Resveratrol Red Wine Extract Plus by Nature's Bounty

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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EFFECTIVE

• Vitamin C deficiency. Oral or intramuscular vitamin C is effective for preventing or treating vitamin C deficiency. Details: Administering vitamin C orally or intramuscularly prevents and treats vitamin C deficiency, including scurvy. Vitamin C administration can reverse complications of scurvy within 2 days to 3 weeks (4844). In newborns with transient tyrosinemia due to vitamin C deficiency, oral or intramuscular vitamin C can correct this condition (15).

POSSIBLY EFFECTIVE

• Anemia of chronic disease. Oral vitamin C seems to improve markers of anemia in patients on hemodialysis. Details: Meta-analyses of clinical research in hemodialysis patients with anemia shows that treatment with vitamin C 200-300 mg three times weekly for 3-6 months increases hemoglobin levels by approximately 0.9 grams/dL, increases transferrin saturation by about 8%, and decreases the required recombinant human erythropoietin dose by 17 U/kg weekly when compared with standard care (83447,83475).
• Atrial fibrillation. Oral and intravenous vitamin C seems to help prevent atrial fibrillation after cardiac surgeries. Details: Meta-analyses of clinical research show that taking vitamin C prior to and after cardiac surgery reduces the risk of postoperative atrial fibrillation by 27% to 53%. Most studies administered vitamin C at doses of 1-2 grams orally daily for 1-3 days prior to cardiac surgery, followed by 1-2 grams in two divided doses daily for 4-5 days after cardiac surgery. Some studies provided vitamin C intravenously at similar doses, but oral vitamin C seems to be more effective (91233,96703,96705). Despite these findings, a meta-analysis of clinical research conducted only in the U.S. does not support the benefit of vitamin C for reducing postoperative atrial fibrillation (96703). These differences may be related to lifestyle factors such as nutrition, as well as differences in hospital treatments. Vitamin C has also been studied in combination with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with evidence of benefit (90701).
• Bowel preparation. Powdered vitamin C is approved for use as part of a polyethylene glycol-based bowel preparation for colonoscopy. Details: Clinical research shows that treatment with 2 liters of oral solution containing polyethylene glycol (PEG) plus vitamin C achieves a similar quality of bowel cleansing as treatment with 4 liters of PEG when administered on the evening prior to colonoscopy or when administered in a split-dose regimen. Patients given 2 liters of PEG plus vitamin C solution also have better adherence and experience fewer adverse events, such as nausea, vomiting, or abdominal bloating, compared to patients treated with 4 liters of PEG solution without vitamin C (90413,90415,90420,90424,90428). This treatment also appears to be effective and tolerable in elderly patients aged 60-79 years, including those with poor bowel habits and a high number of comorbidities (108085). Other clinical research in older adults undergoing bowel preparation for colonoscopy also shows that taking 1 liter of PEG plus vitamin C (CleanViewAL, Taejoon Pharm) results in similar quality of bowel cleansing overall and per segment with similar tolerability and adverse effects as sodium picosulfate 170 mL plus magnesium citrate or oral sulfate solution alone (111297,112476). The most common PEG plus vitamin C preparation used in clinical research is MoviPrep (Norgine BV), which contains macrogol 3350 100 grams, sodium sulfate 7.5 grams, sodium chloride 2.7 grams, potassium chloride 1 gram, vitamin C 4.7 grams, and sodium ascorbate 5.9 grams per liter of solution (90413,90415,90424). In the U.S., MoviPrep is approved by the Food and Drug Administration (FDA) for bowel preparation prior to a colonoscopy.
• Common cold. Oral high-dose vitamin C might modestly reduce cold symptoms; however, taking vitamin C prophylactically does not seem to prevent the development of a cold. Details: There is substantial controversy about the effectiveness of vitamin C for treating the common cold (1969,1989,7100,9835,9836). The majority of evidence shows that taking high doses of vitamin C orally might decrease the duration of cold symptoms by 1-1.5 days in some patients (1966,1967,1968,1987,6458,7102,9832,83487). However, other studies have found no effect with doses up to 3 grams daily (9833). A meta-analysis of clinical research suggests that vitamin C supplementation decreases the incidence of cold in individuals exposed to physical stress, but not in the general population (83487). Other research suggests vitamin C may be more effective for treating cold symptoms in children than in adults. Also, there may be a dose-dependent response; doses of at least 2 grams daily seem to work better than 1 gram doses (9834). Taking vitamin C supplements prophylactically does not decrease the risk of catching a cold (1966,1967,1968,1987,3042,6458,7101,9832). Dietary intake of vitamin C also does not seem to affect the risk of getting a cold (10780).
• Complex regional pain syndrome. Most research shows that taking oral vitamin C after a wrist or distal radius fracture or after orthopedic surgery seems to reduce the risk of developing complex regional pain. Details: Although some research has found no benefit in patients with distal radius (i.e. wrist) fractures (90411,96702), most clinical research shows that taking vitamin C 500 mg daily, and possibly doses of up to 1500 mg daily, for 45-50 days beginning immediately after fracture can reduce the risk of developing complex regional pain syndrome (2045,16302,96700,96706). Reasons for discrepancies are unclear but might relate to differences in diagnostic criteria for complex regional pain syndrome (96702). Research in patients undergoing orthopedic surgery has also shown benefit with the use of vitamin C for the prevention of complex regional pain syndrome (90422,108076,108087). One meta-analysis of clinical research in patients undergoing wrist, foot, or ankle surgery shows that taking vitamin C 500-1000 mg for 42-50 days following surgery reduces the rate of complex regional pain syndrome, and may improve pain following ankle or foot surgery, when compared with placebo (108076). The validity of these findings is limited by the high heterogeneity of included trials. Another meta-analysis of clinical research in patients undergoing orthopedic surgery (i.e. wrist, knee, ankle, foot, lumbar, rotator cuff) suggests that oral and intravenous vitamin C may have similar effectiveness; however, this evidence is low quality (108087).
• Exercise-induced respiratory infections. High-dose oral vitamin C seems to reduce the risk of respiratory infections associated with strenuous exercise. Details: Some preliminary clinical research suggests that prophylactic use of vitamin C in doses of 600 mg to 1 gram daily for 3-8 weeks before heavy physical exercise, such as a marathon, might prevent upper respiratory infections that sometimes follow heavy exercise (9831,83370). More recently, high doses of vitamin C have been studied. A large clinical study in army recruits undergoing basic military training shows that taking vitamin C 6 grams daily for one month reduces the odds of getting a cold by 20% when compared with placebo (102975).
• Hypercholesterolemia. Oral vitamin C seems to reduce lipid levels in patients with hypercholesterolemia. Details: A meta-analysis of clinical research in patients with hypercholesterolemia shows that taking vitamin C 500 mg daily for at least 4 weeks reduces low-density lipoprotein (LDL) cholesterol by about 8 mg/dL and reduces triglycerides by about 20 mg/dL when compared with control (83445).
• Hypertension. Oral vitamin C seems to modestly reduce blood pressure in patients with hypertension. Details: Vitamin C seems to modestly reduce systolic blood pressure, without meaningful effects on diastolic blood pressure (2044,9822,13162,83483,102974). A meta-analysis of 13 clinical trials in patients with hypertension, with or without other comorbidities, shows that taking a median dose of vitamin C 500 mg daily for 8 weeks reduces systolic, but not diastolic, blood pressure by about 5 mmHg. Some of the studies used vitamin C in combination with other supplements, such as vitamin E and magnesium. When studies assessing vitamin C alone were analyzed, the magnitude of reduction in systolic blood pressure decreased (83483). A newer meta-analysis of small clinical studies in patients with essential hypertension shows that taking vitamin C 200 mg or more daily reduces systolic blood pressure by about 4 mmHg and diastolic blood pressure by about 2 mmHg (102974). However, this newer analysis omitted numerous relevant studies and included studies with normotensive patients and those without an adequate control, limiting the validity of its findings.
• Laser skin resurfacing. Topical vitamin C seems to reduce erythema occurring after cosmetic laser skin resurfacing procedures intended to reduce scars and wrinkles. Details: There is some evidence that an aqueous formulation of topical vitamin C can decrease the degree and duration of erythema following cutaneous carbon dioxide laser resurfacing for scar and wrinkle removal (1959).
• Lead toxicity. Dietary vitamin C seems to lower concentrations of lead in the blood. Details: Observational research has found that consuming more vitamin C from dietary sources is associated with lower blood concentrations of lead. People who consumed at least 340 mg of vitamin C daily as part of the diet had lower blood lead levels than those who consumed less than 100 mg vitamin C daily (3097,3098,3099).
• Nitrate tolerance. Oral vitamin C might prevent nitrate tolerance in some patients. Details: Small clinical studies show that taking vitamin C orally seems to prevent the development of nitrate tolerance in patients taking sublingual nitroglycerin. There is some evidence that short-term vitamin C supplementation can prevent tolerance to the vasodilatory effects of nitrates (1441,1961).
• Postoperative pain. Oral or intravenous vitamin C might prevent acute postoperative pain following certain surgeries. It is unclear if vitamin C reduces chronic postoperative pain. Details: A meta-analysis of 7 small clinical studies in adults undergoing elective surgery shows that receiving perioperative vitamin C, either as 1 gram orally, 2-3 grams intravenously, or 50 mg/kg intravenously, modestly reduces acute pain and opioid requirements for up to 24 hours when compared with control (105457). Most surgeries were laparoscopic and included cholecystectomy, colectomy, hysterectomy; two non-laparoscopic surgeries included uvulopalatopharyngoplasty with tonsillectomy and major abdominal surgery (90418,99840,105457). A meta-analysis of clinical trials in adults undergoing noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, kidney transplantation) shows that administering perioperative vitamin C, either orally or intravenously, reduces postoperative intravenous morphine requirements at 2, 24, and 48 hours after surgery and improves pain scores at 2, 6, and 24 hours after surgery when compared with placebo. The dose of vitamin C did not appear to impact outcomes. However, when only laparoscopic surgeries are included, perioperative vitamin C does not improve pain or morphine use when compared with placebo (108087). A moderate-sized clinical study in adults undergoing transurethral resection of a bladder tumor under general anesthesia shows that administering intravenous vitamin C 1 gram after induction of anesthesia reduces the incidence and severity of catheter-related bladder discomfort immediately after surgery and at 1 and 2 hours postoperatively, but not 6 hours, when compared with placebo. However, vitamin C does not reduce postoperative pain scores or analgesic requirements when compared with placebo (111645). Further research is needed to determine the effects of vitamin C for acute postoperative pain. Vitamin C has also been evaluated for reducing chronic pain after surgery. Clinical research in patients undergoing surgery for foot or ankle trauma shows that taking vitamin C 500 mg orally twice daily postoperatively for 6 weeks reduces pain scores when compared with placebo at 2 weeks and 6 weeks. The mean total amount of diclofenac used for pain relief over the 6-week period is also reduced, from 5.7 grams with placebo to 3.4 grams with vitamin C (102131).
• Wrinkled skin. Topical vitamin C might reduce the appearance of existing wrinkles. Details: Topical preparations containing vitamin C seem to improve the appearance of wrinkled skin. Some evidence shows that vitamin C 3% applied for 12 weeks might reduce facial wrinkles (14008). A small clinical study shows that applying a dissolving microneedle patch containing vitamin C 5.6% every 4 days for 12 weeks to crow's feet on one side of the face reduces wrinkles when compared to control treatment applied on the other side of the face (98780). Other clinical research in females aged 30-60 years shows that applying an oil-soluble cream containing the vitamin C derivative tetra-isopalmitoyl ascorbic acid 1%, 2%, or 3% to the periorbital area twice daily for 8 weeks reduces visual wrinkle grading when compared with placebo. A dose analysis shows greater improvements in wrinkle parameters, average wrinkle depth, and mean depth with the lower concentration, while greater improvements in maximum roughness and maximum depth are observed with the higher concentration (108072). This study only included individuals defined as having Fitzpatrick skin type III or IV; it effects on other skin types is unclear. Preparations containing vitamin C in combination with other ingredients have also been investigated. A small low-quality trial in females with moderately photodamaged and hyperpigmented facial skin shows that applying a moisturizer with vitamin C 30%, vitamin E, and coenzyme Q10 once daily in the morning, along with applying retinol 0.5% once daily or once every other day for 12 weeks, seems to improve skin tone, photodamage, and wrinkles when compared to baseline (99085). In another small trial, a topical preparation containing vitamin C 10% as L-ascorbic acid along with acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (Cellex-C High Potency Serum) applied to photo-aged facial skin for 3 months improves fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). It is unclear if the beneficial effects of these products are due to vitamin C, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Acute bronchitis. Oral vitamin C doesn't seem to improve symptoms of acute bronchitis. Details: A clinical study in adults with acute bronchitis shows that taking vitamin C orally 500 mg on day 1, then 250 mg on days 2 through 5 (similar to an azithromycin regimen) doesn't seem to have any effect on quality of life or bronchitis duration when compared with azithromycin (9827).
