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Chocolate polyphenols, Cocoa polyphenols, Cacao polyphenols, Cacao extract, Chocamine
Chocolate (The extract paired with macronutrients)
Studies assessing the influence of cocoa extract on blood flow note that 5-26g of dark cocoa contains 65-1,095mg of flavanols, and that within this range there are dose-dependent benefits to blood flow. This may be related to the recommended intake of cocoa flavanols (not so much cocoa 'extract', but the flavanols in particular) being in the range of 500-1000mg daily taken with meals.
If chocolate does not state the epicatechin content, consuming between 25-40 grams of a chocolate containing at least 85% cocoa by weight should be targeted (which is approximately 200kcal of chocolate). Dark chocolate that is 50% cocoa by weight may need up to twice the amount, around 400kcal or 100 grams to have the same effects while milk and white chocolate have too low a content of catechins to have any appreciable effect.
It is unsure if this is the optimal dose, but it appears to be more effective than lower doses.
This does not mean you should be pigging out on chocolate. Note the recommended dosage (especially the amount of dark chocolate that will satisfy for a reasonable dose).
Cocoa extract (also referred to as Cocoa polyphenolics) are derived from Cacao seeds as a bitter bulk ingredient for commercial usage and supplementation and as a general statement the phrase "Cocoa extract" refers to the collection of polyphenols found in dark chocolate which confer health benefits. Most of the polyphenols in cocoa are flavonoids, specifically the subset known as flavanols, and so the terms cocoa flavonoids and cocoa flavanols are sometimes used interchangeably with cocoa extract.
Cocoa extract refers to the polyphenolics or 'flavonoids' found in the plant which is eventually used to make chocolate, and these flavonoids are the molecules which mediate the vast majority of health benefits associated with chocolate consumption
Cocoa specifically contains (unsweetened cocoa powder unless otherwise specified):
As a general statement, milk chocolate has little to no cocoa bioactives in it due to extensive processing while milk chocolate and chocolate syrup have negligible quantities. Standard dark chocolate, dutched chocolate, and semisweet baking chips are comparable good sources of catechins and procyanidins while unsweetened baking chocolate is better and unsweetened cocoa powder the best dietary source of these bioactives.
Cocoa extract contains polyphenolics ranging from 8.07 to 484.7mg/g (defatted cocoa powder), which places it as one of the better dietary sources (alongside select herbs used as Spice, dark colored berries, and select vegetables) being reported to sometimes contain up to 10% flavonoids.
In regards to the polyphenolics, cocoa has a large amount of procyanidins (chains of catechin molecules) and a particularly high content of (-)-epicatechin relative to other catechin sources like green tea. Other phenolics such as resveratrol and quercetin seem to be lower than the catechin and procyanidin content and their relevance to cocoa powder is uncertain
Other components of cocoa extract include:
In regards to the low-weight psychoactives cocoa has a low amount of trace amines and xanthines such as caffeine which are not thought to be highly relevant following ingestion of chocolate, excluding potential MAOI interactions due to tyramine.
In general, cocoa is said to have around a 60/40 epicatechin:catechin ratio due to having higher levels of procyanidin B2 (epicatechin dimer) and procyanidin C1 (epicatechin trimer), with lower relative concentrations of procyanidin B1 (epicatechin-catechin) when compared to other procyanidin sources (Grape Seed Extract or Pycnogenol). Natural cocoa products appear to have more total flavonoids than do other dark chocolate or cocoa products, with milk chocolate products having the least amount of flavonoids.
As a general statement towards cocoa products and their flavonoid content, additional processing or manufacturing stages away from pure cocoa will gradually reduce the flavonoid content and total flavonoids tend to reflect the cocoa percentage of the product. The exception to this general rule would be dutch processing (alkalization) which can reduce the (-)-epicatechin, (+)-catechin, and total flavonoid content by upwards of 60% with losses scaling with processing time and affecting other components like procyanidins and Quercetin content. Alkalization has been noted to increase the content of (-)-catechin relative to other processing methods, but this molecule is not normally found in cocoa and is not linked to the health benefits of cocoa products.
Dutch processing, or alkalization of cocoa products, tends to result in an abnormally rapid loss of the beneficial compounds in cocoa products when compared to other processing methods.
'Dark' chocolate, beyond the color and bitterness (from the xanthine molecules), refers to chocolate products which tend to be around 80% cocoa by weight and confer a significantly higher concentration of catechins and other bioactives.
Dark chocolate is the variant of chocolate with a significantly higher cocoa content and thus more of the beneficial compounds in chocolate, conferring benefits at a much lower oral dose
A particular brand of cocoa extract is known as 'chocamine' patented by RFI ingredients, which according to their website the product specifications state that the powder is standardized to theobromine (greater than 12% by weight), caffeine (less than 0.5%), polyphenolics (greater than 5%) and contains added tapioca starch and some other spices (Ginger, allspice, Cinnamon, and vanilla powder in undisclosed amounts).
Chocamine is a theobromine rich cocoa powder
Nitric Oxide is a gasotransmitter involved in relaxing blood vessels, and increasing the activity of this molecule promotes blood flow and in certain instances may also reduce blood pressure.
Cocoa flavanols, particularly (-)-epicatechin, are known to improve blood flow in a way that is prevented by blocking the endothelial nitric oxide synthase (eNOS) enzyme and while biomarkers of nitric oxide activity (such as the nitrate/Nitrate ratio) seem to be increased after (-)-epicatechin ingestion the activity of nitric oxide donor molecules are unaffected even in hypertensives. This suggests that (-)-epicatechin must work via eNOS to promote nitric oxide formation but it is not working via antioxidative means (antioxidants such as Grape Seed Extract may preserve nitric oxide availability in instances of a high bodily oxidative state, but such a mechanism would augment the efficacy of nitric oxide donors), and this is likely traced back to an induction of the eNOS enzyme itself.
