Tweet
.Ephedrine & Ephedra, and the Associated Alkaloids and Compounds
By James Collier
November 2009
Ephedrine (EPH) is a sympathomimetic amine commonly used as a fat loss aid, stimulant, concentration aid, nasal decongestant and to treat low blood pressure associated with anaesthesia. It is one of a group of drugs known as beta-agonists; others include clenbuterol. It is an alkaloid originally derived from various plants and herbs of the genus Ephedra (family Ephedracaee). As a drug, it is most commonly available in the hydrochloride (HCl) and sulphate forms.
Originally ephedrine was a traditional Chinese medicine using the herb má háung (Ephedra Sinica), but now the more common medical form is pseudoephedrine, the alkaloid found in nasal decongestants and other respiratory treatments
Chemistry of Ephedrine
(αR)-α-[(1S)-1-(methylamino)ethyl]benzenemethanol, α-[1-(methylamino)ethyl]benzyl alcohol, or L-erythro-2-(methylamino)-1-phenylpropan-1-ol.
•Ephedrine exhibits optical isomerism and has two chiral centres. By convention the enantiomers with opposite stereochemistry around the chiral centres are designated ephedrine, while pseudoephedrine has same stereochemistry around the chiral carbons: (1R,2R)- and (1S,2S)-enantiomers are designated pseudoephedrine; while (1R,2S)- and (1S,2R)-enantiomers are designated ephedrine.
•As with other phenylethylamines, ephedrine is chemically similar to methamphetamine, although the amphetamines are far more potent and have additional in vivo effects.
•Ephedrine HCl has a melting point of 187-188°C.
•The half-life of ephedrine is 3-6 hours.
Mechanism of Action
Ephedrine is a beta-adrenergic agonist sympathomimetic amine. Its principle actions are on beta-adrenergic receptors, which are part of the sympathetic nervous system (SNS). There is some limited central nervous system (CNS) involvement, but ephedrine only crosses the blood-brain barrier weakly and inefficiently (examples of efficient crossers with similar modes of action are amphetamines).
Ephedrine has two main mechanisms of actions: It activates post-synaptic α-receptors and β-receptors to noradrenaline, but this is a small effect. The larger mechanism of action giving rise to its effects is from the pre-synaptic neuron being unable to distinguish real adrenaline/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.
The way ephedrine works is through its effects on pH. It is an alkaloid, and so having a small amount of ephedrine within a noradrenaline vesicle increases the overall pH of the vesicle. This in turn increases the likelihood that the vesicle will be released during any subsequent action potential the nerve cell experiences. Ephedrine increases the number of vesicles released during each action potential, which extends the time during which noradrenaline is available to have an effect on the post-synaptic neuron, because the reuptake complex has to process both noradrenaline as well as ephedrine which is a longer process.
Ephedrine can also increase the release of dopamine and serotonin in a similar way to how it affects noradrenalin and this has a major effect on it's mode of action. Because of ephedrine's ability to potentiate dopamine neurotransmission, it is sometimes claimed to have addictive properties; and it certainly is associated with dependence. Serotonin is known as the 'happy hormone' and is a chemical released in the brain which helps elevate mood. Ephedrine's role in the serotonin system is poorly understood, but there does seem to be some excitory effect and it does appear to elevate mood though this system.
Effects of Ephedrine
Ephedrine is used as a thermogenic weight loss aid, and is a successful and popular one. Its positive effects here are threefold: It raises metabolic rate though thermogenics with associated lipolysis (fat breakdown). Secondly, ephedrine is an appetite suppressor; ideal when an individual is trying to reduce their calorie intake. Its third positive effect on weight loss is that it helps the user feel like they have more energy and gives a sense of alertness; this is appreciated whilst on a low calorie intake with increased exercise in preventing tiredness.
Another thing worth noting is that ephedrine is reported to have some anti-catabolic properties to muscle. This implies that we can retain some muscle even while cutting. However, this claim isn't well validated with evidence.
