Inositol-Stabilized Arginine Silicate Improves Post-Exercise Cognitive Function in Recreationally Active, Healthy Males: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

Main Article Content

Malkanthi Evans
Alison C McDonald
David C Crowley
Nisrine Zakaria
Najla Guthrie


Cognitive flexibility, Sports performance, Nitric oxide


Introduction: At all competition levels, athletic performance depends on simultaneously handling physiological and cognitive demands. The objective of this study was to determine the efficacy of a patented complex of inositol-stabilized arginine silicate (ASI; Nitrosigine®) to improve cognitive performance following intense exercise.
Methods: Twenty-four healthy, recreationally active males (26.50 ± 4.85 years, 25.31 ± 2.52 kg/m2 BMI) were enrolled in this randomized, double-blind, placebo-controlled crossover study. A single oral dose of 1500 mg ASI or placebo was administered 30 minutes before a maximally graded exercise test. Prior to and following exercise, cognitive function was assessed via the Trail Making Test (TMT). Safety was evaluated at end of study.
Results: Following intense exercise, ASI reduced the time to complete TMT Part A and B (2.80 ± 5.97, 5.54 ± 3.77 seconds, respectively) compared to increased time with placebo (19.82 ± 4.58, 7.68 ± 5.06 seconds, respectively). Differences between ASI and placebo were statistically significant (p = 0.01 TMT A, p = 0.05 TMT B). ASI was found to be safe and well- tolerated with no related adverse events.
Conclusion: Intense exercise resulted in impaired cognitive function, which was prevented by pre-exercise ASI consumption. Future research should examine the efficacy of ASI in athletes, as improvement in cognitive function would be advantageous through enhanced ability to process complex information in quickly changing games or events.