Both procyanidins and (-)-epicatechin in chocolate have been noted to induce eNOS activity in vitro with isolated (-)-epicatechin being most active at a concentration of 1μM 20-40min after incubation, similar to the time (-)-epicatechin acts in humans following oral ingestion. This increase in eNOS protein content is associated with increased phosphorylation of Ser-1177 and Ser-633 (dephosphorylation of Thr-495) secondary to calmodulin associated with eNOS due to PI3K activation. Catechin appears to be 25% as potent as (-)-epicatechin with a mixture of both is less potent than pure epicatechin, which is thought to underlie why cocoa extract may be more potent than other catechin sources such as green tea.
(-)-epicatechin appears to increase the protein content of the eNOS enzyme, which is the rate limiting step of making nitric oxide in blood vessels. By increasing the amount of this protein it allows more nitric oxide to be produced, which then act to enhance blood flow
The activation of eNOS from (-)-epicatechin is known to be calcium-independent (increasing intracellular calcium can inhernetly activate eNOS) but may act at the level of the cell membrane itself, since anchoring dextran to (-)-epicatechin (to restrict it from entering the cell) does not prevent its actions in increasing nitric oxide signalling at a low concentration (100-500nM) nor in activating PI3K/Akt signalling to PDK1, and elsewhere Akt has been noted to associated with heat shock protein 90 (HSP90) to form a complex which then travels to eNOS.
It should also be noted that (-)-epicatechin can increase calcium release in a cell in a manner not related to eNOS activation, and (+)-catechin also has affinity for this receptor but when both are introduced at the same time there may be less potency overall (thought to be from competitively inhibiting (-)-epicatechin binding). This antagonism may be why dark chocolate, a relativly good source of (-)-epicatechin relative to (+)-catechin, may confer more benefits to blood flow than other plant sources of catechins.
(-)-epicatechin appears to act at the cell membrane via PI3K to then activate eNOS through heat shock proteins, but the specific receptor that it acts on in the cellular membrane is currently not known
Cocoa extract is said to influence prostaglandin activity in the human body secondary to the procyanidin content, and incubation of endothelial cells with a cocoa extract (49% procyanidins) at 2µg/mL resulted in decreaes in leukotrienes (LTC4, LTD4, and LTE4) with a doubling of PGI2.
Oral ingestion of a chocolate product with a relatively high procyanidin content (0.4%) relative to a low content (0.009%) can acutely increase plasma prostacyclin by 32% and reduce total leukotrienes by 29%; there were also differences in (-)-epicatechin content in this study.
This mechanism may underlie the anti-asthmatic actions of cocoa extract seen in rodents as pharmaceuticals that act similar to prostacyclin (iloprost) and agents that reduce leukotriene activity (pranlukast and zileuton) confer anti-asthmatic activity, although the theophylline content of cocoa may also have an minor anti-asthmatic role although it is underdosed (relative to its maximum efficacy) in cocoa products.
In an acidic medium such as the stomach, cocoa polyphenolics (monomers such as (-)-epicatechin as well as procyanidins up to five monomers in length) appear to be structurally stable over the course of one hour while administration of famotidine (H2 receptor antagonist which reduces stomach acidity) does not alter absorption rates of cocoa flavanols.
The stomach does not appear to significantly influence the bioavailability or kinetics of the active cocoa molecules as they are stable in acid, so due to this enteric capsules are unlikely to exert unique benefits to supplementation
It is known that some dietary polyphenolics can have their absorption affected by food such as dietary fats and there may be species differences. As cocoa polyphenolics predominately consumed via food products their interactions with dairy products has been investigated, particularly due to how catechins in chocolate as structurally similar to those in tea which have been investigated for their interactions with milk.
Ingestion of milk (250mL) alongside cocoa polyphenolics (70mg (-)-epicatechin) in healthy subjects does not appear to reduce absorption when measured after two hours, as the reduction of serum (-)-epicatechin glucuronide from 330+/-150nM in the water control to 273+/-138nM was not significant while elsewhere in a rat study whole milk and heavy cream successfully lowered absorption relative to skim milk or water. Gastric digestion rate does not appear to be influenced with milk relative to water (humans), but it is possible that coingestion of milk (250mL) with flavanols can increase the time they spend in the body since it reduced how many are eliminated after 24 hours.
One study has noted that coingestion of cocoa flavanols (via 125mg/kg cocoa powder) alongside about dietary carbohydrate (about 1g/kg carbohydrate via bread or sugar products) increased their bioavailability and subsequent AUC to 140% of cocoa alone (measured over 2.5 hours) while dietary fats and protein had no significant influence.
As a general statement high fat meals may reduce absorption of the active molecules which high carb meals may increase their absorption, but practically speaking simply consuming cocoa flavanols via chocolates should have similar absorption rates when compared to isolated dietary supplements since said chocolates contain appreciable levels of both fats and carbohydrates
Oral ingestion of drinks (with some additional macronutrients) containing cocoa was noted to increase serum epicatechin when measured at 120 hours post ingestion to approximately 500ng/mL (2g cocoa), 1,200ng/mL (5g), 3,500ng/mL (13g), and 8,000ng/mL (26g); data derived from graphs.
Twice daily dosing of a cocoa drink (450mg flavanols at each dose) has failed to increase steady state catechin concentrations, thought to be related to a 3.6 hour half-life.
Consumption of dark chocolate (40 grams) can be active in the blood stream two hours after consumption near peak improvements in blood flow and the (-)-epicatechin content appears to reach a concentration of around 118-121nM (0.11-0.12μM) in serum at this time point. Despite differences in effects between healthy controls and those with prooxidative conditions (hypertension, smoking) there do not appear to be differences in overall serum exposure to (-)-epicatechin. Increasing the flavanol content in solid chocolate products causes dose-dependent increases in serum (-)-epicatechin.
Chronic consumption of thrice daily dark chocolate ingestion (200 mg flavanols; (-)-epicatechin content not disclosed) has resulted in increased serum (-)-epicatechin at week six (78.28+/-64.35ng/mL), nine (46.23+/-41.52ng/mL), and twelve (57.68+/-46.54ng/mL) which very high variability.
