Many sports involve repeated bouts of high-intensity exercise. High-intensity exercise is compromised, however, by the early onset of exercise-induced fatigue. Metabolic by-products, ion dysbalance and amount of phosphocreatine are considered the main peripheral causes of fatigue during high-intensity exercise. Intake of nutritional ergogenic aids is commonplace to enhance performance of high-intensity exercise by offsetting the potential mechanisms of fatigue. Creatine, probably one of the best known nutritional aids to enhance performance of high-intensity exercise, has convincingly substantiated its ergogenic potential. Although multi-ingredient supplements are now common, the justification for effectiveness is mostly based on observations with single intake of those ingredients. In this narrative review, the main focus is on the evidence of the effect of co-ingestion of ergogenic aids on performance of high intensity exercise for which the single intake has shown beneficial effects on high-intensity performance.
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Sahlin K. Muscle energetics during explosive activities and potential effects of nutrition and training. Sports Med. 2014;44(Suppl 2):S167–73.
Lanham-New SA, Stear S, Shirreffs S, et al, editors. Sport and exercise nutrition. Chichester: Wiley; 2011.
Enoka RM, Duchateau J. Muscle fatigue: what, why and how it influences muscle function. J Physiol. 2008;586(1):11–23.
Maclaren D, Morton JP, editors. Biochemistry for sport and exercise metabolism. Chichester: Wiley; 2011.
Bagchi D, Nair S, Sen CH. Nutrition and enhanced sports performance: muscle building, endurance and strength. New York: Academic; 2013.
Margolis LM, Pasiakos SM. Optimizing intramuscular adaptations to aerobic exercise: effects of carbohydrate restriction and protein supplementation on mitochondrial biogenesis. Adv Nutr. 2013;4(6):657–64.
Harris RC, Tallon MJ, Dunnett M, et al. The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis. Amino Acids. 2006;30(3):279–89.
Stephens TJ, McKenna MJ, Canny BJ, et al. Effect of sodium bicarbonate on muscle metabolism during intense endurance cycling. Med Sci Sports Exerc. 2002;34(4):614–21.
Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992;83(3):367–73.
Crowe MJ, Leicht AS, Spinks WL. Physiological and cognitive responses to caffeine during repeated, high-intensity exercise. Int J Sport Nutr Exerc Metab. 2006;16(5):528–44.
Tobias G, Benatti FB, de Salles Painelli V, et al. Additive effects of beta-alanine and sodium bicarbonate on upper-body intermittent performance. Amino Acids. 2013;45(2):309–17.
Kilding AE, Overton C, Gleave J. Effects of caffeine, sodium bicarbonate, and their combined ingestion on high-intensity cycling performance. Int J Sports Nutr Exerc Metab. 2012;22:175–83.
Newsholme EA. Basic aspects of metabolic regulation and their application to provision of energy in exercise. In: Poortmans JR, editor. Principles of exercise biochemistry, vol. 38. Basel: Karger; 1993. p. 52–88.
Newsholme EA. Application of knowledge of metabolic integration to the problem of metabolic limitations in sprints, middle distance, and marathon running. In: Poortmans JR, editor. Principles of exercise biochemistry, vol. 38. Basel: Karger; 1993. p. 230–47.
Hirvonen J, Rehunen S, Rusko H, et al. Breakdown of high energy phosphate compounds and lactate accumulation during short supramaximal exercise. Eur J Appl Physiol. 1987;56(3):253–9.
Hirvonen J, Nummela A, Rusko H, et al. Fatigue and changes of ATP, creatine phosphate, and lactate during 400-m sprint. Can J Sports Sci. 1992;17(2):141–4.
Sahlin K. Metabolic changes limiting muscle performance. In Saltin B, editor. Biochemistry of Exercise: Vol. 6. Champaign; Human Kinetics; 1986. pp 323–43.
Blomstrand E, Ekblom B, Newsholme EA. Maximum activities of key glycolytic and oxidative enzymes in human muscle from differently trained individuals. J Physiol. 1986;381:111–8.
Greenhaff PL, Casey A, Short AH, et al. Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary lifting exercise in man. Clin Sci (Lond). 1993;84(5):565–71.
Lehninger AL, Nelson DL, Cox MM. Principles of Biochemistry. 2nd ed. New York: Worth; 1995.
Meyer RA, Sweeney HL, Kushmerick MJ. A simple analysis of the “phosphocreatine shuttle”. Am J Physiol. 1984;246(5 Pt 1):C365–77.
Savabi F, Carpenter CL, Mohan C, et al. The polysome as a terminal for the creatine phosphate energy shuttle. Biochem Med Metab Biol. 1988;40(3):291–8.
