IngredientsFlavanols — formally designated flavan-3-ols in chemical nomenclature — are a distinct subclass of the flavonoid family of plant polyphenols. Flavanols are also referred to as flavan-3-ols because the hydroxyl group is always bound to position 3 of the C ring. As a distinct sub-group of flavonoids, flavanols are broadly characterized by the absence of a double bond between C-2 and C-3 and the absence of a carbonyl group on the C ring (C-4), while featuring a hydroxyl group(s) on C-3 or C-4.
Four main types of flavanols have been found in nature: (i) flavan-3-ols, (ii) flavan-4-ols, (iii) isoflavan-4-ols, and (iv) flavan-3,4-ols. Flavan-3-ols are the most commonly reported among the four types, followed by flavan-4-ols and flavan-3,4-ols, and lastly, isoflavan-4-ols. The principal individual monomeric flavan-3-ols found in human food and studied in clinical research include (+)-catechin, (−)-epicatechin, (−)-epigallocatechin (EGC), (−)-epigallocatechin gallate (EGCG), and (−)-epicatechin gallate (ECG). Catechin and epicatechin differ at the stereochemistry around the 2 and 3 positions of the central heterocyclic ring: catechin is 2,3-trans whereas epicatechin is 2,3-cis.
Flavanols also occur as oligomeric and polymeric structures. In natural sources, they may occur in free forms (aglycones), as glycosylated or acylated derivatives, and as oligomeric and polymeric structures such as the flavan-3-ol-derived condensed tannins (or proanthocyanidins). Proanthocyanidins (PACs), which are oligomers or polymers of flavan-3-ols, possess potent antioxidative activity and are known to exert a variety of beneficial health effects. In cocoa, these oligomeric chains are specifically called procyanidins. The unique blend of compounds in the cocoa bean are called cocoa flavanols, and include simple forms such as (−)-epicatechin and (+)-catechin, as well as linked chains of flavanols known as procyanidins.
The term "flavanols" is sometimes used loosely interchangeably with "catechins," though strictly speaking, catechins refers to the monomeric forms, while flavanols as a class encompasses both monomers and their polymeric derivatives. Flavanols, sometimes called flavan-3-ols or catechins, are a type of chemical compound found in various fruits, vegetables, and plants.
Flavanols are among the most widely distributed plant polyphenols. Flavanols have been found in common foods, including cereals, legumes, fruits, vegetables, forages, hops, beers, red wine, tea, cocoa, grapes, and apples.
Among dietary polyphenols more broadly, the most abundant flavonoids in the diet are flavanols (catechins plus proanthocyanidins), anthocyanins, and their oxidation products. In terms of phenolic potency, cocoa has more phenolics and higher antioxidant capacity than green tea, black tea, or red wine.
Cocoa processing clearly affects the flavanol and methylxanthine content of the final product and therefore affects its potential biological activity. Despite the health benefits associated with the ingestion of the bioactive compounds in cocoa, the high concentrations of polyphenols in raw cocoa beans negatively influence taste, confer astringency and bitterness, and affect digestibility. It is therefore necessary to process cocoa beans to develop the characteristic color, taste, and flavor. Processing, however, affects the composition and quantities of the bioactive compounds, resulting in modification of the health-promoting properties of cocoa beans and chocolate.
Flavan-3-ol bioavailability depends on numerous factors, including digestive release, absorption, metabolism, and elimination. In addition to these in vivo factors, the complexity of whole-food systems — including physical form, flavan-3-ol form and dose, macronutrient and micronutrient profile, and processing — influences the absorption efficiency and circulating profile of flavan-3-ols.
Flavanols are available in a variety of forms, both as dietary constituents and as concentrated supplements:
The most extensively documented traditional use of flavanol-rich plants relates to Theobroma cacao. Cocoa beans are native to South America, and various cultures including the Aztecs and Mayans first consumed them thousands of years ago. These cultures used cocoa beans as a stimulant, which they believed could reduce fatigue. Cocoa is made from the bean of the cacao tree, Theobroma cacao, and has a long history of medicinal use and potential health benefits based upon its flavanol and procyanidin content, also found in tea, grapes, wine, and other foods.