Consumption of low doses of dark chocolate (85% cocoa or greater) appears to result in low micromolar concentrations of (-)-epicatechin
In regards to procyanidins specifically, consumption of chocolate (0.375g/kg) containing 2.8% procyanidins (thus 10.5mg/kg procyanidins) has been noted to increased blood levels of procyanidin B2 to 100nM after two hours (Cmax) with approximately 50nM at both the one and four hour marks returning to baseline after eight hours. A study elsewhere using the same chocolate product noted lower serum concentrations of 16+/-5nM after 30 minutes and a peak of 41+/-4nM after two hours. in human plasma after the consumption of a flavanol-rich cocoa|published=2002 Oct|authors=Holt RR1, Lazarus SA, Sullards MC, Zhu QY, Schramm DD, Hammerstone JF, Fraga CG, Schmitz HH, Keen CL|journal=Am J Clin Nutr]
Oral ingestion of (-)-epicatechin in mice at 125mg/kg bodyweight for 13 days has been noted to reach brain tissue, reaching a wet weight of 4.3ng/mg (-)-epicatechin and 1.5ng/mg 3'-O-methyl(-)-epicatechin; increasing the oral dose 10-fold resulted in brain concentrations of 7.3ng/mg and 16ng/mg respectively with all aforementioned numbers collectively referring to both free forms and conjugations. There is no detectable 4'-O-methyl(-)-epicatechin in the brain following (-)-epicatechin ingestion and the presence of the aforementioned two compounds has been confirmed elsewhere with shorter dosing periods.
Ingestion of catechin from cocoa is subject to methylation to produce either 3'-O-methylcatechin or 4'-O-methylcatechin.
Consumption of any food deemed palatable is able to increase opioidergic activity via a hypothalamic release of β-endorphin, and chocolate has been implicated in opioidergic activity as one study noted a reduction (lessening) of a negative mood state associated with palatable chocolate but not unpalatable chocolate.
In a mouse study assessing the actions of (-)-epicatechin (125-750mg/kg) on memory, despite an increase in memory formation being noted there did not appear to be any enhancement of newborn cellular survival in the hippocampus.
It was noted that (-)-epicatechin increased vascularity of the DG subregion of the hippocampus, with no significant influence on CA1 or CA3 areas and without affecting the overall size of any area. This effect was traced back to increased spine density in DG granule cells, and a few genes involved in learning were upregulated including synaptosomal-associated protein 25 (SNAP-25) and kinesin family member 17 (Kif17) alongside some involved in angiogenesis and some downregulation of inflammatory genes.
It appears that the scent of dark chocolate (relative to no inhalation of aromatics) is enough to potentially reduce appetite in women.
In otherwise healthy young adults subject to a cognitive task, it appears that five days supplementation of 172mg cocoa flavanols (final dose 90 minutes before testing) increases blood oxygenation level-dependent (BOLD) contrast indicating increased cerebral oxygenation specifically in the prefrontal cortex, anterior cingulate cortex (ACC), and parietal cortex; this was not accompanied by altered reaction times which increased activity of the ACC is thought to result in.
This was accompanied by an increase in blood flow that peaked two hours after supplementation (40% increase) and returned to baseline within six hours, suggesting the peripheral phenomena is linked to the neural.
In otherwise healthy youth, cocoa flavanols appear to enhance blood flow to the brain and alongside the increase in blood flow there appears to be an increase in cerebral oxygenation
In a cohort of 37,103 men (Sweden) followed for 10.2 years found a decreased risk of stroke associated with chocolate with the highest quartile (25%) of consumption, with a median intake of 62.9g weekly, having an 0.83 relative risk compared to the no chocolate intake; the CI was 0.70-0.99.
Epidemiological research a potential protective effect of cocoa flavanol ingestion against strokes when consumed in the diet
50g of dark chocolate (125mg (-)-epicatechin) given two hours prior to a psychosocial stressor in otherwise healthy men, relative to placebo chocolate, attenuated the rise of salivary cortisol and adrenaline with no influence on noradrenaline nor ACTH in a manner correlating with serum (-)-epicatechin.
A possible mechanism for cocoa extract in interacting with mood may be its ability to prevent increases in the activity of the indoleamine 2,3-dioxygenase (IDO) enzyme during cellular inflammation as seen in vitro with concentrations that can be biologically relevant in the gut as the increase in IDO mediates conversion of L-tryptophan into L-kynurenine via the L-kynurenine pathway;) while beneficial for pathogen defense, excessive activation is thought to deplete L-tryptophan and thus reduce the amount available for serotonin biosynthesis.
There is evidence for alterations in IDO activity in mood disorders (neopterin being a biomarker of IDO activity) such as seasonal affective disorder and depression, and the gut was mentioned specifically due to intestinal peyer's patches allowing exposure of oral bioactives to immune cells without absorption of said bioactive from the gut being required; the gut contains a high degree of bodily serotonin (upwards of 95%) and the concentration of cacao flavanols required to inhibit IDO may be too high for serum activity.
It is possible that cocoa components can exert an antiinflammatory effect on immune cells (macrophages and PMBCs) in the gut which, quite indirectly, exerts a mood elevating state related to serotonin. Although the current theory, the relevance of this signalling pathway to chocolate's effects on mood is not conclusively demonstrated
Consumption of chocolate alongside water has been noted to reduce (lessen) a negative mood state in response to a film without affecting positive or neutral mood states and a later experiment noted that this was due to the palatability of chocolate as a chocolate product that was not deemed palatable failed to replicate the effects.
There is an ability of chocolate to reduce negative mood states associated solely with how much users like to taste chocolate, since consumption of sweets that the consumer enjoys can per se improve mood state. It is likely any treat that the consumer likes can have similar effects
In older adults (40-65yrs), supplementation of 500mg cocoa polyphenols for 30 days (but not 250mg) was associated with an improved mood state mainly around calmness and contentness; 250mg was ineffective.
One study conducted on elderly persons with mild cognitive decline noted that cocoa flavanols were able to improve cognitive performance in a relatively dose dependent manner at both 520mg and 990mg daily, as assessed by Trail making tests and Verbal Fluency. Elsewhere, there has been a failure of 250-500mg cocoa polyphenols for 30 days at improving attention (speed, continuity, and power of attention).
In mice, ingestion of (-)-epicatechin at 500μg/g (0.05%; 125mg/kg in reference to body weight) of the diet for 42 days noted that consumption of epicatechin resulted in improvements in memory retention when given to mice and had more prominent effects when the mice experienced daily exercise; this effect is nonsignificantly greater when given at six-fold the oral dose (750mg/kg) although higher doses of (-)-epicatechin do not have the same effects.
