by Thomas Incledon, PhD(c), RD, LD/LN, RPT, NSCA-CPT, CSCS
Introduction
What is this stuff?
Agmatine is a metabolite of arginine. Remember arginine? Years ago it was advocated heavily by the life extensionists as a big GH releaser. The problem was that it didn’t work consistently from person to person or even for the same person. If you cut off the carboxylic end of the arginine molecule (a process called decarboxylation) you get agmatine. It is therefore not referred to as an amino acid like arginine is, but rather an amine (the COOH that was removed from arginine was the acidic part). The significance of this amine is that it can bind to both imidazoline and alpha 2-adrenoreceptors. Clonidine, which can stimulate GH, also binds to imidazoline receptors (1) and yohimbine can bind to the alpha 2-adrenoreceptors (2). This is what makes agmatine such an interesting compound—it is being touted as having the ability to stimulate anabolic hormone release and impart other benefits. Some of this is true and some is wishful hoping. To date, no supplement studies on humans with agmatine have been published. All the stuff I will present is based on animal studies or isolated human cells. This article will cover what science has shown thus far and then you can decide if this stuff is worth taking.
Agmatine is found in a variety of mammalian tissues including brain, human plasma (3), liver, kidney (4), stomach, aorta, small intestine, spleen, adrenal, aorta, and skeletal muscle (5). It is also found in many commonly eaten foods such as cheese, fish, iceberg lettuce, endive, Chinese cabbage, wine, beer, and Sake. The significance of this fact is that it means agmatine is involved in biogenic pathways in our bodies. These pathways are not clearly understood, but this sets up an exciting opportunity for research to find out what these pathways are and how they function.
Neural Effects
There is a central distribution of agmatine in the brain. It is synthesized, stored, and released in brain tissue. It is also contained in nerve cells, interacts with specific receptors, and elicits biological reactions within the central nervous system (brain and spinal cord), yet its role is not clear (6). In this regard, the amine may act like a neurotransmitter of neurons involved in behavioral and visceral control (7). It has already received attention as a potential antidepressant and protects against neurotrauma and neurodegenerative disorders (8). There is potential for this agent to protect against lack of oxygen to the brain—like in the event of a stroke. This is not to say that taking agmatine will prevent a stroke or side effects after having one. It may, however, decrease the chances of having one or reduce the number of side effects after the fact.
Hormonal Effects
Since there is a potential role of agmatine as a neurotransmitter in the brain, scientists wondered if it could stimulate any hormones. Sure enough, they found that agmatine stimulates luteinizing hormone releasing-hormone (LHRH) and luteinizing hormone (LH) in female rats via intracerebroventricular injection (1). If you don’t remember or didn’t know, in the center of the brain is a mass of neurons called the hypothalamus. The hypothalamus can be stimulated to release LHRH. LHRH then signals the pituitary gland to release LH. LH in turn can stimulate estradiol (an estrogen) from the ovaries in female rats and testosterone from the testes in male rats. The problems with applying this study to humans are that: 1) the agmatine was injected into the rats’ brains and 2) no one has shown the same mechanisms of LHRH stimulation in humans yet. Let’s say that it does work. It still wouldn’t be practical unless it can be proven to work orally, sublingually or subcutaneously. Those are practical methods that most of us would be willing to try. While in general the mechanisms of LHRH stimulation are very close in rats and humans, they are not identical, and when dealing with neurotransmitters, close is not good enough.
Agmatine can also stimulate insulin release in isolated rat pancreatic cells when exposed to glucose (9). It did not stimulate insulin in the absence of glucose. It was enhanced by theophylline and suppressed by the absence of extracellular calcium (10). It was a weak stimulator of lipogenesis in mice and did not cause any significant reductions in blood glucose in mice (11). At this point it is difficult to interpret the data that is available. Everyone wants to think that taking agmatine will stimulate protein synthesis, but in the case of insulin, if lipogenesis is low, then so is protein synthesis. More work needs to be done here and this is another very interesting area to explore.
A few months ago, an article appeared in another magazine that said agmatine stimulates growth hormone (GH) release. A review of Medline did not show this to be true. The relationship between agmatine and GH release is this: in normal growth hormone releasing-hormone (GHRH), the amino acid arginine is in position 29 on the peptide chain. By replacing arginine with agmatine in position 29, the GHRH analog is far more potent in stimulating the release of GH in cows (12). The same results should be seen with humans, but how do you get the whole peptide into your blood intact in a practical way? It will be some time before this gets worked out. Also keep in mind that agmatine comprises position 29 in both GH stimulators (13, 14, 15) and inhibitors (16). The main point here is that there has been no evidence to date that agmatine by itself can stimulate GH release.
Cardiovascular Effects
Agmatine can increase sodium excretion and induce vasodilation (17). There have been some reports that it can regulate vascular function by stimulating noradrenaline, but other work indicates that it may not affect cardiovascular response (18). The majority of work in this area seems to indicate that it can lower heart and lower blood pressure or not affect either at all. There isn’t any indication that agmatine should cause hypertension (high blood pressure) or tachycardia (elevated heart rate).
