Cacao

Chocolate/Drug Interactions:

  • NoteNote: Chocolate contains caffeine. Interaction information associated with caffeine is not specifically discussed in this monograph. For more information, the Natural Standard monograph on caffeine is available.
  • Activated charcoalActivated charcoal: In human research, chocolate milk improved the taste of activated charcoal over water alone (226).
  • AnalgesicsAnalgesics: In lab and human studies, theobromine found in chocolate has been shown to suppress capsaicin-induced cough and directly inhibit capsaicin-induced sensory nerve depolarization (85). According to secondary sources, a large intake of cocoa products (containing greater than 400mg of caffeine daily) may increase acetaminophen and aspirin effectiveness by up to 40%.
  • Angiotensin-converting enzyme (ACE)Angiotensin-converting enzyme (ACE): In vitro, cocoa extract inhibited ACE and increased nitric oxide, in human research only the inhibition of ACE occurred (227). In a case report, prolonged use of diabetic chocolate and angiotensin-converting enzyme inhibitor resulted in prolonged angioedema in an elderly patient (169).
  • Antianxiety agentsAntianxiety agents: In human research, dark chocolate reduced urinary levels of cortisol and catecholamines; stress-related differences in energy metabolism and gut microbial activities were partially normalized (228).
  • Antiarrhythmic agentsAntiarrhythmic agents: In human research, a high-flavanol cocoa drink resulted in increases in circulating nitric oxide (NO) species in plasma (21 ? 3 to 29 ? 5nM/L) and flow-mediated dilation (FMD) (4.5 ? 0.8% to 6.9 ? 0.9%) after ingestion (167). According to secondary sources, mexiletine reduced caffeine elimination by 30-50% and mexiletine may theoretically increase the effects of caffeine found in cocoa.
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Several human studies have shown evidence that cocoa flavanols, their metabolites, and possibly other cocoa constituents inhibit platelet adhesion, aggregation, and activity (26; 8; 11; 27; 12; 9; 28; 29; 16; 30; 31; 32; 33; 34; 35; 36; 37; 38). In human research, a flavan-3-ol enriched dark chocolate increased induced bleeding time ex vivo (145). However, other research has found that cocoa polyphenol supplementation had no effect on platelet activation (26; 229; 61). In human research, ingestion of cocoa butter increased tissue plasminogen activator activity, plasma factor VII coagulant activity, and plasma FVIIa, while decreasing plasminogen activator type 1 activity (230; 231; 232). In human research, cocoa consumption had an aspirin-like effect on primary hemostasis (30). In vitro, several cocoa flavonols inhibited platelet aggregation, although the effects of cocoa flavanols and aspirin did not appear to be additive (33). According to secondary sources, chocolate may increase the effects of anticoagulants, such as warfarin.
  • Antidepressants, selective serotonin reuptake inhibitors (SSRIs)Antidepressants, selective serotonin reuptake inhibitors (SSRIs): According to secondary sources, chocolate may stimulate the hypothalamus, inducing pleasurable sensations as well as affecting serotonin levels. While serotonin has a pleasurable effect, in high concentrations it may be converted to melatonin, which, in large amounts, reduces sexual drive. The effects of chocolate with antidepressant agents are not well understood.
  • Antidiabetic agentsAntidiabetic agents: Clinical study has indicated that caffeine intake induced a rise in blood glucose levels that was insulin-independent (139). In human research dark, but not white, chocolate improved insulin sensitivity (39; 40; 43; 47). The homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower after dark chocolate ingestion. Both the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index (ISI) were significantly higher after dark chocolate ingestion. In human research, dark chocolate increased insulin levels in some (19), but not all (20; 22; 65; 140; 45; 66), studies. Changes in glucose levels were lacking in some studies (20; 22; 65; 140; 66; 47; 67; 52); although decreases were observed in others (24; 44). In human research, effects on HbA1c were mixed (65; 144).
  • AntihypertensivesAntihypertensives: Theoretically, a large intake of cocoa products may cause hypertension, due to cocoa's tyramine content. According to human research, a high intake of cocoa products (containing greater than 400mg of caffeine daily) may increase blood pressure, due to cocoa's caffeine content (141; 142; 52; 8). However, several human studies have shown that chocolate, cocoa, or related products, but not cocoa butter, reduced blood pressure (39; 40; 41; 24; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 56; 57; 58; 59). Other human studies have shown a lack of change in blood pressure or heart rate (or mixed results) after consumption of high-flavonol cocoa supplementation or other products (60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 37; 71; 55; 144). Other research has shown a decrease in post-exercise blood pressure while effects on pre-exercise blood pressure were lacking (214).Other human study has shown that flavanols from cocoa products improved NO-dependent vasorelaxation in hypertensives (39) and that acute administration of caffeine augmented endothelium-dependent vasodilatation in healthy young men through an increase in NO production (141). Such cocoa-associated increases in NO levels may be reversed by L-NMMA (167).
