Ephedrine Science
By David Tolson
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1. What is ephedrine?
Ephedrine is one of the most effective and controversial substances used for weight loss. It is a potent fat loss agent and CNS stimulant (especially when combined with caffeine) and also effective in the treatment of asthma. However, there are also many reports of adverse events that are possibly associated with ephedrine use that have prompted many people to call for further regulation of the compound.
Chemically, ephedrine is a phenylpropanolamine, a class of stimulant compounds that include ephedrine, psuedoephedrine, norephedrine, and cathine. Ephedra (also known as Ma Huang), a traditional Chinese herb, contains varying concentrations of phenylpropanolamines and other alkaloids and is the primary source of ephedrine sold in most over the counter preparations. Ephedra has been in use for over 5000 years for its stimulant and antiasthmatic properties.
Despite its popularity, ephedra is a very misunderstood substance, especially concerning its pharmacology. It is also misunderstood because the differences between chronic and acute effects are often not emphasized. This article will shed some light on how ephedrine works, and also provide information on side effects and the best ways to minimize them.
2. What application does ephedrine have?
Not only does ephedrine increase the rate at which fat is lost, it preserves muscle at the same time, making it an ideal dieting aid for athletes.
Fat loss - The most comprehensive look at the use of ephedrine for weight loss is a recent meta-analysis published in The Journal of the American Medical Association. This meta-analysis was done by the request of the US Department of Health and Human Services (1). It reviewed 44 controlled trials on the use of ephedrine for weight loss. It found that on average, ephedrine increased weight loss 1.3 lbs. per month more than placebo, while ephedra increased weight loss 1.8 pounds more than placebo. However, combinations of ephedrine or ephedra with caffeine or herbs containing caffeine resulted in an average weight loss of 2.2 lbs. per month.
Muscle preservation - One of the evils of dieting is that at least some loss in muscle mass in generally expected. Losing weight is simple compared to losing weight while maintaining, or even gaining muscle. Through nutrient repartitioning, ephedrine promotes fat loss while preserving fat-free mass (2). This has been confirmed in trials that have measured bodyfat levels (3-6). Additionally, in two shorter trials in which no weight loss was seen, the treated group was shown to have a better nitrogen balance in one (7), implying lean tissue growth, and in the other, the ephedrine/caffeine group lost 4.5 kg of body fat and gained 2.8 kg of fat-free mass compared to the placebo group (8), showing that ephedrine can cause fat loss and muscle gain even when you aren't losing weight.
3. How does ephedrine work?
One of the reasons ephedrine is such a powerful agent is that it operates through a variety of mechanisms, including increasing levels of norepinephrine, epinephrine, and dopamine, and stimulating both alpha and beta adrenoreceptors.
Appetite suppression - Ephedrine (through facilitating the release of adrenaline and noradrenaline) stimulates the alpha(1)-adrenoreceptor subtype, which is known to induce hypophagia (appetite suppression) (9, 10). It is estimated that appetite supression accounts for 75-80% of the weight loss attributed to ephedrine (2, 4).
Increased energy expenditure - 50 mg of ephedrine alone increases total energy expenditure by about 4% when administered acutely (11), but 60 mg per day increases metabolic rate by 10% when used chronically (12). Although beta(1), beta(2), and beta(3)-adrenoreceptors all play a role in ephedrine-induced thermogenesis, the fact that tolerance develops quickly to most of the cardiovascular effects but the thermogenic effects appear to be enhanced over time may be explained by direct activation of beta(3) or "atypical" adrenoreceptors (10), which is responsible for at least 40% of the thermogenesis induced by ephedrine (13).
Increased protein synthesis - Similar to clenbuterol, which is commonly used to lose fat while maintaining muscle, ephedrine is a beta(2) agonist. Stimulating the beta(2)-adrenoreceptors increases protein synthesis and counteracts the catabolism of muscle commonly seen with low calorie diets (10).
