Endurance Chocolate by Maine Natural Health

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Although there has been interest in using oral aspartic acid for athletic performance, there is insufficient reliable information about the clinical effects of aspartic acid for this purpose.
• Fatigue. Although there has been interest in using oral aspartic acid for fatigue, there is insufficient reliable information about the clinical effects of aspartic acid for this purpose.
• Muscle strength. It is unclear if oral aspartic acid is beneficial for muscle strength. Details: Preliminary clinical research shows that taking D-aspartic acid 3-6 grams orally daily for 1-3 months does not improve muscle strength when compared with placebo in resistance-trained males (94497,97576). The effect of D-aspartic acid in untrained males, or in any females, is not clear.
• Opioid withdrawal. Although there has been interest in using oral aspartic acid for opioid withdrawal, there is insufficient reliable information about the clinical effects of aspartic acid for this purpose. More evidence is needed to rate aspartic acid for these uses.

(Read more about ASPARTIC ACID)

POSSIBLY EFFECTIVE

• Athletic performance. In some adults, taking beta-alanine appears to improve some, but not all, measures of athletic performance. Beta-alanine appears to work better for exercises that lasts at least 1 minute in duration; however, many other factors likely alter efficacy, such as the type of exercise, the subject's training experience, and the dosing regimen. Details: Many small clinical trials have evaluated the effects of beta-alanine supplementation in untrained individuals, recreational athletes, and professional athletes in a variety of sports and activities, including running, cycling, swimming, basketball, football, soccer, rowing, water polo, wrestling, weight lifting, skiing, and others. However, the results of individual trials are conflicting. Furthermore, studies have included multiple endpoints that have been both lab-based, such as time to exhaustion, strength endurance, time trials, and power output, and field-based, such as performance times (18227,94333,94334,94335,94336,94337,94338,94339,94340,94341)(94342,94343,94345,94346,94347,94348,94349,97956,97958,97960)(97962,97969,97970,97971,97972,101027,101028,101029,101030,104144)(104145,106710,106711,106713,106717,106718,112794). Meta-analyses of clinical trials show that taking beta-alanine 2-6.4 grams orally daily for 3-12 weeks provides minor improvements in exercise capacity and performance when compared with control (18227,94357,106717). In one meta-analysis, exercise capacity improved by an average of approximately 3% when compared with placebo (18227). However, meta-analyses suggest that improvements in exercise performance are less than exercise capacity (18227,94357). The majority of this research has only included males. Preliminary clinical research assessing the effect of beta-alanine on exercise capacity in females has not consistently demonstrated a benefit. However, the validity of these studies is limited by small sample sizes (14611,94338,94339,94345,97957,97967,104144,112791). Preliminary clinical research also suggests that beta-alanine is more effective for short exercises, lasting at least 1 minute. Longer exercises, lasting more than 10 minutes, have not been well studied. In addition, the type of athlete and type of exercise most likely to benefit from beta-alanine supplementation is unclear (18227,94357,106717). Pooled analyses have not identified the most effective dose of beta-alanine; however, preliminary subgroup analyses suggest that prolonged supplementation of at least 3-6 weeks may be needed to gain benefits (94357,106717). There does not seem to be a relationship between the daily beta-alanine dose and exercise-related outcomes, although one analysis suggests outcomes may be related to the total cumulative dose; most studies have used a total daily dose of 2.4-6.4 grams (18227,94357,101026,101027,101028,101029,101030,106712,106717). The majority of studies have evaluated various marketed formulations of beta-alanine (Carnosyn, Natural Alternatives International; Sustained Release Beta-Alanine, Musashi; Balance 100% unflavored pure beta-alanine, Vitaco Health; Intra X cell, Athletics Edge Nutrition) (94333,94335,94336,94337,94339,94342,94346,94347,94348,94349)(101028,101029,101030,104144,106710,106711,106718). Beta-alanine has also been studied in combination with 1 additional ingredient, namely sodium bicarbonate or creatine. Preliminary clinical research in physically active or trained males shows that taking beta-alanine 6-6.4 grams orally daily for 4-6 weeks with sodium bicarbonate 300-500 mg/kg orally daily for 1-7 days does not increase exercise capacity or exercise performance while cycling or sprinting when compared with individual supplementation (97959,97964,97966,101028). In contrast, preliminary clinical research in male athletes participating in martial arts or rowing shows that taking beta-alanine with sodium bicarbonate modestly increases exercise performance when compared with either ingredient taken alone (97962,97963). Other preliminary clinical research in healthy, untrained males shows that taking beta-alanine 1.6 grams daily for 28 days with creatine 5 grams twice daily for 22 days, followed by four times daily for 6 days, modestly increases power output during cycling when compared with placebo or taking either supplement alone (97973). In another very small clinical study in trained military males, taking beta-alanine 6.4 grams daily for 28 days with creatine 0.3 grams/kg daily for the last 7 days improves leg muscle power but not anaerobic power or muscle strength when compared with beta-alanine plus placebo (112793). Beta-alanine has also been studied in combination with multiple other ingredients. Preliminary clinical research shows that taking a specific product containing beta-alanine, creatine monohydrate, arginine, alpha-ketoisocaproate, and leucine (NO-Shotgun) or a different product containing beta-alanine, L-histidine, and carnosine (BETAFOR3MAX, Martinez Nieto S.A.) for 28 or 7 days, respectively, also improves strength and power output when compared with placebo (34451,106714). However, another very small crossover clinical study in healthy males shows that taking 6 mg/kg of a multi-ingredient pre-workout supplement containing beta-alanine, L-tyrosine, L-citrulline maleate, arginine alpha-ketoglutarate, L-taurine, and caffeine 30 minutes prior to weight training does not increase bench press strength endurance when compared with an equivalent amount of anhydrous caffeine (111250). It is unclear if these effects are due to beta-alanine, other ingredients, or the combination.
• Physical performance. Preliminary clinical research shows that taking beta-alanine improves exercise capacity and fatigue, but not strength or exercise performance, in older adults. Details: Clinical research in older adults shows that taking beta-alanine 2.4-3.2 grams daily for 4-12 weeks increases exercise capacity and delays fatigue during exercise when compared with placebo (16442,97955,97965). In addition, preliminary clinical research in older adults shows that taking an oral nutritional supplement fortified with beta-alanine 0.8-1.2 grams twice daily for 12 weeks increases exercise capacity when compared with taking the oral nutritional supplement alone (97961). Taking beta-alanine 2.4 grams daily also minimizes the reduction of executive functioning after cycling in older adults when compared with placebo (97955). However, 2 clinical studies in older adults show that taking beta-alanine (Natural Alternatives International) 2.4-3.2 grams daily for 10-12 weeks with or without an endurance-based resistance-training program does not improve strength, power, fatigue, or performance when compared with the resistance training program alone or placebo (101031,112792).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral beta-alanine is beneficial for cognitive decline in older adults. Details: A small clinical study in older adults shows that taking beta-alanine 1200 mg twice daily for 10 weeks reduces symptoms of depression and might improve cognitive function in subjects with borderline or low cognitive function at baseline when compared with placebo. However, beta-alanine supplementation does not improve cognitive function in older adults with normal cognitive function at baseline and does not benefit mood, anxiety, or executive function when compared with placebo (112792).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral beta-alanine improves physical function in people with COPD. Details: A small clinical study in adults with COPD shows that taking beta-alanine (SR CarnoSyn, Natural Alternatives International, Inc) 800 mg four times daily for 12 weeks does not improve exercise capacity, muscle function, or physical activity when compared with placebo (112790).
• Cognitive function. Oral beta-alanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in trained military males shows that taking beta-alanine 6.4 grams daily for 28 days with creatine 0.3 grams/kg daily for the last 7 days modestly improves mathematical processing when compared to baseline, but not when compared with beta-alanine plus placebo. However, improvement from baseline was not found in the group taking beta-alanine plus placebo (112793).
• Exercise-induced muscle breakdown. It is unclear if oral beta-alanine improves muscle recovery after exercise. Details: Preliminary clinical research in untrained adults shows that taking beta-alanine 4.8 grams orally daily for 4 weeks does not improve muscle recovery after resistance exercises when compared with placebo (101026).
• Menopausal symptoms. Although there has been interest in using oral beta-alanine for menopausal symptoms, there is insufficient reliable information about the clinical effects of beta-alanine for this purpose.
• Obesity. It is unclear if oral beta-alanine improves body composition in adults. Details: A meta-analysis of several small clinical studies in active and sedentary adults shows that supplementing with beta-alanine 1.6-6.4 grams daily for 3-10 weeks does not reduce body mass, fat mass, body fat percentage, or free fat mass when compared with various controls. Subgroup analysis of dose, duration, and type of additional training did not change the results (112789).
• Sarcopenia. Although there has been interest in using oral beta-alanine for sarcopenia, there is insufficient reliable information about the clinical effects of beta-alanine for this purpose. More evidence is needed to rate beta-alanine for these uses.

