Efedra

Ephedra (Ephedra sinica and Related Species)

1. Identity and Botanical Description

Taxonomy and Nomenclature

The genus Ephedra of the family Ephedraceae contains more than 60 species of nonflowering seed plants distributed throughout Asia, America, Europe, and North Africa. The species most commonly referenced in medicine and dietary supplementation are Ephedra sinica Stapf, Ephedra intermedia Schrenk & C.A. Mey., and Ephedra equisetina Bge. Ephedrae herba, commonly referred to as Mahuang (麻黄) in Chinese, is the dried herbaceous stem of these three officially recognized pharmacopeial species, as codified by the Chinese Pharmacopoeia Commission (2020).

Ephedra sinica is the species most widely used for its medicinal properties and is found growing wild in Mongolia, the southeastern provinces of Russia, and in northeastern China. Among North American species, the genus includes plants commonly known as joint firs and Mormon tea — including green Mormon tea (E. viridis), California joint fir (E. californica), Nevada joint fir (E. nevadensis), rough joint fir (E. aspera), and Torrey's Mormon tea (E. torreyana). These plants have been used by indigenous peoples and pioneers as sources of food and medicinals, and stem fragments are used in a tea-like preparation known variously as Mormon tea, Mexican tea, and desert tea.

Common Names and Forms

Ephedra is known by numerous common names across cultures: Ma Huang (麻黄) in Traditional Chinese Medicine; Mormon tea, Indian tea, and desert tea for North American species; and Somlata or Soma in certain South Asian traditions. The dried stems and leaves of the Ephedra plant can be prepared as capsules, tablets, tinctures, and teas. In China, the drug Ma Huang has always been defined in Chinese Materia Medica texts as the aerial parts of several species of Ephedra. The less commonly used root of Ephedra species is known as Ma Huang Gen, which has long been seen as acting in opposition to the aerial parts — for example, being prescribed for checking excessive perspiration of a weak patient.

Alkaloid Content by Species

Some species in the Ephedra genus have no alkaloid content and are therefore essentially inert. However, the most commonly used species, E. sinica, has a total alkaloid content of 1–3% by dry weight. Ephedrine constitutes 40–90% of the alkaloid content, with the remainder consisting of pseudoephedrine and the demethylated forms of each compound. The total content of ephedrine and pseudoephedrine, determined by UPLC-UV, has been found to vary between 20.8 mg/g dry weight (E. distachya subsp. helvetica) and 34.7 mg/g dry weight (E. monosperma).

2. Traditional and Historical Use

Traditional Chinese Medicine (TCM)

Ephedrae herba is an ancient herbal medicine with a broad spectrum of pharmacological activities that has been used for thousands of years in China, and is one of the most commonly used herbal components of TCM formulas. Known and used for at least 5,000 years in TCM, Ephedra sinica (called Ma Huang in Chinese) is the plant from which ephedrine is derived. Around 2,700 BC, it was described in the famous work attributed to the Chinese emperor Shen Nung.

Ma Huang is a plant used in Traditional Chinese Medicine for a wide range of conditions, and is most famous today as a treatment for asthma. Classically, Ephedra and its compound preparations have been used for colds, bronchial asthma, and nasal congestion. Ephedra sinica shows significant activity in asthma, fever, rheumatoid arthritis, and also promotes diuresis and sweating.

Ayurvedic and South Asian Traditions

Ephedra has been a common herbal medicine in China for thousands of years, and several species are important in Ayurvedic medicine. Derived from the dried rhizome and root of the plant, ephedra has been used as a medicinal herb for thousands of years in India, China, and Japan, and is commonly consumed in low doses and in combination with other herbs to promote urination and to treat asthma, bronchitis, and coughs. In Ayurvedic contexts, Ephedra gerardiana, native to the high-altitude Himalayan region, has been associated with the Sanskrit name Somlata and used to treat respiratory disorders, fever, and difficulty in urination.

