Heavy resistance training and supplementation with the alleged testosterone booster NMDA has no effect on body composition, muscle performance, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained males.

Author:Willoughby, Darryn S.
Position::Research article - Report


Within the nutritional/sport supplement industry there are a vast amount of products that are marketed as "testosterone boosters." Many of these products contain a proprietary blend of various ingredients alleged to increase endogenous testosterone levels. However, in most cases there is little data, either on the complete product itself or the various active ingredients typically contained within a proprietary blend, to substantiate manufacturers' claims. In many cases, the studies that are available which are used to substantiate product claims involve animal or cell culture models; therefore, the results may not be germane to humans. Nevertheless, the nutrition/sport supplement industry often attempts to take advantage of this, often times irrelevant, information by manufacturing products with the intent of them acting as "testosterone boosters" in their ability to increase endogenous testosterone levels, presumably by activation of the hypothalamo-pituitary-gonadal (HPG) axis, and subsequently augmented when combined with resistance training. Furthermore, these products usually have no data available, yet are still being marketed on the premise that increases in endogenous testosterone will result in increases in muscle mass, especially when ingested in conjunction with a resistance training program.

One such product is NMDA (Muscle Warfare, Wellington, FL), a proprietary blend nutritional product that is an alleged testosterone booster. It is advertised to be a N-methyl-D-aspartate receptor activator and testosterone releaser. Based on the manufacturers' rationale, the N-methyl-D-aspartic acid receptor would be up-regulated due to the presence in the NMDA product of D-aspartic acid (D-Asp), N-methyl-D-aspartate (NMD-Asp), trimethyl glycine, and S-adenosyl methionine (SAMe). As a result, the HPG axis would be activated, as evidenced by increases is circulating gonadotrophin releasing hormone (GnRH). Therefore, luteinizing hormone (LH) and testosterone would also be subsequently increased due to an upregulation in the HPG axis. In addition, the herbs Eurycoma Longfolia Jack and Mucuna Pruriens contained in the product, which are alleged to be testosterone GnRH release triggers and inhibitors of prolactin and cortisol, will also help synergize the activation of the HPG axis. While there are data available in both animals and humans on various ingredients contained in the NMDA product that are associated with increases in testosterone and inhibition of prolactin and cortisol, there are no data available on the actual product itself, particularly in response to resistance training.

Elevations in circulating testosterone are known to augment muscle protein synthesis, thereby resulting in enhanced muscle mass and strength. In humans, testosterone is synthesized and released through an elaborate hormonally-orchestrated signaling cascade referred to as the HPG axis. In order for this axis to be up-regulated, D-Asp, an endogenous amino acid present in nervous tissues and endocrine glands of humans (D'Aniello et al., 2007), plays an important neuromodulating role. In males, D-Asp endogenously synthesizes testosterone by first converting to NMD-Asp by D-aspartate methyltransferase (NMDA synthetase). In the hypothalamus, NMD-Asp binds to its receptor, a subtype of the L-glutamate receptor, and potentiates transmission via glutaminergic neurons (Katane & Homma, 2011), which results in the release of GnRH (D'Ainello, 2007). The release of GnRH from the hypothalamus then triggers the release of prolactin, follicle stimulating hormone (FSH), and LH from the pituitary gland. The effect of the latter two hormones on the testes is that FSH stimulates spermatogenesis and LH stimulates testosterone synthesis (D'Ainello, 2007). In addition, D-Asp-induced neuromodulation induces aromatase activity, the enzyme responsible for the conversion of testosterone to 17|3-estradiol (Assisi et al., 2001; Raucci et al., 2005).