4. What other benefits does ephedrine have?
Exercise performance - Ephedrine may increase performance when taken before exercise. Six studies have measured the effect of ephedrine on exercise performance, five of which have shown a positive effect. The combination of ephedrine and caffeine improved anaerobic performance and increased time to exhaustion in three cycle ergometer studies, improved run times on the Canadian Forces Warrior Test (a 3.2 km run wearing 11 kg of equipment), and improved muscular endurance on a superset of bench press and leg press. In the one study that came out negative, ephedrine failed to improve tolerance to walking at temperatures over 100 degrees (1).
Cholesterol levels - Weight loss normally causes a corresponding decrease in HDL ("good") cholesterol (19). Not only does ephedrine prevent this decrese in HDL cholesterol or even slightly reverse it (6, 19), treatment also decreases LDL ("bad") cholesterol by about 10 mg/dl over six months (6). For most individuals, this is a 5-10% reduction.
5. What are the side effects?
There are many side effects associated with ephedrine both real and imagined. Some of the most common are dry mouth, insomnia, and headaches (21), as well as anxiety (1), but all of these diminish with repeated use. The more serious side effects are exacerbated by the way ephedrine is commonly used – larger, acute doses at irregular intervals. Many people believe that ephedrine is not working if they can't "feel" it, when the maximum thermogenic effect occurs only after tolerance to most of the other effects (such as anxiety, higher blood pressure, etc.) has developed.
Cardiovascular problems - Ephedrine has been associated with raises in blood pressure and about a 2.3-fold increase in heart palpitations (1). However, these figures are often grossly misread, especially in application to the use of ephedrine for weight loss. Studies that measure cardiovascular symptoms such as blood pressure, heart rate, and palpitations over extended periods of treatment find that they quickly become transient with tolerance (2, 10, 19-22). As stated above, this discrepancy – tolerance to negative effects while fat loss continues - is probably due to ephedrine's action as a direct beta(3) agonist, while tolerance to the increases in noradrenaline, adrenalin, and dopamine levels develop relatively rapidly. Despite this relative safety, those with high blood pressure or other cardiovascular problems should not use ephedrine and especially an ephedrine/caffeine mixture unless they are under strict medical supervision, and it would be wise for anyone using ephedrine to get their blood pressure checked regularly.
Glucose metabolism - It is likely that ephedrine decreases insulin sensitivity, at least in the short term. Two studies have shown ephedrine to increase insulin levels, one of which found that ephedrine decreased glucose uptake after acute administration (23, 24), but two others showed no difference in insulin levels and glucose metabolism after chronic treatment with ephedrine and caffeine (19, 20). It is therefore likely that tolerance develops quickly to this side effect as well, but ephedrine should still only be used with caution by those with diabetes or insulin resistance.
Addiction - Many studies have been done comparing the reinforcing effects of ephedrine in animals to other psychostimulants such as cocaine and amphetamine, and have focused on its effects on dopamine release. Like cocaine and amphetamine, ephedrine increases the activity of dopaminergic systems. A study on rhesus monkeys found that ephedrine had a similar reinforcing effect to cocaine (14), and a rat study found that ephedrine could act as a substitute for rats habituated to cocaine (15). However, route of administration makes a big difference in abuse potential, and cocaine is usually smoked or snorted while ephedrine is taken orally when used for weight loss. Also, another rat study found that rats would not discriminate between ephedrine and saline solution (16).
When it comes to addiction and abuse potential, human studies can be much more enlightening. Two single dose studies have been done with humans using the Addiction Research Centre Inventory (ARCI), which is used to measure the addictive characteristics of a drug. In the more recent of the two, the primary psychological effect noted was "decreased tiredness," and ephedrine (both nasally and orally) did not change any of the ARCI subscales, including the "amphetamine" subscale (17). In the other study, which was more comprehensive, ephedrine increased ratings for both euphoria and anxiety, and had reinforcing strength less than half of that of amphetamine. Amphetamine produced higher scores on the euphoria subscale and lower scores on the anxiety subscale. The author of this study concluded that the abuse potential for ephedrine was relatively low, and comparable to that of caffeine (18). This is in agreement with real world data - despite the fact that it has been available over the counter for over 20 years, there is a low incidence of abuse with ephedrine and few reports of long-term abuse (16).
