Cocoa Cherry StandardBar by Standard Process

Dementia. It is unclear if consuming dewaxed brown rice improves cognitive function in adults with dementia. Details: A small clinical study in elderly nursing home residents with low cognitive function shows that eating dewaxed brown rice with 3 meals daily for 6 months improves scores on the Revised Hasegawa's Dementia Scale to a greater extent than eating white rice (103626).
Diabetes. It is unclear if consuming brown rice as part of the diet is beneficial for improving glycemic control in adults with type 2 diabetes; the available research is conflicting. Details: Meta-analyses of clinical trials evaluating adults with type 2 diabetes shows that consuming a diet containing brown rice 50-450 grams daily for 4-104 weeks does not improve glycated hemoglobin (HbA1c) levels or fasting blood glucose levels when compared with a white rice diet (108661,108662). Clinical trials using non-glutinous brown rice for 24 hours or 16 weeks show similar results (96996,96998). However, not all research agrees. Preliminary clinical research in adults with type 2 diabetes shows that eating glutinous brown rice twice daily for 8 weeks modestly reduces HbA1c levels, compared with no change in those eating white rice (96995). Preliminary clinical research also shows that eating glutinous brown rice as the staple food over a 24-hour period helps with acute glycemic response when compared with white rice (96996). Other preliminary clinical research in females with type 2 diabetes shows that following a brown rice diet for 12 weeks reduces HbA1c and fasting blood glucose by 3% to 5% and reduces body weight and body fat by approximately 2% when compared with no intervention (18660). Clinical trials in adults with type 2 diabetes also report conflicting effects of brown rice on body weight, waist circumference, body fat, lipids, and blood pressure when compared with white rice (108661,108662). However, the limited studies showing positive benefits of brown rice report very minor effects with unclear clinical implications. The reasons for these discrepancies are unclear but may be related to the slight differences between the varieties of brown rice.
Impaired glucose tolerance (Prediabetes). It is unclear if consuming brown rice as part of the diet is beneficial for improving glycemic control; the available research is conflicting. Details: A meta-analysis of clinical trials evaluating adults with prediabetes shows that consuming a brown rice-based diet for 6-12 weeks does not improve glycated hemoglobin (HbA1c) levels, fasting blood glucose levels, body weight, or waist circumference when compared with a white rice-based diet (108662). However, some preliminary clinical research in middle-aged females with prediabetes shows that replacing staple white rice in the diet with pre-germinated brown rice for 4 months modestly reduces fasting blood glucose and HbA1c levels when compared with baseline. There were also small improvements in body fat, body mass, systolic and diastolic blood pressure, and total cholesterol levels when compared with baseline (96997). The validity of these findings is limited by the lack of a comparator group.
Metabolic syndrome. It is unclear if consuming brown rice reduces the prevalence of metabolic syndrome or improves metabolic parameters in patients with this condition. Details: Preliminary clinical research in adults with metabolic syndrome shows that eating brown rice ad libitum for 16 weeks does not improve metabolic factors or reduce the number of patients still meeting the diagnosis of metabolic syndrome when compared with eating white rice ad libitum (96998). However, other clinical research shows that eating 200 grams daily of cooked, pre-germinated brown rice for 3 months reduces the number of patients meeting the diagnosis of metabolic syndrome by 30%, compared with a reduction of 10% in those eating 200 grams daily of cooked white rice (103627). This suggests that any benefit might be related to regular consumption of brown rice. A small clinical study in overweight adults with metabolic syndrome shows that eating brown rice with 2 meals per day, 6 days per week for 3 months, reduces glycated hemoglobin (HbA1c) when compared with eating the same amount of white rice (103623). Other preliminary clinical research shows that eating sticky or glutinous brown rice for 8 weeks modestly improves body weight, some measures of insulin resistance, and levels of low-density lipoprotein (LDL) cholesterol when compared with baseline (96999). The validity of these findings is limited by the lack of a comparator group.
Obesity. Although there is interest in using oral brown rice for weight loss, there is insufficient reliable information about the clinical effects of brown rice for this purpose.
Psoriasis. Although there is interest in using oral brown rice for psoriasis, there is insufficient reliable information about the clinical effects of brown rice for this condition. More evidence is needed to rate brown rice for these uses.

LIKELY EFFECTIVE

Atopic dermatitis (eczema). Consuming casein peptide as part of formula with or without breastmilk for up to 6 months reduces the risk of atopic dermatitis in infants. Details: Clinical research shows that feeding infants a casein peptide-based formula (Nutramigen or Progestimil, Mead Johnson), with or without breastmilk for 4-6 months, reduces the risk for atopic dermatitis during the first 9-24 months of life by 52% to 73% when compared to cow's milk formula (91655,91656,91658). The benefits of casein peptides appear to be most significant in infants with a family history of atopy (91655,91656). Additionally, the benefit of using a casein peptide-based formula during the first 4 months of life persists into childhood, with a 29% reduced risk of developing atopic dermatitis at 6 years of age when compared to cow's milk formula (91659,91660). Clinical research also shows that casein peptide formula is equally effective to hydrolyzed whey protein formula for reducing the risk for atopic dermatitis in infants (91657,91658,91659,91660,91661).
Atopic disease. Consuming casein peptide as part of formula during the first 4 months of life reduces the risk of atopic disease in infants with a family history of atopy. The benefits of casein peptide in infants without a family history of atopy is unclear. Details: Clinical research in infants with a family history of atopy shows that taking a casein peptide-based formula (Nutramigen, Mead Johnson) during the first 4 months of life, or after weaning from breastmilk, reduces the risk for atopic manifestations during the first 12-18 months of life by 39% to 44% when compared with cow's milk formula (91656,91658). This benefit persists over time, with a 20% reduced risk for developing atopic disease at 6 years of age when compared to cow's milk formula (91660). However, it may not be beneficial in children without a family history of atopy. One large, ancillary clinical study in children at increased risk for development of type 1 diabetes, but not specifically at risk for atopy, shows that using an extensively hydrolyzed casein peptide formula (Nutramigen, Mead Johnson) in infancy for up to 6-8 months does not prevent persistent asthma, allergic rhinitis, or atopic dermatitis development when compared with using a conventional formula containing 80% intact cow's milk protein and 20% hydrolyzed milk protein (Enfamil, Mead Johnson). The validity of these findings is limited by the patient population and the unclear duration of follow up (106564).
Food allergies. Consuming casein peptide formulas is a safe alternative to cow's milk in children with cow's milk allergy. Details: Clinical research shows that specific casein peptide formulas are a safe and well-tolerated alternative for children with documented allergy to cow's milk. Evaluated formulas include Alimentum (Abbot Laboratories), Damira 2000 (Nutrition & Sante S.L.), Frisolac Allergycare (Friesland Nutrition), and Nutramigen (Mead Johnson) (91663,91664,91665,111439). A cost-effective analysis in children with cow's milk allergy also suggests that using casein peptide-based formula is cost-effective dominant and reduces other allergic manifestations when compared with soy-based formula (111438).

