Bioactive flavonoids include several subclasses, among them flavanols, a group of monomeric flavan-3-ols and their oligomeric or polymeric counterparts, procyanidins. Epicatechin and catechin are flavan-3-ols found abundantly in tea (Camellia sinensis, Theaceae), apples (Malus pumila syn. M. domestica, Rosaceae), berries (many genera and species), grapes (Vitis vinifera, Vitaceae), and most notably cocoa (Theobroma cacao, Malvaceae), whose main bioactive compound is epicatechin. Epidemiological studies indicate a positive link between epicatechin-rich foods and cognition, including reports of reduced risk for dementia and cognitive decline, and better scores on task performance with higher flavonoid intake. In older Asian and Norwegian cohorts, tea drinkers generally had less cognitive decline based on task performance scores than non-tea drinkers. In a Norwegian cohort, wine (from grape) drinkers also had better performance scores than non-wine drinkers; cocoa consumers also had significantly better scores than non-chocolate consumers on five of six tasks. Epidemiological studies do not permit determination of cause and effect. They have not evaluated the effects of epicatechin but of complex foods and beverages with many other compounds that may affect cognition. Effects of green tea, for example, are as often attributed to its epigallocatechin-e-gallate (EGCG) as to epicatechin. No randomized placebo-controlled trials (RCTs) of epicatechin and human cognition have been reported. The authors review RCTs and mechanistic studies using cocoa flavanols (CFs) with determined amounts of epicatechin.
CFs have been studied in young adults, including young women, middle-aged people, and older adults, but mostly in separate, differently-designed RCTs. Unsurprisingly, results also differ; however, supplementation over longer periods has produced better results than acute dosing, and cognitive benefits may be more evident in older people than younger adults, including improved mood and feelings of contentment. This is attributed to a “ceiling effect” in young people functioning close to their maximum ability. Acute CF doses have mostly been studied in young adults (<40 years of age); seven of nine such trials report cognitive benefits. One study of CF supplementation in middle-aged people showed no benefits. Improvements in performance were not seen after 24 hours or four weeks of CF supplementation in older adults who had hypertension or type 2 diabetes, but improvements have been reported in healthy older adults. In older adults, data from electrophysiological brain imaging indicate the possibility that CF benefits may be due to improved neural efficiency, or the ability to perform the same task with less neural activation; improved efficiency may result in better or faster performance scores. Twelve weeks supplementation with high-dose CFs (900 mg/day; 138 mg epicatechin) brought faster responses than a matched low CF control on a Modified-Benton test. The 630-millisecond advantage “equates to around three decades of aging” and included slower responses in the control group from baseline and faster responses in the high CF group. Reaction times were inversely related to cerebral blood volume changes in the dentate gyrus area of the hippocampus, an exciting basis for future studies.
Potential mechanisms for the effects of flavanols on brain health need further exploration. The previous emphasis on antioxidant properties has begun to be supplanted by impacts on synaptic plasticity through a cascade of cell signaling mechanisms. Difficulty in assigning specific mechanisms of action for epicatechin is increased by its less robust effects on biomarkers in vitro than in vivo due to limited in vivo absorption. Extensive conjugation of flavanols occurs in the small and large intestine, liver, and in cells; the gut microbiota, in particular, is subject to variation. Given the importance of the microbiota to flavanol metabolization, studies that limit polyphenol intake may unintentionally negatively affect its composition and thus flavanol bioavailability. CFs have shown prebiotic effects in fecal samples. Flawed methodologies and a lack of purified standards hamper research. Studies of epicatechin conjugates have had small sample sizes and, as with RCTs, differing designs that limit comparability. Furthermore, while epicatechin has been shown to cross the blood-brain barrier (BBB) in vitro and to be conjugated with glucuronic acid in endothelial cells, and other data support the probable ability of epicatechin and its metabolites to enter the brain, there is no evidence of biological activity of any of its metabolites that would exert direct brain effects.
Indirect effects that have received some research attention include improved blood flow. Cocoa intake is linked to a lowered risk of several blood flow-related conditions and, in intervention studies, positive effects on blood pressure and platelet function. Cocoa exerts a specific effect on endothelial function as demonstrated by increased flow-mediated dilation (FMD), whether taken habitually, acutely or acutely after chronic increase. Increased FMD has been reported in young and elderly participants following acute and two-week supplementation of epicatechin in cocoa; a lack of similar results in a study of four weeks duration may have been due to the low dose used or the epicatechin source, acacia (Acacia spp., Fabaceae) heartwood extracted with aqueous alcohol. Cerebral blood flow (CBF) increases with acute CF consumption by young and older adults. A reduction in CBF velocity after milk or dark chocolate consumption compared to white chocolate was interpreted as indicating increased CF-mediated cerebrovascular efficiency in post-menopausal women. The relationship of CF intake to endothelial function and higher levels of plasma nitric oxide (NO) is extremely complex and requires further study. A wealth of evidence indicates the importance of increases in plasma NO metabolites following intake of flavanol-rich food and epicatechin to CFs’ effects on CBF and peripheral blood flow. To more fully understand epicatechin’s effects, it is important that future studies concurrently measure CBF and cognition. Several additional research needs and complexities are detailed.
Two authors are employees of Nestec SA (Lausanne, Switzerland; Singapore, China), a subsidiary of Nestlé Ltd. (Vevey, Switzerland),
Haskell-Ramsay CF, Schmitt J, Actis-Goretta L. The impact of epicatechin on human cognition: the role of cerebral blood flow. Nutrients. July 2018;10(8):E986 doi: 10.3390/nu10080986.