Effects of Cocoa-Derived Polyphenols on Cognitive Function in Humans. Systematic Review and Analysis of Methodological Aspects


The effects of cocoa-derived polyphenols on cognitive functions have been analyzed through numerous studies using different interventions (doses, vehicles, time frame, cognition tests, and characteristics of participants) which may hamper the interpretation and comparison of findings across investigations. Thus, a systematic review was conducted to analyze the effects of cocoa-derived polyphenols intake on human cognition and discuss the methodological aspects that may contribute to the heterogeneity of findings. Randomized clinical trials evaluating the effect of cocoa polyphenols on cognitive function in healthy subjects were selected according to selection criteria. Twelve studies were selected. Quality was assessed according to the Cochrane risk for bias tool. The most common risk for bias was the lack of information about the sequence generation process. Effects on cognitive function were observed after consumption of 50 mg/day of (−)-epicatechin and in studies using a component-matched placebo and cocoa as the polyphenol vehicle given to healthy adults (18–50 years). Memory (n = 5) and executive function (n = 4) showed the most significant effects with medium and large effect sizes after intake of intermediate doses of cocoa flavanols (500–750 mg/day). Overall, this set of studies suggest a positive effect of cocoa polyphenols on memory and executive function. However, the available evidence is very diverse and future studies may address the identified sources of variation to strengthen current evidence on this promising field.

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Fig. 1


  1. 1.

    Scalbert A, Williamson G (2000) Dietary intake and bioavailability of polyphenols. J Nutr 130(8S Suppl):2073S–2085S.

  2. 2.

    Tsao R (2010) Chemistry and biochemistry of dietary polyphenols. Nutrients 2(12):1231-1246.

  3. 3.

    Abbas M, Saeed F, Anjum FM, Afzaal M, Tufail T, Bashir MS, Ishtiaq A, Hussain S, Suleria HAR (2017) Natural polyphenols: an overview. Int J Food Prop 20(8):1689–1699.

  4. 4.

    Vogiatzoglou A, Mulligan AA, Luben RN, Lentjes MAH, Heiss C, Kelm M, Merx MW, Spencer JPE, Schroeter H, Kuhnle GGC (2014) Assessment of the dietary intake of total flavan-3-ols, monomeric flavan-3-ols, proanthocyanidins and theaflavins in the European Union. Br J Nutr 111(8):1463–1473.

  5. 5.

    Vogiatzoglou A, Mulligan AA, Bhaniani A, Lentjes MAH, McTaggart A, Luben RN, Heiss C, Kelm M, Merx MW, Spencer JR, Schroeter H, Khaw KT, Kuhnle GGC (2015) Associations between flavan-3-ol intake and CVD risk in the Norfolk cohort of the European prospective investigation into cancer (EPIC-Norfolk). Free Radic Biol Med 84:1–10.

  6. 6.

    Gu L, House SE, Wu X, Ou B, Prior RL (2006) Procyanidin and catechin contents and antioxidant capacity of cocoa and chocolate products. J Agric Food Chem 54(11):4057–4061.

  7. 7.

    Andujar I, Recio MC, Giner RM, Rios JL (2012) Cocoa polyphenols and their potential benefits for human health. Oxid Med Cell Long 906252.

  8. 8.

    Adamson GE, Lazarus SA, Mitchell AE, Prior RL, Cao G, Jacobs PH, Kremers BG, Hammerstone JF, Rucker RB, Ritter KA, Schmitz HH (1999) HPLC method for the quantification of procyanidins in cocoa and chocolate samples and correlation to total antioxidant capacity. J Agric Food Chem 47(10):4184–4188

  9. 9.

    Katz DL, Doughty K, Ali A (2011) Cocoa and chocolate in human health and disease. Antioxid Redox Signal 15(10):2779–2811.

  10. 10.

    Tomas-Barberan FA, Cienfuegos-Jovellanos E, Marin A, Muguerza B, Gil-Izquierdo A, Cerda B, Zafrilla P, Morillas J, Mulero J, Ibarra A, Pasamar MA, Ramon D, Espin JC (2007) A new process to develop a cocoa powder with higher flavonoid monomer content and enhanced bioavailability in healthy humans. J Agric Food Chem 55(10):3926–3935.

  11. 11.

    Serafini M, Bugianesi R, Maiani G, Valtuena S, De Santis S, Crozier A (2003) Plasma antioxidants from chocolate. Nature 424(6952):1013.

