Effect of Fortified Cocoa-Based Products with Cocoa Flavanols: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Celia Rodriguez-Pérez.

Cocoa’s healthy benefits may be attributed to the potent antioxidant activity of cocoa polyphenols, mainly flavanols, which have been characterised as existing in a high concentration in cocoa. However, the phenolic composition of cocoa and cocoa-derived products is highly variable, and manufacturing processes might significantly reduce their phenolic content. For that reason, the full characterisation of cocoa and cocoa-derived products before evaluating their bioactivity is crucial. Although studies differ widely in methodology, dosage, duration, and target population, beneficial effects of flavanol-rich cocoa consumption have been observed at doses ranging from 45.3 mg/d to 1078 mg/d, especially on cardiovascular health and cognitive function. It should be noted that some cocoa-derived products contain added sugars and additional fats that could have harmful effects, so consumption of such products should be occasional and moderate. It is also for this reason that the fortification of such products with cocoa flavanols could be effective in enhancing their beneficial effects whilst maintaining a lower level of consumption.

  • cocoa
  • flavanols
  • fortified
  • human health
  • cardiovascular health

1. Introduction

Cocoa is extracted from cocoa beans that are the fatty seeds of the Theobroma cacao tree. For consumption, the Theobroma cacao beans are processed as a paste (‘cocoa liquor’) containing non-fat cocoa solids and cocoa butter. ‘Cocoa powder’ results from eliminating cocoa butter from the liquor. In contrast, ‘chocolate’ combines cocoa liquor with additional cocoa butter and sugar; it is frequently enhanced with other components such as nuts or milk [1]. In Europe, the average per capita chocolate consumption reached 5 kg per year in 2022, and it is expected to grow at an average annual rate of around 4.8% between 2022 and 2027 [2]. Cocoa is rich in phenolic compounds (PCs), with the highest content of these being present in pure cocoa powder, followed by baking chocolate and dark chocolate; the lowest polyphenol content is found in so-called “white chocolate”, which is made from the cocoa butter [3,4][3][4].
PCs are considered essential in diet. They are classified into various groups according to their chemical structure, with phenolic acids and flavonoids being the most abundant phenolic compounds in diet. Numerous studies have evaluated their effects on human health, attributing to them an important role in protecting the organism against external stimuli and in the elimination of reactive oxygen species [5]. PCs are synthetised by plants under normal and stress conditions and have various functions such as attracting insects for pollination and protecting against pathogens and ultraviolet radiation [6]. Thus, these compounds are present in foods such as tea, cocoa, fruits, vegetables, and honey, and their content varies widely depending on the variety, plant origin, agronomic and storage conditions, harvesting time, and climate, among other factors [7]. Improvements in lipid profiles, blood pressure, insulin resistance and systemic inflammation have been observed following consumption of PCs-rich foods, and these improvements are associated with improved cardiovascular health. In the central nervous system, these compounds counteract chronic and acute inflammatory processes, possess neuroprotective activity, and effectively reduce some signs and symptoms of neurodegenerative conditions, thus contributing to maintaining good brain health and overall quality of life [5].
The long-recognized health benefits of cocoa may be attributed to the potent antioxidant activity of cocoa polyphenols, mainly flavanols, which are found in cocoa in a higher concentration (460–610 mg/kg of flavanol monomers; 4–5 g/kg of flavanol polymers) than in other plant-derived foods such as beans, apricots, blackberries, apples, and tea leaves [8]. The main flavonoids contained in cocoa are flavan-3-ols and their oligomers and polymers (procyanidins). In addition, cocoa contains flavonoids such as epicatechin, quercetin and isoquercetin; flavones such as luteolin and apigenin; flavanones such as naringenin; anthocyanins and phenolic acids (Figure 1). These compounds are highly related to antioxidant activity [9]. Specifically, cocoa flavanols benefit the cardiovascular system, have anti-inflammatory properties, reduce insulin resistance and enhance the growth of beneficial gut microbiota [1,3,10,11][1][3][10][11]. In addition, cocoa consumption has numerous health benefits that potentiate cognitive function, although the actions of cocoa on the nervous system have scarcely been investigated [12]. Since 2014, it has been possible to claim that ‘cocoa flavanols help maintain the elasticity of blood vessels, which contributes to normal blood flow’ [13]. Nevertheless, it is important to note that the phenolic composition of cocoa and cocoa-derived products is highly variable, and their contents in foods can be influenced by factors such as the genotype of the cocoa plant (Forastero/Amazónico, Criollo or Trinitario), the region, the method of cultivation, and the manufacturing processes (fermentation, drying, roasting, and particularly alkalizing, which decreases the phenolic content) [11,14,15][11][14][15]. According to other published studies, the decrease in phenolic compounds is 2–4 g/100 g dry weight, as raw cocoa nibs contain 6–8 g/100 g dry weight and cocoa powder contains 4 g/100 g dry weight [16]. In addition, the roasting process results in the epimerisation of (−)-epicatechin to (−)-catechin, and the epimerisation of (+)-catechin to (−)-catechin, and alkalinization also increases the levels of (−)-catechin, which is absorbed more poorly than the (+)-enantiomer. Therefore, both cocoa and chocolate contain mainly (−)-epicatechin and a large amount of (−)-catechin (which is less fully absorbed), while the concentration of (+)-catechin is very low in contrast to raw cocoa beans [16].