(Read more about BETA-ALANINE)

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about COCOA)

POSSIBLY INEFFECTIVE

• Athletic performance. Most studies show that oral ribose is not beneficial for improving athletic performance. Details: Clinical studies in trained cyclists show that taking ribose in various dosing regimens, including 10 grams daily for 5 days, 8 grams four times over 36 hours, or a single dose of 3 grams with folate 150 mcg, does not improve anaerobic cycling performance when compared with dextrose, cellulose, or maltodextrin (15724,15727,15728). In trained rowers, taking ribose 10 grams daily for 8 weeks was less beneficial than taking dextrose 10 grams daily for improving rowing performance in time trials (15725). One small study in healthy adults with various levels of fitness shows that taking D-ribose 10 grams daily for 5 days does not improve anaerobic cycling performance when compared with dextrose. However, in individuals with the lowest level of fitness, defined as a lower peak oxygen uptake at baseline, D-ribose might improve power output when compared with dextrose (100680). Research in untrained individuals has also failed to show benefit. Taking ribose 4 grams four times daily for 6 days or a single small dose of ribose (2D-Ribose ATP, GNC) 625 mg did not increase maximal intermittent exercise performance or power output when compared with placebo (15723,15729). Limited research has evaluated ribose in combination with other ergogenic ingredients. One small study in resistance trained males shows that taking a combination supplement of ribose 2 grams, glutamine 3 grams, and creatine 5 grams daily for 8 weeks does not improve muscle strength, endurance, or body composition when compared with control (15726).
• McArdle disease. Oral ribose does not seem to improve exercise tolerance in patients with McArdle disease. Details: A very small study shows that taking ribose 60 grams daily for 7 days does not improve exercise tolerance in patients with McArdle disease when compared with placebo (5678).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Chronic fatigue syndrome (CFS). It is unclear if oral ribose is beneficial in patients with CFS. Details: A small clinical study shows that taking a ribose supplement (CORvalen, Valen Labs) 5 grams three times daily might improve energy, sleep, and sense of well-being when compared to baseline in patients with CFS with or without fibromyalgia (15218). The validity of these findings is limited by the lack of a comparator group.
• Cognitive function. It is unclear if oral ribose is beneficial for improving cognition. Details: A small clinical study in healthy adults shows that taking D-ribose 1 gram twice daily 1 week before experimentation, in addition to 1 gram supplemental doses on the experimentation day, does not improve performance during fatigue-inducing mental tasks when compared with placebo (37735). This finding is limited because the dose of D-ribose may have been too low to produce an effect.
• Congestive heart failure (CHF). It is unclear if oral ribose is beneficial in patients with CHF. Details: A very small clinical study in patients with CHF shows that taking ribose 5 grams three times daily for 3 weeks does not affect left ventricular ejection fraction, but does seem to improve quality of life, when compared with placebo (15730). Another very small clinical study in patients with NYHA class III-IV heart failure shows that taking ribose 5 grams three times daily for 8 weeks might improve ventilatory efficiency and oxygen uptake when compared with baseline (71601). This second study is limited by a lack of placebo control group.
• Coronary artery bypass graft (CABG) surgery. Although there is interest in using oral ribose for improving recovery after CABG, there is insufficient reliable information about the clinical effects of ribose for this condition.
• Coronary heart disease (CHD). It is unclear if oral ribose is beneficial for improving exercise tolerance in patients with CHD. Details: A small clinical trial in patients with CHD shows that taking ribose 60 grams daily by mouth for 3 days increases time to onset of moderate angina and time to ST depression during treadmill walking exercise testing when compared with placebo (5664). Another small clinical trial in patients with CHD taking part in a physical exercise program shows that taking a combination product containing D-ribose 2.5 grams, creatine 1 gram, thiamine 0.33 mg, and vitamin B6 0.42 mg twice daily for 2 weeks, then once daily for 1 month, improves measures of exercise tolerance when compared with placebo (103291). However, it is unclear if these findings are due to D-ribose, other ingredients, or the combination.
• Fibromyalgia. It is unclear if oral ribose is beneficial in patients with fibromyalgia. Details: A small clinical study shows that taking a ribose supplement (CORvalen, Valen Labs) 5 grams three times daily might improve energy, sleep, sense of well-being, and pain when compared to baseline in patients with fibromyalgia with or without chronic fatigue syndrome (CFS) (15218). The validity of these findings is limited by the lack of a comparator group.
• Heart failure. It is unclear if oral ribose is beneficial in patients with heart failure with preserved ejection fraction. Details: A small clinical study of patients with heart failure with preserved ejection fraction shows that taking ribose powder 15 grams daily for 12 weeks increases Kansas City Cardiomyopathy Questionnaire scores, vigor scores, and ejection fraction while decreasing biomarkers associated with disease severity and worsened prognosis, including B-type natriuretic peptides and lactate/adenosine triphosphate ratio, when compared with placebo. However, ribose supplementation did not lead to improvements in walking distance (108959).
• Muscle soreness. It is unclear if oral ribose is beneficial for preventing muscle soreness from exercise. Details: A small clinical study in healthy untrained adult males shows that taking a solution containing D-ribose 15 grams one hour before and one hour after performing 140 plyometric frog hops, and another 3 doses every 12 hours afterwards, seems to reduce muscle soreness when compared with placebo (105899).
• Restless legs syndrome (RLS). Although there is interest in using oral ribose for RLS, there is insufficient reliable information about the clinical effects of ribose for this condition.
• Seizures. Although there is interest in using oral ribose for seizures, there is insufficient reliable information about the clinical effects of ribose for this condition. More evidence is needed to rate ribose for these uses.

(Read more about RIBOSE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. It is unclear if oral stevia is beneficial in patients with diabetes; the available research is conflicting. Details: A small single-dose study shows that taking stevia leaf extract 1000 mg, standardized to contain 91% stevioside, along with a meal reduces postprandial glucose levels by 18% in adults with type 2 diabetes when compared with a starch control (11812). However, clinical research in patients with type 1 or type 2 diabetes shows that taking stevioside 250 mg three times daily for 3 months does not affect blood glucose levels or glycated hemoglobin (HbA1C) when compared with baseline (16705). Also, a small clinical study in patients with diabetes shows that drinking 200 mL of black tea, sweetened with stevia extract 2%, three times daily for 8 weeks does not affect glycemic indices when compared with drinking tea sweetened with sucralose (103695).
• Hypertension. It is unclear if oral stevia is beneficial in patients with hypertension; the available research is conflicting. Details: Some clinical research in patients with mild to moderate hypertension shows that taking stevioside, a constituent of stevia, 750-1500 mg in three divided doses daily reduces systolic blood pressure by 10-14 mmHg and diastolic blood pressure by 6-14 mmHg within one week to three months of treatment initiation and continuing for up to 2 years (11809,11810). However, other clinical research in patients with mild hypertension shows that taking stevioside in doses up to 15 mg/kg daily does not significantly reduce blood pressure (16706).
• Obesity. It is unclear if oral stevia is beneficial in patients with obesity; the available research is conflicting. Details: Although a small clinical study in healthy adults shows that drinking water with stevia (Truvia) 245 ppm as a single dose reduces appetite and energy intake when compared with drinking water alone (103697), other small, single-dose studies have shown no effect of stevia 15.3 mg or 1 gram as a single dose on satiety, energy intake, or fullness when compared with either water alone or a non-nutritive sweetener (103696,110124). A small clinical study in healthy adults shows that taking an aqueous stevia leaf extract (SweetLeaf) twice daily for 12 weeks does not affect body weight, compared with an increase in weight in the control group. This suggests that stevia extract may have attenuated weight gain in this study (106458). More evidence is needed to rate stevia for these uses.

(Read more about STEVIA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 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.