North American Indigenous and Pioneer Use

Native Americans and Mormon pioneers drank a tea brewed from other Ephedra species, called "Mormon tea" and "Indian tea." American Ephedra has been used for millennia by native people in the American West as a medicine, known for its use in addressing urinary and breathing difficulties, as well as occasional digestive distress. The common name "Mormon tea" originates from the 19th-century LDS (Latter-day Saint) pioneers who settled in the American West. In keeping with their religious prohibition on hot drinks — interpreted to mean coffee and tea — they brewed a caffeine-free infusion from American species of Ephedra as an alternative.

Isolation of Ephedrine in the Modern Era

In 1923, scientists discovered that the Ma Huang plant has two primary active ingredients: ephedrine (2-methylamino-1-phenyl-1-propanol) and pseudoephedrine — the same drugs commonly used in many nasal decongestant medications. This discovery, largely driven by K.K. Chen working in conjunction with C.F. Schmidt, catalyzed Western pharmaceutical interest in the plant and ultimately led to the synthetic manufacture of ephedrine for clinical use.

3. Key Constituents and Active Compounds

Overall Phytochemical Profile

Approximately 281 chemical constituents have been isolated from Ephedrae herba, including alkaloids, flavonoids, tannins, polysaccharides, volatile oils, organic acids, and other compounds. Among these constituents, alkaloids and volatile oils are the most abundant and represent the major bioactive constituents.

The pharmacological properties are mainly determined by various chemical constituents, including alkaloids, flavonoids, polysaccharides, organic acids, tannins, and volatile oils. Ephedra herbs contain roughly 0.15% of volatile oils comprising more than 200 different chemicals including alcohols and terpenes.

Alkaloids: Primary Bioactive Components

Alkaloids are the main active components of Ephedra, of which a total of 29 have been identified. The contents of three pairs of stereoisomeric amphetamine alkaloids are highest: L-ephedrine and D-pseudoephedrine, L-norephedrine and D-norpseudoephedrine, and L-methylephedrine and D-methylpseudoephedrine. These three pairs of stereoisomers are generally considered to be the active ingredients of Ephedra and are collectively referred to as ephedrines.

Despite originating from the same plant, Ephedrae herba (stem) and Ephedrae radix et rhizoma (root) contain distinct types of alkaloids, resulting in differences in clinical applications. Phenylpropanoid alkaloids constitute the alkaloid component of the Ephedra stem, whereas macrocyclic spermine alkaloids are found in the Ephedra root.

The medicinal significance of Ephedra is based on the sympathomimetic properties of ephedrine-type alkaloids. Ephedrine, pseudoephedrine, methylephedrine, norpseudoephedrine, and norephedrine have all been extracted from the Ma Huang plant. However, ephedrine and pseudoephedrine are the only two active components found consistently in Ma Huang products, with ephedrine being the predominant alkaloid; the other alkaloids are usually found only in small or trace amounts.

Non-Alkaloid Constituents

Ephedra contains flavonoids — including leucodelphinidin, leucopelargonine, leucoanthocyanidin, lucenine, vicenin-1, and vicenin-2 — as well as tannins and benzylmethylamine. The non-alkaloid components exhibit antioxidant, immunosuppressive, and hypoglycemic properties. Evidence shows that Ephedra extracts without alkaloids have similar efficacy in treating some diseases with no adverse reactions.

4. Mechanisms of Action

Sympathomimetic Activity of Ephedrine

Ephedrine sulfate is a sympathomimetic amine that directly acts as an agonist at α- and β-adrenergic receptors and indirectly causes the release of norepinephrine from sympathetic neurons. Initial studies classified ephedrine as an indirectly acting sympathomimetic; subsequent studies showed that ephedrine acts by a mixed action — by releasing noradrenaline and by acting directly on receptors. However, some recent studies in rats have shown a predominant direct action on adrenergic receptors.