  • Anti-inflammatory agentsAnti-inflammatory agents: Intake of flavonoid-rich chocolate by human subjects decreased the plasma concentrations of proinflammatory cysteinyl leukotrienes and inhibited the proinflammatory enzyme myeloperoxidase (233; 234). In humans, cocoa flavanols also inhibited monocyte and neutrophil activation (33). In vitro evidence suggests that some cocoa-derived flavanols may reduce the production and effect of proinflammatory mediators either directly or by acting on signaling pathways (77). The effects of chocolate with anti-inflammatory agents are not well understood.
  • Antilipemic agentsAntilipemic agents: In human research, hypercholesterolemia occurred after completion of a clinical study that measured the effects of flavanol-rich food (167). In clinical study, large consumption of cocoa butter has been observed to lower both LDL and HDL cholesterol (235). In human research, chocolate or cocoa products reduced LDL cholesterol (39; 60; 35; 41; 192; 43; 47; 193; 144), total cholesterol (60; 43; 193), and triglycerides (65; 236), or increased HDL cholesterol (237; 238; 17; 35; 239; 140; 47; 181; 71; 155). In other human studies, consumption of cocoa products did not alter cholesterol levels (240; 61; 241; 64; 44; 66; 48; 67; 194; 52; 59). The effects of chocolate on antilipemic agents are not well understood.
  • Antineoplastic agentsAntineoplastic agents: In vitro, cocoa procyanidins induced apoptosis of leukemia cells (176).
  • AspirinAspirin: In human research, chocolate had a significant role in augmenting the anti-platelet effects of aspirin (242).
  • Calcium saltsCalcium salts: Based on human data, calcium supplementation may be used as a means of reducing the energy value of chocolate by reducing absorption of cocoa butter by 13% (243).
  • CannabinoidsCannabinoids: According to laboratory and human research, chocolate contained several biologically active constituents (methylxanthines, biogenic amines, and cannabinoid-like fatty acids, anandamide) that are associated with abnormal behaviors and psychological sensations that parallel those of other addictive substances (146; 147). In vitro studies indicate that chocolate contained unsaturated N-acylethanolamines, which may activate cannabinoid receptors or increase endocannabinoid levels, resulting in heightened sensitivity and euphoria (244).
  • Cardiovascular agentsCardiovascular agents: Evidence from population-based studies suggest that a diet high in flavonoids may be associated with reduced cardiovascular and stroke risk (29; 245; 246; 247; 248; 16; 249; 250; 251; 252); however, an association between cocoa consumption and improvement in the arterial stiffness values was lacking in a separate study (253). According to reviews, flavonoids from cocoa and chocolate have a number of properties that may contribute to cardiovascular (CVD) protection, including antioxidant and antiplatelet activity, immunoregulatory properties, inhibition of low-density lipoprotein oxidation, reduced clot formation and thrombosis, improved endothelial function and flow-mediated dilation, blood pressure reduction, decreased inflammation, improved insulin sensitivity, improved lipid profile, and enhanced bioavailability and bioactivity of nitric oxide (254; 255; 256; 257; 258; 259; 260; 261; 129; 262; 263; 264; 265; 266; 267; 120; 268; 269; 270; 271; 272; 273; 274; 275). Although it remains controversial whether dietary consumption of chocolate improves vascular function, improvements in FMD have been noted in the majority of studies (7; 6; 187; 153; 4; 214; 276; 38; 36; 37; 25; 144; 55); benefit was noted in meta-analyses (65; 47; 59).
  • CNS stimulantsCNS stimulants: It has been suggested that chocolate consumption may be associated with nervousness, irritability, shakiness, sleep disturbances, and neck pain (220; 136). Theoretically, the use of caffeine-containing agents may have additive effects with the caffeine present in cocoa.
  • Cognitive agentsCognitive agents: In a clinical trial of individuals with mild cognitive performance, a high flavanol cocoa drink improved cognitive performance over a low flavanol drink (156). Although dark chocolate lacked any major cognitive benefits in healthy adults after a single dose or chronic dosing (178; 68; 190; 183), there was evidence of benefit of cocoa flavanols in a separate study in healthy adults (191).
  • Dental and periodontal agentsDental and periodontal agents: Preliminary study suggests a mouthwash containing cacao bean husk extract reduced salivary mutans streptococci (MS) content to a similar extent as a chlorhexidine (CHX) mouth rinse in children (202).
  • Drugs used for osteoporosisDrugs used for osteoporosis: In epidemiological study, increased chocolate intake was associated with decreased bone density in older women (171).
