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The ECA Stack Explained

by Bill Calberry

In the past several years the increasingly widespread use of Ephedra based products as thermogenic/lipolytic agents by the general public, has raised the marketing and sale of so called "fat-burners" from a relatively small and obscure segment of the supplement industry, to a mainstream multimillion dollar business in its own right. In fact the use, and inevitable abuse, of products containing Ephedra, has become so common that they have been demonized in the mainstream media to a far greater extent than even anabolic/androgenic steroids in recent years. A phenomena that to those in the know, is regarded as both laughable and baffling at the same time.

Although Ephedra has been used widely in Chinese folk medicine for well over two thousand years, and western medicine has also been making use of it for it's effect as a smooth muscle dilator to treat ailments such as asthma, bronchitis, and severe nasal congestion for decades; very little attention to it's capacity to stimulate an increase in lipolysis (the breakdown and release of fatty acids for use as energy) had been paid outside of academic circles until recently. It's probably safe to say however, that most people in western countries now know at least one person that has used a product containing Ephedra to aid their fat-loss efforts in the recent past. Yet despite the popularity and pervasive use of Ephedra (and the even more popular combination of Ephedra, Caffeine, and Aspirin; the so-called ECA stack) there remains a very poor level of comprehension with regard to what it is and how it works; this is true among both the pro and anti-Ephedra segments of the general population.

Therefore, in an effort to try to clear up some of the misconceptions, and explain exactly how Ephedra, and by extension the ECA stack, may work to increase lipolysis I decided to bash out the following article. As a professional trainer I often get questioned about the efficacy of ECA "fat-burners", and the advisability of their use. Unfortunately, I am not always afforded the time to sit down with someone and thoroughly answer such questions. Therefore my intention here is to create a resource that will explain things well enough to give people a clear picture, and arm them with the facts, when time prevents me from doing so directly. I will warn you now that the article gets a little technical however, and does touch on some relatively specific aspects of lipolysis. Although some may find it hard going at times if they lack a science background, I have made every attempt to ensure that I have explained myself well enough for most to be able to grasp the salient points without much difficulty; so bear with it.

I'll begin by outlining briefly what Ephedra is, and what effect it has in the body. Following that I'll explain the sequence of events involved in lipolysis, how Ephedra influences the process, and then examine how that influence varies over time. Finally I will discuss why Caffeine and Aspirin are often combined with Ephedra in order to create a more effective lipolytic agent. In the end I hope to have provided you with an overall grasp of the subject, and cleared up many of the misconceptions people tend to harbor with regard to the subject.

To begin with, let's look at the nature of Ephedra itself. Ephedra is an herbal extract containing an alkaloid compound known as Ephedrine. Alkaloids are a group of nitrogen containing substances that are generally naturally occurring, tend to have a strong effect in the human body in relatively small amounts, and are structurally similar to ammonia. Ephedrine is what is known as a Sympathomimetic, which is to say that it has the effect of stimulating the Sympathetic Nervous System. It has been shown to have lipolytic (causing the breakdown of triglycerides stored in fat cells into glycerol and fatty-acid molecules), mildly thermogenic (stimulating an increase in heat production via increased metabolic activity) and anorectic (appetite suppressing) properties.

Through its action on the Sympathetic branch of the Central Nervous System, Ephedrine also produces peripheral vasoconstriction (decrease in the size of blood vessels in the extremities) and therefore elevation of blood pressure, bronchodilation (relaxation of respiratory tissues and opening of the airways - hence it use in treating respiratory ailments), cardiac stimulation (elevated heart rate), and a decrease of intestinal tone & motility (slowing of secondary digestive processes).

The most common sources of Ephedra (and therefore the Ephedrine alkaloid) are the Chinese herb MaHung, and the somewhat lesser known Sida-Cordifolia plant. Due to regulatory policies in most western countries it is not possible to legally obtain pure pharmaceutical grade Ephedrine directly without just medical cause, therefore most "over the counter" products utilize the herbal sources of the alkaloid. You can in most places however, also obtain (pharmaceutical-grade) Ephedrine-HCL (hydrochloride) over the counter, which is a very similar compound having much the same effect, and which is commonly sold in low dose (8mg) tablets as a decongestant.

