Mechanism of effect in weight loss
The effects of the ECA stack in weight loss are primarily due to the ephedrine component. Ephedrine acts both as a beta agonist and stimulates the release of norepinephrine. Increased circulating norepinephrine in the body then acts on white adipose tissue by increasing cAMP levels. This causes a thermogenic effect, raising body temperature and increasing the user's metabolism in conjunction with the rest of the stack.[citation needed]

However, the body's negative feedback system then activates to normalize the metabolism. This is done via the production of phosphodiesterase inside the cells, and prostaglandins outside the cell, which both lower cAMP levels within the cell.

Caffeine inhibits the production of phosphodiesterase inside the cell and therefore slows cAMP breakdown. It also binds with and competitively inhibits adenosine receptors in the brain, triggering the release of epinephrine and increasing cAMP levels further.

Aspirin inhibits prostaglandin production outside of the cells, which, in conjunction with caffeine, greatly prolongs the thermogenic effects and increased metabolism by sustaining elevated cAMP levels.

Ephedrine also has an anorectic, or appetite-suppressing, effect. However, these effects only last for about two weeks if the stack is not cycled, as the body becomes tolerant to ephedrine to some degree.[citation needed] It is estimated that 60%–75% of the weight loss from using the ECA stack comes from the anorectic effect, and the remainder from thermogenesis.[citation needed]

The final component in weight loss of the ECA stack is that of a simple stimulant; the higher epinephrine and norepinephrine levels result in increased aerobic exercise performance and less fatigue.[citation needed]

Mechanisms of effect in energy gain
Ephedrine acts to increase energy by its actions as a sympathomimetic amine. It directly acts in the brain to increase the release of norepinephrine into the synaptic cleft, and also partially serves as a norepinephrine reuptake inhibitor, thereby also partially functioning as a dopamine reuptake inhibitor due to the shared action between the two terminals. Caffeine blocks adenosine receptors which lessens feelings of tiredness, and also increases dopamine levels, resulting in greater concentration, focus, and memory. The effects of caffeine on dopamine levels are usually short lived, but ephedrine's partial action as a dopamine reuptake inhibitor lengthens the duration.[citation needed]

Dosage
Typically the ECA stack is consumed two or three times per day in a 1:10:10 or 1:10:15 ratio of ephedrine:caffeine:Aspirin. These ratios vary across studies and across users but despite variance they all seem to be effective.[citation needed] Usually, no more than 25 mg of ephedrine, 200 mg of caffeine and 325 mg of Aspirin is consumed in a single dose. It is not recommended that the stack be taken past late afternoon as this may contribute to insomnia.

Addiction
While Aspirin is not physically addictive, caffeine is, and users develop a tolerance to lowered adenosine levels, leading to withdrawal symptoms from adenosine sensitivity if caffeine use is discontinued too quickly. Ephedrine is also physically addicting. Psychological addiction to ephedrine and caffeine are also possible.

Risks
The primary risk of the ECA stack is in the effect of ephedrine on the heart. Ephedrine has been linked to deaths in people with valve damage, heart problems and heart disease, but also in previously healthy young adults when taken in high doses. It is not recommended that stimulants be taken in users with a pre-existing heart condition. Additionally, there is some evidence that the long term use of amphetamines can lead to heart damage, but this has not been shown for ephedrine use.

Caffeine and ephedrine also act to raise blood pressure by approximately 4–7 mmHg on average,[citation needed] so users with existing hypertension must be careful that the stack does not increase their blood pressure to dangerous levels — especially during exercise (for example, by lifting exceptionally heavy weights).

Other risks include insomnia, dry mouth, irritability, stress, headache, anxiety, dizziness, nausea, irregular heartbeat, interaction with MAO inhibitors, trembling hands, increased need for water and potassium, and psychosis resulting from the long-term use of ephedrine.

