Ephedra

Scientific Name(s): Ephedra sinica Stapf., Ephedra intermedia Schrenk et Meyer, or Ephedra equisetina Bge. Family: Ephedraceae (ephedra)

Common Name(s): Ephedra , ma huang , yellow horse , yellow astringent , pinellia .

Uses

The whole Ephedra sinica plant has traditionally been used to treat symptoms of bronchial asthma, colds, influenza, allergies, and hives in teas or tinctures. Because of adverse events and lack of efficacy, use is not recommended for weight loss or increased athletic performance. Ephedra-containing supplements are banned for sale in the United States.

Dosing

Ephedra-containing dietary supplements are currently banned in the United States. Dosages of ephedra more than 32 mg/day have resulted in adverse reactions.

Contraindications

Cardiovascular and cerebrovascular adverse events have been documented in case reports.

Pregnancy/Lactation

Documented adverse reactions. Avoid use.

Interactions

Interactions are likely to be similar to those established for synthetic ephedrine and include monoamine oxidase inhibitors (MAOIs), the anesthetic propofol, cholinergic agents such as tricyclic antidepressants, caffeine, theophylline, and steroids such as dexamethasone.

Adverse Reactions

Reported adverse reactions include arrhythmia and sudden death, myocardial infarction, stroke, psychiatric symptoms, autonomic hyperactivity, seizures, and ischemic colitis and gastric mucosal injury.

Toxicology

Toxicological data are limited. Periconceptional use of ephedra-containing products has been associated with an increased adjusted odds ratio for anencephaly.

Botany

Ephedra species grow as low, shrubby plants with small leaves on jointed, ribbed green stems. They are dioecious (ie, male and female flowers are usually found on separate plants). The 3-source species are native to China, where the aboveground parts are collected in the fall and dried for use. Ephedras are gymnosperms and are most closely related to conifers, although many aspects of their botany are different. About 45 Ephedra species exist, varying in their alkaloid content. American, Chilean, and European species are considered to be relatively low in alkaloid content, while Chinese and Indian varieties contain larger amounts of active alkaloids.

The root of E. sinica or E. intermedia , known as “ma huang gen,” is considered by Chinese traditional practitioners to be a distinct drug product from the aboveground parts. A chapter on ephedra has been included in the Flora of China , a collaborative plant project. 1 , 2 , 3 , 4 , 5

History

Ma huang is one of the earliest and best known drugs of Chinese traditional medicine. It is mentioned in the Shen Nong Ben Cao Jing , one of the premodern classics of Chinese medicine written around 100 AD. Ma huang was used to induce perspiration and treat the symptoms of bronchial asthma, colds, and influenza; it is still in traditional use today.

The earliest scientific work on ephedra, and consequently on ephedrine, is attributed to the Japanese organic chemist and pharmacologist Nagayoshi Nagai (1844 to 1929), followed by his colleague Kinnosuke Miura (1864 to 1950), who identified the potential toxicity of the alkaloids. As a weight loss agent, ephedra has been commonly combined with caffeine; however, more recently the ephedra component has been replaced with bitter orange in US dietary supplements. 1 , 5

Chemistry

Chemical investigations of ephedra in the early 20th century resulted in the isolation of the alkaloids ephedrine and pseudoephedrine, which were identified as the major pharmacologically active compounds in the aboveground portions of the plant. The ephedra alkaloids possess 2 adjacent chiral atoms that could generate 4 possible isomers for every planar structure; however, the plant produces only 2 of the possible isomers. 6 Synthetic ephedrine and pseudoephedrine are usually produced as a racemate, and therefore contain all of the possible isomers. A total of 6 major alkaloids of this type are found in the 3 species known as Ephedrae herba ; the major alkaloid of all species is ephedrine, with pseudoephedrine the next most abundant, and norephedrine, norpseudoephedrine, methylephedrine, and methylpseudoephedrine making up the balance. 7 The proportion of single alkaloids and total alkaloid content of the aboveground portions can vary widely, from 0.5% to 2.5%, with the highest concentration of alkaloids found in the fall. Biosynthesis of ephedra alkaloids has been studied; ephedrine is formed from pyruvate and benzoic acid. 8 , 9 The supercritical fluid extraction of ephedrine from E. sinica has been studied using a mixture of carbon dioxide, diethylamine, and methanol. 10

