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POSSIBLY INEFFECTIVE

• Night vision. Most research suggests that oral bilberry does not improve night vision in healthy individuals. Details: There is contradictory evidence about the effectiveness of bilberry for improving night vision; however, much of the research is of poor quality. In general, the most rigorous research shows that bilberry is not effective for improving night vision in healthy individuals (8139,9739,14280,35446). Whether bilberry can improve night vision in patients with night blindness is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of elderly Norwegian males with subjective cognitive impairment shows that drinking 330 mL of bilberry and red grape juice twice daily for 9 weeks does not improve measures of memory or motor skills when compared with placebo (110641).
• Age-related macular degeneration (AMD). Although there has been interest in using oral bilberry for AMD, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Asthenopia (eye strain). Small clinical studies suggest that oral bilberry fruit extract may improve objective measures of asthenopia, but it is unclear if oral bilberry improves subjective symptoms of asthenopia. Details: Two small clinical studies in adults who report general eye strain or those who look at computer or other display screens at work for long periods of time show that taking bilberry-derived anthocyanins 43.2 mg daily for 6 weeks or bilberry extract 240 mg daily for 12 weeks improves objective measures of eye strain after staring at computer screens when compared with placebo (103190,104195). However, bilberry extract did not improve subjective measures of eye strain in the study that evaluated these outcomes (104195). This study may have been underpowered to detect significant differences between groups. Bilberry has also been evaluated in combination with other ingredients for improving eye strain. A small clinical trial in patients with eye strain shows that a combination of fish oil, lutein, and bilberry extract containing bilberry anthocyanidins 59 mg, taken daily for 4 weeks, reduces dry eye, lower back pain, shoulder stiffness, and stuffy head when compared with placebo (35470). It is unclear if these effects are due to bilberry, other ingredients, or the combination.
• Atherosclerosis. Although there has been interest in using oral bilberry for atherosclerosis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Cataracts. Although there has been interest in using oral bilberry for cataracts, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Chronic venous insufficiency (CVI). It is unclear if oral bilberry is beneficial in patients with CVI. Details: One small clinical study in patients with CVI shows that taking bilberry extract containing anthocyanins 173 mg daily for 30 days reduces symptoms of CVI when compared with placebo (35510).
• Diabetes. It is unclear if oral bilberry is beneficial in patients with diabetes. Details: One small clinical trial in patients with type 2 diabetes shows that taking a specific extract of bilberry fruit (Mirtoselect, Indena S.p.A) 470 mg once, prior to taking an oral glucose tolerance test, lowers plasma glucose levels when compared with placebo (91507). However, a small crossover trial in Chinese patients with type 2 diabetes shows that taking bilberry fruit extract 700 mg twice daily for 4 weeks does not improve glycated hemoglobin (HbA1c), body weight, blood pressure, or lipid levels when compared with placebo (104194). The validity of the HbA1c-related findings is limited due to the short study duration.
• Diabetic retinopathy. It is unclear if oral bilberry is beneficial in patients with diabetic retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also reduced flow velocity in those with high-flow, diabetic retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Dry eye. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with severe dry eye symptoms suggests that taking bilberry extract 600 mg and docosahexaenoic fish oil 240 mg once daily for 3 months may modestly improve measures of tear quality and patient-reported scores for dry eye symptoms when compared with control (112415). However, the validity of these results is limited by the lack of a statistical comparison between groups. Additionally, it is unclear if these effects are due to bilberry, fish oil, or the combination.
• Dysmenorrhea. It is unclear if oral bilberry is beneficial in patients with dysmenorrhea. Details: One small clinical study in patients with dysmenorrhea shows that a specific bilberry product (Tegens) containing bilberry anthocyanoside 160 mg, taken twice daily beginning 3 days prior to menses and continuing for 8 days, reduces pelvic pain, lumbosacral pain, breast pain, nausea, vomiting, and headache when compared with placebo (35512).
• Exercise-induced muscle soreness. It is unclear if oral bilberry is beneficial for reducing exercise-induced muscle soreness. Details: A small clinical study in trained athletes shows that drinking 200 mL of bilberry juice, containing about 744 mg phenols and 80 mg anthocyanins, twice daily for 5 days prior to running a half-marathon modestly worsens muscle soreness immediately after the run when compared with placebo. There was no longer a difference in muscle soreness between groups within 1-2 days after the run (99540).
