Cacao (Globule) by Boiron Canada Inc

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Dietary cocoa seems to be beneficial for CVD prevention. Oral cocoa extract may reduce the risk of CVD-related death, but it is unclear if it can prevent other CVD-related outcomes like myocardial infarction (MI) or stroke. Details: A large clinical trial in adults without CVD shows that taking a specific cocoa extract daily for around 3.5 years reduces the risk of CVD-related death by 27%, but does not reduce the risk of cardiovascular events, including MI or stroke, or overall mortality when compared with placebo. This specific cocoa extract contained 500 mg of flavanols, including 80 mg of epicatechins (108898). In 2023, the US Food and Drug Administration (FDA) approved a qualified health claim stating that very limited scientific evidence suggests that the cocoa flavanols in high flavanol cocoa powder, for products containing at least 4% naturally conserved cocoa flavanols, may reduce the risk of cardiovascular disease (110017). Observational research in adults without CVD has also found that consuming a higher amount of cocoa is associated with a 10% lower risk of CVD and an up to 50% lower risk of CVD-related mortality when compared with consuming lower amounts of cocoa. Consuming more than 90 grams of cocoa per week did not add further benefit (14288,97192). Additional clinical research shows that taking cocoa flavanols 450 mg twice daily for one month improves cholesterol levels and blood pressure values, resulting in improved Framingham Risk Scores in healthy patients. These scores correspond to a 21% decrease in the 10-year risk for coronary heart disease, a 22% decrease in the risk for CVD, a 31% decrease in the risk for MI, and a 30% decrease in the risk for CVD-related mortality (92273). There is also evidence that consuming cocoa might improve flow-mediated dilatation, a measure of endothelial dysfunction. Meta-analyses of clinical research have found that increased cocoa or chocolate intake significantly improves flow-mediated dilatation. This is seen with intakes of 19-54 grams of cocoa daily, 46-100 grams of dark chocolate daily, or cocoa products containing 16.6-1080 mg of flavonoids daily (17187,42059,42137).
• Hypertension. Oral cocoa seems to be beneficial for modestly decreasing blood pressure in hypertensive patients. It is unclear if dietary cocoa is beneficial for preventing hypertension. Details: Overall, clinical research shows that chocolate or cocoa containing 25-1080 mg daily of flavonoids modestly reduces blood pressure in hypertensive patients (14306,15655,15752,42092,42107,42169,97190,103247). Meta-analyses of clinical research show that consuming commercially available dark chocolate or flavanol-enriched chocolate/cocoa products daily for 2-8 weeks reduces systolic blood pressure (SBP) by around 4 mmHg and diastolic blood pressure (DBP) by around 2 mmHg in patients with hypertension when compared to control products with low levels of flavanols or no flavanols (42169,97190). Additionally, a meta-analysis of clinical trials in middle-aged and elderly patients with or without hypertension shows that consuming cocoa products daily for 4-18 weeks reduces SBP and DBP by around 3 mmHg and 1.5 mmHg, respectively, when compared with control products (103249). Blood pressure lowering seems to occur more readily in hypertensive or pre-hypertensive individuals when compared with normotensive individuals (14306,15655,15752,42092,42107,42169,97190,103247). Consumption of cocoa might also reduce the risk of developing hypertension in normotensive patients. Observational research has found that long-term consumption of moderate amounts of cocoa (2.2 grams to 6.1 grams daily) is associated with a 7% lower risk of hypertension when compared with consumption of less than 0.61 grams daily. However, consumption of amounts greater than 6.1 grams daily does not seem to reduce hypertension risk. Also, this benefit seems to be limited to patients consuming cocoa from plain chocolate, as consumption of cocoa from desserts was linked with a 9% greater risk of hypertension (103248).