(Read more about SWEET CHERRY)

POSSIBLY EFFECTIVE

• Athletic performance. Regular consumption of whey protein in conjunction with exercise may improve muscle strength and performance. However, inconsistent consumption of whey protein, as well as intake of whey protein without concomitant exercise, may not be beneficial. Details: Most clinical research shows that taking whey protein 1.2-1.5 grams/kg or 30-33 grams daily in combination with strength training for 6-21 weeks can increase lean body mass, strength, and muscle hypertrophy in healthy young adults (16728,16729,16748,46552,85765,85910,91806,96025,102173). Higher doses of whey protein, such as 46-77 grams daily, have also been shown to increase strength when combined with athletic training (98886,98888). Some clinical research shows that whey protein hydrolysate (Lacprodan HYDRO.365, Arla Food Ingridiens Group P/S) twice daily for 1 week may slightly improve running speed (91793). However, less frequent intake or lower doses of whey protein do not seem to be beneficial for muscle strength. Some clinical research in middle-aged males shows that taking whey protein 35 grams three times weekly with resistance training for 14 weeks does not improve strength or muscle mass when compared with placebo (46736,85893). A small clinical study in trained males shows that taking whey protein 25 grams daily has no effect on body mass or strength after 2 weeks of detraining and 4 weeks of retraining when compared with maltodextrin (96021). Also, consuming whey protein without concomitant exercise does not seem to improve body composition or strength. Some clinical research shows that whey protein does not improve muscle mass or strength in obese postmenopausal patients who are losing weight through diet without exercise (98889). Some research has compared whey protein to other types of protein. A meta-analysis of preliminary clinical research, as well as individual clinical studies, show that whey protein is similarly beneficial to soy, beef, chicken, and dairy (casein with whey) protein for improving muscle strength (85941,98871,98888,105591). However, the validity of these findings is limited by the small size and high heterogeneity of the studies.

