What is Agmatine Sulfate and What Does it Do?

Agmatine is amazing! But what is it, really!? This fascinating neurotransmitter has been used in research for pain-relief, cognitive enhancement, and anti-inflammation studies and is prized by many bodybuilders for its pre-workout abilities.[1] It was first discovered by a German scientist called Albrecht Kossel, in 1910 – but it took over 100 years for researchers to figure out what it actually does! [2] In the human body, Agmatine is made from the amino acid, L-arginine. It is also a product of bacterial metabolism so it can be found in a number of fermented foods, including wine, beer, sake, tofu, and soy sauce.[3] Although it is found in the brain, the comound is actually produced mostly by gut bacteria.[4] Agmatine is a neurotransmitter, which means that it helps signals to pass between nerve cells in the central nervous system.[5] Other well-known neurotransmitters include acetylcholine, serotonin, and GABA. As a neuromodulator, Agmatine interacts with many different neurotransmitter systems in the brain.[6] In the United States, this compound is not regulated by the FDA and is available as a dietary supplement. The neurotransmitter itself is a little unstable, which is why Agamatine is sold in the sulfate form. This helps to allow for easier storage and a longer shelf-life and may help to improve its efficiency.

How Agmatine Works

Agmatine works in a number of ways to produce its effects and benefits (see our article on Top Agmatine Benefits). It acts as a neuromodulator, neuroprotector, and cytoprotector to defend the body against stress and toxins.¹ You might already know that Agmatine regulates nitric oxide (NO) synthesis. The neuromodulator regulates the set of nitric oxide synthase enzymes (iNOS, eNOS, and nNOS) to reduce their production of NO in various parts of the body.[7] Although nitric oxide has many benefits in the body, too much of it can be a bad thing (as with everything!). According to a recent literature review: “The increased formation of NO was found to have neurotoxic effects and can contribute to the pathogenesis of stroke and other neurodegenerative disorders.”[8] Too much nitric oxide is bad for both acute and chronic inflammation in the body, and Agmatine may help to reduce these effects by regulating its production.   Other important ways that this supplement works: ☞ Binds to NMDA receptors and prevents glutamate from binding at these receptors. This protects cells and prevents cell death from glutamate toxicity.[9] ☞ Binds strongly to α-2-adrenergic receptors and improves their activity.[10] These receptors are targeted by many different neurotransmitters and man-made compounds. Activating them helps to reduce blood pressure, and also stimulates nitric oxide synthesis.[11] ☞ Blocks the actions of nicotinic acetylcholine receptors.[12] Other compounds with similar effects are used as muscle relaxants and to reduce and control blood pressure.[13] ☞ Binds to, and activates imidazoline receptors with good efficacy.[14] Activating these receptors causes the body to release β-endorphins (natural ‘feel-good’ compounds that help to reduce pain and stress).[15] ☞ Activates AMPA receptors in mTOR (rapamycin) biochemical pathway. The mTOR protein regulates cell growth and is used in protein synthesis, and activating this pathway is known to improve mood.[16] ☞ Activates the Nrf2 pathway.[17] This biochemical system is a powerful producer of antioxidant proteins in the body and helps to protect cells against the negative effects of stress, toxins, and inflammation.[18]  

Agmatine as a Pre-Workout and Cognitive Enhancer

Athletes and bodybuilders often wonder about using this supplement as a pre-workout to improve energy and performance. It is an ingredient in many pre-workouts, so it seems pretty logical to ask about using Agmatine alone. Agmatine has regulatory effects on nitric oxide – it can both decrease its production (at low serving sizes), and stimulate its synthesis (at larger servings).[19] While many pre-workouts are used because of their pro-NO effects, Agmatine sulfate is not necessarily the best option to boost nitric oxide levels. That doesn’t mean that it can’t be used as a pre-workout! Recent studies show that blood glucose levels tend to decrease after taking Agmatine. Its interactions with imidazoline receptors mean that the supplement allows for extra glucose to be deposited into skeletal muscle cells – boosting energy levels.¹⁴ This accounts for the reduction in blood glucose – what was circulating in the blood has been deposited into muscle cells. Furthermore, its effects at α-2-adrenergic receptors and on NMDA receptors means that it is able to produce a noticeable improvement in energy levels. These benefits are also great for anyone looking to improve mental focus and alertness. Recent studies have found that it accumulates in areas of the brain that are associated with learning and memory – indicating that it has a role to play in these functions.[20] Overall – a moderate pre-workout and effective cognitive booster!  

Agmatine Sulfate for Mood and Stress

Recently, studies have shown that this supplement may be effective at reducing stress and improving mood, through its numerous effects on neurotransmitter systems and other biochemical systems in the body. These benefits are especially related to its effects on releasing endorphins – natural ‘feel-good’ hormones that help to reduce stress and improve mood. A number of studies have pointed to the efficacy of these effects. In one study, the long-term effects (4 - 5 years) of daily large servings was researched. The authors note that it can sometimes be used for pain relief, especially relating to the nervous system. They also note that it is effective for mood, stress, and cognition. The researchers found that no adverse effects were reported in over 1015 people who partook in the study.[21] Overall – Good increase in mood and supports stress-reduction!  

How to Take Agmatine?

Agmatine has been studied at large servings, for long periods of time and there were no adverse effects reported. However, it is still not recommended to exceed the serving size suggestion for this supplement. The recommended serving size for Agmatine is 600 – 1200 mg, taken once to twice per day. Agmatine Sulfate is usually sold in a powder form. Use a micro-scoop to measure the correct serving size. This supplement has a high solubility in water so it can easily be dissolved. It can be taken with a glass water, juice, or simply washed down the throat. You could also add the supplement to a healthy smoothie to kick-start your day!  