Controversy and legality
Due to deaths linked to ephedrine and its potential use as a precursor in illegal methamphetamine manufacture, many countries have taken steps to regulate ephedrine. If ephedrine cannot be obtained, pseudoephedrine, ephedrine's optical isomer, can be substituted, but many countries are restricting sales of over the counter pseudoephedrine as well, because it is likewise used as a precursor in methamphetamine manufacture. Contrary to popular belief studies have shown pseudoephedrine to have a thermogenic effect; approximately three times less than L-ephedrine.[citation needed]

Many people have felt that ephedrine is not worth the risks, and have tried "ephedrine free" stack formulas. However, there is no proof that any of these formulations are actually effective, whereas a great deal of evidence exists to support the effectiveness of the ECA stack, albeit with apparent risks.

Status in The United States
Currently in the United States, ephedrine is legal, but the FDA bars marketing any supplements containing ephedrine as weightloss or bodybuilding supplements. To be legal, ephedrine must be marketed for medical conditions such as asthma. In addition, the FDA recently barred the sale of herbal supplements containing ephedra (a herb which contains both ephedrine and pseudoephedrine) under any circumstances. Ephedrine is still commonly available as a bronchodilator in several over the counter asthma medications from companies such as Biotek and Vasopro as well as in Primatine tablets.

As of 4/14/2005, U.S. District Judge Tena Campbell struck down the FDA's ban of weight loss supplements containing ephedrine alkaloids in the US, which may pave the way for its reintroduction as a weight loss supplement in the US. The ban on marketing ephedrine as a weightloss supplement at the moment is being challenged by several companies. A judge in Utah has ruled in favor of a pharmaceutical company that challenged the FDA's ban and the company may once again release products containing ephedrine back into the market.

Ephedrine

Pharmacokinetics
Ephedrine, pseudoephedrine, methylephedrine, norpseudoephedrine, and norephedrine have all been extracted from the ma huang plant. However, ephedrine and pseudoephedrine are the only 2 active components found consistently in ma huang products, with ephedrine being the predominant alkaloid.1,6 The other alkaloids are usually found only in small or trace amounts. For example, capsules containing 375 mg of ma huang have been found to contain an average of 4.84 mg (range, 3.8 to 5.9 mg), 1.22 mg (range, 0.77 to 1.82 mg), and 0.31 mg (range, 0.19 to 0.46 mg) of ephedrine, pseudoephedrine, and methylephedrine, respectively.1 The levels of ephedrine alkaloids can also vary depending on the product and the ephedra species used.6,7 In an investigation of 9 commercially available supplements, Gurley et al6 observed considerable variability in both the ephedrine (range, 1.08 to 13.54 mg) and pseudoephedrine (range, 0.52 to 9.46 mg) contents. Two of the products contained measurable quantities of ephedrine only, which led the authors to speculate whether the product actually contained ma huang (as claimed on the label) or was instead spiked with synthetic ephedrine. Unfortunately, ma huang product labels usually indicate how much of the ephedra herb is present, but few identify the ephedrine alkaloid content.
Synthetic ephedrine is easily absorbed after oral administration, with peak plasma levels occurring within an hour of ingestion.8 Its plasma half-life is approximately 3 to 6 hours, which varies depending on urine pH.2,9 After absorption, ephedrine is excreted, primarily unchanged, in the urine: less than 10% is excreted as norephedrine. When ephedrine is ingested in the form of ma huang, the elimination kinetics are similar to those for synthetic ephedrine.1,7 Reports conflict, however, regarding absorption kinetics. Gurley et al7 investigated 3 brands of ma huang and observed absorption kinetics similar to those following ingestion of a 25-mg synthetic ephedrine capsule. In contrast, White et al1 observed that it took longer for the ephedrine to reach peak levels in the plasma (approximately 4 hours) when ingested in the form of ma huang.

Ergogenic Claims
Because ephedrine is a sympathomimetic and a central nervous system stimulant, it is commonly used as an energy enhancer. Ma huang-containing products are marketed and used to improve aerobic performance and endurance, reduce fatigue, increase alertness, improve reaction time, and even increase strength. These products are also marketed to body builders (and those simply concerned with cosmetic appearance) with the claim that they can improve body composition via thermogenic and lipolytic effects. The lipolytic effects have also led to the claim that ma huang can improve endurance via increased fat utilization and glycogen sparing during exercise. Because of this, it is very common to find ma huang products that also contain other thermogenic and lipolytic supplements, such as caffeine (usually found in the form of guarana).