Side Effects
What’s this, a section on side effects? Most of the time when you read an article it paints a fairytale story of how good something is without saying anything bad about the product. That is ridiculous because everything has a side effect. The question is, can you tolerate it? Agmatine is no exception. In experimental studies with rats, it increased gastric secretions and worsened gastric mucosal injury (19). Therefore, if you’ve had recent GI surgery or are prone to ulcers, you should avoid this supplement. Now, depending on your goals, this next side effect could be good or bad. Agmatine increased caloric intake and carbohydrate feeding in rats (20). This means it could stimulate you to eat more calories and to take in more of those calories as carbohydrates. If you’re trying to gain weight, this supplement may help. However, if you are trying to lose weight, this supplement may make it harder for you to cut back on your calories.
What’s Next
It was my intent to provide you with the current pertinent information on this product. I have not seen it available for sale yet. Hopefully, you can make your own choice as to whether or not to take it. If you want some last minute words of advice I say wait until science has a chance to determine how well AND if it even works. We all know that science is slow, but rushing things may only mean that you threw away some more money. As always please feel free to email me with questions:
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References
1. Kalra, S.P., et al. Agmatine, a nivel hypothalamic amine, stimulates pituitary luteinizing hormone release in vivo and hypothalamic luteinizing hormone-releasing in vivo. Neuroscience Letters. 194 (3): July 21, 1995; 165-168.
2. Gao, Y., et al. Agmatine: a novel vasodilator substance. Life Sciences. 1995. 57(8):PL83-86.
3. Feng, Y., et al. Determination of agmatine in brain and plasma using high-performance liquid chromatography with fluorescence detection. Journal of Chromatography. B: Biomedical Science Applications. April 11, 1997; 691(2):277-286.
4. Lortie, M.J., et al. Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat. Journal of Clinical Investigation. January 15, 1996; 97(2):413-420.
5. Raasch, W. et al. Agmatine, the bacterial amine is widely distributed in mammalian tissues. Life Sciences. 1995. 56(26):2319-2330.
6. Reis, D.J. and S. Regunathan. Agmatine a novel neurotransmitter? Advances in Pharmacology. 42:645-649, 1998.
7. Otake, K., et al. Regional localization of agmatine in the rat brain: an immunocytochemical study. Brain Research. March 16, 1998; 787(1):1-14.
8. Gilad, G.M., et al. Agmatine treatment is neuroprotective in rodent brain injury models. Life Sciences. 1996; 58(2): PL 41-46.
9. Morgan, N.G., et al. Characterization of the imidazoline binding site in regulation of insulin secretion. Annals of the New York Academy of Sciences. July 12, 1995. 763:361-373.
10. Sener, A., et al. Stimulus-secretion coupling of arginine-induced insulin release. Insulinotropic action of agmatine. Biochemical Pharmacology. January 15, 1989. 38(2):327-330.
11. Weitzel G., et al. Insulin-like partial effects of agmatine derivatives in adipocytes. Hoppe-Seylers Zeitschrift fur Physiologische Chemie. January 1980; 361(1):51-60.
12. Roberge, S., et al. Evaluation of the biological potency of new agmatine analogs of growth hormone-releasing hormone in the brain. Proceedings of the Society for Experimental Biology and Medicine. May 1992; 200(1):109-114.
13. Izdebski, J., et al. Synthesis and biological evaluation of superactive agonists of grwoth hormone-releasing hormone. Proceedings of the National Academy of Sciences of the United States of America. May 23, 1995. 92(11):4872-4876.
14. Zarandi, M., et al. Potent agonists of growth hormone-releasing hormone. Part I. International Journal of Protein and Peptide Research. March 1992; 39(3):211-217.
15. Zarandi, M., et al. . Potent agonists of growth hormone-releasing hormone. Part II. Peptide Research. July-August 1992; 5(4):190-193.
16. Zarandi, M., et al. Synthesis and biological activities of highly potent antagonists of growth hormone-releasing hormone. Proceedings of the National Academy of Sciences of the United States of America. December 6, 1994. 91(25):12298-12302.
17. Penner, S.B. and D.D. Smyth. Natriuresis following central and peripheral administration of agmatine in the rat. Pharmacology. September 1996; 53(3): 160-169.
18. Sun, M.K., et al. Cardiovascular responses to agmatine, a clonidine-displacing substance, in anesthized rat. Clinical & Experimental Hypertension. Jan-Feb 1995; 17(1-2): 115-128.
19. Glavin, G.B. et al. Agmatine, an endogenous imidazoline receptor agonist, increases gastric secretion and worsens experimental gastric mucosal injury in rats. Journal of Pharmacology and Experimental Therapeutics. August 1995. 274(2):741-744.
20. Prasad, A. and C. Prasad. Agmatine enhances calorie intake and dietary carbohydrate preference in satiated rats. Physiology & Behavior. October 1996. 60(4):1187-1189.
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