Colic. Clinical research shows that consuming casein peptides as part of formula reduces crying, short-term, in infants with colic. Details: Clinical research in infants with colic shows that replacing cow's milk formula with a specific casein peptide formula (Nutramigen, Mead Johnson) significantly reduces crying and colic when compared with cow's milk formula. However, this effect appears to diminish after more than four days of use (91262). Preliminary clinical research shows that consuming specific casein peptide formulas (Alimentum, Abbot Laboratories; Nutramigen, Mead Johnson) for 7 days reduces daily crying time by up to 5 hours and reduces crying intensity when compared with baseline in infants with colic (91264). The validity of this finding is limited by the lack of a comparator group.
Diabetes. Consuming casein peptides with carbohydrates may be beneficial for reducing postprandial glucose and insulin levels in adults with type 2 diabetes. Casein peptides have also been evaluated for the prevention of type 1 diabetes in infants, with inconclusive results. Details: In adults with type 2 diabetes, casein protein may improve postprandial glucose levels. Most clinical research shows that consuming casein peptides in conjunction with a carbohydrate bolus increases postprandial insulin response by 26% to 300% and reduces postprandial glucose levels by 5% to 28% when compared with consuming carbohydrates alone (91276,91295,91297,91299). These effects seem to persist with casein peptide doses as low as 12 grams daily, but not 6 grams daily (91300). Preliminary clinical research also shows that adding leucine 5 grams or 0.1 grams/kg to casein peptides increases postprandial insulin levels by 52% to 200%, reduces postprandial glucose levels by 5% to 12%, and improves 24-hour glucose levels by 11% when compared with consuming carbohydrates alone (91296,91297). However, some preliminary clinical research shows that consuming casein peptides 0.4 grams/kg with each meal for one day does not improve glycemic control (91298). These differing outcomes might be related to the forms of carbohydrates used, which include carbohydrate boluses and carbohydrate-containing meals. Additionally, the evidence for the effects of intact casein protein, as opposed to casein peptides, on postprandial insulin and glucose levels is conflicting (91276,91299). Clinical research in infants 6-8 months of age who are genetically predisposed to type 1 diabetes shows that administering a specific casein peptide-based formula (Nutramigen, Mead Johnson) in place of breastmilk decreases the development of one or more diabetes-associated auto-antibodies when compared with cow's milk formula. However, there was no difference in type 1 diabetes incidence after 10 years. This study was not powered to detect a difference in this outcome (91675).
Hypertension. The casein peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), sometimes referred to as lactotripeptides, can modestly reduce blood pressure in patients with hypertension. Lower doses given for shorter durations seem to produce greater effects, and the effects may be more pronounced in Japanese patients than in European patients. Details: The most comprehensive meta-analysis to-date in patients with hypertension shows that taking casein peptides reduces systolic blood pressure (SBP) by 3 mmHg and diastolic blood pressure (DBP) by 1.5 mmHg. The average dose of casein peptides was 10.5 mg daily, including IPP 5.2 mg and VPP 5.3 mg daily, for about 8 weeks. However, there may be an inverse dose-response relationship; daily doses of casein peptides of 10 mg or less, lasting for 8 weeks or less, reduced blood pressure to a greater degree when compared with higher doses given for longer durations. Furthermore, casein peptides produced by fermentation resulted in modestly greater blood pressure reduction when compared with casein peptides produced by enzymatic hydrolysis (103765). Patient ethnicity may also play a role in the magnitude of effect. Other meta-analyses show a 1-6 mmHg reduction in SBP and 0.6-1.5 mmHg reduction in DBP when compared with control (103762,103763,103765,111437). A small clinical study in healthy Japanese males and postmenopausal adults with prehypertension shows that supplementation with casein peptides IPP 2 mg and VPP 1.4 mg daily for 8 weeks reduces home-monitored 7-day mean DBP, but not SBP, by 0.9 mmHg, compared with an increase of 1.2 mmHg in those receiving placebo (106565). Although findings are positive overall, the validity of the above meta-analysis, as well as older or less comprehensive analyses, is limited by the poor reporting and methodology of the included studies (103763,103765,103770,103772). Some limited research in patients with metabolic syndrome shows conflicting blood pressure lowering effects. A small clinical study shows that taking IPP/VPP (Calpis Co., Ltd.) 10.2 mg in the morning before breakfast daily for 4 weeks lowers 24-hour ambulatory systolic blood pressure by 2 mmHg, but not diastolic blood pressure, when compared with placebo (103764). However, another study shows that taking casein peptides 5-25 mg daily with plant sterols 2 grams daily orally for 12 weeks does not reduce blood pressure when compared with placebo (103767). Notably, this study was not adequately powered to detect small changes in blood pressure.
Neonatal jaundice. Clinical research suggests that consuming casein peptide reduces the risk of jaundice in neonates. Details: Preliminary clinical research shows that feeding newborns a specific casein peptide formula (Nutramigen, Mead Johnson) for 3 weeks reduces the risk of jaundice when compared with whey-predominant formula (91642) or human milk (91642,91651). Other preliminary clinical research in breastfed newborns shows that taking 5 mL of casein peptide formula, created by enzymatic hydrolysis, 6 times daily for 7 days decreases transcutaneous bilirubin levels when compared with breastfeeding alone (91643).

Asthma. Consuming casein peptide does not appear to reduce the risk of asthma in infants. Details: Most clinical research shows that feeding infants a casein peptide-based formula (Nutramigen or Progestimil, Mead Johnson), with or without breastmilk for 4 months, does not reduce the risk for asthma in the first 4 months to 6 years of life in children with a family history of atopy (91655,91659,91660). However, one preliminary clinical study shows that feeding infants Nutramigen beginning at about 3.8 months of age decreases wheezing by 61% compared to cow's milk formula; the incidence of asthma was not evaluated (91656).
Infant development. Consuming casein peptide does not appear to affect growth or development in healthy infants, or in premature or low-birth weight infants. Details: Most clinical research shows that using casein peptide-predominant formula for 6 weeks to 6 months in premature, low-birth weight, or healthy infants does not affect growth when compared with breast milk, whey protein-based formula, rice hydrolysate formula, cow's milk formula, or amino acid-based formula (86085,91644,91672,91673). Additionally, feeding infants a specific casein peptide formula (Nutramigen, Mead Johnson) for 4 months does not affect growth at 6 or 10 years when compared with whey protein-based formula, cow's milk formula, or breast milk (86085,91644). However, clinical research suggests that a casein peptide-based formula might be beneficial in infants with cow's milk allergy. One study in this population shows that casein peptide-based formula significantly increases growth from 6-12 months of age when compared with soy-based formula (91672).

Acne. It is unclear if oral casein peptides are beneficial in patients with acne. Details: Preliminary clinical research in adults with moderate to severe acne shows that taking a specific casein peptide (Lactium) 150 mg orally daily for 84 days does not reduce acne lesion count when compared with control. However, the study may have been inadequately powered to detect a difference between groups (111436).
Aging skin. It is unclear if oral casein peptides are beneficial in patients with aging skin. Details: A small clinical study in healthy, normotensive older Japanese adults shows that taking casein peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP) orally once daily for 48 weeks reduces facial pigmentation area by about 15%, compared with an increase of about 6% in patients taking placebo (106563).
Anxiety. Although there has been interest in using oral casein peptides for anxiety, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
Athletic performance. It is unclear if oral casein peptides are beneficial for athletic performance. Details: Preliminary clinical research in overweight male police officers shows that taking casein peptides 1.5 grams/kg orally daily in two divided doses for 12 weeks, in conjunction with resistance training, decreases body fat percentage by 3%, increases lean body mass by 2 kg, and improves chest, shoulder, and leg press strength by around 30% when compared with whey protein (85648).
Cancer. Although there has been interest in using oral casein peptides for cancer, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
Diarrhea. It is unclear if oral casein peptides are beneficial in patients with diarrhea. Details: Preliminary clinical research in male children with persistent diarrhea shows that consuming a casein peptide-based diet during hospitalization is less effective for reducing stool output than a yogurt-based diet (91648).
Epilepsy. Although there has been interest in using oral casein peptides for epilepsy, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
Exercise-induced muscle soreness. It is unclear if oral casein peptides are beneficial in patients with exercise-induced muscle soreness. Details: Preliminary clinical research in male cyclists shows that drinking 200 mL of a carbohydrate beverage containing 1.8% casein peptides every 5 km followed by 500 mL after cycling completion reduces exercise-induced muscle soreness and improves late-exercise time-trial performance when compared with drinking a carbohydrate beverage alone (91256).
Fatigue. Although there has been interest in using oral casein peptides for fatigue, there is insufficient reliable information about the clinical effects of casein peptides for this purpose.
Hyperlipidemia. Low quality research suggests that oral casein peptides are not beneficial in patients with hyperlipidemia. Details: A meta-analysis of randomized trials in subjects with and without hyperlipidemia shows that using casein peptide-based diets for 1-48 weeks does not improve low-density lipoprotein cholesterol, high-density cholesterol, or triglyceride levels when compared with control (111437).
Insomnia. It is unclear if oral casein peptides are beneficial in patients with insomnia. Details: A small clinical study in Korean patients with poor sleep quality shows that taking a specific product (Lactium, Ingredia) containing bovine alpha-s1 casein peptides 300 mg one hour before bedtime for 4 weeks modestly improves sleep efficiency based on subjective reports and actigraphy measures when compared with placebo (103774). Casein peptides have also been studied as part of combination products. A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, and L-theanine 50 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline. However, it does not affect blood pressure, heart rate, or cortisol levels (108556). It is unclear if these effects are due to L-theanine, alpha-s1-casein tryptic hydrolysate, or the combination.
Physical performance. It is unclear if oral casein peptides are beneficial for physical performance. Details: Preliminary clinical research in healthy older males shows that taking casein peptides 10 grams before and after resistance training for 8 weeks does not improve strength or body composition when compared with placebo (91255).
Stress. Although there has been interest in using oral casein peptides for stress, there is insufficient reliable information about the clinical effects of casein peptides for this purpose. More evidence is needed to rate casein peptides for these uses.