POSSIBLY INEFFECTIVE

• Chronic obstructive pulmonary disease (COPD). Oral whey protein does not seem to improve COPD symptoms. Details: Clinical research in adults with COPD shows that taking a specific whey protein supplement (ImuPower) 12 grams twice daily for 6 weeks can improve shortness of breath, but not lung function, exercise tolerance, or quality of life, when compared with placebo (86302). Other clinical research shows that taking a pressurized whey protein supplement 20 grams daily for 16 weeks, in combination with strength training for weeks 8-16, does not improve exercise tolerance, lung function, or muscle function when compared with placebo (86025).
• Osteoporosis. Oral whey protein does not seem to improve bone mineral density in older adults. Details: Clinical research shows that taking whey protein 30-45 grams daily for up to 2 years does not improve bone density when compared with a low-protein placebo in postmenopausal patients and males over 70 years of age (86074,91796). Taking whey protein 20-60 grams daily for 36 weeks also does not improve bone density when compared with an isoenergetic placebo in overweight or obese adults undergoing an exercise program (96027). The effect of whey protein in patients with osteoporosis has not been evaluated.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral whey protein is beneficial for age-related cognitive impairment. Details: Preliminary clinical research in older adults with subjective cognitive decline shows that taking whey peptide 1 gram for 12 weeks does not improve memory, executive functioning, or attention when compared with placebo. However, in a subgroup of patients with high levels of fatigue, whey peptide modestly improved memory (98885).
• Asthma. It is unclear if oral whey protein is beneficial in children with asthma. Details: A very small clinical study in children with asthma shows that taking a specific type of whey protein (HMS 90, Immunotec Inc.) 20 grams daily for 30 days does not improve lung function when compared to baseline (85833). The validity of this finding is limited by the lack of a comparator group.
• Atopic dermatitis (eczema). It is unclear if consuming infant formula containing whey protein reduces the risk of developing eczema. Details: A high-quality meta-analysis of small clinical studies shows that use of infant formula containing hydrolyzed whey protein for 4-6 months is no better than standard milk formula for reducing the risk of eczema (105585). This is in contrast to older meta-analyses that found benefit after consumption of fully or partially hydrolyzed whey protein (85987,86007,86048). However, these older publications had notable conflicts of interest and did not include small negative studies (105585). In 2011, the US Food and Drug Administration (FDA) allowed a qualified health claim in healthy infants with a family history of allergy who are not solely breastfed. It stated that feeding a formula of 100% partially hydrolyzed whey protein instead of formula containing intact cow's milk proteins from birth up to 4 months of age may reduce the risk of atopic dermatitis throughout 1-3 years of age. However, the FDA has concluded that there is very little scientific evidence to support this claim (102311).
• Atopic disease. It is unclear if consuming infant formula containing whey protein reduces the risk of developing atopic disease. Details: A high-quality meta-analysis of small clinical studies shows that use of infant formula containing hydrolyzed whey protein for 4-6 months is no different than standard milk formula for reducing the risk of atopic disease. However, there was a non-significant trend to reduced risk in the hydrolyzed whey protein group (105585). This finding conflicts with older meta-analyses which found benefit with hydrolyzed whey protein formula (85987,86007). However, these older publications had notable conflicts of interest and did not include small negative studies (105585).
• Cystic fibrosis. It is unclear if oral whey protein is beneficial for children or adults with cystic fibrosis. Details: A small clinical study in patients with cystic fibrosis shows that taking pressurized whey protein, 20 grams in children and 40 grams in adults, daily for 28 days, improves lung function in children, but not adults, when compared with baseline (85995). The validity of this finding is limited by the lack of a comparator group.
• Diabetes. It is unclear if oral whey protein is beneficial for improving glycemic control in people with type 2 diabetes. Details: A small clinical study in patients with well-controlled diabetes shows that consuming a 220 kcal drink containing whey protein concentrate 50 grams (Beit Haemek Advanced Technologies, Beit Haemek) before a meal lowers blood glucose levels by 28% and increases insulin levels in the first 3 hours after a meal when compared with drinking water (91795). However, whey protein does not seem to have long-term benefit on glycemic control when added to an exercise regimen. Another small clinical study in middle-aged males with type 2 diabetes shows that adding 20 grams of whey protein daily for 10 weeks to high-intensity mixed-mode interval training (MMIT) does not further improve glycemic control or body composition when compared to MMIT with placebo (98883).
• Exercise-induced asthma. It is unclear if oral whey protein is beneficial for exercise-induced asthma. Details: A small clinical study in patients with exercise-induced asthma shows that taking whey protein 30 grams daily for 10 days improves lung function when compared to baseline (85791). The validity of this finding is limited by the lack of a comparator group.