The physiological consequences of adrenergic receptor activation are well characterized. Stimulation of alpha-1-adrenergic smooth muscle receptors within vasculature results in a rise in systemic vascular resistance and, consequently, systolic and diastolic blood pressure. Direct stimulation of beta-1 receptors by ephedrine and norepinephrine increases cardiac chronotropy and inotropy. Finally, beta-2-adrenergic receptor stimulation in the lungs results in bronchodilation with ephedrine administration, though it is not as pronounced as its cardiovascular effects.

Thermogenic and Lipolytic Mechanisms

Ephedrine has been used alone or in combination with other drugs as a weight-loss agent. The weight loss has been attributed to thermogenic and lipolytic effects which, in combination with central nervous system-stimulating effects, have also resulted in its use as an ergogenic aid. Ephedra is both a stimulant and a thermogenic; its biological effects are due primarily to its ephedrine and pseudoephedrine content.

Tachyphylaxis

Classically considered to exert its effects primarily by an indirect, "tyramine-like" sympathomimetic mechanism, ephedrine exhibits tachyphylaxis (acute tolerance) when administered repeatedly. More recent studies indicate that ephedrine also exerts direct effects (at least in rats and mice) mediated by direct stimulation of adrenergic receptors and/or trace amine-associated receptors (e.g., TAAR1).

Tolerance to ephedrine sulfate may develop, but temporary discontinuance of the drug restores its original effectiveness.

Pseudoephedrine's Distinct Action

Ephedrine alkaloids also function as indirect adrenoreceptor agonists, augmenting the availability and action of norepinephrine in the brain and in the heart. Unlike pseudoephedrine, ephedrine also mediates its effects via circulating epinephrine and is a bronchial dilator that has been used in the treatment of asthma.

5. Scientific Evidence by Area of Application

5.1 Weight Loss and Obesity

The U.S. Food and Drug Administration (FDA) banned the sale of dietary supplements containing ephedrine alkaloids in the United States in 2004. Prior to the ban, ephedra was an ingredient in some dietary supplements promoted for weight loss, increased energy, and enhanced athletic performance.

The most comprehensive pre-ban synthesis of evidence came from a RAND Corporation evidence report commissioned by NIH and AHRQ. RAND identified 52 controlled clinical trials of synthetic ephedrine or botanical ephedra used for weight loss or athletic performance in humans.

The principal published meta-analysis from this work (Shekelle et al., 2003, JAMA) concluded that ephedrine and ephedra promote modest short-term weight loss — approximately 0.9 kg per month more than placebo — in clinical trials. There are no data regarding long-term weight loss, and evidence to support use of ephedra for athletic performance is insufficient.

A separate meta-analytic review examining controlled trials confirmed that ephedra and ephedrine provide modest, short-term improvements in weight loss, but are associated with increased rates of side effects. When ephedrine was combined with caffeine, three trials compared ephedrine plus caffeine with ephedrine alone, and the pooled estimate of the rate of weight loss for the combined group was an effect size of −0.31 (95% CI: −0.60, −0.02), equating to a weight loss of 0.8 pounds per month more for ephedrine plus caffeine compared with ephedrine alone.

Prior to the ban, research showed that dietary supplements containing ephedrine alkaloids — usually in combination with caffeine — had modest short-term effects on weight loss. However, this benefit was considered insufficient to outweigh the serious risks of these supplements. No studies had assessed long-term effects on weight.

Regarding dosages studied in human trials, doses of ephedrine and related compounds in obesity studies ranged from 60 to 150 mg/day.

Evidence strength: Modest and consistent short-term evidence for weight loss exists from multiple randomized controlled trials, but the evidence is limited to short timeframes, and all long-term data are absent. The risk-benefit calculation led to regulatory prohibition in the United States.

5.2 Athletic Performance Enhancement

Both the International Olympic Committee and the National Collegiate Athletics Association have banned ephedrine and ephedrine alkaloids. Evidence regarding athletic performance was insufficient to allow any conclusions to be reached in the pre-ban evidence review commissioned by the NIH and AHRQ. Ephedrine appears to be an effective CNS stimulant with thermogenic and lipolytic effects. However, its ergogenic advantages are highly debatable, and the dangers associated with its immediate and prolonged use are well documented.