A large number of analytical methods for ephedra alkaloids have been devised. Gas chromatography has been used, as well as chiral gas chromatography and gas chromatography-mass spectrometry of both plant material and urine specimens. 11 , 12 , 13 , 14 Numerous high-performance liquid chromatography (HPLC) methods have been developed, 7 , 15 , 16 , 17 , 18 , 19 including analysis of urine samples 20 and a liquid chromatography-mass spectrometry method for dietary supplements. 21 Capillary electrophoresis and isotachophoresis also have been applied, with some methods using cyclodextrin as a matrix to resolve optically isomeric alkaloids. 22 , 23 , 24 , 25 , 26 , 27 Carbon-13 nuclear magnetic resonance also has been used to qualitatively and quantitatively analyze ephedra alkaloids. 28

Several systematic studies of alkaloid content in commercial ephedra samples have been conducted. One study used capillary electrophoresis to analyze 22 samples from Taiwan herbal markets and found that E. sinica samples were generally higher in alkaloid content than E. intermedia samples (1.6% vs 1.2%, respectively). The relative amounts of specific alkaloids in aboveground parts correlated well with the species studied, while root samples had no detectable alkaloids. 29 Because crude ephedra can be used as a starting substance for the synthesis of amphetamines, the profile of impurities was used to determine the origin of illicit amphetamine in Japan. 30 Another study examined 20 different dietary supplements from the United States market by HPLC and found that some products had no ephedra alkaloids, some had only ephedrine (suggesting the use of synthetic material), and others were properly labeled and contained the specified amount of alkaloid. 31 American species of ephedra have been found to be devoid of or have very low amounts of alkaloids. Thus, species such as Ephedra nevadensis (Mormon tea) are not appropriate substitutes. 32

Other types of compounds also have been isolated from ma huang. Tetramethylpyrazine has been identified as a pharmacologically active constituent of stems, and analytical methods have been developed. 14 , 33 , 34 In the roots, which do not contain appreciable amounts of ephedrine alkaloids, feruloylhistamine 35 and ephedradines A-D 36 , 37 were isolated. The flavonoid derivative ephedrannin A was also isolated from the root. 38 The polysaccharide ephedrans A-E have been isolated from ephedra stems. 39 The roots of ephedra have yielded a variety of hypotensive compounds, including the flavonoid ephedrannin A, 38 feruloylhistamine, 35 and the spermine alkaloids ephedradines A-D, 36 which were not found in the aboveground parts.

Uses and Pharmacology

The US Food and Drug Administration (FDA) first banned the sale of all dietary supplements containing ephedra in April 2004 based on a lack of evidence to support efficacy claims and more than 16,000 reported cases of adverse reactions. The ban was later overturned by a federal judge in April 2005 for products containing ephedra 10 mg or less. However, in May 2007, the ban was upheld by the US Supreme Court based on a final FDA regulation declaring dietary supplements containing adulterated ephedrine alkaloids as presenting an unreasonable risk of illness or injury under conditions of use recommended or suggested in the labeling, or if no conditions of use are suggested or recommended, under ordinary conditions of use. 40 , 41

Athletic performance
Animal data

Ephedra-containing dietary supplements are banned by the FDA, making data from animal studies of their use as a performance enhancer irrelevant.

Clinical data

The use of ephedra-containing products in sports has been reported. 42 , 43 , 44 Few trials evaluating the ergogenic efficacy of ephedrine alone exist, and results suggest slight effects on performance. 42 , 45 However, combinations of ephedrine and caffeine have been reported to increase endurance in running and cycling experiments. 44 , 45 Most studies have been conducted by one group, 46 , 47 and because of the different types of exercise studied (endurance and power), the results cannot be pooled for analysis. 45 Because most classes of amphetamines are banned by the International Olympic Committee (except for medical use of ephedrine) and ephedra-containing supplements are banned by the FDA, further trials evaluating their efficacy are unlikely. 42 , 43

Weight loss
Animal data

Ephedra-containing supplements are banned by the FDA, making data from animal studies for use as a weight-loss aid irrelevant.

