In Depth Explore Into D-Aspartic Acid and N-Methyl-D-Aspartic Acid
D-aspartic acid (DAA) an endogenous excitatory amino acid is now widely used as daily supplement to promote muscle growth, improve recovery and support the feeling of well being. As reviewed by Antimo D’Aniello in his article1, DAA can stimulate the secretion of prolactin (PRL), luteinizing hormone (LH) and growth hormone (GH) in pituitary gland. And it is also involved in the release of testosterone and progesterone in the testes. The secretion of the above hormones mostly contributes to the wonderful effects of DAA.
In fact, rather than directly interact with the nervous—endocrine system, DAA carries out most of its function by converting to N-Methyl-D-Aspartic acid (NMDA) in the presence of NMDA synthetase which is present in rats and many other animals2-4 (Refer to Figure 1 for details). NMDA, a well-known activator of NMDA receptor, is estimated to be 100 times more potent than DAA in stimulating the NMDA receptor 5. When the two excitatory amino acids of NMDA and DAA are used in combine, rather than compete with each other, they work synergistically and the endocrine stimulating effect is almost doubled2,3 as shown in Figure 1.
Figure 1 Effects of D-Asp, NMDA and D-AP5 on GH and LH release from isolated adenohypophysis and adenohypophysis
Results indicate ng/ml medium. Adenohypophysis was incubated alone or with hypothalamus in 2 ml of medium at 37 °C for 60 min under moderate agitation. Values represent the mean±SD of 5 experiments. D-AP5 is a specific NMDA receptors antagonist. * different from control (P<0.05) **Different from control (P<0.01).
Figure 2 Pathway of the involvement of D-Asp and NMDA in the hormone release of the hypothalamic–hypophysis–gonad axis. In the brain, L-Asp is converted into D-Asp by an aspartate racemase and, in turn, D-Asp is converted intoNMDAby a D-aspartate methyltransferase (NMDA synthetase). In the hypothalamus NMDAinduces the release of GHRH, GnRH and PRFs factors, which at the pituitary gland, stimulate the release of GH, LH, FSH, and PRL. LH and FSH, in turn, stimulate testosterone and progesterone in the testis or ovary. However, D-Asp has also aminor direct action on the pituitary gland in the release of LH and FSH, as well as on testes or ovary in the release of testosterone and progesterone, respectively.
Advantages of Methyl-EAA® over DAA and NMDA
From the above introduction, most of the reader may wonder why we don’t substitute DAA with NMDA as DAA is just the precursor of NMDA and is 100 times less effective than the latter. Here we give out the two main reasons. The first one is that NMDA is commercially more expensive and its major use is in the field of research rather than for daily supplement. The second and the more important one is that NMDA receptor is so widely expressed throughout the nervous system and it may over-excite the NMDA sensitive nerves leading to cell death or associating with neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s disease6-8. It is the severe side effects that keep NMDA from being accepted as a daily supplement.
Now this is where new products, registered as Methyl-EAA® and also known as NMA, may fit in. The main ingredient of NMA is N-Methyl-DL-Aspartic acid. And to be accurate it is the 1:1 mixture of N-methyl-D-Aspartic acid and N-methyl-L-Aspartic acid. Because N-methyl-L-Aspartic acid has no biological effect, Methyl-EAA® is estimated to be half as potent as NMDA. In other words, Methyl-EAA® is more potent than DAA and a little bit weaker than NMDA. However, for the adverse effects, Methyl-EAA® is less toxic than NMDA while a little bit “toxic” than DAA. So it might be a good candidate to substitute DAA as a daily supplement. Instead of totally replacing DAA with Methyl-EAA®, we highly recommend the use of both DAA and Methyl-EAA® (1.5 g DAA+100mg Methyl-EAA®) as a compound supplement plan. There are two main reasons. The first one is to maximize the effectiveness and minimize the possible adverse effect with both DAA and Methyl-EAA® are applied at low dosage. The second one is that research also shows that the D-Aspartate oxidase which may terminate the action of both DAA and Methyl-EAA® oxidizes DAA at very high rate but Methyl-EAA® at relatively low rate9. Therefore addition of Methyl-EAA® as a supplement may prolong the desired effect which can’t be obtained by simply elevating the dosage of DAA. In short, with both DAA and Methyl-EAA® at recommended dosage, we can get maximal and prolonged favorable effect while avoiding the undesirable adverse effects.
1. Antimo D'Aniello 2007 D-Aspartic acid: An endogenous amino acid with an important neuroendocrine role. Brain Research Reviews 53, 215–234
2. D'Aniello, A., Di Fiore, M.M., Fisher, G.H., Milone, A., Seleni, A., D'Aniello, S., Perna, A., Ingrosso,D., 2000. Occurrence of D-Aspartic acid and N-methyl-D-aspartic acid in rat neuroendocrine tissues and their role in the modulation of luteinizing hormone and growth hormone release. FASEB J. 14, 699–714.
3. D'Aniello, G., Tolino, A., D'Aniello, A., Fisher, G.H., Di Fiore, M.M., 2000. The role of the aspartic acid and N-methyl-D-aspartic acid in the regulation of prolactin release. Endocrinology 141, 3862–3870
4. D'Aniello, A., De Simone, A., Spinelli, P., D'Aniello, S., Branno, M.,Aniello, F., Rios, J., Tsesarkaja, M., Fisher, G., 2002. A specific enzymatic high-performance liquid chromatography method to determine N-methyl-D-aspartic acid in biological tissues. Anal. Biochem. 308, 42–51.
5. Tyler W. LeBaron 2011 Testosterone Booster Recommendation Report. http://www.musclefeast.com/uploads/file/T-Booster%20recommendations.pdf
6. Choi DW, Koh JY, Peters S. 1988 Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci; 8: 185–196.
7. Villmann C, Becker CM. 2007 On the hypes and falls in neuroprotection: targeting the NMDA receptor. Neuroscientist; 13: 594–615. 8. Benarroch EE. 2011 NMDA receptors: recent insights and clinical correlations. Neurology; 76: 1750–1757.
9. D'Aniello, A., Vetere, A., Petrucelli, A., 1993. Further study on the specificity of D-amino acid oxidase and of D-aspartate oxidase and time course for complete oxidation of D-amino acid, Comp. Biochem. Physiol. 105B, 731–734.