• Glaucoma. Small clinical studies suggest that oral bilberry fruit extract, when taken with maritime pine extract, may lower intraocular pressure in patients with glaucoma. It is unclear if oral bilberry alone is beneficial in patients with glaucoma. Details: One small, uncontrolled clinical trial in Japanese patients with open-angle glaucoma shows that taking a specific product (Sante Glagenox, Saten Pharmaceutical Co. Ltd.) containing bilberry fruit extract 90 mg and maritime pine extract 40 mg daily for 4 weeks reduces intraocular pressure by 8.7% when compared to baseline (104192). Another small clinical study in patients with high intraocular pressure shows that taking a specific product (Mirtogenol) containing bilberry fruit extract (Mirtoselect, Indena S.p.A.) 80 mg and maritime pine extract (Pycnogenol, Horphag Research) 40 mg twice daily for 6 months lowers intraocular pressure and improves intraocular blood flow when compared with no treatment (35456). It is unclear if these findings are due to bilberry, maritime pine, or the combination. A retrospective chart review of patients with normal tension glaucoma has found that taking bilberry anthocyanin 60 mg twice daily for at least 12 months is associated with improvements in visual function when compared to pretreatment (35472).
• Hemorrhoids. Although there has been interest in using oral bilberry for hemorrhoids, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Hyperlipidemia. It is unclear if oral bilberry is beneficial in patients with hyperlipidemia. Details: A small clinical study in adults with hyperlipidemia shows that taking bilberry-derived anthocyanins 320 mg daily for 4 weeks does not improve total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, or triglyceride levels. Further, no improvements in other biomarkers of cardiovascular disease were reported (110640). The validity of this study is limited by its short duration.
• Hypertension. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with hypertension shows that consuming 500 mL of a juice containing bilberry, red grape, and chokeberry, with or without black currant (MANA Blue, TINE SA), daily for 12 weeks does not improve blood pressure when compared with placebo (92371).
• Hypertensive retinopathy. It is unclear if oral bilberry is beneficial in patients with hypertensive retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also increased flow velocity for those with ischemic, hypertensive retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Impaired glucose tolerance (prediabetes). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with impaired glucose tolerance and two markers of metabolic syndrome shows that consuming a diet high in whole grain products, fatty fish, and bilberries three times daily for 12 weeks reduces levels of plasma glucose when compared to baseline (35468). However, it is unclear if these findings are due to bilberry, another component of the diet, or the combination.
• Irritable bowel syndrome (IBS). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in adults with IBS shows that consuming a formula containing powdered bilberry fruit, aerial agrimony parts, cinnamon quills, and slippery elm bark modestly improves bowel movement frequency and reduces symptoms such as abdominal pain, bloating, flatulence, and straining when compared to baseline (35462). It is unclear if these findings are due to bilberry, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral bilberry is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that consuming a diet containing 400 grams of fresh bilberries daily does not affect body weight, glucose metabolism, or lipid metabolism when compared with a control diet (35473).
• Myopia. It is unclear if oral bilberry is beneficial in patients with myopia. Details: One small clinical trial in adults with myopia shows that a specific fermented bilberry fruit extract (Fermented Blueberry, Ajinomoto, Co., Inc.) 200 mg, taken twice daily for 4 weeks, improves night vision as well as the eye's ability to adjust focus when compared with placebo. The amplitude of accommodation was also significantly increased from 4.62 to 5.33 (91505).
• Obesity. It is unclear if oral bilberry is beneficial in patients with obesity. Details: One small clinical study in obese and overweight females shows that consuming 100 grams of frozen, whole bilberries daily for 33-35 days decreases weight and waist circumference when compared to baseline (35463). The validity of these findings is limited by the lack of a comparator group.
• Osteoarthritis. Although there has been interest in using oral bilberry for osteoarthritis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Ulcerative colitis. It is unclear if oral bilberry is beneficial in patients with ulcerative colitis. Details: One small, open-label clinical study in adults with mild-to-moderate ulcerative colitis shows that consuming sieved bilberries and concentrated bilberry juice (Symrise GmbH & Co) 160 grams daily for 6 weeks induces remission in 46% of patients. Furthermore, 91% of patients achieved remission at the end of treatment, and 72% of patients achieved remission at the end of the study (91506). The validity of these findings is limited by the lack of a comparator group.
• Urinary tract infections (UTIs). Although there has been interest in using oral bilberry for UTIs, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Varicose veins. Although there has been interest in using oral bilberry for varicose veins, there is insufficient reliable information about the clinical effects of bilberry for this purpose. More evidence is needed to rate bilberry for these uses.