Neurotoxicity - In rat studies, large, acute doses of ephedrine have a neurotoxic effect through a similar mechanism to amphetamine (damage to dopaminergic terminals) (40, 41). This neurotoxicity is mediated by hyperthermia and dopamine depletion. Ephedrine is not as neurotoxic as amphetamine, with small doses having no neurotoxic effect (40). No extensive human studies have been done with regard to ephedrine and thermal regulation or neurotoxicity, but a study with 5 mg/kg of caffeine and 1 mg/kg of ephedrine given before prolonged exercise at a high temperature found that body temperature increases were sufficiently offset by increased heat loss mechanisms (42). The best ways to avoid possible neurotoxicity would be to avoid large, acute dosing schedules and drink plenty of water.
6. What form of ephedrine is best?
The two primary sources of ephedrine are ephedra extracts and synthetic ephedrine HCl. Herbal extracts are the more common of the two because there are much fewer legal restrictions. However, there is also not nearly as much standardization, and ephedra may contain additional compounds that could be toxic. With both choices, there are both potential benefits and drawbacks.
The ratio of ephedrine to other ephedrine alkaloids (including pseudoephedrine) present in extracts typically ranges between 10:1 and 1:2 (or about 30-90% of alkaloids present as ephedrine), with very few products containing ephedrine as the only alkaloid (25-26). It is good to discriminate between products standardized for ephedrine and those standardized for total ephedrine alkaloids. Most extracts contain pseudoephedrine, and a good number also contain norephedrine and norpseudoephedrine (26). Combinations of ephedrine alkaloids, especially with caffeine, may produce toxic effects. For example, methylephedrine (which generally makes up 0-5% of the alkaoids in extracts) combined with caffeine may produce effects similar to those of methamphetamine (26). There are probably other alkaloids present as well, which may account for the reports of poisoning from ephedra products – a recent study found that ma-huang extracts had toxic effects that could not be accounted for by the ephedrine alkaloid contents (25). Another important difference between ephedra and pure ephedrine is that the absorption rate is slower for ephedra (27).
Finally, there is the issue of label claims. Three years ago, a study was done on 20 ephedra-containing products and found that half of them either exceeded or failed to meet label claims by a degree of over 20%. Two of the products that met label claims were Xenadrine RFA-1 (standardized to ephedrine) and Ripped Fuel (standardized to ephedrine alkaloids). As with other supplements, it is best to stick to reliable, well-known brands when purchasing ephedra products even if the price is slightly higher.
Because of the potential problems with ephedra extracts, many seek out pure ephedrine products as a safer alternative. Products containing pure ephedrine are generally sold for bronchiodilation or similar medical purposes only. Single entity ephedrine products (those that contain only ephedrine) are List I, meaning they are relatively highly controlled by the DEA. There are limits on the amount that can be bought by an individual, and the buyer's driver's license and other personal information has to be submitted beforehand. Products that combine ephedrine with another substance (such as VasoPro Ephedrine HCl) are relatively unrestricted. The most common combination is ephedrine and guaifenesin. Guaifenesin is a nasal decongestant and is very safe but still may cause problems if taken in chronic, excessive amounts. There are some case reports of stones caused by excessive amounts of guaifenesin, but these were individuals who were taking very large amounts of guaifenesin/ephedrine products regularly for stimulant purposes (28). It is doubtful that it would be a problem at the dosages used for weight loss, but it is still something to consider.
7. How should ephedrine be taken?
Ephedrine is generally taken twice daily with a total dosage of 20-60 mg. Some users prefer taking twice as much in the morning as the second dose (for example, 40 mg and then 20 mg). The most common schedule is 20 mg of ephedrine and 200 mg of caffeine twice daily, and a study comparing various ephedrine/caffeine mixtures found this to be an ideal dose (2). For maximum effect, ephedrine should be taken in combination with a calorie restricted diet and a regular exercise schedule.