Abstract 442 | PDF Downloads 115


1. Pomportes L, Brisswalter J, Hays A, Davranche K. Effects of Carbohydrate, Caffeine, and Guarana on Cognitive Performance, Perceived Exertion, and Shooting Performance in High-Level Athletes. Int J Sports Physiol Perform. 2019;14(5):576-582.
2. Thompson C, Wylie LJ, Fulford J, et al. Dietary nitrate improves sprint performance and cognitive function during prolonged intermittent exercise. Eur J Appl Physiol. 2015;115(9):1825-1834.
3. Cona G, Cavazzana A, Paoli A, Marcolin G, Grainer A, Bisiacchi PS. It's a Matter of Mind! Cognitive Functioning Predicts the Athletic Performance in Ultra-Marathon Runners. PLoS One. 2015;10(7):e0132943.
4. Verburgh L, Scherder EJ, van Lange PA, Oosterlaan J. Executive functioning in highly talented soccer players. PLoS One. 2014;9(3):e91254.
5. Marcora SM, Staiano W, Manning V. Mental fatigue impairs physical performance in humans. J Appl Physiol (1985). 2009;106(3):857-864.
6. Lambourne K, Tomporowski P. The effect of exercise-induced arousal on cognitive task performance: a meta- regression analysis. Brain Res. 2010;1341:12-24.
7. Ament W, Verkerke GJ. Exercise and fatigue. Sports Med. 2009;39(5):389-422.
8. Eudy AE, Gordon LL, Hockaday BC, et al. Efficacy and safety of ingredients found in preworkout supplements.
Am J Health Syst Pharm. 2013;70(7):577-588.
9. National Institutes of Health. Dietary Supplements for Exercise and Athletic Performance. Published 2017. Accessed 2017.
10. Alvares T, Meirelles C, Bhambhani Y, Paschoalin V, Gomes PS. L-Arginine as a Potential Ergogenic Aid in Healthy Subjects. Sports medicine. 2011;41:233-248.
11. Brooks JR, Oketch-Rabah H, Low Dog T, et al. Safety and performance benefits of arginine supplements for military personnel: a systematic review. Nutr Rev. 2016;74(11):708-721.
12. Zak RB, Camic CL, Hill EC, Monaghan MM, Kovacs AJ, Wright GA. Acute effects of an arginine-based supplement on neuromuscular, ventilatory, and metabolic fatigue thresholds during cycle ergometry. Appl Physiol Nutr Metab. 2015;40(4):379-385.
13. Forbes SC, Harber V, Bell GJ. The acute effects of L-arginine on hormonal and metabolic responses during submaximal exercise in trained cyclists. Int J Sport Nutr Exerc Metab. 2013;23(4):369-377.
14. Kalman D, Harvey PD, Perez Ojalvo S, Komorowski J. Randomized Prospective Double-Blind Studies to Evaluate the Cognitive Effects of Inositol-Stabilized Arginine Silicate in Healthy Physically Active Adults. Nutrients. 2016;8(11).
15. Kocoloski GM, Crecelius AR. Effects of Single-Dose Dietary Nitrate on Oxygen Consumption During and After Maximal and Submaximal Exercise in Healthy Humans: A Pilot Study. Int J Exerc Sci. 2018;11(3):214-225.
16. Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci. 2007;8(10):766-775.
17. Smriga M, Ando T, Akutsu M, Furukawa Y, Miwa K, Morinaga Y. Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans. Biomed Res. 2007;28(2):85-90.
18. Paul V, Perumal E. Involvement of nitric oxide in learning & memory processes. The Indian journal of medical research. 2011;133:471-478.
19. Dubey H, Gulati K, Ray A. Effects of Nitric Oxide (NO) Modulators on Cognitive Function and Brain Oxidative Stress in Experimental Model of Alzheimer’s Disease in Rats. Journal of Pharmacological Reports. 2018; 2(2):1-7.
20. Proctor SD, Kelly SE, Vine DF, Russell JC. Metabolic effects of a novel silicate inositol complex of the nitric oxide precursor arginine in the obese insulin-resistant JCR:LA-cp rat. Metabolism. 2007;56(10):1318-1325.
21. Kalman DS, Feldman S, Samson A, Krieger DR. A clinical evaluation to determine the safety, pharmacokinetics, and pharmacodynamics of an inositol-stabilized arginine silicate dietary supplement in healthy adult males. Clin Pharmacol. 2015;7:103-109.
22. Juturu V, Komorowski J. Arginine silicate complex and use thereof. cipo/cpd/eng/patent/2494155/summary.html. Published 2011. Accessed 2017.
23. Rood-Ojalvo S, Sandler D, Veledar E, Komorowski J. The benefits of inositol-stabilized arginine silicate as a workout ingredient. Journal of the International Society of Sports Nutrition. 2015;12(Suppli1):P14.
24. Huijgen B, Leemhuis S, Kok N, et al. Cognitive Functions in Elite and Sub-Elite Youth Soccer Players Aged 13 to 17 Years. PLoS One. 2015;10(12):e0144580.
25. Marsh DW, Richard LA, Verre AB, Myers J. Relationships among balance, visual search, and lacrosse-shot accuracy. J Strength Cond Res. 2010;24(6):1507-1514.
26. Fossum B, Holmberg H, Reinvang I. Spatial and symbolic factors in performance on the Trail Making Test. Neuropsychology. 1992;6(1):71-75.
27. Gaudino EA, Geisler MW, Squires NK. Construct validity in the Trail Making Test: what makes Part B harder? J Clin Exp Neuropsychol. 1995;17(4):529-535.
28. Kortte K, Horner M, Windham W. The Trail Making Test, Part B: Cognitive Flexibility or Ability to Maintain Set? Applied neuropsychology. 2002;9:106-109.
29. Jung YP, Earnest CP, Koozehchian M, et al. Effects of acute ingestion of a pre-workout dietary supplement with and without p-synephrine on resting energy expenditure, cognitive function and exercise performance. J Int Soc Sports Nutr. 2017;14:3.
30. Meeusen R, Decroix L. Nutritional Supplements and the Brain. Int J Sport Nutr Exerc Metab. 2018;28(2):200-211.
31. Han DH, Park HW, Kee BS, Na C, Na DH, Zaichkowsky L. Performance enhancement with low stress and
anxiety modulated by cognitive flexibility. Psychiatry Investig. 2011;8(3):221-226.
32. Kalman D, Harvey P, Perez Ojalvo S, Komorowski J. Randomized Prospective Double-Blind Studies to Evaluate the Cognitive Effects of Inositol-Stabilized Arginine Silicate in Healthy Physically Active Adults. Nutrients. 2016;8(11):736. 33. Vestberg T, Reinebo G, Maurex L, Ingvar M, Petrovic P. Core executive functions are associated with success in young elite soccer players. PLoS One. 2017;12(2):e0170845.