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POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). In otherwise healthy adults, most population research shows that light to moderate consumption of alcoholic beverages, including wine, reduces the risk of developing coronary heart disease, myocardial infarction (MI), and ischemic stroke and reduces the risk of cardiovascular death. However, the definition of "moderate consumption" is unclear. Details: Consumption of alcoholic drinks, including wine, by otherwise healthy adults seems to reduce the risk of developing CVD. Moderate alcohol use (one to two drinks daily) reduces the risk of coronary heart disease, atherosclerosis, and MI by approximately 30% to 50% when compared with nondrinkers (2267,2268,2271,6888,6892,8648,8649,10128,11879,96690). Other observational research has found that drinking one or fewer glasses of wine weekly over 10 years is associated with a 60% lower risk of cardiovascular events. Light to moderate alcohol consumption also seems to reduce the risk of ischemic stroke (2271,2279,6834,6842,6893). But one large analysis has shown that individuals who report light to moderate consumption of alcohol have overall healthier lifestyles than those who abstain from alcohol and that adjusting for these lifestyle factors attenuates any of the cardioprotective epidemiological effects that have been associated with light to moderate alcohol intake (107884). Drinking more than one glass of wine weekly is not associated with lower cardiovascular risk when compared with abstaining from alcohol (102886).There is some evidence that light to moderate consumption of alcoholic drinks (one to two drinks daily), including wine, can also reduce the risk of all-cause mortality in people who are middle-aged or older (2058,6823,6837,6843). Conversely, consuming any amount of alcohol can increase the risk of hemorrhagic stroke (841,2271,6842). Light to moderate consumption of alcohol might also reduce the risk of cardiovascular mortality in otherwise healthy adults (2058,2270,6835,6837). Light to moderate alcohol consumption in the year prior to a first acute MI is associated with reduced cardiovascular and all-cause mortality risk when compared with non-drinkers (8650). Consumption of one alcoholic beverage daily or consuming alcohol on at least 3 to 4 days weekly is a good rule of thumb for people who drink alcohol. Tell patients not to exceed two drinks daily. More than two drinks daily can increase the risk of cardiovascular and overall mortality (841,2060,2261,6173,6890,8648,11879). Alcohol consumption has also been evaluated in patients with existing CVD, with some mixed findings. A meta-analysis of cohort data as well as published observational and randomized controlled studies in patients with existing CVD has found that consumption of 6-8 grams of alcohol daily is associated with a 21%, 27%, and 50% reduction in all-cause mortality, cardiovascular mortality, and cardiovascular events, respectively, when compared with non-drinkers (107817). Conversely, in males with established coronary heart disease (CHD), consumption of 1-14 alcoholic drinks weekly, including wine, does not seem to have any effect on CVD or all-cause mortality when compared with males who drink less than one drink weekly. Further, in males with a history of MI, consuming three or more drinks daily is associated with increased mortality (6173).
• Cognitive function. Consumption of up to one alcoholic drink daily seems to improve general cognitive function in older males. Details: Observational research has found that elderly males who have a history of consuming up to one alcoholic drink daily seem to maintain better general cognitive function during their late 70s and 80s when compared with non-drinkers (6824,6829). However, consumption of more than four drinks daily during middle age seems to be associated with significantly poorer cognitive function in later life (6824).
• Diabetes. Light to moderate consumption of alcohol, including wine, is associated with a reduced risk of developing type 2 diabetes and a reduced risk of coronary heart disease (CHD) in those with existing type 2 diabetes. However, the benefits of wine in the management of type 2 diabetes are unclear. Details: Observational research in healthy males has found that light to moderate alcohol consumption from wine and other sources is associated with a reduced risk of developing type 2 diabetes (6172,6891). A meta-analysis of 13 population studies has found that drinking about 1.5-2 five-oz glasses of wine daily is associated with the greatest reduction in the risk of developing diabetes in both males and females, with a 20% lower risk when compared with never drinking wine (96699). Additionally, in patients with a history of gestational diabetes, consuming approximately 3 servings of wine weekly is associated with a 44% to 54% lower risk of developing type 2 diabetes when compared with no consumption in age-adjusted and multivariate analyses, although this result was no longer significant when adjusted for BMI. Consumption of 1-2 servings of wine weekly was associated with a 42% lower risk of developing type 2 diabetes in age-adjusted analyses only (105948). Light to moderate alcohol consumption, including wine, is also associated with a reduced risk of coronary heart disease (CHD) in males and females with type 2 diabetes when compared with non-drinkers with type 2 diabetes. The risk reduction for CHD associated with light to moderate alcohol consumption in patients with type 2 diabetes is similar to that found in people without diabetes who consume light to moderate amounts of alcohol (8653,8654). Additionally, a cross-sectional study in patients with type 2 diabetes has found an inverse association between moderate alcohol consumption and carotid intima media thickness (107816). However, despite these promising results in observational research, clinical studies specifically addressing wine consumption in patients with type 2 diabetes show mixed results. A meta-analysis of 9 small clinical studies, most of which had a short follow-up period, shows that moderate wine consumption does not improve glycemic control, blood pressure, or lipid levels when compared with control beverages or alcohol abstinence in patients with type 2 diabetes (103187). However, another study not included in the above analysis that evaluated people with diabetes who abstained from alcohol prior to the study shows that drinking 5 oz of white wine, but not red wine, daily for 2 years reduces fasting blood glucose by 17 mg/dL and reduces homeostatic model assessment of insulin resistance (HOMA-IR) score by 1.2 when compared with drinking mineral water. In a subgroup analysis of slow ethanol metabolizers (homozygous carriers of the wild-type C alcohol dehydrogenase alleles, ADH1B*1), drinking red or white wine improves glycemic control when compared with patients that are fast ethanol metabolizers (homozygous for ADH1B*2) (96697). Another clinical study in patients with type 2 diabetes who are consuming a Mediterranean diet shows that drinking 150 mL of red or white wine daily with dinner for 2 years prevents progression of carotid atherosclerosis, though no progression occurred in a control group consuming 150 mL of mineral water daily with dinner (99641).
