Abstract
Caffeine is a popular ergogenic aid due to its primary physiological effects that occur through antagonism of adenosine receptors in the central nervous system. This leads to a cascade of physiological reactions which increases focus and volition, and reduces perception of effort and pain, contributing to improved exercise performance. Substantial variability in the physiological and performance response to acute caffeine consumption is apparent, and a growing number of studies are implicating a single-nucleotide polymorphism in the CYP1A2 gene, responsible for caffeine metabolism, as a key factor that influences the acute responses to caffeine ingestion. However, existing literature regarding the influence of this polymorphism on the ergogenic effects of caffeine is controversial. Fast caffeine metabolisers (AA homozygotes) appear most likely to benefit from caffeine supplementation, although over half of studies showed no differences in the responses to caffeine between CYP1A2 genotypes, while others even showed either a possible advantage or disadvantage for C-allele carriers. Contrasting data are limited by weak study designs and small samples sizes, which did not allow separation of C-allele carriers into their sub-groups (AC and CC), and insufficient mechanistic evidence to elucidate findings. Mixed results prevent practical recommendations based upon genotype while genetic testing for CYP1A2 is also currently unwarranted. More mechanistic and applied research is required to elucidate how the CYP1A2 polymorphism might alter caffeine’s ergogenic effect and the magnitude thereof, and whether CYP1A2 genoty** prior to caffeine supplementation is necessary.
Similar content being viewed by others
Abbreviations
- AA:
-
AA homozygotes for the CYP1A2 gene
- AC:
-
AC heterozygotes for the CYP1A2 gene
- CC:
-
CC homozygotes for the CYP1A2 gene
- M/F:
-
Male/Female
- Caff:
-
Caffeine
- Pla:
-
Placebo
- RPE:
-
Ratings of perceived exertion
- TT:
-
Time trial
- MPO:
-
Mean power output
- PPO:
-
Peak power output
- VAT:
-
Visual attention test
- CODAT:
-
Change-of-Direction and Acceleration Test
- CMJ:
-
Counter-movement jump
- HR:
-
Heart rate
- 1-RM:
-
1 Repetition maximum
- BT7M:
-
Ball throw 7-m
- BT7M + GK:
-
Ball throw 7-m with goalkeeper
- BT9M:
-
Ball throw 9-m
- BT9 + GK:
-
Ball throw 9-m with goalkeeper
References
Addicott MA, Yang LL, Peiffer AM, Burnett LR, Burdette JH, Chen MY, Hayasaka S, Kraft RA, Maldjian JA, Laurienti PJ (2009) The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate? Hum Brain Mapp 30(10):3102–3114. https://doi.org/10.1002/hbm.20732
Algrain HA, Thomas RM, Carrillo AE, Ryan EJ, Kim C-H, Lettan RB, Ryan EJ (2016) The effects of a polymorphism in the cytochrome P450 CYP1A2 gene on performance enhancement with caffeine in recreational cyclists. J Caffeine Res 6(1):34–39
Anderson DE, Hickey MS (1994) Effects of caffeine on the metabolic and catecholamine responses to exercise in 5 and 28 degrees C. Med Sci Sports Exerc 26(4):453–458
Apostolidis A, Mougios V, Smilios I, Frangous M, Hadjicharalambous M (2020) Caffeine supplementation is ergogenic in soccer players independent of cardiorespiratory or neuromuscular fitness levels. J Int Soc Sports Nutr 17(1):31. https://doi.org/10.1186/s12970-020-00360-x
Arnaud MJ (2011) Pharmacokinetics and metabolism of natural methylxanthines in animal and man. Handb Exp Pharmacol 200:33–91. https://doi.org/10.1007/978-3-642-13443-2_3
Astorino TA, Roberson DW (2010) Efficacy of acute caffeine ingestion for short-term high-intensity exercise performance: a systematic review. J Strength Cond Res 24(1):257–265. https://doi.org/10.1519/JSC.0b013e3181c1f88a
Astorino TA, Cottrell T, Lozano AT, Aburto-Pratt K, Duhon J (2012) Increases in cycling performance in response to caffeine ingestion are repeatable. Nutr Res 32(2):78–84. https://doi.org/10.1016/j.nutres.2011.12.001
Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004) Adenosine and sleep-wake regulation. Prog Neurobiol 73(6):379–396. https://doi.org/10.1016/j.pneurobio.2004.06.004
Beaudoin MS, Graham TE (2011) Methylxanthines and human health: epidemiological and experimental evidence. Handb Exp Pharmacol 200:509–548. https://doi.org/10.1007/978-3-642-13443-2_21
Beaumont R, Cordery P, Funnell M, Mears S, James L, Watson P (2017) Chronic ingestion of a low dose of caffeine induces tolerance to the performance benefits of caffeine. J Sports Sci 35(19):1920–1927. https://doi.org/10.1080/02640414.2016.1241421