Although the mild thermogenic properties of Ephedrine and the resulting positive impact on metabolism (and therefore total energy consumption and the potential for accelerating the depletion of fatty tissues) is easily grasped by most (it stimulates an increase in the level of circulating Adrenaline, i.e. Epinephrine or Adr, and therefore metabolic activity and resultant heat production in many tissues throughout the body); the mechanism by which it creates an increase in lipolytic activity is a bit more involved. To explain this it is necessary to outline the process by which Lipolysis can be initiated via Sympathetic CNS activity, and subsequently regulated in the first place.

Initiation of Lipolysis via stimulation of the Sympathetic Nervous System by a Sympathomimetic such as Ephedrine is accomplished by means of what is termed a second messenger system involving the indirect activation of beta-receptor sites on Adipocytes (fat cells), and is attenuated by feedback inhibition. In other words the Ephedrine alkaloid itself does not directly affect the rate of Lipolysis within Adipocytes. Instead it acts as what is called a first messenger to set in motion a series of events that results in the activation of beta-receptors on the surface of the cell membranes, and the subsequent creation of another substance (a second messenger) within the cells that then catalyses the final reaction(s) in which triglycerides are actually broken down so they can be released into the blood stream for use as fuel.

Therefore contrary to popular belief, Ephedrine itself is not, strictly speaking, a beta-agonist in the same way as other compounds like Clenbuterol and Albuterol (favorites for decades of Bodybuilders in the final phases of contest preparation) that interact directly with the beta-receptor sites on cells. Regulation or attenuation by feedback inhibition simply means that the body limits the extent to which the process can proceed by releasing various substances which have the ability to block or inhibit lipolytic activity at one or more levels, and that the scale of the inhibitory response tends to vary in direct proportion to the degree of stimulation (the greater the stimulation, the greater the extent to which the body will act to limit the effect).

The process by which Ephedrine stimulates lipolysis begins after it circulates to reach and bind with receptor sites on neurons belonging to the Sympathetic Nervous System. By binding to those sites it sets in motion the following sequence of events.

  1. There is an immediate increase in the secretion of Adrenaline (Epinephrine or Adr) and Noradrenaline (Nor-epinephrine or NA) from the pre-synaptic nerve terminals.
  2. Circulating NA then binds to Adrenergic (having the property of producing or being activated by Epinephrine or chemically similar substances) receptor sites on the surface of all cells containing those sites (the highest concentration of Adrenergic receptors occurs on Adipocytes and skeletal muscle cells).
  3. The binding of NA to beta-adrenergic receptors on fat cells causes Stimulatory Guanine Nucleotide Regulatory Proteins (G-proteins) on the inside of the cell membranes that are coupled to the receptors to activate the enzyme Adenylate-Cyclase.
  4. Adenylate-Cyclase then converts Adenosine Triphosphate (or ATP, which is the molecule used to power all biological processes) inside the cell to 3'-5' Cyclic Monophosphate (cAMP). The creation of cAMP (the second messenger) within the cells represents the end of the direct chain of events initiated by Ephedrine itself (the first messenger).
  5. Much of the 3'-5' cAMP that is created is then quickly reconverted back to ATP (it is an unstable molecule that cannot naturally exist for long), but some survives long enough to bind to the regulatory sub-unit of the enzyme Protein Kinase-A (pkA) within the cell.
  6. When bound to cAMP, pk-A is then able to release its active (catalytic) sub-unit.
  7. The catalytic sub-unit of pk-A then phosphorylates (causes to bind with inorganic Phosphate, or Pi) the Hormone Sensitive Lipase (HSL) enzyme converting it to its active form, HSL-P.
  8. The presence of HSL-P then catalyses a 3-step hydrolysis reaction (a reaction involving a water molecule represented as HOH that is broken into two parts, H+ and OH-, and then combined with another substance AB that is broken, usually by an enzyme such as HSL-P, into A+ and B-, such that the result is two new compounds AOH and HB). This reaction sequentially reduces triglycerides stored within Adipocytes to Glycerol and Free-Fatty-Acids (each step removes one of the three fatty-acids from the molecule of glycerol). Those fatty acids can then be released into the blood stream and ultimately oxidized to release energy.

