Agmatine sulfate

Agmatine is said to produce an unprecedented "pump". Both user experiences and research show that agmatine works as an NO booster. Exactly how and to what extent, however, is still unknown.

Agmatine sulfate

Depending on which source you read, agmatine is either heavily underrated or overrated. In any case, more research needs to be done to know what use it is to us.

Agmatine as a painkiller

What we do know from research is that agmatine can relieve lower back pain [1,2]. Still, we already know plenty of painkillers. Although agmatine may be very interesting as a painkiller in certain cases, that is probably not why you are reading this article.

Agmatine for better glucose uptake

More interesting here is that, according to research, insulin sensitivity is increased, resulting in better uptake of glucose by, among others, the muscles [2]. In this case, however, the agmatine was administered via infusion, although in very small amounts compared with studies in which it was taken orally. The question, therefore, is to what extent this also happens with oral intake and what dosage is needed for it.

Agmatine as a fat burner

Other research has also shown that agmatine can work as a fat burner by imitating the effects of a low-calorie diet [3].

Agmatine as an NO booster

The best-known effect of agmatine among strength athletes, however, is that it is said to provide a "pump", an increased blood supply through dilation of the blood vessels, as we know from well-known NO boosters. That is where I will focus most of my attention.

Agmatine sulfate

Agmatine sulfate is a metabolite of the amino acid arginine. That means arginine can be converted into agmatine. This requires so-called decarboxylation, the splitting off of carbon dioxide from a carboxylic acid.

That probably means absolutely nothing to you, and it does not have to. For now, it is important to remember that arginine can be converted into agmatine sulfate (hereafter called: agmatine).

Three types of Nitric Oxide Synthase (NOS)

To understand how agmatine works as an NO booster, you need to know how NO (Nitric Oxide, which among other things causes blood vessels to dilate) is produced.

NO is produced from arginine with the help of (iso)enzymes. These enzymes, called Nitric Oxide Synthase (NOS), which act as catalysts in this process, can be divided into [9]:

• endothelial NOS (eNOS or NOS3) - Vasodilation
• neuronal NOS (nNOS or NOS1) - Nervous system and cell communication in skeletal muscles  [9]
• cytokine inducible (iNOS or NOS2) - Immune system
• Bacterial NOS (bNOS) - Protects (good) bacteria [10,11]

Depending on which type of enzyme produced the NO, it can have different functions, some positive and others negative. Agmatine ensures that "the good NOS" becomes more active, while "the bad NOS" is inhibited.

"Good NOS" Endothelial NOS (eNOS/NOS3)

NO produced with the help of the enzyme eNOS causes the well-known vasodilation known as the "pump". This increases vascularity, making veins more visible because of increased blood flow. The role of eNOS is to protect the heart and blood vessels by ensuring free passage through the vessels [12,13,14].

"Bad NOS" Cytokine inducible/inflammatory NOS (iNOS/NOS2)

While eNOS/NOS3 mainly has beneficial properties, overproduction of iNOS can cause inflammation of neurons and cell damage in the nervous system [15]. It may also be involved in the final phase of a cerebral infarction [16].

Agmatine lowers iNOS and increases eNOS

Agmatine inhibits the activity of the iNOS enzyme, which means it can protect neurons from the damage that NO (produced by iNOS) can cause [4,17]. By contrast, agmatine actually increases the activity of eNOS [12].

These results show that agmatine inhibits the production of nitric oxide by decreasing the activity of NOS-2 in macrophages and astroglial cells by decreasing the levels of NOS-2 protein. These findings provide a molecular basis for the neuroprotective and anti-inflammatory actions of agmatine.

-S. Regunathan, University of Mississippi Medical Center

Moreover, the level and expression of eNOS was increased by agmatine treatment, whereas inducible NOS (iNOS) and MMP-9 protein expressions were decreased in the brain. These results suggest that agmatine protects microvessels in the brain by activation eNOS as well as reduces extracellular matrix degradation during the early phase of ischemic insult.

- C.H. Mun, Yonsei University College of Medicine

Agmatine as an NO booster

In many advertisements, agmatine is simply described as an NO booster, which is rather confusing because this only looks at the effect on eNOS, while iNOS is actually inhibited.

Admittedly, NO made by eNOS is the NO we mean when we talk about NO boosters. NO boosters are so popular because they dilate blood vessels, increasing blood flow. This increases oxygen and nutrient delivery to the muscles and gives the "pump effect" of pumped-up muscles during and shortly after a workout. This is therefore the effect of eNOS and not of iNOS. When you read the studies on agmatine, this can be very confusing because one study states that it increases NO, while another states that NO is inhibited. If you do not know that these are two different types of NO, none of it makes sense.

