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Ephedra
Botanical Names: Ephedra sinica Stapf., Ephedra equisetina Bunge., Ephedra intermedia Shenk and CA Meyer.
Pharmacopoeial Name: Ephedrae herba.
Common Names: Ephedra, Ma-huang, Ma huang , jointfir.
Related Species
The three main Ephedra spp. ( E. sinica, E. equisetina, E. intermedia ) are official in the Chinese and Japanese pharmacopoeias. Commercial sources also include E. distachya L. and E. geradiana Wall. ex Stapf. The latter is common in medicinal use in India. The North American species known as Mormon or Brigham Tea ( E. nevadensis S. Wats.) contains little or no alkaloid and is not used medicinally.
Habitat and Cultivation
Widespread perennial shrub native to China, Mongolia, Tibet, Siberia, Japan, India, Pakistan, and Afghanistan; it is also extensively cultivated.
Parts Used
Dried aerial parts (stems); the roots and rhizomes, known as Ma Huang gen , are a separate medicinal agent in Chinese medicine with distinct actions and uses.
Common Forms
- Dried: Powdered stems.
- Tincture: 1:4, 45% alcohol (BHP).
- Standardized Extracts: Unavailable.
Alkaloid content of ephedra-containing dietary supplement combinations in the United States and elsewhere are often not accurately labeled, and significant product variability has been demonstrated. 1-3Crude herb extracts are subject to seasonal and species variations in alkaloid content. 4 Ephedra is a component of several commercially available Chinese standard formulae.
Overview
Ephedra has a long history of use in Chinese medicine, dating from 3100
The activity of the crude herb is dominated by sympathomimetic phenethylamine alkaloid constituents, principally ephedrine and pseudoephedrine. Synthetic (racemic) ephedrine itself was produced by Merck in 1926 and introduced into clinical medicine as a treatment for pediatric asthma in 1927; thereafter it rapidly replaced epinephrine because it could be orally administered. Then, as now, the undesirable central stimulating effects of ephedrine were considered limiting factors on its clinical use.
Ephedra monographs by both the World Health Organization (WHO) 7 and the German Commission E support its traditional use for catarrhal conditions of the respiratory tract. 8 The clinical literature on ephedra appears extensive but actually is dominated by a persistent confusion of the crude herb with isolated ephedrine alkaloid. To a limited degree, pharmacokinetic and pharmacodynamic data suggest a similarity between crude ephedra and ephedrine, and the general sympathomimetic activity of ephedra is broadly correlated with ephedrine content. However, aspects of ephedra pharmacology, such as cytotoxicity or phosphodiesterase inhibition, cannot be attributed to ephedrine alone. 9-11In answer to the question of whether there is full equivalence between synthetic ephedrine and ephedra, eminent German phytotherapist Weiss replied, “On the whole yes, but not quite.” 5
The problems of literature interpretation and data comparison are compounded by the variable ingredients and combinations of agents contained in dietary supplements marketed as “weight loss” products that have been used in clinical trials. 2,9Caffeine or caffeine-containing herbs such as guaraná (Paullinea cupana) may be present, with aspirin or salicylate-containing herbs such as willow bark (Salix alba) sometimes combined with micronutrients such as trivalent chromium. Most recent trials have invariably examined these combination products and often incorrectly describe the results as referring to “ephedra.” This in turn casts some methodological doubts on metastudies such as the Cantox and RAND reports, and although both reviews acknowledged the problem, their conclusions should be critically qualified in this regard. 12,13
In the U.S., ephedra-containing supplements previously permitted under the Dietary Supplement Health and Education Act (DSHEA) have been banned since 2003, largely because of inappropriate consumption of ephedrine-containing weight loss and “natural stimulant” products resulting in a significant number of adverse events (see Note: Regulation, Safety, and Ephedra Weight Loss Products).
