Strong guy curlingIntroduction

Well, after a lengthy battle, The Man™ finally succeeded in taking the safe, inexpensive, and effective appetite suppressant/thermogenic that is ephedra away from us. We had a design for an ephedra and caffeine (EC) replacement for over a year before the ban, but with the uber-popular EC still around, it sat in waiting. However, when ephedra’s head was laid on the chopping block, it was time to get it rolling.

And, as “luck” would have it, we had on ice a few ingredients, and a lot of research, that allowed us to not only bring forth an adequate replacement, but to take the formula beyond what the EC stack ever dreamed. We did not just create the new EC stack; we created a whole different monster.

We are proud to give you:

H.E.A.T. Stack ™

“H.E.A.T.” stands for Hordenine, Evodiamine, Alpha-yohimbine, and Tyramine. And, in the right combination, they are far, far more than a clever acronym. They represent the most elegant and effective appetite suppressant/thermogenic stack in the supplement world to date. So, without further adieu, let’s look at the science to see how and why “H.E.A.T.” should quickly become a common part of your bodybuilding vocabulary.

While H.E.A.T.’s ancestors did wonders for appetite suppression (mostly because you are too tweaked to eat), they were modest thermogenics (fat burners) at best. And, worse than that, they were all out enemies of central hunger and metabolic control centers (aka the Adipostat ), and they caused hypersensitivity to cortisol and the stress response. In English, this means that once you stopped them, you were left in a metabolic state worse than when you started. In other words, while you were taking 3 steps forward with one leg, the other was taking two steps back.

The H.E.A.T. Stack™ not only addresses these shortcomings, but it also provides superior elevations in mood; it is also much smoother than EC, and much, much more so than yohimbine based preparations. Instead of cracked out over stimulation, rapid heart rate, increased blood pressure, and anxiety, H.E.A.T. provides a nice, subtle stimulation, along with a “giddy” mood and energy increase, and excellent appetite control.


Ephedra, and its most common replacement until now, yohimbine, primarily work by increasing the activity of norepinephrine (NE) – this is especially true for yohimbine. As mentioned, this is quite good for short-term appetite suppression, but we want more than that. Of the beta adrenergic receptors, NE is fairly selective for beta1 receptors which primarily increase heart rate and lipolysis (1). Its thermogenic activity is mostly indirect, via an increase in free fatty acids which modestly activate uncoupling proteins (2, 3). Simply eating less will do this, so big deal.

Norepinephrine has the greatest overall affinity for alpha2 receptors, which actually inhibit lipolysis and thermogenesis (4, 5). So, as soon as it starts doing its magic, it activates its own negative feedback loop, putting a muzzle on fat loss. This is not ideal, to say the least.

On the other hand, it is a weaker agonist at the beta2 and beta3 receptors. Beta2 receptors (Clenbuterol is a selective agonist here) are true thermogenics – i.e. they directly increase the oxidation of fatty acids (6).

In addition, unlike beta1 receptors, beta2 receptors cause vasodilation in muscle tissue, which will increase delivery of nutrients to that area, thus helping with nutrient partitioning. These receptors are typically activated by NE’s big brother epinephrine (remember that word) when muscle needs extra fuel, and it does this at the expense of adipose stores. NE, on the other hand, causes vasoconstriction.

Beta3 receptor activation performs miracles in rats, but not so much in humans. They are expressed in lower numbers, and they do not directly produce thermogenesis. In humans, they act to increase uptake of fatty acids into peroxisomes and mitochondria, so you burn fat instead of carbohydrates for energy production. Increased free fatty acid oxidation in muscle is one of the primary determinants of leanness, so Beta3 receptors are still a worthy target.

So, ideally, we want to be hitting beta2 and beta3 receptors hard, and avoiding beta1 receptors. And as we alluded to, these are not even the greatest shortcomings of the flawed focus on just jacking up norepinephrine.

The worst part happens in the brain, where NE will contribute to dysfunction of the Adipostat via increased glutamate and cortisol activity, both of which are strongly correlated with obesity (7, 8). Adipostatic signals such as leptin are secreted in proportion to body fat and nutrient intake, and robustly reduce food intake and body weight by directly stimulating receptors locally in the brain (9). So when this gets screwed up, the brain starts constantly thinking it needs food and that the body needs to hold onto energy stores — even when you are overfed and getting fatter and fatter.

