Scientific Name(s): Theobroma cacao L. subsp. cacao
Common Name(s): Cacao, Cocoa
The cocoa tree grows to heights exceeding 8 m. The fruits are borne on the trunk and branches, with the seeds imbedded in a sticky pulp. The fruits are large and football shaped, with quarter-sized seeds referred to as cocoa beans. Cacao is often used to describe the raw material, while cocoa is used to describe the processed products. Although several varieties of cacao exist, the forastero variety from West Africa accounts for more than 90% of world production.10
The Olmecs, one of the first civilizations of the Americas (1500 BC to 400 BC) are credited with the first use of cocoa. Its consumption as a beverage was continued by the Mayas (250 AD to 900 AD). Cortez described the preparation and use of a beverage called chocalatl, made of the seeds of T. cacao. The Mayan word cacao entered scientific nomenclature in 1753, and the words theo ("god") and broma ("nectar" or "food") are Latinized Greek. Recipes using cacao were recorded in 15th century Mayan codices.11, 12
Cacahuatl (cacao) beans, resembling almonds, have been used as currency. In Aztec society, cocoa beans were used to pay annual taxes to the Emperor.11
The medicinal use of chocolate has a long history in North America dating to the 16th century.13 In the 1600s, it was argued that "chocolate" should be considered a medicine because it changed a patient's health. At that time, physicians also stated that all that was necessary for breakfast was chocolate, because it yielded good nourishment for the body.14 In the Rules for Regulating Salem Hospital published in 1773, chocolate was listed under "patient's diet."13
Documents have been discovered indicating that chocolate was used naturopathically and prescribed to patients by some physicians for a variety of diseases during the 18th and 19th century in America, including cholera, consumption (tuberculosis), scarlet fever, smallpox, typhus, and yellow fever.13
During the 20th century (especially after the 1930s), the consumption of chocolate shifted from medicinal to confectionery. In the last 2 decades there has been a resurgence in the interest of chocolate/cocoa as providing health benefits.5, 6, 7
The cocoa seeds (beans) are ground into a liquid mass called cocoa liquor, containing about 55% cocoa butter removed by hydraulic pressing. The remaining cocoa cake is dried and ground to a fine powder with a fat content of about 22%. Specially treated cocoa powder, called alkalinized cocoa has improved color, flavor, and dispersability compared with unalkalinized powder. Cocoa butter, also known as theobroma oil, may have a faint chocolate odor that can be removed following further purification. Cocoa contains more than 300 volatile compounds, the most important flavor components being aliphatic esters, polyphenols, aromatic carbonyls, and theobromine10 which also prevent rancidity of the fat.15 Cocoa is also a dietary source of resveratrol.90
The pharmacologically active ingredients of cocoa seeds include amines, alkaloids, fatty acids, polyphenols (including flavonoids), tyramine, magnesium, phenylethylamine, and N-acylethanolamines.16, 17
Cocoa contains the amines and alkaloids theobromine (0.5% to 2.7%), caffeine (approximately 0.25% in cocoa), theophylline, tyramine, phenylethylamine, and trigonelline.10, 18 A standard chocolate bar (40 to 50 g) contains theobromine (86 to 240 mg) and caffeine (9 to 31 mg).19 The characteristically bitter taste of cocoa is generated by the reaction of diketopiperazines with theobromine during roasting. Theobromine is produced commercially from cocoa husks.10
Cocoa butter contains triglyceride fatty acids consisting mainly of oleic (37%), stearic (34%), and palmitic (26%) acids.18 About 75% of the fats are present as monounsaturates.10 Cocoa butter has a high digestibility, similar to that of corn oil, with a digestible energy value of approximately 37 kilojoule/g in humans; therefore, it cannot be considered to be low calorie.20 However, one randomized trial demonstrated that supplementation of chocolate with calcium 0.9% (0.9 g/day) reduced the absorption of cocoa butter, thus reducing the digestible energy value.21
Cocoa is rich in polyphenols that have beneficial effects on cardiovascular disease.22 In cocoa, the polyphenols of particular interest are flavanols, a subclass of flavonoids, which are in turn a subclass of polyphenols. Cocoa is more than 10% flavanol by weight. Flavanols can be monomeric: in cocoa beans these are mainly (−)-epicatechin and (+)-catechin, dimeric (consisting of 2 units of epicatechin with differing linkages), or polymeric (combinations of monomers and chains of up to 10 units or more have been found). These polymers are known as procyanidins.1, 7, 16, 23, 24, 25, 26, 27, 28, 29, 30