2. Effects in Healthy Subjects

Table 1 shows the effects of HF cocoa on exercise performance and oxidative stress in healthy subjects. A study conducted with 44 male endurance athletes reported a significant increase from baseline in the plasma ratio of follistatin/myostatin by modifying the levels of follistatin. Follistatin promotes adipose tissue browning and decreases body fat levels, and counteracts the myostatin blockade of muscle growth, making it an indicator of improved muscle function. Moreover, a decrease in body fat after 10 weeks of flavanol-rich cocoa consumption (425 mg flavanols/day) was observed. However, this may have led to a decrease in leptin levels (the hormone secreted by adipose tissue that sends the satiety signal to the brain, promotes lipolysis and depresses lipogenesis) [17]. In contrast, Patel et al. [18] observed no effects on exercise performance after a single dose of a chocolate bar containing from 88 to 1060 mg of flavanols in a study involving 15 healthy subjects aged 30 years on average. On the other hand, consumption of HF cocoa containing 425 mg of flavanols for 10 weeks reduced oxidative stress in a study with 56 male endurance athletes; however, no effects on aerobic capacity or exercise performance were observed [19]. Another study with 20 healthy men also reported a significant decrease in oxidative stress after a single dose of an HF cocoa drink (containing 187 mg of flavanols) compared to a control drink (14 mg of flavanols) [20]. Similarly, the study developed by Zhu et al. in 2005 showed a significant reduction in the susceptibility of erythrocytes to free radical-induced haemolysis, after consumption of 12.5–25 mg flavanols/kg body weight contained in cocoa beverages, compared to baseline [21].
Table 1.
Effects on exercise performance and oxidative stress in healthy subjects.
Dose Duration Subjects DoseEffects Ref
Duration Subjects Effects Ref
HF cocoa (425 mg) or

maltodextrin		 weeks 44 male endurance athletes

34.5 ± 7.5 years		 ↑* plasma follistatin

↓* body fat

↓* plasma leptin		 [17]
HF (1060 mg), MF (746 mg), LF (406 mg), or control (CON) (88 mg) chocolate bar

Cross-over		 Single dose 15 healthy subjects (10 males, 5 females)
HF (563 mg) or LF (38 mg) cocoa drink Single dose 10 healthy and physically active men

22.6 ± 0.3 years		 ↑** blood glucose pre-exercise [34]


30 ± 7 years No effects on oxygen consumption respiratory exchange ratio or (HR)
HF (179 mg), non-flavanol containing cocoa drink or placebo 12 weeks 61 healthy, middle-aged and elderly subjects (13 males, 48 females)

75.9 ± 5.8 years		 ↓** glycaemia

↓** TG		[18]


↑** HDL

↑** physical performance

↑** skeletal mass index

↑** quality of life		 [22] HF (425 mg) cocoa or

maltodextrin		 10 weeks 56 male endurance athletes

35.8 ± 8.1 years		 ↓** oxidative stress

No effect on aerobic capacity or exercise performance		 [19]
HF soluble cocoa (45.3 mg) or milk 4 weeks 24 healthy (11 males, 13 females) and 20 moderately hypercholesterolemic (9 males, 11 females) subjects

28 ± 8 years		 ↑** HDL

↑* dietary carbohydrate, protein and fibre intake

↓* IL-10		 [23] HF (187 mg) or LF (14 mg) cocoa drink

Cross-over		 Single dose 20 healthy males

20–40 years		 ↓** oxidative stress [20]
HF (520 mg) or LF (88.5 mg) chocolate bar

Cross-over		 Single dose 32 healthy sleep-deprived subjects (16 males, 16 females) HF (25 mg/kg body weigh), MF (18.78 mg/kg) or LF (12.5 mg/kg) cocoa drink