250-500mg of cocoa flavonols daily for 30 days in otherwise healthy older adults has failed to improve quality of working memory or secondary memory while elsewhere supplementation of 37g of 60% dark chocolate (400mg procyanidins) with 8 ounces of chocolate beverage containing a similar procyanidin content failed to improve working, moderate, or long-term memory as assessed by a battery of tests.
Cocoa flavanols (procyanidins 2-10 monomers in length) may inhibit fat absorption, where the tested chocolate with the highest phenolic content (48.1%) inhibiting pancreatic lipase 25–53% at 20μM (more potency associated with longer chain procyanidins). Phospholipase A2 was inhibited by 46–74% at 100μM.
The procyanidins found in cocoa may be able to inhibit some fat absorption when coingested, although the practical significance of this information is not known (as procyanidins are commonly seen as a minor constituent of chocolate)
In mice given (-)-epicatechin at 1mg/kg twice daily for 15 days paired with physical exercise, the combination of those two factors relative to control appeared to result in an increase of mitochondrial proteins notably complex II of the electron transport chain and two markers of the mitochondrial membrane (porin and mitofilin).
In regards to epidemiological research, there appears to be an association between higher chocolate intake and lower morbidity/mortality and risk for cardiovascular disease, as well as a protective effect as assessed by some other biomarkers (such as blood pressure).
Rodent studies suggest benefical effects of (-)-epicatechin ingestion on the heart tissue itself in regards to promoting its energetic capacities at a relatively low human equivalent dose (0.08mg/kg twice daily), suggesting a possible protective effect of chocolate ingestion
One study looking at coronary circulation in healthy subjects given chocolate products noted that dark chocolate (550mg polyphenols) reported an increased coronary flow velocity reserve (CFVR) by 26% which did not occur after white chocolate ingestion, and this change did not seem to be dependent on changes in oxidation status of the blood or blood pressure.
An increase in coronary blood flow has been noticed not related to blood oxidation status nor changes in blood pressure following ingestion of dark chocolate in otherwise healthy subjects
Some studies in humans have noted transient increases in blood pressure to a mild degree (4mmHg) when chocolate products are acutely ingested, which do not appear to be due to increases in resting blood pressure, although acute ingestion of chocolate does not always cause this. It is possible that the small xanthine content of chocolate (Caffeine and its metabolites theobromine and theophylline) accounts for this transient increase secondary to increased cardiac output (known to result from acute ingestion of xanthines).
Chocolate products have the potential to acutely increase blood pressure, which may be due to the xanthine content rather than the flavanol content. This acute increase does not appear to result in a long-term increase in resting blood pressure
Various polyphenols from cocoa appear to dose-dependently (2.5-40µM) protect red blood cells from lysis against oxidative stressors with longer chain procyanidins being more effective than monomers such as catechin at lower concentrations, with 1mg/mL of the mixed (acetone) extract slightly outperforming Vitamin C as a reference in vitro.
Oral ingestion of 100mg of cocoa flavanols in rats (500-666mg/kg) appears to be enough to confer protection to red blood cells against AAPH (oxidative stressor) and in humans given chocolate at 0.25, 0.375, and 0.50g/kg bodyweight (2.8% procyanidins and 1.2% monomers) noted that all doses protected red blood cells from hemolysis with the middle dose being most effective.
Aortic pulse wave velocity (PWV) is a measure used to assess aortic stiffness, a hardening of the aorta from calcification which is the long-term target of Vitamin K for cardiovascular health and is a good independent predictor of all-cause mortality at all ages with anything that can reduce calcification thought to be protective.
When testing cocoa in otherwise healthy adults on this parameter, 10g of 75% dark chocolate daily for a month has resulted in a decrease in PWV of 5% (6.13+/-0.41m/s to 5.83+/-0.53m/s) which is an effect not observed with acute usage of a higher dose of cocoa (100 grams) in the same demographic.
It is possible that prolonged ingestion of cocoa products can result in a reduction in arterial calcification
In vitro, it appears that cocoa polyphenolics is able to inhibit LDL and vLDL oxidation with similar or lesser potency to a similar concentration of Green Tea Catechins. Despite the potency in vitro, studies assessing oral intake of cocoa flavanols have noted that diets containing the procyanidins (466mg) have caused only mild increases in lag time by 8% or none at all while large acute doses of flavanols (1,095mg) fail to appreciably influence LDL oxidation rates.
While epicatechin and the procyanidins found in cocoa can technically reduce LDL oxidation rates due to their antioxidant properties, this is an effect demonstrated in vitro and does not appear to apply to oral ingestion possibly due to the low absorption of (-)-epicatechin relative to the dose required for direct antioxidant effects.
Ingestion of dark chocolate (30g of 70% cocoa) in prehypertensive subjects can increase the amount of nitric oxide in serum within 15 days by 54% as assessed by serum biomarkers.
It is unsure if this is related to the antioxidant properties of cocoa (which are thought to be the mechanism by which agents like Grape Seed Extract or Vitamin C aid nitric oxide), as at least one study has noted increased blood flow independent of changes in oxidation of LDL (biomarker of oxidation).
In regards to blood flow and circulatory health, cocoa flavanols are thought to improve circulation secondary to causing production of nitric oxide. This is likely due to epicatechin or other catechins directly stimulating the nitric oxide synthase enzyme
One study using oral ingestion of cocoa (450mg polyphenols and 87mg (-)-epicatechin) twice daily for two weeks in hypertensives noted an increase in insulin-induced artery width associated with supplementation and improvements in blood pressure seen in hypertensives seem to coexist with improvements in insulin sensitivity and β-cell function. Studies that assess blood vessel diameter under resting conditions without insulin stimulation usually find no significant interaction between cocoa flavanols and vessel diameter.
In type II diabetics on medication, daily ingestion of dark chocolate (963mg flavanols with 203mg (-)-epicatechin, taken in three divided doses) appears to cause a baseline increase in blood flow by 30% with further spikes two hours after each oral dose lasting for four hours; this occured without improvements in glycemic control nor blood pressure.