Flavanols are found in the beans of the cocoa tree (Theobroma cacao), native to Central or South America. Foods derived from cocoa beans were long prized in native cultures and later in Europe for their perceived medicinal qualities.
Camellia sinensis — the source of green, white, oolong, and black tea — has been cultivated and consumed in China and across East and Southeast Asia for thousands of years. Traditional Chinese Medicine (TCM) used tea preparations for their purported properties in supporting digestion, alertness, and overall vitality. Green tea, which undergoes minimal oxidation and therefore retains high levels of EGCG and other flavan-3-ols, has been consumed ceremonially and medicinally across China, Japan, and Korea.
The primary bioactive monomeric flavanols identified in research include:
Flavonoids are natural substances synthesized in several parts of plants that exhibit high antioxidant capacity. They are a large family presenting several classes based on their basic structure. Flavonoids have the ability to control the accumulation of reactive oxygen species (ROS) by scavenging ROS when they are formed. Several in vitro and in vivo studies have reported the health-promoting effects of flavanol-rich foods (mainly green tea, cocoa, or grape seeds) and isolated flavanols (epigallocatechin gallate, epicatechin, procyanidins), playing an important role in protection against obesity, diabetes, and metabolic syndrome. They can modulate the immune system, inflammatory status, and gut microbiota due to the presence of 4–5 hydroxyl groups in their molecules, which provide them with prominent antioxidant potential.
A central and well-documented mechanism is the enhancement of nitric oxide (NO) bioavailability. Flavanols may act in part through signaling pathways that affect vascular function, nitric oxide availability, and the release of endothelial-derived relaxing and constricting factors. The modulatory effects of (poly)phenols on vasodilation and vascular tone via the nitric oxide (NO) signaling pathway have been well established. They can interact with signaling pathways involving kinases such as PI3K/Akt and eNOS, leading to an increase in NO production.
The bioavailability of cocoa flavanols is very low and their bioactivity in vivo seems to be greatly mediated by derived phenolic metabolites formed by intestinal microbiota. Microbial-derived flavanol metabolites including 3,4-dihydroxyphenylacetic acid (DHPAA), 2,3-dihydroxybenzoic acid (DHBA), and 3-hydroxyphenylpropionic acid (HPPA) can influence endothelial function; a mixture of flavanol colonic metabolites significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production.
The positive properties of flavanols have been associated with modulation of different molecular pathways, and importantly, to the regulation of immunological reactions (pro-inflammatory cytokines, chemokines, adhesion molecules, nuclear factor-κB [NF-κB], inducible enzymes), and the activity of cells of the immune system.
Flavanols can modulate the composition and function of the gut microbiome in a prebiotic-like manner, resulting in positive regulation of metabolic pathways and immune responses, and reduction of low-grade chronic inflammation. Flavanols are naturally occurring polyphenols abundant in fruits and vegetables to which beneficial effects on health have been attributed, including against metabolic diseases such as diabetes, obesity, and metabolic syndrome. The biotransformation of flavanols by gut bacteria increases their bioavailability, generating a number of metabolites with potential to affect human metabolism, including during metabolic diseases.
Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. Dietary consumption of cocoa flavanols may slow cognitive decline through beneficial effects on cerebral vasodilation, and thus on brain blood flow and perfusion, and angiogenesis.
The cardiovascular effects of flavanols — particularly from cocoa and tea — constitute the most extensively studied and robustly evidenced area of flavanol research. Evidence spans in vitro studies, short-term randomized controlled trials, meta-analyses, and one landmark large-scale trial.
