Medically reviewed on August 20, 2018
Scientific Name(s): Theobroma cacao L. subsp. cacao . Family: Sterculiaceae
Common Name(s): Cacao , cocoa . Materials derived from the cacao seeds (beans) include cocoa solid (the nonfat component of cocoa beans that is finely ground into a powder), cocoa butter (the fat component extracted by grinding and pressing the beans), and chocolate (a combination of cocoa solids, cocoa butter, and sugar). 1
Cocoa solid, cocoa butter, and chocolate are all rich sources of antioxidants. 2 Epidemiological studies show an inverse association between the consumption of cocoa and the risk of cardiovascular disease. 3 , 4 The likely mechanisms are antioxidant activity; improvement in endothelial function, vascular function, and insulin sensitivity; as well as attenuation of platelet reactivity and reduction in blood pressure. 5 , 6
No specific dosing recommendations can be made. Further studies characterizing the polyphenol content of cocoa products and method of measurement are needed. 1 , 7 In one study, 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
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
None well documented.
Children consuming large amounts of chocolate and caffeinated beverages may exhibit tics or restlessness. Ingredients in chocolate may precipitate migraine headaches, and cocoa products may be allergenic.
Cocoa is nontoxic when ingested in typical confectionery amounts.
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 (1,500 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 theobromine, 10 which also prevent rancidity of the fat. 15
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 antioxidants, 10 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. 39Cardiovascular 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 outcomes, 5 , 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. 41Clinical data
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 study, 4 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.Intervention studies
Numerous intervention trials have shown that consumption of flavanol-containing cocoa products can improve endothelial function, 41 , 43 , 44 , 45 , 46 vascular function, 44 , 47 , 48 and insulin sensitivity 47 ; as well as attenuate platelet reactivity 46 , 47 , 49 , 50 , 51 , 52 and reduce blood pressure. 5 , 47Endothelial 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
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. 46Platelet reactivity
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. 51Insulin sensitivity
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. 47Blood pressure
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. 52Cardiorespiratory stimulant
Theobromine, the primary alkaloid in cocoa, is a weak CNS stimulant, with only one-tenth the cardiac effects of other methylxanthines (eg, caffeine, theophylline). 53Clinical data
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. 55Mood disorders
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 , 31Clinical data
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. 57Other uses
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 flow, 58 suggesting that cocoa may play a role in the treatment of cerebral impairment, including dementia and stroke.Cancer
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. 59Magnesium deficiency
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.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
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
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: cimetidine, 9 disulfiram, 64 estrogens, 65 fluconazole, 66 mexiletine, 67 oral contraceptives, 65 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
Cocoa may be allergenic and has caused occupational asthma in confectionery factory workers. 75 A high prevalence of chronic respiratory symptoms has also been recorded in workers exposed to cocoa. 76
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
Bibliography1. Cooper KA, Donovan JL, Waterhouse AL, Williamson G. Cocoa and health: a decade of research. Br J Nutr . 2008;99(1):1-11.
2. Vinson JA, Proch J, Bose P, et al. Chocolate is a powerful ex vivo and in vivo antioxidant, an antiatherosclerotic agent in an animal model, and a significant contributor to antioxidants in the European and American diets. J Agric Food Chem . 2006;54(21):8071-8076.
3. Buijsse B, Feskens EJ, Kok FJ, Kromhout D. Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen elderly study. Arch Intern Med . 2006;166(4):411-417.
4. Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr . 2007;85(3):895-909.
5. Erdman JW Jr, Carson L, Kwik-Uribe C, Evans EM, Allen RR. Effects of cocoa flavanols on risk factors for cardiovascular disease. Asia Pac J Clin Nutr . 2008;17(suppl 1):284-287.
6. Engler MB, Engler MM. The emerging role of flavonoid-rich cocoa and chocolate in cardiovascular health and disease. Nutr Rev . 2006;64(3):109-118.
7. Ariefdjohan MW, Savaiano DA. Chocolate and cardiovascular health: Is it too good to be true? Nutr Rev . 2005;63(12, pt 1):427-430.
8. Briggs GB, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation . 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1998.