Prolactin is a hormone synthesized in the adenohypohyseal lactotrophs, has no known target organ or defined role in male reproduction. Yet, expression of prolactin receptors on the choroid plexus and hypothalamus presupposes a latent role for this hormone in the regulation of male fertility (Grattan, 2001; Mangurian et al., 1992). Although the functional significance of prolactin to male reproduction has not been unequivocally established, the hormone has been associated primarily with male infertility (Gill-Sharma, 2009). Cortisol is a glucocorticoid hormone produced by the adrenal gland and its release is controlled by the hypothalamus, and its primary functions are to increase blood sugar through gluconeogenesis, suppress the immune system, and aid in fat, protein and carbohydrate metabolism. Elevated levels of cortisol, if prolonged, can lead to proteolysis and muscle wasting (Simmons et al., 1984). Prolactin and cortisol release are both governed by the hypothalamo-pituitary axis (HP axis) where prolactin is released directly from the pituitary gland; however, cortisol is released further downstream, from the adrenal gland.

Due to the lack of scientific data on the nutritional supplement, NMDA, and having to rely on manufactures' claims and anectodtal reports regarding the effectiveness of NMDA supplementation in increasing endogenous testosterone levels, it is tenuous at best to assume that the NMDA product may prove beneficial as a means in which to increase muscle performance associated with heavy resistance training. While there are data available on some of the active ingredients contained in the NMDA product, there appears to be no scientific studies, human or animal, dealing with the supplementation of NMDA. As a result, we hypothesized that NMDA would not increase endogenous testosterone levels or improve muscular performance associated with resistance training. Therefore, the purpose of this study was to determine the effects of resistance exercise and NMDA supplementation on body composition, muscle strength, serum cortisol, prolactin, and hormones associated with the HPG axis in resistance-trained males. It was hypothesized that NMDA would not increase endogenous testosterone, blunt the levels of cortisol and prolactin, or improve muscle mass and strength associated with resistance training.


Experimental approach

In a randomized, double-blind design, participants engaged in 28 days of heavy resistance training while also ingesting 1.78 g-day-1 of either placebo or NMDA. Testing and evaluation occurred before (Day 0) and after (Day 29) and involved assessments of body composition, muscle strength, and serum hormones associated with the HPG axis. This approach was based on the premise that after ingesting the NMDA supplement, muscle mass and strength may be preferentially affected compared to placebo, due to elevations in endogenous testosterone and decreases in cortisol and prolactin.


Twenty apparently healthy, resistance-trained [consistent (at least thrice weekly) resistance training for one year prior to the study] males with an average age of 21.42 [+ or -] 3.16 yr, height of 1.81 [+ or -] 0.07 m, and total body mass of 79.1 [+ or -] 16.13 kg completed the study. Enrollment was open to men of all ethnicities. All participants underwent a mandatory medical screening, and anyone with contraindications to exercise as outlined by the American College of Sports Medicine and/or who had consumed any nutritional supplements (excluding multi-vitamins) within three months, or anabolic steroids six months prior to the study, were not allowed to participate. All eligible participants signed a university-approved informed consent document based on the guidelines set forth by the Institutional Review Board for the Protection of Human Subjects of Baylor University. Additionally, all experimental procedures involved in this study conformed to the ethical considerations of the Helsinki Code.

Testing sessions

The study included baseline testing at Day 0 followed by a follow-up testing session at Day 29 in which blood samples were obtained, dietary intake and body composition assessed, and muscle strength tests performed.

Strength assessment

Upper- and lower-body one repetition maximum (1-RM) strength tests were performed using the free weight bench press and angled leg press exercises (Nebula, Versailles, OH), respectively, based on our previous studies (Shelmadine et al., 2009; Spillane et al., 2011; Willoughby and Leutholtz, 2013). As a warm-up, an estimated 50% 1-RM was utilized to complete 10 repetitions. After a two-min rest period, a load of 70% of estimated 1-RM was utilized to perform five repetitions. At this point, the weight was gradually increased until a 1-RM was reached with each following lift, with a two-min rest period in between each successful lift. Test-retest reliability of performing these strength assessments on subjects within our laboratory has demonstrated low mean coefficients of variation and high reliability for the bench press (1.9%, intraclass r = 0.91)...

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