Pomegranate + Blackcurrant Juice Concentrate by Jarrow Formulas

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. Although there has been interest in using oral black currant berry for Alzheimer disease, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Atopic dermatitis (eczema). Topical black currant seed oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children aged 2-18 years with atopic dermatitis shows that using a specific cream containing black currant seed oil, sunflower oil, and balloon vine (Defensil), with added dexpanthenol and ceramide, twice daily for 4 weeks, improves atopic dermatitis severity scores similarly to urea 5% cream. About 38% of patients had a 50% improvement in severity score with the combination cream, compared with 35% with urea cream (105538).
• Colic. Although there has been interest in using oral black currant leaf for colic, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Common cold. Although there has been interest in using oral black currant berry for common cold, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Cough. Although there has been interest in using oral black currant leaf for cough, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Diarrhea. Although there has been interest in using oral black currant leaf for diarrhea, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Dry eye. Oral black currant has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults with dry eye disease shows that taking a specific combination product containing black currant 100 mg, L-carnitine 50 mg, elderberry fruit extract 300 mg, zinc 10 mg, and Eleutherococcus root 50 mg (Meramirt CM) orally once daily improves dry eye symptom scores when compared with no intervention. Contrast sensitivity scores also improved when compared with baseline in the treated group, but not in the control group (111295). It is unclear if this effect is due to black currant, other ingredients, or the combination.
• Dysmenorrhea. Although there has been interest in using oral black currant seed oil for dysmenorrhea, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Glaucoma. It is unclear if oral black currant is beneficial in patients with glaucoma. Details: Preliminary clinical research in adults with glaucoma shows that taking black currant anthocyanins 50 mg orally daily for 4 weeks decreases intraocular pressure (IOP) by 1.5 mmHg when compared with placebo (93696). However, other preliminary clinical research in patients with open-angle glaucoma shows that taking black currant anthocyanins 50 mg orally daily along with standard medications for glaucoma for 24 months does not improve IOP when compared with placebo (93695). Preliminary subgroup analyses suggest that patients taking one or less antiglaucoma medications, but not more than one, may benefit the most from black currant (93695,93696).
• Gout. Although there has been interest in using oral black currant leaf for gout, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Hyperlipidemia. It is unclear if oral black currant seed oil is beneficial in patients with hyperlipidemia. Details: Preliminary clinical research in adults with hyperlipidemia shows that taking black currant seed oil 18 grams orally twice daily for 6 weeks reduces total cholesterol by about 16%, reduces triglycerides by about 34%, and increases high-density lipoprotein (HDL) cholesterol by about 35% when compared with baseline (17638). However, the validity of this study is limited by the lack of a comparator group.
• Hypertension. It is unclear if oral black currant seed oil is beneficial in patients with hypertension. Details: Preliminary clinical research in males with borderline hypertension shows that taking black currant seed oil 6 grams orally daily for 8 weeks does not reduce blood pressure when compared with safflower oil 6 grams daily. However, when stress is induced by a mental arithmetic exercise, black currant seed oil appears to induce a 40% reduction in systolic and diastolic blood pressure elevations in these patients (35994).
• Influenza. Although there has been interest in using oral black currant berry for influenza, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Insect bite. Although there has been interest in using topical black currant leaf for insect bite, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Japanese cedar pollinosis. It is unclear if oral black currant extract is beneficial in patients with Japanese cedar pollinosis. Details: Preliminary clinical research in patients with Japanese cedar pollinosis shows that taking a black currant polysaccharide extract 540 mg orally twice daily for 8 weeks does not improve nasal symptom scores or swelling when compared with placebo (17635).
• Liver disease. Although there has been interest in using oral black currant leaf for liver disease, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Menopausal symptoms. Although there has been interest in using oral black currant seed oil for menopausal symptoms, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Muscle fatigue. It is unclear if oral black currant juice extract is beneficial in patients with muscle fatigue. Details: Preliminary clinical research in office workers shows that black currant juice extract, containing 10.83% anthocyanins, taken once orally and dosed as anthocyanins 17 mg/kg, reduces muscle stiffness scores after typing for 30 minutes when compared with placebo (17633).
• Osteoarthritis. Although there has been interest in using oral black currant leaf for osteoarthritis, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Peripheral arterial disease (PAD). Although there has been interest in using oral black currant juice for PAD, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Premenstrual syndrome (PMS). Although there has been interest in using oral black currant seed oil for PMS, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Rheumatoid arthritis (RA). It is unclear if oral black currant seed oil is beneficial in patients with RA. Details: A small clinical study in patients with RA shows that taking black currant seed oil 10.5 grams orally daily for 24 weeks reduces tenderness scores when compared with placebo (35990).
• Rhinosinusitis. Oral black currant has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients over 12 years of age with chronic sinusitis shows that taking a combination product containing black currant, Boswellia serrata, bromelain, and vitamin D (Flogostop Forte, Humana Italia) with inhaled corticosteroids daily for 30 days reduces rhinorrhea, hyperemia of mucosa, and local inflammation when compared with inhaled corticosteroids alone (111501). It is unclear if these findings are due to black currant, other ingredients, or the combination.
• Seizures. Although there has been interest in using oral black currant leaf for seizures, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Upper respiratory tract infection (URTI). Although there has been interest in using oral black currant berry for URTIs, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Urinary tract infections (UTIs). Although there has been interest in using oral black currant leaf for UTIs, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Venous insufficiency. Although there has been interest in using oral black currant for venous insufficiency, there is insufficient reliable information about the clinical effects of black currant for this purpose.
• Wound healing. Although there has been interest in using topical black currant leaf for wound healing, there is insufficient reliable information about the clinical effects of black currant for this purpose. More evidence is needed to rate black currant for these uses.