For those who have a decent grasp of this material already, it's obvious I've left out a lot of the particulars, but that pretty much covers the high points. Anyone with a deeper interest in the process can investigate the various metabolic pathways and biochemistry involved on their own using the steps I've mapped out as a guide for their readings though. In any event, all that's really important for most to understand is the basic flow of events leading to Lipolysis as a result of Ephedrine use. You certainly don't need to understand all the specifics to be able to grasp the value and limitations of Ephedra as a "fat-loss" agent, and how best to use it for that purpose. To summarize then:

  1. Ephedrine stimulates the release of NA by the sympathetic nervous system
  2. NA binds with beta-adrenergic receptors on fat cells
  3. G-proteins on the inside of the cells activate the Adenylate-Cyclase enzyme
  4. Active Adenylate-Cyclase causes ATP to be converted to cAMP
  5. Some of that cAMP binds to enzyme pk-A
  6. Enzyme pk-A then releases its catalytic sub-unit
  7. The pk-A sub-unit causes the phosphorylation of HSL to HSL-P
  8. HSL-P catalyzes the reduction of stored triglycerides (fat) to glycerol and fatty-acids

Now, as I've already stated with regard to steps One and Two, the Ephedrine molecule itself does not directly interact with the fat cells, but instead causes the release of NA and Adr, which in turn bind to beta-adrenergic receptors on the cells. What I did not yet mention is that NA and Adr can also bind with alpha-adrenergic receptors as well. As a result they are what are termed non-specific adrenergic agonists (though they can also be referred to correctly as both an alpha and a beta agonist). In terms of the impact on Lipolysis, this results initially in a generalized effect, because while beta-receptor activation tends to increase lipolytic activity within Adipocytes, alpha-receptor activation (particularly alpha-2 class receptors) tends to inhibit lipolysis. Therefore the net effect on lipolysis initially tends to be dependant on the ratio of alpha to beta-receptor sites on each fat cell. (The ratio of alpha to beta concentration on fat cells in different areas of the body is genetically predetermined, and also tends to follow gender specific patterns, which is in part responsible for why men and women tend to store more fat in specific areas of the body). Therefore at first glance the non-specific nature of increased NA and Adr levels seems like is should result in a stalemate with regard to overall Lipolytic activity, or at best only slightly elevated levels assuming a particular individual generally possesses more beta than alpha receptors on his or her fat cells overall. In fact this is generally the case for most people when they first begin using an Ephedra product. The situation changes however with continued (chronic) use, as various regulatory mechanisms of the body begin to come into play.

In general whenever you artificially elevate or suppress the level of any compound(s) (particularly hormones or their precursors) within the body, above or below normal levels, whether by directly introducing the substance(s) (or synthetic equivalents), by introducing another substance that in turn results in an increase or decrease in the level of a particular compound, or by exposing the body to environmental factors that cause a shift in the internal biochemical environment; the body will attempt to compensate for the effect either by decreasing it's own production of the substance(s) in question and/or by increasing production of other substances that inhibit the resulting effect. This is because the primary and dominant function of the human body is to maintain homeostasis (a stable internal environment) thus ensuring survival. To this end, the body has evolved with a myriad of internal checks, balances and interrelated feedback mechanisms that allow it to precisely monitor and adjust virtually every aspect of itself to some extent, so that it can maintain homeostasis under a wide range of conditions. In the case of what happens when you introduce Ephedrine into the body and therefore cause an increase in Adr and NA levels, it is not the initial effect but the net effect over time as the body begins to react and adjust it's internal environment to compensate and restore homeostasis, and our knowledge of how to manipulate that, which can have the greatest impact on resulting lipolytic activity. Although many of the specific homeostatic mechanisms and events involved in the body's response to Ephedrine are far beyond the scope of this article, with some still the subject of ongoing research; a quick summary of a few of the most prevalent and dramatic reveals how this compound can in fact be used to boost lipolytic activity overall (to some extent).