An increase in insulin-mediated vasodilation may also occur and contribute to the effects of chocolate on blood flow
In otherwise healthy young subjects, ingestion of a flavanol rich dark chocolate (100g) has acutely increased arterial diameter in both a resting and hyperemic state resulting in an increase in both flow-mediated vasodilation (FMD; 1.43%) and a decrease in the aortic augmentation index (ALX; 7.8%); these benefits occurred without alterations in plasma antioxidant status and elsewhere have been noted to extend to an improvement in coronary flow velocity reserve (CFVR) and are due to the flavanol content as a low flavanol content in the same style of study fails to have benefit. If ingested for a month, healthy young adults may experience benefits to blood flow even with 10 grams of dark chocolate (75% cocoa) increasing FMD 9.31% relative to baseline (with no change in control).
In otherwise healthy older individuals given drinks containing various dosages of cocoa (2, 5, 13, and 26g or placebo) and measured over the next 120 minutes, it was found that 5-26g cocoa (65-1,095mg total flavanols) was able to increase blood flow as assessed by FMD in a dose-dependent and linear manner, which correlated with serum polyphenolics, namely (-)-epicatechin which appears to be the isomer of the catechins which is active by increasing nitric oxide synthase activity  Oral ingestion of isolated (-)-epicatechin appears to mimick the effects seen with cocoa polyphenols.
Dark chocolate has elsewhere been noted to be effective in diabetics, smokers, and those at risk for cardiovascular disease. Overall this topic has been subject to meta-analysis assessing various health demographics and there did appear to be an average increase in blood flow assessed via FMD reaching 2% (95% CI or 1.6-2.39%) with comparable increases with a single dose (2.25%) or daily dosing for up to 12 weeks (1.76%) but slightly more benefits in those with elevated cardiovascular disease (CVD) risk factors (2.36%) than in healthy people (1.53%).
It should be noted that some trials have failed to find improvements in blood flow with at least one study noting some degree of 'response' that while hypertensive subjects noted a benefit in blood flow from 75g dark chocolate over a week, that those with worse symptoms (Framingham risk score and reactive hyperemeia index) had less efficacy.
Appears to promote circulation in a dose-dependent manner, which correlates very well with serum (-)-epicatechin. Cocoa polyphenolics may be epicatechin prodrugs in regards to improving blood flow, and overall the increase in blood flow following cocoa ingestion appears to be somewhat reliable in regards to both health state (healthy or mildly diseased) and in regards to how long supplementation is continued
One of the mechanisms that cocoa flavanols possesses is thought to be reduction of blood pressure via inhibition of angiotension converting enzyme (ACE), establishing a role of cocoa flavanols as an ACE inhibitor although its interactions with nitric oxide are also relevant to blood pressure (being the major mechanism related to blood flow), potentially related to how an insulin-mediated interaction with nitric oxide can widen blood vessels after cocoa ingestion.
Beyond blood flow, it has been thought that cocoa flavanols can reduce blood pressure by both related mechanisms (the increase in blood vessel width related to nitric oxide) but also by other possible means such as ACE inhibition
Short term studies have noted minor transient increases in blood pressure (alongside an increase in blood flow) or reductions in blood pressure, while in hypertensives there is similar variability with one study noting a decrease in ambulatory blood pressure associated with dark chocolate consumption (100 grams for two weeks) while a similar study using the dose of cocoa via beverage in hypertensives failed to find any effect. When an increase in blood pressure occurs, it appears to be transient and mild (4mmHg) and does not appear to be associated with an increase in basal or resting blood pressure.
In healthy individuals (young adult soccer players) consumption of a low dose of flavanols (168mg) via chocolate for one week appeared to be associated with minor reductions in systolic (5%), diastolic (7%) and mean (6%) blood pressure relative to cream chocolate control.
One meta-analysis of 20 studies concluded that consumption of cocoa products (usually dark chocolate or cocoa supplementation) is associated with a small 2-3mmHg reduction of systolic blood pressure.
While benefits to blood pressure appear to be more variable than benefits to blood flow, there may be a minor reduction in blood pressure with chronic consumption of cocoa flavanols.
(-)-epicatechin is known to exert a protective effect on fibrinogen against the free radical known as peroxynitrate (ONOO-) in vitro at 1-10μM, as (-)-epicatechin can effectively sequester ONOO- which is known to modify the structure of proteins in excess concentrations. Epicatechin can reduce this modification to proteins in general and when it does this for fibrinogen the result is less ability to clot the blood.
In vitro it seems that epicatechin can prevent oxidative changes to a major protein involved in blood clotting which should result in cocoa flavonoids being able to preserve the clotting response; this mechanism is not yet tested in humans
In otherwise healthy men who consume dark chocolate (50g) two hours prior to a psychosocial test known to promote blood clotting it appears that consumption of the dark chocolate is associated with less biomarkers of clotting (D-Dimer) than white chocolate not containing flavonoids; this is not related to changes in catecholamines such as adrenaline which were unaffected.
40 grams of dark (85% cocoa) chocolate appears to be capable of reducing platelet viscosity in smokers when measured two hours after consumption, an effect accompanied by reduction in oxidation (48% reduction in ROS), the prostaglandin 8-iso-PGF2α (10%) and NOX2 activity (22%) and unique to smokers as it did not occur in nonsmoking controls; this may be related to a known higher baseline oxidation and NOX2 activity in smokers. Elsewhere in healthy nonsmoking individuals given 700mg cocoa flavonoids daily for a week or 900mg total polyphenolics acutely, the platelets removed from subjects appear to be resistant to aggregation when stimulated by clotting factors such as Arachidonic acid, ADP, or adrenaline with some differences between the two sexes (although both find overall anticlotting actions).
The concentration of (-)-epicatechin required to increased nitric oxide concentration in a platelet, approximately 0.1μM (100nM), appears to be feasible in the blood following ingestion of 40g dark chocolate. Comparatively speaking, the effects seem to be similar to aspirin in concept although 900mg cocoa polyphenolics (total (-)-epicatechin and procyanidins) is less potent than a baby aspirin (81mg) when both are taken acutely.
