Ephedrine

Ephedrine

1. Identity

Chemical and Botanical Names

Chemically, ephedrine is a substituted amphetamine and is the (1R,2S)-enantiomer of β-hydroxy-N-methylamphetamine. Its full systematic IUPAC name is (1R,2S)-2-(methylamino)-1-phenylpropan-1-ol. Ephedrine is a sympathomimetic amine that acts on part of the sympathetic nervous system (SNS), working by inducing the release of norepinephrine and hence indirectly activating the α- and β-adrenergic receptors.

Ephedrine was first isolated in 1885 and came into commercial use in 1926. It is on the World Health Organization's List of Essential Medicines. Ephedrine is listed as an essential medicine by the World Health Organization for the prevention of low blood pressure induced by spinal anesthesia, whereas pseudoephedrine is a widely used decongestant.

Botanical Source

Ephedra sinica Stapf (Ephedraceae) is a widely used Chinese medicinal plant known by the Chinese name Ma Huang. Ephedra sinica, E. intermedia, and E. equisetina are the three Ephedra species characterised as ingredients of the Chinese drug 'Ma-Huang' and listed in each edition of the Chinese Pharmacopoeia. Ephedra sinica is the species most widely used for its medicinal properties and is found growing wild in Mongolia, southeastern provinces of Russia, and in northeastern China.

In the 2020 edition of the Pharmacopoeia of the People's Republic of China, Ephedra includes the dried straw stems of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C. A. Mey, and Ephedra equisetina Bge. The North American species Ephedra nevadensis, known as Mormon tea, contains little or no ephedrine or other alkaloids.

Common Forms and Preparations

Ma huang refers to a preparation of plant material from Ephedra sinica (Chinese ephedra). The dried stems and leaves of the Ephedra plant could be prepared as capsules, tablets, tinctures, and teas. The three species of this shrubby plant that are sources of the drug are native to China, where the aboveground parts are collected in the fall and dried for drug use. Depending on the use and dosage of ephedrine, it can be administered intravenously, orally, or nasally.

Oral formulations of ephedrine have been used historically to treat asthma via pulmonary vasoconstriction and reduction in airway edema along with beta-induced bronchodilation, but it is rarely used for this purpose in modern medicine due to unwanted cardiac effects and availability of more selective beta-agonists such as albuterol. Ephedrine is also available in a fixed-dose combination with guaifenesin to temporarily relieve mild asthma symptoms with an expectorant.

2. Traditional and Historical Use

Traditional Chinese Medicine

In China, Ma Huang has been used to treat asthma and hay fever for more than 5,000 years. Ma huang is one of the earliest and best-known drugs of Chinese traditional medicine, referenced in the Shen Nong Ben Cao Jing, one of the foundation books of Chinese medicine (about 100 AD). Ma huang is mentioned in the Han dynasty Shen Nong Ben Cao Jing (Divine Farmer's Classic of the Materia Medica) for its benefits on lung obstructions like wheezing. Its principal action through Chinese traditions was as a heating medicine, to treat febrile congested catarrhal conditions of the respiratory system. It promotes sweating, calms dyspnoea, and is indicated for 'exterior repletion cold damage patterns with aversion to cold.'

Ma huang was traditionally used by Chinese herbalists during the early stages of respiratory infections and was also used for the short-term treatment of certain kinds of asthma, eczema, hay fever, narcolepsy, and edema. It was and still is used to induce perspiration and to treat the symptoms of bronchial asthma, colds, and influenza. The root of E. sinica or E. intermedia is known as ma huang gen and is considered to be a distinct drug.

Ayurvedic and Wider Asian Use

Ephedra has been a common herbal medicine in China for thousands of years, and several species are important in Ayurvedic medicine. Various Asian plants, particularly ma huang (Ephedra sinica), have been used as sources of the drug ephedrine.

Discovery and Entry into Western Medicine

Ephedrine was first isolated and characterized by Nagai in 1885, but it was then forgotten until it was rediscovered by Chen and Schmidt in the early 1920s. 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. Based on the findings reported by numerous clinical investigators, Chen and Schmidt proposed a host of therapeutic uses including asthma, hay fever, bronchitis, emphysema, whooping cough, spinal anesthesia, hypotension, shock, nasal congestion, mydriasis, hives, menstrual cramps, and as an antidote for narcotic drugs. Ephedrine's bronchodilator action made it useful to treat asthma, whooping cough, and bronchitis, at a time when the only other available bronchodilator was theophylline. It was also useful as a nasal decongestant for the common cold and for various allergic disorders, such as rhinitis.

