Tsuda Y, Murakami R, Yamaguchi M, Seki T. Acute supplementation with an amino acid mixture suppressed the exercise-induced cortisol response in recreationally active healthy volunteers: a randomized, double-blinded, placebo-controlled crossover study. J Int Soc Sports Nutr. 2020;17(1):39.
To determine the effects of an acute, single dose of an amino acid mixture containing arginine, valine, and serine on male participants with an established high cortisol response to exercise
Randomized, double-blinded, placebo-controlled crossover study
Capsules containing either 1.8 g of arginine, 1.1 g of valine, and 0.1 g of serine or placebo (empty capsules) 30 minutes before participants carried out an exercise trial on a cycle ergometer (Aerobike 75XLIII) at 50% VO2 max for 80 min with a 3-min rest at the midpoint. Researchers gave participants a cup containing the amino acid mixture or the placebo and instructed them to swallow all of the capsules, without handling them, to maintain the blinding of placebo.
To prevent dehydration, subjects drank equal amounts of water during a 3-min rest.
According to the study authors, indirect actions of the aminos acids may explain the decrease in exercise-induced cortisol.
After a 1-week washout period, participants returned to cross over to the other arm of the study.
Researchers collected brachial vein blood samples immediately before and after exercise.
Twenty “recreationally active” males aged 20 to 39 years (mean 32.3 ± 1.2 years), mean body mass index (BMI) 22.3 ± 0.4. After removal of 5 participants due to abnormal blood analysis or protocol deviations, 15 participants contributed to the final analysis.
Study Parameters Assessed
- Plasma cortisol (mcg/dL)
- Adrenocorticotropic hormone (ACTH, pg/mL)
- Cortisol/ACTH ratio
- Blood glucose (mg/dL)
- Plasma lactate (mg/dL)
- Plasma ammonia (mcg/dL)
- Serum creatine phosphokinase (CPK, U/L)
- Serum total ketone bodies (µmol/L)
- Serum free fatty acids (mEq/L)
Primary Outcome Measures
Plasma cortisol concentration changes in blood within each group (intervention and placebo) and between groups
Cortisol: In the placebo group, postexercise plasma cortisol was significantly higher than preexercise cortisol (9.51 ± 0.85 vs 14.39 ± 2.15, P<0.05), while there was no significant difference in the treatment group (9.71 ± 0.93 vs 9.99 ± 1.23, P=0.846).
ACTH: In the placebo group, plasma ACTH significantly increased postexercise (24.21 ± 2.91 vs 53.17 ± 6.97, P<0.01), while in the treatment group the change was not significant (27.33 ± 3.60 vs 46.92 ± 10.41, P=0.057).
Cortisol/ACTH ratio: Participants in both the placebo and treatment groups showed a significant increase in cortisol/ACTH ratio after exercise compared to before exercise (P<0.01).
Cortisol: The pre- to post-exercise increase in plasma cortisol was significantly lower in the treatment group compared to placebo (0.28 [−2.75, 3.31] vs 4.87 [0.89, 8.86], P<0.05).
ACTH: There was no significant difference between the 2 groups for the changes in plasma ACTH during exercise (28.96 [13.5, 44.4] for the placebo group vs. 19.59 [−0.7, 39.8] for the treatment group, P=0.454).
Cortisol/ACTH ratio: The changes in the cortisol/ACTH ratio before and after exercise were not significantly different between the 2 groups.
Blood glucose, plasma lactate, plasma ammonia, serum CPK, serum total ketone body, and serum free fatty acid all significantly changed postexercise compared to pre-exercise (P<0.01) within each group. All of these analytes significantly increased after exercise, except for blood glucose, which significantly decreased in both groups (P<0.01).
When the amino acid intervention group was compared to the placebo, however, there were no significant differences between the groups for any of the aforementioned analytes.