The increased aggregative potential of platelets seen in prooxidative states (studies assessing smokers) seems to be remedied with ingestion of dark chocolate while not necessarily affecting otherwise healthy states, but may also extend to instances of acute stress. In this sense, cocoa flavonoids seem to have a conditional anticlotting effect with a potency lesser than aspirin
One meta-analysis looking at interventions using cocoa products of variable time lengths (2-12 weeks) noted that overall there was no significant reduction of triglycerides, as the apparent reduction of 5.06mg/dL was too variable (with the 95% CI ranging between a reduction of -13.45mg/dL to an increase of 3.32mg/dL); the studies assessed that had the largest observed reductions tended to also have nonsignificant results due to excess variability between subjects.
A small meta-analysis on the ingestion of cocoa products assessing five studies on healthy persons with the other five being on hypertensive, overweight or obese, or diabetic subjects found that ingestion of variable doses of cocoa flavanols (88-963mg) or procyanidins (213-754mg) was indicative of a reduction in LDL cholesterol 5.90mg/dL (95% CI of a 1.32-10.47mg/dL reduction) whereas HDL-C and total cholesterol did not appear to be significantly affected overall.
In instances of acute hyperglycemia (following an oral glucose tolerance test), subjects who ingested 100g of dark chocolate for three days appeared to not have any increase in blood pressure or impairments to blood flow that were seen with the white chocolate control.
Ingestion of 100g chocolate in otherwise healthy individuals does not appear to increase insulin secretion in response to an oral glucose tolerance test.
One study using oral ingestion of cocoa (450mg polyphenols and 87mg (-)-epicatechin) twice daily for two weeks in hypertensives noted an increase in insulin-induced artery width associated with supplementation.
Insulin is known to promote an increase in Nitric Oxide bioavailability, which then acts to augment insulin-mediated glucose uptake forming a reciprocal relationship. Due to the ability of (-)-epicatechin to promote nitric oxide bioavailability and it being known to increase insulin-mediated vasodilation it's influence on glucose uptake as a result of enhanced insulin signalling has been investigated.
Healthy adults given 100 grams of dark chocolate (500mg total flavanols) daily for 15 days, relative to white chocolate control, have been noted to experience an increase in insulin sensitivity (HOMA, QUICKI, and ISI) when subject to a glucose load; the average insulin sensitivity index (ISI) appeared to be near doubled with dark chocolate (15.18+/-7.69) relative to white chocolate control (7.4+/-3.5). An improvement in insulin sensitivity (via HOMA2) has also been noted with overweight adults given 451mg flavanols daily for 12 weeks in a manner that did not interact with modest physical exercise while three days supplementation of 100g dark chocolate in otherwise healthy adults is perhaps too short of a time to have an appreciable effect on insulin sensitivity.
Elsewhere, essential hypertensives given a cocoa beverage with 450mg flavanols (87mg (-)-epicatechin) for two weeks failed to see any improvement in insulin sensitivity during a hyperinsulinemic isoglycemic glucose clamp despite an increase in insulin-mediated vasodilation although the same (-)-epicatechin dose via 100 grams of dark chocolate in a similar population improved insulin sensitivity during an oral glucose tolerance test alongside improvements in blood flow and pressure in both those with unimpaired insulin sensitivity and insulin resistant hypertensives (1009mg total polyphenolics with 111mg epicatechin daily for 15 days).
Short term ingestion of dark chocolate (100g of 70% cocoa) in overweight women for one week has been noted to not have an effect on circulating interleukins IL-1α, IL-1β, or IL-6 but reduced concentrations of interleukin 1 receptor antagonist (IL-1Ra) by 33+/-4% relative to baseline; IL-1Ra is known to be antiinflammatory via preventing the actions of IL-1α and IL-1β but is also secreted in high amounts from visceral fat where it is thought to be a biomarker for leptin resistance. Due to a reduction in waist circumference seen in this sample of women, it was thought to be indicative of leptin resensitivity rather than a proinflammatory mechanism per se.
Currently hypothesized to influence leptin metabolism in subjects with visceral fat due to influences on a biomarker of leptin sensitivity, but no studies have currently assessed leptin levels or sensitivity with prolonged cocoa ingestion
Fat oxidation rates during modest exercise in overweight adults who previously had 451mg cocoa flavanols for 12 weeks (alongside an exercise program) does not appear to alter fat oxidation rates relative to either exercise without the flavanols, flavanols without exercise, or neither.
Studies in overweight or obese adults that incorporate dark chocolate into their dietary regimen have failed to note any inherent weight loss effect of 50g dark chocolate (2135mg polyphenolics) over four weeks despite benefits to blood flow.
A pilot study using six middle aged subjects (41+/-5 years) of average weight given 1mg/kg (-)-epicatechin twice a day for one week was able to increase the follistatin to myostatin ratio by 49.2+/-16.6%; exact levels of myostatin and follistatin in these subjects before and after supplementation was not disclosed.
When (-)-epicatechin is fed orally to mice at 2mg/kg daily (in two divided doses of 1mg/kg) for two weeks, the 18% increase in myostatin and 30% decrease in follistatin which normally occurs are prevented while in young mice given the same dose of (-)-epicatechin reduces myostatin 15% with no influence on follistatin.
Cocoa powder (6.43% (-)-epicatechin content and 3.54% procyanidin B2) at 50mg/kg daily in mice for two weeks has been noted to reduce blood glucose thought to be secondary to an increase in fat oxidation in skeletal muscle, a hypothesis supported by an increase in resting energy expenditure (RER) and expression of CPT2 and UCP1 proteins independent of any changes in locomotor activity.
These beneficial bioenergetic changes at the level of the mitochondria have been noted in a preliminary study of five humans who had impaired mitochondria function and structure (type II diabetic and with heart failure) when given 100 mg (-)-epicatechin daily for three months. An improvement of mitochondria cristae has been noted both in mice with poor oxidative metabolism in skeletal muscle as well as the aforementioned human study.
Consumption of 100g dark chocolate (70% cocoa) has been noted to nonsignificantly increase plasma non-esterified fatty acids (NEFA) when consumed acutely two hours prior to cycling exercise relative to milk chocolate and to increase serum free fatty acids when 40g is consumed before a 90 minute cycle, with no obervable changes in total triglyceride content or in biomarkers of metabolic rate or fat oxidation rates.