• Exercise-induced muscle damage. It is unclear if oral whey protein is beneficial for attenuating exercise-induced muscle damage; evidence is conflicting. Details: A meta-analysis of small heterogeneous clinical studies in trained and untrained adults shows that supplementation with a median dose of whey protein 25 grams (range 20-120 grams) given after and/or before exercise modestly improves muscle recovery measured over 3 days when compared with control (98881). Individual studies included in the analysis used whey protein 1.5 grams/kg daily for up to 2 weeks (86044), and whey protein isolate or whey protein hydrolysate (NatraPro or NatraBoost XR, MG Nutritionals) 25 grams three times in 24 hours (85915). Other small studies have not found benefit, but it is unclear if they were adequately powered. One small clinical study in healthy untrained males shows that taking whey protein 36.6 grams daily, starting 7 days before and continuing until 4 days after arm exercise, does not prevent muscle soreness over 5 days or attenuate reductions in strength (96024). Another small study in untrained healthy males shows that taking whey protein isolate (biPro, Eden Prairie) 0.3 grams/kg three times daily for 5 days does not reduce self-reported delayed onset muscle soreness, but may reduce creatine kinase, a biomarker of muscle damage, when compared with water (104758). Whey protein may not be beneficial for recovery from exercise in trained athletes. Small clinical studies show that consuming a whey protein beverage before or after exercise does not improve muscle recovery for trained adult and adolescent athletes when compared with a carbohydrate or non-caloric control (86303,91799,105592).
• Hepatitis. It is unclear if oral whey protein is beneficial for hepatitis. Details: A small clinical study in patients with chronic hepatitis B shows that taking a specific type of whey protein (Immunocal) 12 grams twice daily for 12 weeks can reduce liver transaminase levels and can increase glutathione (GSH) levels when compared with baseline. However, whey protein supplementation does not seem to improve liver function in patients with chronic hepatitis C (85687). The validity of these findings is limited by the lack of a comparator group.
• HIV/AIDS. It is unclear if oral whey protein is beneficial for improving immune function in children with HIV/AIDS. Details: One small clinical study in children with rapidly progressive HIV infection shows that taking whey protein at levels corresponding to 20% to 50% of total required protein for 4 months does not affect CD4 or CD8 cell count or the ratio of CD4+/CD8+ when compared with baseline. However, the occurrence of acute co-infections might be reduced with whey protein supplementation when compared with control (85781).
• HIV/AIDS-related wasting. Although oral whey is an adequate source of protein, it is unclear if it is better than other protein sources for reducing HIV/AIDs-related wasting. Details: A small open-label clinical study in malnourished patients with HIV shows that taking whey protein (dose unspecified) daily for 14 weeks increases muscle and fat mass when compared with baseline (85693). The validity of these findings is limited by the lack of a comparator group. Another small study in patients with HIV, stable weight, and a history of unintentional weight loss shows that taking whey protein 40 grams daily for 12 weeks does not affect weight or muscle mass when compared with taking an isocaloric control (85921). These study findings are limited because they cannot be generalized to patients with active weight loss or wasting. Another limitation is the higher dropout rate in the whey protein group due to gastrointestinal adverse events.
• Hyperlipidemia. It is unclear if oral whey protein is beneficial for lowering cholesterol levels. Details: A very small clinical study in overweight males with hyperlipidemia shows that taking whey protein 26.6 grams daily while participating in a resistance training program for 12 weeks reduces total cholesterol levels when compared with baseline but not when compared with placebo (85941). A meta-analysis of small heterogeneous clinical studies in healthy adults, as well as those with obesity and/or mild hypertension, shows that consuming whey protein alone or with other interventions seems to reduce lipid levels when compared with control (105586). However, most included studies were in patients without hyperlipidemia; it is unclear if whey protein is beneficial in patients with hyperlipidemia. Furthermore, these findings are limited by the variability in whey protein dosing, study duration, and patient population.
• Hypertension. It is unclear if oral whey protein reduces blood pressure. Details: Preliminary clinical research shows that drinking a beverage containing whey protein 2.6 grams daily for 12 weeks does not lower blood pressure in patients with mild hypertension when compared with placebo (85835). Also, taking whey protein 28 grams twice daily in water for 8 weeks reduces 24-hour systolic and diastolic blood pressure by 2.9 mm Hg and 2 mmHg, respectively, when compared with maltodextrin or casein in adults with mild hypertension and prehypertension. There were also improvements in endothelial function (96019).
• Mitochondrial myopathies. It is unclear if oral whey protein improves symptoms in patients with mitochondrial myopathies. Details: A small clinical study in individuals with mitochondrial diseases shows that taking a whey protein supplement 10 grams daily for one month does not improve muscle strength or quality of life when compared with placebo (85984).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral whey protein improves NASH. Details: A small clinical study in patients with untreated NASH shows that taking whey protein 20 grams daily for 12 weeks can reduce liver function tests, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and reduce hepatic macrovesicular steatosis when compared with baseline (85961). The validity of these findings is limited by the lack of a comparator group.