N-acylethanolamines are compounds found in chocolate that are structurally similar to anandamine, which is similar to the cannabinoid responsible for euphoria from cannabis. These compounds may not exert their effect by binding with the tetrahydrocannabinol receptors, but by inhibiting breakdown of endogenously produced anandamine, thus prolonging a "natural high."12, 31, 32
Uses and Pharmacology
Cocoa has been reported to be a source of natural antioxidants10 the free radical scavengers that preserve cell membranes, protect DNA, prevent the oxidation of low-density lipoprotein (LDL) cholesterol that leads to atherosclerosis, and prevent plaque formation in arterial walls.33 The antioxidant activity of cocoa has been attributed to the procyanidins and their monomeric precursors, epicatechin and catechin, which inhibit oxidation of LDL.34, 35, 36 Dark chocolate and cocoa inhibit LDL oxidation and increase high-density lipoprotein (HDL)-cholesterol concentrations.37, 38
Although, the relatively high stearic acid content in cocoa products was once purported to reduce the risk of coronary heart disease (CHD), it is no longer considered to play a role in the reduction of CHD risk.39
Data suggest that flavonoid-rich food contributes to cancer prevention. An in vitro study showed that breast cancer cells are selectively susceptible to the cytotoxic effects of cocoa-derived pentameric procyanidin and suggest that inhibition of cellular proliferation by this compound is associated with the sire-specific dephosphorylation or down-regulation of several cell cycle regulatory proteins.59
Cardiovascular disease and its risk factors
Research suggests that the flavonoid constituents, in particular flavanols, in cocoa may be beneficial in cardiovascular disease. Consumption of foods rich in flavanols are also associated with improved cardiovascular outcomes5, 40 suggesting that this specific group of flavonoids may have potent cardioprotective qualities.5 One study concluded that epicatechin content was likely to be the main factor in cocoa's association with beneficial health effects.41
Multiple epidemiological studies have found an inverse association between the consumption of flavonoid-containing foods and the risk of cardiovascular disease.3, 4, 39, 42 Two of these studies provide data specific to the effects of cocoa.3, 4
In a study of 470 elderly men, blood pressure was measured at baseline and then 5 years later, with causes of death ascertained during 15 years of follow-up.3 Diet was assessed at 5-year intervals, with cocoa intake estimated from the consumption of cocoa-containing foods; mean intake among users was approximately 2.11 g/day. The mean systolic blood pressure in the highest tertile of cocoa intake was 3.7 mm Hg lower, and the mean diastolic blood pressure was 2.1 mm Hg lower compared with the lowest tertile; 314 men died, 152 of cardiovascular diseases. When compared with that of the lowest tertile, the adjusted relative risk for men in the highest tertile was 0.5 for cardiovascular mortality and 0.53 for all-cause mortality.
In another study4 34,489 cardiovascular disease-free postmenopausal women were followed for 16 years. After multivariate analysis, a borderline inverse relationship between chocolate intake and cardiovascular disease mortality was observed.
Numerous intervention trials have shown that consumption of flavanol-containing cocoa products can improve endothelial function41, 43, 44, 45, 46 vascular function44, 47, 48 and insulin sensitivity47; as well as attenuate platelet reactivity46, 47, 49, 50, 51, 52 and reduce blood pressure.5, 47
Habitual intake of any chocolate-containing food was studied for its effect on cardiovascular risk in a prospective manner using data from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort (N = 20,951). The sum weight of chocolate-containing food items (ie, chocolate squares, chocolate snack bars, hot chocolate powder) was measured using a food frequency questionnaire; flavonoid and cocoa content were not measured. Higher intake (up to 100 g/day) was associated with decreased risk of cardiovascular disease and stroke, especially mortality. The multivariate-adjusted hazard ratio (HR) for CHD was 0.88 (95% confidence interval [CI], 0.77 to 1.01) for the top quintile (16 to 99 g/day) compared to nonconsumers, and for stroke and cardiovascular disease, it was 0.77 (95% CI, 0.62 to 0.97) and 0.86 (95% CI, 0.76 to 0.97), respectively. Additionally, the updated meta-analysis conducted by the same authors that included these data showed similar results.83
A meta-analysis looking specifically at chocolate consumption on heart failure risk identified 5 studies that met eligibility criteria; all were high quality. The studies included 4 cohorts and 1 post hoc analysis of a randomized controlled trial; a total of 106,109 participants were enrolled and follow-up ranged from 9 to 14 years. A nonlinear dose response was observed with low to moderate chocolate consumption, but not high dose, associated with a reduced risk of heart failure (HR, 0.86; 95% CI, 0.82 to 0.91). A low to moderate dose was defined as a median intake of less than 7, 50 g servings/week mostly in the form of chocolate bars.88