Recreational and Performance Enhancing Uses of Ephedrine
Ephedrine is most renowned for its use as a performance enhancing drug by bodybuilders. However, in practice this is only a modest percentage of its users. It's effects as a 'fat burner' have lead to its use extending to an array of other sports where the individual wishes to improve their power to weight ratio, like boxing, MMA and cycling; as well as to the mainstream weight loss market with many people who do not engage in any serious exercise using it to help lose weight or to 'tone up'. There is no doubt here that it is very effective in doing this. The fact that it improves energy levels and gives a bit of a 'buzz' is seen as an additional positive by these users.
Also, ephedrine is used recreationally as a 'party drug'. Some party-goers will use ephedrine or related ephedra herbs during a night out for its 'buzz' effects. Indeed, ephedrine is widely used by drug dealers to 'cut' cocaine and amphetamine sulphate, because it's cheap, gives a 'buzz' and does not have the negative effects that other 'cutting agents' have.
More interestingly and less commonly known, is the use of ephedrine as a mind enhancing drug in improving concentration. Anecdotal reports have suggested that ephedrine helps studying, thinking and concentration to a greater extent than caffeine. Some students have used ephedrine or ephedra-containing herbal supplements for their revision. Indeed, this application has also been a reason for its use by elite athletes and weightlifters.
Possible Side Effects
Although weight loss and performance aids containing ephedrine and related compounds are given out willy-nilly, users need to be aware that the products are potentially dangerous and are not without the risk of problems. There are a number of possible side effects from using ephedrine, pseudoephedrine, synephrine or the herbal versions. These include:
•anxiety
•shaking
•increased sweating
•light-headedness
•dizziness
•light headache
•gastrointestinal distress (e.g. stomach cramps)
•wakefulness and insomnia
•irregular heartbeat
•increased heart rate
•heart palpitations
•increased blood pressure
•stroke
•seizures
•psychosis
•thirst
•irritability and aggression
Use of ephedrine and related compounds can also worsen depression in people prone to feeling depressed. The increased sweating and raised metabolic rate mean you will need to drink more fluid. It has also been reported that some long term users (over 6 months) display some addiction and dependency.
Some of the above side effects may actually be viewed as positive effects by some people. For instance, new users may experience a wired feeling which is best described as slightly 'jumpy', which is perfectly normal and gradually subsides, and, for some, not entirely unpleasant. Heart rate will increase, and the user will be aware of it increasing. As a result, users typically experience an increase in gym performance especially during aerobic activity.
Ephedrine does actually have a very good safety record, especially considering how widely it is used in sports. Where there have been adverse reactions, there has been some underlying condition which would contra-indicate its use. However, possibly due to media sensationalism, ephedrine has been linked to a few deaths, despite the fact that its use is a lot wider than sports. One important negative effect of ephedrine concerns its effect on increasing core body temperature: If abused by athletes exercising in hot conditions, ephedrine has been linked to causing heatstroke and deaths have been attributed to its use in this way.
Doses, Dependency and Tolerance
Typical doses from where we can feel ephedrine working start from below 25mg, and this level has been shown to have a positive thermogenic effect and will aid weight loss. If tolerated this dose can be increased to 25mg twice a day, and further increased to 50mg twice per day. Some ephedrine preparations are available as 30mg tablets, so this slightly higher dose is often used.
Ephedrine does give rise to both tolerance and dependency. It is very common for users to quickly get used to their dose and feel no effect therefore they up the dose, and in a few weeks it's not unheard of for a user to be using well in excess of 100mg two or three times per day. This is potentially very dangerous. It should be noted that although the individual may not feel the effects associated with ephedrine is it still exhibiting thermogenic and weight loss activity and, thus is tricking the user who may be tempted to up the dose. This can lead to a loss of control and the use of dangerous doses.
By increasing the dose, ephedrine can also give rise to dependency. Some people, especially people with busy active lifestyles, depend on ephedrine's use after just a few weeks and feel they have to rely on ephedrine to get through the day or to lose weight. This is not a desirable situation to be in and if it's the case then the individual should completely cease its use for at least a few weeks and then re-start on a more controlled plan.
Ephedrine is best cycled and not used for long periods. There are a number of regimens: Some advocate its use on just 5 days per week so as to minimise tolerance; in practice this may just be using ephedrine on training days. Others prefer 2 weeks on, 2 weeks off; some use it continuously for 6 weeks, then have a break.
