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Ephedra

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

Medically reviewed by Drugs.com. Last updated on Jul 15, 2024.

Clinical Overview

Use

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.

Scientific Family

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.Lee 2011, USDA 2007, Chaw 2000, Bowe 2000, Fu 2000

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.Lee 2011, Fu 2000

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.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

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.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

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.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

Other effects

Antiviral

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

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.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

Dosing

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

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.Ulbricht 2008, Scott 2002, Tang 2011

Alkalinizing agents: Alkalinizing agents may increase the serum concentration of alpha-/beta-agonists (indirect-acting). Monitor therapy.Brater 1980, Kuntzman 1971, Wilkinson 1968, Zimmerman 1988, Zimmerman 1990

Alpha-1 blockers: Alpha-1 blockers may diminish the vasoconstricting effect of alpha-/beta-agonists. Similarly, alpha-/beta-agonists may antagonize alpha-1 blocker vasodilation. Monitor therapy.Amadesi 2001, Auvi-Q September 2012, Beretta-Piccoli 1985,, Harada 1999, Schafers 1999

Antihypertensive agents: Herbs (hypertensive properties) may diminish the antihypertensive effect of antihypertensive agents. Monitor therapy.Jalilil 2013

Antipsychotic agents (phenothiazines): Alpha-/Beta-agonists may enhance the arrhythmogenic effect of antipsychotic agents (phenothiazines). Thioridazine is of most concern. Consider therapy modification.Chouinard 1978, Forster 1954, Giles 1968, Yagiela 1985

Atomoxetine: Atomoxetine may enhance the hypertensive effect of sympathomimetics. Atomoxetine may enhance the tachycardic effect of sympathomimetics. Monitor therapy.Cantilena 2012, Hammerness 2009, Kelly 2005, Michelson 2003, Sofuoglu 2009, Spencer 2002, Strettera 2017

Benzylpenicilloyl polylysine: Alpha-/Beta-agonists may diminish the diagnostic effect of benzylpenicilloyl polylysine. Consider therapy modification.Pre-Pen October 2009

Cannabinoid-containing products: Cannabinoid-containing products may enhance the tachycardic effect of sympathomimetics. Monitor therapy.Benowitz 1977, Foltin 1987, Foltin 1990, Foltin 1995, Gash 1978, Lukas 1994, Williamson 2000

Carbonic anhydrous inhibitors: Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting). Monitor therapy.Brater 1980, Delbeke 19991, Kuntzman 1971, Wilkinson 1968, Zimmerman 1988, Zimmerman 1990

Chloroprocaine: Chloroprocaine may enhance the hypertensive effect of alpha-/beta-agonists. Monitor therapy.Clorotekal 2017, Nesacaine 2010

Clozapine: Clozapine may diminish the therapeutic effect of alpha-/beta-agonists. Monitor therapy.John 2010, Leung 2015

Cocaine (topical): Cocaine (topical) may enhance the hypertensive effect of sympathomimetics. Consider therapy modification.Ashchi 1995, Barnett 1998, Laffey 1999, Lormans 1992, McGovern 2015, Miller 1978, Nicholson 1995, Sundboll 2014

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of doxofylline. Monitor therapy.Doxofylline December 2015

Droxidopa: Ephedra may enhance the hypertensive effect of droxidopa. Monitor therapy.Northera February 2014

Ergot derivatives: Ergot derivatives may enhance the hypertensive effect of alpha-/beta-agonists. Ergot derivatives may enhance the vasoconstricting effect of alpha-/beta-agonists. Avoid combination.Cafergot March 2006, Chan 2011, DHE 45 July 2002, Ergonovine March 2009, Parlodal January 2012

Fentanyl: Alpha-/beta-agonists (indirect-acting) may decrease the serum concentration of fentanyl. Specifically, fentanyl nasal spray serum concentrations may decrease and onset of effect may be delayed. Monitor therapy. This interaction is only expected to occur with intranasally administered fentanyl.Lazanda June 2011

Guanethidine: Guanethidine may enhance the arrhythmogenic effect of sympathomimetics. Guanethidine may enhance the hypertensive effect of sympathomimetics. Monitor therapy.Deshmankar 1967, Gulati 1966, Ismelin July 2014, Laurence 1963, Muelheims 1965, Simonyi 1972