As stated, initial elevation of Adr and NA secretion by the sympathetic nervous system results in a general increase in activation of both alpha and beta adrenergic receptor sites. This in turn is likely, in the best case scenario, to result in only a mild increase in overall lipolytic activity based the ratio of alpha to beta receptors in a given individual. However with chronic stimulation of adrenergic receptors, the following effects begin to manifest. First of all there is a general tendency for all classes of receptors to become desensitized to activation by NA or Adr either by homologous desensitization (the receptors binding site becomes translocated inside the cell membrane so it is no longer accessible to external substances) or by heterologous desensitization (the receptor is phosphorylated rendering it inactive). However, the presence of increased amounts of circulating NA and Adr also tends to increase the conversion of T4 to T3 (T4 and T3 are thyroid hormones). Elevated T3 has been shown to stimulate an increase (as high as 5X) in the number of beta-3 receptors in white adipose tissue (the kind that sits over top of skeletal muscle). This is good for lipolysis, not only because it increases the ratio of beta to alpha receptors in general, so that even with desensitization occurring there is more beta activation, but also because beta-3 receptors seem to be the most resistant to both forms of desensitization in the first place. In addition beta-2 activation also seems to result in a marked increase in glucagon (a steroid hormone) secretion, which can increase protein synthesis in skeletal muscle (thus elevating metabolic rate) and bind to all classes of beta-receptors in place of NA and Adr to activate G-proteins and initiate lipolysis. With three different substances then competing to bind with beta-receptors this tends to slow desensitization overall. For these reasons the best results due to Ephedrine use tend to occur after it becomes chronic. Specifically, the best response seems to occur after 2-3 weeks and up until about 12 weeks. After 12 weeks T4 to T3 conversion seems to drop off markedly and desensitization proceeds in all classes of adrenergic receptors to the point where further effect is negligible. The point however, is that you should not expect a noticeable effect until after 2-3 weeks of using an ECA product; and that there is little point in continuing use much beyond 12 weeks.

As stated earlier Ephedrine induced lipolysis is also under direct control of feedback inhibition. In order to limit the extent to which lipolysis can proceed (and to give the body a means by which to essentially "turn it off" when necessary, thus preserving homeostasis), the body begins to produce elevated amounts of three compounds in response to any dramatic and sustained increase in lipolytic activity. These are Phosphodiesterases (PDE's), Prostaglandins (PG's), and Adenosine. Of course these too can also be blocked or inhibited by the body using yet another set of compounds when levels are elevated, and sustained lipolysis is necessary, but I won't get into that. Briefly then, PDE's are compounds that break 3'-5'cAMP into inactive fragments thus preventing step five in the process of lipolysis from occurring (refer to summary above). PG's are compounds that are produced from fatty acids in almost every tissue of the body. They are of numerous types, and are involved in many different processes, including the inflammation of tissues and the accompanying increase in sensitivity to pain. E2-PG's specifically have an affinity for receptors that are coupled to regulatory G-proteins, like alpha-adrenergic receptors and can therefore act to increase alpha activation thus inhibiting lipolysis. Adenosine is a compound that is produced by fat cells in response to beta-receptor activation. In the synaptic space Adenosine interacts with its own receptors on Adipocytes that are coupled to regulatory G-proteins similar to those coupled to alpha-receptors. In this way Adenosine has a similar effect on lipolysis as alpha activation would (to counter it).