Evaluation of study results from 2 Swedish cohorts (N=72,495) plus a meta-analysis of these 2 studies combined with 3 additional cohorts identified through a systematic review of studies published up to September 2017 (N=107,959) sought an association between chocolate consumption and the risk of atrial fibrillation. No association was found in the dose-response meta-analysis, the stratified analysis by gender, or the categorical analysis between the highest vs the lowest category of chocolate consumed. Although the sample sizes were large, limitations included no discernment between milk or dark chocolate, confounders associated with observational study design, and assessment of chocolate consumption only at baseline.89
Consumption of chocolate bars resulted in reductions in systolic and diastolic blood pressure. In one study of normotensive subjects, systolic blood pressure decreased 8.2% within 4 weeks of consuming the chocolate bars, with a 5% reduction relative to baseline still apparent at 8 weeks. Similar reductions in diastolic blood pressure were noted at 4 weeks (8.2%) and remained at 6 weeks (3.4%); however, at 8 weeks, the diastolic blood pressure was no longer lower (2.2%). Because the study population was not hypertensive, the results are notable.5
A meta-analysis was performed of 5 randomized, controlled studies involving 173 subjects. After cocoa diets, the mean systolic blood pressure was 4.7 mm Hg and the diastolic 2.8 mm Hg lower than in the cocoa-free controls.52 However, because the flavanol content in chocolate is impacted not only by the variety and ripeness of cocao beans, but also the processing procedures of raw cocoa, it’s critical to compare dosages of flavanols rather than just the amounts of chocolate or concentration of cocoa administered. A 2012 Cochrane meta-analysis of 20 randomized controlled trials (N = 856) investigated the effects of chocolate or cocoa products on blood pressure. When mostly healthy, normotensive subjects received daily flavanol-rich (30 to 1,080 mg), low-flavanol (6.4 and 41 mg), or flavanol-free cocoa products for 2 to 18 weeks, a small but statistically significant reduction in blood pressure of a little more than −2 mm Hg was observed with flavanol-rich cocoa products. Subgroup analysis revealed that the reduction was significant only when compared to flavanol-free controls and not low-flavanol controls. Adverse effects more common in the flavanol-rich intervention groups included GI complaints and distaste of the product. Similar conclusions were noted in the 2017 updated meta-analysis that added 17 trials to the review for a total of 1,804 mainly healthy participants. Subgroup analysis reflected a slightly increased mean systolic reduction of −4 mm Hg in hypertensive patients compared to no significant reduction in normotensive participants. The quality of the data in the update was downgraded from high to moderate due to unexplained heterogeneity among the trials.85, 87
Endothelial and vascular function
Populations that consume cocoa routinely excrete more nitric oxide (NO) metabolites than genetically similar groups with less consumption. This indicator of higher NO production is associated with a lower incidence of cardiovascular disease.41
Results of another study demonstrated that daily consumption of a high-flavanol cocoa drink led to a sustained reversal of endothelial dysfunction, reaching a plateau level of improved flow-mediated dilation after 5 days. Increases observed in circulating nitrite, but not in circulating nitrate, paralleled the observed flow-mediated dilation augmentation.44
In a study of smokers, the ingestion of a flavanol-rich cocoa drink increased the circulating pool of nitric oxide and endothelium-dependent vasodilation.45 Endothelial dysfunction and inflammation biomarkers were evaluated after 35 pre-hypertensive adults ingested pure epicatechin (100 mg/day) and quercetin-3-glucoside (160 mg/day) for 4 weeks in a randomized, placebo-controlled, double-blind, crossover study. Of the 5 endothelial dysfunction biomarkers measured, soluble endothelial selectin was significantly reduced by epicatechin (P = 0.03) and quercetin (P = 0.03) supplementation. No other biomarkers were significantly affected by epicatechin.82