Boobis LH. Metabolic aspects of fatigue during sprinting. In: Macleod R, Maughan M, Nimmo M, Reilly T, et al., editors. Exercise: Benefits, Limitations, and Adaptations. London: E&FN spon; 1987. p. 116–43.
Hultman E, Bergstrom M, Spriet LL, et al. Energy metabolism and fatigue. In: Taylor AW, Gollnick PD, Green HJ, et al., editors. Biochemistry of Exercise, vol. 7. Champaign, Il: Human Kinetics; 1990. p. 73–92.
Hultman E, Greenhaff PL. Skeletal muscle energy metabolism and fatigue during intense exercise in man. Sci Prog. 1991;75(298 Pt 3–4):361–70.
Storey KB, Hochachka PW. Activation of muscle glycolysis: a role of creatine phosphate in phosphofructokinase regulation. FEBS Lett. 1974;46(1):337–9.
Cheetham ME, Boobis LH, Brooks S, et al. Human muscle metabolism during sprint running. J Appl Physiol. 1986;61(1):54–60.
McCartney N, Spriet LL, Heigenhauser GJ, et al. Muscle power and metabolism in maximal intermittent exercise. J Appl Physiol. 1986;60:1164–9.
Spriet LL, Söderlund K, Bergstrom M, et al. Anaerobic energy release in skeletal muscle during electrical stimulation in men. J Appl Physiol. 1987;62:611–5.
Söderlund K, Hultman E. ATP and phosphocreatine changes in single human muscle fibers after intense electrical stimulation. Am J Physiol. 1991;261(6 Pt 1):E737–41.
Hultman E, Bergström J, Anderson NM. Breakdown and resynthesis of phosphorylcreatine and adenosine triphosphate in connection with muscular work in man. Scand J Clin Lab Invest. 1967;19(1):56–66.
Infante AA, Klaupiks D, Davies RE. Phosphorylcreatine consumption during single working contraction of isolated muscle. Biochim Biophys Acta. 1965;94:504–15.
Spande JI, Schottelius BA. Chemical basis of fatigue in isolated mouse soleus muscle. Am J Physiol. 1970;219(5):1490–5.
Edström L, Hultman E, Sahlin K, et al. The contents of high-energy phosphates in different fiber types in skeletal muscles from rat, guinea-pig and man. J Physiol. 1982;332:47–58.
Greenhaff PL, Nevill ME, Söderlund K, et al. The metabolic responses of human type I and II muscle fibres during maximal treadmill sprinting. J Physiol. 1994;478:149–55.
Söderlund K, Greenhaff P, Hultman E. Energy metabolism in type I and type II human muscle fibers during short term electrical stimulation at different frequencies. Acta Physiol Scand. 1992;144(1):15–22.
Tesch PA, Thorsson A, Fujitsuka N. Creatine phosphate in fiber types of skeletal muscle before and after exhaustive exercise. J Appl Physiol (1985). 1989;66(4):1756–9.
Balsom PD, Seger JY, Sjödin B, et al. Maximal intensity intermittent exercise: effect of recovery duration. Int J Sports Med. 1992;13(7):528–33.
Balsom PD, Seger JY, Sjödin B, et al. Physiological responses to maximal intensity intermittent exercise. Eur J Appl Physiol. 1992;65(2):144–9.
Bogdanis GC, Nevill ME, Lakomy HKA, et al. Human muscle metabolism during repeated maximal sprint cycling. J Physiol. 1993;467:77P.
Greenhaff PL, Hultman E, Harris RC. In: Poortmans JR (editor). Carbohydrate metabolism. Medicine and Sport Science Vol 46. Principles of Exercise Biochemistry. Basel: Karger 2004. pp. 101–51
Donaldson SKB, Hermansen L, Bolles L. Differential direct effects of H+ on Ca2+- activated force of skinned fiber from the soleus, cardiac, and adductor magnus muscles of rabbits. Pflüg Archiv. 1978;376(1):55–65.
Sahlin K, Edström L, Sjöholm H. Fatigue and phosphocreatine depletion during carbon dioxide induced acidosis in rat muscle. Am J Physiol. 1983;245(1):C15–20.
Danforth WH. Activation of the glycolytic pathway in muscle. In: Chance B, Estabrook RW, editors. Control of energy metabolism. New York: Academic; 1965. p. 287–98.
Goldstein ER, Ziegenfuss T, Kalman D, et al. International society of sports nutrition position stand: caffeine and performance. J Int Soc Sports Nutr. 2010;7(1):5.
Stuart GR, Hopkins WG, Cook C, et al. Multiple effects of caffeine on simulated high-intensity team-sport performance. Med Sci Sports Exerc. 2005;37(11):1998–2005.
Carr AJ, Hopkins WG, Gore CJ. Effects of acute alkalosis and acidosis on performance: a meta-analysis. Sports Med. 2011;41:801–14.
