Natural Remedies
Ephedra's Alkaloids Provide its Kick
By Steven J. Dentali, Ph.D.
Ma huang became an economically important medicinal plant in North America by virtue of a cultural ambassador. That is, it was introduced to Western medical practice by an Asian chemist who, after being trained in the West, studied the chemistry and pharmacognosy of a familiar herb from home.
For more than 5,000 years, the Chinese have made extensive use of ma huang (Ephedra sinica, E. equisetina, and related species), primarily for asthma and other respiratory conditions.1 In 1924, Harvard-trained Chinese chemist K.K. Chen and German pharmacologist C.F. Schmidt presented a report describing the alkaloid ephedrine, the primary active ingredient isolated from ma huang, and several of its actions. They recognized the possible use of ephedrine for treating circulatory collapse during surgery and as a bronchodilator in asthma—strong medicine for serious conditions.2
Alkaloids are chemical substances that contain nitrogen, though not all nitrogen-containing compounds are alkaloids. Alkaloids often possess strong pharmacological activity and are usually spelled with an -ine ending. Some familiar alkaloids are caffeine, cocaine, morphine, nicotine and quinine.
About 40 different species of ephedra grow in many regions of the world, including North America. American species do not contain measurable alkaloids, but Asian species contain varying amounts of several pharmacologically active ephedrine alkaloids, primarily ephedrine and pseudoephedrine. These usually comprise between 0.5 and 2.5 percent by weight of dried ephedra tops, the part of the herb used medicinally. Considerable variations in alkaloid content occur among species and with time of harvest. The plant's alkaloid content is usually highest in the fall.3 Extracts of this plant have become important to the drug industry because of the nervous system effects of the alkaloids they contain. They have also found their way into dietary supplements. Including these stimulatory alkaloids in self-medication products has presented some significant problems, which have not gone unnoticed by regulatory agencies (see sidebar).
Pharmacological Effects
Although ephedra extracts should not be confused with the alkaloids they contain, a study of the latter is the best way to understand the extracts' general pharmacological effects and potential toxic risks. The alkaloid ephedrine, ranging from 30 to 90 percent of the alkaloid content of ephedra, is primarily responsible for ephedra's bronchodilatory action. Ephedrine quickly relieves the spasm of bronchial muscle that causes an asthma attack.4 Ephedrine also raises blood pressure and increases heart rate.5 These actions stimulate the sympathetic portion of the autonomic nervous system.
Biologically speaking, sympathetic action is sympathetic to danger. Our autonomic nervous system functions either in a parasympathetic, or housekeeping mode of relaxing and digesting, or a sympathetic one of preparing to fight the perceived saber-toothed tiger. The body naturally responds to sympathetic hormones secreted by the adrenal glands, producing adrenaline that raises blood pressure, pumps more blood, and shunts it away from the internal organs to skeletal muscles in arms and legs. Pupils dilate and take in more light for better vision, and bronchioles open for easier breathing. This concerted response makes one ready to do battle or flee, the so-called fight-or-flight response.
The ephedrine alkaloids have a chemical structure close to that of the body's natural adrenaline and act in a similar fashion. Like adrenaline, they belong to the class of adrenergic or adrenalinelike amines. When John Travolta plunged a syringe into Uma Thurman's heart in Pulp Fiction's drug-overdose scene, he was directly administering adrenaline to treat cardiac failure. Unlike adrenaline, ephedrine is active only orally, but its effects last about 10 times longer, making it an extremely useful tool in Western medicine. Its ability to increase blood pressure, cardiac output and heart rate has been used to control dangerous drops in blood pressure during spinal and epidural anesthesia. Ephedrine's pharmacological action is comparable to amphetamine but at about one-fifth the potency.6 Theoretically, this means increasing a dose of ephedrine fivefold would produce an effect close to the same original dose of amphetamine.
Pseudoephedrine is much less active in increasing blood pressure but is still a good bronchodilator. It is used in many popular over-the-counter (OTC) preparations as a nasal decongestant, usually at 30 mg per dose.7 A lesser alkaloid, norephedrine, also called phenylpropanolamine, is similar to ephedrine in its nervous-system stimulant effects but has fewer cardiovascular stimulant effects than ephedrine. It also is approved as an OTC weight-loss aid.8
Weighing in on Ephedrine
The stimulatory effects of ephedrine alkaloids make them popular ingredients in weight-loss and performance products. One theory describing the weight-loss action of products containing ephedrine alkaloids is that they increase the rate of thermogenesis, or heat production, in the body. Many dietary supplements geared toward weight loss combine a source of ephedrine with other stimulants such as caffeine.