9. Brinker FJ. Herb Contraindications and Drug Interactions . 2nd ed. Sandy, OR: Eclectic Medical Publications; 1998.
10. Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics . 2nd ed. New York, NY: John Wiley and Sons; 1980.
11. Coe S, Coe M. The True History of Chocolate . London, England: Thames and Hudson; 1996.
12. Lee R, Balick M. Rx: chocolate. Explore (NY) . 2005;1(2):136-139.
13. Pucciarelli DL, Grivetti LE. The medicinal use of chocolate in early North America. Mol Nutr Food Res . 2008;52(10):1215-1227.
14. Dillinger TL, Barriga P, Escárcega S, Jimenez M, Salazar Lowe D, Grivetti LE. Food of the gods: cure for humanity? A cultural history of the medicinal and ritual use for chocolate. J Nutr . 2000;130(8)(suppl):2057S-2072S.
15. Waterhouse AL, Shirley JR, Donovan JL. Antioxidants in chocolate. Lancet . 1996;348(9030):834.
16. Arts IC, Hollman PC, Kromhout D. Chocolate as a source of tea flavonoids. Lancet . 1999;354(9177):488.
17. Bruinsma K, Taren DL. Chocolate: food or drug? J Am Diet Assoc . 1999;99(10):1249-1256.
18. Robbers JE, Speedie MK, Tyler VE. Pharmacognosy and Pharmacobiotechnology . Baltimore, MD: Williams & Wilkins; 1996.
19. Mumford GK, Evans SM, Kaminski BJ, et al. Discriminative stimulus and subjective effects of theobromine and caffeine in humans. Psychopharmacology (Berl) . 1994;115(1-2):1-8.
20. Shahkhalili Y, Duruz E, Acheson K. Digestibility of cocoa butter from chocolate in humans: a comparison with corn-oil. Eur J Clin Nutr . 2000;54(2):120-125.
21. Shahkhalili Y, Murset C, Meirim I, et al. Calcium supplementation of chocolate: effect on cocoa butter digestibility and blood lipids in humans. Am J Clin Nutr . 2001;73(2):246-252.
22. Vita JA. Polyphenols and cardiovascular disease: effects on endothelial and platelet function. Am J Clin Nutr . 2005;81(1)(suppl):292S-297S.
23. Hammerstone JF, Lazarus SA, Schmitz HH. Procyanidin content and variation in some commonly consumed foods. J Nutr . 2000;130(8)(suppl):2086S-2092S.
24. Wollgast J, Anklam E. Review of polyphenols in Theobroma cacao : changes in composition during the manufacture of chocolate and methodology for identification and quantification. Food Res Intern . 2000;33(6):423-447.
25. Fisher ND, Hollenberg NK. Flavanols for cardiovascular health: the science behind the sweetness. J Hypertens . 2005;23(8):1453-1459.
26. Schramm DD, Wang JF, Holt RR, et al. Chocolate procyanidins decrease the leukotriene-prostacyclin ratio in humans and human aortic endothelial cells. Am J Clin Nutr . 2001;73(1):36-40.
27. Rein D, Paglieroni TG, Pearson DA, et al. Cocoa and wine polyphenols modulate platelet activation and function. J Nutr . 2000;130(8)(suppl):2120S-2126S.
28. Weisburger JH. Chemopreventive effects of cocoa polyphenols on chronic diseases. Exp Biol Med (Maywood) . 2001;226(10):891-897.
29. Lazarus SA, Hammerstone JF, Schmitz HH. Chocolate contains additional flavonoids not found in tea. Lancet . 1999;354(9192):1825.
30. Keen CL, Holt RR, Oteiza PI, Fraga CG, Schmitz HH. Cocoa antioxidants and cardiovascular health. Am J Clin Nutr . 2005;81(1 suppl):298S-303S.
31. di Tomaso E, Beltramo M, Piomelli D. Brain cannabinoids in chocolate. Nature . 1996;382(6593):677-678.
32. Parker G, Parker I, Brotchie H. Mood state effects of chocolate. .J Affect Disord . 2006;92(2-3):149-159.
33. Alspach G. The truth is often bittersweet . . . : chocolate does the heart good. Crit Care Nurse . 2007;27(1):11-15.
34. Wang JF, Schramm DD, Holt RR, et al. A dose-response effect from chocolate consumption on plasma epicatechin and oxidative damage. J Nutr . 2000;130(8)(suppl):2115S-2119S.