Contra-Indications
If you are considering using ephedrine, synephrine or any herbal compound mentioned in this article, then you must always consult your doctor. If you are considering using pseudoephedrine, please consult a pharmacist.
Ephedrine should not be used by anyone with underlying heart disease, high blood pressure, history of heart disease of any type, stroke or other cardiovascular disease, depression, anxiety, bi-polar, metabolic acidosis, diabetes mellitus or if any of the side effects listed above are a recurrent problem.
Adverse Drug Interactions
Ephedrine should not be used in conjunction with the any of the following drugs or groups of drugs:
•SNRI antidepressants (serotonin-norepinephrine re-uptake inhibitors)
•Bupropion and other NDRI antidepressants (norepinephrine-dopamine re-uptake inhibitor)
•Concurrent or recent use of monoamine oxidase inhibitors (MAOIs)
•General anaesthesia with halogenated hydrocarbons (particularly cyclopropane or halothane)
•Beta-blockers
Synephrine
Synephrine is substance similar to ephedrine, which acts on α1-adrenergic receptors to constrict blood vessels and increase blood pressure and heart rate. In fact, its action is remarkably like ephedrine, yet it has not been banned in the same way as ephedrine and herbal forms of ephedrine have. This has lead it to be used more and more in weight loss formulas now labelled as 'ephedra-free'. However, the effects are just the same and, although no formal tests have been done, it's likely that the negative effects are also the same. Therefore it seems ludicrous that it isn't governed by the same legislation.
Synephrine is mainly derived form citrus aurantium (see below). Many diet products contain synephrine along with caffeine. Some reports have indicated that such diet pills cause numerous harmful effects. There have been reports of increased risk of ischemic stroke, increased blood pressure, arrhythmias and cardiac infarction with synephrine use (Bouchard et al 2005). Nevertheless, synephrine remains a popular, though slightly inferior, substitute to ephedrine.
Pseudoephedrine
Pseudoephedrine (PSE) is the form of ephedrine found as a nasal-decongestant in over-the-counter (OTC) preparations, for example Sudafed™. However, its use as a nasal decongestant is being phased out due to its ease of purchase and subsequent use in the manufacture of methamphetamine. Nevertheless, it remains very popular.
Pseudoephedrine's mode of action is similar to that of ephedrine, though it has weaker beta-adrenergic agonistic activity. It does cause a release of noradrenalin from vesicles in neurones, which cases muscles to contract and blood vessels to constrict. This means less fluid can leave the vessels and enter the nose, throat and sinus linings, which results in decreased inflammation of nasal membranes as well as decreased mucus production. The vasoconstriction that pseudoephedrine produces, is believed to be principally an alpha-adrenergic receptor response. While all sympathomimetic amines, to some extent, have decongestant action, pseudoephedrine shows greater selectivity for the nasal mucosa and a lower affinity for CNS adrenergic-receptors than ephedrine.
Even though ephedrine and pseudoephedrine have very slightly different mechanisms of action (adrenoceptor agonists and catecholamine-releasing actions), they are similar enough so that pseudoephedrine does act as a thermogenic compound. However, has been shown to be less effective (Wellman & Marmon 1985). Indeed, Greenway et all (1999) showed that at a dose of 120mg pseudoephedrine, an amount 4-6 times higher than the ephedrine dose used, there is insignificant thermogenesis.
Pseudoephedrine has a half-life of 9-16 hours.
Geranamine / Methylhexaneamine
This psychoactive drug is commonly called geranamine or methylhexaneamine but is also sometimes called forthan, forthane, floradrene or 1,3 dimethylamylamine (DMAA). It is used as a nasal decongestant acting as a noradrenalin reuptake inhibitor. It is often confused with ephedrine as the effects experienced are remarkably similar. However, as it comes under different regulations, it is found in some dietary supplements along with caffeine and other ingredients.
Geranamine is not FDA approved in its own right, although it is a component of geranium oil which is approved for use in foods, hence it is classified as a dietary supplement rather than a pharmaceutical product. Geranamine is a component of the oil from Pelargonium graveoles which is approved for use in foods, but it only comprises 0.66% of geranium oil and pure synthetic geranamine is thus quite different from geranium oil.