Until it was banned by the U.S. Food and Drug Administration (FDA) in 2004, ephedra was most often taken by young and middle-aged adults for weight loss, increased energy, and bodybuilding.

3. Key Constituents and Active Compounds

Ephedrine Alkaloids

The main active constituents of E. sinica are the unique and taxonomically restricted adrenergic agonists phenylpropylamino alkaloids, also known as ephedrine alkaloids: (1R,2S)-norephedrine, (1S,2S)-norpseudoephedrine, (1R,2S)-ephedrine, (1S,2S)-pseudoephedrine, (1R,2S)-N-methylephedrine, and (1S,2S)-N-methylpseudoephedrine. Alkaloids are the main active components of Ephedra, in which a total of 29 have been identified.

A main component of ephedra is composed of alkaloids such as L-ephedrine, pseudoephedrine, norephedrine, and norpseudoephedrine; of these, ephedrine is the largest component at 30 to 90% of total alkaloids. The summed content of ephedrine and pseudoephedrine obtained by UPLC-UV method varies between 20.8 mg/g dry weight (E. distachya subsp. helvetica) and 34.7 mg/g dry weight (E. monosperma).

Ephedra has a complex chemical composition and contains various types of compounds, including alkaloids, flavonoids, tannins, polysaccharides, and organic phenolic acids. Its active constituents mostly include Ephedra alkaloids, and the nonalkaloid components exhibit antioxidant, immunosuppressive, and hypoglycemic properties.

Biosynthesis

The final steps of ephedrine and pseudoephedrine biosynthesis in members of the plant genus Ephedra involve N-methylation of norephedrine and norpseudoephedrine, respectively. GC-MS analysis of freshly picked young E. sinica stems enabled the detection of 1-phenylpropane-1,2-dione and (S)-cathinone, the first two putative committed biosynthetic precursors to the ephedrine alkaloids.

4. Mechanisms of Action

Sympathomimetic Activity: Direct vs. Indirect

Classically considered to exert its effects primarily by an indirect "tyramine-like" sympathomimetic mechanism — since it exhibits tachyphylaxis (acute tolerance) when administered repeatedly — more recent studies indicate that ephedrine also exerts direct effects (at least in rats and mice) that are mediated by direct stimulation of adrenergic receptors and/or trace amine-associated receptors (e.g., TAAR1). Initial studies classified ephedrine as an indirectly acting sympathomimetic; subsequent studies showed ephedrine acts by mixed action by releasing noradrenaline and by acting directly on receptors. However, a few recent studies in rats have shown predominant direct action on adrenergic receptors.

Receptor-Level Effects

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.

Ephedrine's indirect mechanism results in a sustained or even increased heart rate due to norepinephrine's ability to bind alpha and beta receptors, whereas more direct sympathomimetics like phenylephrine result in reflex bradycardia.

CNS Stimulation

Endogenous catecholamines released by ephedrine directly or indirectly stimulate the sympathetic nervous system, resulting in central nervous system symptoms such as mental excitement, insomnia, and wakefulness.

Thermogenic Synergy with Caffeine

It has been suggested that the thermogenic effects of combining ephedrine and caffeine are synergistic. The increased catecholamine release after ephedrine ingestion is subjected to negative feedback systems, which then tend to inhibit catecholamine release and actions. These negative feedback systems include adenosine and prostaglandin release in the synaptic junction and elevated phosphodiesterase enzyme activity, which results in degradation of cyclic adenosine monophosphate (cAMP). Caffeine interferes with this negative feedback mechanism by inhibiting both adenosine and phosphodiesterase activity and preventing degradation of cAMP.

The individual effects of ephedrine and caffeine were modest, but the drugs in combination produced significant cardiovascular, metabolic, and hormonal responses. These enhanced effects appear to be a result of pharmacodynamic rather than pharmacokinetic interactions.

