Comparison of DAA, DAACC, NMDA & NMA on the Function as Testosterone Booster

I. Testosterone Booster
Testosterone booster supplements are widely used nowadays, not only to improve athletic performance and build muscles, but to sharpen memory, boost libido, improve energy levels, and fat loss, etc. Because of all the remarkable benefits, different categories of testosterone booster supplements are offered on the market today, among which the products made from D-Aspartic Acid and its derivativesD-Aspartic acid calcium chelate, N-Methyl-D-Aspartic acid and N-Methyl-DL-Aspartic acid, possess good reputation for their safety and high efficacy.

II. Research Background of the 4 Compounds

1. DAA (D-Aspartic acid) Aspartic acid is one of the 20 common amino acids that are used by the body to construct proteins and is considered to be non-essential since it can be made from oxaloactetate, an intermediate of the tricarboxylic acid cycle. There are two isomers of aspartic acid, the L-isomer and the D-isomer. Only the L-isomer is used in proteins while the d-isomer is used as a neurotransmitter as d-aspartic acid and N-methyl-D-aspartic acid. D-aspartic acid is known to stimulate the NMDA receptor. More recently, D-aspartic acid has been shown to have some intriguing effects in several animal species and humans. D-aspartic acid has been shown to enhance gonadotropin, releasing hormone from the hypothalamus as well as growth hormone (GH) and luteinizing hormone (LH) release from the pituitary (1,

2).

Sodium D-aspartic acid has also been shown to directly increase testosterone production by the testes (3, 4, 5), DAA does this by increasing the levels of
(6).

steroidogenic acute regulatory (StAR) protein

StAR plays a critical role in the production of steroid hormones in the testes and adrenals. In fact, StAR
(6, 7).

mediates the rate-limiting step in steroid hormone production, the importation of cholesterol into the mitochondria

All steroid hormones are

manufactured from cholesterol in the mitochondria and if cholesterol doesnt get into the mitochondria, then steroid hormones, and more specifically, testosterone does not get produced. DAA increases StAR which increases cholesterol entry into the mitochondria which results in increased testosterone production. A study dosed 3.12 grams of sodium-DAA to adult males (27 to 37 yrs old) for 12 days resulting in a 42% increase in average testosterone levels (3). These may not seem like huge increases in testosterone but these are controlled, scientific results in normal healthy men. Evidence exists in the literature that shows DAA to be more effective at increasing LH levels in animals that have been castrated suggesting that DAA may be even more effective in hypogonadal males or those whose natural production may be suppressed following a steroid cycle. Recommended Dosage: the dosage used in the study showing DAA to increase testosterone levels was 3 gram taken in the morning. However, a loading phase of 3g morning and 3g evening would be recommended. 2. DAACC(D-Aspartic acid calcium chelate) DAA is an natural amino acid that has been shown to raise testosterone levels in men, but, unfortunately, straight DAA has terrible water solubility (less than 1 gram will dissolve in 220 milliliters of water). This means that it basically sits in the digestive tract as a gritty powder and absorbs very slowly. Furthermore, at higher dosages this powder can cause digestive disturbances in susceptible individuals. Researchers then improved the absorption and bio-availability of regular DAA by chelating it with calcium, called D-Aspartic acid calcium chelate (DAACC), thereby increasing its water solubility over 75 times. Once DAACC is remarkably stable over a wide pH range and will mix instantly, it becames more user friendly (9). In some DAACC products they also contain Sarcosine, which works synergistically to greatly enhance the activity at the receptor. However, some investigations show the concerns about the side effect may be caused by calcium chelate. The mechanism of aspartate stimulating NMDA receptor is