Taking ephedrine without a tolerance developed as an "energizer" may not be the best idea. Although studies show it to cause performance increase, it should be kept in mind that taking large amounts of ephedrine pre-workout without a tolerance may result in dangerously high blood pressure. If it is used this way, it should be kept in mind that more is not better – a study comparing various doses found that lower amounts had the same benefit as higher ones, but with less incidence of side effects (29).
The safest and most effective way to take ephedrine is on a chronic basis for as long as weight loss is desired - at least for a period of up to six months, as long term safety has not been thoroughly analyzed. Most labels recommend a period of no longer than 3 months. Additionally, it is best to start out with half of the dosage for the first few days until tolerance develops, and similarly use half of the dosage for the last few days to lessen the possible withdrawl symptoms. There is little evidence to warrant many of the cycling schedules commonly seen (such as 5 days on, 2 days off), as they may be more effective at retaining the anorectic effect but they also significantly increase the chances of an adverse event and the incidence of negative side effects (such as anxiety and insomnia). On the other hand, chronic use has been proven effective with minimal side effects in a multitude of studies.
8. What are some good supplements to take along with ephedrine?
Many supplements are commonly stacked with ephedrine. Listed here are some of the substances that may have a synergistic effect with ephedrine.
Caffeine - It has been repeatedly shown that caffeine enhances the thermogenic response to ephedrine (10, 22, 23, 30). This is because one of the main negative feedback mechanisms after adrenoreceptor activation is an increase in phosphodiesterase enzyme levels, and caffeine is a phosphodiesterase inhibitor (10, 30). Phosphodiesterase is the enzyme that breaks down cAMP, and a cAMP increase is one of the last steps in the lipolytic cascade induced by ephedrine. Adenosine antagonism by caffeine may also have a synergistic effect, but probably only plays a minimal role (30).
Aspirin - Another negative feedback mechanism that may blunt the thermogenic response to ephedrine is prostaglandin release (10). Therefore, it is theorized that a prostaglandin inhibitor such as aspirin will potentiate the thermogenic response. The studies in this area are conflicting. In two studies done by Horton measuring the thermogenic response to a single dose of ephedrine, one found aspirin to increase thermogenesis in obese but not lean women, and another found no potentiation by aspirin with an ephedrine/caffeine combination in both lean and obese women (31, 32). However, a rat study found aspirin to markedly potentiate weight loss caused by ephedrine (33). Another complication here is that anti-inflammatories may interfere with protein synthesis (34). In the end, the addition of aspirin is a toss-up, as it probably potentiates the fat loss but may also be catabolic to muscle.
Yohimbine - There is a major problem that ephedrine doesn't address, which is the issue of the alpha(2)-adrenoreceptors. This is yet another negative feedback mechanism – when norepinephrine levels go up, they activate alpha(2) receptors which in turn inhibit the release of norepinephrine. Areas of "stubborn fat" tend to have a higher quantity of alpha(2) receptors, so inhibiting this feedback mechanism is important. Yohimbine HCl is a potent alpha(2) antagonist (35), and inhibits the ephedrine-mediated alpha(2) agonism (36). This combination should be used with caution, as yohimbine may complicate some of the cardiovascular effects of ephedrine (37). If this is a concern, an effective alternative to oral yohimbine is Lipoderm-Y, which delivers yohimbine to the area of choice while avoiding the negative side effects associated with systemic delivery.
L-Tyrosine - L-Tyrosine, a precursor to catecholamines, significantly increases the central effects of ephedrine (such as anorexia), but not the peripheral effects (such as thermogenesis) (38, 39). This effect is dose-dependant (38). For this reason, it can be used in conjunction with ephedrine to increase the anorectic effects, but it may also increase the negative CNS side effects.
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