• Helicobacter pylori. Moderate to high alcohol consumption seems to reduce the risk of Helicobacter pylori infection. Details: Observational research has found that moderate to high consumption of alcohol, more than 75 grams weekly, from beverages such as beer and wine, is associated with a reduced risk of Helicobacter pylori infection (8034).
• Osteopenia. Observational research suggests that moderate alcohol consumption may improve bone mineral density (BMD) in postmenopausal patients. Details: Observational research has found that moderate alcohol consumption in postmenopausal patients is associated with increased BMD in the trochanter, femoral neck, mid-radius, and lumbar spine (6825,6836,8655). Alcohol intake of one-half to one drink daily seems to have the greatest effect on BMD when compared with non-drinkers and heavy drinkers of alcohol (8655).
• Overall mortality. Light to moderate alcohol consumption seems to reduce the risk of all-cause mortality in middle-aged or older adults. Details: Observational research has found that light to moderate consumption of alcohol is associated with a reduced risk of all-cause mortality in people who are middle-aged or older (2058,6823,6837,6843).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if wine consumption is beneficial for preventing Alzheimer disease. Details: A meta-analysis of observational research has found that light to moderate consumption of alcohol (less than 7.5 drinks weekly or 12.5 grams daily), preferably wine, is associated with a reduced risk of developing dementia, including Alzheimer disease, when compared with non-drinkers. The lowest risk of dementia was observed with consumption of 4 drinks weekly or 6 grams daily (97063).
• Anxiety. It is unclear if alcohol consumption is beneficial for anxiety. Details: The effect of alcohol on anxiety is complex and may be affected by the psychological state of the user. It sometimes reduces anxiety, sometimes increases it, and sometimes has no effect (2266).
• Atherosclerosis. It is unclear if moderate alcohol consumption is beneficial for atherosclerosis. Details: A cross-sectional study in patients with type 2 diabetes has found an inverse association between moderate alcohol consumption and carotid intima media thickness (107816).
• Cancer. It is unclear if wine consumption is beneficial for preventing cancer or cancer-related mortality. The available evidence suggests variable effects depending on cancer type. Details: Observational research has found that intake of up to 21 alcoholic drinks weekly, including wine, might slightly reduce the risk of cancer-related mortality (6823). Moderate consumption of wine has also been associated with a DECREASED risk of developing bladder cancer (97989), brain cancer (96695), renal cell cancer (97060,97064), and multiple myeloma (97990). However, wine intake is not associated with changes in the risk of colorectal cancer (103189), endometrial cancer (97065) or gastric cancer (96694). Furthermore, wine consumption has been associated with an INCREASED risk of breast cancer (96686) and skin cancer (97991). Results of a meta-analysis suggest that moderate to heavy consumption of alcohol, including wine, in males is associated with an 11% reduction in the risk of developing non-Hodgkin lymphoma (99638).
• Congestive heart failure (CHF). While light to moderate consumption of alcohol is associated with a reduced risk of developing CHF in older adults and a reduction in all-cause mortality in those with ischemic left ventricular (LV) dysfunction, it is unclear if moderate wine consumption is associated with these benefits. Details: Observational research in adults 65 years or older has found that consuming 1-4 alcoholic drinks daily is associated with a reduced risk of CHF (8104). There is conflicting evidence about whether moderate alcohol consumption improves outcomes in patients that already have CHF, although no exacerbation of CHF was found. Consumption of 1-14 alcoholic drinks per week is associated with reduced all-cause mortality in people with ischemic LV dysfunction when compared with non-drinkers with ischemic LV dysfunction. This benefit does not seem to occur for those patients with non-ischemic LV dysfunction (6827). However, other observational research has not found an inverse association between moderate wine consumption and rates of all-cause mortality, sudden death, or hospitalization in chronic heart failure patients (96689).
• Dementia. It is unclear if wine consumption is beneficial for dementia. Details: A meta-analysis of observational research has found that light to moderate consumption of alcohol (less than 7.5 drinks weekly or 12.5 grams daily), preferably wine, is associated with a reduced risk of all-cause dementia when compared with non-drinkers. The lowest risk of dementia was observed with consumption of 4 drinks weekly or 6 grams daily. However, consumption of 23 or more alcoholic drinks weekly is associated with an increased risk of all-cause dementia (97063).
• Depression. It is not clear if wine consumption is beneficial for depression. Details: Observational research has found that low to moderate consumption of wine (2-7 drinks weekly) is associated with a 32% lower rate of depression when compared with not consuming wine (96696).
• Metabolic syndrome. There is limited evidence on the consumption of red wine for metabolic syndrome. Details: Observational research has found that moderate red wine consumption (at least one 5-ounce glass daily) is associated with a 44% lower odds of developing metabolic syndrome when compared with not drinking any red wine. The association appears to be strongest for females less than 70 years-old and for people who currently smoke or have a history of smoking. Drinking white wine does not seem to affect the risk of metabolic syndrome (97062).
• Obesity. It is unclear if wine consumption is beneficial in patients with obesity. Details: Some observational research in non-smokers has found that higher wine consumption in adolescence is linked to lower mid-life body mass index (BMI) when compared with lower wine consumption. No association between wine consumption and mid-life BMI was reported in adolescent smokers over a 20-year follow-up (103188). It is unknown if wine consumption reduces the risk of developing obesity or improves weight loss in obese patients.
• Systemic lupus erythematosus (SLE). It is unclear if wine consumption is beneficial in preventing SLE in females. Details: Observational research has found that modest daily alcohol consumption is associated with a reduced risk of developing SLE in females. When the data were stratified by alcohol type, 2 or more servings of wine weekly was associated with a 35% reduced risk of developing SLE when compared with not drinking alcohol (96684).
• Wound healing. Although there has been interest in topical wine for wound healing, there is insufficient reliable information about the clinical effects of alcohol for this purpose. More evidence is needed to rate wine for these uses.