Agmatine does indeed increase NO through eNOS, but it does so in a different way than the well-known NO boosters arginine and citrulline [4,5,6,7,8]. It is also not clear whether the increase in NO is caused by the effect on eNOS or by an effect in the brain. Agmatine acts as an agonist of so-called imidazoline receptors. Research from 1995 showed a link between activation of these receptors by agmatine and a vasodilating effect [26].

Agmatine vs arginine and citrulline

Simplified: citrulline can be converted in the body into arginine, which can be broken down into agmatine.

Arginine is one of the first well-known NO boosters. It can be converted into NO in the body. With oral intake, however, 40% of the arginine is already broken down in the liver before it reaches the bloodstream [18]. Citrulline is therefore a better alternative because it is converted into arginine in the body, and as a result, relatively more of the ingested citrulline ultimately arrives as arginine where it needs to do its work [19].

The question now is: which is the stronger NO booster, agmatine or citrulline? Unfortunately, no research has yet been done comparing the two. We also do not know what their combined effect is if you take arginine/citrulline together with agmatine. In practice, citrulline and agmatine are often combined by people who swear it gives them the biggest pump ever, while others saw no difference when they added agmatine to citrulline or vice versa.

Agmatine has only attracted researchers' attention again since 1994, and a great deal is still unknown. For now, more research needs to be done to understand the exact action of agmatine and to know whether combining it with other NO boosters makes sense.

In practice, however, agmatine does seem to be a stronger NO booster if we look at the dosages people use. At dosages of 1.5 grams of agmatine, we hear user experiences comparable to those with 5 grams of citrulline.  This still needs to be confirmed in research.

Does agmatine increase Luteinizing Hormone and therefore testosterone?

Agmatine increases the amount of Luteinizing Hormone (LH)[20]. Increased LH normally signals the testes to produce more testosterone (see image on the right). So you could conclude that agmatine also increases testosterone, but this direct link has not yet been studied.

Research from the 1980s showed that the substance clonidine, a so-called α2-adrenergic agonist, can activate certain receptors in the brain, which leads to more LH [21,22]. A few years later, it was discovered that agmatine has the same effect on these receptors as clonidine [23,24], which was confirmed in a 1995 study [20].

These studies imply that the endogenous imidazoline receptor agonist, agmatine, may serve as an excitatory neurotransmitter/neuromodulator in the hypothalamic control of LH release and we suggest that the previously reported excitatory effects of clonidine on LH release may be attributed to stimulation by clonidine of imidazoline receptors.

-S.P. Kalra, Universiv of Florida College of Medicine

Again: no study has yet been conducted demonstrating the direct effect of agmatine on testosterone, but it seems plausible that there is a positive link.

Agmatine and fat burning

As mentioned in the introduction, research has shown that agmatine can work as a fat burner by imitating the effects of a low-calorie diet [3]. Rats on a comparable diet gained less weight when they received agmatine through their drinking water. Unfortunately, the amount of muscle mass and body fat percentage were not examined. The processes influenced by agmatine could namely lead to both more fat burning and muscle breakdown. It did appear, however, that the muscles themselves contained more protein than fat after agmatine intake. From that you could infer that the rats had become stronger.

These metabolic changes were coupled with reduced weight gain and a curtailment of the hormonal and metabolic derangements associated with high fat diet-induced obesity. The findings suggest that AGM elevated the synthesis and levels of cAMP, thereby mimicking the effects of caloric restriction with respect to metabolic reprogramming.

-I. Nissim, Children's Hospital of Philadelphia

These last-mentioned effects were seen at intakes of 4.4 to 6 grams (55 to 70mg per kilo of body weight). However, this concerns rats. Converted to humans, that would amount to about one gram per day [25].

More research needed on agmatine

NO booster and testosterone-increasing, that is all nice, but ultimately you want to know what agmatine actually does to muscle strength and mass. First, those effects on NO and testosterone need to be studied further and confirmed, but research must also be done on the effects that interest us most. The research on fat burning is a good example to underline that need. That research raises doubts as to whether muscle breakdown might actually be increased along with increased fat burning.

Studies should therefore be carried out on agmatine and its effect on muscle strength and mass. Simply divide a number of people (preferably as many as possible) into a test group and a placebo group (randomized double blind), control as many other variables as possible such as diet and training, and look at the differences in strength, muscle mass and body fat percentage.

Does that "pump" really provide extra strength, or is it merely a temporary visual effect, if such an effect exists at all?

When I know, you will know!

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