POSSIBLY INEFFECTIVE

• Hypercholesterolemia. Oral cocoa does not seem to be beneficial for reducing cholesterol levels in patients with hypercholesterolemia. Details: Some preliminary clinical research in healthy, normocholesterolemic males shows that diets high in stearic acid from cocoa butter result in lower cholesterol levels when compared with diets high in myristic acid from dairy butter. However, a diet high in stearic acid from cocoa butter does not significantly lower cholesterol when compared to baseline in this population (15063). A meta-analysis of 10 clinical studies shows that cocoa or dark chocolate can reduce total cholesterol and low-density lipoprotein (LDL) cholesterol in normocholesterolemic patients (42125). However, some preliminary clinical research in patients with hypercholesterolemia shows that drinking a high-flavanol cocoa beverage daily for 6 weeks does not reduce cholesterol when compared with a low-flavanol cocoa beverage (42013). Also, while some clinical research shows that taking cocoa powder 26 grams with sugar daily for 12 weeks can increase high-density lipoprotein (HDL) cholesterol levels when compared with sugar alone in normocholesterolemic and hypercholesterolemic patients (42026), taking cocoa or dark chocolate 13-41 grams daily does not seem to lower total cholesterol or LDL cholesterol in these patients (42026,42029,42225).
• Stretch marks (striae gravidarum). Topical cocoa butter does not seem to be beneficial for preventing stretch marks during pregnancy. Details: Clinical research shows that topical application with a cream containing cocoa butter 25% to the abdomen daily, starting during the second and third trimesters and continuing until delivery, does not prevent stretch marks when compared with a placebo cream (105261). Other clinical research shows that topical application with a cream containing cocoa butter and vitamin E as tocopheryl acetate to the abdomen, breasts, and thighs, daily, starting during the second trimester and continuing until delivery, does not reduce the prevalence or severity of stretch marks when compared to a cream not containing these ingredients (105262). More research is needed in individuals of all skin types.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral cocoa is beneficial for improving cognitive function in healthy older adults. Details: Some small clinical studies in healthy adults over the age of 60 with or without existing cognitive impairment show that sub-chronic intake of cocoa at doses of 45 mg, 520 mg, or 990 mg once daily for 8 weeks, or as a cocoa drink containing flavanols 609 mg daily for 30 days, modestly improves some measures of cognitive function, including task switching, visual attention, and verbal fluency (42184,92269). However, it does not improve performance on the mini mental state exam (92269). Also, one clinical study in healthy adults aged 60 years and older shows that consuming a dark chocolate bar containing 11 grams of cocoa and drinking 237 mL of an artificially sweetened drink containing 11 grams of cocoa daily for 6 weeks does not improve neuropsychological function when compared with placebo (42050). Additional preliminary clinical research in postmenopausal females aged 50-64 years shows that adding chocolate 10 grams daily, containing 99% cocoa, for 6 months does not improve most measures of cognitive function when compared with not taking cocoa (105259). Reasons for the discrepancies are unclear but may relate to the dose of cocoa, the duration of intake, or the specific cognitive testing procedures conducted.
• Age-related testosterone deficiency. Oral cocoa has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy middle-aged adults shows that taking a combination product containing cocoa seed extract and pomegranate rind (Tesnor, Gencor) daily for 56 days increases serum testosterone levels and hand-grip strength and improves measures of sexual function and psychological well-being when compared with placebo (111527). It is unclear if these effects are due to cocoa, pomegranate, or the combination.
• Aging skin. It is unclear if oral cocoa is beneficial for aging skin. Details: Preliminary clinical research in adults with aging skin shows taking a specific product (GliSODin Skin Nutrients Advanced Anti-Aging Formula, Isocell North America Inc.) 780 mg three times daily, containing cocoa extract, as well as superoxide dismutase, krill oil, sea buckthorn, hyaluronic acid, and other nutrients, in combination with daily use of tazarotene cream 0.1%, for 90 days improves fine wrinkling, photodamage, and skin elasticity when compared with tazarotene cream and placebo (91778). Additional preliminary clinical research in patients with photoaged skin shows that drinking a cocoa drink containing 320 mg of flavanols daily for 24 weeks improves wrinkle depth and skin elasticity, but not skin hydration, when compared with placebo (92274).
• Asthma. Although there has been interest in using oral cocoa for asthma, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Athletic performance. Although there has been interest in using oral cocoa for improving athletic performance, there is insufficient reliable information about the clinical effects of cocoa for this use.
• Atrial fibrillation. It is unclear if dietary cocoa is beneficial for preventing atrial fibrillation. Details: Most population research has found that chocolate consumption is not associated with a reduced risk of atrial fibrillation (97188,97189).