• Asthma. Oral vitamin C doesn't seem to prevent asthma or improve lung function. Details: Although some observational research has found that some patients with asthma might have lower serum vitamin C levels (5873), other observational research found that increased dietary vitamin C intake is not associated with a reduced risk of asthma or improved lung function (15006,34567). In addition, clinical research shows that supplemental intake of vitamin C does not reduce asthma symptoms, improve lung function, or reduce the use of inhaled steroids in asthma patients (90409).
• Atherosclerosis. Oral vitamin C does not seem to reduce the progression of atherosclerosis. Details: A clinical study shows that taking a specific combination product containing slow-release vitamin C 250 mg and vitamin E 136 IU (CellaVie, Ferrosan A/S) twice daily modestly slows the 3-year progression of atherosclerosis of the carotid artery in males, but not females. This result persisted at a 6-year follow-up of this study (1918,10473). However, when this form of vitamin C is used alone, it does not slow the 3-year progression of atherosclerosis of the carotid artery (1918).
• Bladder cancer. Oral vitamin C does not reduce the risk of bladder cancer or mortality from bladder cancer. Details: Epidemiological research has found that supplemental vitamin C intake is not associated with mortality rate in patients with bladder cancer (9839). A secondary analysis of a large clinical trial, the Physicians' Health Study II, in healthy men aged at least 50 years also shows that taking vitamin C 500 mg daily alone or with vitamin E 400 IU daily for up to 10 years does not reduce the risk of developing bladder cancer or bladder cancer-related deaths when compared with placebo (90097).
• Cardiovascular disease (CVD). Oral vitamin C does not seem to be beneficial for either primary or secondary CVD prevention. Details: Vitamin C does not seem to be beneficial for primary prevention of CVD. Some population research has found that higher supplemental vitamin C or dietary vitamin C has been associated with a reduced risk of developing CVD (10358,14108,109779), while other observational research has found no benefit (34566,10358,14108). However, meta-analyses of clinical research in healthy patients show that vitamin C supplementation does not prevent CVD or coronary heart disease when compared with control (97308,104025). In 2004, the American Heart Association stated that current evidence does not justify use of antioxidants such as vitamin C for reducing the risk of CVD (12142). Evidence is also negative for secondary prevention in people with coronary heart disease. Population studies have found that higher serum vitamin C was associated with no effect or decreased CVD mortality from CVD (3910,5878). A meta-analysis of two large clinical trials shows that vitamin C supplementation does not reduce CVD events or CVD mortality when compared with control (97308).
• Colorectal cancer. Oral vitamin C does not seem to prevent colorectal cancer. Details: Population research has found that dietary vitamin C intake is not associated with a reduced risk of developing colon cancer. When total vitamin C intake from food and supplements is considered, there is a modest association (34600). However, most clinical trials show that supplemental vitamin C, alone or along with other antioxidants, does not reduce the risk of colorectal cancer development, colorectal cancer or adenoma recurrence, or colorectal cancer-related mortality (34580,34581,34594,90097,90089,92903).
• Coronavirus disease 2019 (COVID-19). Oral vitamin C, even at high doses, does not seem to speed recovery from COVID-19 in non-hospitalized patients. An analysis of clinical research suggests that oral or intravenous vitamin C might reduce mortality in patients hospitalized with COVID-19; however, given that nearly all individual studies are small and do not show benefit, larger and higher-quality studies are needed to confirm these findings. Details: A clinical study in adult outpatients with confirmed COVID-19 shows that taking oral vitamin C (ascorbic acid) 8000 mg in 2-3 divided doses daily, alone or with zinc gluconate 50 mg daily, for 10 days does not reduce symptom severity when compared with standard care (104450). The study was terminated prior to complete enrollment due to futility and apparent lack of effect from vitamin C and/or zinc supplementation. Limitations of this study include a lack of placebo control and blinding. Additionally, this study has been criticized for methodologic concerns (106624). Another small clinical trial in adult outpatients with confirmed COVID-19 shows that taking vitamin C 1000 mg daily for 14 days does not improve symptoms or quality of life when compared with placebo (109462). Vitamin C has also been evaluated in patients hospitalized with COVID-19. Individual prospective and retrospective studies in critically ill patients hospitalized with COVID-19 in various countries have found that administering vitamin C, either enterally as 500-1000 mg daily or intravenously as 8-24 grams daily or 50 mg/kg daily, does not significantly reduce in-hospital or short-term mortality, hospital length of stay, or end-organ failure when compared with control groups receiving standard care alone. Additionally, all but one study found no change in the need for mechanical ventilation (105458,105465,106937,106938,108075,108079,108081). One small study found a small improvement in survival rate when compared with standard care; however, the overall survival rate in this study was low (108075). Additionally, one clinical study in patients hospitalized in Turkey with COVID-19 shows that adding high-dose intravenous sodium ascorbate 50 mg/kg to a treatment regimen of hydroxychloroquine, azithromycin, and zinc may improve recovery time, with 57% and 39% of patients achieving total recovery at day 15 in the vitamin C and control groups, respectively (108071). However, the validity of this trial is limited due to unclear reporting. Additionally, these small studies were likely underpowered to detect differences between the vitamin C and control groups. A meta-analysis of 10 clinical trials and 9 observational studies in patients hospitalized with COVID-19 shows that receiving oral or intravenous vitamin C daily reduces the odds of in-hospital mortality by 41% when compared with control. When only clinical trials were considered, the odds of in-hospital mortality were decreased by 56%; however, this reduction was only identified in studies using vitamin C 10 grams daily or less. Conversely, supplementation with vitamin C increased the length of intensive care unit (ICU) stay by nearly 2 days and did not impact length of hospital stay or reduce the need for mechanical ventilation, liver injury, or cardiac injury (109955). Given that most individual studies in this analysis did not show improvements in mortality with vitamin C, larger and higher-quality prospective studies are needed to determine the role of vitamin C in hospitalized patients with COVID-19. Vitamin C has also been evaluated in patients with long COVID. Preliminary clinical research in adults with long COVID and persistent fatigue shows that taking a specific combination product containing vitamin C 500 mg and L-arginine 1.66 grams (Bioarginina C, Farmacetici Damor) for 28 days increases 6-minute walk test distance by 10% and reduces self-reported fatigue when compared with placebo (110390).
• Fetal and premature infant mortality. Oral vitamin C does not seem to prevent neonatal death. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of neonatal death (83472,96707).
• Fractures. Oral vitamin C does not seem to improve fracture healing. Details: Clinical research shows that taking vitamin C 500 mg daily for 50 days following an acute distal radial fracture does not improve physical function, symptoms, or healing rates when compared with placebo (90411).
• Helicobacter pylori. Oral vitamin C does not seem to improve eradication of H. pylori. Details: Most clinical research shows that treatment with vitamin C, alone or in combination with vitamin E, does not improve the eradication rate of H. pylori when taken with a standard eradication regimen when compared with the eradication regimen alone (83476,90094).
• Hereditary motor and sensory neuropathy. Oral vitamin C does not seem to improve neuropathy in these patients. Details: In a meta-analysis of five studies in patients with Charcot-Marie-Tooth disease type 1A, taking vitamin C 1-4 grams orally daily for 1 year did not improve neuropathy when compared with placebo (99084). Continuing vitamin C 4 grams daily for 2 years also does not improve neuropathy in these patients (90419).
• Interferon-related retinopathy. Oral vitamin C does not seem to improve retinopathy associated with interferon therapy. Details: A small clinical study in patients with chronic hepatitis C receiving interferon therapy shows that taking vitamin C 600 daily orally does not seem to reduce the risk of retinopathy from interferon therapy when compared with control (10355).
• Leukemia. Oral vitamin C does not seem to reduce the risk of leukemia or mortality from leukemia. Details: A large clinical trial in men aged at least 50 years shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing leukemia or leukemia-related deaths when compared with placebo (90097).
• Low birth weight. Oral vitamin C does not seem to reduce the risk of infants being born with a low birth weight. Details: Meta-analyses of clinical research show that maternal use of oral vitamin C alone or with other supplements does not reduce the risk of giving birth to infants with low birth weight when compared with control (83450,83472).
• Lung cancer. Oral vitamin C does not seem to reduce the risk of lung cancer. Details: Two meta-analyses of clinical research suggest that taking vitamin C, alone or in combination with vitamin E, does not reduce the incidence of lung cancer or lung cancer-related mortality (34528,34632). Also, a clinical study in females shows that taking supplemental vitamin C 500 mg daily, with or without vitamin E and beta carotene, is associated with an INCREASED risk of lung cancer when compared with placebo (34580).
• Melanoma. Oral vitamin C does not seem to reduce the risk of melanoma. Details: Clinical research shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing melanoma or melanoma-related deaths when compared with placebo in men aged at least 50 years (90097).
• Miscarriage. Oral vitamin C does not seem to reduce the risk of miscarriage. Details: A meta-analysis of clinical research shows that taking vitamin C alone or with other supplements does not reduce the risk of miscarriage when compared with control (94820).
• Overall mortality. Oral vitamin C does not reduce overall mortality. Details: Although population research suggests that higher dietary intake and higher plasma vitamin C levels are associated with a reduced risk of mortality from all causes (3910,109779), vitamin C supplementation does not seem to affect overall mortality. Meta-analyses of clinical research show that taking vitamin C supplements does not reduce overall mortality when compared with control (34622,111641). Clinical studies of vitamin C used in combination with vitamin E, beta carotene, and/or selenium and zinc, also show no benefit for overall mortality (9817,14109).
• Pancreatic cancer. Oral vitamin C does not seem to prevent pancreatic cancer. Details: Observational research has found that increased dietary vitamin C intake is associated with up to a 30% reduced risk of pancreatic cancer (99083,99086). However, clinical research shows that supplemental vitamin C 500 mg daily does not reduce the risk of pancreatic cancer in females (34580). Also, taking vitamin C in combination with beta-carotene plus vitamin E does not reduce the risk of pancreatic cancer (12185,34581).
• Pre-eclampsia. Oral vitamin C does not seem to prevent pre-eclampsia. Details: Despite some early positive research in high-risk pregnancies, the majority of meta-analyses and clinical studies show that taking vitamin C alone or with vitamin E or other supplements does not reduce the risk of pre-eclampsia when compared with control. There is even some concern that vitamin C supplementation may increase the risk of gestational hypertension (3236,83450,83472,83474,96707).
• Preterm labor. Oral vitamin C does not seem to prevent preterm labor. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of preterm labor when compared with control (83450,83472,96707).
• Prostate cancer. Oral vitamin C does not seem to prevent prostate cancer. Details: A large-scale clinical study (The SU.VI.MAX study) shows that a combination of vitamin C 120 mg, vitamin E (alpha-tocopherol) 30 mg, beta-carotene 6 mg, selenium 100 mcg, and zinc 20 mg, taken daily for an average of 8 years, does not reduce the risk of prostate cancer overall. However, it might reduce the risk of prostate cancer in those who have normal PSA levels. It does not seem to be beneficial for reducing the risk of prostate cancer in patients with PSA levels above 3 mcg/L (14135). Another large scale study (Physician's Health Study II) shows that taking vitamin C 500 mg daily for an average of 8 years does not significantly reduce the risk of prostate cancer when compared with placebo (16708). Similarly, results from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial seem to show that supplemental or dietary intake of vitamin C does not reduce the risk of prostate cancer when compared to individuals not taking vitamin C (14124).
• Radiation dermatitis. Topical vitamin C does not seem to prevent radiation dermatitis in cancer patients. Details: A small clinical study shows that applying a 10% vitamin C solution does not appear to protect from radiation dermatitis when applied to the scalps of patients treated with radiation for intracranial tumors (789).
• Small for gestational age (SGA). Oral vitamin C does not seem to reduce SGA. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of small for gestational age birth when compared with control (83450,83472).
• Stillbirth. Oral vitamin C does not seem to prevent stillbirth. Details: Meta-analyses of clinical research show that maternal use of vitamin C alone or with other supplements does not reduce the risk of stillbirth when compared with control (83472,96707).

