L-Ornithine an Anti-Stress Agent: Lower Cortisol, Higher DHEA, Better Sleep W/ Only 400mg of Ornithine Pre-Bed. Plus: Mini-Review of Add. Benefits - Burns, Gut Health, etc.

Stressed? Maybe ornithine can help. Or is this study just a hoax!?

Sounds like marketing shenanigan, right? "Lower Cortisol, Higher DHEA, Better Sleep W/ Only 400mg of Ornithine Pre-Bed." Ok, if it was marketing it would probably say "with only 5g of ornithine." I mean, 400mg that's not enough to generate significant revenues - is it?

But before we get to the marketing side of things, let's first look at the science, researchers from the Research Laboratories for Health Science & Food Technologies present in a recent paper in the Nutrition Journal, an open-access journal which charges scientists a certain fee for processing their papers.

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In their 8 week study, Mika Miyake et al. provided fifty-two apparently healthy Japanese adults who had previously felt slightly stressed and fatigue with either L-ornithine (400 mg/day) or placebo capsules.

The participants were advised to take one (400mg) capsule everyday before going to bed for eight weeks. At the end of the study period, all participants arrived at the laboratory fasted for blood sampling and a handful of other tests.

Figure 1: Effect of L-ornithine supplementation on serum stress markers.Means of the change from 0 weeks of each stress marker level (A, DHEA-S; B, cortisol; C, cortisol/DHEA-S) to 2, 4, and 8 weeks: mean ± SE. White circles (○) indicate the placebo and black circles (●) indicate L-ornithine. (Miyake. 2014)

The blood was analyzed for serum cortisol and DHEAS levels. In addition, the perceived mood and quality of sleep were measured by the Profile of Mood States (POMS) tests, the Athens Insomnia Scale (AIS), and Ogri-Shirakawa-Azumi sleep inventory MA version (OSA-MA).

Figure 2: Effect of L-ornithine supplementation on OSA.Means of the change from 0 weeks of each OSA score (A, sleepiness on rising; B, initiation and maintenance of sleep; C, frequent dreaming; D, refreshing; E, sleep length) to 1, 2, 3, 4, 5, 6, 7 and 8 weeks: mean ± SE. White circles (○) indicate the placebo and black circles (●) indicate L-ornithine

Significant changes were observed for serum cortisol levels and the cortisol/DHEA-S ratio. Both were significantly decreased in the L-ornithine group in comparison with the placebo group. The POMS and OSA-MA tests (not shown in Figure 1) revealed that similar beneficial effects occurred for anger (sign. reduced) and perceived sleep quality, which were both improved in the L-ornithine group compared to the placebo group.

Is there anything else ornithine is good for? Sugino et al. report that l-ornithine supplementation (2-6g/day) attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism (2008). It enhances wound healing in mice and man (Shi. 2002; Coudray-Lucas. 2000). It improves muscle protein synthesis after surgery (Wernerman. 1987). Just like arginine, it holds the potential to improve gut health (Cynober. 1994; de Oca. 1997; Raul. 1995). But it is, unlike arginine, is no insulin secretagogue (=won't trigger an insulin release; Bucci. 1992) - Bottom line: Lots of potential, but nothing that would make it a "must have" supplement.

Quite impressive results, considering the fact that we are talking about a minimal amount of an amino acids fitness enthusiasts know mainly as an ineffective growth hormone booster (Lambert. 1993). What did you say? "Bias"? Well, the product used in the study is produced by the Kyowa Hakko Bio Company a company that is an affiliate of Kirin Company Limited, to which the authors belong, but that does not mean that the results are inaccurate.

Nevertheless, I would advise you to keep it in mind before you buy a 5kg bag of ornithine as an anti-stress treatment for the next 10 years - maybe 25g for an 8-week test-run are a better idea. Not necessarily because of a potential bisa, but rather in view of the small number of study participants  and the fact that we don't know exactly the mechanism that triggers the increase in DHEA, decrease in cortisol and overall anti-stress effect.

Even in animal models, where similar effects on the HPTA have been observed (Kurata. 2012), it is not clear, whether all this may in fact be a result of the  influence L-ornithine has on the urea cycle (converts ammonia to urea in the liver), as some scientists apparently believe. Overall, we are thus dealing with an interesting finding, but one that needs independent confirmation from a larger trials, and one I would have significantly more faith in if I know exactly how it came about (mechanistically) | Comment on Facebook!