A study comparing the effects of dark and white chocolate on flow-mediated dilation found that dark chocolate improved flow-mediated dilation after 2 hours compared with baseline, with the effect lasting about 8 hours. White chocolate had no effect on flow-mediated dilation.46 Similar results were found between dark chocolate (more than 85% cocoa) compared to milk chocolate (less than 35% cocoa) in a single-blind, crossover, interventional trial in 20 patients with peripheral artery disease. Two hours after ingestion, 40 g of dark chocolate significantly improved maximal walking distance, maximum walking time, and serum nitrite/nitrate compared with baseline; no changes were observed following 40 g milk chocolate consumption. Data from the in vitro analysis suggested the mechanism is possibly related to nitrite/nitrate regulation that is implicated in flow-mediated dilation.84
Because endothelial dysfunction has been observed during hyperglycemia, the effects of flavanol-rich dark chocolate on flow-mediated dilation was investigated in 12 healthy volunteers. In a randomized, blind, crossover trial, a 100 g flavanol-rich dark chocolate bar that was consumed each morning for 3 days significantly protected endothelial function (P = 0.0007), prevented an increase in blood pressure (systolic blood pressure, P < 0.0001; diastolic blood pressure, P = 0.019), and prevented an increase in endothelian-1 subsequent to the glucose load test when compared to ingestion of a 100 g white chocolate bar that contained only trace amounts of polyphenols (P = 0.0023). No significant differences were observed in glucose and insulin responses.86
In a crossover study, 15 healthy subjects were randomly assigned to consume 100 g of dark chocolate or 90 g of white chocolate for 15 days after a 7-day, cocoa-free, run-in phase. They were then crossed over after another 7-day, cocoa-free, period. The homeostasis model assessment of insulin resistance was lower after dark chocolate ingestion. The quantitative insulin sensitivity check index was also higher after dark chocolate ingestion.47 However, no significant differences were observed in glucose and insulin responses with administration of a 100 g flavanol-rich dark chocolate bar for 3 days versus a white chocolate bar with trace polyphenols in 12 healthy volunteers in a randomized, blind, crossover trial.86
In the previous study, 2 hours after ingestion of dark chocolate, the shear stress-dependent platelet function was also reduced. No effect was seen with white chocolate.46
In a study evaluating the effect of cocoa ingestion on modulated human platelet activation and primary hemostasis, cocoa consumption suppressed ADP- or epinephrine-stimulated platelet activation and platelet microparticle formation, and had an aspirin-like effect on primary hemostasis.49
Findings were similar in another study of 32 healthy subjects who consumed 234 mg of cocoa flavanols and procyanidins or placebo per day for 28 days. The active group had lower P-selectin expression and lower ADP-induced aggregation and collagen-induced aggregation than did the placebo group.51
Theobromine, the primary alkaloid in cocoa, is a weak CNS stimulant, with only one-tenth the cardiac effects of other methylxanthines (eg, caffeine, theophylline).53
Theobromine has activity similar to that seen with caffeine (ie, increases in energy, motivation to work, and alertness).19
Theobromine, when ingested in the form of a large chocolate bar, did not cause any acute hemodynamic or electrophysiologic cardiac changes in young, healthy adults.53 Theobromine pharmacokinetics were similar in healthy men when measured after 14 days of abstention from all methylxanthines and then after 1 week ingestion of dark chocolate (theobromine 6 mg/kg/day).54 However, the results of these studies cannot be extrapolated to patients with any condition(s) or disease(s), nor to the effects of chronic chocolate consumption.
Use of chocolate as an inhaler has been studied. This edible inhaler, the Chocuhaler, produced a clinical effect when used to administer albuterol.55
Free radical damage has been implicated as a cause of cognitive decline and memory loss in aging. A study using functional magnetic imaging in healthy young people found that ingestion of flavanol-rich cocoa was associated with increased cerebral blood flow58 suggesting that cocoa may play a role in the treatment of cerebral impairment, including dementia and stroke.
Food and pharmaceutical additives
Cocoa products are used extensively in the food and pharmaceutical industries. Cocoa powder and cocoa butter are often mixed with chocolate liquor (ground cacao seeds), sugar, milk, and other flavors.
Cocoa butter is also used as a suppository and ointment base, as an emollient, and as an ingredient in various topical cosmetic preparations.5, 62 Cocoa butter suppositories have been used since the early 1900s to relieve hemorrhoids, and the ointment has been applied to the breasts of nursing women.14
In rats, the magnesium contained in cocoa has been shown to prevent and correct chronic magnesium deficiency.60, 61 Low intakes of magnesium may be responsible for some cardiovascular alterations as well as renal, GI, neurological, and muscular disorders. The use of cocoa to treat or prevent magnesium deficiency in humans has not been explored.