LIKELY INEFFECTIVE

• Sepsis. Intravenous vitamin C, alone or in combination with thiamine and/or hydrocortisone, does not prevent organ failure, reduce intensive care or hospital length of stay, or reduce mortality in sepsis or septic shock. Details: Observational research suggests that patients with septic shock are more likely to have low plasma levels of vitamin C (100317). However, two randomized clinical trials in patients with sepsis show no benefit with intravenous vitamin C, with or without thiamine, for improving organ function and preventing organ failure when compared with control treatment (102130,104027). A clinical study in patients with septic shock shows that administering an intravenous bolus of vitamin C 1000 mg followed by a continuous infusion of 250 mg/hour for 96 hours, starting within 24 hours of vasopressor initiation, does not improve 28-day or intensive care unit (ICU) mortality when compared with placebo. A subgroup analysis shows that the addition of corticosteroids does not affect outcomes in either group (108078). This study may have been inadequately powered to detect a difference between groups. Also, a larger clinical trial in adults with sepsis receiving vasopressor therapy in the ICU shows that intravenous administration of vitamin C 50 mg/kg every 6 hours for up to 4 days increases the risk of death or persistent organ dysfunction at day 28 by 14% to 21% when compared with placebo. There were no differences in mortality at 6 months (109459,111643). Vitamin C has also been frequently studied in patients with sepsis and septic shock in a specific combination regimen (HAT therapy) which includes intravenous vitamin C 1.5-2 grams with hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours. While some retrospective research has found HAT therapy to be beneficial in sepsis (100315,102980), high quality, prospective clinical research has not confirmed these findings (105447,106620,109956). Several meta-analyses of randomized controlled trials and small clinical studies in patients with sepsis or septic shock show that intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, does not reduce short- or long-term mortality, ICU or hospital length of stay, kidney injury, or duration of mechanical ventilation, but modestly improves duration of vasopressor use and procalcitonin clearance, when compared with placebo or standard care. These analyses also show mixed results with respect to improvement in sequential organ failure assessment (SOFA) scores within 72 hours (105447,106620,106935,108073,109460,111298,111300,111301,111642,112479). Most studies included in the analyses administered HAT therapy for 2-10 days and compared it with normal saline control or with hydrocortisone alone (102129,102998,104027,104028,104032,105446). Although some subgroup analyses suggests that intravenous vitamin C alone in patients with sepsis may improve short-term mortality (106620,111298), other meta-analyses have not shown this benefit in subgroup analyses (111300). In addition, meta-analyses have identified significant publication bias (111298,111300). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for some domains, HAT therapy was worse when compared with placebo (111299). Studies evaluating intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, in mixed critically ill populations have also shown mixed findings. One such large meta-analysis of 27 randomized controlled trials and 21 observational studies shows that intravenous vitamin C reduces in-hospital mortality by 19% and ICU stay by about 1 day, but does not have a significant effect on hospital stay, mortality at 1 month, ICU mortality, or kidney injury, when compared with placebo or standard care. Also, effects on in-hospital mortality were no longer significant when data from randomized controlled trials were considered alone (106933). Other meta-analyses including 15-16 randomized controlled trials show that intravenous vitamin C, alone or as a component of HAT therapy, does not reduce overall, ICU, or in-hospital mortality when compared with control (106934,109957). A subgroup analysis in one of these analyses suggests that intravenous vitamin C as monotherapy, or in doses of at least 10 grams daily, may improve overall mortality (106934). Vitamin C also does not appear to benefit complications from sepsis, such as vasoplegic shock. A small clinical study in adults in the ICU with vasoplegic shock mostly secondary to sepsis and requiring moderate vasopressor support shows that administering intravenous vitamin C as sodium ascorbate 1.5 grams every 6 hours for 5 days or until cessation of vasoactive therapy does not reduce the duration of vasopressors, vasopressor dose, hospital or ICU length of stay, or mortality outcomes when compared with placebo (112475).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atrophic acne scars. It is unclear if applying topical vitamin C after microblading improves atrophic acne scars. Details: A clinical study in adults with mild to severe atrophic acne scarring shows that applying a serum containing vitamin C 17% to the face after a once-monthly home microblade treatment for 4 months improves the appearance of acne scars at month 5 when compared with baseline (108086). Although this study enrolled a control group that used topical insulin in place of vitamin C, no between-group statistical comparisons were conducted, limiting the validity of this study.
• Age-related macular degeneration (AMD). Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Most clinical research shows that taking the antioxidants vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily, with or without elemental zinc 80 mg, reduces the risk of visual acuity loss by 23% to 27% and reduces the risk of progression to advanced AMD at 5 years by 25% to 32% in patients at high risk for developing advanced AMD (7303,7304,11326,90069). The antioxidant plus zinc combination seems to reduce the risk of progression to advanced AMD in these patients more than taking the antioxidants without zinc (7303,90069). There is not enough evidence to know if taking the antioxidants or antioxidants plus zinc prevents progression to advanced AMD in patients with early stage AMD (7303,7304). The effect of vitamin C intake on developing AMD is unclear. Some population studies have found no association between dietary or supplemental vitamin C intake on risk of developing AMD (14007,14257). In one population study, vitamin C intake was associated with increased odds of developing age-related maculopathy (9823); however, in another population study, intake of vitamin C along with other antioxidants and zinc was associated with a reduced risk of AMD (14257). More evidence is needed to determine what role, if any, vitamin C intake has on the risk of developing AMD.
• Aging skin. Topical vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females aged 30-65 years shows that applying a specific liquid (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Albuminuria. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking vitamin C 1250 mg plus vitamin E 680 IU daily for 4 weeks can reduce the excretion of albumin by about 19% when compared with placebo in patients with type 2 diabetes (10434).
• Allergic rhinitis (hay fever). It is unclear if oral vitamin C is beneficial in patients with hay fever. Details: Epidemiological research has found that higher vitamin C plasma levels are not associated with a decreased risk of allergic rhinitis (15200). However, clinical research shows that some forms of vitamin C might help. In one small clinical study, intranasal vitamin C administered three times daily for 2 weeks reduces nasal secretions, nasal blockage, and edema in up to 74% of patients with perennial allergic rhinitis (15201). Another small clinical study in patients with seasonal allergic rhinitis shows that taking a single oral dose of vitamin C 2 grams reduces bronchial responsiveness to histamine at one hour after ingestion (15202). However, in another small study in patients with seasonal allergic rhinitis taking vitamin C orally in doses up to 4 grams daily for 3 days does not appear to suppress cutaneous or nasal response to histamine when compared to placebo (15203).
• Alzheimer disease. It is unclear if dietary vitamin C helps to prevent this condition. Details: Most epidemiological research has found that dietary intake of vitamin C is associated with a 17% reduced risk of developing Alzheimer disease (4636,9824,10131,13165,90082).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral vitamin C helps to prevent ALS. Details: Observational research has found that increased dietary or supplemental intake of vitamin C is not associated with risk of developing ALS (90412).
• Anthracycline cardiotoxicity. Although there is interest in using oral vitamin C for anthracycline-induced cardiac toxicity, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Aspirin-associated gastric damage. It is unclear if oral vitamin C helps to prevent gastric damage caused by aspirin. Details: Some clinical research shows that vitamin C 480 mg might prevent gastric damage associated with taking aspirin 400 mg by decreasing blood loss and preventing decreased gastric blood flow (10357). However, a small clinical study in healthy patients shows that taking vitamin C 500 mg as ascorbic acid with aspirin 600 mg actually increases gastrointestinal permeability to a greater extent than either ingredient taken alone (98781).
• Athletic performance. It is unclear if oral vitamin C improves athletic performance. Details: Although some small preliminary clinical studies suggest that vitamin C might improve certain biomarkers during exercise (82922), a meta-analysis of small clinical trials in older and younger adults shows that taking vitamin C 500-1000 mg daily, with or without vitamin E, does not improve endurance, lean mass, or muscle strength when compared with placebo (102973). A more recent, small clinical study in recreationally trained males shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg daily for 10 weeks while participating in a resistance training program does not improve measures of muscle strength when compared with placebo (109959).
• Atopic disease. It is unclear if dietary vitamin C helps to prevent atopic disease. Details: Population research has found that higher intake of vitamin C is not associated with a reduced risk of eczema, wheeze, IgE-mediated food allergy, or allergic sensitization (90098).
• Attention deficit-hyperactivity disorder (ADHD). Small clinical studies suggest that high-dose oral vitamin C may not improve symptoms in patients with ADHD. Details: Some research suggests that taking megadose vitamins, including vitamin C, does not improve ADHD symptoms (9957,9958,9959). However, other preliminary clinical research shows that taking 25 mg of vitamin C in combination with flaxseed oil providing alpha-linolenic acid 200 mg twice daily might improve measures of attention, impulsivity, restlessness, and self-control in children with ADHD when compared with baseline (14443). It is not clear if these effects are due to vitamin C, flaxseed oil, or the combination.
• Autism spectrum disorder. It is unclear if oral vitamin C is beneficial in patients with autism spectrum disorder. Details: One small clinical study shows that taking vitamin C 8 grams per 70 kg daily for 10 weeks modestly reduces autism symptom severity in school children when compared with placebo (83604).
• Bleeding. It is unclear if intravenous vitamin C can reduce bleeding after total abdominal hysterectomy. Details: A small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery reduces postoperative hemorrhage volume by around 40 mL when compared with placebo (109465).
• Brain tumor. It is unclear if oral vitamin C helps to prevent brain tumors. Details: Population research has found that vitamin C intake is associated with a 14% reduced risk of glioma. This risk reduction was more prevalent in America compared to other geographic locations (98782).