Typical doses of geranamine range from 40-50mg in a serving, and has been described by users as 'a different type of "energy" to ephedrine; not as intense, but still very noticeable'
The main ephedra herbs are:
Má Háung
The most common herbal form of ephedrine is má háung (Ephedra Sinica) and it was the traditional Chinese form. The plant is standardised to varying degrees so the user must calculate exactly how much ephedrine is contained in the preparation. For example if you see on a label: má háung 335mg (standardised to 6% ephedra alkaloids) this is the equivalent of 20mg pure ephedrine.
Soma
Ephedra distachya (aka Ephedra vulgaris) contains a form of ephedrine called soma and had religious links in Hinduism.
Sida Cordifolia
Sida cordifolia is also known as bala and is from the family Malvaceae, and contains significant amounts of ephedrine and pseudoephedrine. It is used as a source of ephedrine in weight loss formulas because, mainly, its name is not so maligned and using herbal names is more fashionable. There are products available which contain it with forms of caffeine and aspirin, and these are essentially forms of the ECA stack (see below).
In addition to the metabolic stimulatory effects, cayenne pepper can also blunt appetite leading to a reduced intake of food.
Yohimbine aka Yohimbe Extract
Although marketed as a supplement, yohimbine is a psychoactive drug with stimulant and aphrodisiac effects. It is an alkaloid and is found naturally in yohimbe (Pausinystalia yohimbe or Corynanthe yohimbe) where it is known as yohimbe extract. It is also found naturally in Indian Snakeroot (Rauwolfia serpentina), along with several other active alkaloids. Yohimbe extract is available in OTC supplements and as yohimbine HCl in prescription medicine for the treatment of sexual dysfunction.
Supplementation with yohimbine has been shown to improve fat loss in athletes (Ostogic 2006) and from this study its use in weight loss formulas has risen dramatically. However, it's not without its side effects, many of which are similar to the ones experiences with ephedrine; so caution should be heeded when both compounds are used in conjunction. Interestingly, the ECY stack (ephedrine / caffeine / yohimbine) is being used more and more, and there are also some commercial ECYA formulas available.
Catechin aka Green Tea Extract
Green tea extract is known as catechin, or, more precisely, epigallocatechin gallate (EGCG). EGCG is a powerful polyphenolic anti-oxidant with the asscoaited benefits, but, more importantly, it's been shown to be lipolytic independent of caffeine (Dulloo et al 1999). Green tea extract is often found in weight loss preparations with ephedrine or synephrine.
Legality of Ephedrine and Pseudoephedrine
In the UK ephedrine is regulated as a prescription only medicine (POM), i.e. it may only be lawfully supplied within a registered pharmacy and while a responsible pharmacist is present. The maximum amount of ephedrine legally available without prescription in one sale is 180mg.
One product commonly sold within these restrictions is ChestEze (aka Do Do ChestEze) tablets which consist of nine pills of 18.31mg ephedrine HCl, 30mg caffeine and 100mg anhydrous theophylline. ChestEze is sold as a nasal decongestant but is commonly abused by bodybuilders and those looking to lose weight, and there are issues here with people reacting badly to theophylline. Higher strengths of pure ephedrine are available as POMs but are not currently Controlled Drugs under the Misuse of Drugs Act.
Like ephedrine, pseudoephedrine is available on prescription or over the counter under the supervision of a qualified pharmacist. As of 2009 UK pharmacies sell Sudafed (pseudoephedrine HCl) in 12 tablet pack size containing 60mg per pill.
In 2004, the US FDA imposed a ban on ephedrine alkaloids that are marketed for reasons other than asthma, colds, allergies, other disease or traditional Asian use. This means that all ephedra compounds are not allowed, though currently this doesn't extend to synephrine. The legality of ephedrine and ephedra compounds in the USA is ever changing, and there are many politicians wishing to be viewed as proactive over the use of drugs in sports. Ephedrine is still legal in many clinical areas, like in respiratory medicines, but purchasing is currently limited and monitored, with specifics varying from state to state.
In the USA the law changed in 2006 concerning the sale of pseudoephedrine-containing products. The Federal statute included a number of strict requirements for merchants who sell pseudoephedrine including keeping a record of customers, limits on daily and monthly amounts sold.