While NE is artificially elevated with E or Y, this is not generally noticeable, especially short-term. But, when you cycle off, the body takes its terrible revenge.


Caffeine tends to be included in most thermogenics. It is cheap, it provides good stimulation, and it potentiates the effects of stimulants and catecholamine signaling via adenosine blockade (10, 11). Thus, it will increase short-term appetite suppression and help with fat loss peripherally, via norepinephrine and dopamine potentiation. It will make things even worse for the adipostat via NE but better via dopamine.

It also has negative effects on nutrient partitioning at the cellular level. Adenosine senses fuel availability, so antagonism tricks the cell into thinking it is full and energized. A full cell is a nutrient insensitive cell, so caffeine will inhibit nutrient uptake, and the excess will just float around and cause problems. High serum lipid and glucose levels are also strongly associated with obesity, insulin and leptin resistance, as well as cardiovascular disease (12, 13).

Because of the trade-offs, we went back and forth on caffeine, finally deciding to leave it out and just let the user have some coffee with it if they really wanted that extra kick. Coffee is yummy and part of a major social scene, anyway. Those who are pretty lean will get the most positives and least negatives from adding caffeine.

Beyond Ephedra

To get around the problems centrally and improve things peripherally, we need to attack fat loss from several fronts — directly and indirectly, short-term and long-term. First, we do not jack up NE quite so much. As we have discussed, peripherally it will have positive effects on fat loss and it will decrease appetite, so we do not want to get rid of it altogether — we want it just right.


Secondly and perhaps most importantly, we increase Dopamine (DA), , which centrally antagonizes the negative actions of NE (14). Reduced dopaminergic tone is found in thrifty phenotypes – meaning people with “slow metabolisms” (14). Central dopamine signaling is lower in the obese (15), and dopamine receptor agonists reduce body fat (16).

Increasing dopamine is especially important and effective on a diet. DA, NE (peripherally), and epinephrine all fall during calorie restriction, but DA exhibits the greatest drop (17). Central dopamine infusion potently reduces meal size (18) and DA receptor activation produces amphetamine-like effects on food intake and bodyweight (19).

We also benefit peripherally from increasing dopamine via increases in adenyl cyclase, natriuretic peptide (a hot future fat loss target), and vasodilation in skeletal muscle, for greater fat burning and better nutrient partitioning (20, 21).

The importance of dopamine is difficult to overstate.


Next, we want to hit the long ignored and neglected Epinephrine (EP) , which has stronger activity on thermogenesis via beta2 and beta3 receptors compared to NE (22). In obesity, epinephrine levels are low or normal, whereas NE levels are elevated (23). Beta2 receptor mediated lipolysis and free fatty acid oxidation is impaired in obesity (24, 25), and along with the beta2 receptor, defects of the beta3 receptor are significantly correlated with obesity IN HUMANS (26). This is not the case with beta1 polymorphisms.

Activation of beta2 receptors, unlike beta1, directly up-regulates uncoupling proteins 2 and 3 in skeletal muscle. (27). B2 directly increases energy expenditure, regardless of FFA levels (28, 29). Finally, of profound interest for fat loss, Epinephrine’s beta2 activity also causes desensitization of the anti-fat loss alpha2 receptors (30). Not surprisingly, EP is also superior to NE for increasing energy expenditure. Epinephrine increases energy expenditure by as much as 29% (31) — IN HUMANS! NE, on the other hand, increases it by less than 10%. (32, 33).

Finally, unlike NE, epinephrine’s effects are mediated in skeletal muscle (34). Not only is skeletal muscle the desired site for increased substrate utilization if leanness is the goal, but the differing mechanisms for increased energy expenditure with EP and NE suggests that they should be quite synergistic for promoting fat loss.


Finally, with Evodiamine, we add another system to the mix: the vanilloid pathway. The vanilloid pathway interacts with and enhances the other ingredients and systems we are discussing. We’ll get into this in more detail with our discussion on Evodiamine.

Now that we know what we want to do with the physiology, let’s take a look at the science of the individual ingredients to see how we achieve this superior biochemical state.

The Ingredients


Tyramine is a trace amine found in the human body and many foods such as wine and aged cheese. How it has generally been overlooked as a supplement is pretty baffling to me. This is an AMAZING little compound. I can only assume it is a result of the folklore of the so-called “cheese effect” rather than any careful examination of the scientific literature.