Ephedrine and Caffeine
It has been suggested that the thermogenic effects of combining ephedrine and caffeine are synergistic (the effect of the 2 drugs combined is greater than their additive effects).10–12 Similar to ephedrine, caffeine has been suggested to have stimulating effects on the central nervous system (CNS) and energy metabolism.13 However, the primary reason for combining the 2 drugs is to potentiate the effects of the ephedrine.5 Ephedrine exerts its thermogenic effects via catecholamine release. The increased catecholamine release after ephedrine ingestion is subjected to negative feedback systems, which then tend to inhibit catecholamine release and actions. These negative feedback systems include adenosine and prostaglandin release in the synaptic junction and elevated phosphodiesterase enzyme activity, which results in degradation of cyclic adenosine monophosphate (cAMP). Caffeine interferes with this negative feedback mechanism by inhibiting both adenosine and phosphodiesterase activity and preventing degradation of cAMP.5 Aspirin has a similar effect via its inhibition of prostaglandin synthesis. Thus, it is conceivable that either of these mechanisms could potentiate the thermogenic effects of ephedrine. Because of this, some of the more popular weight-loss supplements on the market today combine ma huang (ephedrine), guarana (caffeine), and white willow bark extract (aspirin).

Effects on Performance
Many of the ergogenic claims associated with ephedrine originated from earlier studies investigating its anti-obesity and anoretic effects. Ephedrine and the combination of ephedrine and caffeine have been considered effective weight-loss agents,11,14–16 although not all studies support this claim.17–19 Originally, the observed weight loss was attributed solely to the appetite-suppressing effects of ephedrine20; however, other mechanisms have more recently been suggested.14,17,19 In 3 weight-loss studies,11,15,16 body weight (as opposed to body composition) was the only variable assessed. Thus, it is unknown whether the weight loss was due to a reduction in fat mass or a loss of lean tissue and water mass. However, each of the authors suggested that increased energy expenditure (and primarily fat metabolism) accounted for most of the weight loss.

Thermogenesis and Lipolysis
The measurement of oxygen consumption (O2) is the primary index and documented evidence of a person's aerobic metabolism and energy expenditure. Thus, thermogenic claims associated with ephedrine have been supported, as increases in resting O2 have been observed after both acute and chronic ephedrine ingestion.14 Similarly, ephedrine and combined ephedrine and caffeine have been observed to partially prevent the usual fall in resting metabolic rate during a calorie-restricted diet.17–19 However, the higher metabolic rates observed in these studies were not always associated with weight loss.17,19 There is also support for lipolytic claims, as significant increases in both fat oxidation and fat loss have been observed when ephedrine is administered in combination with caffeine.17 In contrast, however, ephedrine ingestion alone failed to produce such changes.14 Only clinically obese individuals were used as subjects in these investigations; thus, it is likely that the subjects may have had deficient metabolic rates or fat metabolism or both. Unfortunately, it is common practice for supplement manufacturers to take results from deficiency studies and generalize them to young, healthy, athletic individuals when advertising their products. Those of us in the research community know that this cannot and should not be done.