(Read more about BLACK CURRANT)

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.

(Read more about GRAPE)

POSSIBLY EFFECTIVE

• Hypertension. Oral pomegranate juice seems to modestly reduce blood pressure. Details: Most clinical research evaluating pomegranate juice for reducing systolic blood pressure (SBP) and diastolic blood pressure (DBP) shows modest benefits (8310,13023,13691,69372,69373,69374). A meta-analysis of results from eight clinical studies including 574 patients shows that pomegranate juice reduces SBP by about 5 mmHg, but does not affect DBP, when compared with placebo. Doses of pomegranate juice ranged from 43-330 mL daily for 2 weeks to 18 months. Changes in SBP and DBP were not related to the dose or duration of pomegranate juice consumption (96247).

POSSIBLY INEFFECTIVE

• Diabetes. Most oral pomegranate products do not seem to be beneficial for diabetes. It is unclear if pomegranate seed powder is beneficial. Details: A meta-analysis of clinical research shows that taking pomegranate has no effect on glycated hemoglobin (HbA1c) or plasma levels of insulin, lipids, or fasting glucose when compared with placebo in patients with type 2 diabetes. Various formulations, including juice, fruit extract, peel extract, and seed oil, were used in these studies (105265). However, a more recent clinical trial shows that drinking a beverage twice daily for 8 weeks, made by soaking a 'tea bag' containing pomegranate seed powder 5 grams in hot water for 10 minutes, modestly reduces levels of fasting blood glucose, HbA1c, total cholesterol, and triglycerides when compared with placebo. Fasting blood glucose levels were reduced by approximately 4%, compared with a 6% increase in the placebo group (105270).
• Hyperlipidemia. Oral pomegranate does not seem to be beneficial for hyperlipidemia. Details: Most clinical research shows that taking pomegranate does not increase high-density lipoprotein (HDL) cholesterol levels or reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride levels when compared with placebo (13022,13023,13690,69142,69168,69276). A meta-analysis of results from 12 clinical studies including 545 patients with or without hyperlipidemia shows that taking pomegranate daily for at least 10 days and up to 1 year does not improve blood lipid levels when compared with placebo. Pomegranate formulations evaluated in these studies include juice, seed oil, whole fruit, extract, and vinegar beverage; no specific form or dose of pomegranate was associated with improvements in cholesterol or triglyceride levels (96248). One preliminary clinical study has evaluated pomegranate juice in combination with other fruits. Results from the study show that taking a specific pomegranate-containing combination product (Radical Fruits, Garden of Life) 900 mg orally three times daily before meals reduces total and LDL cholesterol and increases HDL cholesterol in males with hypercholesterolemia (69170). However, it is unclear if these benefits are due to pomegranate, other ingredients, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atherosclerosis. It is unclear if oral pomegranate juice is beneficial for preventing atherosclerosis. Details: Preliminary clinical research shows that drinking pomegranate juice 50 mL daily reduces intima-media thickness of the carotid artery by up to 35% after one year when compared to baseline in patients with atherosclerosis and carotid artery stenosis (13023).
• Athletic performance. It is unclear if oral pomegranate extract is beneficial for athletic performance. Details: Preliminary clinical research in trained male cyclists shows that taking pomegranate extract (POM Wonderful LLC) 15 mg/kg daily for 8 days moderately reduces the amount of oxygen needed to perform submaximal exercise when compared with placebo. However, pomegranate extract does not improve performance in a timed trial (99100). Other preliminary clinical research in regionally competitive male cyclists shows that taking pomegranate extract (Pomanox P30, Euromed S.A.) 750 mg daily for 15 days increases the time to exhaustion by 94 seconds after a prolonged submaximal effort, as well as the time to reach the anaerobic threshold by about 55 seconds, when compared with placebo. There was no effect on the restoration of force or on oxygen consumption (101881).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral pomegranate juice is beneficial for COPD. Details: A small clinical trial shows that drinking pomegranate juice 400 mL daily for 5 weeks does not improve symptoms or respiratory function in patients with COPD when compared with placebo (13692).