• Chronic fatigue syndrome (CFS). It is unclear if oral cocoa is beneficial for CFS. Details: In patients with CFS, preliminary clinical research shows that consuming 45 grams of a polyphenol-rich chocolate in three divided doses daily for 8 weeks can reduce fatigue by 35%, anxiety by 37%, and depression by 45%, and can increase overall function by 30%, when compared with pretreatment (42116).
• Cirrhosis. It is unclear if oral cocoa is beneficial for cirrhosis. Details: Clinical research shows that consuming a liquid test meal (Ensure Plus) in addition to dark chocolate (Lindt Excellence 85% Cocoa, Lindt & Sprüngli) 0.55 grams/kg can reduce the postprandial increase in hepatic venous pressure gradient in patients with cirrhosis when compared with the test drink alone (42164).
• Cognitive function. Research on the use of oral cocoa for improving cognitive function in healthy adults is conflicting. Details: A large clinical trial in older adults shows that taking cocoa extract containing 500 mg of flavanols daily for 3 years does not improve measures of cognitive function including global cognition, episodic memory, and executive function when compared with placebo, even when taken with a multivitamin-mineral product (Centrum Silver) (111524). Also, in middle-aged participants, clinical research shows that taking 20 grams of a dark chocolate drink mix containing 250 mg or 500 mg of polyphenols as a single dose does not seem to improve measures of cognitive function (92272). In contrast, clinical research in healthy younger individuals shows that consuming a single dose of cocoa flavanols 520-994 mg as a specific powder (Cocoapro) improves some, but not all, measures of cognitive function when examined in a situation of sustained mental effort (42093). Additionally, consuming a single dose of cocoa flavanols 900 mg as a specific powder (Acticoa) seems to improve reaction time during cognitive testing when compared with placebo in healthy adults and patients with type 1 diabetes (103251). However, acute dosing with cocoa flavanols 374-747 mg as specific powders (Acticoa) or cocoa extract capsules (Naturex) does not seem to improve measures of cognitive function, visual working memory, or ability to focus during testing in young people (99984,99985,109448). Reasons for the discrepancies are unclear but may relate to the dose of cocoa, the duration of intake, the level of stress during cognitive testing, or the specific cognitive testing procedures conducted.
• Cognitive impairment. Oral cocoa flavanols have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: A large clinical study in adults at least 55 years of age with subjective or mild cognitive impairment shows that consuming dark chocolate containing 500 mg cocoa flavanols and taking fish oil containing DHA 1.1 grams and EPA 0.4 grams daily for 12 months does not improve cognitive function scores when compared with placebo (111453).
• Constipation. Oral cocoa husk has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with chronic constipation shows that taking 2-4 sachets containing cocoa husk 8-16 grams and beta-fructosans 2-4 grams daily for 4 weeks can reduce hard stools by 45% and reduce transit time by 36 hours when compared with a placebo (42016).
• Diabetes. Several small clinical studies suggest that oral cocoa may cause small but clinically insignificant improvements in glycemic control in patients with diabetes. However, cocoa does not appear to be beneficial for the prevention of diabetes. Details: While some individual studies show conflicting results (97252,99982), two similar meta-analyses of 8-9 small clinical trials in patients with diabetes show that taking cocoa 1-54 grams daily for up to 52 weeks reduces fasting blood glucose by around 7-9 mg/dL and low-density lipoprotein (LDL) cholesterol by around 10-15 mg/dL, but does not improve glycated hemoglobin (HbA1c), insulin levels, blood pressure, total cholesterol, or high-density lipoprotein (HDL) cholesterol, when compared with control (109447,109449). This slight improvement in fasting blood glucose, along with a lack of effect on HbA1c, suggests that cocoa is unlikely to lead to clinically meaningful improvements in glycemic control. Population research has found that eating up to 60 grams of chocolate per week is associated with a lower risk of developing diabetes. Higher consumption was not found to affect diabetes risk (97192). However, secondary analysis of a large clinical study in adults aged 74 on average shows that taking an extract containing cocoa flavanols 500 mg daily, with or without a multivitamin, for about 3.5 years does not reduce the risk of developing self-reported type 2 diabetes when compared with placebo. Subgroup analysis based on body mass index, level of physical activity, or multivitamin consumption did not change results (111619).
• Exercise-induced muscle damage. It is unclear if oral cocoa flavanols are beneficial for preventing exercise-induced muscle damage. Details: Preliminary clinical research shows that taking a single dose of cocoa flavanols (Chococru Extraordinary Flavanol Cocoa) 830 mg or 1245 mg within 5 minutes of a strenuous exercise protocol does not reduce exercise-induced muscle damage over 72 hours when compared with a control providing no cocoa flavanols (105260).
• Fatigue. It is unclear if oral cocoa is beneficial for fatigue. Details: A moderate-size clinical study in otherwise healthy females aged 40-60 years with fatigue shows that consuming a beverage containing cocoa flavanols 240 mg daily for 8 weeks does not improve self-reported fatigue scores when compared with placebo (111620).
• Heart failure. It is unclear if dietary cocoa is beneficial for heart failure prevention. Details: Population research has found that consuming up to 250 grams of chocolate weekly is associated with reduced risk of heart failure. However, consuming 300 grams weekly or more does not appear to affect the risk of heart failure (97187,97191).