5. Scientific Evidence by Area of Use

5.1 Perioperative Hypotension

Ephedrine is a medication used to manage and treat clinically significant hypotension. It is in the sympathomimetic class of drugs. The FDA-approved primary indication for ephedrine is the treatment of clinically significant hypotension perioperatively. Induction of general anesthesia and ongoing anesthesia during operative cases results in vasodilatation and hypotension, requiring treatment with vasopressors.

Experts currently recommend either IV ephedrine or phenylephrine for treatment of hypotension during neuraxial anesthesia; however, consideration should be given to selection of phenylephrine in the absence of maternal bradycardia because of improved fetal acid-base status in uncomplicated pregnancies. Ephedrine has been used in pregnant women for treatment of hypotension during spinal anesthesia; available data support efficacy and safety of ephedrine sulfate injection for such use. Some evidence indicates that fetal acidosis is more likely to occur with ephedrine than phenylephrine. Low umbilical artery pH (≤7.2) has been reported at the time of delivery in neonates whose mothers were exposed to ephedrine.

Evidence strength: Strong for the perioperative setting based on decades of clinical use and inclusion in major anesthesia guidelines; comparative evidence favors phenylephrine over ephedrine for obstetric neuraxial anesthesia when maternal bradycardia is absent.

5.2 Bronchodilation and Asthma

When first introduced into pharmacy, ephedrine's main use was as a bronchodilator to open up the airways of asthma sufferers. The use of Ma Huang to suppress cough can be traced back to the oldest written record of Chinese medicinal plants. Oral formulations of ephedrine have been used historically to treat asthma via pulmonary vasoconstriction and reduction in airway edema along with beta-induced bronchodilation, but it is rarely used for this purpose in modern medicine due to unwanted cardiac effects and availability of more selective beta-agonists such as albuterol.

Ephedrine is used orally as a bronchodilator for symptomatic treatment of asthma and in fixed-combination with guaifenesin as self-medication for the temporary relief of mild symptoms of intermittent asthma, such as wheezing, chest tightness, and shortness of breath.

Evidence strength: The bronchodilator effect of ephedrine is pharmacologically established through beta-2 receptor agonism. However, in modern clinical practice, ephedrine has been largely superseded by more selective beta-2 agonists such as albuterol that carry a more favorable cardiovascular risk profile.

5.3 Weight Loss

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.

A 2021 systematic review and meta-analysis (10 randomized controlled trials, searched through July 2021) reported: a total of 10 articles were included; compared with the placebo group, the ephedrine-containing product group was associated with greater weight loss, with a mean difference of −1.97 kg (95% CI: −2.38, −1.57).

A key randomized double-blind placebo-controlled trial involving 180 obese patients receiving a calorie-restricted diet tested ephedrine/caffeine (20 mg/200 mg), ephedrine alone (20 mg), caffeine alone (200 mg), or placebo three times daily for 24 weeks: mean weight losses were significantly greater with the combination than with placebo from week 8 to week 24 (ephedrine/caffeine, 16.6 ± 6.8 kg vs. placebo, 13.2 ± 6.6 kg; P = 0.0015). Weight loss in both the ephedrine-only and the caffeine-only groups was similar to that of the placebo group. Side effects (tremor, insomnia, and dizziness) were transient and after eight weeks of treatment they had reached placebo levels. Systolic and diastolic blood pressure fell similarly in all four groups. The authors concluded that the ephedrine/caffeine combination is effective, while caffeine and ephedrine separately are ineffective for the treatment of human obesity.

Thermogenic claims associated with ephedrine have been supported, as increases in resting oxygen consumption have been observed after both acute and chronic ephedrine ingestion. Ephedrine and combined ephedrine and caffeine have been observed to partially prevent the usual fall in resting metabolic rate during a calorie-restricted diet. However, the higher metabolic rates observed in these studies were not always associated with weight loss. There is also support for lipolytic claims, as significant increases in both fat oxidation and fat loss have been observed when ephedrine is administered in combination with caffeine. In contrast, ephedrine ingestion alone failed to produce such changes.

Evidence strength: Moderate. A statistically significant but modest degree of short-term weight loss has been demonstrated in RCTs, principally with ephedrine combined with caffeine rather than with ephedrine alone. Most studies were short-term, and almost no new research on ephedra in people has been performed in the years since its use in dietary supplements was banned in the United States.