Beedie CJ, Stuart EM, Coleman DA, Foad AJ (2006) Placebo effects of caffeine on cycling performance. Med Sci Sports Exerc 38(12):2159–2164. https://doi.org/10.1249/01.mss.0000233805.56315.a9
Bell DG, McLellan TM (2002) Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers. J Appl Physiol 93(4):1227–1234. https://doi.org/10.1152/japplphysiol.00187.2002
Bell DG, Jacobs I, Ellerington K (2001) Effect of caffeine and ephedrine ingestion on anaerobic exercise performance. Med Sci Sports Exerc 33(8):1399–1403. https://doi.org/10.1097/00005768-200108000-00024
Benowitz NL, Jacob P 3rd, Mayan H, Denaro C (1995) Sympathomimetic effects of paraxanthine and caffeine in humans. Clin Pharmacol Ther 58(6):684–691. https://doi.org/10.1016/0009-9236(95)90025-X
Bruce M, Scott N, Lader M, Marks V (1986) The psychopharmacological and electrophysiological effects of single doses of caffeine in healthy human subjects. Br J Clin Pharmacol 22(1):81–87. https://doi.org/10.1111/j.1365-2125.1986.tb02883.x
Calzetta L, Spina D, Cazzola M, Page CP, Facciolo F, Rendina EA, Matera MG (2011) Pharmacological characterization of adenosine receptors on isolated human bronchi. Am J Respir Cell Mol Biol 45(6):1222–1231. https://doi.org/10.1165/rcmb.2011-0056OC
Carswell AT, Howland K, Martinez-Gonzalez B, Baron P, Davison G (2020) The effect of caffeine on cognitive performance is influenced by CYP1A2 but not ADORA2A genotype, yet neither genotype affects exercise performance in healthy adults. Eur J Appl Physiol. https://doi.org/10.1007/s00421-020-04384-8
Castorena-Torres F, Mendoza-Cantu A, de Leon MB, Cisneros B, Zapata-Perez O, Lopez-Carrillo L, Salinas JE, Albores A (2005) CYP1A2 phenotype and genotype in a population from the carboniferous region of coahuila. Mex Toxicol Lett 156(3):331–339. https://doi.org/10.1016/j.toxlet.2004.12.005
Childs E, Hohoff C, Deckert J, Xu K, Badner J, de Wit H (2008) Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 33(12):2791–2800. https://doi.org/10.1038/npp.2008.17
Christensen PM, Shirai Y, Ritz C, Nordsborg NB (2017) Caffeine and bicarbonate for speed. A meta-analysis of legal supplements potential for improving intense endurance exercise performance. Front Physiol 8:240. https://doi.org/10.3389/fphys.2017.00240
Cohen BS, Nelson AG, Prevost MC, Thompson GD, Marx BD, Morris GS (1996) Effects of caffeine ingestion on endurance racing in heat and humidity. Eur J Appl Physiol 73(3–4):358–363. https://doi.org/10.1007/BF02425499
Collomp K, Ahmaidi S, Audran M, Chanal JL, Prefaut C (1991) Effects of caffeine ingestion on performance and anaerobic metabolism during the Wingate Test. Int J Sports Med 12(5):439–443. https://doi.org/10.1055/s-2007-1024710
Courtney S, Klein AC, Martin M, Saunders MJ, Flohr JA, Bechtel MK, Dunham W, Hancock M, Womack CJ (2012) The effect of caffeine on performance in collegiate tennis players. J Caffeine Res 2(3):6. https://doi.org/10.1089/caf.2012.0019
Daly JW, Butts-Lamb P, Padgett W (1983) Subclasses of adenosine receptors in the central nervous system: interaction with caffeine and related methylxanthines. Cell Mol Neurobiol 3(1):69–80
Davis JM, Zhao Z, Stock HS, Mehl KA, Buggy J, Hand GA (2003) Central nervous system effects of caffeine and adenosine on fatigue. Am J Physiol Regul Integr Comp Physiol 284(2):R399-404. https://doi.org/10.1152/ajpregu.00386.2002
Dittrich N, Serpa MC, Lemos EC, De Lucas RD, Guglielmo LGA (2019) Effects of caffeine chewing gum on exercise tolerance and neuromuscular responses in well-trained runners. J Strength Cond Res. https://doi.org/10.1519/JSC.0000000000002966
Djordjevic N, Ghotbi R, Jankovic S, Aklillu E (2010) Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 -163C>A polymorphism. Eur J Clin Pharmacol 66(7):697–703. https://doi.org/10.1007/s00228-010-0823-4
Doering TM, Fell JW, Leveritt MD, Desbrow B, Shing CM (2014) The effect of a caffeinated mouth-rinse on endurance cycling time-trial performance. Int J Sport Nutr Exerc Metab 24(1):90–97. https://doi.org/10.1123/ijsnem.2013-0103
Doherty M, Smith PM (2005) Effects of caffeine ingestion on rating of perceived exertion during and after exercise: a meta-analysis. Scand J Med Sci Sports 15(2):69–78. https://doi.org/10.1111/j.1600-0838.2005.00445.x