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LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods. Bilberry has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. Bilberry fruit extracts have been used with apparent safety in clinical trials at a dose of up to 160 mg daily for up to 6 months (39,40,8139,9739,14280,35472,35510,35512,103190,104192,104195). A higher bilberry extract dose of 1.4 grams daily has been used with apparent safety for up to 4 weeks (104194). Whole bilberries or bilberry juice have also been consumed with apparent safety in quantities of 100-160 grams daily for up to 35 days (35463,91506).

POSSIBLY UNSAFE ...when the leaves are used orally in high doses or for a prolonged period. Death can occur with chronic use of 1.5 gram/kg daily (2).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts commonly found in foods. However, there is insufficient reliable information available about the safety of bilberry when used in medicinal amounts during pregnancy and lactation; avoid using.

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

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

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

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

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LIKELY SAFE ...when used orally, responsibly, and in moderation (11880,97061).

POSSIBLY UNSAFE ...when used orally in excess of 1 to 2 five-oz glasses of wine daily. Larger amounts can cause significant adverse effects (11880). There is insufficient reliable information available about the safety of wine when used topically.

PREGNANCY: LIKELY UNSAFE
when used orally; alcohol is a teratogen. Use during pregnancy is associated with significant risk of spontaneous abortion, fetal alcohol syndrome, and developmental and behavioral dysfunction in infants and children exposed to alcohol in utero (8100); avoid using.

LACTATION: LIKELY UNSAFE
when used orally. Alcohol is secreted in breast milk. Chronic use can cause abnormal psychomotor development and disrupt the infant's sleep-wake pattern. Alcohol also seems to reduce milk production (11878); avoid using.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details In vitro, animal, and clinical research suggest that anthocyanidin extracts from bilberry can inhibit platelet aggregation (16631,35455,35503,35504,35505).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry leaf or fruit extract may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research suggests that bilberry leaf extract might have blood glucose-lowering activity (1264). Also, one small clinical trial in patients with type 2 diabetes shows that taking bilberry fruit extract 470 mg as a single dose prior to an oral glucose tolerance test lowers plasma glucose levels when compared with placebo (91507).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might decrease levels of drugs metabolized by CYP2E1.  Details Animal research shows that exposure to small concentrations of bilberry extract in drinking water for around one month increased CYP2E1 activity by 31%. However, exposure over a 2-month period did not increase CYP2E1 activity (103191). This effect has not been reported in humans.

ERLOTINIB (Tarceva) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might reduce the efficacy of erlotinib.  Details In vitro research suggests that bilberry fruit extract and its constituents, delphinidin and delphinidin-3-O-glucoside, inhibit the activity of erlotinib (97031). This interaction has not been reported in humans.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, grape extracts may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro evidence suggests that grape extracts might decrease platelet aggregation (53017,53087).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Ingesting grape juice with cyclosporine can reduce cyclosporine absorption.  Details A small pharmacokinetic study in healthy young adults shows that intake of purple grape juice 200 mL along with cyclosporine can decrease the absorption of cyclosporine by up to 30% when compared with water (53177). Separate doses of grape juice and cyclosporine by at least 2 hours to avoid this interaction.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, grape juice might reduce the levels of CYP1A2 substrates.  Details A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of CYP1A2 (2539).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D It is unclear if grape juice or grape seed extract inhibits CYP2C9; research is conflicting.  Details In vitro evidence shows that grape seed extract or grape juice might inhibit CYP2C9 enzymes (11094,53011,53089). However, a small pharmacokinetic study in healthy adults shows that drinking 8 ounces of grape juice once does not affect the clearance of flurbiprofen, a probe-drug for CYP2C9 metabolism (11094). The effects of continued grape juice consumption are unclear.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grape seed extract may increase the levels of CYP2D6 substrates.  Details In vitro evidence suggests that grape seed extract might inhibit CYP2D6 enzymes (53011). However, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grape seed extract might increase the levels of CYP2E1 substrates.  Details In vitro and animal research suggests that grape seed proanthocyanidin extract inhibits CYP2E1 enzymes (52949). However, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D It is unclear if grape seed extract inhibits or induces CYP3A4; research is conflicting.  Details In vitro evidence suggests that grape seed extract might inhibit CYP3A4 enzymes (53089). However, evidence from animal research shows that grape seed extract may induce CYP3A4 in the liver (53011). So far, these interactions have not been reported in humans.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, long-term intake of grape seed extract might decrease the effects of midazolam.  Details Animal research shows that subchronic ingestions of grape seed extract can increase the elimination of intravenous midazolam by increasing hepatic CYP3A4 activity. Single doses of grape seed extract do not appear to affect midazolam elimination (53011).

PHENACETIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grape juice might decrease phenacetin absorption.  Details A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of cytochrome P450 1A2 (CYP1A2) (2539).

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ACITRETIN (Soriatane) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Concomitant use increases the risk of long-term teratogenic effects.  Details Alcohol increases the transesterification of acitretin to etretinate, which is a teratogen that can remain in the body for years after discontinuation of acitretin. Patients of reproductive potential should avoid alcohol completely while taking acitretin and at least 2 months after discontinuation (108003).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Concomitant use may interfere with blood glucose control.  Details Alcohol can impair gluconeogenesis and may increase the risk of acute hypoglycemia when used concomitantly with antidiabetes drugs (2262). However, the carbohydrates in wine may also worsen glycemic control in patients with diabetes.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use may interfere with blood pressure control.  Details Clinical research suggests that consumption of alcohol can increase both systolic and diastolic blood pressure (34015,34050,34052,34053). However, acute alcohol intoxication can also increase the risk of hypotension and additive effects with antihypertensive drugs (2262).

ASPIRIN Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = C Concomitant use may increase the risk of gastrointestinal (GI) bleeding.  Details Concomitant use of aspirin with alcohol may increase the risk of GI bleeding (2262).

BUPROPION (Wellbutrin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use may increase the risk of adverse effects from alcohol.  Details In patients taking bupropion, there have been rare reports of adverse psychiatric events or reduced alcohol tolerance. Additionally, in chronic alcohol users, abrupt discontinuation of alcohol while taking bupropion may increase the risk of seizure (108023).

CEFAMANDOLE (Mandol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = C Concomitant use may cause a disulfiram-like reaction.  Details Cefamandole can cause a disulfiram-like reaction when taken with alcohol (2262).