5.4 Athletic Performance Enhancement

The literature on ephedrine's ergogenic effects documents pharmacologically plausible mechanisms (thermogenesis, stimulant activity), but clinical trial evidence is limited and mixed. The RAND Corporation review cited in published analyses examined the evidence base and found that the RAND reviewers' comprehensive 300-plus page technology assessment and evidence report found that ephedra and ephedrine, both alone and in combination with caffeine, could induce adverse responses — a finding used to support the 2004 FDA ban.

Extracts of Ephedra shrubs contain highly active α- and β-adrenergic agonists that have profound effects on the heart and vasculature. Evidence for their effectiveness (in sport performance) is limited. Professional sports bodies moved to prohibition prior to the FDA ban: professional sports leagues, college athletics associations, and the military were among the first to prohibit the use of these supplements among their members.

Evidence strength: Preliminary and limited. The combination of ephedrine and caffeine showed some ergogenic signals in small trials, but high-quality clinical evidence is sparse, and the safety-to-benefit ratio in athletic contexts has not been established.

5.5 Nasal Decongestion

One contraindication of ephedrine is acute hypertension and tachycardia. The same properties and mechanisms that make ephedrine effective for reducing anesthesia-induced hypotension make it an effective decongestant and bronchodilator. It reduces swelling by constricting blood vessels in nasal passages, and it widens the bronchi by binding to beta-adrenergic receptors in the lungs.

Evidence strength: Pharmacologically well-established; clinical data confirm decongestant activity. Pseudoephedrine, a stereoisomer, is the more commonly used OTC decongestant today, as pseudoephedrine is commonly found in preparations for treating nasal and sinus congestion via mucosal vasoconstriction, and although similar to ephedrine, pseudoephedrine has fewer CNS effects.

5.6 Other Clinical Indications

In Stokes-Adams syndrome with complete heart block, ephedrine has a value similar to that of epinephrine. It is indicated as a central nervous system stimulant in narcolepsy and depressive states. It is also used in myasthenia gravis. These indications have historical and pharmacological basis but have largely been supplanted in contemporary clinical practice by more targeted pharmacotherapies.

6. Body Systems and Health Areas

Modern medical studies have shown that Ephedra has a wide range of pharmacological effects on the central nervous system, cardiovascular system, and smooth muscle. The following body systems are directly affected:

• Cardiovascular system: Ephedrine is a non-catecholamine sympathomimetic with cardiovascular effects similar to those of adrenaline (epinephrine): increased heart rate and blood pressure.
• Respiratory system: Beta-2-adrenergic receptor stimulation in the lungs results in bronchodilation with ephedrine administration.
• Central nervous system: Endogenous catecholamines released by ephedrine directly or indirectly stimulate the sympathetic nervous system, resulting in CNS symptoms such as mental excitement, insomnia, and wakefulness.
• Metabolic/adipose: Ephedrine promotes sympathetic neuronal actions, causing the heart to beat more strongly and quickly. It also increases metabolism and suppresses appetite, thus promoting body fat decomposition.
• Genitourinary: Decreased urination due to vasoconstriction of renal arteries; difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation.

7. Dosage Forms and Reported Dosages

Perioperative / Parenteral Use

• For the treatment of clinically important hypotension occurring in the setting of anesthesia: initial dose of 5–10 mg IV bolus (must dilute), with additional boluses as needed, not to exceed a total cumulative dosage of 50 mg.
• The usual parenteral dose is 25 to 50 mg given subcutaneously or intramuscularly. Intravenously, 5 to 25 mg may be administered slowly, repeated in 5 to 10 minutes if necessary.
• Clinically, ephedrine is licenced for treatment of nocturnal enuresis and hypotension associated with anaesthesia at 3–12 mg boluses IV.

Oral Use (Historical / OTC Bronchodilator)

• An initial oral dose of 12.5 mg to 25 mg every 4 hours is reported for adults; for children 12 years or older, the same range of 12.5 mg to 25 mg every 4 hours is noted.
• For prescription ephedrine, the dosage should not exceed 150 mg per day in adults or 75 mg per day in children.