Ehlert AM, Twiddy HM, Wilson PB (2020) The effects of caffeine mouth rinsing on exercise performance: a systematic review. Int J Sport Nutr Exerc Metab. https://doi.org/10.1123/ijsnem.2020-0083
El-Sohemy A, Cornelis MC, Kabagambe EK, Campos H (2007) Coffee, CYP1A2 genotype and risk of myocardial infarction. Genes Nutr 2(1):155–156. https://doi.org/10.1007/s12263-007-0043-4
Engels HJ, Haymes EM (1992) Effects of caffeine ingestion on metabolic responses to prolonged walking in sedentary males. Int J Sport Nutr 2(4):386–396. https://doi.org/10.1123/ijsn.2.4.386
Fitts RH (2016) The role of acidosis in fatigue: pro perspective. Med Sci Sports Exerc 48(11):2335–2338. https://doi.org/10.1249/MSS.0000000000001043
Fredholm BB, Irenius E, Kull B, Schulte G (2001a) Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 61(4):443–448
Fredholm BB, Ap IJ, Jacobson KA, Klotz KN, Linden J (2001b) International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53(4):527–552
Gaesser G, Rich R (1985) Influence of caffeine on blood lactate response during incremental exercise. Int J Sports Med 6(04):207–211
Gazzaz M, Kinzig M, Schaeffeler E, Jubner M, Hsin CH, Li X, Taubert M, Trueck C, Iltgen-Breburda J, Kraus D, Queckenberg C, Stoffel M, Schwab M, Sorgel F, Fuhr U (2018) Drinking ethanol has few acute effects on CYP2C9, CYP2C19, NAT2, and P-Glycoprotein Activities but somewhat inhibits CYP1A2, CYP2D6, and Intestinal CYP3A: So What? Clin Pharmacol Ther 104(6):1249–1259. https://doi.org/10.1002/cpt.1083
Giersch GE, Boyett JC, Hargens TA, Luden ND, Saunders MJ, Daley H, Hughey CA, El-Sohemy A, Womack CJ (2018) The Effect of the CYP1A2− 163 C> a polymorphism on caffeine metabolism and subsequent cycling performance. J Caffeine Adenosine Res 8(2):65–70
Glaister M, Chopra K, Pereira De Sena A, Sternbach C, Morina L, Mavrommatis Y (2020) Caffeine, exercise physiology, and time-trial performance: no effect of ADORA2A or CYP1A2 genotypes<sup></sup>. Appl Physiol Nutr Metab. https://doi.org/10.1139/apnm-2020-0551
Goldstein ER, Ziegenfuss T, Kalman D, Kreider R, Campbell B, Wilborn C, Taylor L, Willoughby D, Stout J, Graves BS, Wildman R, Ivy JL, Spano M, Smith AE, Antonio J (2010) International society of sports nutrition position stand: caffeine and performance. J Int Soc Sports Nutr 7(1):5. https://doi.org/10.1186/1550-2783-7-5
Goncalves LS, Painelli VS, Yamaguchi G, Oliveira LF, Saunders B, da Silva RP, Maciel E, Artioli GG, Roschel H, Gualano B (2017) Dispelling the myth that habitual caffeine consumption influences the performance response to acute caffeine supplementation. J Appl Physiol 123(1):213–220. https://doi.org/10.1152/japplphysiol.00260.2017
Goods PS, Landers G, Fulton S (2017) Caffeine ingestion improves repeated freestyle sprints in elite male swimmers. J Sports Sci Med 16(1):93–98
Graham TE, Sathasivam P, Rowland M, Marko N, Greer F, Battram D (2001) Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test. Can J Physiol Pharmacol 79(7):559–565
Greer F, McLean C, Graham TE (1998) Caffeine, performance, and metabolism during repeated Wingate exercise tests. J Appl Physiol 85(4):1502–1508. https://doi.org/10.1152/jappl.1998.85.4.1502
Grgic J (2018) Caffeine ingestion enhances Wingate performance: a meta-analysis. Eur J Sport Sci 18(2):219–225. https://doi.org/10.1080/17461391.2017.1394371
Grgic J, Trexler ET, Lazinica B, Pedisic Z (2018) Effects of caffeine intake on muscle strength and power: a systematic review and meta-analysis. J Int Soc Sports Nutr 15:11. https://doi.org/10.1186/s12970-018-0216-0
Grgic J, Grgic I, Pickering C, Schoenfeld BJ, Bishop DJ, Pedisic Z (2019a) Wake up and smell the coffee: caffeine supplementation and exercise performance-an umbrella review of 21 published meta-analyses. Br J Sports Med. https://doi.org/10.1136/bjsports-2018-100278
Grgic J, Mikulic P, Schoenfeld BJ, Bishop DJ, Pedisic Z (2019b) The influence of caffeine supplementation on resistance exercise: a review. Sports Med 49(1):17–30. https://doi.org/10.1007/s40279-018-0997-y
Grgic J, Pickering C, Bishop DJ, Del Coso J, Schoenfeld BJ, Tinsley GM, Pedisic Z (2020a) ADOR2A C allele carriers exhibit ergogenic responses to caffeine supplementation. Nutrients. https://doi.org/10.3390/nu12030741
Grgic J, Pickering C, Bishop DJ, Schoenfeld BJ, Mikulic P, Pedisic Z (2020b) CYP1A2 genotype and acute effects of caffeine on resistance exercise, jum**, and sprinting performance. J Int Soc Sports Nutr 17(1):21. https://doi.org/10.1186/s12970-020-00349-6