• Coronary heart disease (CHD). It is unclear if oral pomegranate juice is beneficial for patients with CHD. Details: Some preliminary clinical research shows that drinking pomegranate juice (POM Wonderful Pomegranate Juice, POM Wonderful LLC) 240 mL daily for 3 months decreases stress-induced myocardial ischemia in patients with CHD. The average improvement in myocardial perfusion was about 17% with pomegranate juice, compared with an 18% worsening of myocardial perfusion in patients taking placebo (13691). However, other preliminary clinical research in patients with moderate CHD risk shows that drinking the same pomegranate juice product 240 mL daily for 18 months does not improve carotid intima-media thickness when compared to control (17329). It is not known if drinking pomegranate juice can prevent or reduce the risk of a myocardial infarction or other cardiovascular outcomes.
• Dental plaque. It is unclear if rinsing the mouth with pomegranate extract is beneficial for reducing dental plaque. Details: Preliminary clinical research shows that rinsing with pomegranate extract mouthwash for one minute once or twice daily reduces dental plaque in patients with or without fixed orthodontic appliances. The antiplaque activity of pomegranate extract is similar to that of chlorhexidine (69171,69316).
• Erectile dysfunction (ED). It is unclear if oral pomegranate juice is beneficial for ED. Details: In patients with mild-to-moderate ED, preliminary clinical research shows that drinking pomegranate juice daily for 4 weeks does not improve symptoms of ED when compared with placebo (69175).
• Exercise-induced muscle soreness. It is unclear if oral pomegranate juice is beneficial for reducing exercise-induced muscle soreness. Details: Preliminary clinical research shows that drinking pomegranate juice (POM Wonderful Pomegranate Juice, POM Wonderful LLC) 250 mL twice daily for 15 days reduces post-exercise muscle soreness in elbow flexor, but not knee extensor, muscles in resistance-rained males when compared with placebo (69355). However, in non-resistance trained males, drinking the same pomegranate juice 250 mL twice daily for 9 days does not reduce exercise-induced muscle damage or delayed onset soreness of elbow flexor muscles when compared with placebo (101880).
• HIV/AIDS. Although there has been interest in using oral pomegranate for HIV/AIDS, there is insufficient reliable information about the clinical effects of pomegranate for this condition.
• Influenza. Although there has been interest in using oral pomegranate for influenza prevention, there is insufficient reliable information about the clinical effects of pomegranate for this purpose.
• Intrauterine growth restriction (IUGR). It is unclear if oral pomegranate juice is beneficial for preventing brain injury in IUGR neonates. Details: In patients with an IUGR pregnancy, clinical research shows that drinking pomegranate juice 8 ounces daily from 24-34 weeks' gestation until delivery reduces the risk of an MRI-diagnosed gray matter brain injury in the infant by approximately 28%. There was no effect on brain volume or white matter injury (105267).
• Kidney failure. It is unclear if oral pomegranate juice is beneficial for patients on hemodialysis; the available research is conflicting. Details: Some preliminary clinical research shows that taking pomegranate juice (Nutrafood) 100 mL during the first dialysis treatment hour three times weekly for one year reduces antihypertensive medication requirements and the rate of second hospitalization due to infection when compared with placebo. Consuming pomegranate juice also increases high-density lipoprotein (HDL) cholesterol in patients with baseline levels of 40 mg/dL or less and reduces triglycerides in patients with baseline levels of at least 200 mg/dL (91698,91699). Preliminary clinical research also shows that taking pomegranate juice 100 mL immediately after dialysis three times weekly for 8 weeks reduces triglycerides by approximately 20%, as well as systolic and diastolic blood pressure by 5% and 7%, respectively, when compared with baseline. HDL cholesterol was also increased by approximately 23%. These changes were significant when compared with placebo (101882). However, pomegranate juice did not affect total cholesterol, low-density lipoprotein (LDL) cholesterol, liver enzymes, or incidence of cardiovascular events when compared with placebo (91698,91699,101882). Other preliminary clinical research shows that drinking pomegranate juice (POM Wonderful Pomegranate Juice, POM Wonderful LLC) 100 mL or taking pomegranate juice extract tablets (POM Wonderful LLC) 1050 mg daily prior to each dialysis session for 4 weeks does not improve blood pressure, lipids, or markers of inflammation and oxidative stress when compared to baseline in patients receiving maintenance hemodialysis (91697). Although the reason for these conflicting findings is not clear, it may have to do with the timing of consumption. The evidence suggests that offering pomegranate during dialysis or after completion of dialysis might be more effective than prior to dialysis.