COCOA

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).

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.

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.

LIKELY EFFECTIVE

Constipation. Rectal glycerol is beneficial in children and adults with constipation. Details: Glycerol rectal suppositories and enemas are approved by the US Food and Drug Administration (FDA) for over-the-counter use to treat occasional constipation in adults and children at least 2 years of age (15).

Athletic performance. Oral glycerol may improve hydration during exercise, but clinical studies evaluating glycerol for improving measures of athletic performance are limited and conflicting. Details: Several clinical studies show that glycerol increases serum osmolality and improves hydration status during exercise (2475,2476,93757,93760,93761,93765). One meta-analysis, including 14 studies and 99 patients, shows that glycerol-induced hyperhydration increases body water by approximately 2.5-fold when compared with water-induced hyperhydration (93757). Also, taking glycerol along with table salt 7.5 grams per liter fluid seems to improve hydration status when compared withg glycerol alone (99162). Research regarding the effects of glycerol on thirst, comfort, temperature regulation, sweating, and heart rate is conflicting (2475,2476,93760,99162). While glycerol may improve hydration status during exercise, it is unclear whether it can improve measures of athletic performance. An early meta-analysis including a total of 36 athletes shows that taking glycerol increases endurance performance by 2.6%. Although this is a small difference, it might be considered meaningful to athletes (93757). Some small clinical studies in athletes suggest that glycerol increases endurance and time to exhaustion, with no effect on heat regulation (2475,2479,93764). However, other small studies suggest that glycerol does not reduce perceived exhaustion or improve exercise performance (2476,93760). Also, glycerol has not been shown to increase time to exhaustion in triathletes (2492). When used to improve athletic performance, glycerol is most often taken at doses of 1-1.5 gram/kg in conjunction with approximately 1.5 L of fluid, 60-120 minutes before competition, and in some cases continued during the competition (2475,93757,93760,93764).
Ichthyosis. Topical application of a specific product containing glycerol and paraffin may improve symptoms of ichthyosis in children. The benefits of topical glycerol alone in these patients is unknown. Details: A large clinical trial in children aged 1 month to 18 years shows that applying a specific product (Dexeryl, Pierre Fabre Laboratoires) containing glycerol 15% and paraffin 10% for 4 weeks reduces symptoms of non-bullous ichthyosis by at least 50% in an additional 17% of children when compared with a placebo cream. Applying this specific product also improves pruritus by an additional 45% when compared with placebo (93756). It is unclear if these findings are due to glycerol, paraffin, or the combination.

Meningitis. Some clinical research suggests that oral glycerol does not reduce the risk of mortality or seizures in adults and children with bacterial meningitis, although it may reduce certain sequelae. Details: A meta-analysis of five low-quality clinical trials including 1,270 patients shows that adjunctive treatment with glycerol as an oral osmotic agent does not reduce the risk of mortality, seizures, or gastrointestinal symptoms in adults and children with acute bacterial meningitis, although it may modestly reduce the risk of deafness and residual neurological deficit in surviving children (99160). Clinical research included in the meta-analysis has used glycerol 1.5 grams/kg every 6 hours in children aged 2 months to 16 years (93762,93763).
Prematurity. Rectal glycerol does not appear to reduce the time to enteral feeding in premature infants. Details: Glycerol is used as an enema or given by suppository to facilitate the evacuation of meconium in premature infants in order to reduce the time to enteral feeding. However, two meta-analyses of small studies in preterm infants, that include some of the same studies, show that administering glycerol suppositories does not reduce the number of days to full enteral feeds when compared with placebo or no treatment (99166,112003). However, the interpretation of these findings is limited by the heterogeneity of dosages used in the included studies.

LIKELY INEFFECTIVE

Stroke. Intravenous glycerol may not improve mortality or symptoms in patients with acute ischemic stroke. Details: Several clinical studies show that intravenous administration of glycerol does not improve symptoms of acute stroke (2480,2481,2482,2484,2486). Additionally, one clinical study in elderly patients with acute ischemic stroke shows that while glycerol can improve initial survival, it does not reduce the risk of overall mortality when compared with placebo (2483).

Dandruff. Topical glycerol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical trial in adults with dandruff shows that applying a leave-in hair lotion containing glycerol 10%, stearic acid 2.5%, and sunflower seed oil 0.6%, 3 times weekly for 8 weeks, modestly reduces dandruff severity throughout use and for up to one week after the last application when compared with a placebo lotion. The glycerol lotion also reduced total water loss from the scalp by 8% and increased moisturization by 23% (93758). It is unclear if these findings are due to glycerol, other ingredients, or the combination.
Dry skin. Topical glycerol has only been evaluated in combination with other ingredients for the management of dry skin associated with kidney failure; its effect when used alone is unclear. Details: One small, open-label clinical study in adults with kidney failure and moderate to severe uremic xerosis shows that applying an emulsion containing glycerol 15% and paraffin 10% twice daily for 7 days reduces the severity of xerosis when compared with a placebo emulsion. The glycerol-containing emulsion produces a treatment response in an additional 29% of patients, improves quality of life, and reduces scale density and thickness when compared with placebo (93754). It is unclear if these findings are due to glycerol, paraffin, or the combination.
Glaucoma. Although there has been interest in using oral glycerol for glaucoma, there is insufficient reliable information about the clinical effects of glycerol for this purpose.
Intracranial hypertension. Although there has been interest in using intravenous glycerol to reduce intracranial pressure in patients with brain tumors, central nervous system (CNS) trauma, encephalitis, idiopathic intracranial hypertension, meningitis, and Reye syndrome, there is insufficient reliable information about the clinical effects of glycerol for this purpose.
Meniere disease. It is unclear if intravenous glycerol is beneficial in patients with Meniere disease. Details: A small, uncontrolled clinical study in adults with unilateral, intractable Meniere disease shows that intravenous administration of glycerol 10% at a dose of 0.5 grams/kg once daily for 2 consecutive days, twice monthly for 6 months, reduces the frequency of vertigo attacks and improves quality of life when compared to baseline. Patients reported an average of 3.2 vertigo attacks per month at baseline and 1.2 vertigo attacks per month after 6 months of treatment (106649). The lack of a control group limits the validity of these findings.
Neonatal jaundice. It is unclear if rectal glycerol improves jaundice-related outcomes in premature infants. Details: A small clinical study in neonates receiving phototherapy for jaundice shows that administering glycerol suppositories has no effect on the duration of phototherapy needed for jaundice treatment, or on bilirubin levels or the rate of bilirubin decline when compared with no glycerol suppositories (99165).
Obesity. It is unclear if oral glycerol is beneficial in patients who are overweight or obese. Details: One small clinical study in adults on a low-calorie diet shows that taking glycerol 7.5 grams before meals for 6 weeks does not increase weight loss when compared with placebo (2485).
Otitis externa. Topical glycerol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with otitis externa shows that inserting ribbon gauze soaked in glycerol and ichthammol into the ear canal reduces pain and swelling as effectively as the application of antibiotic and steroid drops three times daily (93759). It is unclear if these findings are due to glycerol, ichthammol, or the combination. More evidence is needed to rate glycerol for these uses.