  • Fertility agentsFertility agents: According to human research, high intake of cocoa products may reduce the ability to become pregnant (130).
  • Gamma-aminobutyric acid (GABA)Gamma-aminobutyric acid (GABA): In human research, chocolate enriched with GABA reduced stress (277).
  • Gastrointestinal agentsGastrointestinal agents: In human trials, chocolate consumption was associated with a higher incidence of flatulence, irritable bowel syndrome, upset stomach, gastric upset, borborygmi, bloating, nausea, vomiting, and constipation or obstipation (148; 149; 150; 151; 152; 153; 48; 50; 154; 155; 156; 57; 70). Chocolate consumption has been implicated as a provoking factor in gastroesophageal reflux disease (GERD) (157; 158; 159; 151).
  • Hepatotoxic agentsHepatotoxic agents: Results of a randomized clinical trial suggest that dark chocolate reduced the postprandial increase in hepatic venous pressure gradient (HVPG) in patients with cirrhosis by improving flow-mediated hepatic vasorelaxation (72). In a clinical trial, chocolate decreased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in pregnant women (56).
  • ImmunosuppressantsImmunosuppressants: Clinical evidence indicates that cocoa husk may induce production of positive antigliadin and antiendomysium antibodies (201). According to a review, cocoa has an immunostimulant effect (278).
  • Iron saltsIron salts: In human research, cocoa inhibited iron absorption (162; 163; 164).
  • Neuroprotective agentsNeuroprotective agents: According to a review, flavonoids found in chocolate, such as epicatechin, enter the brain and induce brain perfusion, angiogenesis, neurogenesis, and alterations in neuron morphology. They are also reported to improve cognition and decrease the risk of stroke and Alzheimer's disease in animal models (279).
  • SalbutamolSalbutamol: In a case report, atrial fibrillation was associated with chocolate intake abuse as well as abuse of salbutamol inhalation (170).
  • SunscreensSunscreens: High-flavanol chocolate droplets increased the minimal erythema dose in patients with skin phototypes I or II (180).
  • VasopressorsVasopressors: In humans, cocoa consumption suppressed epinephrine-stimulated platelet activation (30).

    • Chocolate/Herb/Supplement Interactions:

  • NoteNote: Chocolate contains caffeine. Interaction information associated with caffeine is not specifically discussed in this monograph. For more information, the Natural Standard monograph on caffeine is available.
  • Activated charcoalActivated charcoal: In human research, chocolate milk improved the taste of activated charcoal over water alone (226).
  • AnalgesicsAnalgesics: In lab and human studies, theobromine found in chocolate has been shown to suppress capsaicin-induced cough and directly inhibit capsaicin-induced sensory nerve depolarization (85). According to secondary sources, a large intake of cocoa products (containing greater than 400mg of caffeine daily) may increase acetaminophen and aspirin effectiveness by up to 40%.
  • Antianxiety agentsAntianxiety agents: In human research, dark chocolate reduced urinary levels of cortisol and catecholamines; stress-related differences in energy metabolism and gut microbial activities were partially normalized (228).
  • AntiarrhythmicsAntiarrhythmics: In human research, a high-flavanol cocoa drink resulted in increases in circulating nitric oxide (NO) species in plasma (21 ? 3 to 29 ? 5nM/L) and flow-mediated dilation (FMD) (4.5 ? 0.8% to 6.9 ? 0.9%) after ingestion (167). According to secondary sources, mexiletine reduced caffeine elimination by 30-50% and mexiletine may theoretically increase the effects of caffeine found in cocoa.
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Several human studies have shown evidence that cocoa flavanols, their metabolites, and possibly other cocoa constituents inhibit platelet adhesion, aggregation, and activity (26; 8; 11; 27; 12; 9; 28; 29; 16; 30; 31; 32; 33; 34; 35; 36; 37; 38). In human research, a flavan-3-ol enriched dark chocolate increased induced bleeding time ex vivo (145). However, other research has found that cocoa polyphenol supplementation had no effect on platelet activation (26; 229; 61). In human research, ingestion of cocoa butter increased tissue plasminogen activator activity, plasma factor VII coagulant activity, and plasma FVIIa, while decreasing plasminogen activator type 1 activity (230; 231; 232). In human research, cocoa consumption had an aspirin-like effect on primary hemostasis (30). In vitro, several cocoa flavonols inhibited platelet aggregation, although the effects of cocoa flavanols and aspirin did not appear to be additive (33). According to secondary sources, chocolate may increase the effects of anticoagulants, such as warfarin.