Hyaluronidase: Hyaluronidase may enhance the vasoconstricting effect of alpha-/beta-agonists. Consider therapy modification. Avoid the use of hyaluronidase to enhance dispersion or absorption of alpha-/beta-agonists. Use of hyaluronidase for other purposes in patients receiving alpha-/beta-agonists may be considered as clinically indicated.Hylenex August 2011

Inhalational anesthetics: Ephedra may enhance the arrhythmogenic effect of inhalational anesthetics. Avoid combination.Ephedrine sulfate February 2005, Hahm 2007, Takaori 1965, Tucker 1974

Iobenguane: Alpha-/Beta-agonists (indirect-acting) may diminish the therapeutic effect of iobenguane radiopharmaceutical products. Avoid combination.AdreView March 2013, Azedra July 2018

Linezolid: Linezolid may enhance the hypertensive effect of sympathomimetics. Consider therapy modification.Hendershot 2001, Zyvox June 2010,

Monoamine oxidase inhibitors: Monoamine wxidase inhibitors may enhance the hypertensive effect of alpha-/beta-agonists (indirect-acting). While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination.Dingemanse 1993,, Dingemanse 1996, Elis 1967, Harrison 1989, Jenkins 1965, Low-Beer 1963, Wright 1978

Serotonin/Norepinephrine reuptake inhibitors: Serotonin/Norepinephrine reuptake inhibitors may enhance the tachycardic effect of alpha-/beta-agonists. Serotonin/Norepinephrine reuptake inhibitors may enhance the vasopressor effect of alpha-/beta-agonists. Consider therapy modification.Anon 1978, Boakes 1973, Cymbalta August 2008, Effexor February 2008, Gershon 1962, Khurana 2003, Knoll-Kohler 1989, Meechan 2002, Mitchell 1970, Prestiq April 2008, Stevens 2008, Svedmyr 1968

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of solriamfetol. Monitor therapy.Sunosi March 2019

Spironolactone: Spironolactone may diminish the vasoconstricting effect of alpha-/beta-agonists. Monitor therapy.Aldactone January 2008

Sympathomimetics: Sympathomimetics may enhance the adverse/toxic effect of other sympathomimetics. Monitor therapy.Foradil September 2001, ProAmatine February 2017

Tedizolid: Tedizolid may enhance the hypertensive effect of sympathomimetics. Tedizolid may enhance the tachycardic effect of sympathomimetics. Monitor therapy.Flanagan 2013, Hendershot 2001, Sivextro June 2014, Zyvox September 2013

Urinary acidifying agents: Urinary acidifying agents may decrease the serum concentration of alpha-/beta-agonists (indirect-acting). Monitor therapy.Kuntzman 1971, Wilkinson 1968, Zimmerman 1988

Ma huang drug interactions (more detail)

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.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

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.Chen 2010, Chen 2010

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

A case of acute bilateral angle-closure glaucoma was reported in a 52-year-old female associated with ma-huang within 24 hours of first dose. She had no past medical history and presented in the emergency department with acute bilateral ocular pain, decreased visual acuity, headache, nausea, and vomiting.Ryu 2017

Data collected between 2004 and 2013 from 8 US centers in the Drug-induced Liver Injury Network revealed that 15.5% (130) of hepatotoxicity cases were caused by herbals and dietary supplements, whereas 85% (709) of cases were related to prescription medications. Of the 130 cases of liver injury related to supplements, 65% were from non-bodybuilding supplements and occurred most often in Hispanics/Latinos compared with 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 proportion of severe liver injury cases was significantly higher for supplements than for conventional medications (P=0.02). Of the 217 supplement products implicated in liver injury, 175 had identifiable ingredients, of which ephedra was among the 32 (18%) single-ingredient products.Navarro 2014 The European Association for the Study of the Liver (EASL) clinical practice guideline for drug-induced liver injury (2019) recommends physicians consider herbal and dietary supplements as potential causative agents associated with liver injury (Level 4; Grade C), including ephedra (Ma Huang).EASL 2019

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

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Toxicology

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

References

Disclaimer

This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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