Exercise Performance
While the research concerning ephedrine and performance in an athletic population is limited, most investigations do not support ergogenic claims.21–25 As mentioned previously, o2 is a primary measure of aerobic performance and, although ephedrine ingestion has been observed to increase resting o2 and fat oxidation in healthy individuals,26,27 these changes have not been observed during exercise.12,22,24,28 Similar observations have been made after pseudoephedrine ingestion, as no differences in O2 occurred in comparison with placebo conditions during exercise.25,29 As with O2 and fat oxidation, a number of other performance measures have been unaffected by supplementation.23–25 Sidney and Lefcoe24 administered 24 mg of ephedrine and found no improvements in muscle strength, endurance, or power; lung function; reaction time; hand-eye coordination; anaerobic capacity or speed; cardiorespiratory endurance; ratings of perceived exertion; or recovery. Similarly, Gillies et al23 reported that a single 120-mg dose of pseudoephedrine had no effect on 40-km cycling time, maximal muscle force, or muscle endurance during repeated isometric contractions. More recently, Swain et al25 administered pseudoephedrine (1 and 2 mg/kg) to trained cyclists and found no changes in ratings of perceived exertion or time to exhaustion.
One group of researchers, however, has observed performance changes when combining ephedrine with caffeine. Bell et al12 observed that the combination significantly increased cycling time to exhaustion by 38% over a placebo condition, while ephedrine and caffeine given separately failed to provide such an effect. In another study, the combination of ephedrine and caffeine improved cycling time to exhaustion by 64% over a placebo condition.28 In both studies, ratings of perceived exertion were significantly lower after supplementation, but heart rate was significantly elevated as well. The authors attributed the improvement to CNS stimulation, as no changes were observed for O2, carbon dioxide production, or fat oxidation. It is important to note that one would have to double the serving size of typical sport supplements containing both ephedrine and caffeine (Table) to achieve the doses used in these 2 studies. More recently, Bell and Jacobs30 administered 75 mg of ephedrine with 375 mg of caffeine and observed a slight (5%) but significant improvement in running time during a Canadian Forces Warrior Test (3.2 km run while wearing field gear). Unfortunately, the literature supporting the ergogenic claims associated with ephedrine in a healthy population appears to be limited to just one group of researchers. Negative side effects were commonly observed during these investigations and others involving both healthy and obese individuals.7,11,12,14–18,21,25,26,28

Side Effects
The spectrum of adverse health events associated with the use of ephedrine-containing products cannot be overlooked. The Food and Drug Administration (FDA) has received more than 1000 reports of adverse effects (including deaths) in persons ingesting nutritional supplements containing ephedrine and associated alkaloids.31 These side effects vary and do not always depend on the dose consumed.32 Although the occurrence of side effects was likely the result of misuse in many cases, such side effects have been regularly observed in subjects involved in clinical trials in which the dosages were controlled.7,11,12,14–18,21,25,26,28
Some of the minor side effects associated with ephedrine include tremors, palpitations, headache, restlessness, anxiety, and insomnia.9,17,25,32 Because of its direct sympathomimetic effects, ephedrine can increase heart rate, contractility, cardiac output, and peripheral resistance. Thus, increases in both heart rate and blood pressure are common observations after ephedrine ingestion.10,12,21,23–25,32 This is also true after ma huang ingestion, as significant increases in heart rate and blood pressure have been observed.1,7 Although these effects are not serious in most users, the consequences can be severe in those with underlying heart disease, hypertension, or diabetes and those sensitive to ephedrine.6 The more serious side effects include seizures, severe hypertension, arrhythmias, psychosis, hepatitis, stroke, myocardial injury, and intracranial hemorrhage.3,32–38 The adverse effects do not always depend on the dose consumed, as serious problems can occur in susceptible persons with use of low dosages.9,32 Furthermore, the toxicity of sympathomimetic agents is exacerbated by physical exercise, dehydration, and increases in body temperature,22 which are all commonly experienced during athletic training.

Although few in number, cases of fatal intoxication after ephedrine ingestion have been reported.8,32 In instances of ephedrine overdose, cardiovascular and CNS stimulant effects predominate. The most common causes of death are myocardial infarction and cerebrovascular accident.32 The recent death of a young, apparently healthy male college student brought attention to the possible dangers associated with ma huang–containing products. The individual regularly consumed a product containing ephedrine and caffeine known as Ripped Fuel (Twin Laboratories Inc, Ronkonkoma, NY).4 The official autopsy report and death certificate read “patchy myocardial necrosis associated with ephedrine toxicity from protein drink containing ma huang extract.” The blood and urine ephedrine levels suggested that the death was not caused by an acute poisoning but was the result of prolonged use.