  • Antidepressants, selective serotonin reuptake inhibitors (SSRIs)Antidepressants, selective serotonin reuptake inhibitors (SSRIs): According to secondary sources, chocolate may stimulate the hypothalamus, inducing pleasurable sensations as well as affecting serotonin levels. While serotonin has a pleasurable effect, in high concentrations it may be converted to melatonin, which, in large amounts, reduces sexual drive. The effects of chocolate with antidepressant agents are not well understood.
  • Anti-inflammatory herbsAnti-inflammatory herbs: Intake of flavonoid-rich chocolate by human subjects decreased the plasma concentrations of proinflammatory cysteinyl leukotrienes and inhibited the proinflammatory enzyme myeloperoxidase (233; 234). In humans, cocoa flavanols also inhibited monocyte and neutrophil activation (33). In vitro evidence suggests that some cocoa-derived flavanols may reduce the production and effect of proinflammatory mediators either directly or by acting on signaling pathways (77). The effects of chocolate with anti-inflammatory agents are not well understood.
  • AntilipemicsAntilipemics: In human research, hypercholesterolemia occurred after completion of a clinical study that measured the effects of flavanol-rich food (167). In clinical study, large consumption of cocoa butter has been observed to lower both LDL and HDL cholesterol (235). In human research, chocolate or cocoa products reduced LDL cholesterol (39; 60; 35; 41; 192; 43; 47; 193; 144), total cholesterol (60; 43; 193), and triglycerides (65; 236), or increased HDL cholesterol (237; 238; 17; 35; 239; 140; 47; 181; 71; 155). In other human studies, consumption of cocoa products did not alter cholesterol levels (240; 61; 241; 64; 44; 66; 48; 67; 194; 52; 59). The effects of chocolate on antilipemic agents are not well understood.
  • Antineoplastic agentsAntineoplastic agents: In vitro, cocoa procyanidins induced apoptosis of leukemia cells (176).
  • AntioxidantsAntioxidants: Cocoa can be a rich source of flavonoids, such as flavan-3-ols, epicatechin, catechin, and procyanidins, compounds which have been reported to increase serum antioxidant capacity and reduce the rate of free radical formation in experimental animal and in vitro models as well as human trials (1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18). In human research, dark chocolate increased antioxidant levels and decreased oxidative stress associated with exercise (F2-isoprostane levels and oxidized LDL cholesterol, malondialdehyde); reduced DNA damage was also noted (19; 20; 21; 22; 23; 24; 25). However, in some human studies, cocoa polyphenols did not change total antioxidant concentration (229; 280; 281; 21). The antioxidant levels and clinical antioxidant effects of chocolate have been the topic of reviews (details lacking) (282; 283).
  • CaffeineCaffeine: Theoretically, the use of caffeine-containing agents may have additive effects with the caffeine present in cocoa.
  • CalciumCalcium: Based on human data, calcium supplementation may be used as a means of reducing the energy value of chocolate by reducing absorption of cocoa butter by 13% (243).
  • CannabinoidsCannabinoids: According to laboratory and human research, chocolate contained several biologically active constituents (methylxanthines, biogenic amines, and cannabinoid-like fatty acids, anandamide) that are associated with abnormal behaviors and psychological sensations that parallel those of other addictive substances (146; 147). In vitro studies indicate that chocolate contained unsaturated N-acylethanolamines, which may activate cannabinoid receptors or increase endocannabinoid levels, resulting in heightened sensitivity and euphoria (244).
  • Cardiovascular agentsCardiovascular agents: Evidence from population-based studies suggest that a diet high in flavonoids may be associated with reduced cardiovascular and stroke risk (29; 245; 246; 247; 248; 16; 249; 250; 251; 252); however, an association between cocoa consumption and improvement in the arterial stiffness values was lacking in a separate study (253). According to reviews, flavonoids from cocoa and chocolate have a number of properties that may contribute to cardiovascular (CVD) protection, including antioxidant and antiplatelet activity, immunoregulatory properties, inhibition of low-density lipoprotein oxidation, reduced clot formation and thrombosis, improved endothelial function and flow-mediated dilation, blood pressure reduction, decreased inflammation, improved insulin sensitivity, improved lipid profile, and enhanced bioavailability and bioactivity of nitric oxide (254; 255; 256; 257; 258; 259; 260; 261; 129; 262; 263; 264; 265; 266; 267; 120; 268; 269; 270; 271; 272; 273; 274; 275). Although it remains controversial whether dietary consumption of chocolate improves vascular function, improvements in FMD have been noted in the majority of studies (7; 6; 187; 153; 4; 214; 276; 38; 36; 37; 25; 144; 55); benefit was noted in meta-analyses (65; 47; 59).