This combination is controversial because the stimulatory effects of ephedrine alkaloids can cause the same adverse effects as amphetamines, ranging from insomnia to dependence. At levels only a few times greater than the active dose, ephedrine alkaloids are toxic.9,10 This means that ephedra's therapeutic window of action is small. Taking too much can have dangerous stimulatory consequences on the heart and blood vessels. Some people seem to be particularly sensitive to these stimulants, and even at the recommended dosage the products can have untoward effects.
A new player has entered the diet-aid marketplace in recent years. Extracts from sour orange (Citrus aurantium), also used in traditional Chinese medicine, contain synephrine, an adrenergic amine, and other similar alkaloids.11 Synephrine and an extract of C. aurantium containing it raised arterial blood pressure in at least one animal study.12
More carefully controlled clinical trials, as well as basic pharmacologic studies, are needed if we are to believe in the validity of thermogenesis via ephedra or C. aurantium extracts. At least as likely a cause of weight loss by people consuming these products is the amphetaminelike effects of the alkaloids. This action causes weight loss by allaying appetite, speeding up metabolism and increasing physical activity, just as amphetamines do. Someone skipping meals, eating less, or increasing physical activity is likely to lose weight. Until critically reviewed evidence surfaces that these materials operate by a mechanism other than adrenergic amines, the reasonable assumption is that they do not.
Of particular concern about weight-loss products containing these alkaloids is that long-term use of alkaloid-containing stimulants tends to deplete magnesium stores. This leaves muscles overstimulated and eventually weakened. Under the worst circumstances, sudden irregular heartbeats known as paroxysmal atrial tachycardia (PAT) or more frequent premature ventricular contractions arise. Patients with mitral valve prolapse—a heart condition and side effect of fen/phen, the herbal variety of which contains ephedra—are particularly at risk for triggering PAT and ventricular arrhythmias. They also risk fainting because of erratic blood pressure.
Just because something is natural does not make it harmless. Ephedra is a prime example. Used by an experienced herbal medicine practitioner, it can be a useful tool. Used by the average consumer with little understanding of its potential toxicity, it can cause dangerous side effects. It is not an herb to be taken lightly or casually recommended. For those looking to shed a few pounds, the healthiest way is through the usual lifestyle changes of adequate exercise and a sensible diet.
Sidebars:
Legislating Alkaloid Awareness
Commission E Monograph: Ephedra
Steven J. Dentali, Ph.D., is a pharmacognosist who wrote safety reviews on ephedra and kava for the Herb Research Foundation and served on the FDA ephedrine alkaloid working group.
References
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2. Chen KK, Schmidt CF. Action of ephedrine, the active principle of the Chinese drug ma-huang. J Pharmacol Exp Therap 1924;24:339-57.
3. Feng CT, Read BE. Comparison of Ephedra equisetina and Ephedra sinica and their seasonal content of ephedrine. Chinese J Physiol 1928;2:87-96.
4. [Anonymous]. The ephedras. Lawrence Rev Nat Products 1989 Jun.
5. Bensky D, Gamble A. Chinese herbal medicine: materia medica. Seattle (WA): Eastland Press; 1986. p 32-4.
6. Martin WR, et al. Physiologic, subjective, and behavorial effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 1971;12:245-58.
7. Storms WW, et al. SCH 434: a new antihistamine/decongestant for seasonal allergic rhinitis. J Allergy Clin Immun 1989;83:1083-90.
8. Dollery C, editor. Phenylpropanolamine (hydrochloride). In: Therapeutic Drugs. (Scotland): Churchill Livingstone; 1991. p 91-3.
9. Bruno A, et al. Stroke associated with ephedrine use. Neurology 1993;43:1313-6.
10. Whitehouse AM, Duncan JM. Ephedrine psychosis rediscovered. Br J Psychiatry 1987;150:158-261.
11. Hu S, Wang G. Textual studies on shangzhou zhiqiao fructus Aurantii. Chung Kuo Chung Yao Tsa Chih 1996;21:137-8, 189.
12. Huang YT, et al. Fructus aurantii reduced portal pressure in portal hypertensive rats. Life Sci 1995;57:2011-20.