Christensen PM, Petersen NH, Friis SN, et al. Caffeine, but not bicarbonate, improves 6 min maximal performance in elite rowers. Appl Physiol Nutr Metab. 2014;39(9):1058–63.
Juel C. Regulation of pH in human skeletal muscle: adaptations to physical activity. Acta Physiol (Oxf). 2008;193(1):17–24.
Pruscino LC, Ross MLR, Gregory JR, et al. Effects of sodium bicarbonate, caffeine, and their combination on repeated 200-m freestyle performance. Int J Sports Nutr Exerc Metab. 2008;18(2):116–30.
Carr AJ, Christopher JG, Dawson B. Induced alkalosis and caffeine supplementation: effects on 2,000-m rowing performance. Int J Sports Nutr Exerc Metab. 2011;21(5):357–64.
Felippe LC, Lopes-Silva JP, Bertuzzi R, et al. Separate and combined effects of caffeine and sodium bicarbonate intake on judo performance. Int J Sports Physiol Perform. 2016;11(2):221–6.
Marriott M, Krustrup P, Mohr M. Ergogenic effects of caffeine and sodium bicarbonate supplementation on intermittent exercise performance preceded by intense arm cranking exercise. J Int Soc Sports Nutr. 2015;12:13.
Danaher J, Gerber T, Wellard RM, et al. The effect of β-alanine and NaHCO3 co-ingestion on buffering capacity and exercise performance with high-intensity exercise in healthy males. Eur J Appl Physiol. 2014;114(8):1715–24.
Bellinger PM, Howe S, Shing C, et al. The effect of combined β-alanine and NaHCO3 supplementation on cycling performance. Med Sci Sports Exerc. 2012;44(8):1545–51.
De Salles Painelli V, Roschel H, De Jesus F, et al. The ergogenic effect of beta-alanine combined with sodium bicarbonate on high-intensity swimming performance. Appl Physiol Nutr Metab. 2013;38(5):525–32.
Ducker KJ, Dawson B, Wallman KE. Effect of β-alanine and sodium bicarbonate supplementation on repeated-sprint performance. J Strength Cond Res. 2013;27(12):3450–60.
Mero AA, Hirvonen P, Saarela J, et al. Effect of sodium bicarbonate and beta-alanine supplementation on maximal sprint swimming. J Int Soc Sports Nut. 2013;10:52.
Bellinger PM. β-alanine supplementation for athletic performance: an update. J Strength Cond Res. 2014;28(6):1751–70.
Hobson RM, Harris RC, Martin D, et al. Effect of β-Alanine with and without sodium bicarbonate, on 2000 m rowing performance. Int J Sport Nutr Exerc Metab. 2013;23(5):480–7.
Sale C, Saunders B, Hudson S, et al. Effect of β-alanine plus sodium bicarbonate on high-intensity cycling capacity. Med Sci Sport Exerc. 2011;43(10):1972–8.
Brosnan JT, da Silva RP, Brosnan ME. The metabolic burden of creatine synthesis. Amino Acids. 2011;40:1325–31.
Volek JS, Duncan ND, Mazzetti SA, et al. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Med Sci Sports Exerc. 1999;31(8):1147–56.
Vandenberghe K, Gillis N, Van Leemputte M, et al. Caffeine counteracts the ergogenic action of muscle creatine loading. J Appl Physiol. 1996;80(2):452–7.
Vanakoski J, Kosunen V, Meririnne E, et al. Creatine and caffeine in anaerobic and aerobic exercise: effects on physical performance and pharmacokinetic considerations. Int J Clin Pharmacol Ther. 1998;36:258–62.
Hespel P, Op’t Eijnde B, Van Leemputte M. Opposite actions of caffeine and creatine on muscle relaxation time in humans. J Appl Physiol. 2002;92(2):513–8
Harris RC, Sale C, Delves SK. Modification of the ergogenic effects of creatine loading by caffeine. Med Sci Sports Exerc. 2005;37:S348–S349
Doherty M, Smith PM, Davison RC, et al. Caffeine is ergogenic after supplementation of oral creatine monohydrate. Med Sci Sports Exerc. 2002;34(11):1785–92.
Lee CL, Lin JC, Cheng CF. Effect of caffeine ingestion after creatine supplementation on intermittent high-intensity sprint performance. Eur J Appl Physiol. 2011;111(8):1669–77.
Trexler ET, Smith-Ryan AE, Roelofs EJ, et al. Effects of coffee and caffeine anhydrous intake during creatine loading. J Strength Cond Res. (in press).
Trexler ET, Smith-Ryan AE. Creatine and caffeine: considerations for concurrent supplementation. Int J Sport Nutr Exerc Metab. (in press).