Historical/Ethnomedicine Precedent
Chinese traditional uses include acute wind-cold syndromes (characterized by chills, mild headaches, fevers without sweating, runny or stuffy nose, and body or joint aches) as well as bronchial asthma and allergic rhinitis. Several millennia-old classical Chinese formulae contain Ma Huang, including Ma Huang Tang (ephedra decoction), She Gan Ma Huang Tang (belamcanda and ephedra decoction), Ge Gan Tang (pueraria decoction), and Xiao Qing Long Tang (minor blue dragon decoction). In these combinations, ephedra comprises 15% to 25% of the total prescription, delivering 60 to 90 mg total alkaloid daily at normal adult dose levels.
In Chinese medicine, a further distinction is made between the stems of the plant, Ma Huang, and the root, Ma Huang gen . The roots contain dimeric flavonols and macrocyclic alkaloids not found in the aerial parts. In Chinese medicine the root is considered antisudorific, used for night sweats and excessive perspiration, whereas the stem is diaphoretic.
Known or Potential Therapeutic Uses
Asthma, coryza of common colds, fevers, allergic and vasomotor rhinitis, hives, and topical use for insect bites, stings, and allergic irritations of the skin and enuresis.
A recent comprehensive meta-analysis of these trials supports a moderate short-term weight loss effect from ephedra alkaloids when combined with stimulants such as caffeine. 14,15Ephedrine and pseudoephedrine are approved for use in over-the-counter (OTC) bronchodilator and nasal decongestant products. Ephedrine has limited use in the hospital setting for the management of hypotension during epidural block and inhalational anesthesia in the operating room (intravenous and intramuscular). Ephedrine has been historically used as a mydriatic and also as a pharmacotherapeutic agent for Stokes-Adams heart block, for enuresis, and for myasthenia gravis, in which latter its mechanism of action is unclear. 16 Some herbal texts also mention the latter two indications, but these are not general practice today, although some urologists continue to investigate the use of ephedrine for enuresis. 17
Key Constituents
Phenylethylamine alkaloids, from approximately 0.5% to more than 2.4% total. (See Note.)
Catechin tannins, including epicatechin and epigallocatechin as well as catechin and gallocatechin.
Volatile oil, including terpinol, cineole, and tetramethylpyrazine; biflavonols.
The roots contain dimeric flavonols and spermine alkaloids not found in the stems.
Note: Proportions of the different alkaloids vary. The majority is 1R,2S-ephedrine (up to 80%), which occurs alongside the optical isomer 1S,2S-pseudoephedrine and their corresponding nor- and methyl- derivatives. The ratio of ephedrine to pseudoephedrine is variable and even reversed in some minor species of Ephedra . 4 Alkaloid composition can be used to “fingerprint” product samples containing ephedra herb because of the four possible optical isomers of ephedrine, only 1R,2S-ephedrine and 1S,2S-pseudoephedrine occur naturally. 18
Therapeutic Dosing Range
Adults
- Dried prepared herb for traditional decoction: 3 to 9 g daily. Typical recommended doses in Chinese and Western herbal practice deliver between 60 to 90 mg total alkaloid daily.
- Commission E: 15 to 30 mg single dose and maximum of 300 mg daily total ephedra alkaloid.
- OTC ephedrine: Up to 150 mg alkaloid daily.
- OTC pseudoephedrine: Up to 240 mg alkaloid daily.
Children
Not to be administered to children under 6 years of age.
Pediatric dose up to 0.5 mg total alkaloid per kg body weight daily; according to Commission E and WHO figures. 7,8
Strategic Considerations
Ephedra alkaloids act as combination direct and indirect sympathomimetic agents at all alpha and beta adrenoceptor subtypes and have multiple effects on catecholamine pathways. 19 As a result, ephedra may interact with a variety of drugs that directly target the sympathetic nervous system. They may also indirectly interact with other classes of drug, such as antihypertensives or antiarrhythmics that do not directly affect the adrenergic pathways.