Chronic venous insufficiency (CVI). Oral grape leaf extract might improve CVI symptoms. It is unknown if other grape products are beneficial for CVI. Details: Some clinical trials in patients with CVI show that taking a specific grape leaf extract, known as red vine leaf extract (AS 195, Antistax, Boehringer Ingelheim), seems to improve leg edema after 6 weeks of treatment when compared with placebo. Doses of 360 mg and 720 mg daily were both effective, but the higher dose produced a slightly greater effect. Patients also reported decreases in subjective complaints such as tired or heavy legs, tension, and tingling and pain after 2-12 weeks of treatment (2538,52985,53005,53206).

Allergic rhinitis (hay fever). Oral grape seed extract does not seem to improve hay fever symptoms. Details: A clinical study in patients with seasonal allergic rhinitis shows that taking grape seed extract 100 mg twice daily for 8 weeks before ragweed pollen season does not seem to decrease seasonal allergic rhinitis symptoms or antihistamine usage when compared with placebo (9182).
Chemotherapy-induced nausea and vomiting (CINV). Drinking grape juice does not seem to improve CINV. Details: Clinical research shows that taking 4 ounces of chilled Concord grape juice 30 minutes prior to meals for a week following each of four cycles of chemotherapy does not seem to reduce CINV when compared with placebo (53175).
Lower urinary tract symptoms (LUTS). Drinking grape juice does not seem to improve LUTS. Details: Clinical research in middle-aged and older men with LUTS shows that drinking 100% Concord grade juice 240 mL daily for 3 months does not improve symptoms when compared with placebo (96190).
Mastalgia. Oral grape seed extract does not seem to improve mastalgia symptoms. Details: Clinical research in patients treated for early breast cancer using high-dose radiotherapy shows that taking the grape seed extract constituent proanthocyanidin 100 mg orally three times daily for 6 months does not reduce breast tissue hardness, pain, or tenderness when compared with placebo (53048).
Obesity. Oral grape products do not seem to improve weight loss. Details: Clinical research in overweight or obese individuals shows that drinking Concord grape juice 480 mL daily for 12 weeks does not improve weight or body composition when compared to baseline (53181). Furthermore, taking grape pomace alone or in combination with schisandra fruit extract daily for 4-10 weeks does not improve body composition, abdominal fat, or body weight when compared with control (96200,99269,99270). Taking grape pomace 7-8 grams daily for 4-6 weeks seems to improve insulin resistance by about 33%, but does not affect blood lipids or blood pressure, when compared with placebo in overweight or obese adults with at least one metabolic syndrome factor (99269,99270).