an agonist-binding to NR2 subunits of NMDA receptors, then a non-specific cation channel is opened, which can allow the passage of Ca2+ and Na+ into the cell and K+ out of the cell (see Fig. 1). The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor also increases the concentration of Ca2+ in the cell. The Ca2+ can in turn function play as a second messenger in various signaling pathways.(14, 15, 16, 17). The DAACC compound additionally offers plenty of Ca2+ ion, and the additive effect may promote the high levels of Ca2+ ion in cells. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.(19) Recommended Dosage: DAACC dissolves practically instantly in any beverage and it is essentially tasteless. it is recommended that people take 1-2 servings a day, and often users may find it advantageous to "load" with 2 servings (6 grams) a day for two to four weeks and then "coast" with 1 serving (3 grams) a day for the remainder of the cycle. Cycles can last anywhere from 3 weeks to indefinitely. 3. NMDA (N-Methyl-D-Aspartic acid) DAA is an amino acid that is naturally found in high quantities in the reproductive organs, hypothalamus and pituitary. Through methyl-transferase reaction called NMDA synthetase, DAA is converted into NMDA there, which is a potent stimulator of the NMDA Receptor pathway. (8) NMDA is deemed 100 times more potent than D-Aspartic Acid at stimulating the NMDA receptor and is a potent synergist to the formula. turn is directly involved in the regulation of GnRH secretion from the hypothalamus and of GH from the adenohypophysis. However, because NMDA is a potent glutamate agonist at stimulating the NMDA receptor, it is also termed an excitotoxin. Low doses can potentially hyper-stimulate the receptor and kill the cells. Nevertheless it was also demonstrated that creatine exhibits a significant protective effect against neurotoxic agents such as NMDA; therefore, combining creatine (and maybe Taurine) with this booster may nullify any negative side effects of the receptors being over stimulated. 9 NMDA also may increase estradiol concentrations, increasing the risk of gynecomastia (man boobs). One reason is that DAA could increase the activity of the aromatase enzyme cytochrome P-450 which catalysis the conversion of tst to 17-estradiol. Therefore there is enough zinc and possibly some types of aromatase inhibitor is warranted. 9 Therefore,

DAA is considered having a minor role as an effector molecule for hormone release, but that it mainly acts as the precursor for NMDA synthesis, which in

Recommended Dosage: Investigation on dosing with NMDA needs to be done with caution in case an excitotoxin. Usually the testosterone booster of NMDA is recommended to be taken with creatine, Taurine, prolactin inhibitor, aromatase inhibitor, and the dosing could be 30-50mg each serving. 4. NMA (N-Methyl-DL-Aspartic acid) Now its well-known about D-Aspartic acid (DAA) and its application in Testosterone elevating, and scientific researches revealed that part of the effect is accomplished via NMDA receptor pathway. People also would like to apply N-methyl-D-Aspartic acid (NMDA) to sporting nutrition industry as one endocrine regulation tool, because NMDA is deemed 100 times more potent than DAA at stimulating the NMDA receptor. However, NMDA is such an expensive compound comparing with DAA, so its application is still quite limited. N-methyl-DL-aspartic acid (NMA), also an analog of the putative excitatory neurotransmitter aspartate, was used to stimulate the hypothalamus to the attribute of neuroexcitatory, NMA is usually administered in the LHRH-stimulating Furthermore, the experiment length also influenced GH secretion of goats.(18) Since NMA is the raceme form of methylated D-aspartic acid, its the 1:1 mixture of N-methyl-D-Aspartic acid and N-methyl-L-Aspartic acid (NMLA). Thus NMA possesses at least as 50% similarity as NMDA, which means as much as 50% of the NMDA potency for stimulating NMDA receptor. Therefore, NMA possesses at least as 50 times potency as DAA for stimulating NMDA receptor. In the meanwhile, its unnecessary to worry about the part of NMLA would affect the efficacy of NMA. In another article, there was a research attempting to compare the biofunctions of specific isomers (NMDA, NMA, NMLA) for increasing blood concentrations of Grow Hormone (on barrows). The results showed both NMDA and NMA could significantly increase the animals GH secretion. NMLA group appeared the similar increasing trend, but the data were not statistically significant.(20) NMA potentially boosts the endocrine, not only Testosterone, but also Growth Hormone (GH) and Luteinizing Hormone (LH). However, the cost of NMA is just two-fold as DAA and 1/20 of that of NMDA, so NMA can provide the optimal cost-effective performance (see Chart 1.). In addition, one experiment of excitant effect on mammalian neurons, 31 amino acids as potential excitants were tested (12). NMDA was proved to be the strongest excitant (rated 100), and NMA showed significantly weaker excitotoxity (rated 45-65). All these significant advantages make NMA a promising candidate for endocrine regulation formulation in the future. experiments (11).