Evidence strength: Insufficient. The evidence base on athletic performance was too small and inconsistent to support conclusions, and no post-ban human trials have been conducted.

5.3 Respiratory and Bronchodilator Effects

Ephedra, which has multiple targets and multiple function pathways, can effectively be used for the treatment of asthma. The ephedrine, pseudoephedrine, and volatile oils contained in Ephedra have antiasthmatic effects, among which ephedrine is the most powerful. Ephedra can be used clinically to treat asthma because it can regulate the immune imbalance in Th1/Th2 and Th17/Treg cells.

Synthetic ephedrine and pseudoephedrine are found in over-the-counter decongestants and cold medicines and are used to treat asthma. Ephedrine is not approved in the United States as a drug for weight loss or to enhance athletic performance. Derivatives of ephedrine are used to treat low blood pressure, but alternatives with reduced cardiovascular risk have replaced it for treating asthma.

Evidence strength: The bronchodilatory mechanism of ephedrine is pharmacologically well-established. Its use in asthma treatment has largely been supplanted by more selective and safer agents (e.g., selective β₂ agonists), but the physiological basis of its airway effects is not disputed.

5.4 Nasal Decongestion

Alpha-adrenergic receptor activation results in vasoconstriction, which can contribute to increased blood pressure and alleviate nasal congestion by reducing blood flow to the nasal passages. Pseudoephedrine, one of the primary alkaloids of Ephedra, remains in widespread regulated use globally as a nasal decongestant in over-the-counter cold and flu preparations.

Evidence strength: Well-established for isolated pseudoephedrine and ephedrine in pharmaceutical contexts. Evidence specific to the whole herbal preparation (Ephedrae herba) for decongestion in humans is less systematically studied.

5.5 Cardiovascular and Vasopressor Uses

Ephedrine stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Ephedrine is used as a pressor agent during spinal anesthesia when hypotension frequently occurs. Intravenous ephedrine produces a more favorable prolonged pressor response compared to phenylephrine, accompanied by a sustained increase in heart rate, stroke volume, and cardiac index.

Evidence strength: The use of injectable ephedrine sulfate as a vasopressor in clinical anesthesia settings is supported by substantial evidence and is an FDA-approved drug application, distinct from dietary supplement use.

5.6 Anti-inflammatory, Antiviral, and Other Pharmacological Activities

In vitro and in vivo pharmacological studies on the crude extracts, fractions, and isolated compounds of Ephedra species showed anti-inflammatory, anticancer, antibacterial, antioxidant, hepatoprotective, anti-obesity, antiviral, and diuretic activities. Ephedrae herba's multiple pharmacological activities include a diuretic effect, anti-allergic effect, blood pressure regulatory effect, anti-inflammatory effect, anti-oxidation effect, and anti-viral effect.

Evidence strength: Preliminary. The majority of findings in these non-weight-loss domains are based on in vitro or animal models. Human clinical trials in these areas are sparse, and robust conclusions cannot be drawn.

6. Body Systems and Health Areas

• Respiratory system: Bronchodilation, relief of asthma and bronchospasm, nasal decongestion; historically one of the most prominent therapeutic uses.
• Cardiovascular system: Modern medical studies have shown that Ephedra has a wide range of pharmacological effects on the central nervous system, cardiovascular system, and smooth muscle. Its stimulant action increases heart rate, contractility, and blood pressure.
• Central nervous system: CNS stimulation, increased alertness, reduced fatigue; these properties have driven its use as a performance-enhancing and weight-loss supplement.
• Metabolic/endocrine system: Thermogenesis and increased energy expenditure via sympathetic stimulation; lipolytic effects studied primarily in the context of obesity.
• Immune system: Modern pharmacological studies show that Ephedra sinica has excellent medicinal value, with effects including anti-inflammatory and immunomodulatory effects.
• Urinary/renal system: Traditional use for promoting diuresis, documented across TCM and indigenous traditions.

