 The bulk of evidence regarding adverse reactions comes from case reports. Larger studies that appear to demonstrate safety are difficult to extrapolate to supplements because they often look at pure, minor constituents (such as pseudoephedrine), which are used under controlled conditions.53 Although Ephedra products make up a modest amount of overall supplement sales (0.82%), they account for an inordinately large number of reported adverse events (64%).54 Insight into the potential toxicity of these agents may be obtained by considering their pharmacologic properties. Ephedra alkaloids are ␣and ␤-adrenergic agonists that stimulate the release of endogenous catecholamines. The physiologic effects of compounds with these properties have been known for decades. In addition to effects on blood pressure (which can lead to hypertensive urgencies/emergencies)55 and cardiac performance, they cause vasoconstriction and vasospasm, including coronary vasospasm. The latter effect may be more pronounced in individuals with higher vagal tone,56 a group which includes well-conditioned, athletic individuals. Moreover, there is some evidence that, along with spasm, Ephedra alkaloids may induce hypercoagulable states, low flow, and oxygen supply– demand imbalance within the coronary circulation.57 This could account for reported cases of myocardial infarction in otherwise healthy young people without significant underlying coronary artery disease.17,58-61 Myocardial ischemia has also been reported when Ephedra alkaloids are combined with other medications that cause increased adrenergic tone, such as bupropion17 or monoamine oxidase inhibitors.62,63 Catecholamines also decrease myocardial refractoriness, which can predispose the heart to arrhythmias, and indeed ventricular arrhythmias have been reported in pregnant women using over-the-counter decongestants19 as well as in others using Ephedra alkaloids recreationally.55 Table 1 summarizes adverse cardiovascular events noted in the literature. Cerebrovascular events associated with Ephedra use are another area of concern. Cases of stroke in

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Table 1. Adverse Cardiac Events Source

Study Type

No. of Subjects

Reported Events (No. of subjects)

Haller and Benowitz

Case review

46*

Shekelle et al14

Meta-analyis/case review

98†

Pederson et al7 Zahn et al55 Wahl et al56

Case report Case report Case report

1 1 2

Rezkalla et al57 Derreza et al58

Case report Case report

1 1

Weiner et al59

Case report

1

Samenuk et al

Case review

21

Cockings and Brown61 Lefebvre et al63

Case report Case report

1 1

Hypertension (17), palpitations/tachycardia/ arrhythmias (19), myocardial infarction (2), cardiac sudden death (8) Palpitations (51), hypertension (7), tachycardia (6), myocardial infarction (11), cardiac sudden death (15), near sudden death (3), cardiomyopathy (4), ventricular tachycardia (1) Myocardial infarction Hypertension, ventricular tachycardia Coronary vasospasm and non–Q-wave myocardial infarction (2) Myocardial infarction Coronary vasospasm, ST-elevation myocardial infarction Coronary vasospasm, ST-segment elevation myocardial infarction Myocardial infarction (10), cardiac sudden death (11) Myocardial infarction Hypertension

5

60

*Total N ⫽ 140, of which 46 were cardiac and considered “definitely,” “probably,” or “possibly” related to ephedra use. †Pooled adverse cardiac effects from clinical trials reviewed and case reports (exclusive of the others mentioned).

connection with the use of ephedrine and related compounds have been reported.60,64-68 Morgenstern et al69 recently published a case-control study examining the risk of hemorrhagic stroke associated with these compounds. Overall, they found a trend toward increased risk at doses ⬎32 mg/d. These doses are much lower than those used in studies examining safety and those examining Ephedra compounds as pharmacotherapy for weight loss, in which doses ranged from 90 to 150 mg/d. A similar study of phenylpropanolamine, an alkaloid commonly found in appetite suppressants and cold remedies,

found a significant increase in hemorrhagic stroke among women.16 This latter report prompted the FDA to request that drug companies manufacturing products that contain phenylpropanolamine discontinue them or reformulate them so as to exclude the alkaloid.70 Table 2 summarizes adverse cerebrovascular events associated with Ephedra alkaloids in the literature. Toxicity may not be limited to the pharmacologic effects of the alkaloids themselves. Lee et al71 found toxicity to a line of cultured neurons when they were exposed to various ma-huang prepara-

Table 2. Adverse Cerebrovascular Events Source

Study Type

No. of Subjects

Reported Events (No. of subjects)

Haller and Benowitz Shekelle et al14

Case review Meta-analysis/case review

11* 25†

Samenuk et al60 Vahedi et al64 Mourand et al65 Yin66 Stossel et al67 Kaberi-Otarod et al68

Case Case Case Case Case Case

16 1 1 1 2 1

Stroke (10), transient ischemic attack (1) Stroke (22), transient ischemic attack (1), sudden death related to intracerebral hemorrhage (2) Stroke (16) Stroke Intracranial hypertension/stroke Intracerebral hemorrhage/vasculitis Intracerebral hemorrhage Stroke

5

review report report report report report

*Total N ⫽ 140, of which 11 were cerebrovascular and considered “definitely,” “probably,” or “possibly” related to ephedra use. †Pooled adverse cerebrovascular events from clinical trials and case reports (exclusive of the others mentioned).

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tions. The authors note that methods of extraction of the alkaloids and grinding of the plant may lead to unrecognized adulterants finding their way into the final product.

Regulation Revisited Based on the evidence of adverse outcomes, professional sports leagues, college athletics associations, and the military were among the first to prohibit the use of these supplements among its members. Several states passed legislation banning the sale of Ephedra. The FDA was slower in announcing a national ban, likely because the DSHEA demanded such a high burden of proof. However, in testimony before the House Subcommittee on Commerce, Trade, and Consumer Protection72 in July 2003, FDA Commissioner Mark McClellan noted that there was now reasonable evidence that Ephedra-containing compounds pose a threat to the public health and have not been proven to offer the benefits often claimed by manufacturers. He went on to mention that though the FDA had not yet issued a formal ban, it was in the midst of implementing more stringent labeling and manufacturing requirements on these supplements and was launching investigations into manufacturers who make inaccurate or misleading claims. A formal ban was finally announced in December 2003 with implementation set for April 2004. Yet, even after this long and winding road towards regulation, the threat from Ephedra still exists. Recent commentaries73,74 have noted that the national ban has several loopholes. Extracts sold as dietary supplements and athletic enhancers are prohibited, but those marketed as herbal remedies are not. Moreover, compounds similar to Ephedra that technically do not fall into the Ephedra family of alkaloids are not covered by the ban. Synephrine, also known as bitter orange, is a prime example. This agent is derived from the fruit Citrus aurantium, an orange with a thick rind and very sour juice that is indigenous to Southeast Asia but has since been cultivated worldwide. Synephrine shares structural similarity with Ephedra alkaloids and other cathecholamines and has ␣-adrenergic properties. It may thus pose the same risks to consumers as its banned cousins, although supplements containing synephrine are often sold under the misleading phrase Ephedra free.

Conclusion The use of Ephedra alkaloids is associated with significant health risk and no significant health benefit. Despite a recently implemented FDA ban, they as well as related supplements remain on the market. Because of the widespread availability and deceptive advertising for these agents, physicians should question patients about use and discourage patients from taking them. Furthermore, physicians should actively encourage state and federal agencies to implement more comprehensive regulation of these potentially deadly substances.

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