Side Effects and Warnings

Apart from the study we mentioned above, where over 1050 participants took part, over the course of 4-5 years, not much other research has been done on this supplement's side effects. This is a pretty large study, though, and the fact that no adverse effects were reported is significant. In another study, over 51 days, researchers tested the effects of different serving sizes – 1.4 grams, 2.7 grams, and 3.6 grams, taken daily in three divided servings. At the largest serving size, some participants reported stomach cramps, which faded after a few days.[22] Summary: Most studies show no side effects when used at the correct serving size.  

Summary – What is Agmatine Sulfate?

★ A naturally-occurring neurotransmitter produced in the human body from L-arginine. It is also synthesized by bacteria and is found in a few fermented food types. ★ The sulfate form allows better absorption and storage stability. ★ This neurotransmitter interacts with many different biochemical systems in the brain and body. ★ It produces mood improvements, helps support healthy cognitive performance, and can be used to increase energy levels.  ★ It is also effective at protecting the body against stress and toxins, through its anti-inflammatory and antioxidant effects. ★ Researchers have studied this supplement for use in pain relief.  ★ The recommended serving size is 600 – 1200 mg, taken once to twice per day. ★ Most studies show that no side effects are reported when used at the correct serving size.          

References:

[1] Kamel, P. (2018). “Agmatine”. Examine.com [online] Available at: https://examine.com/supplements/agmatine/ [2] Kossel, A. (1910). ""Über das Agmatin"". Zeitschrift für Physiologische Chemie (in German). 66: 257–261. [3] Galgano, F., Caruso, M., Condelli, N., & Favati, F. (2012). Focused review: agmatine in fermented foods. Frontiers in microbiology, 3, 199. doi:10.3389/fmicb.2012.00199 [4] 1: Raasch W, Regunathan S, Li G, Reis DJ. (1995). Agmatine, the bacterial amine, is widely distributed in mammalian tissues. Life Sci, 56(26):2319-30. [5] Reis, D.J., Regunathan, S. (2000). Is agmatine a novel neurotransmitter in brain? Trends Pharmacol Sci, 21(5):187-93. Review. [6] Reis D.J., Regunathan, S. (1998). Agmatine: a novel neurotransmitter? Adv Pharmacol, 42:645-9. [7] Auguet, M., Viossat, I., Marin, J.G., Chabrier, P.E. (1995). Selective inhibition of inducible nitric oxide synthase by agmatine. Jpn J Pharmacol, 69(3):285-7. [8] Víteček, J., Lojek, A., Valacchi, G., Kubala, L. (2012). Arginine-Based Inhibitors of Nitric Oxide Synthase: Therapeutic Potential and Challenges. Mediators of Inflammation, 2012:318087. [9] Kim, H.S., Park, I.S., Lim, H.K., Choi, H.S. (1999). NMDA receptor antagonists enhance 5-HT2 receptor-mediated behaviour, head-twitch response, in PCPA-treated mice. Arch Pharm Res, 22(2):113-8. [10] Molderings, G.J., Menzel, S., Kathmann, M., Schlicker, E., Göthert, M. (2000). Dual interaction of agmatine with the rat alpha(2D)-adrenoceptor: competitive antagonism and allosteric activation. Br J Pharmacol, (7):1706-12. [11] Giovannitti, J. A., Thoms, S. M., & Crawford, J. J. (2015). Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anaesthesia progress, 62(1), 31-9. [12] Loring, R.H. (1990). Agmatine acts as an antagonist of neuronal nicotinic receptors. Br J Pharmacol, 99(1):207-11. [13] Nicotinic Antagonists. (2018). Drugbank.ca. [online] Available at: https://www.drugbank.ca/categories/DBCAT000919 [14] Chang, C.H., Wu, H.T., Cheng, K.C., Lin, H.J., Cheng, J.T. (2010). “Increase of beta-endorphin secretion by agmatine is induced by activation of imidazoline I(2A) receptors in adrenal gland of rats.” Neurosci Lett,  14;468(3):297-9 [15] Dalayeun, J.F., Norès, J.M., Bergal, S. (1993). Physiology of beta-endorphins. A close-up view and a review of the literature. Biomed Pharmacother, 7(8):311-20. [16] Neis, V.B., Moretti, M., Bettio, L.E., Ribeiro, C.M., Rosa, P.B., Gonçalves, F.M., Lopes, M.W., Leal, R.B., Rodrigues, A.L. (2016). Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling. Eur Neuropsychopharmacol, 26(6):959-71. [17] Freitas, A.E., Egea, J., Buendía, I., Navarro, E., Rada, P., Cuadrado, A., Rodrigues, A.L., López, M.G.. (2015). Agmatine induces Nrf2 and protects against corticosterone effects in hippocampal neuronal cell line. Mol Neurobiol, 51(3):1504-19. [18] Freitas, A.E., Egea, J., Buendia, I., et al. (2016). Agmatine,  by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone-Induced Depressive-Like Behavior in Mice. Mol Neurobiol, 53(5):3030-3045. [19] Satriano, J. (2003). Agmatine: at the crossroads of the arginine pathways. Ann N Y Acad Sci, 1009:34-43. Review. [20] Liu P, Jing Y, Collie ND, Chary S, Zhang H. Memory-related changes in L-citrulline and agmatine in the rat brain. Hippocampus. 2009 Jul;19(7):597-602. [21] Gilad, G.M., Gilad, V.H. (2014). Long-term (5 years), high daily dosage of dietary agmatine--evidence of safety: a case report. J Med Food, 17(11):1256-9. [22] Keynan, O., Mirovsky, Y., Dekel, S., Gilad, V.H., Gilad, G.M. (2010). Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial. Pain Med, 11(3):356-68.