• Menopausal symptoms. It is unclear if oral pomegranate seed oil or pomegranate extract is beneficial for menopausal symptoms. Details: Preliminary clinical research shows that taking a specific pomegranate seed oil (Delima, Pekana Naturheilmittel GmbH) 30 mg orally twice daily for 12 weeks does not reduce the frequency of hot flashes when compared with placebo in postmenopausal adults experiencing at least 5 hot flashes per day. However, pomegranate seed oil might improve sleep in some patients with sleep disturbances attributed to menopause (91685). A clinical study in healthy, perimenopausal and menopausal adults with untreated menopausal symptoms shows that taking pomegranate extract 3 mL three times daily for 4 weeks reduces symptoms, including hot flashes and vertigo, and improves physical and mental quality of life when compared with placebo. Additionally, these improvements were sustained 3 weeks after discontinuing treatment (108484). The validity of this study is limited by the short duration of treatment.
• Metabolic syndrome. It is unclear if oral pomegranate juice is beneficial for metabolic syndrome. Details: Preliminary clinical research shows that drinking pomegranate juice 240 mL daily for one month improves endothelial dysfunction in adolescents with metabolic syndrome when compared with drinking grape juice 240 mL daily (53174,69362).
• Muscle strength. It is unclear if oral pomegranate juice is beneficial for increasing muscle strength. Details: Preliminary clinical research shows that taking a specific pomegranate extract (POMx, POM Wonderful LLC) 480 mL twice daily modestly improves recovery of strength 2-3 days after eccentric exercise but does not reduce muscle soreness after exercise when compared with placebo (69261).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral pomegranate seed oil or pomegranate extract improves anthropometric measures in adults with NAFLD. Details: A small clinical study in overweight and obese adults with NAFLD shows that taking a dried pomegranate extract, standardized to contain 90 mg of ellagic acid, twice daily for 12 weeks reduces body mass index and body weight when compared with placebo. A 5 kg weight reduction occurred in the pomegranate group, compared to a small increase in weight in the placebo group. Pomegranate also improved diastolic blood pressure, as well as lipid and glycemic parameters; however, the patients included in this study had normal baseline parameters, limiting the validity of this finding (108481). Pomegranate has also been evaluated in combination with other ingredients. One small clinical crossover study in obese females with NAFLD shows that taking a specific combination product (Xanthigen, Polinat) containing pomegranate seed oil 300 mg and brown marine algae 300 mg (standardized to fucoxanthin 2.4 mg) modestly reduces body weight and liver fat content when compared with placebo (69257).
• Obesity. It is unclear if oral pomegranate is beneficial for obesity. Most evidence suggests that it is not beneficial, although some studies have yielded conflicting findings. Details: A meta-analysis of 513 participants shows that taking pomegranate extract, juice, or concentrate for 2-26 weeks does not reduce body weight, body mass index, waist circumference, or body fat percentage when compared with placebo or other control (101883). However, most of these studies were not designed to investigate weight as the primary outcome, and some preliminary clinical research in overweight or obese individuals suggests that some pomegranate products might have some benefit. Drinking pomegranate juice 120 mL daily for one month helps these individuals maintain weight when compared with placebo, although it does not appear to improve glucose, insulin secretion, or insulin sensitivity (91693).
• Oropharyngeal candidiasis. It is unclear if topical pomegranate peel extract is beneficial for oropharyngeal candidiasis. Details: Preliminary clinical research in patients with candidiasis associated with denture stomatitis shows that applying a gel containing the extract of pomegranate fruit peel to the gums three times daily for 15 days seems to be as effective as miconazole gel for improving symptoms of candidiasis (13689).