• HIV/AIDS-related dyslipidemia. It is unclear if oral cocoa is beneficial for HIV/AIDS-related dyslipidemia. Details: Preliminary clinical research in patients with HIV shows that consuming dark chocolate 65 grams containing cocoa 36 grams for 15 days does not affect low-density lipoprotein (LDL) cholesterol or total cholesterol levels when compared with a white chocolate placebo. However, it slightly increases levels of high-density lipoprotein (HDL) cholesterol (96472).
• Impaired glucose tolerance (prediabetes). It is unclear if oral cocoa is beneficial in patients with prediabetes. Details: A small clinical study in premenopausal adults with overweight or obesity and mild insulin resistance shows that drinking a cocoa drink high in flavanols twice daily for 4 weeks does not improve measures of insulin resistance or insulin-mediated glucose uptake when compared with a low-flavanol cocoa drink (111532).
• Influenza. Although there has been interest in using oral cocoa for influenza, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Insect repellent. It is unclear if topical cocoa oil is beneficial as an insect repellent. Details: Preliminary clinical research shows that topical application of cocoa oil, 1 mL on each leg and 0.5 mL on each forearm, reduces bites from black flies (Simulium damnosum) by 99% (41954).
• Isolated systolic hypertension. It is unclear if oral cocoa is beneficial for isolated systolic hypertension. Details: Preliminary clinical research shows that consuming 100 grams daily of cocoa polyphenol-rich dark chocolate might modestly reduce systolic and diastolic blood pressure in elderly patients with isolated systolic hypertension (13166).
• Menopausal symptoms. It is unclear if oral cocoa is beneficial for menopausal symptoms. Details: In postmenopausal individuals aged 50-64 years, preliminary clinical research shows that adding chocolate 10 grams daily, containing cocoa 99%, for 6 months reduces body fat mass by approximately 0.6 kg and body fat percentage by 0.8%, and modestly improves some measures of quality of life, when compared with no treatment (105255,105258). However, there was no effect on all measures of quality of life, general menopausal symptoms, weight, body mass index, or most measures of cognitive function (105255,105258,105259).
• Multiple sclerosis (MS). Although there has been interest in using oral cocoa for MS, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Muscle strength. Oral cocoa seed extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy males shows that taking a combination product containing cocoa seed extract and pomegranate rind extract 400 mg daily for 8 weeks increases testosterone levels, hand grip strength, and upper arm circumference when compared with placebo (108485).
• Nipple fissures. It is unclear if topical cocoa butter is beneficial for the treatment or prevention of nipple fissures. Details: A small clinical study in breastfeeding adults shows that applying topical cocoa butter to the nipple and areola after each breastfeeding session for 10 days immediately postpartum reduces nipple pain, rashes, and cracks when compared with the topical application of the mother's breastmilk (111525). The validity of this study is limited by a lack of blinding and a high dropout rate.
• Obesity. It is unclear if oral cocoa is beneficial for obesity. Details: Preliminary clinical research in overweight or obese premenopausal females shows that following a reduced-calorie diet in addition to consuming two squares of dark chocolate and drinking 8 ounces of a sugar-free cocoa beverage daily for 18 weeks does not increase weight loss when compared with the reduced-calorie diet plus a non-chocolate snack (42130,99983).
• Parkinson disease. It is unclear if oral cocoa is beneficial for Parkinson disease. Details: Preliminary clinical research shows that consuming a single dose of dark chocolate 200 grams containing approximately 80% cocoa does not improve motor function in patients with Parkinson disease when compared with a white chocolate control, although there seems to be some improvements after one hour when compared with baseline (42156).
• Peripheral arterial disease (PAD). It is unclear if oral cocoa is beneficial for PAD. Details: A small clinical study in patients with PAD shows that drinking a flavanol-rich cocoa beverage 15 grams daily for 6 months increases 6-minute walking distance by up to 43 meters when compared with placebo (103250). Cocoa has also been studied in adults with diabetes at risk for developing PAD, with conflicting results. A small clinical study in adults with and without diabetes shows that taking a single dose of cocoa flavanols 790 mg does not improve peripheral microvascular or macrovascular parameters compared with placebo (111529). However, another small clinical study in healthy adults and those with diabetes at risk for PAD shows that taking cocoa flavanols (CocoaVia, Mars Inc) 1350 mg improves endothelial function in the brachial and femoral arteries after 2 hours when compared with placebo, suggesting that cocoa flavanols might reduce the risk of developing PAD in both populations studied (111528). The validity of this study is limited by the small sample size and short study duration.
• Stroke. It is unclear if dietary cocoa is beneficial for stroke prevention. Details: Population research has found that the highest dietary intake of chocolate is associated with a 16% reduced risk of stroke when compared with the lowest intake (97192). More evidence is needed to rate cocoa for these uses.