  • Cognitive agentsCognitive agents: In a clinical trial of individuals with mild cognitive performance, a high flavanol cocoa drink improved cognitive performance over a low flavanol drink (156). Although dark chocolate lacked any major cognitive benefits in healthy adults after a single dose or chronic dosing (178; 68; 190; 183), there was evidence of benefit of cocoa flavanols in a separate study in healthy adults (191).
  • CopperCopper: Cocoa was a surce of copper in a study of copper deficiency (284).
  • Dental and periodontal agentsDental and periodontal agents: Preliminary study suggests a mouthwash containing cacao bean husk extract reduced salivary mutans streptococci (MS) content to a similar extent as a chlorhexidine (CHX) mouth rinse in children (202).
  • Fertility agentsFertility agents: According to human research, high intake of cocoa products may reduce the ability to become pregnant (130).
  • Gamma-aminobutyric acid (GABA)Gamma-aminobutyric acid (GABA): In human research, chocolate enriched with GABA reduced stress (277).
  • Gastrointestinal agentsGastrointestinal agents: In human trials, chocolate consumption was associated with a higher incidence of flatulence, irritable bowel syndrome, upset stomach, gastric upset, borborygmi, bloating, nausea, vomiting, and constipation or obstipation (148; 149; 150; 151; 152; 153; 48; 50; 154; 155; 156; 57; 70). Chocolate consumption has been implicated as a provoking factor in gastroesophageal reflux disease (GERD) (157; 158; 159; 151).
  • GinsengGinseng: Flavors in chocolate have been used to modify ginseng flavors (285).
  • Hepatotoxic agentsHepatotoxic agents: Results of a randomized clinical trial suggest that dark chocolate reduced the postprandial increase in hepatic venous pressure gradient (HVPG) in patients with cirrhosis by improving flow-mediated hepatic vasorelaxation (72). In a clinical trial, chocolate decreased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in pregnant women (56).
  • HypoglycemicsHypoglycemics: Clinical study has indicated that caffeine intake induced a rise in blood glucose levels that was insulin-independent (139). In human research dark, but not white, chocolate improved insulin sensitivity (39; 40; 43; 47). The homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower after dark chocolate ingestion. Both the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index (ISI) were significantly higher after dark chocolate ingestion. In human research, dark chocolate increased insulin levels in some (19), but not all (20; 22; 65; 140; 45; 66), studies. Changes in glucose levels were lacking in some studies (20; 22; 65; 140; 66; 47; 67; 52); although decreases were observed in others (24; 44). In human research, effects on HbA1c were mixed (65; 144).
  • HypotensivesHypotensives: Theoretically, a large intake of cocoa products may cause hypertension, due to cocoa's tyramine content. According to human research, a high intake of cocoa products (containing greater than 400mg of caffeine daily) may increase blood pressure, due to cocoa's caffeine content (141; 142; 52; 8). However, several human studies have shown that chocolate, cocoa, or related products, but not cocoa butter, reduced blood pressure (39; 40; 41; 24; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 56; 57; 58; 59). Other human studies have shown a lack of change in blood pressure or heart rate (or mixed results) after consumption of high-flavonol cocoa supplementation or other products (60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 37; 71; 55; 144). Other research has shown a decrease in post-exercise blood pressure while effects on pre-exercise blood pressure were lacking (214). Other human study has shown that flavanols from cocoa products improved NO-dependent vasorelaxation in hypertensives (39) and that acute administration of caffeine augmented endothelium-dependent vasodilatation in healthy young men through an increase in NO production (141). Such cocoa-associated increases in NO levels may be reversed by L-NMMA (167).
  • ImmunosuppressantsImmunosuppressants: Clinical evidence indicates that cocoa husk may induce production of positive antigliadin and antiendomysium antibodies (201). According to a review, cocoa has an immunostimulant effect (278).
  • IronIron: In human research, cocoa inhibited iron absorption (162; 163; 164).
  • Neuroprotective agentsNeuroprotective agents: According to a review, flavonoids found in chocolate, such as epicatechin, enter the brain and induce brain perfusion, angiogenesis, neurogenesis, and alterations in neuron morphology. They are also reported to improve cognitionand decrease the risk of stroke and Alzheimer's disease in animal models (279).
  • Osteoporosis agentsOsteoporosis agents: In epidemiological study, increased chocolate intake was associated with decreased bone density in older women (171).
  • Plant sterolsPlant sterols: In human research, plant sterols in chocolate had benefits on cardiovascular risk factors (42).
  • ProbioticsProbiotics: A review has been published on gut microbial metabolic activity in response to dark chocolate intake (239). In human research, high cocoa flavanols increased the bifidobacterial and lactobacilli populations; clostridia counts were decreased in the gut (236).