• Polycystic ovary syndrome (PCOS). It is unclear if oral pomegranate juice is beneficial for PCOS. Details: In patients with PCOS, preliminary clinical research shows that taking pomegranate juice 45 mL daily for 8 weeks reduces systolic and diastolic blood pressures by 10 and 4 mmHg, respectively, when compared with a control group not taking pomegranate juice. Triglyceride and high-density lipoprotein (HDL) cholesterol levels were also modestly improved. However, there was no effect on glycemic measures, and low-density lipoprotein (LDL) cholesterol levels increased by 6 mg/dL (105266). Another clinical trial in patients with PCOS shows that taking synbiotic pomegranate juice containing inulin and lactobacillus as 2 liters weekly for 8 weeks improves insulin sensitivity, body mass index, waist circumference, and testosterone levels when compared with baseline or a control juice. However, patients consuming a drink containing only the synbiotic ingredients experienced the same improvements, whereas patients consuming only regular pomegranate juice experienced no benefits, suggesting that pomegranate was not responsible for these changes (101884).
• Prostate cancer. It is unclear if oral pomegranate extract or juice is beneficial for prostate cancer. Details: Preliminary clinical research shows that pomegranate might slow prostate cancer progression in some patients after surgery or radiation for prostate cancer. The length of time to doubling of prostate specific antigen (PSA) was longer in those who took a specific pomegranate extract (POMx, POM Wonderful LLC) 1-3 grams daily, as well as those who drank 8 ounces of pomegranate juice daily, for up to 24 months (14137,14388,91695). However, the results from a large well-designed study do not support these findings. This study shows that taking 8 ounces of a pomegranate liquid extract does not increase the length of time to doubling of PSA (105271). In patients with favorable-risk localized prostate cancer, a small clinical trial also shows that taking pomegranate fruit extract (POMx, POM Wonderful) 1000 mg daily for 12 months does not affect the length of time to doubling of PSA, although there were some changes in tumor markers of DNA damage (105269). Pomegranate has also been evaluated in combination with other ingredients. Preliminary clinical research in patients with localized prostate cancer shows that taking a combination supplement containing pomegranate powder 100 mg, broccoli powder 100 mg, turmeric powder 100 mg, and green tea extract 20 mg daily for 6 months slows the increase in PSA levels when compared with placebo (89730). It is not clear if this effect is due to pomegranate, the other ingredients, or the combination.
• Rheumatoid arthritis (RA). It is unclear if oral pomegranate extract is beneficial for RA. Details: Preliminary clinical research shows that taking a specific pomegranate extract (POMx, POM Wonderful LLC) 5 mL twice daily for 12 weeks decreases disease activity and reduces tender joint count by 62% when compared to baseline in patients with RA (91686). The validity of these findings is limited by the lack of a control group.
• Rhinosinusitis. It is unclear if intranasal pomegranate extract is beneficial for chronic rhinosinusitis. Details: A clinical study in adults with chronic rhinosinusitis or rhinitis persisting longer than 12 weeks, with or without the presence of nasal polyps, shows that using a nasal spray containing pomegranate extract in an unknown dose twice daily for 30 days does not improve objective or subjective nasal or sinus symptoms when compared with placebo nasal spray. In a subgroup of patients with chronic rhinitis, including allergic and nonallergic rhinitis, improvement in thick nasal discharge is also observed in those receiving the pomegranate nasal spray; however, the study does not report outcomes for each subtype of rhinitis (108480).
• Stroke. Although there has been interest in using oral pomegranate for stroke recovery, there is insufficient reliable information about the clinical effects of pomegranate for this purpose.
• Sunburn. It is unclear if oral pomegranate extract is beneficial for sunburn prevention. Details: A small clinical study shows that taking pomegranate extract standardized to contain ellagic acid 100-200 mg daily for 4 weeks does not reduce skin pigmentation caused by UV light exposure when compared with placebo (69172). However, this study was not adequately powered to detect a difference between treatments.
• Trichomoniasis. It is unclear if oral pomegranate extract is beneficial for trichomoniasis. Details: A very small clinical study in patients with vaginal Trichomoniasis suggests that taking pomegranate extract might help to eradicate Trichomonas vaginalis infection (69286). The validity of this finding is limited by the small study size, unclear reporting, and lack of a control group. More evidence is needed to rate pomegranate for these uses.

