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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 (, 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).
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 (, 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).
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