35. Rein D, Lotito S, Holt RR, Keen CL, Schmitz HH, Fraga CG. Epicatechin in human plasma: in vivo determination and effect of chocolate consumption on plasma oxidation status. J Nutr . 2000;130(8)(suppl):2109S-2114S.
36. Osakabe N, Baba S, Yasuda A, et al. Daily cocoa intake reduces the susceptibility of low-density lipoprotein to oxidation as demonstrated in healthy human volunteers. Free Radic Res . 2001;34(1):93-99.
37. Kondo K, Hirano R, Matsumoto A, Igarashi O, Itakura H. Inhibition of LDL oxidation by cocoa. Lancet . 1996;348(9040):1514.
38. Wan Y, Vinson JA, Etherton TD, Proch J, Lazarus SA, Kris-Etherton PM. Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans. Am J Clin Nutr . 2001;74(5):596-602.
39. Mennen LI, Saphinho D, de Bree A, et al. Consumption of foods rich in flavonoids is related to a decreased cardiovascular risk in apparently healthy French women. J Nutr . 2004;134(4):923-926.
40. Erdman JW Jr, Balentine D, Arab L, et al. Flavonoids and heart health: proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC. J Nutr . 2007;137(3)(suppl 1):718S-737S.
41. Schroeter H, Heiss C, Balzer J, et al. (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A . 2006;103(4):1024-1029.
42. Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ . 1996;312(7029):478-481.
43. Fisher ND, Hughes M, Gerhard-Herman M, Hollenberg NK. Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens . 2003;21(12):2281-2286.
44. Heiss C, Finis D, Kleinbongard P, et al. Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week. J Cardiovasc Pharmacol . 2007;49(2):74-80.
45. Heiss C, Kleinbongard P, Dejam A, et al. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol . 2005;46(7):1276-1283.
46. Hermann F, Spieker L, Ruschitzka F, et al. Dark chocolate improves endothelial and platelet function. Heart . 2006;92(1):119-120.
47. Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr . 2005;81(3):611-614.
48. Vlachopoulos C, Aznaouridis K, Alexopoulos N, Economou E, Andreadou I, Stefanadis C. Effect of dark chocolate on arterial function in healthy individuals. Am J Hypertens . 2005;18(6):785-791.
49. Rein D, Paglieroni TG, Wun T, et al. Cocoa inhibits platelet activation and function. Am J Clin Nutr . 2000;72(1):30-35.
50. Pearson DA, Paglieroni TG, Rein D, et al. The effects of flavanol-rich cocoa and aspirin on ex vivo platelet function. Thromb Res . 2002;106(4-5):191-197.
51. Murphy KJ, Chronopoulos AK, Singh I, et al. Dietary flavanols and procyanidin oligomers from cocoa ( Theobroma cacao ) inhibit platelet function. Am J Clin Nutr . 2003;77(6):1466-1473.
52. Taubert D, Roesen R, Schömog E. Effect of cocoa and tea intake on blood pressure: a meta-analysis. Arch Int Med . 2007;167(7):626-634.
53. Baron AM, Donnerstein RL, Samson RA, Baron JA, Padnick JN, Goldberg SJ. Hemodynamic and electrophysiologic effects of acute chocolate ingestion in young adults. Am J Cardiol . 1999;84(3):370-373, A10.
54. Shively CA, Tarka SM Jr, Arnaud MJ, Dvorchik BH, Passananti GT, Vesell ES. High levels of methylxanthines in chocolate do not alter theobromine disposition. Clin Pharmacol Ther . 1985;37(4):415.
55. Hayden MJ, Wildhaber JH, Eber E, Devadason SG. The Chocuhaler : sweet deliverance in asthma management. Med J Aust . 1995;163(11-12):587-588.
56. Willner P, Benton D, Brown E, et al. “Depression” increases “craving” for sweet rewards in animal and human models of depression and craving. Psychopharmacology (Berl.) . 1998;136(3):272-283.