• Breast cancer. It is unclear if oral vitamin C helps to prevent breast cancer, its recurrence, or breast cancer-related mortality. Details: Some epidemiological research has found that dietary vitamin C is associated with a reduced risk of breast cancer (1444,10823,10824). However, other epidemiological research has found no association with dietary or supplemental vitamin C (10825,10826,108080). One cohort study found no association between breast cancer risk and total, dietary, or supplemental vitamin C, regardless of dose, treatment duration, or formulation (single ingredient or combination product). Additionally, hormone and menopausal status did not appear to impact risk. Vitamin C intake might be associated with a reduced risk in individuals with a family history of breast cancer in first-degree relatives (108080). In patients with breast cancer, supplemental or dietary intake of vitamin C might be associated with a reduced risk of mortality. A meta-analysis of results from population research shows that vitamin C supplementation following breast cancer diagnosis is associated with a 15% lower risk of breast cancer-related mortality when compared with no supplementation (90416). A large, observational study in patients with breast cancer undergoing radiation therapy has found that vitamin C supplementation does not reduce the risk of breast cancer recurrence over a period of 5 years when compared with no supplementation. Although the vitamin C group had notably less aggressive tumor types, recurrence-free survival was similar in both vitamin C and control groups (108082). The validity of these findings is limited due to unknown doses of vitamin C and the inclusion of various breast cancer subtypes.
• Burns. Small studies suggest that intravenous vitamin C may modestly improve symptoms in patients with severe burns. Details: A small clinical study in patients with severe burns shows that administering vitamin C intravenously (IV) 66 mg/kg hourly over 24 hours, as part of fluid resuscitation using lactated ringer solution, reduces wound edema and the volume of fluid needed when compared with fluid resuscitation alone (83145). A retrospective review of adults hospitalized with severe burns has found that those who receive a continuous IV infusion of at least 10 grams of vitamin C within 2 days of admission have an in-hospital mortality rate of 46%, compared with 58% for those who do not receive vitamin C (102128).
• Cancer. It is unclear if oral or intravenous vitamin C helps to prevent cancer or cancer-related mortality. Details: Some population research has found that DIETARY intake of vitamin C is linked with a lower risk of cancer and cancer-related mortality (3910,5878,10819,109779). However, clinical research shows that taking vitamin C SUPPLEMENTS does not reduce the risk for cancer (10819,14109,34580,90097). In people with cancer, although some clinical research has shown that taking high-dose vitamin C supplements can improve survival rates (9809,96704), other clinical research has not shown this benefit (4842,4843). In 2003, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that some scientific evidence suggests that antioxidant vitamins, such as vitamin C, may reduce the risk of certain forms of cancer. However, the FDA has determined that there is little scientific evidence supporting this claim (102334). Preliminary clinical research has also evaluated vitamin C supplements in patients with cancer. High-dose oral vitamin C, 10 grams daily, in patients with advanced cancer does not seem to improve survival or decrease disease progression (4842,4843,106617). However, preliminary clinical research suggests high doses of vitamin C, given intravenously, might have a beneficial effect on some outcomes, including survival rate in some patients with cancer (9809,96704,106617). However, there is no benefit to other patients studied in the case reports and this has not been tested in well-designed clinical trials (9809,96704).
• Carpal tunnel syndrome. Vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamins C, E, B1, B2, B6, and B12, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, and turmeric twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to vitamin C, other ingredients, or the combination.
• Cataracts. It is unclear if oral vitamin C helps to prevent cataracts. Details: Population research has found that people with the highest total intake of vitamin C have about a 19% reduced risk of developing cataracts when compared with those with the lowest total intake. The greatest benefit is observed for nuclear cataracts (96711). A separate study found that higher supplemental intake of vitamin C for 10 years is associated with a 60% reduction in the incidence of nuclear and cortical cataracts (4208). Other population research has found that the highest blood levels of vitamin C are associated with a 33% reduced odds of developing age-related cataract, but any benefit seems to be limited to Asian populations (90944). One prospective clinical study shows that taking vitamin C plus vitamin E and beta-carotene does not prevent the development or progression of age-related loss of vision due to cataracts in well-nourished people taking the supplement for an average of 6.3 years (7304).
• Cervical cancer. It is unclear if oral vitamin C helps to prevent cervical cancer. Details: Observational research has found that higher vitamin C intake is associated with a 33% to 42% reduced odds of cervical neoplasm. Increasing vitamin C intake by 50 mg daily is associated with an 8% reduced odds of cervical neoplasm (34609,98771).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral vitamin C for CFS, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Colistin-induced nephrotoxicity. It is unclear if intravenous vitamin C helps to prevent nephrotoxicity from colistin. Details: A small clinical study shows that intravenous administration of vitamin C 2 grams every 12 hours along with colistin for around 9-10 days does not prevent nephrotoxicity when compared with colistin therapy alone (99839). However, this study was limited by a lack of statistical power to detect differences between the study groups.
• Contrast induced nephropathy. It is unclear if oral vitamin C helps to prevent contrast-induced nephropathy (CIN). Details: Some clinical research shows that taking vitamin C before and after coronary angiography reduces the risk of developing CIN by 33% to 55% when compared with placebo in patients with renal dysfunction (12234,90421). However, other clinical evidence published since 2012 suggests that vitamin C given orally and/or intravenously before and after angiography does not reduce the risk of CIN compared with control in high-risk patients with chronic renal insufficiency or diabetes (91232,91236,90410,90425). Reasons for the discrepancies are not entirely clear. However, it is possible that the lack of significant benefit from vitamin C in the latter studies results from the fact that incidences of CIN have become less common than in the past due to avoidance of dehydration, use of smaller catheters, and use of contrast agents with reduced nephrotoxicity (90429).
• Coronary artery bypass graft (CABG) surgery. It is unclear if intravenous vitamin C helps to improve patient outcomes after CABG surgery. Details: A small clinical study shows that giving vitamin C 5 grams intravenously (IV) before anesthesia induction and 5 grams in the cardioplegia solution used during surgery shortens the length of stay in the intensive care unit (ICU) by about 8 hours (102127). However, some limited research suggests that IV vitamin C does not resolve cardiac surgery complications. A small clinical study in patients with vasoplegia after receiving CABG and other cardiac surgeries shows that receiving IV vitamin C 1.5 grams every 6 hours after being admitted to the ICU does not improve vasoplegia when compared with control (102981).
• Delirium. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001).
• Dental plaque. It is unclear if vitamin C in a chewing gum helps to reduce dental plaque formation. Details: A small clinical study in patients with calculus shows that chewing 10 pieces of gum, each containing 60 mg of vitamin C, daily for 3 months reduces the formation of dental calculus, visible plaque, and the number of bleeding sites when compared not chewing gum (83303). The validity of this finding is limited by a lack of placebo group.
• Depression. It is unclear if oral vitamin C is beneficial for the treatment or prevention of depression. Details: A small clinical study in children and adolescents shows that taking vitamin C 500 mg orally twice daily in combination with fluoxetine 10-20 mg daily for 6 months reduces most symptoms of major depressive disorder when compared with taking fluoxetine alone (90404). However, a small clinical study in adults shows that taking vitamin C up to 1000 mg daily for 2 months does not improve the response rate or decrease symptoms of depression in adults also taking citalopram when compared with citalopram alone (96708). Reasons for these conflicting results may relate to the age of the patients, study duration, or differences in antidepressant medication being taken. One clinical guideline also provisionally recommends against the use of oral vitamin C to treat patients with depression based on low-quality evidence (110318). Some research has also evaluated vitamin C intake for the prevention of depression. A secondary analysis of pre- and peri-menopausal adults enrolled in the Study of Women's Health Across the Nation (SWAN) program suggests that vitamin C intake is inversely associated with depressive symptoms. This association persisted regardless of age, race, physical activity, body mass index, antidepressant use or menopausal status (108083). The validity of these findings is limited due to the secondary nature of this study; additionally, follow-up time is unclear.
• Diabetes. It is unclear if oral vitamin C prevents diabetes. Some low-quality research suggests that vitamin C might improve glycemic control in patients with diabetes. Details: Population research has not found a link between dietary vitamin C and the risk of developing type 2 diabetes (14004). However, low certainty clinical research has found some benefit of taking vitamin C supplements for glycemic control. Two meta-analyses of several small, heterogeneous clinical studies in patients with type 2 diabetes show that taking vitamin C 200-3000 mg daily for 2-48 weeks reduces fasting blood glucose by approximately 11 mg/dL (112478) and glycated hemoglobin (HbA1c) by an average of 0.5% when compared with placebo, standard treatment, or no treatment (105461,112478). Subgroup analyses suggest that durations of supplementation longer than 12 weeks show greater glycemic benefit, and although one meta-analysis suggests there is no dose-response relationship (105461), another meta-analysis suggests that doses of vitamin C 1000 mg and higher are most beneficial for improving glycemic indices (112478). Some research has evaluated the effects of vitamin C supplementation on the lipid profile in patients with diabetes, with mixed findings. One meta-analysis of 17 small clinical studies shows that taking vitamin C 200-3000 mg daily for 2 to 48 weeks improves levels of triglycerides and total cholesterol, but not low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol. Subgroup analysis suggests that study durations of at least 12 weeks show greater benefit (106621). However, two other meta-analyses in patients with diabetes, one of 16 small heterogenous clinical studies and one of 11 small clinical studies, show no clinically important improvement in lipid levels after vitamin C supplementation (105461,105464).
• Dry mouth. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical trial in patients receiving radiotherapy for head and neck cancer shows that taking vitamin E 100 IU and vitamin C 500 mg twice daily for an average of 3 months improves dry mouth when compared to baseline (99080). The validity of these results is limited by the lack of comparison with a control group.
• Endometrial cancer. Increased dietary vitamin C has been linked to reduced risk of endometrial cancer. Details: Population research has found that intake of vitamin C from dietary sources is associated with a slightly decreased risk of endometrial cancer when compared with control. However, this benefit is not observed when results from a prospective cohort study are assessed (34578).
• Endometriosis. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with endometriosis and pelvic pain shows that taking vitamin C 1000 mg and vitamin E 800 IU daily for 8 weeks improves dysmenorrhea, dyspareunia, and chronic pelvic pain scores when compared with placebo. Vitamin C and vitamin E supplementation also reduces some biochemical markers of oxidative stress when compared with placebo (106622).
• Endoscopy-associated adverse effects. It is unclear if a topical vitamin C spray reduces mucosal irritation in patients undergoing Lugol chromoendoscopy. Details: A small clinical trial in patients receiving a Lugol chromoendoscopy shows that spraying a vitamin C 2% solution after the application of the Lugol iodine 2% solution reduces the severity of mucosal irritation, heartburn, and pain when compared with using a normal saline spray after the Lugol iodine 2% solution (104030).
