Citrulline & Glutathione - GSH Amplifies & Prolongs CIT's NO Boosting Effects During + After Biceps Workout

From a physiological perspective NO is not primarily there to make you look vascular and pumped, boys.

If you've read the headline and are asking yourselves "Why on earth would I even want to spend money on cosmetic pump?", you probably need a reminder of the multiple important functions nitric oxide (NO) serves in your body: (1) With their ability to relax the musculature of your blood vessels to increase the blood flow through your veins, normal NO levels are required to guarantee optimal blood flow to every body part; (2) since this includes your sexual organs, normal NO levels are also a prerequisite for normal / optimal sexual function; (3) having enough NO is also required to keep your immune defenses up, because the white blood cells need it in their fight against intruders; and if heart disease, sexual dysfunction and immune health are all things you don't care about (4) you may be interested to hear that your brain and metabolic health critically depend on normal NO levels, as well.

You can learn more about citrulline at the SuppVersity

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Now that you've got the primer on "nitric oxide beyond the pump" you may be happy to hear that a very common NO supplement, i.e. citrulline, actually delivers. But there's more: In a very recent study, scientists from the Baylor University demonstrated for KYOWA HAKKO BIO CO (so this is sponsored research) that a combined treatment with citrulline and glutathione leads to significant increases in the levels of cGMP, nitrite, and NOx (nitric oxide metabolite) in cells, rodents and humans.

Figure 1: Overview of the design of the "human part" of the study (McKinley-Barnard. 2015).

In the latter part of the study (the human part), the researchers had sixty six participants randomly assigned (in a double-blind fashion) to one of four groups (n = 15 per group) involving 7 days of the oral ingestion of four capsules containing a total daily dose of either: cellulose placebo (2.52 g/day), L-citrulline (2 g/day), GSH (1 g/day), or L-citrulline (2 g/day) + GSH (200 mg/day). Supplementation compliance was monitored by participants returning empty containers of their supplement on day 7, and also by completing a supplement compliance questionnaire.

What is glutathione and why would you combine it with citrulline? Glutathione is a low molecular weight, water-soluble tripeptide composed of the amino acids cysteine, glutamic acid, and glycine. Glutathione is an important antioxidant and plays a major role in the detoxification of endogenous metabolic products, including lipid peroxides.

Contrary to what many believe, oral GSH supplements work | more

In some cell types, GSH appears to be necessary for NO synthesis and NO has been shown to be correlated with intracellular GSH (Ghigo. 1996). GSH stimulates total L-arginine turnover and, in the presence of GSH, NOS activity is increased (Hofmann. 1995). For the authors of the study at hand this means that "GSH may play an important role in protection against oxidative reaction of NO, thus contributing to the sustained release of NO" (McKinley-Barnard. 2015) - reason enough for them to believe that "combining L-citrulline with GSH may augment the production of NO" (ibid).

Each participant ingested all four capsules containing their respective daily supplement dose each evening for six consecutive days until at Visit 3 (Day 7), participants were provided the final daily dose of their respective supplement ingested one hour prior to performing a previously familiarized biceps training program consisting of  3 sets of 15 repetitions with as much weight as they could lift per set (typically 70–75 % of 1RM | 10s rest between sets, only) on a selectorized weight machine (Body Master, Rayne, LA).

Figure 2: Nitrate concentration and change in plasma NOx in rodents (NO metabolites | McKinley-Barnard. 2015). 

Figure 2, which depicts data from the rodent study, already suggests that only citrulline or citrulline and glutathione would trigger significant increases in NO production in the 20-22 year-old healthy, well-trained (at least three resistance training sessions per week) participants, while GSH alone would trigger only a minor increases of the nitric oxide levels.

Figure 3: Changes in NO metabolites (NOx) and cGMP levels (McKinley-Barnard. 2015) in the human study.

The data in Figure 3 (left) which tells you that the increase in stable NO metabolites (NOx) in the blood of the subjects in the citrulline + GSH group was the highest. What may surprise you, though, is that the increase in nitric oxide that is obviously partly mediated by an increase in c-GMP (Figure 3, right) levels was not only maintained after the workout, the levels even kept increasing.
This is in contrast to your regular "pump" formula (using only citrulline), where the levels drop back to baseline ( and potentially even lower - after all only 30 min were monitored) after the workout.

Why is that important? Well, if you look back at the "nitric oxide beyond the pump" list from the introductory paragraph, you will notice that almost all of these "beyond the pump" effects are health-relevant during, but also and even more so after the workout.

8g/day Citrulline Increase Leg Workout Performance - More Reps on Leg Press, Hack Squat & Leg Ext. in Exp. Gymrats (more). Whether CIT + GSH can do more, remains to be seen!

Bottom line: We still need more, non-sponsored research to figure out how practically significant the results of the study at hand actually are. Important questions, like "Which one, citrulline alone or citrulline + GSH is the better performance booster?", "Does the effect last or will your body get used to it?", "Is chronic ingestion of the supplement necessary or does it suffice to take it pre-workout?", or "Does the lasting increase in stable nitric oxide metabolites McKinley-Barnard and her colleagues observed in the CIT + GSH group actually have meaningful health-effects?" still have to be addressed, before one can wholeheartedly recommend taking (probably pretty expensive) citrulline + GSH supplements | Comment on Facebook!

References:

• Ghigo, D., et al. "Correlation between nitric oxide synthase activity and reduced glutathione level in human and murine endothelial cells." Amino acids 10.3 (1996): 277-281.
• Hofmann, Heinrich, and Harald HHW Schmidt. "Thiol dependence of nitric oxide synthase." Biochemistry 34.41 (1995): 13443-13452. 
• McKinley-Barnard, Sarah, et al. "Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis." Journal of the International Society of Sports Nutrition 12.1 (2015): 27.