The “cheese effect” refers to the increase in blood pressure that can occur when taking a MAO inhibitor and consuming foods that are high in tyramine. However, the dangers of tyramine have been greatly overstated (35). Even as much as 400mg of tyramine, in the absence of MAO inhibition, caused a significant increase in systolic blood pressure in only 3 of 12 subjects (36). With pharmacological inhibition of both MAO-A and MAO-B, 50mg of tyramine is enough to cause this increase (37), so you do want to avoid this combination. But aside from that, this is a very safe compound.

With that out of the way, let us look at the many positives. Tyramine will go a very long way toward replacing ephedra with its stimulation of NE release (38). In fact, it is used clinically for this very purpose. It does so by acting as a competitive inhibitor of NE uptake at its transporter. Nerve terminals take up tyramine instead of NE, leaving more NE free to work its magic. In addition, it aids the cause further by competing strongly with NE for metabolism by MAO-A (39).

Tyramine’s greatest magic, though (remember, we go way beyond ephedra today), is in increasing dopamine. Not only is tyramine directly converted to dopamine by the enzyme CYP-2D6, but it also decreases its metabolism via MAO-A inhibition. Tyramine also strongly inhibits dopamine uptake — IC50 in the nanomolar range (40). This is EXTREMELY potent.

In fact, the literature has found tyramine to be superior at increasing dopamine than increasing NE — it increased NE from 11pg/ml to 150-200pg/ml, but increased dopamine from 11pg/ml to 660pg/ml (41). The adipostat LOVES this 3-fold difference. And, injections of tyramine cause an overall vasodilation in skeletal muscle consistent with increased dopamine, as opposed to vasoconstriction, which would be consistent with NE (42). This is good, good stuff.

Finally, some very new research has identified a “trace amine receptor”, which is very strongly activated by tyramine. Activation of this receptor results in an increase in the lipolytic 2nd messenger adenyl cyclase (43). A number of drugs involved in dopaminergic transmissions and appetite suppression, including amphetamine, MDMA, and dopamine metabolites are all quite active at trace amine receptors (44). Thus, one might also expect this to contribute to the positive effects on mood and energy seen with the H.E.A.T. Stack™.

Alpha-Y ™

Alpha-Yohimbine (Alpha-Y™) is the steak to tyramine’s lobster as far as what makes the H.E.A.T. Stack™ so special. Alpha-Y™ is an analogue of yohimbine, but its potency at the subreceptors of alpha2 differs quite a bit–most notably at the alpha2b and alpha2c adrenergic subreceptors. It is 3 times more potent at alpha2b and 4 times more potent at alpha2c. It is equipotent at alpha2a (45).

Alpha-Y’s superior potency at the other receptors lets us hit them hard, while moderating activity at alpha2a. Alpha2a is the primary receptor subtype, making up 90% (46). It mediates most the classic effects of alpha2 receptor blockade such as increased NE, heart rate, blood pressure, and anxiety (47).

Alpha2a inhibition increases NE by up to 200% while increasing dopamine by only about 80% (48). Disruption of this subreceptor also increases corticosterone (rat version of cortisol) by 100-200% (49). And as we have discussed, these would have negative long-term consequences on the adipostat.

The alpha2c receptor on the other hand, plays only a minor role in the negative feedback signal on NE, but it plays a major role in certain brain areas where sympathetic innervation is low, and the dopamine system is prominent (50). These just happen to be the areas that are critical for reward, reinforcement, and metabolic control, such as the VMH, VTA, and striatum (51). In these areas, dopamine is the primary agonist at alpha2 receptors, and alpha2c makes up the majority of these receptors (52).

Thus, it will block dopamine’s negative feedback signal and increase dopaminergic tone. The dopamine precursor, L-dopa, is higher in alpha2c knockout mice (53). A2c disruption increases, and overexpression decreases, the response to amphetamine stimulation (54). Alpha2c activation (which would decrease dopamine) results in behavioral despair (depression) and elevated cortisol levels (55).

Alpha2c is also the primary subtype in skeletal muscle and an antagonist causes selective femoral vasodilation (56). If that were not handy enough, the only other place the alpha2c subreceptors are highly expressed is in the adrenal medulla, where it modulates negative feedback on epinephrine, much like alpha2a does on NE (57). In other words, in addition to the dopamine increase, Alpha-Y™ allows for a much greater increase in EP levels, with its superior effect on thermogenesis, energy expenditure, and nutrient partitioning. So, we can see that Alpha-yohimbine’s potent antagonism of alpha2c is the good shit.

