Glutathione Enhances Gains from L-Citrulline?! Not so fast, Setria..

Setria Glutathione Citrulline

We’re getting tons of emails from trade magazines about this study, so we decided to look into it. But what we found did not exactly meet expectations.

Glutathione is an important and powerful antioxidant used to prevent oxidative stress and damage to cells in everything from winemaking to skincare products. Too much oxidative stress, caused by free radicals in the bloodstream, is linked to heart disease, Alzheimer’s Disease,[1] Parkinson’s Disease,[2] chronic fatigue, depression, and more. Since exercise can also temporarily increase oxidative stress[3] — contributing to soreness and fatigue — athletes should also be interested in preventing its prolonged release.

Glutathione isn’t orally bioavailable – is there a better “carrier”?

The benefits of glutathione supplementation would seem obvious – but until recently, due to its poor oral bioavailability,[4] if you wanted a glutathione supplement you’d have to schedule an IV drip at your local naturopathic or alternative medicine clinic.

Some are hoping that to change soon, due to a new “performance blend” of glutathione and L-Citrulline manufactured by Kyowa Hakko, makers of Cognizin citicoline and Sustamine L-Glutamine. A new study suggests it may have additional benefits for athletes.

But unfortunately, upon closer look, we have some serious concerns with the way this study was configured.

The new Baylor Glutathione Citrulline Performance Study

Baylor Department of Health, Human Performance, and Recreation

At time of press, Baylor’s researchers did not respond to our writing team’s request for comment.

The double-blind study, conducted at Baylor University with funding from Kyowa Hakko,[5] suggested that a blend of glutathione and L-citrulline, marketed under the name Setria Performance Blend, may increase lean body mass – but only temporarily!

75 male participants were given either 2.2g Setria Performance Blend, 2g L-citrulline-malate, or 2.52g placebo for eight weeks of resistance training, then measured for changes in lean mass and 1RM (one rep max) on the bench and leg press. (HINT! Read the last sentence again. Can you find the confound?) The researchers hypothesized that the glutathione would help prevent oxidative stress while synergizing with the ergogenic effects of the l-citrulline. This would allow it to stay in the bloodstream longer for increased nitric oxide uptake into the muscles, which would in turn lead to an increase in strength and lean body mass via more efficient muscle protein synthesis.

Better gains after 4 weeks…

Glutathione Citrulline Strength

There were no statistically significant strength increases on bench press, while all were significantly increased in leg press — but not significantly different from each other.

After four weeks, the researchers reported an increase in muscle mass and bench press and leg press strength for all three groups. The researchers went on to note that the most significant difference in strength and lean mass was in the group supplementing with Setria Performance Blend – a greater increase in strength and lean body mass than either the group receiving the placebo or the group receiving citrulline malate alone.

…but things even out after another 4

However, after another four weeks of testing, the gap had closed, leading to no statistically significant difference in lean body mass, fat mass, or water retention between the groups. Additionally, there was no noticeable difference in strength between the three groups – even from those with greater lean body mass!

The researchers speculated that the increased lean body mass was due to more efficient muscle protein synthesis from the less-degraded l-citrulline in the bloodstream. The benefits of l-citrulline are well-documented.

Glutathione Citrulline Lean Mass

So many questions here. Why did things get worse in the second four weeks for the Setria group? Why did the placebo group lose lean mass? Were they “over-reaching” or “under eating” as the researchers hypothesize, or was this just a poorly run resistance training study?

The confound: a lower dose of citrulline malate?!

However, different forms of l-citrulline were used between the groups, so it’s tough to say for sure how the glutathione made a difference! Realize that citrulline malate contains roughly 56.6% citrulline, so we’re really comparing 2.2g Setria (consisting of 200mg glutathione + 2g L-citrulline) against 1.13g citrulline (the rest being malic acid).

Why not compare apples against apples? Why use citrulline malate, which yields a lower dose of citrulline? This alone obfuscates anything you can hope to gleam from the study.

Instead, the researchers were also unsure why the gap closed after an additional four weeks of study, but offered the explanations that the different groups may not have been eating enough to get the full benefit of their training, or, conversely, had overtrained.

Further drawbacks of this study

Beyond the citrulline malate confound, remember that Kyowa Hakko funded the study, and one of their employees also designed the experiment, performed the statistical analysis, and assisted in the preparation of the manuscript! Flashbacks to the government’s cover-up of DMAA’s basis in nature, anybody?

Biased Research

So the company funding the study,with a material interest in the study, also had an employee do the math and help write the manuscript.

Meanwhile, the data doesn’t really back up the conclusions nor the headlines in other trade magazines – the correlations really aren’t that strong between the different groups and its rather sporadic.

The fact that the lean body mass decreased from four to eight weeks in the Setria and placebo groups suggests bad experimental design (the researchers hypothesized “eating less” and “over-reaching”) — these variables should be better accounted for in a proper study.

Meanwhile, nothing interesting happened in the strength category — nobody had statistically significant gains in bench press, and everyone had similar increases in leg press that were not significantly different from each other.

Overall, there are just too many red flags here to take this study seriously.

Previous three-phase study showed similar “mixed” results

Setria Nitric Oxide

In 2015, we saw straight citrulline yield higher NOx (nitrate + nitrite) levels than citrulline + glutathione when measured immediately post workout. So… should athletes just stick to citrulline alone pre workout??