• Obesity. It is unclear if oral whey protein is beneficial for weight loss when used without dietary modifications. Adding whey protein to a calorie-restricted diet or an exercise regimen does not seem to improve weight loss. Details: Most research in overweight and obese individuals shows that taking whey protein along with a low-calorie diet and/or in addition to an exercise program does not further increase weight loss when compared with the low-calorie diet or exercise alone (85897,86069,86130,91794,91798,91802,96027,102172). However, a small clinical study in patients who have regained weight after bariatric surgery shows that following a low-calorie diet and taking whey protein 0.5 grams/kg daily for 16 weeks reduces body weight by about 2 kg and fat mass by about 3 kg when compared with following a low-calorie diet alone (96022). When whey protein is taken without diet modifications, studies have yielded conflicting results. One small clinical study in overweight and obese adults shows that taking whey protein isolate 27 grams twice daily for 12 weeks does not reduce body weight when compared with a glucose control (86011). However, another small clinical study in overweight and obese adults shows that taking whey protein concentrate 52 grams daily for 23 weeks reduces weight by 1.8 kg and fat by 2.4 kg when compared with a carbohydrate control, but is no better than taking soy protein isolate 52 grams (86077). In contrast, a small clinical study in overweight males shows that taking whey protein concentrate 65 grams before lunch daily for 12 weeks decreases calorie intake and reduces weight by about 1 kg when compared with taking soy protein isolate 60 grams (91801). In contrast to adults, supplementation with whey protein might increase weight in adolescents. A clinical study in overweight adolescents shows that consuming 1 liter of a milk-based whey protein drink daily for 12 weeks increases weight and body mass index when compared with a water control (86144).
• Parkinson disease. It is unclear if oral whey protein improves symptoms of Parkinson disease. Details: Clinical research in a small group of patients shows that taking a specific type of whey protein isolate (HMS 90/Immunocal) 10 grams twice daily for 6 months does not improve symptoms of Parkinson disease when compared with placebo (96026). However, this study may have been inadequately powered to detect a difference between groups.
• Polycystic ovary syndrome (PCOS). It is unclear if oral whey protein improves symptoms and metabolic effects of PCOS. Details: One small clinical study in patients with PCOS shows that taking 240 kcal as a nutritional supplement containing pure whey protein 96% daily, in addition to a calorie-restricted diet for 2 months, reduces body weight, fat mass, and cholesterol and apolipoprotein B levels when compared with a simple sugar control supplement. However, the whey protein supplement does not improve glucose or insulin levels, and seems to decrease high-density lipoprotein (HDL) cholesterol levels (85912). The validity of this study is limited by its small size and a significant dropout rate.
• Polymyalgia rheumatica. It is unclear if oral whey protein improves muscle function in patients with polymyalgia rheumatica. Details: A small clinical study in patients with polymyalgia rheumatica shows that taking a whey protein-enriched dairy product twice daily for 8 weeks does not improve lower limb muscle function, walking speed, chair stand test performance, peak jump power, or peak jump force when compared with a regular dairy product (Play, Valio Ltd.) (86075).
• Psoriasis. It is unclear if oral whey protein improves psoriasis. Details: A small clinical study in patients with stable psoriasis shows that taking a specific whey protein extract product (Dermylex, Advitech, Inc.) 5 grams daily for 8 weeks modestly decreases symptom severity when compared with placebo (85885).
• Sarcopenia. Research on the use of oral whey protein in older adults with sarcopenia is conflicting. Details: Small clinical studies in trained older females show that consuming whey protein 35 grams three times weekly for 12 weeks, either before or after resistance training, modestly increases skeletal muscle mass, strength, and functional capacity when compared with resistance training and insufficient protein intake (98887,98890). Research on the use of whey supplementation without exercise is conflicting. A small clinical study in older adults with low muscle mass living in China shows that taking whey, or a whey-soy protein blend, 16 grams daily for 6 months slightly attenuates muscle loss when compared with no intervention (105603). However, a clinical study in healthy, active older adults living in Denmark shows that taking whey protein hydrolysate 20 grams twice daily does not increase muscle size or strength when compared with a carbohydrate control (105593). This finding may not be generalizable to frail adults or those with existing sarcopenia. Whey protein with or without exercise has shown benefit when used in combination with other nutrients. Specifically, whey protein 60 grams has been used with creatine 5 grams, calcium 800 mg, vitamin D 1000 IU, and omega-3 fatty acids 3 grams (Infinit Nutrition) for 6 weeks (96016). A beverage with leucine-enriched whey protein 20 grams has been used in combination with vitamin D 800 IU (Nutricia Advanced Medical Nutrition) daily for 6 weeks (96017). Another beverage containing whey protein 20 grams and vitamin D 800 IU has been used daily for 6 months (98882).
• Sepsis. It is unclear if oral whey protein is beneficial in children with sepsis. Details: A very small clinical study in long-term intensive care pediatric patients shows that taking a specific whey protein supplement (Beneprotein) 0.3 grams/kg daily for up to 28 days has a similar effect on the time to onset and the rate of hospital-acquired infection or sepsis when compared with taking a combination of zinc, selenium, glutamine, and metoclopramide. It is not clear how these results compare to patients receiving no supplementation (86095). More evidence is needed to rate whey protein for these uses.