CEFOPERAZONE (Cefobid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = C Concomitant use may cause a disulfiram-like reaction.  Details Cefoperazone can cause a disulfiram-like reaction when taken with alcohol (2262).

CETIRIZINE (Zyrtec) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of CNS impairment.  Details Cetirizine may cause somnolence in some patients. There is some concern that taking cetirizine in conjunction with alcohol might reduce alertness and impair CNS performance (108022).

CHLORPROPAMIDE (Diabinese) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Concomitant use may cause a disulfiram-like reaction.  Details Chlorpropamide can cause a disulfiram-like reaction when taken with alcohol (506).

CISAPRIDE (Propulsid) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Concomitant use may increase blood alcohol levels and adverse effects.  Details Concomitant use of alcohol can increase blood alcohol levels and adverse effects (2262). Also, red wine increases plasma cisapride concentrations, possibly by reducing metabolism (1383).

CITALOPRAM (Celexa) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of adverse effects from alcohol.  Details Some case reports suggest that citalopram may reduce alcohol tolerance and increase the risk of adverse effects from alcohol (108024).

CNS DEPRESSANTS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = C Concomitant use may increase sedative and other adverse effects.  Details Concomitant use of alcohol with CNS depressants can increase sedative and other adverse effects, potentially through inhibition of the metabolism of certain CNS depressants (2262).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Red wine can reduce the levels and clinical effects of cyclosporine.  Details Red wine reduces plasma cyclosporine concentrations, possibly by reducing cyclosporine absorption. There is evidence the reduction in cyclosporine AUC by red wine is less in Asians (8% to 14%) than Caucasians (35% to 36%) (1384,1387,8977).

DISULFIRAM (Antabuse) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = C Concomitant use may cause a disulfiram reaction.  Details Disulfiram can cause a disulfiram reaction when taken with alcohol (2262). Patients taking disulfiram should not consume any alcohol.

DOXYCYCLINE (Vibramycin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Chronic alcohol use might reduce the levels and clinical effects of doxycycline.  Details Although acute alcohol ingestion does not seem to significantly impact the pharmacokinetics of doxycycline, chronic alcohol ingestion has been shown to significantly reduce the half-life and serum concentration of doxycycline (107998).

ELUXADOLINE (Viberzi) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = A Chronic or excessive alcohol use might increase the risk of pancreatitis from eluxadoline.  Details In clinical studies, the risk of pancreatitis with eluxadoline was increased in chronic alcohol users and in those with acute intake of 3 or more alcoholic beverages daily (108004).

ERYTHROMYCIN Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = C Concomitant use may increase blood alcohol levels and adverse effects.  Details Concomitant use of erythromycin with alcohol can increase blood alcohol levels and adverse effects (2262).

FELODIPINE (Plendil) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Consumption of red wine can rapidly increase felodipine levels and adverse effects.  Details Red wine taken on an empty stomach can cause "dose dumping" of extended-release felodipine, possibly by changing absorption or metabolism. Red wine can delay the appearance of felodipine in plasma until 4 hours after dosing and can rapidly increase its plasma concentration, producing peak serum levels 3 to 4 times higher than when felodipine is given with water. This can cause an increase in adverse effects 5 hours after dosing (11976).

FLIBANSERIN (Addyi) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = A Concomitant use increases the risk of severe hypotension and syncope.  Details Alcohol use is contraindicated in patients taking flibanserin due to the risk of severe hypotension and syncope (108002).

GRISEOFULVIN (Fulvicin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = C Concomitant use may cause a disulfiram-like reaction.  Details Griseofulvin can cause a disulfiram-like reaction, including tachycardia and facial flushing, when taken with alcohol (2262).

H2-BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = C Concomitant use might increase blood alcohol levels and adverse effects.  Details Concomitant use of the H2-blockers cimetidine and ranitidine with low doses of alcohol (0.15 grams/kg) might increase blood alcohol levels and adverse effects. Effects with higher doses of alcohol (0.3-1.5 grams/kg) are variable (2262).

HEPATOTOXIC DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = C Concomitant use of alcohol with hepatotoxic drugs may increase the risk of hepatotoxicity.  Details Concomitant use of excessive amounts of alcohol with potentially hepatotoxic drugs can increase the risk of liver damage (2262).

LEVOCETIRIZINE (Xyzal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of CNS impairment.  Details Levocetirizine may cause somnolence in some patients. There is some concern that taking levocetirizine in conjunction with alcohol might reduce alertness and impair CNS performance (108026).

LEVOMILNACIPRAN (Fetzima) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use may increase the absorption and elimination of levomilnacipran.  Details In vitro research shows that alcohol increases the release of levomilnacipran from extended-release capsules, resulting in complete drug release in 4 hours (108024). This effect has not been evaluated in humans.

METFORMIN (Glucophage) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = C Concomitant use may increase the risk of lactic acidosis.  Details Concomitant consumption of large amounts of alcohol can increase the risk of lactic acidosis with metformin (107995).

METRONIDAZOLE (Flagyl) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = C Concomitant use may cause a disulfiram-like reaction.  Details Although there is some disagreement over the likelihood of a disulfiram-like reaction with concomitant use of alcohol and metronidazole (108000), prescribing materials recommend discontinuing alcohol intake during the use of metronidazole. In the US, it is recommended to discontinue alcohol during and for at least three days after therapy with metronidazole (107999); in Canada, it is recommended to discontinue alcohol during and for at least 1 day after therapy with metronidazole (108001).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Concomitant use may cause hypertensive crisis.  Details Wine contains tyramine (105702), which is metabolized by monoamine oxidase. Concurrent use of MAOIs with tyramine-containing beverages can lead to elevated levels of tyramine in the body. This can increase the effects of tyramine, which has been reported to cause hypertension, headache, and hypertensive crisis in numerous cases (100189,100192,101010). Sensitivity to tyramine can increase up to 10-fold to 100-fold in people using an MAOI (100189,101010).

NARCOTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = C Concomitant use of large amounts of alcohol may decrease the metabolism of narcotic drugs.  Details Concomitant consumption of large amounts of alcohol can decrease the metabolism of narcotic drugs (2262).

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = C Concomitant use may increase the risk of gastrointestinal (GI) bleeding.  Details Concomitant use of NSAIDs with alcohol may increase the risk of GI bleeding (2262).

PHENYTOIN (Dilantin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = C Concomitant use may decrease the effectiveness of phenytoin.  Details Chronic, heavy alcohol use can induce the metabolism, reducing therapeutic effectiveness of phenytoin (2262).

SECNIDAZOLE (Solosec) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use may cause a disulfiram-like reaction.  Details Although high quality evidence is lacking, there is concern that secnidazole can cause a disulfiram-like reaction when taken with alcohol. Prescribing materials in the US recommend discontinuation of alcohol during and for at least two days after therapy with secnidazole (107996).

SULFONAMIDE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = C Concomitant use may cause a disulfiram-like reaction.  Details Sulfonamide antibiotics can cause a disulfiram-like reaction when taken with alcohol (2262).

TINIDAZOLE (Tindamax) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use may cause a disulfiram-like reaction.  Details Although high quality evidence is lacking, there is concern that tinidazole can cause a disulfiram-like reaction when taken with alcohol. Prescribing materials in the US recommend discontinuation of alcohol during and for at least three days after therapy with tinidazole (107997).

TOLBUTAMIDE (Orinase) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = C Theoretically, concomitant use may cause a disulfiram-like reaction.  Details Tolbutamide can cause a disulfiram-like reaction when taken with alcohol (2262).

VARENICLINE (Chantix) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use may increase the risk of adverse effects from alcohol.  Details There have been reports of patients experiencing increased effects from alcohol while taking varenicline. Some cases involved unusual and sometimes aggressive behavior and were accompanied by amnesia (108021). Caution patients to use alcohol with caution when taking varenicline, as it may alter alcohol tolerance.

VASODILATORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Concomitant use may increase the risk of acute hypotension.  Details Acute alcohol intoxication can increase the risk of hypotension and additive effects with vasodilators (2262).

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = C Alcohol can alter the effects of warfarin, although the exact effect depends on the nature of alcohol consumption.  Details Acute alcohol intoxication can decrease metabolism and increase the effects of warfarin. In contrast, chronic, heavy alcohol use can induce metabolism of warfarin, reducing therapeutic effectiveness (2262).

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General ...Orally, bilberry fruit, juice, and extracts seem to be well tolerated.
Most Common Adverse Effects:
Orally: Dark-colored stools, flatulence, and gastrointestinal discomfort.

Gastrointestinal ...In one small clinical trial, mild-to-moderate flatulence was reported in 33% of patients taking sieved bilberries and concentrated bilberry juice (91506). However, the patients in this study had ulcerative colitis, and the study lacked a control group, limiting the validity of this finding. In another small clinical study of males with age-related cognitive impairment, temporary adverse gastrointestinal (GI) effects were reported in 13% of patients drinking a combination of bilberry and grape juice. However, the adverse GI effect rate was identical in patients drinking a placebo juice (110641). A post-marketing surveillance report of 2295 patients using bilberry extract (Tegens) found that 1% of patients complained of GI discomfort and less than 1% experienced nausea or heartburn (35500).
Theoretically, fresh bilberry fruit may have laxative effects. One clinical trial noted an increased frequency of bowel movements following the administration of a combination formulation containing aerial agrimony parts, cinnamon quills, powdered bilberry fruit, and slippery elm bark (35462). It is unclear if these effects were due to bilberry, other ingredients, or the combination.

Other ...Orally, bilberry may cause discoloration of feces and the tongue. In one study, a dark-bluish to black discoloration of both the feces and the tongue was observed following consumption of sieved bilberries and concentrated bilberry juice. In one patient, a slight discoloration of the teeth has also been observed (91506). In another study, 50% of patients reported dark green stools after taking bilberry extract 700 mg twice daily for 4 weeks (104194).

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

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

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

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

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

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

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

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

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

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

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General ...Orally, the side effects of wine depend on the amount of alcohol ingested and can vary among individuals.
Most Common Adverse Effects:
Orally: Most adverse effects are associated with alcohol content and include abdominal pain, aggression, blackouts, central nervous system (CNS) depression, confusion, diarrhea, drowsiness, emotional lability, flushing, hypoglycemia, hypothermia, indigestion, lack of coordination and trouble walking, migraines, nausea, neuropathies, perceptual and sensational disturbances, and vomiting.
Serious Adverse Effects (Rare):
Orally: Chronic heavy alcohol ingestion (three or more drinks daily) can lead to amnesia, cardiac myopathy, cirrhosis, dementia, hepatotoxicity, malnutrition, myocardial infarction (MI), physical dependence, and somnolence. Other effects of chronic use are chronic cerebellar syndrome, hypomagnesemia, Korsakoff's psychosis, pancreatitis, skeletal myopathies, various types of cancer, and Wernicke's encephalopathy.
Chronic ingestion of three or more alcoholic beverages daily is associated with an increased risk of all-cause mortality, ischemic stroke, and hypertension. Consumption of any amount of alcohol can increase the risk of hemorrhagic stroke.