(Read more about POMEGRANATE)

LIKELY SAFE ...when used orally and appropriately. Black currant juice, leaves, and flowers have Generally Recognized As Safe (GRAS) status in the US (4912). Black currant juice up to 3000 mL daily for up to 3 weeks (17636,35987), black currant extracts 1080 mg daily for 8 weeks (17635,93695), and black currant seed oil products up to 10.5 grams daily for 24 weeks (4016,17634,17638,35990) have also been used safely in clinical research. There is insufficient reliable information about the safety of black currant when used topically.

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

(Read more about BLACK CURRANT)

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.

(Read more about GRAPE)

LIKELY SAFE ...when pomegranate fruit or fruit juice is used orally and appropriately. Pomegranate juice has been safely used in studies lasting up to 3 years (4912,8310,13022,13023,13690,14137,14388,17329,91693).

POSSIBLY SAFE ...when pomegranate extract is taken orally and appropriately. A specific pomegranate ellagitannin-enriched polyphenol extract (POMx, POM Wonderful) 1-3 grams daily has been safely used for up to 18 months (17729,69261,91686,91695,91697,99100,105269). ...when pomegranate seed oil is used orally and appropriately. Pomegranate seed oil 60 mg daily has been used with apparent safety for up to 12 weeks (91685). ...when a hot water extract of pomegranate seed powder is used orally and appropriately. Pomegranate seed powder 5 grams daily has been used with apparent safety for up to 8 weeks (105270). ...when pomegranate extract is used topically on oral mucosa (13689).

POSSIBLY UNSAFE ...when the pomegranate root, stem, and peel are used orally in large amounts. Bark of the pomegranate root and stem contains the piperidine alkaloids pelletierine, pseudopelletierine, isopelletierine, and methyl isopelletierine. These alkaloids have muscle relaxant properties that have been associated with paralysis and death in animals (13687,13694,13695). Dried pomegranate peel may contain aflatoxin, which is a potent hepatocarcinogen and toxin (92018).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when the fruit or fruit juice is consumed orally and appropriately (13686,105267). There is insufficient reliable information available regarding the safety of using other forms of pomegranate or other parts of the plant during pregnancy or lactation; avoid using.

(Read more about POMEGRANATE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black currant seed oil might increase the risk of bleeding if used in combination with anticoagulant or antiplatelet drugs.  Details Gamma-linolenic acid (GLA), a constituent of black currant seed oil, appears to have antiplatelet effects (1979,35995).