  12. 12.

    Actis-Goretta L, Leveques A, Giuffrida F, Romanov-Michailidis F, Viton F, Barron D, Duenas-Paton M, Gonzalez-Manzano S, Santos-Buelga C, Williamson G, Dionisi F (2012) Elucidation of (−)-epicatechin metabolites after ingestion of chocolate by healthy humans. Free Radic Biol Med 53(4):787–795.

  13. 13.

    Ottaviani JI, Borges G, Momma TY, Spencer JP, Keen CL, Crozier A, Schroeter H (2016) The metabolome of [2-(14)C](−)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives. Sci Rep 6:29034.

  14. 14.

    Mena P, Bresciani L, Brindani N, Ludwig IA, Pereira-Caro G, Angelino D, Llorach R, Calani L, Brighenti F, Clifford MN, Gill CIR, Crozier A, Curti C, Del Rio D (2019) Phenyl-gamma-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivity. Nat Prod Rep 36(5):714–752.

  15. 15.

    Duenas M, Gonzalez-Manzano S, Gonzalez-Paramas A, Santos-Buelga C (2010) Antioxidant evaluation of o-methylated metabolites of catechin, epicatechin and quercetin. J Pharm Biomed Anal 51(2):443–449.

  16. 16.

    Ottaviani JI, Momma TY, Kuhnle GK, Keen CL, Schroeter H (2012) Structurally related (−)-epicatechin metabolites in humans: assessment using de novo chemically synthesized authentic standards. Free Radic Biol Med 52(8):1403–1412.

  17. 17.

    Figueira I, Garcia G, Pimpao RC, Terrasso AP, Costa I, Almeida AF, Tavares L, Pais TF, Pinto P, Ventura MR, Filipe A, McDougall GJ, Stewart D, Kim KS, Palmela I, Brites D, Brito MA, Brito C, Santos CN (2017) Polyphenols journey through blood-brain barrier towards neuronal protection. Sci Rep 7(1):11456.

  18. 18.

    Unno K, Pervin M, Nakagawa A, Iguchi K, Hara A, Takagaki A, Nanjo F, Minami A, Nakamura Y (2017) Blood-brain barrier permeability of green tea catechin metabolites and their neuritogenic activity in human Neuroblastoma SH-SY5Y cells. Mol Nutr Food Res 61(12).

  19. 19.

    Noe V, Penuelas S, Lamuela-Raventos RM, Permanyer J, Ciudad CJ, Izquierdo-Pulido M (2004) Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr 134(10):2509–2516

  20. 20.

    Sudano I, Flammer AJ, Roas S, Enseleit F, Ruschitzka F, Corti R, Noll G (2012) Cocoa, blood pressure, and vascular function. Curr Hypertens Rep 14(4):279–284.

  21. 21.

    Sorond FA, Lipsitz LA, Hollenberg NK, Fisher ND (2008) Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr Dis Treat 4(2):433–440

  22. 22.

    Corti R, Flammer AJ, Hollenberg NK, Luscher TF (2009) Cocoa and cardiovascular health. Circulation 119(10):1433–1441.

  23. 23.

    Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, Desideri G, Blumberg JB, Ferri C (2005) Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 46(2):398–405.

  24. 24.

    Muniyappa R, Hall G, Kolodziej TL, Karne RJ, Crandon SK, Quon MJ (2008) Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension. Am J Clin Nutr 88(6):1685–1696.

  25. 25.

    Perez-Cano FJ, Massot-Cladera M, Franch A, Castellote C, Castell M (2013) The effects of cocoa on the immune system. Front Pharmacol 4:71.

  26. 26.

    Camps-Bossacoma M, Massot-Cladera M, Abril-Gil M, Franch A, Perez-Cano FJ, Castell M (2017) Cocoa diet and antibody immune response in preclinical studies. Front Nutr 4:28.

  27. 27.

    Maskarinec G (2009) Cancer protective properties of cocoa: a review of the epidemiologic evidence. Nutr Cancer 61(5):573–579.

  28. 28.

    Selmi C, Mao TK, Keen CL, Schmitz HH, Eric Gershwin M (2006) The anti-inflammatory properties of cocoa flavanols. J Cardiovasc Pharmacol 47(Suppl 2):S163–S171 discussion S172-166

  29. 29.

    Ellinger S, Stehle P (2016) Impact of cocoa consumption on inflammation processes- a critical review of randomized controlled trials. Nutrients 8(6):321.