WADA Position on Ephedrine and Pseudoephedrine
The World Anti-Doping Agency (WADA) 2009 and 2010 Prohibited Lists both include ephedrine under the sub-section 'Specified Stimulants' with the reference:
Each of ephedrine and methylephedrine is prohibited when its concentration in urine is greater than 10 micrograms per millilitre'. And pseudoephedrine is prohibited when its concentration in urine is greater than 150 micrograms per millilitre.
Although the half life of ephedrine is 3-6 hours, it's said that to be sure that it is undetectable, there should be 72 hours from last administration. Random drug testing would mean that ephedrine may be detected.
Pseudoephedrine was on the banned substances International Olympic Committee (IOC) list until 2004. The gymnast Andrea Răducan was stripped of her gold medal at the 2000 Sydney Olympics after testing positive for pseudoephedrine. She took two pills given to her by the team coach for a cold. Although she was stripped of the overall gold medal, she kept her other medals, and, unlike in most other doping cases, was not banned from competing again. Pseudoephedrine has a longer half life than ephedrine (9-16 hours), but the levels allowed by the WADA mean that restricted use of nasal decongestants can be used. However, caution is recommended and alternative medication is advisable. The use of pseudoephedrine in competitions is being monitored by the WADA during 2010 who may review their ruling. WADA (2009) noted the following about pseudoephedrine:
• Until 2003, the stimulant pseudoephedrine had been prohibited in sports with a threshold of 25µg/mL. Pseudoephedrine has been included in the Monitoring Program since 2004. Results from the Monitoring Program over the past 5 years have shown a sustained increase in urinary concentrations of pseudoephedrine. In addition, there is clear evidence of abuse in some sports and some regions which show clusters of samples with high pseudoephedrine concentrations many times in excess of concentrations normally found. Furthermore, the available literature demonstrates scientific proof of its performance enhancing effects at certain doses. Therefore, the List Committee has reintroduced pseudoephedrine as a specified stimulant in the 2010 Prohibited List at a urinary threshold of 150µg/ml based on the results from controlled excretion studies as well as the literature. Given the wide availability of pseudoephedrine-containing medicines, WADA recommends that the reintroduction of pseudoephedrine is supported by active information/education campaign by all stakeholders.
• Although pseudoephedrine is now prohibited, it will remain in the Monitoring Program for urinary concentrations below 150µg/ml.
Popularity of Ephedrine and Related Compounds as 'Supplements'
There is no doubt that the popularity of ephedrine, ephedra herbs and related compounds is rife in many sports, bodybuilding and the general weight loss community. This is primarily because the products 'work' and the 'buzz' they produce is deemed favourable. The adverse reactions are scarce, but they do exist so anyone considering using ephedrine or related herbs needs to be cautious. Also the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK are clamping down on supplements sold legally containing ephedrine and related ingredients. Many health stores have been visited and had their stocks confiscated. However, the products or specific ingredients which are being regulated is unclear, and it appears that synephrine is ok for now, at least. As a consequence of this, people are tending to source their ephedrine through the black market.
A Final Note of 'Fat Burning' Supplements
Ephedrine and other thermogenic 'fat burning' supplements are merely there to supplement or
References:
• Bouchard et al (2005). Ischemic Stroke Associated With Use of an Ephedra-Free Dietary Supplement Containing Synephrine. Mayo Clin Proc. 80(4):541-545
• Dulloo et al (1999). Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr 70: 1040-1045
• Greenway et al (1999). Double-blind, randomized, placebo-controlled clinical trials with non-prescription medications for the treatment of obesity. Obes Res 7(4):370-8
• Ostogic (2006). Yohimbine: the effects on body composition and exercise performance in soccer players. Res Sports Med 14(4):289-99
• Plantenga et al (2006). Metabolic Effects of Spices, Teas and Caffeine. Physiol and Behav 89: 85-91
• Wellman & Marman (1985). Comparison of brown adipose tissue thermogenesis induced by congeners and isomers of phenylpropanolamine. Life Sci 37(11):1023-8
• The World Anti-Doping Agency (2008). The World Anti-Doping Code: The 2009 Prohibited List - International Standard
• The World Anti-Doping Agency (2009). The World Anti-Doping Code: The 2010 Prohibited List - International Standard
• The World Anti-Doping Agency (2009). 2010 Prohibited List: Summary of Major Modifications