This follows a three-phase study performed by the same Baylor / Kyowa Hakko team (Sarah McKinley-Barnard, Tom Andre, Kyowa Hakko’s Masahiko Morita, and Darryn S. Willoughby) that was published in 2015.[6] In that study, the third phase — performed on humans for seven days — actually did compare L-citrulline alone vs. L-citrulline + glutathione, measuring nitric oxide, nitrite, and cGMP levels.

The results were mixed, at best. For instance, when measuring nitric oxide levels immediately post workout, citrulline alone actually outperformed citrulline + glutathione, and several other parameters failed to reach statistical significance.

All things considered, this leads us to wonder if this whole glutathione + citrulline idea is simply just a dead end when it comes to actual human performance. In theory, it’s good. In rats, it’s good. In reality, nothing noticeably interesting really seems to be happening.

Why not just take NAC?

Alternatively, you could take a large quantity of N-Acetyl Cysteine (NAC), a precursor to glutathione that helps your body produce more.[7] It turns out that NAC supplementation enhances muscle cysteine and glutathione levels and prevents fatigue during endurance training in athletes,[8] which may seem like a more bioavailable solution in the first place.

NAC and Nitric Oxide don’t play well for performance

NutraBio L-Citrulline

If nothing else, we learned once again that L-Citrulline is great for nitric oxide production and possibly lean mass. But next time we need to compare apples to apples.

However, NAC has its own limitations, which is why glutathione supplementation is still being explored. Not only does NAC alone not appear to help muscle protein synthesis or nitric oxide metabolism like Setria Performance Blend was hoped to, some studies also suggest that NAC may inhibit the body’s nitric oxide production by interfering with the absorption of nitrite in the kidneys![9] Finding an appropriate “carrier” for glutathione could still have benefits, but due to the confounds in this study, we cannot yet be sure that citrulline is that molecule.

More — and better — research is required

Clearly more research is needed, but the implications of an orally bioavailable version are exciting and we hope someone can nail it someday soon. However, the citrulline / citrulline malate confound makes this study practically useless, even for those who are looking for a solid four weeks of “beginner gains” per the headlines.

No doubt, Setria can be useful because L-citrulline is useful, but is this glutathione really doing anything? We just don’t know until there’s a true 1:1 comparison and less conflicted research.

Until then, we are not impressed.

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About the Author: Mike Roberto

Mike Roberto

Mike Roberto is a research scientist and water sports athlete who founded PricePlow. He is a biohacker with extensive experience in supplementation and dietary modification, whose personal expertise stems from several "n=1" experiments done on himself.

Mike's goal is to bridge the gap between nutritional research scientists and non-academics who seek to better their health in a system that has catastrophically failed the public.

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References

  1. Valko, M, et al; “Free radicals and antioxidants in normal physiological functions and human disease”; The International Journal of Biochemistry & Cell Biology; Volume 39, Issue 1, 2007, Pages 44-84; https://www.sciencedirect.com/science/article/pii/S1357272506002196?via%3Dihub
  2. Hwang, Onyou. “Role of Oxidative Stress in Parkinson’s Disease.” Experimental Neurobiology 22.1 (2013): 11–17; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620453/
  3. Powers, Scott K, and Malcolm J. Jackson; “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production.” Physiological reviews 88.4 (2008): 1243–1276; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909187/
  4. Allen, Jason, and Ryan D. Bradley. “Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human Volunteers.” Journal of Alternative and Complementary Medicine 17.9 (2011): 827–833; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162377/
  5. Paul Hwang, Flor E. Morales Marroquín, Josh Gann, Tom Andre, Sarah McKinley-Barnard, Caelin Kim, Masahiko Morita, and Darryn S. Willoughby; “Eight weeks of resistance training in conjunction with glutathione and L-Citrulline supplementation increases lean mass and has no adverse effects on blood clinical safety markers in resistance-trained males”; Journal of the International Society of Sports Nutrition; 15:30; 2018; https://jissn.biomedcentral.com/articles/10.1186/s12970-018-0235-x
  6. Sarah McKinley-Barnard, Tom Andre, Masahiko Morita, Darryn S. Willoughby; “Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis”; Journal of the International Society of Sports Nutrition; 2015; 12:27; https://jissn.biomedcentral.com/articles/10.1186/s12970-015-0086-7
  7. Atkuri, Kondala R. et al. “N-Acetylcysteine – a Safe Antidote for Cysteine/glutathione Deficiency.” Current opinion in pharmacology 7.4 (2007): 355–359; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540061/
  8. Medved, I, et al; “N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals”; J Appl Physiol (1985); 97(4):1477-85; https://www.ncbi.nlm.nih.gov/pubmed/15194675/
  9. Dimitrios Tsikas, et al; “N-Acetylcysteine (NAC) inhibits renal nitrite and nitrate reabsorption in healthy subjects and in patients undergoing cardiac surgery: Risk of nitric oxide (NO) bioavailability loss by NAC?”; International Journal of Cardiology; Volume 177, Issue 1, Pages 30–33; November 15, 2014; https://www.internationaljournalofcardiology.com/article/S0167-5273(14)01829-4/pdf

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