Gu L, Gonzalez FJ, Kalow W, Tang BK (1992) Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 2(2):73–77. https://doi.org/10.1097/00008571-199204000-00004
Guest N, Corey P, Vescovi J, El-Sohemy A (2018) Caffeine, CYP1A2 genotype, and endurance performance in athletes. Med Sci Sports Exerc 50(8):1570–1578. https://doi.org/10.1249/mss.0000000000001596
Guest NS, Horne J, Vanderhout SM, El-Sohemy A (2019) Sport nutrigenomics: personalized nutrition for athletic performance. Front Nutr 6:8. https://doi.org/10.3389/fnut.2019.00008
Guest NS, Corey P, Tyrrell PN, El-Sohemy A (2020) Effect of caffeine on endurance performance in athletes may depend on HTR2A and CYP1A2 genotypes. J Strength Cond Res. https://doi.org/10.1519/JSC.0000000000003665
Hall KT, Loscalzo J, Kaptchuk TJ (2015) Genetics and the placebo effect: the placebome. Trends Mol Med 21(5):285–294. https://doi.org/10.1016/j.molmed.2015.02.009
Han XX, Bonen A (1998) Epinephrine translocates GLUT-4 but inhibits insulin-stimulated glucose transport in rat muscle. Am J Physiol 274(4):E700-707. https://doi.org/10.1152/ajpendo.1998.274.4.E700
Han XM, Ouyang DS, Chen XP, Shu Y, Jiang CH, Tan ZR, Zhou HH (2002) Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2. Br J Clin Pharmacol 54(5):540–543. https://doi.org/10.1046/j.1365-2125.2002.01686.x
Higgins JP, Babu KM (2013) Caffeine reduces myocardial blood flow during exercise. Am J Med 126(8):730–738. https://doi.org/10.1016/j.amjmed.2012.12.023
Hill AV (1925) The physiological basis of athletic records1. Nature 116(2919):544–548. https://doi.org/10.1038/116544a0
Hodgson AB, Randell RK, Jeukendrup AE (2013) The metabolic and performance effects of caffeine compared to coffee during endurance exercise. PLoS ONE 8(4):e59561. https://doi.org/10.1371/journal.pone.0059561
Hunter AM, St Clair Gibson A, Collins M, Lambert M, Noakes TD (2002) Caffeine ingestion does not alter performance during a 100-km cycling time-trial performance. Int J Sport Nutr Exerc Metab 12(4):438–452
Jaaskelainen SK, Lindholm P, Valmunen T, Pesonen U, Taiminen T, Virtanen A, Lamusuo S, Forssell H, Hagelberg N, Hietala J, Pertovaara A (2014) Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation. Pain 155(10):2180–2187. https://doi.org/10.1016/j.pain.2014.08.029
Jodra P, Lago-Rodriguez A, Sanchez-Oliver AJ, Lopez-Samanes A, Perez-Lopez A, Veiga-Herreros P, San Juan AF, Dominguez R (2020) Effects of caffeine supplementation on physical performance and mood dimensions in elite and trained-recreational athletes. J Int Soc Sports Nutr 17(1):2. https://doi.org/10.1186/s12970-019-0332-5
Kamimori GH, Karyekar CS, Otterstetter R, Cox DS, Balkin TJ, Belenky GL, Eddington ND (2002a) The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Int J Pharm 234(1–2):159–167
Keisler BD, Armsey TD 2nd (2006) Caffeine as an ergogenic aid. Curr Sports Med Rep 5(4):215–219
Klein CS, Clawson A, Martin M, Saunders MJ, Flohr JA, Bechtel MK, Dunham W, Hancock M, Womack CJ (2012) The effect of caffeine on performance in collegiate tennis players. J Caffeine Res 2(3):111–116
Koonrungsesomboon N, Khatsri R, Wongchompoo P, Teekachunhatean S (2018) The impact of genetic polymorphisms on CYP1A2 activity in humans: a systematic review and meta-analysis. Pharmacogenomics J 18(6):760–768. https://doi.org/10.1038/s41397-017-0011-3
Lane JD, Steege JF, Rupp SL, Kuhn CM (1992) Menstrual cycle effects on caffeine elimination in the human female. Eur J Clin Pharmacol 43(5):543–546
Lara B, Ruiz-Moreno C, Salinero JJ, Del Coso J (2019) Time course of tolerance to the performance benefits of caffeine. PLoS ONE 14(1):e0210275. https://doi.org/10.1371/journal.pone.0210275
Lara B, Gutierrez-Hellin J, Garcia-Bataller A, Rodriguez-Fernandez P, Romero-Moraleda B, Del Coso J (2020a) Ergogenic effects of caffeine on peak aerobic cycling power during the menstrual cycle. Eur J Nutr 59(6):2525–2534. https://doi.org/10.1007/s00394-019-02100-7
Lara B, Gutierrez Hellin J, Ruiz-Moreno C, Romero-Moraleda B, Del Coso J (2020b) Acute caffeine intake increases performance in the 15-s Wingate test during the menstrual cycle. Br J Clin Pharmacol 86(4):745–752. https://doi.org/10.1111/bcp.14175
Lau CE, Falk JL (1995) Dose-dependent surmountability of locomotor activity in caffeine tolerance. Pharmacol Biochem Behav 52(1):139–143. https://doi.org/10.1016/0091-3057(95)00066-6