  • StimulantsStimulants: It has been suggested that chocolate consumption may be associated with nervousness, irritability, shakiness, sleep disturbances, and neck pain (220; 136). Ephedra (ma huang) may theoretically interact with chocolate, due to its caffeine content.
  • SunscreensSunscreens: High-flavanol chocolate droplets increased the minimal erythema dose in patients with skin phototypes I or II (180).
  • Vasoconstrictor herbs and supplementsVasoconstrictor herbs and supplements: In humans, cocoa consumption suppressed epinephrine-stimulated platelet activation (30).
  • VitaminsVitamins: Research in humans indicates that consumption of cocoa flavanol-enriched snack bars may significantly reduce serum beta-carotene levels (60). Based on human data, calcium supplementation may be used as a means of reducing the absorbable energy value of chocolate by reducing absorption of cocoa butter by 13% (243).

    • Chocolate/Food Interactions:

  • NoteNote: Chocolate contains caffeine. Interaction information associated with caffeine is not specifically discussed in this monograph. For more information, the Natural Standard monograph on caffeine is available.
  • Beta-carotene-containing productsBeta-carotene-containing products: Research in humans indicates that consumption of cocoa flavanol-enriched snack bars may significantly reduce serum beta-carotene levels (60).
  • Caffeine-containing productsCaffeine-containing products: Theoretically, the use of caffeine-containing agents may have additive effects with the caffeine present in cocoa. Drinks that contain caffeine include coffee, tea (black or green), guarana, mate, and cola.
  • Calcium-containing productsCalcium-containing products: Based on human data, calcium supplementation may be used as a means of reducing the energy value of chocolate by reducing absorption of cocoa butter by 13% (243).
  • CoffeeCoffee: An increase in chocolate consumption showed a positive association with change in coffee intake during clinical study (286).Consumption of coffee may theoretically cause additive effects with the caffeine present in cocoa products.
  • High fat mealHigh fat meal: In human research, a flavanol-rich cocoa resulted in improved FMD following a high fat meal (64).
  • Iron-containing productsIron-containing products: In human research, cocoa inhibited iron absorption (162; 163; 164).
  • MilkMilk: In human research, milk decreased the urinary excretion of cocoa flavan-3-ol metabolites or altered excretion of specific metabolites; changes in plasma pharmacokinetics were lacking (287; 288; 289; 290).
  • SugarSugar: In human research, total flavanol absorption was lower after consumption of a maltitol-containing chocolate vs. a sucrose-containing equivalent (291).
  • Tyramine/tryptophan-containing foodsTyramine/tryptophan-containing foods: Theoretically, a large intake of cocoa products (containing greater than 400mg of caffeine daily) may cause hypertension, due to cocoa's tyramine content, based on a secondary source.

    • Chocolate/Lab Interactions:

  • NoteNote: Chocolate contains caffeine. Interaction information associated with caffeine is not specifically discussed in this monograph. For more information, the Natural Standard monograph on caffeine is available.
  • AntibodiesAntibodies: Clinical evidence indicates that cocoa husk may induce production of positive antigliadin and antiendomysium antibodies (201).
  • Blood pressureBlood pressure: Theoretically, a large intake of cocoa products (containing greater than 400mg of caffeine daily) may cause hypertension, due to cocoa's tyramine content. Based on human study, a high intake of cocoa products (containing greater than 400mg of caffeine daily) may increase blood pressure, due to cocoa's caffeine content (141; 142; 52; 8). However, several human studies have shown that chocolate, cocoa, or related products, but not cocoa butter, reduced blood pressure (39; 40; 41; 24; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 56; 57; 58; 59). Other human studies have shown a lack of change in blood pressure or heart rate (or mixed results) after consumption of high-flavonol cocoa supplementation or other products (60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 37; 71; 55; 144). Other research has shown a decrease in post-exercise blood pressure while effects on pre-exercise blood pressure were lacking (214). Other human study has shown that flavanols from cocoa products improved NO-dependent vasorelaxation in hypertensives (39) and that acute administration of caffeine augmented endothelium-dependent vasodilatation in healthy young men through an increase in NO production (141). Such cocoa-associated increases in NO levels may be reversed by L-NMMA (167).
  • C-reactive protein (CRP)C-reactive protein (CRP): In human research, the effects of dark chocolate have been investigated on CRP levels (details lacking) (35). In other studies, use of dark chocolate reduced CRP levels (22; 236) or lacked effect (65; 47; 67; 194; 43; 184).
  • Calcium levelsCalcium levels: Based on human data, calcium supplementation may be used as a means of reducing the energy value of chocolate by reducing absorption of cocoa butter by 13% (243). In a study of pediatric patients with idiopathic chronic constipation supplemented with cocoa husk, no significant changes in relation to plasma levels of calcium were observed (201).