Aging skin. Oral grape skin extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in adults with signs of aging skin shows that taking a specific combination product (Celergen, Laboratories-Dom) containing grape skin extract 10 mg, marine collagen peptides 570 mg, coenzyme Q10 10 mg, luteolin 10 mg, and selenium 0.05 mg, one capsule with breakfast and dinner for 2 months, might improve skin elasticity when compared with baseline. However, there was no effect on moisture or biological skin age (97930). It is not clear if these effects are due to grape skin extract, the other ingredients, or the combination.
Age-related macular degeneration (AMD). Although there is interest in using oral grape seed for AMD, there is insufficient reliable information about the clinical effects of grape for this condition.
Atherosclerosis. Oral grape seed extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking a specific combination product (Karinat, INAT-Farma) containing grape seed extract constituent proanthocyanidin 40 mg, garlic 100 mg, hops 160 mg, green tea 115 mg, vitamin C 30 mg, silicon 8 mg, vitamin E 6.6 mg, and beta-carotene 0.5 mg three capsules daily for 12 months might slow the progression of atherosclerosis as measured by mean carotid intima thickness when compared with placebo. However, the combination product does not seem to affect the growth of existing plaques, and it does not seem to improve lipid parameters (97929). It is not clear if these effects are due to grape seed extract, the other ingredients, or the combination.
Athletic performance. It is unclear if oral grape products are beneficial for athletic performance. Details: A small study in elite athletes shows that taking a specific grape extract (Powergrape, Naturex SA) 400 mg daily for one month can increase total power in a jumping task when compared with placebo, but has no effect on initial power and maintenance of power (53310). Another small study in recreationally active young adults shows that drinking juice prepared from 46 grams of a freeze-dried preparation of whole grapes daily for 6 weeks prior to a running exercise test does not improve maximal oxygen uptake or work capacity during exercise when compared with placebo (91540).
Atopic dermatitis (eczema). Topical grape products have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with atopic dermatitis shows that twice daily application with a cream containing grape polyphenols, vitamin E, and epigallocatechin gallate for 28 days does not improve symptoms or reduce the affected area based on physician assessment when compared with placebo (96196).
Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral grape seed for ADHD, there is insufficient reliable information about the clinical effects of grape for this condition.
Canker sores. Although there is interest in using oral grape seed for canker sores, there is insufficient reliable information about the clinical effects of grape for this condition.
Cardiovascular disease (CVD). It is unclear if oral grape products are beneficial for reducing CVD risk. Details: There is preliminary evidence that taking grape products, such as purple grape juice or red grape juice concentrate, might improve endothelium-dependent vasodilation, prevent low-density lipoprotein (LDL) oxidation, reduce markers of inflammation, and suppress platelet-mediated thrombosis. Theoretically, chronic ingestion of these products might reduce the risk of CVD in various patient populations, including adults with type 2 diabetes or hypercholesterolemia, those undergoing hemodialysis, and children with metabolic syndrome (8745,8746,52954,53030,53062,53106,53155,53174). However, a large meta-analysis shows that although taking grape products, including grape extract, grape juice, raisins, and grape seed extract, reduces levels of blood fats by a small amount in a mixed population of adults, these effects were not present in a subgroup of patients with CVD when compared with placebo. There was a small benefit on total cholesterol and high-density lipoprotein (HDL) cholesterol (102610).
Cognitive function. It is unclear if oral grape products improve cognitive function. Details: Clinical research in healthy adults aged 55-75 years with no cognitive decline shows that taking a specific grape fruit extract (Cognigrape, Bionap srl) 250 mg daily for 12 weeks improves cognitive functioning by 4.5%, and overall neuropsychological status, including attention, language, and recall, by 6%, compared with no change in the placebo group (96198). Also, a preliminary clinical study in middle-aged women under moderate stress shows that drinking Concord grape juice 355 mL daily for 12 weeks improves immediate spacial memory and may improve executive function and verbal recall when compared with placebo (96195).
Cognitive impairment. Small clinical studies suggest that oral grape products may not slow cognitive decline in older patients with cognitive impairment. Details: One very small study in in patients with mild cognitive decline shows that taking a freeze-dried grape powder 36 grams twice daily for 6 months does not improve most measures of cognitive function and memory, including immediate memory, delayed memory, speed of information processing, cognitive ability, or language, when compared with placebo (96199). Another very small study in older adults with signs of memory decline shows that drinking 100% Concord grape juice 6-9 mL/kg daily for 12 weeks does not improve delayed verbal recall or spatial memory when compared with placebo, although it does seem to moderately improve verbal learning (53166).
Colorectal cancer. Oral grape seed extract is has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with colorectal cancer shows that taking a product containing grape seed extract, turmeric extract, fermented soybean extract, green tea extract, spirulina, and Taiwanofungus camphoratus, 1920 mg three times daily for 16 weeks during a chemotherapy regimen might modestly increase the effectiveness of treatment when compared with placebo. No patients in the treatment group experienced disease progression, compared with 15.8% (6 patients) of the placebo group. However, there was no significant effect on overall survival or the best response to treatment (96183).
Constipation. Although there is interest in using oral grape products for constipation, there is insufficient reliable information about the clinical effects of grape for this condition.
Dental caries. Although there is interest in using topical grape seed for dental caries, there is insufficient reliable information about the clinical effects of grape for this purpose.
Diabetes. Oral grape extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study of males with type 2 diabetes mellitus and erectile dysfunction suggests that an oral combination product containing alpha lipoic acid, Gingko biloba, and grape extract (Blunorm Forte, Uriach S.p.A.) taken for 3 months may decrease fasting plasma glucose and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score both alone and when combined with avanafil when compared with baseline and placebo (110707).
Diabetic retinopathy. It is unclear if oral grape seed extract is beneficial in patients with diabetic retinopathy. Details: A preliminary clinical study in patients with non-proliferative diabetic retinopathy shows that taking a specific grape seed proanthocyanidin extract (Entelon, Hanlim Pharm) 50 mg three times daily for 12 months reduces the severity of hard exudates when compared with calcium dobesilate or placebo. Grape seed extract had a treatment success rate 3-fold and 5.5-fold higher than those of calcium dobesilate and placebo, respectively. Treatment success was defined as a 2-grade decrease in hard exudate severity. No significant improvements in retinopathy grade or visual acuity were reported (100954). However, the study may not have been adequately powered to detect a difference in these outcomes.
Erectile Dysfunction (ED). Oral grape extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large study of males with type 2 diabetes mellitus and erectile dysfunction suggests that a specific combination product containing alpha lipoic acid, grape extract, and gingko biloba (Blunorm Forte, Uriach S.p.A.) administered orally for three months with avanafil prior to sexual acts improves International Index of Erectile Function (IIEF) scores when compared with either product alone, placebo, and baseline, and may reduce markers of ED including high sensitivity-c-reactive protein, nitrates/nitrites, and metalloproteinases-2 and -9. These results suggest that an oral combination nutraceutical consisting of alpha lipoic acid, grape extract, and gingko biloba (Blunorm Forte, Uriach S.p.A.) may react synergistically with avanafil to enhance sexual performance in males with type 2 diabetes and erectile dysfunction. It is unclear if this effect is due to the alpha lipoic acid, grape extract, or gingko biloba, but researchers theorize that it may be due to the inhibition of phosphodiesterase-5 enzymes by grape extract (110707).
Hemorrhoids. Although there is interest in using oral grape seed for hemorrhoids, there is insufficient reliable information about the clinical effects of grape for this purpose.
Hypercholesterolemia. Small clinical studies suggest that oral grape products reduce cholesterol levels by a small amount. Details: A large meta-analysis of heterogeneous clinical trials shows that taking grape products, including grape extract, grape juice, raisins, or grape seed extract, for 2-54 weeks reduces levels of total and low-density lipoprotein (LDL) cholesterol, as well as triglycerides, by a small amount when compared with placebo in a mixed population of adults. In a sub-group of patients with any hyperlipidemia, the mean decreases in LDL cholesterol and triglycerides were 11 mg/dL and 14 mg/dL, respectively. There was no effect on levels of high-density lipoprotein (HDL) in the mixed population or in adults with hyperlipidemia (102610). Although some individual studies disagree, the most evidence for benefit is related to use of whole grape extract or grape seed extract. It is not clear if benefit is dependent on dose or duration of use. These results suggest a benefit of grape products in patients with hypercholesterolemia, but any benefit is likely to be small (42585,96816,102610).
Hypertension. Some research suggests that oral grape products may modestly lower blood pressure; however, results are inconsistent. Details: Some clinical trials have shown modest benefit in patients with prehypertension, mild hypertension, or metabolic syndrome (18228,53149,96197), but conflicting results exists (91541,90079). A 2016 meta-analysis including 16 trials of 810 patients shows that when compared with placebo, grape seed extract or polyphenols reduces systolic blood pressure (SBP) and diastolic blood pressure (DBP) by about 6 mmHg and 3 mmHg, respectively, with greatest improvements observed in those with obesity or metabolic syndrome. This meta-analysis suggests that a minimum treatment duration of 8 weeks may be necessary before benefit is seen (96194). However, other research in adults with hypertension shows that taking grape seed polyphenols 1000 mg daily for 6 weeks does not alter blood pressure. Also, when grape seed polyphenols were combined with vitamin C 500 mg daily, some patients experienced an increase in blood pressure and worsening of nighttime and daytime variation in blood pressure (13162,90079). The reason for these conflicting findings is unclear but may due to patient characteristics and comorbidities. A meta-analysis of clinical research in various patient populations shows that taking grape seed extract 150-2100 mg for 2-25 weeks improves DBP and heart rate when compared with control, but does not improve SBP or flow-mediated dilation, regardless of dose, duration, sex, BMI, or health status. Additionally, subgroup analyses suggest that blood pressure effects may be greater in patients who are otherwise healthy, female, overweight, and/or under 50 years of age. Also, the use of lower doses and longer treatment durations may be associated with greater benefit (108090). The validity of these findings is limited by the high heterogeneity of included studies. A clinical study in adults with mildly elevated blood pressure shows that a specific grape seed extract (Enovita; Indena SpA) standardized to provide at least 95% oligomeric proanthocyanins, taken as 150 mg twice daily for 16 weeks, does not reduce SBP or DBP when compared with placebo. However, a subgroup analysis suggests that taking grape seed extract improves blood pressure in males, but not in females, when compared with placebo (108091). Some research has also evaluated the effects of grape juice on blood pressure. Two clinical studies in patients with hypertension show that drinking grape juice can reduce blood pressure when compared to baseline; however, another study shows that drinking grape juice does not reduce blood pressure when compared with placebo in these patients (53018,53156,53199).
Melasma. It is unclear if oral grape seed extract is beneficial in patients with melasma. Details: A very small clinical study in Japanese females with melasma shows that taking grape seed extract (Gravinol, Kikkoman Co) containing 54 mg of proanthocyanidins three times daily for 6-11 months reduces skin hyperpigmentation when compared to pretreatment (53016). The validity of this finding is limited by the lack of a control group.
Menopausal symptoms. It is unclear if oral grape seed extract is beneficial in patients with menopausal symptoms. Details: Preliminary clinical research in adults with at least one menopausal symptom shows that taking grape seed extract (Gravinol, Kikkoman Biochemifa Co) containing proanthocyanidin 200 mg daily for 8 weeks reduces anxiety when compared with placebo. It also reduces hot flashes and other physical symptoms when compared to baseline, but not when compared with placebo. A lower dose of proanthocyanidin 100 mg daily does not appear to improve these outcomes. Neither doses improved insomnia or depression (91542).
Metabolic syndrome. Small studies suggest that various oral grape products might improve lipid levels and blood pressure in patients with metabolic syndrome. Details: A meta-analysis of small clinical studies in adults with type 2 diabetes or metabolic syndrome shows that taking grape products, usually grape seed or grape extract, for 4-48 weeks reduces levels of total and low-density lipoprotein (LDL) cholesterol, as well as triglycerides, by a small amount when compared with placebo. The mean decreases in LDL cholesterol and triglycerides were 2.6 mg/dL and 11 mg/dL, respectively (102610). These findings are limited by significant heterogeneity of the included research. Also, a small clinical study in overweight or obese adults, most with metabolic syndrome, shows that taking grape pomace 8 grams daily for 6 weeks improves insulin resistance by about 33%, but does not affect blood lipids, blood pressure, or fasting glucose, when compared with placebo (99270). Some grape products have also shown benefit for improving blood pressure in patients with metabolic syndrome. One small clinical crossover study in males with metabolic syndrome shows that taking 46 grams daily of a freeze-dried, dehydrated preparation of grape polyphenols (equivalent to about 250 grams of fresh grapes daily) for 30 days seems to modestly lower systolic, but not diastolic, blood pressure, and increase brachial artery flow-mediated dilation (FMD) when compared with placebo (18228). Also, a small clinical study in adolescents with metabolic syndrome suggests that drinking natural grape juice 18 mL/kg daily for one month improves FMD when compared with baseline (53174).The validity of this finding is limited by the lack of a control group. A very small clinical study in patients with metabolic syndrome shows that taking a specific grape seed extract (Meganatural BP, Polyphenolics) 150-300 mg daily for 4 weeks modestly reduces blood pressure when compared with placebo (53149). The validity of this finding is limited due to small study size and because patients in the treatment groups had higher blood pressure at baseline.
Minor bleeding. Topical grape vine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that topically applying 4 mL of a specific product (Ankaferd blood stopper) containing grape vine, alpinia, licorice, thyme, and stinging nettle reduces bleeding, but does not improve the surgical time for episiotomy repair, when compared with saline (31010). It is unclear if this effect is due to grape vine, other ingredients, or the combination.
Muscle soreness. It is unclear if oral grape products improve muscle soreness. Details: One small study in active young adults shows that drinking juice, prepared from 46 grams of freeze-dried whole grapes, daily for 6 weeks prior to an eccentric arm exercise test does not reduce muscle inflammation or pain at 24 or 48 hours post-exercise when compared with placebo (91540).
Night vision. Although there is interest in using oral grape seed extract for improving night vision, there is insufficient reliable information about the clinical effects of grape for purpose.
Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral grape seed extract reverses fatty liver in patients with NAFLD. Details: One small clinical study in adults with NAFLD shows that taking grape seed extract 1000 mg twice daily for 3 months improves some, but not all, markers of liver damage and improves the grade of fatty liver change when compared with vitamin C supplementation (53190).
Ocular stress. Although there is interest in using oral grape seed extract for ocular stress, there is insufficient reliable information about the clinical effects of grape for this purpose.
Premenstrual syndrome (PMS). Although there is interest in using oral grape seed extract for PMS, there is insufficient reliable information about the clinical effects of grape for this condition.
Wound healing. Limited research suggests that topical grape seed extract might improve wound healing. Details: A small clinical study in adults undergoing surgical removal of minor skin lesions shows that applying red grape seed extract 2% cream twice daily to the affected areas reduces the time to complete wound healing by about 6 days when compared with a placebo cream (91539). Also, preliminary clinical research in patients recovering from cesarean section shows that applying grape seed extract 5% ointment twice daily to cesarean section wounds for 14 days improves wound healing, as measured by a scoring system assessing redness, edema, ecchymosis, discharge, and wound closure, when compared with a placebo ointment. A 2.5% ointment did not improve wound healing measures when compared with placebo (100955). More evidence is needed to rate grape for these uses.