Laurent D, Schneider KE, Prusaczyk WK, Franklin C, Vogel SM, Krssak M, Petersen KF, Goforth HW, Shulman GI (2000) Effects of caffeine on muscle glycogen utilization and the neuroendocrine axis during exercise. J Clin Endocrinol Metab 85(6):2170–2175. https://doi.org/10.1210/jcem.85.6.6655
Lazarus M, Oishi Y, Bjorness TE, Greene RW (2019) Gating and the need for sleep: dissociable effects of adenosine A1 and A2A receptors. Front Neurosci 13:740. https://doi.org/10.3389/fnins.2019.00740
Lopes-Silva JP, Silva Santos JF, Branco BH, Abad CC, Oliveira LF, Loturco I, Franchini E (2015) Caffeine ingestion increases estimated glycolytic metabolism during taekwondo combat simulation but does not improve performance or parasympathetic reactivation. PLoS ONE 10(11):e0142078. https://doi.org/10.1371/journal.pone.0142078
Loy BD, O’Connor PJ, Lindheimer JB, Covert SF (2015) Caffeine is ergogenic for adenosine A2A receptor gene (ADORA2A) T allele homozygotes: a pilot study. J Caffeine Res 5(2):73–81
Magkos F, Kavouras SA (2005) Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit Rev Food Sci Nutr 45(7–8):535–562. https://doi.org/10.1080/1040-830491379245
Mansour TE (1972) Phosphofructokinase activity in skeletal muscle extracts following administration of epinephrine. J Biol Chem 247(19):6059–6066
Marques AC, Jesus AA, Giglio BM, Marini AC, Lobo PCB, Mota JF, Pimentel GD (2018) Acute caffeinated coffee consumption does not improve time trial performance in an 800-m run: a randomized, double-blind, crossover Placebo-Controlled Study. Nutrients. https://doi.org/10.3390/nu10060657
Martikainen IK, Hagelberg N, Jaaskelainen SK, Hietala J, Pertovaara A (2018) Dopaminergic and serotonergic mechanisms in the modulation of pain: in vivo studies in human brain. Eur J Pharmacol 834:337–345. https://doi.org/10.1016/j.ejphar.2018.07.038
Maughan RJ, Burke LM, Dvorak J, Larson-Meyer DE, Peeling P, Phillips SM, Rawson ES, Walsh NP, Garthe I, Geyer H, Meeusen R, van Loon LJC, Shirreffs SM, Spriet LL, Stuart M, Vernec A, Currell K, Ali VM, Budgett RG, Ljungqvist A, Mountjoy M, Pitsiladis YP, Soligard T, Erdener U, Engebretsen L (2018) IOC consensus statement: dietary supplements and the high-performance athlete. Br J Sports Med 52(7):439–455. https://doi.org/10.1136/bjsports-2018-099027
McClaran SR, Wetter TJ (2007) Low doses of caffeine reduce heart rate during submaximal cycle ergometry. J Int Soc Sports Nutr 4:11. https://doi.org/10.1186/1550-2783-4-11
Mcnaughton L (1987) Two levels of caffeine ingestion on blood lactate and free fatty acid responses during incremental exercise. Res Q Exerc Sport 58(3):255–259
Mielgo-Ayuso J, Marques-Jimenez D, Refoyo I, Del Coso J, Leon-Guereno P, Calleja-Gonzalez J (2019) Effect of caffeine supplementation on sports performance based on differences between sexes: a systematic review. Nutrients. https://doi.org/10.3390/nu11102313
Morales AP, Sampaio-Jorge F, Barth T, Pierucci APTR, Ribeiro BG (2020) Caffeine supplementation for 4 days does not induce tolerance to the ergogenic effects promoted by acute intake on physiological, metabolic, and performance parameters of cyclists: a randomized, double-blind, crossover, Placebo-Controlled Study. Nutrients 12(7):2101
Muñoz A, López-Samanes Á, Aguilar-Navarro M, Varillas-Delgado D, Rivilla-García J, Moreno-Pérez V, Del Coso J (2020) Effects of CYP1A2 and ADORA2A genotypes on the ergogenic response to caffeine in professional handball players. Genes 11(8):933
Namdar M, Schepis T, Koepfli P, Gaemperli O, Siegrist PT, Grathwohl R, Valenta I, Delaloye R, Klainguti M, Wyss CA, Luscher TF, Kaufmann PA (2009) Caffeine impairs myocardial blood flow response to physical exercise in patients with coronary artery disease as well as in age-matched controls. PLoS ONE 4(5):e5665. https://doi.org/10.1371/journal.pone.0005665
Nehlig A (1999) Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev 23(4):563–576
Nehlig A (2018) Interindividual differences in caffeine metabolism and factors driving caffeine consumption. Pharmacol Rev 70(2):384–411. https://doi.org/10.1124/pr.117.014407
Nehlig A, Daval JL, Debry G (1992) Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev 17(2):139–170. https://doi.org/10.1016/0165-0173(92)90012-b