Meta-analyses of RCTs: A meta-analysis searched PubMed for randomized controlled trials published from 1946 through March 2024 on blood pressure and flow-mediated dilation (FMD) after flavan-3-ol-rich food, beverage, or supplement intake. A random-effects meta-analysis of 109 publications including 145 RCTs and 5,205 participants was performed. Flavan-3-ol interventions included epicatechin, epigallocatechin-gallate, cocoa products, tea, grape extract, and apples delivering 586 mg (95% CI 510–662) total flavan-3-ols. Interventions decreased office blood pressure by −2.8/−2.0 mmHg and 24-hour ambulatory BP by −3.7/−2.6 mmHg after chronic repetitive consumption. This analysis of 145 studies shows that foods containing high amounts of flavan-3-ols including tea, cocoa, apples, and grapes possess vascular health effects and should be considered for cardiovascular prevention. Flavan-3-ol-rich foods and supplements decrease blood pressure particularly in people with high blood pressure when consumed daily.
Earlier meta-analytic evidence: Meta-analyses of combined flavonoid subclasses showed significant improvements in flow-mediated dilation (FMD) — both chronic (0.73%, 14 RCTs) and acute (2.33%, 18 RCTs) — and systolic blood pressure (−1.46 mmHg).
Endothelial function: Clinical trials have focused on markers of three key players of atherosclerosis, such as inflammation, platelet aggregation, and NO-induced vasodilatation. In vivo and in vitro studies in various study populations indicate that cocoa flavanol intake improves endothelial function, mediated by increased FMD, by increasing NO activity and reducing oxidative stress as well as inflammatory markers. Clinical trials included in systematic reviews showed that supplementation with flavan-3-ols, mostly derived from cocoa products, significantly reduces blood pressure and improves endothelial function. Studies on catechins from green tea demonstrated better results when involving healthy individuals.
Platelet function: There are clinical trials indicating that platelet aggregation is reduced 2 to 6 hours after cocoa flavanol ingestion. This beneficial effect might be limited or absent in older patients and/or in patients with advanced coronary artery disease.
The Flaviola Health Study (RCT): In a randomised, controlled, double-masked, parallel-group dietary intervention trial (NCT01799005), 100 healthy, middle-aged (35–60 years) men and women consumed either a cocoa-flavanol-containing drink (450 mg) or a nutrient-matched flavanol-free control twice daily for 1 month. The primary endpoint was FMD, with secondary endpoints including plasma lipids and blood pressure. Flavanols are one of the few bioactives for which causality between intake and improvement in arterial function has been formally demonstrated. A recent meta-analysis of forty-two randomised controlled human dietary intervention studies demonstrated significant acute and chronic flavanol-dependent cardiovascular benefits. The observed cardiovascular benefits include recovery of endothelial function, a decrease in blood pressure, and improvements in lipids and insulin.
The COSMOS Trial (large-scale RCT): The most definitive and largest trial to date was the COcoa Supplement and Multivitamin Outcomes Study. This was a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of cardiovascular disease and cancer among 21,442 US adults (12,666 women aged ≥65 years and 8,776 men aged ≥60 years), free of major cardiovascular disease and recently diagnosed cancer. The intervention phase ran from June 2015 through December 2020. Participants were randomly assigned to a cocoa extract supplement (500 mg flavanols/day, including 80 mg (−)-epicatechin) or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction, stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.
During a median follow-up of 3.6 years, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 for MI, 0.91 for stroke, and 0.95 for coronary revascularization. Per-protocol analyses censoring follow-up at non-adherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%.
Evidence strength: The body of evidence for flavanols' short-term effects on endothelial function and blood pressure is robust — based on over 100 RCTs and multiple meta-analyses showing consistent, statistically significant effects. The COSMOS trial provides promising but not conclusive evidence for hard cardiovascular event reduction; the primary composite endpoint did not reach statistical significance, though there was a significant reduction in cardiovascular death as a secondary endpoint. Further long-term trials are needed to establish clinical event prevention definitively.