LIKELY INEFFECTIVE

Alzheimer disease. Lecithin does not improve daily functioning in patients with Alzheimer disease. Details: In patients with Alzheimer disease, taking various types of lecithin, 1.2-45 grams daily for up to 6 months, alone or in combination with various conventional medications, does not improve cognitive function or other measures of disease progression (5149,5151,5152,5156,14817,14823,14825,14837,14838).

Age-related cognitive decline. It is unclear if oral lecithin can slow age-related cognitive decline. Details: A small clinical crossover study in healthy adults aged 64 years and older shows that taking lecithin 26 grams orally daily, alone or in combination with physostigmine, for 5 weeks does not seem to improve memory when compared with placebo (19204).
Anxiety. Although there is interest in using oral lecithin for anxiety, there is insufficient reliable information about the clinical effects of lecithin for this condition.
Atopic dermatitis (eczema). Although there is interest in using oral lecithin for atopic dermatitis, there is insufficient reliable information about the clinical effects of lecithin for this condition.
Bipolar disorder. It is unclear if oral lecithin is beneficial in patients with bipolar disorder. Details: A clinical study in six patients with mania shows that taking lecithin 10 mg three times daily improves symptoms of delusions, incoherent speech, and hallucinations when compared with placebo (14839).
Dry skin. Although there is interest in using topical lecithin for dry skin, there is insufficient reliable information about the clinical effects of lecithin for this condition.
Friedreich ataxia. Small clinical studies suggest that oral lecithin is not beneficial in people with Friedreich ataxia. Details: Preliminary clinical research shows that taking lecithin 25 grams orally daily for 1 month does not have any benefit in people with Friedreich ataxia (59298). Other preliminary clinical research shows that taking lecithin for a longer period of 6 months also does not improve performance (19211).
Hyperlipidemia. Although lecithin may lower cholesterol in healthy people, it does not seem to improve cholesterol levels in people with hyperlipidemia. Details: Some clinical research shows that taking lecithin 20-30 grams daily for up to 11 months decreases cholesterol in healthy people (5147,14820). However, other clinical research shows that lecithin has no effect on low-density lipoprotein cholesterol or total cholesterol levels in people with hyperlipidemia (5148,14820).
Parkinson disease. It is unclear if oral lecithin is beneficial in patients with Parkinson disease. Details: Preliminary clinical research in patients with Parkinson disease shows that taking lecithin 32 grams daily for 8 weeks does not improve symptoms when compared with placebo (19212).
Postoperative pain. It is unclear if oral lecithin is beneficial for reducing postoperative pain. Details: Preliminary clinical research shows that taking lecithin 20 grams prior to surgery increases choline levels, but does not reduce postoperative pain after gynecological surgery, when compared with placebo (91231).
Tardive dyskinesia. It is unclear if oral lecithin is beneficial in patients with tardive dyskinesia. Details: Two small clinical studies in patients with tardive dyskinesia shows that taking lecithin orally for 2 months, alone or in combination with lithium, does not improve symptoms when compared with placebo (14822,14824).
TPN-associated hepatic steatosis. It is unclear if oral lecithin is beneficial in patients with hepatic steatosis associated with long-term total parenteral nutrition (TPN). Details: A small clinical study in patients on long-term TPN with low choline levels suggests that taking lecithin 20 grams orally twice daily for 6 weeks reduces the degree of hepatic steatosis, compared with no significant changes in those taking placebo (5140).
Ulcerative colitis. Oral lecithin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a disease-specific medical food (Profermin, Nordisk Rebalance) containing lecithin, fermented oats, barley malt, and lactobacillus plantarum, as 250 mL twice daily for 24 weeks, decreases disease activity by over 56% when compared with baseline and leads to remission in 46% of patients with mild-to-moderate ulcerative colitis (91228). Other preliminary clinical research in this population shows that taking Profermin 250 mL twice daily for 8 weeks improves disease activity and remission rate when compared with another medical food (Fresubin Original, Fresenius Kabi) (90271). The effects of lecithin alone are unclear. More evidence is needed to rate lecithin for these uses.

Cardiovascular disease (CVD). Although there has been interest in using oral sweet cherry for CVD, there is insufficient reliable information about the clinical effects of sweet cherry for this condition.
Diabetes. Although there has been interest in using oral sweet cherry for diabetes, there is insufficient reliable information about the clinical effects of sweet cherry for this condition.
Gout. Although there has been interest in using oral sweet cherry for gout, there is insufficient reliable information about the clinical effects of sweet cherry for this condition.
Obesity. It is unclear if oral sweet cherry is beneficial for obesity. Details: A small clinical study in adults with obesity shows that consuming sweet cherry juice as 50 mL concentrate and 3-gram powder in 150 mL water twice daily for 30 days modestly lowers blood pressure when compared with placebo. However, sweet cherry does not reduce body weight or body mass index when compared to baseline (111723). The interpretation of these findings is limited by the lack of clarity about the dose of sweet cherry and high rate of patients discontinuing the study.
Osteoarthritis. Although there has been interest in using oral sweet cherry for osteoarthritis, there is insufficient reliable information about the clinical effects of sweet cherry for this condition. More evidence is needed to rate sweet cherry for these uses.

VANILLA

Wrinkled skin. Preliminary clinical research in adult women with sagging facial skin shows that application of a topical serum containing 1% vanilla extract and 1.5% bakuchiol extract to the face and neck twice daily for 56 days improves skin firmness and jowl ptosis when compared with baseline. It is unclear if this effect is due to vanilla extract, bakuchiol extract, or the combination. Also, the validity of this study is limited by the lack of a comparator group (104752). More evidence is needed to rate vanilla for this use.