10 .

Due

According to another injection experiment of NMA

to goats, a long-time secretion of LH for 2 hours was observed, and the Testosterone secretion could be dose-dependent increasing without any problem.

Recommended Dosage: NMA in Pre-workout or Post-workout formulation is 60-100mg each serving for potent GH and Testosterone secretion effects.

III. Comparison of the 4 Compounds

1. General Information Dissolvin W ater Solubility g Efficienc y In Vivo
*2

Compound Name

Molecula CAS No. Molecular Formula r W t. (g/mol)

Excitotoxi ty Rating *1 LD50

Market Price ($/kg)

Recommended Dosage for Testosterone Booster

i.m. DAA 1783-96-6

C4H7NO4

133.1

4-10

Mouse 1000 mg/kg

12~16

3g each serving

4.5g/L

30%

CaC 8 H 12 N
2O 8

DAACC

N/A

304.2

>(4-10)

N/A

20~30

3g each serving

337.5g/L

100%

C 5 H 9 NO
4

i.p. 147.1 100 mouse 137 mg/kg >1,000 30-50mg each serving About 25g/L 100%

NMDA

6384-92-5

Mice NMA 17833-53-3 147.1 45-65 350 mg/kg

C 5 H 9 NO 4
*1. The excitotoxity rating is according to the research in Reference 12.

30~50

60-100mg each serving

About 25g/L

100%

*2. The Dissolving Efficiency In Vivo is estimated with the ratio of dissolved part and recommended dosage. In each serving we usually recommend the nutrition is taken with 200ml water. E.g. in the recommended dosage, 0.9g DAA can dissolve in 200m water, so the dissolving efficiency of DAA is 0.9g/3g, equal to 30%.

2.

Approximately

Estimation

of

Cost-effective

28 26 24 100 25 100

Performance Here we try to utilize the biochemical characteristics, together with the market price information, to analyze the
C o s t- e f f e c tiv e P e rf o rm a n c e

C o s t- E ffe c tiv e P e rfo rm a n c e A d v e rs e E ffe c ts P o te n c y 45-65

comprehensive

cost-effective

performance

of

the

20 18 16 14 12 10 8 6 4 2 0

compounds. The comparison is constructed on the basis of DAA performance, including its ablity for stimulating NMDA receptor and its market price. The other three derivatives performance is approximately estimated with the multiples of the corresponding items. *Abbr. introduction: CEP=Cost-effective Performance A=Ability for Stimulating NMDA Receptor per Unit Weight P=Market Price per Unit Weight

45- 65

>4-10

>4- 10

4-10

4- 10

0.5

1.25

-- (CEP ) DAA =

( A) DAA PDAA ( A) DAACC ( A) DAA = 0.5(CEP ) DAA PDAACC 2 PDAA

DAA DAACC NMDA NMA C h a rt 1 . C o m p a ris o n o f C o s t- e ffe c tiv e P e rfo rm a n c e & A d v e rs e E ffe c ts

-- (CEP ) DAACC =

-- (CEP ) NMDA =

( A) NMDA 100( A) DAA = 1.25(CEP) DAA PNMDA 80 PDAA

A d v e rs e E f f e c ts P o te n c y R a tin g

22

-- (CEP) NMA =

( A) NMA 50( A) DAA = 25(CEP) DAA PNMA 2PDAA

The comparison of the cost-effective performance is visualized by the Chart 1, the adverse effects potency is also listed for comparison.