Cortisol is secreted during vigorous exercise in response to blood glucose depletion. The physiological effect of cortisol is to maintain circulating glucose by increasing glycogen breakdown (glycogenolysis) in muscle and the liver. This is generally due to enhanced secretion of ACTH from the pituitary, which stimulates cortisol release from the adrenal gland.
Interestingly, plasma cortisol increase postexercise was blunted in the amino acid group compared to placebo even though there was no significant difference in ACTH between the 2 groups. Since the ACTH was not significantly decreased with ingestion of the amino acid mixture, the mechanism of action leading to the suppressed cortisol response is unclear.
According to the study authors, indirect actions of the aminos acids may explain the decrease in exercise-induced cortisol. Arginine promotes lipid metabolism,1,2 which may help maintain blood glycogen or glucose levels. Valine (and leucine, but not isoleucine) has been shown to reduce exercise-induced increase in cortisol in rats.3 And serine may enhance production of phosphatidylserine, which was shown in a clinical trial to reduce exercise-induced cortisol.4
While there was a statistically significant reduction in post-exercise cortisol in those who took the amino acid combination, the clinical relevance is unclear. The researchers did not test VO2 max, fatigue, perceived exertion or recovery time. Doing so would have provided additional data to understand if the biochemical changes translated into changes in performance as well.
A previous study done by the same researchers evaluated chronic ingestion (14 days) of the same combination of amino acids and found benefit.5 In that study, volunteers took twice the dose—3.6 g of arginine, 2.2 g of valine, and 0.2 g of serine—for 14 days. They then exercised by cycling, and as with the current study, measurements were taken after exercise. The subjective ratings of fatigue based on a visual analog scale (VAS) and a rating of perceived exertion (RPE) significantly improved compared to placebo. Additionally, the increases in serum total ketone bodies during exercise and plasma tryptophan/branched-chain amino acids (BCAA) were significantly lower in the amino acid group compared to placebo. This implies that long-term and acute dosing of amino acids likely have differing effects.
- Fu WJ, Haynes TE, Kohli R, et al. Dietary L-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J Nutr. 2005;135(4):714-721.
- McKnight JR, Satterfield MC, Jobgen WS, et al. Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health. Amino Acids. 2010;39(2):349-357.
- Tsuda Y, Iwasawa K, Yamaguchi M. Acute supplementation of valine reduces fatigue during swimming exercise in rats. Biosci Biotechnol Biochem. 2018;82(5):856-861.
- Starks MA, Starks SL, Kingsley M, Purpura M, Jager R. The effects of phosphatidylserine on endocrine response to moderate intensity exercise. J Int Soc Sports Nutr. 2008;5:11.
- Tsuda Y, Yamaguchi M, Noma T, Okaya E, Itoh H. Combined effect of arginine, valine, and serine on exercise-induced fatigue in healthy volunteers: a randomized, double-blinded, placebo-controlled crossover study. Nutrients. 2019;11(4):862.
- Blomstrand E, Perrett D, Parry-Billings M, Newsholme EA. Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat. Acta Physiol Scand. 1989;136(3):473-481.
- Blomstrand E, Møller K, Secher NH, Nybo L. Effect of carbohydrate ingestion on brain exchange of amino acids during sustained exercise in human subjects. Acta Physiol Scand. 2005;185(3):203-209.
- Donati Zeppa S, Agostini D, Gervasi M, et al. Mutual interactions among exercise, sport supplements and microbiota. Nutrients. 2019;12(1):17.
- Smriga M, Kameishi M, Tanaka T, Kondoh T, Torii K. Preference for a solution of branched-chain amino acids plus glutamine and arginine correlates with free running activity in rats: involvement of serotonergic-dependent processes of lateral hypothalamus. Nutr Neurosci. 2002;5(3):189-19
- Newsholme EA, Blomstrand E. Branched-chain amino acids and central fatigue. J Nutr. 2006;136(1 Suppl):274s-276s.