Cardiovascular ...Orally, chronic heavy alcohol ingestion of three or more drinks daily is associated with an increased risk of all-cause mortality, atrial fibrillation, cardiac myopathy, hypertension, ischemic stroke, and myocardial infarction (MI) (2261,6843,6892,8102,9004,33984,34028,34054,34058,34059). Consumption of any amount of alcohol can increase the risk of hemorrhagic stroke (841,2271).

Gastrointestinal ...Orally, wine can cause a variety of side effects which depend on the amount of alcohol ingested and can vary among individuals. Some common side effects include abdominal pain, diarrhea, indigestion, nausea, and vomiting. (6843,8972,9004,34013,34031). Chronic alcohol use is also associated with pancreatitis (6843,9004).

Hepatic ...Orally, chronic heavy alcohol ingestion (three or more drinks daily) can lead to cirrhosis and hepatotoxicity (6843,9004).

Immunologic ...People who are allergic to sulfites and/or yeast might react to wine. Wine is associated with triggering asthmatic reactions in people with a history of asthma, possibly due to salicylates and/or added sulfites contained in wines (6174). A case report describes a 33-year-old female who developed allergic reactions ranging from mild symptoms to anaphylaxis after consumption of beer or wine. The allergy was attributed to the yeast Saccharomyces cerevisiae, which is used in the fermentation of both beverages (107819).

Musculoskeletal ...Orally, wine can cause a variety of side effects which depend on the amount of alcohol ingested and can vary among individuals. Some common side effects include lack of coordination and trouble walking. Other effects of chronic use include skeletal myopathies (6843,8972,9004).

Neurologic/CNS ...Orally, wine can cause a variety of side effects which depend on the amount of alcohol ingested and can vary among individuals. Some common side effects include blackouts, central nervous system (CNS) depression, drowsiness, lack of coordination and trouble walking, migraines, neuropathies, and perceptual and sensational disturbances. Chronic heavy alcohol ingestion (three or more drinks daily) can lead to amnesia, dementia, physical dependence, and somnolence. Other effects of chronic use are chronic cerebellar syndrome, Korsakoff's psychosis, and Wernicke's encephalopathy (6843,8972,9004,34055,34068).
Heavy alcohol consumption (fifteen or more drinks weekly) is also associated with a higher percentage of white matter changes and larger ventricular and sulcal size on magnetic resonance imaging (MRI) of the brain. This suggests that heavy alcohol consumption decreases cerebral blood flow and may contribute to brain atrophy (8651). Consumption of any amount of alcohol can increase the risk of hemorrhagic stroke (841,2271).

Oncologic ...There is evidence that heavy alcohol consumption is associated with the mutation of the p53 gene in individuals with esophageal carcinoma (9005). There is also some evidence that heavy consumption of wine is associated with the highest risk of esophageal cancer when compared with heavy consumption of beer and spirits (8972,9004). Chronic heavy alcohol ingestion (three or more drinks daily) can lead to mouth cancer, esophageal cancer, pharyngeal cancer, laryngeal cancer, and liver cancer (6843,8972,9004,31557,33977,34010,34037,34045,34061,34065,34069,34085). Some research suggests an association between alcohol consumption and an increased risk of pancreatic cancer, but other studies do not support this association (8038). Daily consumption of one or more alcoholic drinks in females might increase the risk of breast cancer by 2% to 15% and increase mortality from breast cancer by as much as 30% (6843,8100,8974,9006,96686). There is also evidence suggesting that females who consume alcohol daily have an increased risk of developing breast cancer when the daily intake of folate is 300 mcg or less (8974,9006). However, the association of wine intake and breast cancer risk in females may vary depending on the type of wine. Red wine results in higher levels of free testosterone and luteinizing hormone (LH) and lower hormone binding globulin (SHBG) levels when compared with white wine. This suggests that red wine has similar activity to aromatase inhibitors and may not increase the risk of breast cancer unlike white wine (97992).
Observational research has found that wine consumption is associated with a higher risk of developing skin cancer in females and a higher risk of invasive melanoma in both males and females (97055,97991).

Psychiatric ...Orally, wine can cause a variety of side effects which depend on the amount of alcohol ingested and can vary among individuals. Some common side effects include aggression, confusion, and emotional lability (6843,9004,34040). Chronic heavy alcohol ingestion (three or more drinks daily) can lead to dementia, physical amnesia, and somnolence (6843,8972,9004).

Pulmonary/Respiratory ...Orally, wine can cause a variety of side effects due to the alcohol content. The side effects depend on the amount ingested and can vary among individuals. A common side effect includes respiratory depression (6843,8972,9004). Wine is also associated with triggering asthmatic reactions in people with a history of asthma, possibly due to salicylates and/or added sulfites contained in wines (6174).

Other ...Orally, chronic heavy alcohol ingestion (three or more drinks daily) can lead to malnutrition and poor glycemic control (6843,8972,9004).
There is some evidence consumption of more than six beers per week is associated with a larger waist-to-hip ratio than those consuming an equivalent amount of hard liquor or wine. However, an association between moderate alcohol intake equivalent to approximately three beers per week or less and waist-to-hip ratio does not seem to exist (10164,10165). It is also unclear whether waist-to-hip ratios associated with the intake of wine, beer, or other alcoholic beverages have any clinical significance (9007).

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