Norum M, Risvang LC, Bjornsen T, Dimitriou L, Ronning PO, Bjorgen M, Raastad T (2020) Caffeine increases strength and power performance in resistance-trained females during early follicular phase. Scand J Med Sci Sports. https://doi.org/10.1111/sms.13776
Park J, Gupta RS (2013) Adenosine metabolism, adenosine kinase, and evolution. In: Masino S, Boison D (eds) Adenosine. Springer, New York, pp 23–54
Pataky MW, Womack CJ, Saunders MJ, Goffe JL, D’Lugos AC, El-Sohemy A, Luden ND (2016) Caffeine and 3-km cycling performance: effects of mouth rinsing, genotype, and time of day. Scand J Med Sci Sports 26(6):613–619. https://doi.org/10.1111/sms.12501
Peterson S, Schwarz Y, Li SS, Li L, King IB, Chen C, Eaton DL, Potter JD, Lampe JW (2009) CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 18(11):3118–3125. https://doi.org/10.1158/1055-9965.EPI-09-0589
Pickering C, Grgic J (2019) Caffeine and exercise: What Next? Sports Med 49(7):1007–1030. https://doi.org/10.1007/s40279-019-01101-0
Pickering C, Kiely J (2018) Are the current guidelines on caffeine use in sport optimal for everyone? Inter-individual variation in caffeine ergogenicity, and a move towards personalised sports nutrition. Sports Med 48(1):7–16. https://doi.org/10.1007/s40279-017-0776-1
Polosa R, Blackburn MR (2009) Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease. Trends Pharmacol Sci 30(10):528–535. https://doi.org/10.1016/j.tips.2009.07.005
Poole DC, Ward SA, Gardner GW, Whipp BJ (1988) Metabolic and respiratory profile of the upper limit for prolonged exercise in man. Ergonomics 31(9):1265–1279. https://doi.org/10.1080/00140138808966766
Poole DC, Burnley M, Vanhatalo A, Rossiter HB, Jones AM (2016) Critical power: an important fatigue threshold in exercise physiology. Med Sci Sports Exerc 48(11):2320–2334. https://doi.org/10.1249/MSS.0000000000000939
Porkka-Heiskanen T (2011) Methylxanthines and sleep. In: Fredholm BB (ed) Methylxanthines. Springer, Berlin, pp 331–348
Puente C, Abian-Vicen J, Del Coso J, Lara B, Salinero JJ (2018) The CYP1A2 -163C>A polymorphism does not alter the effects of caffeine on basketball performance. PLoS ONE 13(4):e0195943. https://doi.org/10.1371/journal.pone.0195943
Raguso CA, Coggan AR, Sidossis LS, Gastaldelli A, Wolfe RR (1996) Effect of theophylline on substrate metabolism during exercise. Metab Clin Exp 45(9):1153–1160. https://doi.org/10.1016/s0026-0495(96)90016-5
Rahimi R (2019) The effect of CYP1A2 genotype on the ergogenic properties of caffeine during resistance exercise: a randomized, double-blind, placebo-controlled, crossover study. Ir J Med Sci 188(1):337–345. https://doi.org/10.1007/s11845-018-1780-7
Reis CEG, Dorea JG, da Costa THM (2019) Effects of coffee consumption on glucose metabolism: a systematic review of clinical trials. J tradit Complement Med 9(3):184–191. https://doi.org/10.1016/j.jtcme.2018.01.001
Riksen NP, Smits P, Rongen GA (2011) The cardiovascular effects of methylxanthines. Handb Exp Pharmacol 200:413–437. https://doi.org/10.1007/978-3-642-13443-2_16
Roelands B, Buyse L, Pauwels F, Delbeke F, Deventer K, Meeusen R (2011) No effect of caffeine on exercise performance in high ambient temperature. Eur J Appl Physiol 111(12):3089–3095. https://doi.org/10.1007/s00421-011-1945-9
Romero-Moraleda B, Del Coso J, Gutierrez-Hellin J, Lara B (2019) The effect of caffeine on the velocity of half-squat exercise during the menstrual cycle: a randomized controlled trial. Nutrients. https://doi.org/10.3390/nu11112662
Ruiz-Moreno C, Gutierrez-Hellin J, Amaro-Gahete FJ, Gonzalez-Garcia J, Giraldez-Costas V, Perez-Garcia V, Del Coso J (2020a) Caffeine increases whole-body fat oxidation during 1 h of cycling at Fatmax. Eur J Nutr. https://doi.org/10.1007/s00394-020-02393-z
Ruiz-Moreno C, Lara B, Salinero JJ, Brito de Souza D, Ordovas JM, Del Coso J (2020b) Time course of tolerance to adverse effects associated with the ingestion of a moderate dose of caffeine. Eur J Nutr. https://doi.org/10.1007/s00394-019-02167-2
Ryan EJ, Kim CH, Fickes EJ, Williamson M, Muller MD, Barkley JE, Gunstad J, Glickman EL (2013) Caffeine gum and cycling performance: a timing study. J Strength Cond Res 27(1):259–264. https://doi.org/10.1519/JSC.0b013e3182541d03
Sachse C, Brockmoller J, Bauer S, Roots I (1999) Functional significance of a C–>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 47(4):445–449. https://doi.org/10.1046/j.1365-2125.1999.00898.x