Clinical data

A combination of ephedrine with a caffeine-containing supplement, such as guarana or cola nut, has been most frequently used for weight loss. 41 A meta-analysis evaluating the efficacy of ephedra in weight loss published in 2003 found few published high-quality trials. Of those trials included, the pooled data favored ephedra and ephedrine over placebo in the short-term (less than 6 months), with about 0.9 kg/month weight loss compared with placebo but with wide confidence limits. 45 Other reviews found similar results. 48 , 49 , 50 , 51 The few trials that have been published since the 2004 ban on ephedra products came to similar conclusions, with enhanced thermogenesis proposed as the mechanism of action. 41 , 52

Other effects
Antiviral

Activity against a limited range of viruses has been shown in some, but not all, in vitro studies. 53 , 54 , 55 Antimicrobial activity has been demonstrated in vitro by other Ephedra species ( Ephedra strobiliacea , Ephedra procera , and Ephedra pachyclada spp.). 56

Inflammatory

Ephedra extracts have shown anti-inflammatory and immune effects in experiments in rodents and in vitro studies. Complement activation was inhibited and E. sinica showed protective effects against sequelae of spinal cord injury in one experiment. 57 Chemical constituents ephedrannin A and B suppressed the transcription of tumor necrosis factor-alpha and interleukin-1 beta in macrophages and in induced hepatic failure in mice. 58 , 59 Ephedra constricted isolated rabbit urethra tissue, possibly via arachidonic acid pathways, and alpha-adrenoreceptor stimulation in another laboratory experiment. 60

Dosage

There is a ban on the sale of all ephedra-containing dietary supplements in the United States. Doses of ephedra greater than 32 mg/day have resulted in adverse reactions. 61

The pharmacokinetics of ephedra in humans have been studied, with ephedrine in crude herb requiring twice as long to reach the peak plasma concentration as pure ephedrine dosage forms. 62 Similarly, the combination of a single dose of ephedra and caffeine has been studied; ephedrine and pseudoephedrine had similar peak concentrations at 140 to 150 minutes, while caffeine blood levels peaked at 90 minutes. Overall results were similar to those of individual compounds in pure form. 63

Pregnancy/Lactation

Documented adverse reactions. Avoid use. 64 , 65 It may increase blood pressure and heart rate, cause CNS activity, and stimulate uterine muscle. Periconceptional use of ephedra-containing products has been associated with an increased adjusted odds ratio for anencephaly. 66

Interactions

Although natural forms of ephedra may contain different chemical constituents than those of ephedrine, in general, interactions are likely to be similar to those established for the synthetic form of the latter and include MAOIs, the anesthetic propofol, cholinergic agents such as tricyclic antidepressants, caffeine, theophylline, and steroids such as dexamethasone. 67 , 68 , 69

Adverse Reactions

A clear temporal association for cardiovascular and cerebrovascular adverse reactions and psychiatric symptoms has been shown with ephedra use, but a direct causal relationship is difficult to establish. 44 , 45 , 61 , 70 , 71 A 2- to 3-fold increased odds for risk of adverse psychiatric reactions and heart palpitations was found in one meta-analysis, with a trend toward an increase in risk for hypertension. 45 A review of case reports found a trend toward an increased risk for cardiovascular and cerebrovascular adverse reactions at doses lower than those used for weight loss (ephedra 32 mg/day vs 90 to 150 mg/day, respectively). 61

A clinical trial in which 20 healthy adults were given ephedra 1 g dry extract (or placebo) daily for 14 days found increases in heart rate after taking ephedra. 72 , 73

Case reports of adverse reactions continue to appear in the literature despite the FDA ban on ephedra products and include cardiomyopathies, arrhythmia and sudden death, myocardial infarction, coronary artery aneurysm, stroke, psychiatric symptoms, autonomic hyperactivity, and seizures. 44 , 45 , 49 , 52 , 61 , 65 , 71 , 74 , 75 , 76 , 77 , 78 , 79 Unfavorable effects on glucose and potassium homeostasis have also been demonstrated, and case reports of ischemic colitis and gastric mucosal injury also exist. 65 , 74 , 80 , 81

Toxicology

Toxicological data on ephedra are limited. While ephedra extracts are cytotoxic to cultivated cells, the cytotoxicity is not primarily caused by ephedrine. 49 , 82 N-nitrosamines of ephedrine and pseudoephedrine have been found to be formed under physiological conditions. N-nitrosoephedrine has been shown to be a carcinogen. 83 , 84 Periconceptional use of ephedra-containing products has been associated with an increased adjusted odds ratio for anencephaly. 66

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