A growing body of research examines the effects of flavanols — primarily cocoa flavanols — on brain function, memory, and cognitive aging.
Cerebrovascular reactivity (acute RCT): In a randomized double-blind within-subject acute study in healthy young adults, flavanol intake led to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand was high. Participants who benefited from flavanol intake during hypercapnia were also those who benefited in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols.
CoCoA Study (RCT in elderly): This double-blind, controlled, parallel-arm study was conducted in 90 elderly individuals without clinical evidence of cognitive dysfunction who were randomly assigned to consume daily for 8 weeks a drink containing 993 mg (high flavanol), 520 mg (intermediate flavanol), or 48 mg (low flavanol) cocoa flavanols. Cognitive function was assessed at baseline and after 8 weeks using the MMSE, Trail Making Test A and B, and Verbal Fluency Test. The changes in MMSE score in response to the 3 different treatments were not different. The trial did report improvements in other cognitive performance measures and cardiometabolic parameters at higher flavanol doses.
Hippocampal-dependent memory (RCT): A randomized clinical trial in older adults showed that high dietary intake of cocoa flavanols enhances memory performance and neural function in the dentate gyrus of the hippocampus, a region critical for learning and memory.
COSMOS-Web (large-scale RCT on memory): Results from the COSMOS-Web ancillary trial, which involved 3,960 participants from COSMOS, were published. Participants were randomized to a daily dose of 500 mg cocoa flavanols or placebo for 3 years. Individuals in the intervention arm experienced a modest improvement in hippocampal-dependent memory. These benefits were more pronounced among older adults who had a poor intake of flavanols at baseline — these individuals showed an average increase of 10.5% in memory scores compared with the placebo group, and a 16% increase in their memory scores from baseline.
COSMOS-Mind (RCT on MCI/dementia incidence): The COSMOS-Mind study (N=2,262) was a 2×2 factorial randomized controlled clinical trial administering a telephone-based cognitive battery at baseline and annually for 3 years. Over 3 years, 110 incident MCI and 14 incident dementia cases were adjudicated. Incidence rates did not vary by assignment to multivitamin-mineral or cocoa extract, though statistical power was low.
Evidence strength: Evidence for flavanol benefits on memory — particularly hippocampal-dependent memory in older adults with lower dietary flavanol intake — is promising from several RCTs including the large COSMOS-Web sub-study. However, the effects on global cognition and dementia incidence remain uncertain. The COSMOS-Clinic subcohort did not show a statistically significant benefit on broader cognitive composites. Results are most consistent for individuals with low baseline flavanol intake.
Experimental and clinical studies testing the consumption of cocoa products and cocoa flavanols have noted potential benefits on platelet activation, endothelium-dependent vasodilation, inflammation, blood pressure, and insulin resistance, which may translate into important cardiovascular benefits.
Prospective cohort studies have reported an inverse association between dietary flavanols — at lower concentrations than tested in COSMOS — with cardiovascular disease, carotid atherosclerosis, hypertension, and type 2 diabetes. However, large randomized controlled trials specifically designed to test flavanols' effect on incident type 2 diabetes as a primary endpoint remain limited. Current evidence is primarily observational or from secondary endpoints in cardiovascular trials.
Clinical trials investigating the influence of cocoa flavanol on blood lipids have shown conflicting results. Observed cardiovascular benefits in some trials include improvements in lipids and insulin. The evidence base for lipid lowering as a primary outcome from flavanol supplementation is currently considered mixed, and no consensus exists on a clinically meaningful effect size.
Cocoa extract had no effect on total and site-specific cancers in the COSMOS trial. Several mechanisms have been proposed for flavanols on the inhibition of proliferation, inflammation, invasion, metastasis, and activation of apoptosis. Supplementation had no effect on total and site-specific cancers even though several mechanisms have been proposed for flavanols on the inhibition of these processes. The mechanistic rationale exists at the preclinical level, but human clinical evidence for flavanols reducing cancer risk is currently insufficient.