The alpha2b subreceptor is prominent in development (it is the only adrenergic deletion that impacts survival), but in adults it only affects blood pressure. Namely, its activation increases the hell out of it (58, 59), especially in regard to salt loading (60, 61). Overfeeding also causes an increase in a2b receptor density, concomitant with hypertension via arginine vasopressin (62).

Given the strong correlation between excess energy intake, obesity, hypertension, and the renin-angiotensin-AVP axis –- this cluster is known as Metabolic Syndrome X (63) — the strong antagonism of alpha2b represents another potential goldmine for long-term fat loss and one more nail in the EC stack’s coffin.


Hordenine has quite a bit less direct data than tyramine, but is closely related structurally, and tyramine is formed in the body by demethylation of hordenine (which is also known as N, N, methyl-tyramine). The data that does exist on hordenine mirrors tyramine quite a bit. So in addition to the direct data, one can assume that it also shares a lot of what we talked about with tyramine. Plus, H.E.A.T. is a much better name for a diet stack than E.A.T. J

I.V. administration to horses caused a dramatic increase in NE and physiological parameters consisting with elevated NE. (64). Hordenine was found to inhibit NE uptake, much like tyramine. It is also a highly selective substrate for MAO, though unlike with tyramine, it is selective for MAO-B instead of A, so it will preferentially increase dopamine through this pathway (65).


Evodiamine is a constituent of the glorious Evodia fruit, referred to as a “hot nature” herb in Chinese literature. It shows activity at the vanilloid receptor similar to capsaicin (the active in red peppers). It is particularly interesting in that it enhances thermogenesis, but also causes vasodilation, thus heat generation is accompanied by increased release of heat from the body (66). As a result you will be less likely to become uncomfortably or dangerously overheated, as you would with something like DNP, despite fat being burned like crazy.

Because of the shared activity at the vanilloid receptor, and because they have been found to produce many of the same physiological effects, data on capsaicin should be applicable to evodiamine. Let’s look at direct finding with evodiamine first, then we will look at a few studies with capsaicin.

First, evodiamine will increase catecholamine activities through a couple of mechanisms. Evodiamine increases EP and NE release from adrenal medulla, enhances acetylcholine induced catecholamine release, and reverses insensitivity toward acetylcholine induced release, likely via acetcholineesterase inhibition (67). This would be a peripheral increase, not central, which is quite desirable. It also increases cAMP and cGMP, second messengers in DA, EP, and NE signaling, which would increase lipolysis (68). In other words, it makes the other ingredients work that much better.

Evodiamine displays welcomed antagonism toward several Metabolic Syndrome X related pathways. It decreases Angiotensin II induced aldosterone release, decreases corticosteroid levels (69), and decreases blood pressure (70), via nitric oxide evoked vasodilation (71). As we’ve learned from our previous discussion, this will help preserve normal metabolic functioning, unlike with EC or a yohimbine based thermogenics.

Evodiamine also inhibits gastric emptying and increases plasma CCK (72). In addition to slowing gastric emptying, CCK inhibits food intake and is quite synergistic with leptin, so this is a great little bonus. Capsaicin sensitive nerves have also been found to mediate inhibition of gastric emptying (73)

A couple other components of evodia fruit do some more very nice things that would help with fat loss. Unfortunately, while evodiamine shares other actions with these compounds, making it quite likely they share these components also, there is no direct data on evodiamine in this regard, so that is best kept secret for now.

Finally, rats fed evodiamine had lower bodyfat, plasma free fatty acid, cholesterol, and liver triglyceride levels (74). Red pepper increases thermogenesis and decreases food intake in humans (75). Reduced sensitivity to obesity has been observed a year after capsaicin treatment (76). UCP 1 and UCP3 expression as well as decreased body fat are induced by another capsaicin analogue (77).


Obviously, there are a number of interactions among systems and some of this is quite complicated, so I encourage you to read this multiple times for a full understanding. And, for those who could not care less about the scientific intricacies, I will simply summarize in bullet-point form before bidding you farewell…..

Compared to the EC stack (and yohimbine based formulations), the

caffeine and ephedra free H.E.A.T Stack™

results in:

Superior nutrient partitioning
Superior thermogenesis
Greater energy expenditure increase
Reduced anxiety and jitters
Superior adipostat modulation
Superior mood elevation
Reduced heart rate and blood pressure elevation



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