References:

• Bucci, L. R., et al. "Ornithine supplementation and insulin release in bodybuilders." International journal of sport nutrition 2.3 (1992): 287-291. 
• Coudray-Lucas, Colette, et al. "Ornithine [alpha]-ketoglutarate improves wound healing in severe burn patients: A prospective randomized double-blind trial versus isonitrogenous controls." Critical care medicine 28.6 (2000): 1772-1776.
• Cynober, L. "Can arginine and ornithine support gut functions?." Gut 35.1 Suppl (1994): S42-S45.
• de Oca, Javier, et al. "Effect Of Oral Supplementation Of Ornithine-[Alpha]-Ketoglutarate On The Intestinal Barrier After Orthotopic Small Bowel Transplantation." Transplantation 63.5 (1997): 636-639.
• Kurata, Koji, et al. "Orally administered l-ornithine reduces restraint stress-induced activation of the hypothalamic-pituitary-adrenal axis in mice." Neuroscience letters 506.2 (2012): 287-291.
• Lambert, M. I., et al. "Failure of commercial oral amino acid supplements to increase serum growth hormone concentrations in male body-builders." International Journal of Sport Nutrition 3.3 (1993): 298-305.
• Miyake, Mika, et al. "Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers." Nutrition Journal 13.1 (2014): 53.
• Raul, Francis, et al. "Functional and metabolic changes in intestinal mucosa of rats after enteral administration of ornithine α-ketoglutarate salt." Journal of Parenteral and Enteral Nutrition 19.2 (1995): 145-150.
• Shi, Han Ping, et al. "Effect of supplemental ornithine on wound healing." Journal of Surgical Research 106.2 (2002): 299-302.
• Sugino, Tomohiro, et al. "L-ornithine supplementation attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism." Nutrition research 28.11 (2008): 738-743.
• Wernerman, J., et al. "Ornithine-alpha-ketoglutarate improves skeletal muscle protein synthesis as assessed by ribosome analysis and nitrogen use after surgery." Annals of surgery 206.5 (1987): 674.

High and Low Dose of L-Arginine Equally Ineffective in Promoting Nitric Oxide Synthesis in Young Active Men at Rest - GH and IGF-1 Response Negligible.

Image 1: Arginine based first generation
"nitric oxide booster", such as BSN's
NO-Xplode still have a huge fanbase

"No NO from l-arginine", you probably remember this or similar headlines from a few years ago, when the first studies seemed to indicate that l-arginine, the main "working" ingredient in all the (over-)hyped nitric oxide (NO) boosters that had become an integral part of the line-up of each and every major supplement producer was found not to increase the amount of nitric oxide in their consumers' bloodstream. Although these results stand in stark contrast to the early studies using intravenous infusion of l-arginine, which established the myth of the NO and growth hormone boosting effects of 2-amino-5-guanidinovaleric acid (l-arginine),  a 2007 study by Malinauskas et al. (Malinauskas. 2007) found that 8% of the male student athletes who participated in their survey were still interested in the ingestion of l-arginine containing supplements. Thus, it does not come as a surprise that - even with the rise of the so-called 2nd generation pre-workout products - the classic, l-arginine based products such as NO XPlode, SuperPump and Co. still have a huge fanbase, the majority of whose members, asked about why they are taking the respective product, will certainly answer "for the pump".

A very recent study by Scott C. Forbes and Gordon J. Bell , published in the Journal of Appl. Physiol. Nutr. Metab. (Forbes. 2011), is yet only the latest in series of investigations, which puts into question, how much of a placebo effect may be involved in the real-world observations of "enormous pumps and vasolidation" many consumers of l-arginine based preworkout products report. 14 weight training (4 sessions per week) male participants, who had been free from other nutritional supplements for at least 12 weeks participated in the study. In a double-blind repeated measure design with 3 testing conditions (baseline, placebo/l-arginine, l-arginine/placebo) that were separated by 7 days, the subjects received either high or low dose (0.075 (low) or 0.150g/kg (high)) l-arginine or placebo (flour) solved in 500ml of water after a 10 hour fast. Interestingly,

plasma concentrations significantly increased (p < 0.05) to a similar level [+178% and +204%] above resting values, respectively)at all time points in both the low- and high-dose conditions, while there was no change in the placebo condition over time.

Or, in other words, there was a tight regulation of maximal l-arginine levels in the plasma of the subjects, either via decreased absorption or increased metabolism of the orally ingested l-arginine (it is estimated that with increasing doses >40% of the ingested arginine is degraded by the small intestine). 

Apart from the issue of gastro-intestinal distress, simply increasing the dosage will thus not further increase the availability of arginine in the blood stream, which at the concentration that were observed in this study also failed to induce "a significant main effect for insulin (p < 0.05)". Previous studies using intravenously administered arginine had shown increased insulin secretion and, in some cases, onset hypoglycemia. In absence of these insulinogenic effects, however, there were also

no significant difference over time or between conditions for GH (Fig. 3), IGF-1 (Fig. 4), or glucose, (p > 0.05);

all that, despite the fact that the area under the curve (iAUC), a measure for the total amount of l-arginine that was taken up and metabolized by the subjects, did in fact reveal "a significant difference between the L-arginine conditions and placebo and between the high and low relative doses." With regard to the nitric oxide production, this dose dependent increase in plasma arginine levels turned out to be useless, or in fact counterproductive, as contrary to expectation the  area under the curve (iAUC) "for NOx with the high relative dose was significantly lower than that for the low dose of L-arginine" - a clear sign that "overuse" of large amounts l-arginine could diminishes the already negligible on nitric oxide production at rest.

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Before totally discarding arginine, however, I suggest you tune in to tomorrow's episode of Super Human Radio. In the 2nd installment of the "Amino Acids for Super Humans" series, I will provide further insights into what we really know about arginine and its "metabolic children" ornithine and citrulline and how they may effect how you look, feel and perform in and outside the gym.