(Read more about WHEY PROTEIN)

LIKELY SAFE ...when used orally in amounts found in foods (94500).

POSSIBLY SAFE ...when aspartic acid is used orally and appropriately, short-term. D-aspartic acid 3-6 grams daily has been used with apparent safety in clinical trials for up to 3 months (94497,97576). L-aspartic acid has been used in doses up to 8 grams daily, short-term, without reports of adverse effects (94500).

CHILDREN: POSSIBLY UNSAFE
when aspartic acid is used orally in infants. In rodents, aspartic acid given orally within a few days of birth caused neuronal necrosis in the hypothalamus. This adverse effect was not seen in nonhuman newborn primates and has not been assessed in humans. Until more data is available, the Institute of Medicine (IOM) and the Food and Nutrition Board advise that aspartic acid be avoided in infants (94500). There is insufficient reliable information available about the use of aspartic acid supplements in children and adolescents; avoid using in amounts exceeding those found in food.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (94500).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when aspartic acid is used orally. In rodents, aspartic acid given orally within a few days of birth caused neuronal necrosis in the hypothalamus. This adverse effect was not seen in nonhuman newborn primates and has not been assessed in humans. Until more data is available, the Institute of Medicine (IOM) and the Food and Nutrition Board advise that pregnant or breast-feeding women avoid the use of aspartic acid (94500).

(Read more about ASPARTIC ACID)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Oral beta-alanine, including a specific commercial product (CarnoSyn, Natural Alternatives International), has been used with apparent safety in doses up to 6.4 grams daily for 12 weeks in younger adults (14611,16025,16439,16441,18227,94357,97972,101028,101029,104144,106717), and up to 3.2 grams daily for 12 weeks in adults aged 55 years and older (16442,97955,97961,97965).

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

(Read more about BETA-ALANINE)

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

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

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

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

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

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

(Read more about COCOA)

LIKELY SAFE ...when used in amounts commonly found in food. Consuming ribose up to 36 mg/kg daily from food sources is considered safe by the European Food Safety Authority (103292). ...when used orally and appropriately, short-term (15218,15723,15724,15725,15726,15727,15728,15729,15730). Ribose has been used safely at doses up to 15 grams daily for up to 12 weeks (15218,15725,15727,15730,71601,100680,103291,108959). ...when used intravenously and appropriately, short-term (5662,5663,5676,5680,71603). There is insufficient reliable information available about the safety of ribose when used long-term.

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

(Read more about RIBOSE)

LIKELY SAFE ...when certain stevia constituents, including stevioside and rebaudiosides A, D, and M, are used orally as sweeteners in foods. These constituents have generally recognized as safe (GRAS) status in the US for this purpose (16699,16700,16702,16705,16706,108049). The stevia constituent stevioside has been safely used in doses of up to 1500 mg daily for 2 years (11809,11810,11811). There is insufficient reliable information available about the safety of whole stevia or stevia extracts when used orally. The European Food Safety Authority (EFSA) has determined that the acceptable intake of steviol glycosides is 4 mg/kg daily (106456); however, it is unclear how this relates to the use of whole stevia or stevia extract.

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

(Read more about STEVIA)

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.

(Read more about SWEET CHERRY)

LIKELY SAFE ...when used orally and appropriately. Whey protein up to 30 grams has been safely used in clinical trials for up to 6 months (4930,16728,16729,105587).

CHILDREN: LIKELY SAFE
when used orally and appropriately as a dietary protein in food or infant formula. Hydrolyzed whey protein-based formula has been safely used in infants for up to 6 months in clinical trials (4927,105585,105594).

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

(Read more about WHEY PROTEIN)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking ribose in combination with antidiabetes drugs might increase the risk of hypoglycemia.  Details In clinical research, ribose decreases serum glucose levels in a dose-dependent manner (5667,92891).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ribose with insulin could increase the hypoglycemic effect of insulin.  Details In clinical pharmacokinetic studies, oral administration of ribose modestly increased serum insulin levels (5667,92891).

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ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, stevia might increase the risk for hypoglycemia when combined with antidiabetes drugs.  Details Preliminary clinical research in patients with type 2 diabetes suggests that taking a single dose of stevia extract 1000 mg reduces postprandial blood glucose levels when taken with a meal (11812). However, other clinical research in patients with type 1 or type 2 diabetes suggests that taking stevioside 250 mg three times daily does not significantly affect blood glucose levels or glycated hemoglobin (HbA1C) after three months of treatment (16705).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining stevia or stevia constituents with antihypertensive agents might increase the risk of hypotension.  Details Stevia extract and stevioside might lower blood pressure in patients with hypertension (3745,3747,5031,11809,11810). However, other clinical research suggests that stevioside does not significantly lower blood pressure in patients with hypertension (16706).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, stevia might decrease clearance and increase levels of lithium.  Details Animal research suggests that stevia extracts might have diuretic activity (3746,3747). Theoretically, increased reabsorption of lithium along with sodium might reduce excretion and increase levels of lithium.

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BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, whey protein might reduce the absorption of bisphosphonates.  Details Whey protein contains minerals such as calcium that bind bisphosphonates in the gut (9,12937). Advise patients to take bisphosphonates at least 30 minutes before whey protein, but preferably at a different time of day.

LEVODOPA Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, whey protein might decrease levodopa absorption.  Details Small clinical studies show that concomitant ingestion of protein or high doses of leucine or isoleucine (100 mg/kg) and levodopa can exacerbate tremor, rigidity, and the "on-off" syndrome in patients with Parkinson disease (3291,3292,3293,3294,4944).

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, whey protein might decrease quinolone absorption.  Details Whey protein contains minerals, such as calcium, that can bind to quinolones in the gut (9,10339). To avoid this interaction, advise patients to take oral quinolones at least 2 hours before or 4-6 hours after whey protein.