Within an integrative medical setting, however, the use of ephedra-containing formulae for traditional indications is limited and largely unproblematic when used by professionals trained in botanical medicine. Using traditional formulation models, ephedra is combined with other herbs that mitigate its “warming” energetics and the central nervous system (CNS) stimulatory aspects of its actions. The proportion of ephedra in a given formula is rarely more than approximately 15% to 20% of the total. Administered at therapeutic doses for traditional indications, ephedra is generally considered safe. This is supported by the complete absence of adverse event reports associated with administration of the crude herb or crude herb extracts either alone or in traditional formulations, as opposed to isolated alkaloid in multi-ingredient commercial preparations. Ephedra alkaloids are not degraded by monoamine oxidase, lacking the necessary hydroxyl configuration, and are excreted almost entirely unchanged renally, with a half-life of 3 to 5 hours. 20
Adverse effects of the herb result from the CNS stimulatory actions and sympathomimetic actions and include insomnia, anxiety, tachycardia, tremors, and at higher doses, arrhythmias and increased blood pressure. Prolonged and repetitive use may induce tachyphylaxis, but suggestions of “dependency” are not corroborated by clinical reports. Nonclinical toxicological data is based on studies of the isolated alkaloids, principally ephedrine. Clinical data on safety are derived from adverse drug reactions (ADRs) noted in clinical trials on weight loss, and anecdotal reports following initial use or with abuse of ephedrine-containing combination weight loss products.
Assuming normal clinical practice and basic professional physiology and pharmacology knowledge, ephedra herb and its crude extracts do not present any hazardous interactions issues, despite the recent increases in adverse reports related to weight loss dietary supplements and isolated alkaloids (see Note: Regulation, Safety; and Ephedra Weight Loss Products). Professional management of ephedrine interactions for therapeutic purposes also occurs within the hospital setting, typically in relation to management of anesthesia-induced hypotension.
- MAO-A inhibitors:Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), procarbazine (Matulane), tranylcypromine (Parnate).
- MAO-B inhibitors:Selegiline (deprenyl,
L -deprenil,L -deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); pargyline (Eutonyl), rasagiline (Azilect).
Potentially Harmful or Serious Adverse Interaction—Avoid |
Probability: 1. Certain
Evidence Base: 0 Consensus
Effect and Mechanism of Action
As indirect and direct sympathomimetics, ephedra alkaloids have “double” potential to cause rapid elevations of epinephrine at adrenergic and noradrenergic terminals if cytosolic monoamine oxidase (MAO) is inhibited. Monoamine oxidase inhibitors (MAOIs) cause presynaptic epinephrine accumulation. Ephedra will both promote release of the accumulated presynaptic epinephrine and simultaneously have a direct stimulating effect on the postsynaptic receptors itself. Exaggerated pressor responses will result, with possible hypertensive crisis or hemorrhagic stroke.
Research
The sympathomimetic action of ephedra alkaloids is well established. 50,51 However, the literature seldom mentions that ephedrine, pseudoephedrine, and norephedrine are themselves all unlabeled MAOIs, although weak and reversible in character. 52,53 Thus, they may also affect levels of 5-hydroxytryptamine (5-HT, serotonin) and dopamine both centrally and peripherally, as well as interact with tyramine-containing foods such as aged cheese and red wine. The manufacturers of serotonin agonists such as sibutramine caution against combining with ephedra alkaloids. Although a theoretical basis for this may exist because of the MAOI-like action of ephedra, the risk of serotonin syndrome is apparently low, and reports are lacking. Theoretically the newer, selective MAO-A or MAO-B drugs should be less interactive, but reports show that moclobemide increases the pressor action of ephedrine twofold to fourfold in healthy volunteers. 54 On the other hand, a recent case report describes ephedrine and phenylephrine being used uneventfully to control hypotension during epidural anesthesia in a patient taking moclobemide. 55
Reports
The standard drug interactions literature through the 1960s and 1970s contains isolated reports of fatal intracranial and subarachnoid hemorrhage, but these refer to amphetamines combined with older MAOI drugs. 49 More recently, concerns have been raised about a renewed increase in occurrence of this interaction caused by the increased use of ephedrine-containing weight loss products. 56
Clinical Implications and Adaptations
The older, nonselective, irreversible MAOIs, whether prescribed for hypertension or depression, should never be combined with indirect sympathomimetics. Even the newer, selective, reversible MAOIs should not be combined with sympathomimetics. This established and serious drug interaction can be plausibly extended to ephedra. After use of irreversible MAOIs, renewed MAO synthesis takes time, and 2 weeks has been suggested as a safe period after which ephedrine can be administered. 56
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