It is known that consumption of fatty acids per se can increase total free fatty acids in serum during exercise even without changes in performance although the differing effects between dark chocolate and cocoa-free control with a similar fatty acid profile suggest a role for the catechins.
Oral ingestion of 1mg/kg (-)-epicatechin twice daily in one year old mice (C57BL/6N), an age where physical performance tends to decrease, for 15 days alongside exercise noted improvements in duration and distance until failure relative to exercise alone; ingestion of (-)-epicatechin at this dose without exercise failed to have any effect when compared to control.
In rats that are bred for low endurance performance (LCR rats with defects in aerobic metabolism) the same dose of (-)-epicatechin for a month appeared to increase mitochondrial cristae, angiogenesis, and biogenesis of mitochondria which are thought to be the mechanisms underlying improvements in physical performance (although it was not directly measured in this study). This study noted a 40% increase in expression of VEGF-A, an angiogenic factor, which was normalized 15 days after (-)-epicatechin cessation.
It is further thought to be relevant to glycolytic muscle (in rats, the plantaris muscle) since this muscle type differs in these selectively bred rats relative to those bred for high performance (the soleus muscle does not appear to differ) and the parameters (-)-epicatechin appears to benefit, mitochondrial activity and angiogenesis, are inherently lower in these muscle.
One study in mice specifically looking at detraining noted that administration of 1mg/kg twice daily (-)-epicatechin for 15 days of rest in trained mice prevented improvements in exercise performance from being lost during prolonged rest, which was associated with preventing the exercise-induced increases in complex III and IV of the mitochondria from being reduced.
In soccer players, consumption of chocolate (containing 168mg flavanols; 39mg (-)-epicatechin) once daily for a week was associated with improvements in oxidative status yet failed to influence their performance during sporting (via self-report during the week long intervention).
(-)-epicatechin at a dose where it improved endurance performance in mice after 15 days (1mg/kg twice daily) failed to have any influence on force output or acute contractility (when tested ex vivo) despite being more resistant to fatigue from repeated contractions whereas elsewhere 1mg/kg twice daily in sedentary middle aged adults (42 years of age) appeared to slightly increase grip strength by 7% relative to baseline; no placebo control was used in this latter study.
Dark chocolate (100g of 70% cocoa) given to otherwise healthy men acutely before exercise noted that the increase in plasma (-)-epicatechin was associated with an increase in total antioxidant capacity of the blood immediately before and after exercise but failed to cause any differences in IL-6 concentrations relative to milk chocolate or baseline or in oxidative burst of neutrophils.
In overweight men given 70g high flavanol chocolate (1078mg; 349mg (-)-epicatechin), leukocyte adhesion factor sICAM-1 increased relative to the group given 70g of standard 58% cocoa (259mg; 97mg (-)-epicatechin) while sICAM-3 increased acutely in both groups; when supplementation persisted for four weeks both these adhesion factors decreased with no differences between chocolates in a fasted state or in response to a high fat test meal.
Cocoa procyanidins have been noted to have no influence on IL-5 secretion in PMBCs at rest, but augment the increase when under stimulation from PHA.
Cacao extracts have been noted in vitro to downregulate inflammatory cytokines from macrophages including MCP-1, TNF-α, and IL-6 with a potency greater than a similar concentration of pure (-)-epicatechin (similar antiinflammatory effects seen in whole blood) other studies to find similar actions in macrophages have noted efficacy with the isolated cocoa constituent clovamide when both studies are using LPS as an inflammatory stimuli; when LPS is not present, procyanidins from cocoa have been noted to possess the ability to increase the secretion of IL-1, IL-6, and TNF-α in PMBCs with more potency seen with the longer chain flavanols.
It has been suggested that these constituents are acting via their antioxidant capacities, since there are REDOX sensitive pathways since antioxidants in general may suppress macrophage activation (a major locus, NF-kB, is suppressed by antioxidants and (-)-epicatechin has been noted to suppress NF-kB).
Similar to most antioxidants which are REDOX capable (antioxidant or oxidant dependent on cellular context) (-)-epicatechin and other flavanols in cocoa may have antiinflammatory effects when other inflammatory stimuli are present while inherently having some stimulatory action on macrophages at rest
The indoleamine 2,3-dioxygenase (IDO) enzyme mediates the breakdown of L-tryptophan into L-kyurenine and various metabolites (known as the kynurenine pathway) is induced by IFN-γ in T cells (as well as macrophages, less in B cells and HUVECs) during inflammation and appears to have a role in viral and bacterial infections. IDO is also thought to be a potential link between depression and inflammation as it hypothetically depleted L-tryptophan stores which could have been used to synthesize serotonin, and IDO activity (assessed by neopterin as a proxy measure) is thought to increase with oxidation as the two are correlated in immune cells and in vivo.
In regards to cocoa, the degradation of L-tryptophan (via IDO) in PMBCs appeared to be greatly suppressed to a near absolute degree at a concentration of 5µg/mL when activated by mitogens; THP-1 cells were wholly unaffected.
When tested in guinea pigs sensitized to an antigen (ovalbumin) who were given unsweetened cocoa at one of two doses (300 of 600mg/kg) for 35 days with the final dose an hour before antigen presentation, it was noted that there was a dose-dependent anti-allergic action of supplementation relative to water (as control).
The structure of epicatechin, found in chocolate but is one of the main four Green Tea Catechins, has been found to normalize adverse changes (by the Tat protein; elevated in HIV) with proBDNF and BDNF, which exerted neuroprotective effects against the side-effects of HIV with greater potency than Resveratrol.
(-)-epicatechin is thought to interact with cortisol as the antiinflammatory effects of cortisol are somewhat mitigated by oxidative stress, and the antioxidant abilities of (-)-epicatechin (1-50µM) can preserve the actions of cortisol in isolated monocytes.
A diet high in cocoa flavanols (494mg with 89mg epicatechin and 21mg catechin) daily for four weeks has been noted to increase the bacterial count of bifidobacterial, enterococcus, and lactobacilli strains in the intestines while decreasing clostridia as assessed by fecal examination. This study also noted decreases in blood pressure and C-reactive protein, with the latter correlated to changes in lactobacilli, and the suppression of clostridia histolyticum noted with cocoa flavanols has been noted with isolated (+)-catechin and other Green Tea Catechins.
