Ephedrine is the active constituent of ma huang, an herbal preparation used medically in China for thousands of years. Also commonly known as ephedra, it is derived from several Asian species of Ephedra. Preparations of these species were formerly used in "natural" dieting aids and bodybuilding supplements and also were marketed as "herbal ecstasy." Ephedra and ma huang may cause such side effects as insomnia, restlessness, euphoria, palpitations, and high blood pressure; there have been reports of a number of deaths associated with their use as recreational drugs and dietary supplements. In 2004 the Food and Drug Administration banned sales of dietary supplements containing ephedra because of illnesses and deaths associated with the drug.
In traditional Chinese medicines, the herb má huáng (麻黄, Ephedra sinica) contains ephedrine and pseudoephedrine as its principal active constituents. The same is true of other herbal products containing extracts from Ephedra species. Nagayoshi Nagai was the first one to isolate ephedrine from Ephedra vulgaris in 1885. The substance called soma mentioned in old Hindu books such as the Rig Veda, may have been ephedra extract. This, however, is disputed, as the identity of soma.
The production of ephedrine in China has become a multi-million dollar export industry. Companies producing for export extract US$13 million worth of ephedrine from 30,000 tons of ephedra annually, 10 times the amount that is used in traditional Chinese medicine.
The isomer which is marketed is (-)-(1R,2S)-ephedrine.
As with other phenylethylamines, it is also somewhat chemically similar to methamphetamine, although the amphetamines are more potent and have additional biological effects.
Ephedrine may also be referred to as: (αR)-α-[(1S)-1-(methylamino)ethyl]benzenemethanol, α-[1-(methylamino)ethyl]benzyl alcohol, or L-erythro-2-(methylamino)-1-phenylpropan-1-ol. Ephedrine hydrochloride has a melting point of 187-188°C.
Ephedrine is a sympathomimetic amine, the principal mechanism of its action relies on its direct and indirect actions on the adrenergic receptor system, which is part of the sympathetic nervous system or SNS. Central nervous system or CNS involvement is present, but the predominant clinical effects are caused by involvement with the sympathetic segment of the peripheral nervous system because while ephedrine does cross the blood-brain barrier, it doesn't do this very efficiently (efficient crossers with similar modes of action would include amphetamine and methamphetamine).
Ephedrine increases post-synaptic noradrenergic receptor activity by (weakly) directly activating post-synaptic α-receptors and β-receptors, but the bulk of its effect comes from the pre-synaptic neuron being unable to distinguish between real adrenaline or noradrenaline from ephedrine. The ephedrine, mixed with noradrenaline, is transported through the noradrenaline reuptake complex and packaged (along with real noradrenaline) into vesicles that reside at the terminal button of a nerve cell.
As an alkaloid, having some small amount of ephedrine within a noradrenaline vesicle increases the overall pH of the vesicle. This has the effect of increasing likelihood that the affected vesicle will be released during any subsequent action potential the nerve cell experiences. The nerve cells in question generally fire at some regular baseline rate; the effect of adding ephedrine is to increase the number of vesicles released during each action potential and possibly to extend the time during which noradrenaline has an opportunity to have an effect on the post-synaptic neuron by virtue of the fact that the reuptake complex has to process both noradrenaline AND ephedrine, presumably a longer process.
Ephedrine's mechanism of action on neurotransmission in the brain is wide. Its action as an agonist at most major noradrenaline receptors and its ability to increase the release of both dopamine and to a lesser extent, serotonin by the same mechanism as explained above for norepinephrine, is presumed to have a major role in its mechanism of action.
Because of ephedrine's ability to potentiate dopamine neurotransmission it is thought to have addictive properties by some researchers. The ability to potentiate serotonin and noradrenergic activity is clinically relevant, but is not thought to contribute to the potential for abuse.
While ephedrine's role in the serotonin system is less understood there is preliminary documentation of clinically significant agonism at excitory serotonin receptors, perhaps as a downstream response to the large release of norepinephrine in the nucleus accumbens (commonly referred to as the "pleasure center" of the brain). In mice, stereotypical behaviour was both easily induced by administration of ephedrine and its primary alkaloids and reversed when serotonin antagonists were administered.