Diets and plant extracts rich in flavanols have been reported to lower blood pressure and improve exercise performance in humans. Epidemiological and clinical studies suggest that dietary flavanols can be an important modulator of vascular risk. Further research is needed to clarify the amount, timing, and frequency of flavanol intake for blood pressure regulation and exercise performance. Evidence in this domain is preliminary, with most studies small in scale and limited in duration.
Two regulatory bodies have evaluated the evidence for cocoa flavanols and issued formal opinions:
Dosages used across clinical studies vary substantially depending on the flavanol source and the health outcome studied. The following dosages are drawn directly from cited research:
Bioavailability of flavanols from food and supplements is an important factor modulating their physiological effects. The maximum concentration in plasma rarely exceeds 1 μM after the consumption of 10–100 mg of a single phenolic compound. Monomeric catechins such as epicatechin are more readily absorbed in the small intestine, while larger procyanidins are more dependent on colonic microbial metabolism for bioactivation.
In a study on the bioavailability of cocoa polyphenols in healthy volunteers, Tomás-Barberán et al. demonstrated that the flavonoid composition (mainly flavanol monomers and dimers) of cocoa powder can be enhanced through improved processing of the raw material and that these flavanol-enriched samples lead to increases in the cocoa flavan-3-ols present in plasma and urine, thus increasing their bioavailability.
The role of gut microbiota in flavanol bioactivity is increasingly recognized. From a mechanistic point of view, emerging evidence suggests that microbial metabolites may play a role in the observed cardiovascular effects of flavan-3-ols.
Cocoa and chocolate products are generally safe at typical consumption levels. In a three-month study of healthy men and women, doses up to 1,000 mg of cocoa flavanols from cocoa extract taken twice daily with meals were safe and well-tolerated, with no significant changes in blood pressure, platelet function, cholesterol, or heart rate.
The most common side effects from cocoa extract supplements are gastrointestinal: nausea, stomach discomfort, and digestive upset. These are more frequent when taken on an empty stomach. The COSMOS trial corroborated this: those taking the active cocoa extract supplement were 6% more likely to have nausea, although treatment was broadly well tolerated. There were no safety concerns identified in the COSMOS trial.
Some human studies have shown that high doses of green tea preparations can be potentially toxic. Concentrated green tea extract (EGCG) supplements at very high doses have been associated with rare but serious cases of liver toxicity in the literature. This is distinct from flavanols consumed as food-source tea beverages at typical consumption levels.
Because flavanols have demonstrated antiplatelet effects in clinical trials, platelet aggregation is reduced 2 to 6 hours after cocoa flavanol ingestion. Individuals taking anticoagulant or antiplatelet medications (e.g., warfarin, aspirin, clopidogrel) should be aware that flavanol supplementation at high doses may have additive effects on platelet function, though the clinical significance of this interaction at usual dietary doses has not been definitively established in controlled trials.
Polyphenols, including flavanols, are known to chelate non-heme iron and can reduce its absorption when consumed together with iron-rich meals. This is a well-established interaction for tea polyphenols in particular. Individuals with iron-deficiency anemia or at risk of deficiency should be mindful of consuming high-flavanol tea or supplements concurrent with iron-rich foods or iron supplements.
Cocoa- and tea-derived flavanol products typically co-occur with caffeine and, in the case of cocoa, theobromine. The bean extract also contains methylxanthines (like theobromine and caffeine). Individuals who are sensitive to stimulants should account for methylxanthine content when selecting flavanol sources or extracts.
EGCG and other catechins have been shown in pharmacokinetic studies to interact with cytochrome P450 enzyme pathways, potentially affecting the metabolism of certain medications. The clinical magnitude and relevance of these interactions at dietary intake levels requires individualized consideration based on the specific drug involved.
Health conditions that Flavanols may help support.
Body systems that Flavanols may help support.
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