Fortunately we know that Caffeine, in addition to having it's own positive effect on metabolic activity, also seems to have the ability to inhibit PDE's (although there is some debate over the extent to which oral ingestion can accomplish this), and very effectively blocks Adenosine receptors making it impossible for Adenosine to bind to them. It is also thought to limit re-absorption of NA by nerve terminals, thus maintaining higher circulating levels. Aspirin (along with most other non-steroidal anti-inflammatory drugs or NSAID's) has long been known to be an effective PG inhibitor (hence it's efficacy in treating pain and inflammation). Therefore the stacking of Caffeine and Aspirin with Ephedra is an effective strategy to maximize its lipolytic effect by limiting the effectiveness of the body's feedback inhibition responses to the resulting elevated NA and Adr levels. With regard to how the compounds should be combined and in what dosage, most current research seems to agree that the most effective ratio in which to stack Ephedra, Caffeine, and Aspirin is 1/10/15. The research also shows that the lipolytic effect is dose dependant only up to about 20mg of Ephedra taken 3 times per day. So that the most effective dose would be 20mg Ephedra, 200mg Caffeine, and 300mg Aspirin taken 3-times per day approximately 30 minutes prior to a meal. Amounts exceeding this do continue to have a dose dependent effect on heart rate, blood pressure, etc. but do not generally result in any significant increase in lipolytic activity. Therefore anyone exceeding the optimal dose is not accomplishing anything more than unnecessarily increasing the severity of the peripheral sides effects (elevated heart rate, blood pressure, etc), and they are needlessly wasting money.

While the preceding material serves to explain how the ECA stack may result in increased lipolysis, it leaves unresolved the general issue of overall efficacy. Specifically, it does not address the question of just how effective ECA products are for fat-loss in general.

Before addressing that issue it is important to understand the concept of significance as it applies to the statistical analysis of research data. Quite simply, significance in this context can be considered a gauge of how strong a measured effect is considered to be. This is vitally important because although research may establish that a particular substance does in fact reliably produce a specific effect, the strength of that effect, or its significance, may vary from profound to negligible.

It is quite common in the (nutritional) supplement industry for manufacturers of products to market their wares based on the outcome of research studies and clinical trials. It is also quite common, when one actually examines the studies cited by these companies in their product literature and marketing material, to find that although the data did actually reveal a statistical correlation between the use of Product-X and occurrence of Effect-Y that the effect was of such low statistical significance as to render the product nearly useless for any practical application (at least in any amount you can afford to use on a regular basis).

Getting back to the ECA stack, the important thing to understand is that although it will produce an increase in lipolysis in most people, along with a moderate thermogenic effect; the increase in lipolysis will not be all that significant (although there is a small minority that will experience a greater than average effect, as with any other substance). As for the thermogenic effect, this too will be mild for most people, as Ephedrine typically promotes only a mild increase in metabolic activity (energy consumption).

I must also point out that even if ECA were to produce a substantial increase in lipolysis that simply means that more circulating fatty-acids would be available for use as fuel. It does not mean that your body will automatically use it as such simply because it is available. You must still be following a combined nutrition and exercise program that results in a caloric shortfall, or deficit; such that your body has a reason to use the circulating fat for fuel. This is why the term "fat-burner" is laughable to any who understand what is actually going on. These products might more accurately be termed "fat-releasers".

The bottom line is that in my experience, the use of ECA products in conjunction with a well planned nutrition and training program designed to facilitate depletion of fat stores, might for most people result in a slight acceleration of the "leaning-out" process; but that will probably be so slight that it is quite likely not worth the expense. As for potential side effects, while I definitely believe that the media and government health agencies have completely blown the issue out of all sensible proportion in light of the hard facts that exist, there are issues and possible dangers to be considered for some people. While I won't get into those issues here, I will say that in my opinion you should be well versed regarding the potential side-effects of any product before using it, and Ephedra based products could pose some moderate risks for certain people.

In closing I would suggest that based on my observations and experience, the vast majority of people seeking to get rid of excess body-fat would be far better served to put their time and energy into achieving perfect compliance with their overall nutrition and training program. The potential results that most people throw away every week by failing to eat and train as they should far eclipses the little bit of added progress an ECA-stack or other so-called "fat-burner" might provide.

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