Cross-over		 Single dose 8 healthy male subjects

26 ± 2 years		 ↓* susceptibility to free radical-induced haemolysis (all doses) [21]
Table 2 shows the effects of HF cocoa consumption by healthy individuals on cardiovascular risk factors. In a study conducted in middle-aged and elderly people (55–90 years), a significant improvement in several cardiovascular risk factors was observed, including a reduction in blood glucose and plasma triglycerides, as well as an increase in high-density lipoprotein (HDL) levels, physical performance, skeletal mass index, and quality of life after 12 weeks of consumption of an HF cocoa drink compared to placebo [22]. Similarly, consumption of flavanol-rich soluble cocoa for 4 weeks significantly increased HDL levels in healthy and moderately hypercholesterolemic subjects compared to milk consumption; however, a significant decrease in IL-10 from baseline was also observed [23]. A single dose of a chocolate bar containing 520 mg of flavanols significantly reduced pulse pressure, systolic blood pressure (SBP) and diastolic blood pressure (DBP) and attenuated the increase in pulse wave velocity in healthy sleep-deprived subjects (25.3 ± 3.6 years), as well as increased flow-mediated dilatation (FMD) and improved working memory accuracy compared to a flavanol-poor chocolate bar [24]. Likewise, a single dose of an HF cocoa drink significantly increased plasma levels of flavanols and FMD in healthy women (329 mg of flavanols) [25] and smokers (176–185 mg of flavanols) [26] compared to low-flavanol (LF) drinks. Brachial artery FMD also increased significantly from baseline after one week of consumption of an HF (918 mg) cocoa drink by male smokers aged 27 years [27]. Another study carried out in African Americans and Caucasian Americans showed a significant improvement in microvascular function and nitric oxide (NO) bioavailability, only in African Americans subjects, after a single dose of a cocoa drink containing 247.2 mg of flavanols [28]. A single dose of an HF cocoa drink (897 mg of flavanols) also showed platelet-modulating effects by reducing epinephrine-stimulated platelet activation and function from baseline, although to a lesser extent than aspirin, in healthy subjects from 22 to 49 years of age [29]. Chronic consumption of HF cocoa has also been shown to affect vascular function. Brachial artery FMD and plasma epicatechin significantly increased in a study conducted in healthy subjects after 2 weeks of consuming an HF chocolate bar [30]. Consumption of a cocoa beverage containing 821 mg of flavanols for 5 days increased FMD after hyperaemia in 48-year-old subjects [31], and increased NO-dependent vasodilation to ischaemia in healthy 44-year-old subjects [32]. However, it had no effects on blood pressure (BP). Consumption of HF (750 mg) dark chocolate for 8 weeks also had no effect on BP in prehypertensive healthy subjects (52.6 ± 12.6 years) [33].
Table 2.
Effects on cardiovascular risk factors in healthy subjects.


25.3 ± 3.6 years
↓** pulse pressure, SBP and DBP

↑** FMD

↓** increase in pulse wave velocity

↑** working memory accuracy		 [24]
HF (329 mg) or LF (27 mg) cocoa drink Single dose 10 healthy women

18–65 years		 ↑** FMD and oxygen saturation

↑** plasma epicatechin		 [25]
HF (176–185 mg) or LF (<11 mg) cocoa drink

Cross-over		 Single dose 11 smokers (6 males, 5 females)

31 ± 1 years		 ↑** plasma levels of flavanols

↑** plasma levels of NO

↑** FMD		 [26]
HF (918 mg) cocoa drink 1 week 6 male smokers

27 ± 1 years		 ↑* flow-mediated dilation of brachial artery [27]
HF (247.2 mg/d) cocoa drink or non-flavanol containing drink

Cross-over		 Single dose 7 African American and 7 Caucasian American healthy subjects (8 males, 6 females)

22 ± 4 years		 ↑a microvascular function

↑a NO contribution		 [28]
HF cocoa drink (897 mg) or aspirin (81 mg) Single dose 16 healthy adults (8 males, 8 females)

22–49 years		 ↓* epinephrine-stimulated platelet activation and function [29]
HF (259 mg) or LF (47.6) chocolate bar 2 weeks 22 healthy subjects (11 males, 11 females)

32.2 ± 3.1 years		 ↑** brachial artery FMD

↑** plasma epicatechin		 [30]
HF cocoa drink (821 mg) 5 days 34 healthy subjects (13 males, 21 females)

47.9 ± 3.0 years		 ↑* FMD after hyperaemia

↑ pulse wave amplitude

No effects on BP		 [31]
HF (821 mg) cocoa drink or LF control drink 5 days 27 healthy subjects (11 males, 16 females)