IV. Reference
1. 2. 3. 4. 5. 6. DAniello A. D-Aspartic acid: an endogenous amino acid with an important neuroendocrine role. Brain Res Rev. 2007 Feb;53(2):215-34. Pinilla L, Tena-Sempere M, Aguilar E. Role of excitatory amino acid pathways in control of gonadotrophin secretion in adult female rats sterilized by Topo E, Soricelli A, DAniello A, Ronsini S, DAniello G. The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and DAniello A, Di Fiore MM, DAniello G, Colin FE, Lewis G, Setchell BP. Secretion of D-aspartic acid by the rat testis and its role in endocrinology of the DAniello A, Di Cosmo A, Di Cristo C, Annunziato L, Petrucelli L, Fisher G. Involvement of D-aspartic acid in the synthesis of testosterone in rat testes. Nagata Y, Homma H, Matsumoto M, Imai K. Stimulation of steroidogenic acute regulatory protein (StAR) gene expression by D-aspartate in rat Leydig

neonatal administration of oestradiol or testosterone. J Reprod Fertil. 1998 May;113(1):53-9. testosterone in humans and rats. Reprod Biol Endocrinol. 2009 Oct 27;7:120. testis and spermatogenesis. FEBS Lett. 1998 Sep 25;436(1):23-7. Life Sci. 1996;59(2):97-104. cells. FEBS Lett. 1999 Jul 9;454(3):317-20. 7. Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, Strauss JF 3rd. Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. J Biol Chem. 1997 Dec 19;272(51):32656-62. 8. D'Aniello A, Di Fiore MM, Fisher GH, Milone A, Seleni A, D'Aniello S, Perna AF, Ingrosso D. 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. 2000 Apr;14(5):699-714. 9. 2011 Testosterone Booster Recommendation Report. http://www.musclefeast.com/uploads/file/T-Booster%20recommendations.pdf 10. Gay VL, Plant TM. Sustained Intermittent Release of Gonadotropin-Releasing Hormone in the Prepubertal Male Rhesus Monkey Induced by N-Methyl-DL-Aspartic Acid. Neuroendocrinology 1988;48:147152. 11. Urbanski HF, Ojeda SR. Activation of Luteinizing Hormone-Releasing Hormone Release Advances the Onset of Female Puberty. Neuroendocrinology

1987;46:273276. 12. D. R. CURTIS, J. C. WATKINS .ACIDIC AMINO ACIDS WITH STRONG EXCITATORY ACTIONS ON MAMMALIAN NEURONES. J. Phy8iol. (1963), 166, pp. 1-14. 13. Laube, B; Hirai H, Sturgess M, Betz H, and Kuhse J (1997). "Molecular determinants of antagonists discrimination by NMDA receptor subunits: Analysis of the glutamate binding site on the NR2B subunit". Neuron 18 (3): 493503. 14. Dingledine R, Borges K, Bowie D, Traynelis SF (March 1999). "The glutamate receptor ion channels". Pharmacol. Rev. 51 (1): 761. 15. Liu Y, Zhang J (October 2000). "Recent development in NMDA receptors". Chin. Med. J. 113 (10): 94856. 16. Cull-Candy S, Brickley S, Farrant M (June 2001). "NMDA receptor subunits: diversity, development and disease". Curr. Opin. Neurobiol. 11 (3): 32735. doi:10.1016/S0959-4388(00)00215-4. 17. Paoletti P, Neyton J (February 2007). "NMDA receptor subunits: function and pharmacology". Curr Opin Pharmacol 7 (1): 3947. 18. O.S.Gazal, B.Kouakou, E.A.Amoah, C.R.Barb, J.B.Barrett, and S.Gelaye. Effects of N-methyl-D,L-aspartate on LH, GH, and testosterone secretion in goat bucks maintained under long or short photoperiods. J Anim Sci 2002. 80:1623-1628. 19. Clinical Implications of Basic Research: Memory and the NMDA receptors, Fei Li and Joe Z. Tsien, N Engl J Med, 361:302, July 16, 2009. 20. M. J. Estienne, J. M. Harter-Dennis. et al., N-Methyl-D,L-Aspartate-Induced Growth Hormone Secretion in Barrows: Possible Mechanisms of Action J. Anim. Sci. 1996. 74:597602.