(Read more about COCOA)

LIKELY SAFE ...when used orally and appropriately (13161,14306,14307,14308,15655,15752,17187,92271,92274,103247)(103250,108898). However, cocoa naturally contains caffeine, and caffeine may be unsafe when used orally in doses of more than 400 mg daily (11733,98806). While most cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), one cup of unsweetened, dry cocoa powder can contain up to 198 mg of caffeine (100515). To be on the safe side, cocoa should be used in amounts that provide less than 400 mg of caffeine daily. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine naturally found in ingredients such as cocoa does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Advise patients to consume cocoa in moderation. ...when used topically. Cocoa butter is used extensively as a base for ointments and suppositories and is generally considered safe (11).

CHILDREN: POSSIBLY UNSAFE
when dark chocolate is used orally. Cocoa and dark chocolate products worldwide contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Children are at increased risk of adverse effects from intake of lead and/or cadmium. There is insufficient reliable information available about the safety of other chocolate-based products that typically contain smaller quantities of cocoa.

PREGNANCY: POSSIBLY SAFE
when used orally in moderate amounts. However, due to the caffeine content of cocoa preparations, intake should be closely monitored during pregnancy to ensure moderate consumption. Fetal blood concentrations of caffeine approximate maternal concentrations (4260). Some research has found that intrauterine exposure to even modest amounts of caffeine, based on maternal blood levels during the first trimester, is associated with a shorter stature in children ages 4-8 years (109846). While many cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), unsweetened, dry cocoa powder can contain up to 198 mg of caffeine per cup (100515). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, doses of up to 300 mg daily can be consumed during pregnancy without an increased risk of spontaneous abortion, still birth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). To be on the safe side, cocoa should be used in amounts that provide less than 300 mg of caffeine daily. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cocoa, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

PREGNANCY: POSSIBLY UNSAFE
when used orally in large amounts. Caffeine found in cocoa crosses the placenta producing fetal blood concentrations similar to maternal levels (4260). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Additionally, high intake of caffeine during pregnancy have been associated with premature delivery, low birth weight, and loss of the fetus (6). While many cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), unsweetened, dry cocoa powder can contain up to 198 mg of caffeine per cup (100515). To be on the safe side, cocoa should be used in amounts that provide less than 300 mg of caffeine daily (2708). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cocoa, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Large doses or excessive intake of cocoa should be avoided during pregnancy.

LACTATION: POSSIBLY SAFE
when used in moderate amounts or in amounts commonly found in foods. Due to the caffeine content of cocoa preparations, intake should be closely monitored while breastfeeding. During lactation, breast milk concentrations of caffeine are thought to be approximately 50% of serum concentrations. Moderate consumption of cocoa would likely result in very small amounts of caffeine exposure to a nursing infant (6). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cocoa, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Consumption of excess chocolate (16 oz per day) may cause irritability and increased bowel activity in the infant (6026). Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Large doses or excessive intake of cocoa should be avoided during lactation.

(Read more about COCOA)

ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking cocoa with ACEIs might increase the risk of adverse effects.  Details Human research shows that dark chocolate can inhibit ACE (42112). Additionally, prolonged angioedema in an elderly patient on an ACE inhibitor was precipitated with intake of diabetic chocolate (42049).

ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cocoa might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Cocoa contains caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine does not seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine. It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests. However, methylxanthines appear more likely to interfere with dipyridamole than adenosine-induced stress testing (11771).

ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might increase levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Alcohol reduces caffeine metabolism. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects (6370).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, cocoa may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Clinical research shows that intake of cocoa can inhibit platelet adhesion, aggregation, and activity (6085,17076,41928,41948,41957,41958,41995,42014,42070,42145)(111526) and increase aspirin-induced bleeding time (23800). For patients on dual antiplatelet therapy, cocoa may enhance the inhibitory effect of clopidogrel, but not aspirin, on platelet aggregation (111526).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking cocoa with antihypertensive drugs might increase the risk of hypotension.  Details Clinical research shows that cocoa can modestly decrease blood pressure in hypertensive and normotensive patients (13166,14306,15655,15752,17187,42059,42092,42107,42137,42143)(42169,103249,109446).

BETA-ADRENERGIC AGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, large amounts of cocoa might increase the cardiac inotropic effects of beta-agonists.  Details Cocoa contains caffeine. Theoretically, large amounts of caffeine might increase cardiac inotropic effects of beta-agonists (15). A case of atrial fibrillation associated with consumption of large quantities of chocolate in a patient with chronic albuterol inhalation abuse has also been reported (42075).

CIMETIDINE (Tagamet) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of caffeine in cocoa.  Details Cocoa contains caffeine. Cimetidine decreases caffeine clearance by 30% to 50% (15,506).

CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of caffeine found in cocoa.  Details Cocoa contains caffeine. Oral contraceptives decrease the rate of caffeine clearance by 40% to 65% (2714,11737).

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Caffeine is metabolized by cytochrome P450 1A2 (CYP1A2) (3941,5051,11741,23557,23573,23580,24958,24959,24960,24962), (24964,24965,24967,24968,24969,24971,38081,48603). Theoretically, drugs that inhibit CYP1A2 may decrease the clearance rate of caffeine from cocoa and increase caffeine levels.

DIPYRIDAMOLE (Persantine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, cocoa might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.  Details Cocoa contains caffeine. Caffeine may inhibit dipyridamole-induced vasodilation (11770,11772). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). Methylxanthines appear more likely to interfere with dipyridamole than adenosine-induced stress testing (11771).

DISULFIRAM (Antabuse) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, disulfiram might increase the risk of adverse effects from caffeine.  Details Cocoa contains caffeine. In human research, disulfiram decreases the rate of caffeine clearance (11840).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, using cocoa with diuretic drugs might increase the risk of hypokalemia.  Details Cocoa contains caffeine. In excessive amounts, caffeine can reduce potassium levels due to stimulation of the sodium-potassium pump (23579,37905,37953,38003,38034). Diuretics can also cause lower potassium levels.

EPHEDRINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk for stimulant adverse effects.  Details Cocoa contains caffeine. There is evidence that using ephedrine with caffeine might increase the risk of serious life-threatening or debilitating adverse effects such as hypertension, myocardial infarction, stroke, seizures, and death (1275,6486,10307).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, estrogens might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Estrogen inhibits caffeine metabolism (2714).

FLUCONAZOLE (Diflucan) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, fluconazole might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Fluconazole decreases caffeine clearance by approximately 25% (11022).

FLUTAMIDE (Eulexin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cocoa might increase the levels and adverse effects of flutamide.  Details Cocoa contains caffeine. In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, fluvoxamine might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Fluvoxamine reduces caffeine metabolism (6370).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, abrupt cocoa withdrawal might increase the levels and adverse effects of lithium.  Details Cocoa contains caffeine. There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal (609,610).

METHOXSALEN (Oxsoralen) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, methoxsalen might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Methoxsalen can reduce caffeine metabolism (23572).

METMORPHIN (Glucophage) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, metformin might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Animal research suggests that metformin can reduce caffeine metabolism (23571).

MEXILETINE (Mexitil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, mexiletine might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Mexiletine can decrease caffeine elimination by 50% (1260,11741). Concomitant use might increase the effects and adverse effects of caffeine in cocoa.

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of a hypertensive crisis.  Details Cocoa contains caffeine. Large amounts of caffeine with MAOIs might precipitate a hypertensive crisis (15).

NICOTINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use might increase the risk of hypertension.  Details Cocoa contains caffeine. Concomitant use of caffeine and nicotine has been shown to have additive cardiovascular effects, including increased heart rate and blood pressure. Blood pressure was increased by 10.8/12.4 mmHg when the agents were used concomitantly (36549).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cocoa might decrease the effects of pentobarbital.  Details Cocoa contains caffeine. Caffeine might negate the hypnotic effects of pentobarbital (13742).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, cocoa might reduce the effects of phenobarbital and increase the risk for convulsions.  Details Cocoa contains caffeine. Animal research suggests that caffeine can decrease the anticonvulsant activity of phenobarbital (23558,23559,23561). The exact mechanism of this interaction is unclear.

PHENOTHIAZINES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Phenothiazines can reduce the metabolism of caffeine by inhibiting cytochrome P450 1A2 (CYP1A2) (23573,23574).

PHENYLPROPANOLAMINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Concomitant use of phenylpropanolamine and caffeine might cause an additive increase in blood pressure (11738). Phenylpropanolamine also seems to increase caffeine serum levels (13743).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cocoa might reduce the effects of phenytoin and increase the risk for convulsions.  Details Cocoa contains caffeine. Animal research suggests that caffeine can decrease the anticonvulsant activity of phenytoin (23559,23561). The effect does not seem to be related to the seizure threshold-lowering effects of caffeine. However, the exact mechanism of this interaction is unclear.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, quinolone antibiotics might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Quinolones (also referred to as fluoroquinolones) decrease caffeine clearance (606,607,608).

RILUZOLE (Rilutek) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.  Details Cocoa contains caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2, and concomitant use might reduce metabolism of one or both agents (11739).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use might increase stimulant adverse effects.  Details Cocoa contains caffeine. Concomitant use might increase the risk of stimulant adverse effects (11832).

TERBINAFINE (Lamisil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, terbinafine might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Terbinafine decreases the rate of caffeine clearance (11740).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, cocoa might increase the levels and adverse effects of theophylline.  Details Cocoa contains caffeine. Large amounts of caffeine might inhibit theophylline metabolism (11741). Caffeine decreases theophylline clearance 23% to 29% (506).

TIAGABINE (Gabitril) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, cocoa tea might increase the levels and adverse effects of tiagabine.  Details Cocoa contains caffeine. Animal research suggests that chronic caffeine administration can increase the serum concentrations of tiagabine. However, concomitant use does not seem to reduce the antiepileptic effects of tiagabine (23561).

TICLOPIDINE (Ticlid) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, ticlopidine might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. In vitro evidence suggests that ticlopidine can inhibit caffeine metabolism (23557). However, this effect has not been reported in humans.

VALPROATE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cocoa might reduce the effects of valproate and increase the risk for convulsions.  Details Cocoa contains caffeine. Animal research suggests that caffeine can decrease the anticonvulsant activity of valproate (23558,23559,23561,37882). However, the exact mechanism of this interaction is unclear.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, verapamil might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Verapamil increases plasma caffeine concentrations by 25% (11741).

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General ...Orally and topically, cocoa is generally well tolerated.
Most Common Adverse Effects:
Orally: Borborygmi, constipation, diuresis, gastrointestinal discomfort, headaches, and nausea.
Serious Adverse Effects (Rare):
Orally: Tachycardia.

Cardiovascular ...Some cases of increased heart rate have been reported with oral cocoa use (13161,42132).

Dermatologic ...In some cases, when taken orally, cocoa can cause allergic skin reactions (13161). Topically, cocoa butter has occasionally caused a rash. In animals, it has been shown to block pores and cause acne; however, this has not been found in humans (11).

Gastrointestinal ...In human trials, chocolate consumption was associated with a higher incidence of flatulence, irritable bowel syndrome, upset stomach, gastric upset, borborygmi (a gurgling noise made by fluid or gas in the intestines), bloating, nausea, vomiting, and constipation or obstipation (41986,42221,41921,1374,42220,1373,42099,42097,42156,42123,18229,42169,42111). Chocolate consumption has been implicated as a provoking factor in gastroesophageal reflux disease (GERD) (41974,42005,41946,1374). Unpalatability has been reported (42079,42169). Consumption of chocolate and other sweet foods may lead to increased dental caries (42129,42030).

Genitourinary ...In some cases, when taken orally, cocoa can cause increased urination (13161).

Neurologic/CNS ...In some cases, when taken orally, cocoa can cause shakiness and might trigger migraine and other headaches (13161,42169,92271).

Other ...Due to the high sugar and caloric content of chocolate, there is concern about weight gain in people who consume large amounts of chocolate (17187).

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