PHENOTHIAZINES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black currant seed oil might increase the risk of seizure in patients receiving phenothiazines.  Details Black currant seed oil contains gamma-linolenic acid (GLA). There is some concern that taking supplements containing GLA might cause seizures, or lower the seizure threshold, when taken with phenothiazines, although there is no evidence that black currant seed oil causes seizures (88187). In one report, three patients with schizophrenia who had received phenothiazines developed EEG changes suggestive of temporal lobe epilepsy after starting treatment with GLA, although none experienced an actual seizure (21013). In another report, two patients with schizophrenia who were stabilized on phenothiazines developed seizures when evening primrose 4 grams daily, which contains GLA, was added. One of these patients had a prior history of seizures (21010).

(Read more about BLACK CURRANT)

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).

(Read more about GRAPE)

ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking pomegranate with ACEIs might increase the risk of adverse effects.  Details Pomegranate juice is thought to have ACE inhibitor-like effects (8310).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking pomegranate with antihypertensive drugs might increase the risk of hypotension.  Details Consuming pomegranate juice can modestly lower blood pressure (8310,13023,69373,69374).

CARBAMAZEPINE (Tegretol) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking pomegranate with carbamazepine might increase the risk of adverse effects, although research suggests this interaction is unlikely to be clinically significant.  Details Animal research shows that pomegranate juice may inhibit cytochrome P450 3A4 (CYP3A4) metabolism of carbamazepine and increase levels of carbamazepine by 1.5 times without prolonging the elimination half-life. This suggests that pomegranate juice inhibits intestinal CYP3A4, but might not inhibit hepatic CYP3A4 (13188). However, some human research suggests that pomegranate does not significantly inhibit CYP3A4 drug metabolism in humans (16711,16712,17326).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, pomegranate might increase levels of drugs metabolized by CYP2C9.  Details Some animal and in vitro research shows that pomegranate juice inhibits intestinal, but not hepatic, CYP2C9 isoenzyme activity (17327). However, clinical research shows that neither pomegranate juice nor pomegranate extract have a significant effect on CYP2C9 activity in humans (91694).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, pomegranate might increase levels of drugs metabolized by CYP2D6.  Details In vitro, pomegranate juice inhibits CYP2D6 (13703). However, the clinical significance of this potential interaction in humans is not known.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, pomegranate might increase levels of drugs metabolized by CYP3A4, but most research suggests this interaction is unlikely to be clinically significant.  Details Pomegranate contains several polyphenols that have individually been shown to inhibit CYP3A4. However, there is contradictory evidence about the effect of whole pomegranate juice on CYP3A4 activity. In vitro, pomegranate juice significantly inhibits the CYP3A4 enzyme, with comparable inhibition to grapefruit juice (13188,16711,17326). In an animal model, pomegranate juice inhibits CYP3A4 metabolism of carbamazepine and increases levels of carbamazepine by 1.5 times (13188); however, in human volunteers, drinking a single glass of pomegranate juice 240 mL or taking 200 mL daily for 2 weeks does not significantly affect levels of the CYP3A4 substrate midazolam after oral or intravenous administration (16711,17730). Another study in healthy volunteers shows that consuming pomegranate juice 300 mL three times daily for three days also does not significantly affect levels of simvastatin, a CYP3A4 substrate (16712,91696) This suggests that pomegranate is unlikely to significantly affect levels of CYP3A4 substrates in humans (17326).

ROSUVASTATIN (Crestor) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking pomegranate with rosuvastatin might increase the risk of adverse effects.  Details In one case, a patient taking rosuvastatin 5 mg every other day in combination with ezetimibe 10 mg daily developed rhabdomyolysis after drinking pomegranate juice 200 mL twice weekly for 3 weeks. This patient had a history of elevated creatine kinase levels while not receiving any statin treatment. This suggests a possible underlying myopathy and predisposition to rhabdomyolysis (14465).