  30. 30.

    Hayek N (2013) Chocolate, gut microbiota, and human health. Front Pharmacol 4:11.

  31. 31.

    Macready AL, Kennedy OB, Ellis JA, Williams CM, Spencer JP, Butler LT (2009) Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies. Genes Nutr 4(4):227–242.

  32. 32.

    Socci V, Tempesta D, Desideri G, De Gennaro L, Ferrara M (2017) Enhancing human cognition with cocoa flavonoids. Front Nutr 4:19.

  33. 33.

    Muralidhara KG (2015) Bioactive nutraceuticals and dietary supplements in neurological and brain disease. Academic Press.

  34. 34.

    Heo HJ, Lee CY (2005) Epicatechin and catechin in cocoa inhibit amyloid beta protein induced apoptosis. J Agric Food Chem 53(5):1445–1448.

  35. 35.

    Schroeter H, Bahia P, Spencer JP, Sheppard O, Rattray M, Cadenas E, Rice-Evans C, Williams RJ (2007) (−)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. J Neurochem 101(6):1596–1606.

  36. 36.

    Abd El Mohsen MM, Kuhnle G, Rechner AR, Schroeter H, Rose S, Jenner P, Rice-Evans CA (2002) Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med 33(12):1693–1702

  37. 37.

    Mandel SA, Avramovich-Tirosh Y, Reznichenko L, Zheng H, Weinreb O, Amit T, Youdim MB (2005) Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals 14(1–2):46–60.

  38. 38.

    Nehlig A (2013) The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. Br J Clin Pharmacol 75(3):716–727.

  39. 39.

    van Praag H, Lucero MJ, Yeo GW, Stecker K, Heivand N, Zhao C, Yip E, Afanador M, Schroeter H, Hammerstone J, Gage FH (2007) Plant-derived flavanol (−)epicatechin enhances angiogenesis and retention of spatial memory in mice. J Neurosci 27(22):5869–5878.

  40. 40.

    Scholey A, Owen L (2013) Effects of chocolate on cognitive function and mood: a systematic review. Nutr Rev 71(10):665–681.

  41. 41.

    Sokolov AN, Pavlova MA, Klosterhalfen S, Enck P (2013) Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior. Neurosci Biobehav Rev 37(10 Pt 2):2445–2453.

  42. 42.

    RNaR K (2014) Improving cognitive function from children to old age: a systematic review of recent smart ageing intervention studies. Adv Neurosci 235479.

  43. 43.

    Barnes JN (2015) Exercise, cognitive function, and aging. Adv Physiol Educ 39(2):55–62.

  44. 44.

    Ramirez-Sanchez I, Aguilar H, Ceballos G, Villarreal F (2012) (−)-Epicatechin-induced calcium independent eNOS activation: roles of HSP90 and AKT. Mol Cell Biochem 370(1–2):141–150.

  45. 45.

    Moreno-Ulloa A, Mendez-Luna D, Beltran-Partida E, Castillo C, Guevara G, Ramirez-Sanchez I, Correa-Basurto J, Ceballos G, Villarreal F (2015) The effects of (−)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER). Pharmacol Res 100:309–320.

  46. 46.

    Fisher ND, Hughes M, Gerhard-Herman M, Hollenberg NK (2003) Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens 21(12):2281–2286.

  47. 47.

    Gasperotti M, Passamonti S, Tramer F, Masuero D, Guella G, Mattivi F, Vrhovsek U (2015) Fate of microbial metabolites of dietary polyphenols in rats: is the brain their target destination? ACS Chem Neurosci 6(8):1341–1352.

  48. 48.

    Dangour AD, Dodhia SK, Hayter A, Allen E, Lock K, Uauy R (2009) Nutritional quality of organic foods: a systematic review. Am J Clin Nutr 90(3):680–685.

  49. 49.

    Cochrane Handbook for Systematic Reviews of Interventions (2014) Online Kensaku 35(3): 154–155

  50. 50.

    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097.

  51. 51.

    Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, Cochrane Bias Methods Group, Cochrane Statistical Methods Group (2011) The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343:d5928.

  52. 52.

    Francis ST, Head K, Morris PG, Macdonald IA (2006) The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol 47(Suppl 2):S215–S220

  53. 53.

    Scholey AB, French SJ, Morris PJ, Kennedy DO, Milne AL, Haskell CF (2010) Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J Psychopharmacol 24(10):1505–1514.