57. Small DM, Zatorre RJ, Dagher A, Evans AC, Jones-Gotman M. Changes in brain activity related to eating chocolate: from pleasure to aversion. Brain . 2001;124(9):1720-1733.
58. Francis ST, Head K, Morris PG, Macdonald IA. The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol . 2006;47(suppl 2):S215-S220.
59. Ramljak D, Romanczyk LJ, Metheny-Barlow LJ, et al. Pentameric procyanidin from Theobroma cacao selectively inhibits growth of human breast cancer cells. Mol Cancer Ther . 2005;4(4):537-546.
60. Planells E, Rivero M, Carbonell J, Mataix J, Llopis J. Ability of a cocoa product to prevent chronic Mg deficiency in rats. J Agric Food Chem . 1997;45(10):4017-4022.
61. Planells E, Rivero M, Mataix J, Llopis J. Ability of a cocoa product to correct chronic Mg deficiency in rats. Int J Vitam Nutr Res . 1999;69(1):52-60.
62. Morton JF. Major Medicinal Plants . Springfield, IL: CC Thomas; 1977.
63. Holt RR. Schramm DD, Keen CL, Lazarus SA, Schmitz HH. Chocolate consumption and platelet function. JAMA . 2002;287(17):2212-2213.
64. McEvoy G, ed. Caffeine. In: AHFS Drug Information 2008 . Bethesda, MD: American Society of Health-System Pharmacists; 2008:2541.
65. Pollock BG, Wylie M, Stack JA, et al. Inhibition of caffeine metabolism by estrogen replacement therapy in postmenopausal women. J Clin Pharmacol . 1999;39(9):936-940.
66. Nix D, Zelenitsky S, Symonds W, et al. The effect of fluconazole on the pharmacokinetics of caffeine in young and elderly subjects. Clin Pharmacol Ther . 1992;21:647-651.
67. Carrillo JA, Benitez J. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinet . 2000;39(2):127-153.
68. Carbó M, Segura J, De la Torre R, Badenas JM, Camí J. Effect of quinolones on caffeine disposition. Clin Pharmacol Ther . 1989;45(3):234-240.
69. Hägg S, Spigset O, Mjörndal T, Dahlqvist R. Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol . 2000;49(1):59-63.
70. Brown NJ, Ryder D, Branch RA. A pharmacodynamic interaction between caffeine and phenylpropanolamine. Clin Pharmacol Ther . 1991;50(4):363-371.
71. Zheng XM, Williams RC. Serum caffeine levels after 24-hour abstention: clinical implications on dipyridamole (201)Tl myocardial perfusion imaging. J Nucl Med Technol . 2002;30(3):123-127.
72. Mester R, Toren P, Mizrachi I, Wolmer L, Karni N, Weizman A. Caffeine withdrawal increases lithium blood levels. Biol Psychiatry . 1995;37(5):348-350.
73. Davis RE, Osorio I. Childhood caffeine tic syndrome. Pediatrics . 1998;101(6):E4.
74. Friedman G. Diet and the irritable bowel syndrome. Gastroenterol Clin North Am . 1991;20(2):313-324.
75. Perfetti L, Lehrer SB, McCants M, Malo JL. Occupational asthma caused by cacao. Allergy . 1997;52(7):778-780.
76. Zuskin E, Kanceljak B, Schacter EN, Godnic-Cvar J, Mustajbegovic J, Budak A. Respiratory function and immunological status in cocoa and flour processing workers. Am J Ind Med . 1998;33(1):24-32.
77. Marcus DA, Scharff L, Turk D, Gourley LM. A double-blind provocative study of chocolate as a trigger of headache. Cephalalgia . 1997;17(8):855-862.
78. Peatfield RC. Relationships between food, wine, and beer-precipitated migrainous headaches. Headache . 1995;35(6):355-357.
79. Glover V. A double-blind provocative study of chocolate as a trigger of headache. Cephalalgia . 1997;17:800.
80. Chocolate — food of the gods. Medical Sciences Bulletin . 1985;7(11):4.
81. Duke JA. Handbook of Medicinal Herbs . Boca Raton, FL: CRC Press; 1985.
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