TOLBUTAMIDE (Orinase) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, pomegranate might increase levels of tolbutamide, although research suggests this interaction is unlikely to be clinically significant.  Details Animal research shows that pomegranate juice inhibits the cytochrome P450 2C9 (CYP2C9) metabolism of tolbutamide. Pomegranate juice increased tolbutamide levels by 1.2 times without prolonging the elimination half-life. This suggests that pomegranate juice inhibits intestinal CYP2C9, but might not inhibit hepatic CYP2C9 (17327). Despite this evidence, clinical research shows that neither pomegranate juice nor pomegranate extract have a significant effect on CYP2C9 activity in humans (91694). This interaction does not appear to be clinically significant in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, pomegranate might increase warfarin levels and increase the risk of bleeding. Also, discontinuing regular consumption of pomegranate juice might decrease warfarin levels.  Details In one case report, a patient had a stable, therapeutic bleeding time, as measured by international normalized ratio (INR), while taking warfarin in combination with pomegranate juice 2-3 times per week. The patient became subtherapeutic within about 10 days after discontinuing pomegranate juice, which required a warfarin dose increase (17328). In another case report, a patient with a stable INR for over one year presented with an INR of 14. The patient noted no changes to medications or diet but did report consuming around 3 liters of pomegranate juice over the previous week. The patient's INR stabilized upon moderation of pomegranate juice consumption (24273). The mechanism of this potential interaction is unclear.

(Read more about POMEGRANATE)

General ...Orally, black currant is generally well-tolerated. Topically, there is a limited amount of information on the adverse effects of black currant.

Gastrointestinal ...Of 2154 patients with hyperlipidemia taking black currant seed oil 1. 8 grams twice daily for 6 weeks, 8 reports of mild diarrhea were considered related to the supplement. These adverse reactions were reported 2-10 days after beginning treatment with black currant seed oil (17638).

(Read more about BLACK CURRANT)

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).

(Read more about GRAPE)

General ...Orally, pomegranate fruit juice is generally well tolerated. Pomegranate fruit extract and seed oil seem to be well tolerated. Pomegranate root, stem, and peel should not be used orally in large amounts. Topically, pomegranate fruit extract seems to be well tolerated.
Most Common Adverse Effects:
Oral: Diarrhea, flatulence.

Cardiovascular ...In one clinical trial, 2% of patients experienced hyperlipidemia and hypertension after consumption of pomegranate juice (69175). However, most clinical research shows that pomegranate does not increase cholesterol or blood pressure and may actually improve these parameters in some patients (8310,13022,13023,69168,69373,69374).

Dermatologic ...Topically, pomegranate may cause urticaria (hives) in some patients (8445).

Gastrointestinal ...Orally, pomegranate may cause mild gastrointestinal adverse effects. In one clinical study, drinking pomegranate juice 8 ounces daily caused diarrhea and flatulence in 2% of patients (69175). In another clinical study, taking pomegranate extract (POMx, POM Wonderful LLC) 3000 mg daily caused diarrhea in 10% of patients. This dose of pomegranate extract also caused nausea, abdominal pain, constipation, gastrointestinal upset, and vomiting in a small number of patients (91695).

Immunologic ...Orally, pomegranate fruit or seeds may cause allergic reactions. These allergic reactions occur more commonly in people who are allergic to other plants (7674). In rare cases, pomegranate fruit can cause angioedema. Angioedema seems to occur without warning and in people who have eaten pomegranate for many years. Patients should be told to stop eating pomegranate if swelling of the tongue or face develops (7673). In one report, a patient experienced pomegranate-dependent, exercise-induced anaphylaxis. The patient developed widespread urticaria (hives) and lip edema after eating pomegranate seeds and then exercising (17331). In another report, an atopic patient experienced an allergic reaction to pomegranate fruit. Symptoms included urticaria (hives), facial angioedema, and hypotension (91692).
Topically, pomegranate may cause contact hypersensitivity characterized by urticaria (hives), angioedema, rhinorrhea, red itchy eyes, and dyspnea arising within a few minutes of exposure (8445).

Pulmonary/Respiratory ...Orally, pomegranate juice may cause nasal congestion, but this event is rare. In one clinical study, pomegranate juice was associated with nasal congestion in 2% of patients (69175). There is also one case report of a 7-year-old asthmatic child who developed bronchospasm moments after ingesting several pomegranate seeds (69149).

(Read more about POMEGRANATE)