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, whey protein might decrease tetracycline absorption.  Details Whey protein contains minerals, such as calcium, that bind to tetracyclines in the gut (9,1843). To avoid this interaction, advise patients to take oral tetracyclines at least 2 hours before or 4-6 hours after whey protein.

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General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

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General ...Orally, beta-alanine seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Flushing, paresthesia.

Gastrointestinal ...While rare, digestion problems have been reported with oral beta-alanine use (94341).

Neurologic/CNS ...Orally, beta-alanine can cause a dose-dependent feeling of pins and needles (paresthesias) along with skin flushing (16438,94333,94335,94338,94341,94342,94349,101028,101029,106711). This generally starts on the scalp within 20 minutes of the dose, spreading to most of the body, and lasting for about an hour. This was described as severe at a dose of 40 mg/kg, tolerable at a dose of 20 mg/kg, and very mild at a dose of 10 mg/kg. At the lowest dose it only occurred in 25% of subjects (16438). In some studies, beta-alanine has been given as frequently as 8 times per day so that each dose can be kept below 10 mg/kg (16438,16439). Other clinical research shows that taking beta-alanine in a tablet formulation eliminates the presence of parasthesias at a dose of 1.6 grams when compared with a solution made from powdered beta-alanine. This effect may be due to delayed absorption (97974,97975). Although paresthesias still occur with sustained-release formulations, their presence is less frequent when compared with immediate-release formulations (101029).

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

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

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

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

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

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

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

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General ...Orally and intravenously, ribose is generally well-tolerated for up to 1 month.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal discomfort, headache, hypoglycemia, nausea.
Intravenously: Hypoglycemia.

Endocrine ...Orally, ribose can decrease blood glucose levels (5667,92891). In one pharmacokinetic study, fasting plasma glucose declined after single ribose doses of 2.5-10 grams. At all doses, serum glucose returned to near normal 2 hours post-administration but remained slightly below pre-dose levels for up to 5 hours. One case of symptomatic hypoglycemia 70 minutes post-dose was reported in a 53 kg female who took ribose 10 grams. The reaction was considered mild; however, specific blood glucose levels were not reported (92891).
Intravenously, ribose has been reported to cause hypoglycemia, increased serum insulin levels, and decreased serum phosphate (5650,5662,5663,5676).

Gastrointestinal ...Orally, ribose can cause diarrhea, gastrointestinal discomfort, and nausea (5664,5676,15218,92891). In one study, lowering the dose of ribose resolved the nausea (15218).

Neurologic/CNS ...Orally, ribose can cause headache (5664,92891). It has also been reported to cause a hyperanxious feeling, lightheadedness, increased appetite, and mild anxiety (15218). In one study, lowering the dose of ribose resolved the feeling of anxiety (15218).

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General ...Orally, stevia and steviol glycosides appear to be well tolerated. Most minor adverse effects seem to resolve after the first week of use.
Most Common Adverse Effects:
Abdominal bloating, dizziness, headache, myalgia, nausea, and numbness.
Serious Adverse Effects (Rare):
Allergic reactions.

Gastrointestinal ...Orally, stevia and steviol glycosides such as stevioside, can cause gastrointestinal adverse effects such as abdominal fullness and nausea. However, these generally resolve after the first week of use (11809,11810).

Immunologic ...Theoretically, stevia might cause allergic reactions in individuals sensitive to plants in the Asteraceae/Compositae family (11811). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.

Musculoskeletal ...Orally, stevia and steviol glycosides may cause myalgia, but this generally resolves after the first week of use (11809,11810).

Neurologic/CNS ...Orally, stevia and steviol glycosides may cause headache, dizziness, and numbness (11809,11810).

(Read more about STEVIA)

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).

(Read more about SWEET CHERRY)

General ...Orally, whey protein is generally well tolerated.
Most Common Adverse Effects:
Orally: Acne, bloating, cramps, diarrhea, fatigue, headache, nausea, reflux, reduced appetite, and thirst. Most adverse effects are dose-related.

Cardiovascular ...In one case report, use of an unclear quantity of whey protein over one month was thought to be probably responsible for the development of coronary embolism in three coronary arteries in a 33-year-old male with no history of atherosclerosis risk factors. The patient required treatment with intravenous glycoprotein IIb/IIIa inhibitor and heparin (96023).

Dermatologic ...Orally, whey protein has been reported to trigger the onset or worsening of acne. Multiple case reports in teenagers and young adults have associated intake of whey protein with the development of acne or the worsening of existing acneiform lesions. In these reports, the discontinuation of whey protein was typically associated with the clearance of acne lesions. In some cases, patients who were unresponsive to acne treatments while using whey protein became responsive after whey protein discontinuation (103965,103970,103971). Cow's milk, which is comprised of 20% whey protein, is also thought to exacerbate acne. It is theorized that this effect may be due to the growth factor and alpha-lactalbumin content of whey protein (103971,103982).

Gastrointestinal ...Orally, whey protein, especially in higher doses of 2. 3-6.5 grams/kg daily, may cause increased bowel movements, nausea, thirst, bloating, esophageal reflux, cramps, and reduced appetite (2640,85961,85702,86043,86074,86075,86084,86089,86095).

Hepatic ...In two case reports, acute cholestatic liver injury occurred after consumption of the combination of whey protein and creatine supplements (46701,90319).

Musculoskeletal ...In one case report, a 26-year-old male experienced fasciitis, or swelling of the forearms, hands, and legs, after consuming the supplement Pure Whey (85895).

Neurologic/CNS ...Orally, high doses of whey protein may cause tiredness or fatigue and headache (2640). Mild drowsiness has also been reported (86089,86092,86124).

(Read more about WHEY PROTEIN)