7. Dosage Forms and Reported Dosages

The dried stems and leaves of the Ephedra plant can be prepared as capsules, tablets, tinctures, and teas. As a dietary supplement prior to the U.S. ban, it was commonly sold in standardized extract capsules. Doses of ephedrine and related compounds in human obesity studies ranged from 60 to 150 mg per day.

Dosages of ephedra more than 32 mg/day have been associated with adverse reactions in case reports reviewed in the regulatory literature. For prescription ephedrine, adults are instructed not to exceed 150 mg per day; 75 mg per day for children.

It is important to note that the alkaloid content of herbal preparations varies considerably between species and preparations, making standardization a significant challenge. Pharmacological effects depend on the phytocomposition of individual Ephedra species.

8. Safety Considerations and Drug Interactions

Regulatory Status

The FDA concluded in 2004 that all dietary supplements containing ephedra alkaloids pose a risk of serious adverse health events — including heart attack, stroke, and death — and issued a final rule stating that dietary supplement products containing ephedrine alkaloids cannot be legally sold or marketed in the United States. The final rule took effect on April 12, 2004.

Following the ban, there is a direct relation between the FDA's ban on ephedra sales and a sharp reduction in ephedra-related adverse events reported to U.S. poison centers. The number of poisonings resulting in major effects or deaths decreased by more than 98% since 2002. The 2004 FDA ban proved to be a very effective means of limiting the availability of ephedra and therefore its potential toxicity in the United States.

Outside the United States, ephedra is still used in traditional medicine for weight loss and other therapeutic purposes in Asian countries such as China, the Republic of Korea, and Japan, often in combination with other herbs.

Some supplements contain "ephedra extracts" but do not contain ephedrine alkaloids, so these can be sold legally in the U.S.

Documented Adverse Events

Even in relatively low doses and short-term use, ephedra has been linked to harmful effects like high blood pressure, heart attack, seizure, stroke, and psychosis. Ephedra can be life-threatening or disabling in some people. Ephedra can also cause anxiety, dizziness, dry mouth, headache, heartburn, insomnia, irritability, nausea, personality changes, and other symptoms.

A review of 140 adverse event reports related to the use of dietary supplements containing ephedrine submitted to the FDA between 1997 and 1999 concluded that 31% of reports were "definitely" or "probably" related to the use of ephedrine-containing supplements, and another 31% were deemed "possibly" related. Among adverse events deemed possibly, probably, or definitely related to ephedrine, 47% involved the cardiovascular system and 18% involved the central nervous system. Reported events included hypertension (17 reports), palpitations/tachycardia (13 reports), stroke (10 reports), and seizures (7 reports). Ten events resulted in death, and 13 events produced permanent disability.

Approximately half of the adverse effects of ephedra reported to the FDA are cardiovascular, including coronary artery constriction, vasospasm, arrhythmias, and diseases secondary to hypertension due to the overactivation of the sympathetic nervous system.

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

Use of ephedra or ephedrine and caffeine is associated with increased risk of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations.

No serious adverse events — including death, myocardial infarction, cerebrovascular/stroke events, seizure, or serious psychiatric events — were reported within the 52 controlled clinical trials themselves. However, the controlled trial populations were generally younger and healthier, and trials were short-term, meaning serious events documented in case report literature were not captured in the trial framework.

Drug and Substance Interactions

Ephedrine may interact with other adrenalin-like drugs, MAO inhibitors, beta-blockers, blood pressure medicine, tricyclic antidepressants, diuretics (water pills), digoxin, atropine, theophylline, oxytocin, or St. John's Wort.

The interaction with monoamine oxidase inhibitors (MAOIs) is particularly serious. Monoamine oxidase inhibitors may potentiate the pressor effect of ephedrine sulfate, possibly resulting in a hypertensive crisis. Ephedrine sulfate should not be administered during or within 14 days following the administration of MAO inhibitors. The mechanism involves inhibition of intraneuronal norepinephrine breakdown in sympathetic nerves by MAO inhibitors, leading to an increase in the amount of neuromediator released by pseudoephedrine/ephedrine, which may lead to hypertensive crisis and bradycardia. Due to the long duration of action of MAO inhibitors, a 14-day interval between taking the drugs should be maintained.