In subjects with liver cirrhosis, eating a meal can result in low blood pressure due to a phenomena known as the hepatic venous pressure gradient (HPVG); due to hypertension in the liver, more blood is redirected to the liver to accomodate food intake resulting in a reduction in peripheral blood pressure. This is likely due to decreased nitric oxide bioavailability in the liver and is exacerbated by excess oxidation, with both nitric oxide donors and antioxidants having been at times implicated in being therapeutic.
In these subjects, a liquid meal that contains dark chocolate (85% cocoa) appeared to be associated with less of a post-meal increase in the HPVG relative to a meal without flavonoids thought to be related to improved liver circulation, although despite the hypothesis and benefits to HPVG when measuring portal vein and total blood flow as well as hepatic artery blood flow there did not appear to be any differences between groups; regardless, the peripheral gradient was about halved with dark chocolate and peripheral arterial pressure increased without changes in heart rate.
The post meal reduction in blood pressure that subjects with cirrhosis experience can be attenuated by ingestion of polyphenolic containing dark chocolate products
In diabetic rats, injections of 15-30mg/kg (-)-epicatechin for 35 days appeared to dose-dependently attenuate lipid peroxidation relative to diabetic control; there was no effect of (-)-epicatechin on mice without diabetes and this was associated with a preservation of superoxide dismutase (SOD) activity.
In otherwise healthy subjects given 1g/kg dark chocolate (70% cocoa) and measured two hours later, it appears that supplementation increased the oxygenation of corticol and medullary tissue in the kidneys compared to the control of white chocolate; this effect was correlated with the serum (-)-epicatechin content.
Acute ingestion of 40g dark chocolate in glaucoma patients and normal controls failed to influence blood pressure and intraocular pressure (IOP) any more than white chocolate control, and while there appeared to be increased venule dilation in response to a flicker test this was only present in controls (without glaucoma) given dark chocolate.
Oral administration of 1mg/kg (-)-epicatechin to aged mice appears to attenuate some of the age-related changes in antioxidant proteins and some proteins involved in mitochondrial biogenesis (sirtuins) and reduce the senescence-associated biomarker β-galactosidase compared to aged control.
Cocoa flavanols have been investigated for their effects on the skin due to being minor constituents of cocoa butter, a fat derived from the cacao plant used topically in many skin care products, as trace flavanols remain in the butter conferring aromatic and antioxidant (preservative) properties.
In otherwise healthy women given either ten grams of chocolate with a low flavanol content (200mg) thrice daily for a total of 600mg flavanols or control chocolate failed to observe any differences in photoprotection as assessed by minimum erythema dose (MED).
600mg flavanols daily via three doses of dark chocolate (200mg each) has been noted to slightly increase skin elasticity on the temple, but not arms, relative to control chocolate. There were no observed changes in skin hydration status between groups.
In adult men with a history of acne given either chocolate (in the form of unsweetened capsules) or a visually identical placebo in varying doses (1-6oz) for one week appeared to increase number of lesions relative to placebo. This effect may be limited to the acne prone, as a pilot study using 39g chocolate bars over a week only noted a third of subjects increased lesion count with another pilot study using higher doses (340g or 12oz of milk chocolate) over week in acne prone men noting a similar 4-7 day time course for exacerbation of acne lesions.
Cocoa extract is thought to be beneficial for periperal artery disease (PAD) due to its ability to enhance blood flow, secondary to (-)-epicatechin and related catechins increasing Nitric Oxide (NO) signalling via reducing the activity of NOX-2 in vitro, requiring a mixture of catechins rather than isolated (-)-epicatechin. NOX-2 is a catalytic subunit of NADPH oxidase which produces free radicals, and can cause a reduction of NO signalling as the oxidation promotes conversion into peroxynitrate indirectly reducing NO availability and dark chocolate is well known to suppress NOX2 activity and increase blood flow in instances of low blood flow associated with oxidation which also characterizes PAD.
Dark chocolate, due to the catechins specifically in regards to a high (-)-epicatechin content, are known to acutely benefit any condition where blood flow is impaired associated with elevated oxidation. Peripheral artery disease is one of these conditions
In people diagnosed with PAD given chocolate, ingestion of a single dose of dark chocolate (40 grams of 85% cocoa) but not milk chocolate (40g of 35% cocoa) resulted in an increase in serum epicatechin and other catechins, which was thought to underlie the benefits seen in walking distance (11% increase) and walking time (15% increase) relative to themselves as control.
In contrast to the aforementioned, ingestion of 50 grams of dark chocolate in PAD sufferers without a walking test has failed to influence blood flow at rest and failed to influence any measured circulatory/microcirculatory parameters relative to baseline; white chocolate also ineffective.
It is known that cognitive aging is related to a reduction in blood flow to the brain thought to at least in part underlie associations between dietary flavonoids and reduced risk of cognitive decline seen in both epidemiological research on dementia and rodent interventions and neural susceptability to damage; this potential benefit is similar to what is hypothesized for dietary Nitrate intake, and due to (-)-epicatechin increasing cerebral blood flow it as well as its food source (dark chocolate) are thought to have a protective role. At least two of the brain regions that (-)-epicatechin can increase blood flow to, the prefrontal and parietal cortices, seem to have less blood flow to them during Alzheimer's disease.
When tested in vitro in regards to suppressing NOX2 activity (a mechanism which results in increased blood flow in pro-oxidative states) and increasing secretion of VCAM-1 and E-selectin, concentrations of (-)-epicatechin, EGCG, and catechin that are found in serum after ingestion of 40 grams of dark chocolate (a concentration range of 0.1-10μM) were effective when used together while no constituent was effective on its own; this suggests additive or synergistic effects of catechin constituents in chocolate relative to pure (-)-epicatechin.
(Common misspellings for Cocoa Extract include chocmine, choamine, chocolamine)
(Common phrases used by users for this page include myokines supplements, cocoa powder extract, cocoa extract caffeine, cocao benefits extract, chocamine composition, Brazilian Cocoa Extract)