Safety view details

Below is general information about the safety of the known ingredients contained in the product Cocoa Cherry StandardBar. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROWN RICE

LIKELY SAFE ...when used orally in amounts commonly found in foods. Brown rice has Generally Recognized as Safe (GRAS) status in the US (7705). There is insufficient reliable information available about the safety of brown rice when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in food. Brown rice has Generally Recognized as Safe (GRAS) status in the US (7705). There is insufficient reliable information available about the safety of brown rice when used in medicinal amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (7705). There is insufficient reliable information available about the safety of brown rice when used in medicinal amounts during pregnancy or lactation.

LIKELY SAFE ...when used orally and appropriately. Casein peptides have been safely used in clinical trials lasting up to 5 months (85648,103763,103764,103765,103770,103772).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Casein peptide formulas have been safely used in healthy, premature, and very low birth weight infants (91262,91264,91643,91673,91675).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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.

LIKELY SAFE ...when used rectally and appropriately. Glycerol rectal suppositories and enemas are approved by the US Food and Drug Administration (FDA) for over-the-counter use to treat occasional constipation (15,272). ...when used topically and appropriately as a lotion, emulsion, or humectant (15,272,93754,93758,93759,99164).

POSSIBLY SAFE ...when used orally, short-term. Glycerol has been used with apparent safety in clinical trials at doses of up to 1.5 grams/kg (2474,2475,99162).

POSSIBLY UNSAFE ...when used intravenously. While some research suggests that intravenous glycerol can be safely administered for two consecutive days twice monthly for up to 6 months (106649), in another study, hemolysis was reported in 98% of patients treated with intravenous glycerol for acute ischemic stroke (2482).

CHILDREN: LIKELY SAFE
when used rectally and appropriately. Glycerol rectal suppositories and enemas are approved by the US FDA for over-the-counter use to treat occasional constipation in children 2 years of age and older (15,272). ...when used topically and appropriately as an emulsion or humectant in children 1 month of age and older (15,272,93756).

CHILDREN: POSSIBLY SAFE
when used orally, short-term. Glycerol has been used with apparent safety in clinical trials in children 2 months to 16 years of age at doses of 1.5 gram/kg, up to a maximum dose of 25 grams, taken every 6 hours (93762,93763).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

LIKELY SAFE ...when used orally in amounts commonly found in foods. Grapes and grape skin extracts have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when the whole fruit of the grape, or extracts of the fruit, seed, or leaf, are used orally and appropriately in medicinal amounts. Grape seed extracts have been used with apparent safety in doses up to 200 mg daily for up to 11 months (9182,53016) and in doses up to 2000 mg daily for up to 3 months (53149,53190). Specific grape fruit extracts (Stilvid, Actafarma; Cognigrape, Bionap srl) have been used with apparent safety in doses up to 250-350 mg daily for 3-12 months or 700 mg daily for 6 months (53254,53256,96198). A specific grape leaf extract (AS 195, Antistax, Boehringer Ingelheim) has been used with apparent safety in doses up to 720 mg daily for up to 3 months (2538,52985,53005,53206). A preparation of dehydrated whole grapes, equivalent to 250 grams of fresh grapes daily, has also been used with apparent safety for up to 30 days (18228). A specific grape seed extract (Enovita; Indena SpA) 150 mg twice daily, standardized to provide at least 95% oligomeric proanthocyanins, has been used with apparent safety for up to 16 weeks (108091) ...when used topically and appropriately. Creams and ointments containing grape seed extract 2% or 5% have been used topically with apparent safety for up to 3 weeks (91539,100955). There is insufficient reliable information available about the safety of other grape plant parts when used topically.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods. Grapes and grape skin extracts have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). However, whole grapes should be eaten with caution in children aged 5 years and under. Whole grapes can be a choking hazard for young children (96193). To reduce the risk of choking, whole grapes should be cut in half or quartered before being given to children. There is insufficient reliable information available about the safety of grape when used in medicinal amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of medicinal amounts during pregnancy and breast-feeding; avoid using in amounts greater than what is commonly found in foods.

LIKELY SAFE ...when used orally in amounts commonly found in foods. Lecithin has Generally Recognized As Safe (GRAS) status in the US (2619,105544). ...when used orally and appropriately in medicinal amounts. Lecithin has been used safely in doses of up to 30 grams daily for up to 6 weeks (5140,5149,5152,5156,14817,14822,14838,19212). ...when used topically (4914).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in food amounts. Lecithin has Generally Recognized As Safe (GRAS) status in the US (105544). There is insufficient reliable information available about the safety of medicinal amounts of lecithin during pregnancy or lactation; avoid using.

LIKELY SAFE ...when the fruit is consumed in amounts commonly found in foods (14056,14058,93197,94712). ...when the fruit is used orally in medicinal amounts, short-term. Sweet cherry 280 grams daily for 28 days has been safely used in clinical research (94712). There is insufficient reliable information available about the safety of sweet cherry when used orally in medicinal amounts, long-term.

PREGNANCY AND LACTATION: LIKELY SAFE
when the fruit is consumed in amounts commonly found in foods (14056,14058). There is insufficient reliable information available about the safety of sweet cherry when used in medicinal amounts during pregnancy or lactation.

VANILLA

LIKELY SAFE ...when used orally in amounts commonly found in foods. Vanilla has Generally Recognized Safe (GRAS) status in the US (4912). There is insufficient reliable information available about the safety of vanilla when used orally or topically in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of vanilla when used in amounts in excess of that found in foods; avoid using.

Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product Cocoa Cherry StandardBar. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROWN RICE

None known.

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Theoretically, combining these casein peptides with antihypertensive drugs might increase the risk of hypotension.

Details

Clinical research shows that some casein peptides, including the lactotripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), can modestly reduce blood pressure in patients with hypertension (103763,103765,103770,103772).

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).

None known.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, grape extracts may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.

Details

In vitro evidence suggests that grape extracts might decrease platelet aggregation (53017,53087).

CYCLOSPORINE (Neoral, Sandimmune)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Ingesting grape juice with cyclosporine can reduce cyclosporine absorption.

Details

A small pharmacokinetic study in healthy young adults shows that intake of purple grape juice 200 mL along with cyclosporine can decrease the absorption of cyclosporine by up to 30% when compared with water (53177). Separate doses of grape juice and cyclosporine by at least 2 hours to avoid this interaction.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, grape juice might reduce the levels of CYP1A2 substrates.

Details

A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of CYP1A2 (2539).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

It is unclear if grape juice or grape seed extract inhibits CYP2C9; research is conflicting.

Details

In vitro evidence shows that grape seed extract or grape juice might inhibit CYP2C9 enzymes (11094,53011,53089). However, a small pharmacokinetic study in healthy adults shows that drinking 8 ounces of grape juice once does not affect the clearance of flurbiprofen, a probe-drug for CYP2C9 metabolism (11094). The effects of continued grape juice consumption are unclear.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, grape seed extract may increase the levels of CYP2D6 substrates.

Details

In vitro evidence suggests that grape seed extract might inhibit CYP2D6 enzymes (53011). However, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, grape seed extract might increase the levels of CYP2E1 substrates.

Details

In vitro and animal research suggests that grape seed proanthocyanidin extract inhibits CYP2E1 enzymes (52949). However, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

It is unclear if grape seed extract inhibits or induces CYP3A4; research is conflicting.

Details

In vitro evidence suggests that grape seed extract might inhibit CYP3A4 enzymes (53089). However, evidence from animal research shows that grape seed extract may induce CYP3A4 in the liver (53011). So far, these interactions have not been reported in humans.

MIDAZOLAM (Versed)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, long-term intake of grape seed extract might decrease the effects of midazolam.

Details

Animal research shows that subchronic ingestions of grape seed extract can increase the elimination of intravenous midazolam by increasing hepatic CYP3A4 activity. Single doses of grape seed extract do not appear to affect midazolam elimination (53011).