44 ± 3.4 years		 ↑** pulse wave amplitude

↑** vasodilator response to ischaemia

No effects on BP		 [32]
HF dark chocolate (750 mg), tomato extract capsule (15 mg lycopene), or placebo

Cross-over		 8 weeks 36 prehypertensive healthy subjects (19 males, 17 females)

52.6 ± 12.6 years		 No effects on blood pressure [33]
Heinrich et al. [44][35] studied the effects of consuming a cocoa drink high in flavanols (326 mg) for 6 weeks on UV-induced erythema in healthy women. They observed a significant decrease in erythema and an increase in cutaneous and subcutaneous tissues’ blood flow, as well as in skin density and hydration. Similarly, Mogollon et al. [45][36] reported a significant increase in skin elasticity after 12 weeks of HF (200 mg) chocolate consumption; however, no effect on UV-induced erythema was observed. Consumption of chocolate containing 400 mg of flavanols for 12 weeks by pregnant women significantly increased plasma theobromine levels compared to LF chocolate; however, no effects on FMD or BP were observed [46][37].

3. Subjects with Disease

The effects of HF cocoa in subjects with disease have also been studied. Consumption of an HF (900 mg) cocoa drink for 4 weeks significantly increased FMD and decreased DBP in subjects with end-stage renal disease (mean age 65.5 ± 14 years); however, a significant increase in heart rate (HR) was also observed [47][38]. Several authors have studied the effects in overweight or obese subjects. A single dose of a cocoa drink containing 701 mg of flavanols significantly increased FMD and attenuated the exercise-induced increase in BP in subjects aged 54.9 ± 2.2 years [48][39]. Consumption of cocoa products high in flavanols for 4 weeks significantly increased both the basal and peak diameter of the brachial artery, the basal blood flow volume [49][40] and FMD [50][41], while also reducing the augmentation index (AIX) of the brachial artery (a measure of arterial stiffness), resulting in improved vasodilation [49,50][40][41]. In contrast, no effects on HOMA-IR or insulin-stimulated glucose disposal were observed after consumption of an HF (1218 mg) cocoa drink for 4 weeks by overweight or obese women aged 19–49 years [51][42]. A longer consumption (12 weeks) was tested in 23 subjects aged 44.9 ± 4.4 years, and showed a significant increase in FMD and a reduction in insulin resistance and DBP compared to an LF drink [52][43]. Similarly, consumption of HF cocoa drinks for 4 weeks by subjects with type II diabetes mellitus has been found to significantly increase FMD [53,54][44][45] and plasma levels of flavanol metabolites [54][45]. A significant reduction in DBP and the N-terminal pro-B-type natriuretic peptide (NT-proBNP) was also observed after 4 weeks of consumption of an HF (1064 mg) cocoa drink by subjects with chronic heart failure aged 70 ± 10 years, suggesting an improvement in cardiac function [55][46]. On the other hand, consumption of an HF (750 mg) cocoa drink for 4 weeks by subjects with coronary artery disease (64 ± 3 years) showed a significant improvement in endothelial function [56][47]; however, a lower dose (444 mg) for 6 weeks showed no effect in the same type of patients [57][48]. In a similar way, a study conducted in postmenopausal hypercholesterolemic women showed an improvement in endothelial function after consuming an HF (446 mg) cocoa drink for 6 weeks, as well as a significant increase in HDL levels [58][49]. Another study carried out with subjects with hypertension aged 56.6 ± 11.1 years reported that a single dose of an HF (712–1052 mg) cocoa drink significantly reduced SBP, DBP, and mean BP compared to an LF cocoa drink [59][50]. Two weeks of consuming an HF cocoa drink significantly increased insulin-stimulated changes in brachial artery diameter in hypertensive subjects (mean age 51 years); however, no effect on blood pressure was observed [60][51]. A significant decrease in HR was also observed after 6 weeks of consumption of HF chocolate in hypertensive men, as compared to LF chocolate [61][52]. On the other hand, a significant reduction in fatigability from baseline was observed in subjects with Parkinson’s disease and multiple sclerosis after one week [62][53] and eight weeks [63][54] of consuming an HF (194 mg) cocoa drink, respectively; however, no significant differences were observed compared to the consumption of an LF (18.36 mg) drink. Contrarily, no effect on fatigability measures was observed after a single dose of an HF (350 mg) cocoa drink in patients with multiple sclerosis [64][55], suggesting that a single dose is not enough to produce benefits.

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