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Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies

Sansone, Roberto, Ottaviani, Javier I, Rodriguez-Mateos, Ana, Heinen, Yvonne, Noske, Dorina, Spencer, Jeremy P, Crozier, Alan, Merx, Marc W, Kelm, Malte, Schroeter, Hagen and Heiss, Christian (2016) Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies The American Journal of Clinical Nutrition, 105 (2). pp. 352-360.

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Cocoa flavanol intake, especially that of (−)-epicatechin, has been linked to beneficial effects on human cardiovascular function. However, cocoa also contains the methylxanthines theobromine and caffeine, which may also affect vascular function.


We sought to determine whether an interaction between cocoa flavanols and methylxanthines exists that influences cocoa flavanol–dependent vascular effects.


Test drinks that contained various amounts of cocoa flavanols (0–820 mg) and methylxanthines (0–220 mg), either together or individually, were consumed by healthy volunteers (n = 47) in 4 different clinical studies—3 with a randomized, double-masked crossover design and 1 with 4 parallel crossover studies. Vascular status was assessed by measuring flow-mediated vasodilation (FMD), brachial pulse wave velocity (bPWV), circulating angiogenic cells (CACs), and blood pressure before and 2 h after the ingestion of test drinks.


Although cocoa flavanol intake increased FMD 2 h after intake, the consumption of cocoa flavanols with methylxanthines resulted in a greater enhancement of FMD. Methylxanthine intake alone did not result in statistically significant changes in FMD. Cocoa flavanol ingestion alone decreased bPWV and diastolic blood pressure and increased CACs. Each of these changes was more pronounced when cocoa flavanols and methylxanthines were ingested together. It is important to note that the area under the curve of the plasma concentration of (−)-epicatechin metabolites over time was higher after the co-ingestion of cocoa flavanols and methylxanthines than after the intake of cocoa flavanols alone. Similar results were obtained when pure (−)-epicatechin and the methylxanthines theobromine and caffeine were consumed together.


A substantial interaction between cocoa flavanols and methylxanthines exists at the level of absorption, in which the methylxanthines mediate an increased plasma concentration of (−)-epicatechin metabolites that coincides with enhanced vascular effects commonly ascribed to cocoa flavanol intake.

This trial was registered at as NCT02149238.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Sansone, Roberto
Ottaviani, Javier I
Rodriguez-Mateos, Ana
Heinen, Yvonne
Noske, Dorina
Spencer, Jeremy P
Crozier, Alan
Merx, Marc W
Kelm, Malte
Schroeter, Hagen
Date : 21 December 2016
DOI : 10.3945/ajcn.116.140046
Uncontrolled Keywords : cocoa flavanols, methylxanthines, cardiovascular function, interaction, absorption
Depositing User : Melanie Hughes
Date Deposited : 16 Aug 2018 13:32
Last Modified : 16 Aug 2018 13:32

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