Further specific interactions documented include: digoxin, with concomitant use potentially causing arrhythmia; ergot derivatives, which may enhance the hypertensive effect of ephedrine; and inhalation anesthetics, which may sensitize the heart to arrhythmic actions of ephedrine.

Special care should be used when administering ephedrine to patients with heart disease, angina pectoris, diabetes, hyperthyroidism, prostatic hypertrophy, or hypertension, and to patients receiving digitalis.

Contraindications to pseudoephedrine (and by pharmacological extension, ephedrine) use include hypersensitivity to the drug, cardiovascular diseases such as hypertension and coronary artery disease, impaired function of organs responsible for drug elimination including severe liver or moderate-to-severe renal dysfunction, hyperthyroidism, narrow-angle glaucoma, benign prostatic hyperplasia, diabetes mellitus, and mental agitation.

Concerns surrounding adverse effects have resulted in restrictions on ephedra's use based on patient characteristics such as heart disease, hypertension, diabetes, anxiety, and glaucoma.

Tachyphylaxis and Alkaloid Toxicity

Ephedra alkaloids represent the main cause of toxic reactions. Repeated administration leads to tachyphylaxis, meaning that users may escalate doses to achieve the same effect — a pattern that raises the risk of dose-dependent adverse events. Prolonged use may produce a syndrome resembling an anxiety state.

References

• Phytochemistry and pharmacology of genus Ephedra – PubMed (2018)
• Chemical composition of various Ephedra species – PMC/NIH (2015)
• Ephedrae Herba: A Review of Its Phytochemistry, Pharmacology, Clinical Application, and Alkaloid Toxicity – PMC (2023)
• Ephedrae herba: A comprehensive review of its traditional uses, phytochemistry, pharmacology, and toxicology – ScienceDirect (2023)
• Exploration of chemical components in eight Ephedra species based on HS-GC-MS and UPLC-Q-TOF-MS – PMC/Frontiers in Plant Science (2024)
• Ephedra: Usefulness and Safety – National Center for Complementary and Integrative Health (NCCIH)
• Ephedra and Ephedrine Alkaloids for Weight Loss and Athletic Performance – NIH Office of Dietary Supplements
• Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects – AHRQ Evidence Report/NCBI Bookshelf
• Ephedra and ephedrine for weight loss and athletic performance enhancement – Database of Abstracts of Reviews of Effects (DARE)/NCBI Bookshelf
• Shekelle PG et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003 – PubMed
• Ephedrine – StatPearls/NIH NCBI Bookshelf
• Ephedrine Sulfate Label – U.S. FDA (2022)
• FDA Import Alert 54-13: Ephedra Final Rule – U.S. FDA (2004)
• Reduction in Ephedra Poisonings after FDA Ban – New England Journal of Medicine (2015)
• Ephedra and Its Application to Sport Performance: Another Concern for the Athletic Trainer? – PMC (2003)
• Efficacy and safety of ephedra-containing oral medications: a systematic review, meta-analysis, and exploratory dose–response analysis – Frontiers in Pharmacology/PMC (2024)
• Over a century since ephedrine discovery: an updated revisit to its pharmacological aspects, functionality and toxicity – Food & Function, RSC Publishing (2021)
• Cardiovascular Effects of Ephedra Alkaloids: A Comprehensive Review – ScienceDirect (2004)
• Pseudoephedrine — Benefits and Risks – PMC/NIH (2021)
• An Amide Alkaloid Isolated from Ephedra sinica Ameliorates OVA-Induced Allergic Asthma – PMC (2022)
• Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide – PubMed (1997)
• Ephedra – Memorial Sloan Kettering Cancer Center Integrative Medicine
• Ephedra – Encyclopædia Britannica
• Ephedra: Unsafe and Illegal in Dietary Supplements – Operation Supplement Safety (OPSS)