PHENACETIN

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Grape juice might decrease phenacetin absorption.

Details

A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of cytochrome P450 1A2 (CYP1A2) (2539).

None known.

None known.

VANILLA

None known.

Report an Adverse Reaction to Cocoa Cherry StandardBar

Adverse Effects view details

Below is general information about the adverse effects of the known ingredients contained in the product Cocoa Cherry StandardBar. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROWN RICE

General ...Orally, brown rice is well tolerated when consumed as a food. No adverse effects have been reported when used in medicinal amounts; however, a thorough evaluation of safety outcomes has not been conducted.

General ...Orally, casein peptides are well tolerated in infants and adults. Adverse effects reported in clinical trials did not occur more frequently than with placebo.

COCOA

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).

General ...Orally, rectally, and topically, glycerol seems to be well tolerated. Intravenously, glycerol may be unsafe.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, nausea, vomiting, dizziness, and headache.
Topically: Burning, irritation, and pruritus.
Intravenously: Hemolysis in patients with acute ischemic stroke.

Dermatologic ...Topically, glycerol has been reported to cause burning, irritation, and pruritus (93754,93756). Rectally, the regular administration of glycerol 50% enemas has been reported to cause generalized urticaria in at least two patients; in both patients, symptoms resolved after discontinuation (110019,110025).

Gastrointestinal ...Orally, glycerol can cause bloating, nausea, vomiting, thirst, and diarrhea (15,2475).

Hematologic ...Intravenously, glycerol has been reported to caused hemolysis in people treated for acute ischemic stroke (2480,2482).

Neurologic/CNS ...Orally, glycerol can cause mild headache and dizziness (15,2475).

General ...Orally, the whole fruit, as well as the seed, fruit, and leaf extracts, seem to be well tolerated. Topically, grape seed extracts seem to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, dry mouth, dyspepsia, headache, joint pain, and nausea.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis to grape skin has been reported.

Dermatologic ...Orally, mild hair thinning has been reported in a patient taking a specific grape leaf extract AS195 KG) (2538). Urticaria (hives) has also been reported with this same extract (53206). Cases of contact dermatitis have been reported in grape workers, including those working in California vineyards (53270,53272,53275).

Gastrointestinal ...Orally, abdominal pain and nausea have been reported with use of grape seed extract, but these effects typically occur at rates similar to placebo (9182,13162). In a case report of a 57-year-old man, intermittent nausea, vomiting, and diarrhea occurred over a 10-day period and improved once grape seed extract was stopped (96764). Gastrointestinal adverse effects have also been reported with use of a different grape seed extract (Entelon, Hanlim Pharm). However, the specific types of gastrointestinal effects were not described (100954). A specific grape leaf extract AS195 (Antistax, Boehringer Ingelheim Pharma GmbH & Co. KG) has reportedly caused flatulence, mild constipation, gastrointestinal discomfort, diarrhea, dyspepsia, dry mouth, and retching (2538,52985,53206). Diarrhea, gastrointestinal distress, indigestion, and aversion to taste have been reported with use of Concord grape juice (52972,53166,53175,53181,53199). Loose stools have been reported in a clinical trial of grape pomace (99270). Bowel obstruction caused by intact grapes and grape seeds has been described in case reports (53241,53284,53278). Excessive consumption of grapes, dried grapes, raisins, or sultanas might cause diarrhea due to laxative effects (4201).

Hematologic ...Orally, one case of leg hematoma following a minor trauma was reported in a person using grape leaf extract (2538). Also, one case of bruising was reported in a person drinking Concord grape juice daily for 2 weeks (52972).

Immunologic ...Orally, there is one report of an anaphylactic reaction to oral grape skin extract, which included urticaria and angioedema (4073).

Musculoskeletal ...Orally, musculoskeletal disorders, including back pain, have been reported with use of a specific grape leaf extract AS195 KG) (2538,53206). Joint pain and lumbago have been reported with use of grape seed extract, but these effects occur at rates similar to placebo (91541).

Neurologic/CNS ...Orally, headache has been reported with use of grape seed extract, but this effect occurs at rates similar to placebo (9182,91541). A specific grape leaf extract AS195 (Antistax, Boehringer Ingelheim Pharma GmbH & Co. KG) has reportedly caused dizziness, tiredness, headache, and sleep problems (2538,53206). As a class, nervous system adverse effects have been reported with use of a specific grape seed extract (Entelon, Hanlim Pharm). However, the specific types of adverse neurologic effects were not described (100954).

Ocular/Otic ...Orally, ocular adverse effects have been reported with use of a specific grape seed extract (Entelon, Hanlim Pharm). However, the specific types of ocular adverse effects were not described (100954).

Pulmonary/Respiratory ...Orally, nasopharyngitis and oropharyngeal pain have been reported with use of a specific grape leaf extract AS195 KG) (53206). Sore throat, cough, allergic rhinitis, and nasopharyngitis have been reported with use of grape seed extract, but these effects occur at rates similar to placebo (9182,91541). One case report describes a 16-year-old female who developed increased levels of immunoglobulin E (IgE) following skin-prick exposure to grape vine pollen, as well as positive test responses following bronchial and conjunctival provocation (53301). Reduced forced vital capacity has been described in California grape workers (53080,53081). Occupational eosinophilic lung was diagnosed in a grape grower with a history of asthma. Respiratory exposure to sulfites in grape was implicated as the cause of the adverse reaction (53285).

Other ...Orally, grape products can cause adverse effects due to contamination with pesticides or mycotoxins. Some evidence has shown that pesticides used in vineyards may remain on grape surfaces post-harvesting. For example, the fungicide folpet sprayed on grapevines has been shown to remain on the grape surface. Although there was minimal penetration of the epicuticular wax, it showed high resistance to washing (52935). Carbaryl has been identified in over 58% of juice samples collected in Canada. This pesticide reportedly occurred more frequently in grape than in other juices. However, estimates of short-term intake were below proposed acute reference doses (53003).
Ochratoxin A is a mycotoxin that is suspected to be nephrotoxic, teratogenic, hepatotoxic and carcinogenic and has been identified in grape juice, frozen grape pulps, and red and white wine sold in Rio de Janeiro, Brazil. However, the highest levels identified in grape products were lower than the established virtually safe dose of 5 ng/kg of body weight daily (53010,53004). Ochratoxin A has also been identified in red, but not white, grape juice marketed in Switzerland, Canada, and the U.S. (53292,53020).

General ...Orally, lecithin is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, fullness, and nausea.

Dermatologic ...Orally, lecithin can cause allergic skin reactions in people with egg or soy allergies (15705).

Gastrointestinal ...Orally, lecithin may cause abdominal pain, diarrhea, fullness, and nausea (5140,6243,14817,14822,14838,19204,59281).

Neurologic/CNS ...Orally, lecithin caused CNS complaints and agitation in one patient in a clinical trial (59261).

General ...Orally, sweet cherry is generally well tolerated.

Immunologic ...Orally, sweet cherry can cause allergic reactions in sensitive patients. These reactions can range from mucosal irritation to urticaria, angioedema, dyspnea, cough, and gastrointestinal symptoms (14057).

VANILLA

General ...Orally, vanilla is well tolerated when used in amounts commonly found in foods (4912). Orally and topically, vanilla has been associated with allergic responses including contact dermatitis. Workers preparing vanilla have reported headache, dermatitis, and insomnia, which is historically characterized as "occupational vanillism" (100502).

Dermatologic ...Workers preparing vanilla have reported dermatitis, associated with what is historically characterized as "occupational vanillism" (100502).

Immunologic ...Orally, vanilla resulted in eczematous reactions in children that had been diagnosed with atopic dermatitis (81981). Topically, vanilla has been shown to cause contact dermatitis when used as a lip salve (81988).

Neurologic/CNS ...Workers preparing vanilla have reported headache and insomnia, associated with what is historically characterized as "occupational vanillism" (100502).

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