Snow RJ, McKenna MJ, Selig SE, et al. Effect of creatine supplementation on sprint exercise performance and muscle metabolism. J Appl Physiol (1985). 1998;84(5):1667–73.
Barber JJ, McDermott AY, McGaughey KJ, et al. Effects of combined creatine and sodium bicarbonate supplementation on repeated sprint performance in trained men. J Strength Cond Res. 2013;27(1):252–8.
Mero AA, Keskinen KL, Malvela MT, et al. Combined creatine and sodium bicarbonate supplementation enhances interval swimming. J Strength Cond Res. 2004;18(2):306–10.
Griffen C, Rogerson D, Ranchordas M, et al. Effects of creatine and sodium bicarbonate co-ingestion on multiple indices of mechanical power output during repeated Wingate test in trained men. Int J Sport Nutr Exerc Metab. 2015;25(3):298–306.
Buford TW, Kreider RB, Stout JR, et al. International society of sports nutrition position stand: creatine supplementation and exercise. J Int Soc Sports Nutr. 2007;4:6.
Earnest CP, Snell PG, Rodriguez R, et al. The effect of creatine monohydrate ingestion on anaerobic power indices, muscular strength and body composition. Acta Physiol Scand. 1995;153(2):207–9.
Dangott B, Schultz E, Mozdziak PE. Dietary creatine monohydrate supplementation increases satellite cell mitotic activity during compensatory hypertrophy. Int J Sports Med. 2000;21(1):13–6.
Blancquaert L, Everaert I, Derave W. Beta-alanine supplementation, muscle carnosine and exercise performance. Curr Opin Clin Nutr Metab Care. 2015;18(1):63–70.
Derave W, Ozdemir MS, Harris RC, et al. beta-Alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters. J Appl Physiol. 2007;103(5):1736–43.
Hoffman JR, Landau G, Stout JR, et al. beta-Alanine ingestion increases muscle carnosine content and combat specific performance in soldiers. Amino Acids. 2015;47(3):627–36.
Artioli GG, Gualano B, Smith A, et al. Role of beta-alanine supplementation on muscle carnosine and exercise performance. Med Sci Sports Exerc. 2010;42(6):1162–73.
Smith AE, Walter AA, Graef JL, et al. Effects of beta-alanine supplementation and high-intensity interval training on endurance performance and body composition in men; a double-blind trial. J Int Soc Sports Nutr. 2009;6:5.
Hoffman J, Ratamess N, Kang J, et al. Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int J Sport Nutr Exerc Metab. 2006;16(4):430–46.
Kresta JY, Oliver JM, Jagim AR, et al. Effects of 28 days of beta-alanine and creatine supplementation on muscle carnosine, body composition and exercise performance in recreationally active females. J Int Soc Sports Nutr. 2014;11(1):55.
Lowery RP, Joy JM, Dudeck JE, et al. Effects of 8 weeks of Xpand(R) 2X pre workout supplementation on skeletal muscle hypertrophy, lean body mass, and strength in resistance trained males. J Int Soc Sports Nutr. 2013;10(1):44.
Spradley BD, Crowley KR, Tai CY, et al. Ingesting a pre-workout supplement containing caffeine, B-vitamins, amino acids, creatine, and beta-alanine before exercise delays fatigue while improving reaction time and muscular endurance. Nutr Metab (Lond). 2012;9:28.
Stout JR, Cramer JT, Mielke M, et al. Effects of twenty-eight days of beta-alanine and creatine monohydrate supplementation on the physical working capacity at neuromuscular fatigue threshold. J Strength Cond Res. 2006;20(4):928–31.
Zoeller RF, Stout JR, O’Kroy JA, et al. Effects of 28 days of beta-alanine and creatine monohydrate supplementation on aerobic power, ventilatory and lactate thresholds, and time to exhaustion. Amino Acids. 2007;33(3):505–10.
Green JM, McLester JR, Smith JE, et al. The effects of creatine supplementation on repeated upper- and lower-body Wingate performance. J Strength Cond Res. 2001;15(1):36–41.
Hobson RM, Saunders B, Ball G, et al. Effects of beta-alanine supplementation on exercise performance: a meta-analysis. Amino Acids. 2012;43(1):25–37.
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Conflict of interest
Conrad Earnest is the Director of Research for Nutrabolt International and a research scientist at Texas A&M University. Alireza Naderi, Ryan Lowery, Jacob Wilson and Mark Willems declare that they have no conflicts of interest relevant to the content of this review.
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Naderi, A., Earnest, C.P., Lowery, R.P. et al. Co-ingestion of Nutritional Ergogenic Aids and High-Intensity Exercise Performance. Sports Med 46, 1407–1418 (2016). https://doi.org/10.1007/s40279-016-0525-x
- Creatine Supplementation
- Ergogenic Effect
- Creatine Monohydrate