  • CatecholaminesCatecholamines: According to secondary sources, a large intake of cocoa products (containing greater than 400mg of caffeine daily) may increase urine catecholamine concentrations, due to its caffeine content.
  • Cellular adhesion markersCellular adhesion markers: In a study of hypercholesterolemic postmenopausal women, a high-flavanol cocoa drink did not alter activation of cellular adhesion markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-Selectin, P-selectin) (61). In a study of patients with coronary artery disease who consumed a flavanol-rich chocolate supplement, no acute or chronic changes in soluble cellular adhesion molecules were observed (187).
  • Coagulation panelCoagulation panel: Several human studies have shown evidence that cocoa flavanols, their metabolites, and possibly other cocoa constituents inhibit platelet adhesion, aggregation, and activity (26; 8; 11; 27; 12; 9; 28; 29; 16; 30; 31; 32; 33; 34; 35; 36; 37; 38). In human research, a flavan-3-ol enriched dark chocolate increased induced bleeding time ex vivo (145). However, other research has found that cocoa polyphenol supplementation had no effect on platelet activation (26; 229; 61). In human research, ingestion of cocoa butter increased tissue plasminogen activator activity, plasma factor VII coagulant activity, and plasma FVIIa, while decreasing plasminogen activator type 1 activity (230; 231; 232). In human research, cocoa consumption had an aspirin-like effect on primary hemostasis (30). In vitro, several cocoa flavonols inhibited platelet aggregation, although the effects of cocoa flavanols and aspirin did not appear to be additive (33).
  • CortisolCortisol: In human research, polyphenol poor dark chocolate increased salivary cotisol levels (45).
  • CreatineCreatine: According to secondary sources, consumption of large amounts of cocoa might increase urine creatine concentrations, due to its caffeine content.
  • FerritinFerritin: In human research, cocoa inhibited iron absorption (162; 163; 164). However, in a study of pediatric patients with idiopathic chronic constipation supplemented with cocoa husk, no significant changes in relation serum ferritin were observed (201).
  • Flow-mediated dilation (FMD)Flow-mediated dilation (FMD): Although it remains controversial whether dietary consumption of chocolate improves vascular function improvements in FMD have been noted in the majority of studies (7; 6; 187; 153; 4; 214; 276; 38; 36; 37; 25; 144; 55); benefit was noted in meta-analyses (65; 47; 59).
  • Forearm blood flowForearm blood flow: Study of patients with coronary artery disease consuming a flavanol-rich chocolate supplement revealed no acute or chronic changes in forearm blood flow (187). Other research has shown that caffeine did not alter forearm blood flow when given alone, but may augment the forearm blood flow response to acetylcholine (141).
  • Free fatty acidsFree fatty acids: In human research, dark chocolate increased free fatty acids during exercise (20).
  • GhrelinGhrelin: In human research, suppression of appetite through smelling dark chocolate was correlated with changes in ghrelin (292).
  • Glycemic indicesGlycemic indices: Clinical study has indicated that caffeine intake induced a rise in blood glucose levels that was insulin-independent (139). In human research dark, but not white, chocolate improved insulin sensitivity (39; 40; 43; 47). The homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower after dark chocolate ingestion. Both the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index (ISI) were significantly higher after dark chocolate ingestion. In human research, dark chocolate increased insulin levels in some (19), but not all (20; 22; 65; 140; 45; 66), studies. Changes in glucose levels were lacking in some studies (20; 22; 65; 140; 66; 47; 67; 52); although decreases were observed in others (24; 44). In human research, effects on HbA1c were mixed (65; 144).
  • Heart rateHeart rate: Human studies have lacked a change in blood pressure or heart rate or shown mixed results after consumption of high-flavonol cocoa supplementation (60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 37; 71; 55; 144). It has been proposed that, due to chocolate's caffeine content, when used in excessive doses, tachyarrhythmias may occur, according to secondary sources.
  • Hemoglobin/hematocritHemoglobin/hematocrit: In a study of pediatric patients with idiopathic chronic constipation supplemented with cocoa husk, no significant changes in relation to hemoglobin and hematocrit concentrations were observed (201)
  • Inflammatory mediatorsInflammatory mediators: Intake of flavonoid-rich chocolate by human subjects decreased the plasma concentrations of proinflammatory cysteinyl leukotrienes and inhibited the proinflammatory enzyme myeloperoxidase (233; 234). In humans, cocoa flavanols also inhibited monocyte and neutrophil activation (33). In vitro evidence suggests that some cocoa-derived flavanols may reduce the production and effect of proinflammatory mediators, either directly or by acting on signaling pathways (77). In human research, cocoa powder in skim milk reduced the expression of cellular inflammatory biomarkers on monocytes, as well as serum levels of P-selectin and ICAM-1, vs. skim milk alone (293). In human research, high flavanol chocolate decreased levels of ICAM-1 and E-selectin; effects on P-selectin were lacking (189). Effects on ICAM were lacking in a clinical trial (194).