• Esophageal cancer. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research has found that higher dietary intake of vitamin C is associated with reduced odds of esophageal adenocarcinoma. A 50 gram increase in dietary vitamin C intake is associated with a 13% reduced odds of esophageal cancer (34551,98770). However, a meta-analysis of clinical research shows that taking a vitamin C supplement in combination with beta-carotene and vitamin E does not reduce the risk of esophageal cancer (34581).
• Exercise-induced asthma. Small clinical studies suggest that oral vitamin C may modestly improve symptoms in patients with exercise-induced asthma. Details: A meta-analysis of the available clinical research shows that vitamin C supplementation might reduce exercise-induced breathlessness when compared with placebo or control. However, the available research is of poor quality, and no clear conclusions can be drawn regarding its benefits for exercise-induced asthma (90409).
• Exercise-induced muscle damage. It is unclear if oral vitamin C is beneficial in exercise-induced muscle damage. Details: A small clinical study in healthy females shows that taking vitamin C 1000 mg before moderate intensity cycling does not prevent muscle damage when compared with placebo (99837). Another small clinical study in endurance-trained runners shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg 2 hours prior to an exercise protocol does not reduce delayed onset muscle soreness or improve other markers of exercise-induced muscle damage when compared with placebo (109961).
• Gallbladder disease. It is unclear if oral vitamin C reduces the risk of gallbladder disease. Details: Cross-sectional epidemiological evidence has found that vitamin C supplementation and increased vitamin C serum levels are associated with a decreased risk of developing gallbladder disease in females, but not males (5877).
• Gastric cancer. It is unclear if dietary or supplemental vitamin C reduces the risk of gastric cancer. Details: Most population research has not found an association between DIETARY intake of vitamin C and gastric cancer risk (9194,10822,10819,90083). Also, clinical research shows that taking vitamin C supplements in combination with other antioxidants does not reduce the risk of gastric cancer or precancerous gastric lesions (14447,34581,90085). However, some research suggests that it might be associated with a reduced risk for specific forms of gastric cancer (9838,90083). One clinical study shows that taking vitamin C orally 500 mg daily for 6 months after eradication of Helicobacter pylori infection decreases the incidence of precancerous changes in stomach tissue when compared with no treatment (10359). Also, other clinical research shows that taking vitamin C orally 1 gram daily helps promote the regression of precancerous gastric lesions in people at high risk for gastric cancer (2579). In 2009, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that vitamin C supplements may reduce the risk of gastric cancer. However, the FDA has concluded that it is highly uncertain that vitamin C supplements actually reduce the risk of gastric cancer (102332).
• Gastritis. There is limited evidence on the oral use of vitamin C in omeprazole-induced corpus gastritis. Details: A small clinical study shows that taking vitamin C orally 1200 mg daily along with omeprazole decreases corpus gastritis associated with omeprazole therapy in patients with H. pylori infection (10360).
• Gout. It is unclear if oral vitamin C helps to prevent or manage gout. Details: Population research in men has found that taking vitamin C 500-1500 mg daily from the diet and/or supplements is associated with up to a 34% reduced risk of gout when compared with less than 250 mg daily (16755). Also, men who ingest over 500 mg of vitamin C daily from the diet and supplements have serum uric acid levels that are slightly lower than men who consume less than 90 mg daily (16820). However, taking supplemental vitamin C 500 mg daily for 8 weeks does not seem to lower serum uric acid levels in patients who already have gout (90423).
• Hearing loss. There is limited evidence on the intravenous use of vitamin C in idiopathic sudden sensorineural hearing loss. It is unclear if dietary vitamin C intake can affect the risk of hearing loss. Details: A small clinical study in patients with idiopathic sudden sensorineural hearing loss shows that receiving intravenous high-dose vitamin C 200 mg/kg daily in combination with steroid therapy for 10 days, followed by oral vitamin C 2000 mg daily for 30 days, increases recovery rate two-fold and modestly improves hearing threshold levels when compared with receiving steroid therapy only (90417). In addition, population research in females has found that high dietary intake of vitamin C is associated with a 22% increased risk of developing self-reported hearing loss over a 22-year period when compared with low intake (109807).
• Heart transplant complications. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of vitamin C 500 mg and vitamin E 400 IU, taken twice daily for 1 year starting within the first 2 years after cardiac transplant, reduced the progression of vasculopathy as measured by intravascular ultrasonography (IVUS) when compared with placebo. This suggests that the combination may help slow the progression of CAV (82826).
• Hepatitis C. It is unclear if oral vitamin C is beneficial in patients with hepatitis C. Details: A small clinical study in patients with confirmed hepatitis C shows that taking vitamin C 1000 mg daily with conventional therapy (sofosbuvir plus daclatasvir) for 4 weeks improves serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and albumin when compared with conventional therapy alone (109463).
• HIV/AIDS. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, low-quality study in men with HIV shows that taking vitamin C 250 mg daily in combination with vitamin A, beta-carotene, vitamin E, selenium, and coenzyme Q10 does not improve viral load, although it seems to improve markers of oxidative stress when compared to baseline. However, a 1000 mg dose of vitamin C, as well as higher doses of the other antioxidants, do not seem to provide any additional effect (9830).
• HIV transmission. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in HIV-positive mothers shows that taking vitamin B, vitamin C, and vitamin E daily during pregnancy and while breast-feeding for 20 weeks seems to reduce child mortality and HIV transmission through breast milk when compared with taking vitamin A (9801).
• Hyperphosphatemia. Intravenous vitamin C might be beneficial for reducing phosphate levels in patients with end-stage renal disease. Details: A small clinical study in hemodialysis patients with elevated phosphorus levels suggests that administering vitamin C 500 mg intravenously three times weekly for 8 weeks reduces phosphorus levels about seven-fold when compared with placebo (90414).
• Idiopathic interstitial pneumonia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with idiopathic pulmonary fibrosis, a form of idiopathic interstitial pneumonia, shows that taking a combination of vitamin C 250 mg every other day, vitamin D 50,000 IU daily, and vitamin E 200 IU daily for 12 weeks improves some, but not all, measures of lung function and reduces markers of inflammation and oxidative stress when compared to baseline (109464). The validity of these findings is limited by a lack of placebo control group.
• Infertility. It is unclear if oral vitamin C is beneficial in anovulatory females. Details: A very small clinical study suggests that taking vitamin C 400-1000 mg daily might improve fertility, resulting in ovulation and pregnancy in some anovulatory females, when compared with baseline (14018). The validity of these findings is limited by the small study size and lack of a comparator group.
• Male infertility. It is unclear if oral or intravenous vitamin C is beneficial in males with infertility. Details: A meta-analysis of three small, low-quality clinical trials in males with infertility shows that taking vitamin C up to 1000 mg daily for up to 12 weeks can improve sperm count, motility, and vitality, but does not seem to increase semen volume or sperm concentration, when compared with control (109461). It is unclear if vitamin C can increase pregnancy rates, as these studies did not assess this outcome. A retrospective study in males with or without varicocele-related infertility has found that taking a specific combination product containing vitamin C 90 mg, zinc 10 mg, L-carnitine fumarate 1725 mg, acetyl-L-carnitine 500 mg, coenzyme Q10 20 mg, folic acid 0.2 mg, selenium 0.05 mg, and vitamin B12 0.015 mg (Proxeed Plus, Sigma-Tau) orally twice daily for 6 months improves sperm count, sperm concentration, and sperm motility when compared with baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles. The validity of this study is limited by the lack of a comparator group (111296).
• Mastalgia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin C 100 mg, vitamin B12, and gamma-linolenic acid daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Melasma. It is unclear if topical vitamin C is beneficial in patients with melasma. Details: A small clinical study in patients with bilateral symmetrically distributed facial melasma shows that topical application of 0.5 mL of vitamin C (Cosmotech, Alpha Medical Cosmotech) following dermapen microneedling every 2 weeks for 6 weeks is similarly effective to tranexamic acid for improving melasma severity and pigmented, but not vascular, findings on dermoscopic examination (106939).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin C is beneficial in patients with NAFLD. Details: A clinical study in patients with NAFLD shows that taking vitamin C 250 mg, 1000 mg, or 2000 mg daily for 12 weeks improves some biochemical markers of liver health and glucose metabolism when compared with baseline. However, the improvement from baseline was similar between groups (106942).
• Nonalcoholic steatohepatitis (NASH). Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests vitamin C in combination with vitamin E might improve hepatic fibrosis in patients with NASH. However, it does not seem to decrease liver inflammation (14005).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin C reduces the risk of developing diffuse large B-cell lymphoma. Details: In one population study, higher dietary or supplemental intake of vitamin C was associated with a reduced risk of diffuse large B-cell lymphoma, a type of non-Hodgkin lymphoma, when compared with lower intake in postmenopausal adults (90945).
• Oral cancer. It is unclear if oral vitamin C reduces the risk of developing oral cancer. Details: Population research has found that higher dietary intake of vitamin C is associated with a reduced risk of oral cancer (10821). However, clinical research has not shown benefit with oral vitamin C supplements. A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Oral leukoplakia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not improve leukoplakia symptoms or reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Osteoarthritis. It is unclear if dietary vitamin C reduces the risk of developing osteoarthritis. Details: Observational research has found that increased vitamin C from dietary sources is associated with a reduced risk of cartilage loss and disease progression in people with osteoarthritis (5881).
• Osteoporosis. It is unclear if dietary vitamin C improves bone density or reduces fracture risk in patients at risk for osteoporosis. Details: Some cross-sectional observational research in postmenopausal patients without a history of smoking or estrogen use has found that higher serum vitamin C levels are associated with lower bone mineral density (9828). However, other observational research in a larger population of adults at risk for osteoporosis has found that higher dietary vitamin C intake is not associated with fracture risk (104415).
• Ovarian cancer. Dietary vitamin C might not affect the risk of ovarian cancer. Details: Epidemiological research has found that dietary vitamin C intake is not linked with ovarian cancer risk (9193,102977).
• Pancreatitis. It is unclear if intravenous vitamin C is beneficial in patients with acute pancreatitis. Details: A small meta-analysis of clinical studies in patients with acute pancreatitis shows that intravenous vitamin C does not improve the odds of developing organ failure when compared with placebo or no intervention. Intravenous vitamin C seems to reduce hospital stay, but not in-hospital mortality (106941).
• Parkinson disease. Dietary vitamin C might not affect the risk of developing this condition. Details: Observational research has found that moderate or high dietary intake of vitamin C is not associated with a reduced risk of Parkinson disease (83316).
