Ephedra

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

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

Uses of Ephedra

The whole plant ma huang (ephedra) has been traditionally used to treat symptoms of bronchial asthma, colds, influenza, allergies, and hives in teas or tinctures. However, when the plant's amine alkaloids are concentrated out, use is not recommended, especially when combined with caffeine and other stimulating herbs for weight loss and increased athletic performance.

Ephedra Dosing

Sale of all ephedra-containing dietary supplements in the United States is currently banned. Doses of ephedra greater than 32 mg/day have resulted in adverse reactions.

Contraindications

Cardiovascular and cerebrovascular conditions as well as psychiatric and epileptic conditions have been affected.

Pregnancy/Lactation

Documented adverse reactions. Avoid use.

Ephedra Interactions

Ma huang is contraindicated with monoamine oxidase inhibitors (MAOIs).

Ephedra Adverse Reactions

Reported adverse reactions include arrhythmia and sudden death, myocardial infarction, stroke, psychiatric symptoms, autonomic hyperactivity, and seizures. Unfavorable effects on glucose and potassium homeostasis have also been demonstrated.

Toxicology

Toxicological data on ma huang/ephedra are limited.

Botany

Warning

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. 1

Ephedra species grow as low shrubby plants with small leaves on jointed, ribbed green stems. They are dioecious (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. The ephedras are gymnosperms and are most closely related to conifers, although many aspects of their botany are different. 2 , 3 , 4 The root of E. sinica or E. intermedia , known as “ma huang gen,” is considered to be the source of a distinct substance from the aboveground parts. A chapter on ephedra has been included in the Flora of China , a collaborative plant project. 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 pre-modern classics of Chinese medicine written around 100 AD. Ma huang was used to induce perspiration and to treat the symptoms of bronchial asthma, colds, and influenza, and is still in use today. 5

As a weight-loss agent, ma huang has been commonly combined with caffeine. The origin of this combination can be traced to a Danish physician's empirical observation in the early 1970s that obese asthma patients treated with a combination of ephedrine, caffeine, and phenobarbital lost weight. 6 His so-called “Elsinore pill” became popular in Denmark for weight loss. Because of skin rashes attributed to phenobarbital, this component of the combination was removed without affecting weight loss.

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 can form 4 possible isomers for every planar structure 7 ; however, the plant produces only 2 of the possible isomers. Synthetic ephedrine and pseudoephedrine are usually produced as a racemate. A total of 6 major alkaloids of this type are found in the 3 species known as ma huang; the major alkaloid of all species is ephedrine, with pseudoephedrine the next most abundant, and norephedrine, norpseudoephedrine, methylephedrine, and methylpseudoephedrine making up the balance. 8 The proportion of single alkaloids and total alkaloid content of the aboveground portions can vary widely, from 0.5% to 2.5%. The highest concentration of alkaloids is found in the fall. Biosynthesis of the ephedra alkaloids has been studied; ephedrine is formed from pyruvate and benzoic acid. 9 , 10 The supercritical fluid extraction of ephedrine from E. sinica has been studied using a mixture of carbon dioxide, diethylamine, and methanol. 11

Because of the importance of ephedrine, 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. 12 , 13 , 14 , 15 Numerous high-performance liquid chromatography (HPLC) methods have been developed, 8 , 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 confer resolution of optically isomeric alkaloids. 22 , 23 , 24 , 25 , 26 Carbon-13 nuclear magnetic resonance also has been used to qualitatively and quantitatively analyze ephedra alkaloids. 27

Several systematic studies of alkaloid content in commercial ephedra samples have been made. 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%) and that the relative amounts of specific alkaloids correlated well with the species studied. Root samples had no detectable alkaloids. 28 Because ephedrine 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. 29 Another study examined 20 different 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. 30 American species of ephedra have been found to be devoid of, or to have very low amounts of, alkaloids. Thus, such species as Ephedra nevadensis (Mormon tea) should not be regarded as appropriate substitutes for ma huang. 31

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 , 32 In the roots, which do not contain appreciable amounts of the ephedrine class of alkaloid, feruloylhistamine 33 and ephedradines A-D 34 , 35 were isolated. The flavonoid derivative ephedrannin A was also isolated from the root. 36 The polysaccharide ephedrans A-E have been isolated from ephedra stems. 37 The roots of ephedra have yielded a variety of hypotensive compounds, including the flavonoid ephedrannin A, 36 feruloylhistamine, 33 and the spermine alkaloids ephedradines A-D, 34 which have not been found in the aboveground parts.

Ephedra Uses and Pharmacology

Ephedrine is the main active principle of ephedra and has sympathomimetic activity. 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. 38 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 the individual compounds in pure form. 39

Athletic performance

The use of ephedra-containing products in sports has been reported. 40 , 41 , 42 Few trials evaluating the ergogenic efficacy of ephedrine alone exist, and results suggest slight effects on performance. 40 , 43 However, combinations of ephedrine and caffeine have been reported to increase endurance in running and cycling experiments. 42 , 43 Most studies have been conducted by one group, 44 , 45 and because of the different types of exercise studied (endurance and power), the results cannot be pooled for analysis. 43 Most classes of amphetamines are banned by the International Olympic Committee (except for medical use of ephedrine), and ma huang is banned by the FDA; therefore, further trials evaluating their efficacy are unlikely. 40 , 41

Weight loss

A combination of ma huang with a caffeine-containing supplement such as guarana or cola nut has been most frequently used for weight loss. 6 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. 43 Other reviews found similar results. 46 , 47 , 48 , 49 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. 6 , 50

Other uses

Experiments in animals have examined various activities of ephedra herb, including hypoglycemic, antitussive, anti-inflammatory, and antiviral actions. 37 , 51 , 52 , 53 , 54 , 55

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.

Pregnancy/Lactation

Documented adverse reactions. Avoid use. 56 Ma huang contains ephedrine and related alkaloids. It may increase blood pressure and heart rate, cause CNS activity, and stimulate uterine muscle.

Interactions

The potential for drug-ephedra interactions has been profiled; MAOIs are contraindicated with ephedra. 57

Adverse Reactions

When the amine alkaloids are concentrated out, especially when combined with caffeine and other stimulating herbs, use is not recommended. However, the whole plant in tea or tincture form has been useful for allergies, asthma, hayfever, and hives.

Reported adverse reactions include arrhythmia and sudden death, myocardial infarction, stroke, psychiatric symptoms, autonomic hyperactivity, and seizures. 42 , 43 , 47 , 50 , 58 , 59 , 60 , 61 , 62 Unfavorable effects on glucose and potassium homeostasis have also been demonstrated. 59

A clear temporal association for cardio- and cerebrovascular adverse reactions and psychiatric symptoms has been shown with ephedra use, but a direct causal relationship has been difficult to establish. 42 , 43 , 46 , 58 , 61 , 63 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 towards an increase in risk for hypertension. 43 A review of case-reports found a trend towards an increased risk for cardio- and cerebrovascular adverse reactions at doses lower than those used for weight loss (ephedra 32 mg/day vs 90 to 150 mg/day). 61

Toxicology

Toxicological data on ephedra are limited. While ephedra extracts are cytotoxic to cultivated cells, the cytotoxicity is not primarily caused by ephedrine. 47 , 63 N-nitrosamines of ephedrine and pseudoephedrine have been formed under physiological conditions. N-nitrosoephedrine has been shown to be a carcinogen. 64 , 65

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