  • Lactate dehydrogenase activityLactate dehydrogenase activity: In young male athletes, consumption of flavanol-containing milk chocolate, but not cocoa butter, was associated with a decrease in lactate dehydrogenase activity (41).
  • Lipid panelLipid panel: In human research, hypercholesterolemia occurred after completion of a clinical study that measured the effects of flavanol-rich food (167). In clinical study, large consumption of cocoa butter has been observed to lower both LDL and HDL cholesterol (235). In human research, chocolate or cocoa products reduced LDL cholesterol (39; 60; 35; 41; 192; 43; 47; 193; 144), total cholesterol (60; 43; 193), and triglycerides (65; 236), or increased HDL cholesterol (237; 238; 17; 35; 239; 140; 47; 181; 71; 155). In other human studies, consumption of cocoa products did not alter cholesterol levels (240; 61; 241; 64; 44; 66; 48; 67; 194; 52; 59).
  • Lipid peroxidationLipid peroxidation: In a human study, consumption of dark or white chocolate decreased the concentration of serum LDL diene conjugates, a marker of lipid peroxidation (238). In young male athletes, consumption of flavanol-containing milk chocolate, but not cocoa butter, was associated with a decrease in malondialdehyde (a lipid peroxidation marker) (41).
  • Liver enzymesLiver enzymes: In a clinical trial, chocolate decreased levels of ALT, AST, and ALP in pregnant women (56).
  • Markers of oxidative stressMarkers of oxidative stress: In a human study, consumption of a flavanol-rich cocoa beverage blocked an increase in plasma F(2)-isoprostanes caused by vigorous exercise (185).
  • N-acylethanolamineN-acylethanolamine: In vitro lab studies indicate that chocolate contained unsaturated N-acylethanolamines, which may activate cannabinoid receptors or increase endocannabinoid levels, resulting in heightened sensitivity and euphoria (244).
  • Nitric oxide levelsNitric oxide levels: Significant increases in circulating nitric oxide species have been observed two hours after ingestion of a high-flavanol cocoa drink in smokers (167). Other human study has shown that flavanols from cocoa products may improve NO-dependent vasorelaxation in hypertensives (39). Acute administration of caffeine may augment endothelium-dependent vasodilatation in healthy young men through an increase in NO production (141). These cocoa-associated increases in NO levels may, however, be reversed by L-NMMA (167). In separate human research, cocoa increased blood levels of nitrite (188; 55) or nitric oxide (294; 51), or prevented a decrease in nitric oxide (72). In human research, polyphenol-rich chocolate resulted in an increase in S-nitrosoglutathione (52).
  • Oral contrast agentOral contrast agent: In vitro, an aqueous cocoa solution was found to be a possible oral contrast agent for MRI of the gastrointestinal tract (295).
  • Prostaglandin levelsProstaglandin levels: In human study, cocoa powder and dark chocolate did not adversely affect prostaglandin levels (17).
  • Stool testStool test: In a study of pediatric patients with idiopathic chronic constipation taking a cocoa husk supplement, an increase in the number of bowel movements, a reduction in the percentage of patients who reported hard stools, improved stool consistency, and a moderate trend toward faster bowel transit times was observed (201).
  • UrateUrate: According to secondary sources, large amounts of cocoa might falsely increase serum urate test results determined by the Bittner method, due to its caffeine content. In young male athletes, consumption of flavanol-containing milk chocolate, but not cocoa butter, was associated with a decrease in urate (41).
  • Urinary oxalateUrinary oxalate: Chocolate has been shown to cause a significant increase in urinary oxalate excretion (161).
  • Vanillylmandelic acid (VMAVanillylmandelic acid (VMA): According to secondary sources, large amounts of cocoa may theoretically increase urine VMA concentrations, due to its caffeine content.
  • VitaminsVitamins: Consumption of a cocoa flavanol-enriched snack bar has been observed to significantly reduce lipid-adjusted serum beta-carotene in subjects with hypercholesterolemia but leave lipid-adjusted lycopene, beta-cryptoxanthin, lutein/zeaxanthin, alpha-carotene levels, and levels of serum vitamins A or E unchanged (60). Based on human study, calcium supplementation may be used as a means of reducing the absorbable energy value of chocolate by reducing absorption of cocoa butter by 13% (243).
  • Zinc levelsZinc levels: In a study of pediatric patients with idiopathic chronic constipation supplemented with cocoa husk, no significant changes in relation to plasma levels of zinc were observed (201).