Sacramento JF, Ribeiro MJ, Yubero S, Melo BF, Obeso A, Guarino MP, Gonzalez C, Conde SV (2015) Disclosing caffeine action on insulin sensitivity: effects on rat skeletal muscle. Eur J Pharm Sci Off J Eur Feder Pharm Sci 70:107–116. https://doi.org/10.1016/j.ejps.2015.01.011
Salamone JD, Correa M, Randall PA, Nunes EJ, Pardo M, Lopez-Cruz L (2013) The role of adenosine in the ventral striatal circuits regulating behavioral activation and effort-related decision making: importance for normal and pathological aspects of motivation. In: Masino S, Boison D (eds) Adenosine. Springer, New York, pp 493–512
Salinero JJ, Lara B, Ruiz-Vicente D, Areces F, Puente-Torres C, Gallo-Salazar C, Pascual T, Del Coso J (2017) CYP1A2 genotype variations do not modify the benefits and drawbacks of caffeine during exercise: a pilot study. Nutrients. https://doi.org/10.3390/nu9030269
Salinero JJ, Lara B, Del Coso J (2019) Effects of acute ingestion of caffeine on team sports performance: a systematic review and meta-analysis. Res Sports Med 27(2):238–256. https://doi.org/10.1080/15438627.2018.1552146
Santos Rde A, Kiss MA, Silva-Cavalcante MD, Correia-Oliveira CR, Bertuzzi R, Bishop DJ, Lima-Silva AE (2013) Caffeine alters anaerobic distribution and pacing during a 4000-m cycling time trial. PLoS ONE 8(9):e75399. https://doi.org/10.1371/journal.pone.0075399
Saunders B, de Oliveira LF, da Silva RP, de Salles PV, Goncalves LS, Yamaguchi G, Mutti T, Maciel E, Roschel H, Artioli GG, Gualano B (2017) Placebo in sports nutrition: a proof-of-principle study involving caffeine supplementation. Scand J Med Sci Sports 27(11):1240–1247. https://doi.org/10.1111/sms.12793
Sawynok J (2013) Adenosine and pain. In: Masino S, Boison D (eds) Adenosine. Springer, New York, pp 343–360
Seibert E, Tracy TS (2014) Different enzyme kinetic models. Methods Mol Biol 1113:23–35. https://doi.org/10.1007/978-1-62703-758-7_3
Shabir A, Hooton A, Tallis J, Higgins MF (2018) The influence of caffeine expectancies on sport, exercise, and cognitive performance. Nutrients. https://doi.org/10.3390/nu10101528
Shryock JC, Belardinelli L (1997) Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. Am J Cardiol 79(12A):2–10
Silva-Cavalcante MD, Correia-Oliveira CR, Santos RA, Lopes-Silva JP, Lima HM, Bertuzzi R, Duarte M, Bishop DJ, Lima-Silva AE (2013) Caffeine increases anaerobic work and restores cycling performance following a protocol designed to lower endogenous carbohydrate availability. PLoS ONE 8(8):e72025. https://doi.org/10.1371/journal.pone.0072025
Silveira R, Andrade-Souza VA, Arcoverde L, Tomazini F, Sansonio A, Bishop DJ, Bertuzzi R, Lima-Silva AE (2018) Caffeine increases work done above critical power, but not anaerobic work. Med Sci Sports Exerc 50(1):131–140. https://doi.org/10.1249/MSS.0000000000001408
Skinner TL, Jenkins DG, Coombes JS, Taaffe DR, Leveritt MD (2010) Dose response of caffeine on 2000-m rowing performance. Med Sci Sports Exerc 42(3):571–576. https://doi.org/10.1249/MSS.0b013e3181b6668b
Skinner TL, Jenkins DG, Taaffe DR, Leveritt MD, Coombes JS (2013) Coinciding exercise with peak serum caffeine does not improve cycling performance. J Sci Med Sport 16(1):54–59. https://doi.org/10.1016/j.jsams.2012.04.004
Southward K, Rutherfurd-Markwick K, Badenhorst C, Ali A (2018a) The role of genetics in moderating the inter-individual differences in the ergogenicity of caffeine. Nutrients. https://doi.org/10.3390/nu10101352
Southward K, Rutherfurd-Markwick KJ, Ali A (2018b) The effect of acute caffeine ingestion on endurance performance: a systematic review and meta-analysis. Sports Med 48(8):1913–1928. https://doi.org/10.1007/s40279-018-0939-8
Souza DB, Del Coso J, Casonatto J, Polito MD (2017) Acute effects of caffeine-containing energy drinks on physical performance: a systematic review and meta-analysis. Eur J Nutr 56(1):13–27. https://doi.org/10.1007/s00394-016-1331-9
Spineli H, Pinto MP, Dos Santos BP, Lima-Silva AE, Bertuzzi R, Gitai DLG, de Araujo GG (2020a) Caffeine improves various aspects of athletic performance in adolescents independent of their 163 C > A CYP1A2 genotypes. Scand J Med Sci Sports. https://doi.org/10.1111/sms.13749
Spineli H, Pinto MP, Dos Santos BP, Lima-Silva AE, Bertuzzi R, Gitai DLG, de Araujo GG (2020b) Caffeine improves various aspects of athletic performance in adolescents independent of their 163 C>A CYP1A2 genotypes. Scand J Med Sci Sports. https://doi.org/10.1111/sms.13749
