Scientific Name(s): Ephedra equisetina Bge., Ephedra intermedia Schrenk et Meyer, Ephedra sinica Stapf.
Common Name(s): Ephedra, Ma huang, Pinellia, Yellow astringent, Yellow horse
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.Lee 2011, USDA 2007, Chaw 2000, Bowe 2000, Fu 2000
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.Lee 2011, Fu 2000
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.Freudenberg 1932 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.Jian 1988 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.Grue-Srensen 1988, Grue-Srensen 1994 The supercritical fluid extraction of ephedrine from E. sinica has been studied using a mixture of carbon dioxide, diethylamine, and methanol.Choi 1999
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.Cui 1991, Betz 1997, Li 2001, Spyridaki 2001 Numerous high-performance liquid chromatography (HPLC) methods have been developedJian 1988, Moriyasu 1984, Gurley 1998, Hurlbut 1998, Li 2002, Hong 2011 including analysis of urine samplesGmeiner 2002 and a liquid chromatography-mass spectrometry method for dietary supplements.Gay 2001 Capillary electrophoresis and isotachophoresis also have been applied, with some methods using cyclodextrin as a matrix to resolve optically isomeric alkaloids.Kasahara 1985, Snopek 1988, Liu 1992, Liu 1993, Flurer 1995, Belder 2011 Carbon-13 nuclear magnetic resonance also has been used to qualitatively and quantitatively analyze ephedra alkaloids.Yamasaki 1979
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.Liu 1993 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.Makino 2002 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.Gurley 2000 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.Terry 1927
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.Spyridaki 2001, Lv 2000, Zhao 2009 In the roots, which do not contain appreciable amounts of ephedrine alkaloids, feruloylhistamineHikino 1984 and ephedradines A-DHikino 1983, Tamada 1979 were isolated. The flavonoid derivative ephedrannin A was also isolated from the root.Hikino 1982 The polysaccharide ephedrans A-E have been isolated from ephedra stems.Konno 1985 The roots of ephedra have yielded a variety of hypotensive compounds, including the flavonoid ephedrannin AHikino 1982 feruloylhistamineHikino 1984 and the spermine alkaloids ephedradines A-DHikino 1983 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.FDA 2012, Greenway 2001
Ephedra-containing dietary supplements are banned by the FDA, making data from animal studies of their use as a performance enhancer irrelevant.
The use of ephedra-containing products in sports has been reported.Tokish 2004, Avois 2006, Dhar 2005 Few trials evaluating the ergogenic efficacy of ephedrine alone exist, and results suggest slight effects on performance.Tokish 2004, Shekelle 2003 However, combinations of ephedrine and caffeine have been reported to increase endurance in running and cycling experiments.Dhar 2005, Shekelle 2003 Most studies have been conducted by one groupBell 2001, Bell 2002 and because of the different types of exercise studied (endurance and power), the results cannot be pooled for analysis.Shekelle 2003 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.Tokish 2004, Avois 2006
Ephedra-containing supplements are banned by the FDA, making data from animal studies for use as a weight-loss aid irrelevant.
A combination of ephedrine with a caffeine-containing supplement, such as guarana or cola nut, has been most frequently used for weight loss.Greenway 2001 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.Shekelle 2003 Other reviews found similar results.Pittler 2005, Joyal 2004, Dwyer 2005, Dulloo 2002 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.Greenway 2001, Vukovich 2005 Whereas a variety of herbals (including ephedra) were shown to effectively decrease appetite and food intake in a 2009 systematic review of herbals used for management of obesity, significant adverse effects were reported only in studies using supplements containing ephedra and caffeine.Hasani-Ranjbar 2009 A more recent study in 7 volunteers attributed the weight loss activity of ephedra correlated to the changes in gut microbiota induced by ephedra consumption.Kim 2014
Activity against a limited range of viruses has been shown in some, but not all, in vitro studies.Soltan 2009, Murakami 2008, Lee 2010 Antimicrobial activity has been demonstrated in vitro by other Ephedra species (Ephedra strobiliacea, Ephedra procera, and Ephedra pachyclada spp.).Parsaeimehr 2010
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.Li 2009 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.Kim 2010, Yamada 2008 Ephedra constricted isolated rabbit urethra tissue, possibly via arachidonic acid pathways, and alpha-adrenoreceptor stimulation in another laboratory experiment.Ayajiki 2008
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.Andraws 2005
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.White 1997 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.Haller 2002
Pregnancy / Lactation
Documented adverse reactions. Avoid use.Ernst 2002, Fleming 2008 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.Bitsko 2008
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.Ulbricht 2008, Scott 2002, Tang 2011
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.Dhar 2005, Shekelle 2003, Andraws 2005, Figueredo 2011, Maglione 2005 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.Shekelle 2003 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).Andraws 2005
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.Dhar 2005, Shekelle 2003, Joyal 2004, Vukovich 2005, Andraws 2005, Fleming 2008, Maglione 2005, Haller 2005, Haller 2005, Flanagan 2010, Nazeri 2009, Singh 2008, Cohen 2010 Unfavorable effects on glucose and potassium homeostasis have also been demonstrated, and case reports of ischemic colitis and gastric mucosal injury also exist.Fleming 2008, Haller 2005, Lillegard 2010, Song 2008
Data collected between 2004 and 2013 among 8 US centers in the Drug-induced Liver Injury Network revealed 15.5% (130) of hepatotoxicity cases was caused by herbals and dietary supplements whereas 85% (709) were related to medications. Of the 130 related cases of liver injury related to supplements, 65% were from non-bodybuilding supplements and occurred most often in Hispanic/Latinos compared to non-Hispanic whites and non-Hispanic blacks. Liver transplant was also more frequent with toxicity from non-bodybuilding supplements (13%) than with conventional medications (3%) (P<0.001). Overall, the number of severe liver injury cases was significantly higher from supplements than conventional medications (P=0.02). Of the 217 supplement products implicated in liver injury, ephedra was among the 22% (116) of the single-ingredient products.Navarro 2014
In the 2016 Scientific Statement by the American Heart Association regarding drugs that may cause or exacerbate heart failure, ephedra (ma-huang) and ephedra-like products have been recognized as products with stimulant effects on blood pressure and heart rate as well as an increased risk of mortality and morbidity, and should be avoided. The guidance noted that naturoceuticals are not recommended for the management of heart failure symptoms or for the secondary prevention of cardiovascular events, and that nutritional supplements are not recommended for the treatment of heart failure [Low-quality; Limited].Page 2016
Toxicological data on ephedra are limited. While ephedra extracts are cytotoxic to cultivated cells, the cytotoxicity is not primarily caused by ephedrine.Joyal 2004, Lee 2000 N-nitrosamines of ephedrine and pseudoephedrine have been found to be formed under physiological conditions. N-nitrosoephedrine has been shown to be a carcinogen.Alwan 1986, Tricker 1987 Periconceptional use of ephedra-containing products has been associated with an increased adjusted odds ratio for anencephaly.Bitsko 2008
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