  54. 54.

    Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, Raffaele A, Ferri L, Bocale R, Lechiara MC, Marini C, Ferri C (2012) Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the cocoa, cognition, and aging (CoCoA) study. Hypertension 60(3):794–801.

  55. 55.

    Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, Small SA (2014) Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci 17(12):1798–1803.

  56. 56.

    Massee LA, Ried K, Pase M, Travica N, Yoganathan J, Scholey A, Macpherson H, Kennedy G, Sali A, Pipingas A (2015) The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: a randomized, controlled trial. Front Pharmacol 6:93.

  57. 57.

    Mastroiacovo D, Kwik-Uribe C, Grassi D, Necozione S, Raffaele A, Pistacchio L, Righetti R, Bocale R, Lechiara MC, Marini C, Ferri C, Desideri G (2015) Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the cocoa, cognition, and aging (CoCoA) study--a randomized controlled trial. Am J Clin Nutr 101(3):538–548.

  58. 58.

    Neshatdoust S, Saunders C, Castle SM, Vauzour D, Williams C, Butler L, Lovegrove JA, Spencer JP (2016) High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: two randomised, controlled trials. Nutr Healthy Aging 4(1):81–93.

  59. 59.

    Karabay A, Saija JD, Field DT, Akyurek EG (2018) The acute effects of cocoa flavanols on temporal and spatial attention. Psychopharmacology 235(5):1497–1511.

  60. 60.

    Camfield DA, Scholey A, Pipingas A, Silberstein R, Kras M, Nolidin K, Wesnes K, Pase M, Stough C (2012) Steady state visually evoked potential (SSVEP) topography changes associated with cocoa flavanol consumption. Physiol Behav 105(4):948–957.

  61. 61.

    Pase MP, Scholey AB, Pipingas A, Kras M, Nolidin K, Gibbs A, Wesnes K, Stough C (2013) Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial. J Psychopharmacol 27(5):451–458.

  62. 62.

    Field DT, Williams CM, Butler LT (2011) Consumption of cocoa flavanols results in an acute improvement in visual and cognitive functions. Physiol Behav 103(3–4):255–260.

  63. 63.

    Crews WD Jr, Harrison DW, Wright JW (2008) A double-blind, placebo-controlled, randomized trial of the effects of dark chocolate and cocoa on variables associated with neuropsychological functioning and cardiovascular health: clinical findings from a sample of healthy, cognitively intact older adults. Am J Clin Nutr 87(4):872–880

  64. 64.

    Haskell-Ramsay CF, Schmitt J, Actis-Goretta L (2018) The impact of epicatechin on human cognition: the role of cerebral blood flow. Nutrients 10(8).

  65. 65.

    Barrera-Reyes PK, Hernandez-Ramirez N, Cortes J, Poquet L, Redeuil K, Rangel-Escareno C, Kussmann M, Silva-Zolezzi I, Tejero ME (2018) Gene expression changes by high-polyphenols cocoa powder intake: a randomized crossover clinical study. Eur J Nutr 58:1887–1898.

  66. 66.

    Actis-Goretta L, Leveques A, Giuffrida F, Destaillats F, Nagy K (2012) Identification of O-methyl-(−)-epicatechin-O-sulphate metabolites by mass-spectrometry after O-methylation with trimethylsilyldiazomethane. J Chromatogr A 1245:150–157.

  67. 67.

    Manach C, Milenkovic D, Van de Wiele T, Rodriguez-Mateos A, de Roos B, Garcia-Conesa MT, Landberg R, Gibney ER, Heinonen M, Tomas-Barberan F, Morand C (2017) Addressing the inter-individual variation in response to consumption of plant food bioactives: towards a better understanding of their role in healthy aging and cardiometabolic risk reduction. Mol Nutr Food Res 61(6).

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PBR and JCN were supported by the NESTLE-INMEGEN Chair for Nutrigenomics.


This research received no external funding.

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All authors contributed to the writing of this review.

Correspondence to M Elizabeth Tejero.

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Barrera-Reyes, P.K., de Lara, J.C., González-Soto, M. et al. Effects of Cocoa-Derived Polyphenols on Cognitive Function in Humans. Systematic Review and Analysis of Methodological Aspects. Plant Foods Hum Nutr (2020).

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  • Chocolate
  • Flavanols
  • Cocoa flavanols
  • Epicatechin
  • Cognition
  • Brain function
  • Research methods