Spriet LL, MacLean DA, Dyck DJ, Hultman E, Cederblad G, Graham TE (1992) Caffeine ingestion and muscle metabolism during prolonged exercise in humans. Am J Physiol 262(6 Pt 1):E891-898. https://doi.org/10.1152/ajpendo.1992.262.6.E891
Stavric B, Klassen R, Watkinson B, Karpinski K, Stapley R, Fried P (1988) Variability in caffeine consumption from coffee and tea: possible significance for epidemiological studies. Food Chem Toxicol Int J Publish Br Industrial Biol Res Assoc 26(2):111–118. https://doi.org/10.1016/0278-6915(88)90107-x
Stein JA, Ramirez M, Heinrich KM (2020) Acute caffeine supplementation does not improve performance in trained crossfit((R)) athletes. Sports. https://doi.org/10.3390/sports8040054
Svenningsson P, Nomikos GG, Fredholm BB (1999) The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. J Neurosci Official J Soc Neurosci 19(10):4011–4022
Tallis J, Duncan MJ, James RS (2015) What can isolated skeletal muscle experiments tell us about the effects of caffeine on exercise performance? Br J Pharmacol 172(15):3703–3713. https://doi.org/10.1111/bph.13187
Tarnopolsky M (2000) Cupido C (2000) Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers. J Appl Physiol 89(5):1719–1724. https://doi.org/10.1152/jappl.2000.89.5.1719
Tarnopolsky MA, Atkinson SA, MacDougall JD, Sale DG, Sutton JR (1989) Physiological responses to caffeine during endurance running in habitual caffeine users. Med Sci Sports Exerc 21(4):418–424
Turley KR, Gerst JW (2006) Effects of caffeine on physiological responses to exercise in young boys and girls. Med Sci Sports Exerc 38(3):520–526. https://doi.org/10.1249/01.mss.0000191189.40436.73
Van Soeren MH, Sathasivam P, Spriet LL, Graham TE (1993) Caffeine metabolism and epinephrine responses during exercise in users and nonusers. J Appl Physiol 75(2):805–812. https://doi.org/10.1152/jappl.1993.75.2.805
Venier S, Grgic J, Mikulic P (2019) Acute enhancement of jump performance, muscle strength, and power in resistance-trained men after consumption of caffeinated chewing gum. Int J Sports Physiol Perform. https://doi.org/10.1123/ijspp.2019-0098
Vinetti G, Taboni A, Bruseghini P, Camelio S, D’Elia M, Fagoni N, Moia C, Ferretti G (2019) Experimental validation of the 3-parameter critical power model in cycling. Eur J Appl Physiol 119(4):941–949. https://doi.org/10.1007/s00421-019-04083-z
Whitsett TL, Manion CV, Christensen HD (1984) Cardiovascular effects of coffee and caffeine. Am J Cardiol 53(7):918–922
Womack CJ, Saunders MJ, Bechtel MK, Bolton DJ, Martin M, Luden ND, Dunham W, Hancock M (2012) The influence of a CYP1A2 polymorphism on the ergogenic effects of caffeine. J Int Soc Sports Nutr 9(1):7. https://doi.org/10.1186/1550-2783-9-7
**ao J, Huang WH, Peng JB, Tan ZR, Ou-Yang DS, Hu DL, Zhang W, Chen Y (2014) Quercetin significantly inhibits the metabolism of caffeine, a substrate of cytochrome P450 1A2 unrelated to CYP1A2*1C (-2964G>A) and *1F (734C>A) gene polymorphisms. Biomed Res Int 2014:405071. https://doi.org/10.1155/2014/405071
Acknowledgements
Gabriel Barreto (2017/15314-1), Beatriz Grecco (2020/02391-0), Bruno Gualano (2017/13552-2) and Bryan Saunders (2016/50438-0) have been financially supported by Fundação de Amparo à Pesquisa do Estado de Sao Paulo. Pietro Merola has been financially supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Bryan Saunders has received a grant from Faculdade de Medicina da Universidade de São Paulo (2020.1.362.5.2).
Author information
Authors and Affiliations
Contributions
GB and BS are responsible for the conception of the work. GB, BG, PM and BS wrote the first draft. CR and BG are responsible for editing and adapting the manuscript. All authors approved the final version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
Bryan Saunders has received caffeine supplements free of charge from Farmácia Analítica (Rio de Janeiro, Brazil) for experimental investigations. Farmácia Analítica had no involvement in the manuscript.
Additional information
Communicated by Michael Lindinger.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Barreto, G., Grecco, B., Merola, P. et al. Novel insights on caffeine supplementation, CYP1A2 genotype, physiological responses and exercise performance. Eur J Appl Physiol 121, 749–769 (2021). https://doi.org/10.1007/s00421-020-04571-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00421-020-04571-7