In traditional Chinese medicine, ephedrine has been used in the treatment of asthma and bronchitis for centuries.
An ECA stack is a component found in thermogenic weight loss pills, composed of ephedrine, caffeine and aspirin (many supplement manufacturers include salicin instead of aspirin) working to speed up the metabolism and thus cause food energy to burn faster. The ECA stack is a popular supplement taken by body builders before workouts due to the increased amount of energy and alertness.
For many years, the US Coast Guard recommended ephedrine together with an equal 25 mg dose of promethazine to its sailors to combat seasickness. Promethazine manages nausea and ephedrine fights the ensuing drowsiness. Commonly referred to as the Coast Guard cocktail, ephedrine may still be available for prescription for this purpose.
The approved maximum daily dosage of ephedrine for use as a bronchodilator is 150mg, as specified on the packaging of the bronchodilator and expectorant combination, Bronkaid, made by Bayer pharmaceuticals.
Overdose can lead to death, although the approved dose is not likely to cause severe reactions when used as directed.
Ephedrine can also lead to damage of the brain receptors' over a period of high usage; this is because of its constant action on the neurochemicals. It also leads to high increase in blood pressure which over time can lead to damage in the blood vessels.
Bupropion is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is known as an NDRI (norepinephrine-dopamine re-uptake inhibitor). It has an action which bears more resemblance to amphetamine than to fluoxetine in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some serotonin from presynaptic clefts. It should not be used with ephedrine as it may increase the likelihood of the above side effects.
Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal BP > 130/80 mmHg, and lactation.
Contraindications for the use of ephedrine include: closed angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly cyclopropane or halothane), tachyarrhythmias or ventricular fibrillation, hypersensitivity to ephedrine or other stimulants. Ephedrine should NOT be used at any time during pregnancy unless specifically indicated by a qualified physician and ONLY when other options are unavailable.
Anecdotal reports have suggested that ephedrine helps studying, thinking, or concentrating to a greater extent than caffeine. Some students and some white-collar workers have used ephedrine (or Ephedra-containing herbal supplements) for this purpose, as well as some professional athletes and weightlifters. It is common for many athletes to use stimulants while exercising. Such use of ephedrine has been associated with stimulant dependence, as well as deaths from heatstroke in athletes and circulatory problems such as aortic aneurysm in weightlifters, though these side effects are rare.
As a phenylethylamine, ephedrine has a similar chemical structure to amphetamines. Ephedrine can be used in the synthesis of methamphetamine by chemical reduction; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine. The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in that it uses anhydrous ammonia and lithium metal in the reaction. The second most popular method uses red phosphorus, iodine, and ephedrine in the reaction.
Through oxidation, ephedrine can be easily synthesized into methcathinone. Ephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
Ephedrine has been reported to cause both physical and psychological dependence after excessive long-term use. This is particularly true with oral forms of ephedrine, since parenteral administration is unlikely to occur over long periods.
Several studies have recently compared the quantities of such neurotransmitters as serotonin, dopamine, glutamate, and epinephrine after concurrent administration of ephedrine and various amphetamine-like agents. The results showed that ephedrine has no neurotoxic effect nor has amphetamine counterparts.
Ephedrine increases serum dopamine levels minimally in comparison with an equivalent dose of dextroamphetamine (Dexedrine). Dextromethamphetamine (Desoxyn) raises dopamine levels dramatically (more than two times that of an equivalent dose of dextroamphetamine). This supports the general consensus that ephedrine has more of a peripheral action on the sympathetic nervous system, whereas amphetamines appear to cross the blood brain barrier more freely and tend to have a stronger central action. The fact that dopamine is believed to play a major role in the addiction response has been used in recent years as justification for controlling the distribution of dextroamphetamine and dextromethamphetamine, along with various other amphetamines.
The House passed the Combat Methamphetamine Epidemic Act of 2005 as an amendment to the renewal of the USA PATRIOT Act. Signed into law by president George W. Bush on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of ephedrine-containing products. The federal statute included the following requirements for merchants who sell these products:
The law gives similar regulations to mail-order purchases, except the monthly sales limit is only 7.5 grams.