Ingredients in chocolate with potential psychoactive properties have been identified, including the biogenic stimulant amines caffeine, theobromine, tyramine, and phenylethylamine; however, their concentrations are likely to be too low to have an effect.32 The N-acylethanolamines found in chocolate and cocoa powder may act indirectly by inhibiting breakdown of endogenously produced anadamine, prolonging a "natural high."12, 31
A study in which a depressive mood was induced demonstrated a correlation with an increase in chocolate craving. It has been demonstrated that thoughts of chocolate are overpowering and prey on the mind. Questionnaires filled out by study subjects have shown that there is a weakness for chocolate in individuals who are under emotional stress, bored, upset, or feeling down.56 A study that followed changes in brain activity related to eating chocolate demonstrated that one area of the brain is involved when there is motivation or craving to eat chocolate, while another area is involved when the desire to eat chocolate is decreased or becomes unpleasant. A similar result also has been shown with cocaine craving. Studies are needed to test the importance of this activity related to eating disorders and obesity.57
No specific dosing recommendations can be made. The polyphenols in chocolate come from the cocoa liquor; therefore, the polyphenol content is highest in cocoa powder, followed by dark chocolate, then milk chocolate, with none in white chocolate.1 However, because polyphenols can be destroyed during processing, some products may actually have a low polyphenol content.
In the Zutphen elderly, an inverse relationship was demonstrated between cocoa intake and blood pressure, as well as a 15-year cardiovascular and all-cause mortality; the median cocoa intake among users was 2.11 g/day.3
Further studies characterizing the polyphenol content of cocoa products and method of measurement are needed.1, 7 Most studies have used dark chocolate in order to avoid a possible milk interference; however, one study using milk chocolate found positive effects on blood pressure, plasma cholesterol, and markers of oxidative stress in young men who exercised.1 Because there have been very few dose-response studies, it is difficult to estimate the amount of chocolate necessary for an antioxidant effect.1 In a study of smokers, 40 g of dark chocolate improved flow-mediated dilation and platelet function (polyphenol content was not stated).36 In another study, a half-maximal, flow-mediated dilation 2 hours after consumption was achieved with 616 mg total flavanols.44 In a third study, just 25 g of semisweet chocolate bits containing 200 mg flavanols and procyanidins produced a reduction in platelet-related hemostasis in healthy people.63
Pregnancy / Lactation
Generally recognized as safe (GRAS) when used in moderate amounts or in amounts used in foods. Avoid dosages greater than those found in food because safety and efficacy are unproven. Caffeine content should be restricted during pregnancy.8, 9
Due to cocoa's caffeine content, many interactions are theoretically possible if large doses are consumed.9 The caffeine in cocoa may have an additive effect with other caffeine-containing products.
The following drugs may increase the effects of caffeine in cocoa because they decrease the metabolism or clearance of caffeine: cimetidine9 disulfiram64 estrogens65 fluconazole66 mexiletine67 oral contraceptives65 and quinolone antibiotics.68 Cocoa may increase the risk of toxicity or adverse reactions of clozapine because caffeine inhibits clozapine metabolism.69 The cardiac inotropic effects of beta agonists may be increased by the caffeine content of cocoa.64
Use of large amounts of cocoa with monoamine oxidase inhibitors may precipitate a hypertensive crisis because of cocoa's tyramine content.9
Concomitant use of phenylpropanolamine and cocoa may cause an additive increase in blood pressure because of the caffeine content.70 Theoretically, the caffeine in cocoa might inhibit dipyridamole-induced vasodilation.71 Abrupt withdrawal of caffeine-containing cocoa may increase serum lithium levels.72
Caffeine from the ingestion of large amounts of chocolate, along with 2 to 4 caffeinated beverages, was correlated with the appearance of tics in 2 children.73
Patients diagnosed with irritable bowel syndrome who experience reflux esophageal symptoms should eliminate foods that decrease lower esophageal sphincter pressure, such as chocolate and cocoa-containing products, from their diets.74
Conflicting results were demonstrated when chocolate was tested as an initiator of migraine headaches. Phenolic flavonoids, which are present in red wine and chocolate, may have a role in precipitating migraines.77, 78, 79
In animals, cocoa butter has been shown to be comedogenic; however, this has not been proven in humans.10
Although cocoa is not considered to be toxic in typical confectionery doses, at least 1 report of animal toxicity has been published. A dog that consumed 1 kg of chocolate chips suffered hyperexcitability and convulsions, and subsequently collapsed and died, most likely because of acute circulatory failure secondary to theobromine/caffeine toxicity.80
The plant may contain small amounts of safrole, a carcinogen banned by the Food and Drug Administration.81
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