Weight Loss Research Dosages

• In a key 24-week randomized double-blind trial, 180 obese patients were treated with either an ephedrine/caffeine combination (20 mg ephedrine / 200 mg caffeine), ephedrine alone (20 mg), caffeine alone (200 mg), or placebo three times a day.
• In a separate 4-week trial involving morbidly obese women, 13 subjects were randomly assigned to an ephedrine/caffeine combination (200 mg caffeine / 20 mg ephedrine, n = 6) or placebo (n = 7) administered three times daily orally.

8. Safety Considerations and Drug Interactions

Adverse Effects

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.

Haller and Benowitz (2000) reviewed 140 adverse event reports (AERs) related to the use of dietary supplements containing ephedrine submitted to the FDA between 1997 and 1999. The investigators concluded that 31% of the reports were "definitely" or "probably" related to the use of supplements containing ephedrine, and another 31% were deemed "possibly" related. Among the adverse events deemed definitely, probably, or possibly related to the use of supplements containing ephedrine, 47% involved the cardiovascular system and 18% involved the central nervous system. The adverse events included hypertension (17 reports), palpitations or tachycardia (13), stroke (10), and seizures (7). Ten events resulted in death and 13 produced permanent disability.

Adverse cardiovascular and cerebrovascular effects, including stroke, myocardial infarction, and sudden death, temporally related to ephedra alkaloids use, are well described.

The intake of ephedrine-containing supplements was shown to be associated with a 2.2- to 3.6-fold increase in odds of psychiatric, autonomic, or gastrointestinal symptoms and heart palpitations.

Ephedrine is also arrhythmogenic, or capable of producing irregular heartbeat rhythms. Clinicians should therefore be especially careful in administering ephedrine to patients predisposed to arrhythmias.

Tachyphylaxis

Tachyphylaxis due to noradrenaline depletion can occur with repeated doses. This phenomenon, consistent with an indirect mechanism of action, means that repeated administration leads to diminishing pressor responses.

Drug Interactions

Monoamine oxidase inhibitors (MAOIs): Ephedrine should be avoided or used with caution within 14 days of MAOI therapy due to excessive norepinephrine availability at the synapse, which could cause a hypertensive crisis through the indirect sympathomimetic effect of ephedrine. Prescribing MAOIs with any sympathomimetic agent may precipitate a hypertensive crisis, and it is contraindicated to co-administer these agents. Preparations containing ephedrine, phenylephrine, phenylpropanolamine, or pseudoephedrine such as cold and nasal decongestion remedies should not be given concomitantly with MAOIs for the same reason.

Other sympathomimetics and caffeine: There are theoretical reasons to suspect that ephedra might interact with other stimulants like caffeine. Pharmacodynamic evidence confirms this: the individual effects of ephedrine and caffeine were modest, but the drugs in combination produced significant cardiovascular, metabolic, and hormonal responses; these enhanced effects appear to be a result of pharmacodynamic rather than pharmacokinetic interactions.

Obstetric considerations: Some evidence indicates that fetal acidosis is more likely to occur with ephedrine than phenylephrine. Low umbilical artery pH (≤7.2) has been reported at the time of delivery in neonates whose mothers were exposed to ephedrine.

Regulatory Status

The FDA issued a "Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk" based upon the well-known and scientifically established pharmacology of ephedrine alkaloids, the peer-reviewed scientific literature, published case reports of adverse events, and adverse events reported to the agency. The FDA concluded that dietary supplements containing ephedrine alkaloids pose a risk of serious adverse events, including heart attack, stroke, and death, and that these risks are unreasonable in light of any benefits that may result from the use of these products. The final rule took effect on April 12, 2004.

Over-the-counter dietary supplements containing ephedrine are illegal in the United States, with the exception of those used in traditional Chinese medicine, where its presence is noted by má huáng. Ephedra and its alkaloids are still legal in some countries, and many dietary supplement products — usually supplements for weight loss — containing this ingredient are available from online retail websites.

FDA published the final rule prohibiting the sale of dietary supplements containing ephedra alkaloids on February 11, 2004. When this final rule became effective on April 12, 2004, it was the first time FDA had acted to ban a dietary supplement from the U.S. market.

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