• Periodontitis. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is also unclear if dietary vitamin C reduces the risk of periodontitis. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing vitamin C 100 mg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, selenium, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not improve periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation, among others, when compared with placebo (111708). It is unclear if these effects are due to vitamin C, other ingredients, or the combination. There is also interest in whether dietary vitamin C intake impacts the risk of periodontitis. Observational research in US adults has found that individuals with dietary intake of vitamin C in the third quartile, but not the second or fourth quartiles, have lower odds of periodontitis when compared with vitamin C intake in the lowest quartile. Furthermore, the investigators identified a non-linear relationship between vitamin C intake and periodontitis risk, suggesting that individuals with intakes either much lower or much higher than 158 mg daily are at increased risk of developing periodontitis (109958).
• Peripheral arterial disease (PAD). It is unclear if dietary vitamin C helps to reduce the risk of developing PAD. Details: In females, epidemiological evidence has found that dietary intake of vitamin C of 142 mg daily or greater is associated with a 36% reduced risk of PAD when compared with lower intake levels of less than 80 mg daily (10130).
• Physical performance. It is unclear if oral vitamin C helps to improve physical performance and muscle strength in older people. Details: Population research has found that higher intake of dietary vitamin C is associated with improved physical performance and muscle strength in elderly people (14006). In contrast, a small clinical study in elderly men undergoing strength training shows that taking vitamin C 1000 mg and vitamin E 258IU daily for 12 weeks does not increase strength, and might even attenuate increases in muscle mass, when compared with strength training alone (96701).
• Pneumonia. It is unclear if oral vitamin C helps to prevent pneumonia. Details: A meta-analysis of two small, low-quality clinical studies in children shows that vitamin C does not seem to reduce the occurrence of pneumonia when compared to control (104033).
• Postoperative recovery. It is unclear if oral or intravenous vitamin C improves postoperative recovery. Details: Meta-analyses of clinical research show that oral or intravenous vitamin C can shorten the duration of hospitalization after cardiac surgery when compared with control (91233,96703). However, other research shows no decrease in intensive care or hospital stay with vitamin C supplementation (96705). A meta-analysis of 37 clinical trials in adults undergoing low- to high-risk noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, or kidney transplantation), shows that receiving perioperative vitamin C, either orally or intravenously, does not improve duration of hospitalization or overall mortality when compared with control (108087). There's also some limited evidence that vitamin C might reduce postoperative pulmonary complications such as lung infection, pleural effusion, and pneumothorax. A small clinical trial in low-risk cardiac surgery patients shows that receiving intravenous vitamin C 1 gram 10 minutes after anesthesia might slightly reduce the rate of postoperative pulmonary complications when compared with receiving a saline injection (104034).
• Premature rupture of membranes (PROM). Oral vitamin C seems to reduce the risk of PROM in some patients; however, the addition of oral vitamin E seems to negate any benefit. Details: A meta-analysis of clinical research shows that taking vitamin C alone decreases the risk of both term and preterm PROM by 45% and 34%, respectively, when compared with placebo or control (96707). Also, a more recent clinical study in patients with a history of PROM shows that taking vitamin C 100 mg daily, starting at 14 weeks' gestation, increases the gestational age at recurrent PROM by around 1 week and increases the gestational age at birth by around 1.3 weeks when compared with placebo (109960). Taking vitamin C in combination with vitamin E, however, does not seem to reduce the risk of term or preterm PROM; some research suggests that it might even increase the risk of non-preterm PROM (83472,96707). However, other research shows that taking vitamin C 1000 mg plus vitamin E 400 IU daily, beginning at 24 to 34 weeks gestation and continuing until delivery, may help increase the latency period until delivery by 5 days and increase gestational age at delivery by almost 1 week when compared with placebo in patients with preterm PROM (90078).
• Pressure ulcers. It is unclear if oral vitamin C, when used alone or in combination with other ingredients, can improve the healing of pressure ulcers. Details: A small clinical study in institutionalized patients with pressure ulcers shows that taking vitamin C 500 mg twice daily for 12 weeks does not improve wound closure or increase healing rates when compared with vitamin C 10 mg twice daily (83617). Oral vitamin C has also been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients with pressure ulcers shows that administering an oral nutritional supplement enriched with vitamin C, L-arginine, and zinc improves ulcer healing when compared with a standard diet (31953,87173). Also, clinical research in patients living in long-term care facilities shows that taking an oral nutritional supplement enriched in protein, vitamin C, L-arginine, and zinc daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Radiation proctopathy. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with chronic radiation proctitis shows that vitamin C 500 mg plus vitamin E 400 IU three times daily might improve symptoms when compared with baseline (9825). The validity of these findings is limited by the lack of a comparator group.
• Renal cell carcinoma. It is unclear if increased dietary intake of vitamin C helps to reduce the risk of renal cell carcinoma. Details: Population research has found that increased dietary intake of vitamin C is associated with a 12% reduced risk of renal cell carcinoma (98779).
• Respiratory tract infections. It is unclear if oral vitamin C is beneficial for preventing respiratory tract infections or reducing the duration of these infections. Details: A meta-analysis of clinical research in children and adults shows that, when compared with placebo, oral vitamin C supplementation reduces the average number of symptomatic days per individual, but does not reduce the average symptom days per respiratory episode. Also, vitamin C intake does not reduce the incidence or severity of respiratory disease or improve recovery in hospitalized patients with respiratory tract infections (108077). The validity of this trial is limited by the high heterogeneity of included studies, which evaluated various vitamin C regimens, ranging from 100 mg to 8 grams daily, as preventive therapy or as an adjuvant to active treatment. A clinical study in children aged 3-10 years shows that taking vitamin C 50 mg in combination with a specific product (Lab4) containing Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium animalis subsp. lactis daily for 6 months reduces the incidence of cough and sore throat by 16% and 20%, respectively, when compared with placebo. However, it did not improve total symptoms, nasal congestion, nasal discharge, or sneezing. Also, aside from a 33% reduction in the average number of days with a sore throat, daily supplementation does not reduce the duration of individual symptoms or total symptoms (106943). It is unclear if these effects are due to vitamin C, the probiotics, or the combination.
• Restless legs syndrome (RLS). It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in hemodialysis patients with RLS shows that taking vitamin C 200 mg daily, alone or in combination with vitamin E 400 mg, for 8 weeks reduces the severity of RLS when compared with placebo (90093). More research is needed to determine if vitamin C is beneficial in treating RLS that is not associated with hemodialysis.
• Sunburn. Topical and oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking vitamin C orally in combination with vitamin E seems to prevent ultraviolet (UV) radiation-induced erythema (sunburn) (4715,4716). Vitamin C in combination with high dose oral RRR-alpha-tocopherol (natural vitamin E) seems to protect against skin inflammation after exposure to UV radiation (4715). Also, applying topical vitamin C in combination with topical vitamin E and melatonin seems to provide modest photoprotective effects when used prior to UV exposure. However, it has no effect when used during or after UV exposure (4713,4714).
• Stress. It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in healthy adults shows that taking vitamin C 3000 mg daily for 14 days modestly reduces blood pressure and subjective stress response to psychological stress when compared with placebo (10353).
• Stroke. Observational research has found that although taking vitamin C supplements does not seem to be beneficial, eating more vitamin C-rich food is linked with reduced risk of stroke. Details: Lower plasma levels of vitamin C have been associated with increased stroke risk (90408). Additionally, population research has found that higher dietary intake of vitamin C is associated with a 8% to 19% reduction in stroke risk when compared to lower intake (90408,109779). This reduction appears to be dose-dependent, with each 100 mg/day increase in dietary vitamin C intake associated with about a 17% reduction (90408). However, taking vitamin C supplements has not been found to be associated with reduced stroke risk (1449,90408).
• Tetanus. It is unclear if intravenous vitamin C helps to reduce symptoms of tetanus. Details: A low quality clinical trial in children and young adults with tetanus shows that intravenous vitamin C 1 gram daily along with conventional treatment reduces fatality when compared to control (21539).
• Tooth extraction. It is unclear if oral vitamin C is beneficial for reducing pain or improving healing after tooth extraction. Details: A small clinical study in healthy patients aged 14-41 years who are undergoing bilateral premolar extraction shows that taking vitamin C 200 mg three times daily, beginning immediately after extraction and continued for 10 days, improves pain on days 1-3, and may reduce mesio-distal wound size between days 1 and 7, when compared with placebo, but not when compared with vitamin C 500 mg three times daily. A dose of 500 mg three times daily did not improve pain scores or extraction wound healing when compared with placebo (108084). The validity of this trial is limited by the short duration of treatment; additionally, this study did not report baseline vitamin C levels.
• Urinary tract infections (UTIs). Although there is interest in using oral vitamin C for UTIs, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Vascular dementia. It is unclear if oral vitamin C reduces the risk of vascular dementia. Details: Population research has found that supplemental intake of vitamin C and vitamin E is associated with a reduced risk of vascular dementia in Japanese-American men (4636). However, when cases in which dementia was diagnosed prior to the study are excluded from data analysis, intake of vitamin C and vitamin E is not associated with a reduced risk of vascular dementia in these patients (9824).
• Wound healing. It is unclear if oral vitamin C improves the healing of chronic foot ulcers. It is also unclear if intravenous vitamin C improves healing of surgical wounds after total abdominal hysterectomy. Details: A very small clinical study in adults with chronic foot ulcers shows that taking slow-release vitamin C 500 mg daily for 8 weeks seems to result in a median of 100% ulcer healing, compared with a median of 14% ulcer healing in patients taking glucosamine 1000 mg daily (105456). This finding is limited due to the small and heterogeneous patient population, which included patients with diabetes, vascular disease, and/or vitamin C deficiency. Another small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery does not reduce the rate of surgical site infection or wound dehiscence when compared with placebo (109465). However, this study may not have been adequately powered to detect differences between groups. More evidence is needed to rate vitamin C 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 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, topically, intramuscularly, or intravenously and appropriately. Vitamin C is safe when taken orally in doses below the tolerable upper intake level (UL). Tell patients not to exceed the UL of 2000 mg daily (1959,4713,4714,4844). ...when used intravenously or intramuscularly and appropriately. Injectable vitamin C is an FDA-approved prescription product (15).

POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 2000 mg daily can significantly increase the risk of adverse effects such as osmotic diarrhea and gastrointestinal upset (4844).

CHILDREN: LIKELY SAFE
when used orally and appropriately (4844,10352,14443).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 400 mg daily for children ages 1 to 3 years, 650 mg daily for children 4 to 8 years, 1200 mg daily for children 9 to 13 years, and 1800 mg daily for adolescents 14 to 18 years. Higher doses can cause osmotic diarrhea and gastrointestinal upset (4844).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (4844).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Tell patients over age 19 not to use doses exceeding the UL of 2000 mg daily when pregnant or breast-feeding and for those 14-18 years of age not to use doses exceeding 1800 mg daily when pregnant or breast-feeding. Higher doses can cause osmotic diarrhea and gastrointestinal upset. Large doses of vitamin C during pregnancy can also cause newborn scurvy (4844); avoid using.

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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 = 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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ACETAMINOPHEN (Tylenol, others) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B High-dose vitamin C might slightly prolong the clearance of acetaminophen.  Details A small pharmacokinetic study in healthy volunteers shows that taking high-dose vitamin C (3 grams) 1.5 hours after taking acetaminophen 1 gram slightly increases the apparent half-life of acetaminophen from around 2.3 hours to 3.1 hours. Ascorbic acid competitively inhibits sulfate conjugation of acetaminophen. However, to compensate, elimination of acetaminophen glucuronide and unconjugated acetaminophen increases (6451). This effect is not likely to be clinically significant.

ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, antioxidant effects of vitamin C might reduce the effectiveness of alkylating agents.  Details The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs that generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin C have on chemotherapy.

ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin C can increase the amount of aluminum absorbed from aluminum compounds.  Details Research in animals and humans shows that vitamin C increases aluminum absorption, theoretically by chelating aluminum and keeping it in solution where it is available for absorption (10549,10550,10551,21556). In people with normal renal function, urinary excretion of aluminum will likely increase, making aluminum retention and toxicity unlikely (10549). Patients with renal failure who take aluminum-containing compounds such as phosphate binders should avoid vitamin C supplements in doses above the recommended dietary allowances.

ANTITUMOR ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, the antioxidant effects of vitamin C might reduce the effectiveness of antitumor antibiotics.  Details The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as doxorubicin (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effects, if any, antioxidants such as vitamin C have on chemotherapy.

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase aspirin levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction is not clinically significant.

CHOLINE MAGNESIUM TRISALICYLATE (Trilisate) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase choline magnesium trisalicylate levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046,4531). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Vitamin C might increase blood levels of estrogens.  Details Increases in plasma estrogen levels of up to 55% occur under some circumstances when vitamin C is taken concurrently with oral contraceptives or hormone replacement therapy, including topical products (129,130,11161). It is suggested that vitamin C prevents oxidation of estrogen in the tissues, regenerates oxidized estrogen, and reduces sulfate conjugation of estrogen in the gut wall (129,11161). When tissue levels of vitamin C are high, these processes are already maximized and supplemental vitamin C does not have any effect on estrogen levels. Increases in plasma estrogen levels may occur when patients who are deficient in vitamin C take supplements (11161). Monitor these patients for estrogen-related side effects.

FLUPHENAZINE (Prolixin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, vitamin C might decrease levels of fluphenazine.  Details In one patient there was a clinically significant decrease in fluphenazine levels when vitamin C (500 mg twice daily) was started (11017). The mechanism is not known, and there is no further data to confirm this interaction.

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Vitamin C can modestly reduce indinavir levels.  Details One pharmacokinetic study shows that taking vitamin C 1 gram orally once daily along with indinavir 800 mg orally three times daily reduces the area under the concentration-time curve of indinavir by 14%. The mechanism of this interaction is unknown, but it is unlikely to be clinically significant in most patients. The effect of higher doses of vitamin C on indinavir levels is unknown (11300,93578).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Vitamin C can increase levothyroxine absorption.  Details Two clinical studies in adults with poorly controlled hypothyroidism show that swallowing levothyroxine with a glass of water containing vitamin C 500-1000 mg in solution reduces thyroid stimulating hormone (TSH) levels and increases thyroxine (T4) levels when compared with taking levothyroxine alone. This suggests that vitamin C increases the oral absorption of levothyroxine, possibly due to a reduction in pH (102978).

NIACIN Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = A Vitamin C might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.  Details A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as vitamin C, or to the combination. It also is not known whether it will occur in other patient populations.

SALSALATE (Disalcid) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acidification of the urine by vitamin C might increase salsalate levels.  Details It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams/day vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D High-dose vitamin C might reduce the levels and effectiveness of warfarin.  Details Vitamin C in high doses may cause diarrhea and possibly reduce warfarin absorption (11566). There are reports of two people who took up to 16 grams daily of vitamin C and had a reduction in prothrombin time (9804,9806). Lower doses of 5-10 grams daily can also reduce warfarin absorption. In many cases, this does not seem to be clinically significant (9805,9806,11566,11567). However, a case of warfarin resistance has been reported for a patient who took vitamin C 500 mg twice daily. Cessation of vitamin C supplementation resulted in a rapid increase in international normalized ratio (INR) (90942). Tell patients taking warfarin to avoid taking vitamin C in excessively high doses (greater than 10 grams daily). Lower doses may be safe, but the anticoagulation activity of warfarin should be monitored. Patients who are stabilized on warfarin while taking vitamin C should avoid adjusting vitamin C dosage to prevent the possibility of warfarin resistance.

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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, 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, intravenously, and topically, vitamin C is well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, esophagitis, heartburn, headache, osmotic diarrhea, nausea, vomiting. Kidney stones have been reported in those prone to kidney stones. Adverse effects are more likely to occur at doses above the tolerable upper intake level of 2 grams daily.
Topically: Irritation and tingling.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of carotid inner wall thickening after large doses of vitamin C.
Intravenously: There have been case reports of hyperoxalosis and oxalate nephropathy following high-dose infusions of vitamin C.

Cardiovascular ...Evidence from population research has found that high doses of supplemental vitamin C might not be safe for some people. In postmenopausal adults with diabetes, supplemental vitamin C intake in doses greater than 300 mg per day is associated with increased risk of cardiovascular mortality. However, dietary intake of vitamin C is not associated with this risk. Also, vitamin C intake is not associated with an increased risk of cardiovascular mortality in patients without diabetes (12498).
Oral supplementation with vitamin C has also been associated with an increased rate of carotid inner wall thickening in men. There is preliminary evidence that supplemental intake of vitamin C 500 mg daily for 18 months can cause a 2.5-fold increased rate of carotid inner wall thickening in non-smoking men and a 5-fold increased rate in men who smoked. The men in this study were 40-60 years old (1355). This effect was not associated with vitamin C from dietary sources (1355).
There is also some concern that vitamin C may increase the risk of hypertension in some patients. A meta-analysis of clinical research suggests that, in pregnant patients at risk of pre-eclampsia, oral intake of vitamin C along with vitamin E increases the risk of gestational hypertension (83450). Other clinical research shows that oral intake of vitamin C along with grape seed polyphenols can increase both systolic and diastolic blood pressure in hypertensive patients (13162).

Dental ...Orally, vitamin C, particularly chewable tablets, has been associated with dental erosion (83484).

Dermatologic ...Topically, vitamin C might cause tingling or irritation at the site of application (6166). A liquid containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) has been reported to cause mild tingling and skin tightness (102355). It is unclear if these effects are due to vitamin C, the other ingredients, or the combination.

Gastrointestinal ...Orally, the adverse effects of vitamin C are dose-related and include nausea, vomiting, esophagitis, heartburn, abdominal cramps, gastrointestinal obstruction, and diarrhea. Doses greater than the tolerable upper intake level (UL) of 2000 mg per day can increase the risk of adverse effects such as osmotic diarrhea and severe gastrointestinal upset (3042,4844,96707,104450). Mineral forms of vitamin C, such as calcium ascorbate (Ester-C), seem to cause fewer gastrointestinal adverse effects than regular vitamin C (83358). In a case report, high dose intravenous vitamin C was associated with increased thirst (96709).

Genitourinary ...Orally, vitamin C may cause precipitation of urate, oxalate, or cysteine stones or drugs in the urinary tract (10356). Hyperoxaluria, hyperuricosuria, hematuria, and crystalluria have occurred in people taking 1 gram or more per day (3042,90943). Supplemental vitamin C over 250 mg daily has been associated with higher risk for kidney stones in males. There was no clear association found in females, but the analysis might not have been adequately powered to evaluate this outcome (104029). In people with a history of oxalate kidney stones, supplemental vitamin C 1 gram per day appears to increase kidney stone risk by 40% (12653). A case of hematuria, high urine oxalate excretion, and the presence of a ureteral stone has been reported for a 9-year-old male who had taken about 3 grams of vitamin C daily since 3 years of age. The condition resolved with cessation of vitamin C intake (90936).

Hematologic ...Prolonged use of large amounts of vitamin C can result in increased metabolism of vitamin C; subsequent reduction in vitamin C intake may precipitate the development of scurvy (15). In one case, a patient with septic shock and a large intraperitoneal hematoma developed moderate hemolysis and increased methemoglobin 12 hours after a high-dose vitamin C infusion. The patient received a blood transfusion and the hemolysis resolved spontaneously over 48 hours (112479).

Neurologic/CNS ...Orally, the adverse effects of vitamin C are dose-related and include fatigue, headache, insomnia, and sleepiness (3042,4844,83475,83476).

Renal ...Hyperoxalosis and oxalate nephropathy have been reported following high-dose infusions of vitamin C. Hyperoxalosis and acute kidney failure contributed to the death of a 76-year-old patient with metastatic adenocarcinoma of the lung who received 10 courses of intravenous infusions containing vitamins, including vitamin C and other supplements over a period of 1 month. Dosages of vitamin C were not specified but were presumed to be high-dose (106618). In another case, a 34-year-old patient with a history of kidney transplant and cerebral palsy was found unresponsive during outpatient treatment for a respiratory tract infection. The patient was intubated for acute hypoxemic respiratory failure, initiated on vasopressors, hydrocortisone, and antibacterial therapy, and received 16 doses of vitamin C 1.5 grams. Serum creatinine level peaked at greater than 3 times baseline and the patient required hemodialysis for oliguria and uncontrolled acidosis. Kidney biopsy revealed oxalate nephropathy with concomitant drug-induced interstitial nephritis (106625). In another case, a 41-year-old patient with a history of kidney transplant presented with fever, nausea, and decreased urine output 4 days after receiving intravenous vitamin C 7 grams for urothelial carcinoma. Serum creatinine levels increased from 1.7 mg/dL to 7.3 mg/dL over those 4 days, and hemodialysis was initiated 3 days after admission due to anuria. Renal biopsy confirmed the diagnosis of acute oxalate nephropathy (109962).

Other ...Intravenously, hypernatremia and falsely elevated ketone levels is reported in a patient with septic shock and chronic kidney disease after a high-dose vitamin C infusion. The hypernatremia resolved over 24 hours after cessation of the infusion (112479).

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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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