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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical calendula has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with mild to moderate acne associated with mask wearing shows that topical application of a combination of calendula 4%, licorice root extract 0.3%, and snail secretion filtrate 40% (AI complex) to the face twice daily for 12 weeks modestly reduces inflammatory, but not non-inflammatory or total, acne lesions when compared with placebo. There was no difference in overall treatment success, defined as at least almost clear skin or a large improvement (110322). It is unclear if any benefits are due to calendula, other ingredients, or the combination.
• Bacterial vaginosis. It is unclear if topical calendula is beneficial for improving bacterial vaginosis. Details: A small clinical study in patients with bacterial vaginosis shows that applying 5 grams of vaginal cream containing calendula flower extract before bed for one week improves vaginal burning, odor, painful urination, and painful intercourse when compared to baseline (96649). The validity of these findings is limited by the lack of a comparator group.
• Burns. It is unclear if oral calendula is beneficial for burn healing. Details: A small clinical trial in patients hospitalized for second-degree burns shows that taking calendula 2 grams daily for 2 weeks has a large beneficial effect on wound healing when compared with placebo (110323).
• Chronic obstructive pulmonary disease (COPD). Oral calendula has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in males aged 40-70 years with a history of smoking and stage 2 COPD shows that taking a specific combination of calendula flowers 165 mg, elderberry 165 mg, and heart's ease herb 165 mg (Inflaminat, INAT-Farma), 3 capsules daily for 6 months, modestly improves symptoms, as measured on the breathlessness, cough, and sputum scale (BCSS), and mean forced expiratory volume in 1 second (FEV1) when compared to baseline. However, there was no improvement of COPD exacerbations or other pulmonary function tests (103629). The validity of this finding is limited by the lack of statistical comparison to the placebo group. Furthermore, it is unclear if these effects are due to calendula, the other ingredients, or the combination.
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Calendula in rectal suppositories has only been evaluated in combination with turmeric extract; its effect when used alone is unclear. Details: A small clinical study in patients with CP/CPPS shows that using a rectal suppository containing turmeric extract 350 mg and calendula extract 80 mg daily for one month improves pain, peak urine flow rate, and erectile function when compared with placebo (96648). It is unclear if these effects are due to calendula, turmeric, or the combination.
• Conjunctivitis. Although there is interest in using topical calendula for conjunctivitis, there is insufficient reliable information about the clinical effects of calendula for this condition.
• Diabetic foot ulcers. It is unclear if topical calendula is beneficial for improving diabetic foot ulcers. Details: Observational research has found that applying a calendula hydroglycolic extract spray in addition to standard care and hygiene is associated with reduced bacterial colonization and improved odor in patients that have had a diabetic ulcer for over 3 months (93548).
• Diaper rash. It is unclear if topical calendula is beneficial for improving diaper rash. Details: One preliminary clinical study in children less than 3 years of age shows that topical application of calendula 1.5% ointment three times daily for 10 days improves diaper rash when compared with aloe gel (19779). However, other preliminary clinical research shows that applying calendula 1.5% cream every 4-6 hours for 3 days improves diaper rash in fewer infants when compared to treatment with bentonite 50% mineral solution (93545,93554).
• Dysmenorrhea. Although there is interest in using oral calendula for dysmenorrhea, there is insufficient reliable information about the clinical effects of calendula for this condition.
• Gingivitis. It is unclear if using a mouth rinse with calendula is beneficial for improving gingivitis. Details: Preliminary clinical research in patients with mild gingivitis and bleeding gums shows that rinsing the mouth with a tincture containing calendula 25% (Dr. Willmar Schwabe Germany Home Pharmacy Pvt. Ltd.) twice daily for 6 months decreases plaque, gingivitis, and bleeding by 10% to 18% when compared to rinsing with water (93551). Other preliminary clinical research in adults with mild to moderate gingivitis and mild plaque shows that rinsing the mouth with a combination mouthwash containing a 5% extract of calendula, rosemary, and ginger for 30 seconds twice daily after food for 2 weeks decreases plaque, gingivitis, and bleeding when compared with a placebo mouthwash. The effects of this combination mouthwash appear to be similar to chlorhexidine 0.2% mouthwash (93555). It is unclear if these effects are due to calendula, other ingredients, or the combination.
• Hemorrhoids. Although there is interest in using topical calendula for hemorrhoids, there is insufficient reliable information about the clinical effects of calendula for this purpose.
• Liver disease. Although there is interest in using oral calendula for liver disease, there is insufficient reliable information about the clinical effects of calendula for this condition.
• Mosquito repellent. It is unclear if topical calendula essential oil helps to repel mosquitos. Details: Preliminary clinical research shows that applying calendula 50% essential oil to the skin does not repel mosquitos as effectively as applying DEET. Mean repellency time was about 2 hours for patients applying calendula, which was shorter than the 6 hour repellency with DEET (93562).
• Oral leukoplakia. It is unclear if topical calendula is beneficial for improving oral leukoplakia. Details: Preliminary clinical research in patients with oral leukoplakia shows that applying a gel containing calendula flower extract 0.2% three times daily for one month reduces lesion size by about 2 cm when compared to baseline (96650). The validity of this finding is limited by the lack of a comparator group.
• Oral mucositis. Calendula as a mouth rinse has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with head and neck cancer receiving chemotherapy and radiotherapy shows that rinsing with 7 mL of a specific product (Faringel, Cadigroup) containing calendula powder extract 2%, propolis, aloe vera, and chamomile three times daily for 6 weeks does not prevent oral mucositis when compared with placebo (95879).
• Otitis media. Topical calendula has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with otitis media shows that applying a specific combination product containing calendula, mullein, garlic, and St. John's wort in olive oil (Otikon Otic Solution, Healthy-On Ltd, Petach-Tikva, Israel), five drops into the affected ear three times daily for 3 days, may reduce ear pain when compared with baseline (39500,39552). It is unclear if this effect is due to calendula, other ingredients, or the combination. Furthermore, due to the lack of an adequate control group, it is unclear whether the pain reduction was due to the resolution of otitis media.
• Peptic ulcers. Although there is interest in using oral calendula for peptic ulcers, there is insufficient reliable information about the clinical effects of calendula for this condition.
• Pressure ulcers. It is unclear if topical calendula is beneficial for improving pressure ulcers. Details: Observational research has found that the application of a specific calendula product (Plenusdermax) twice daily is associated with improved healing in patients with pressure ulcers that have not changed in size for at least 3 months (93549). Preliminary clinical research in hospice patients with symptomatic pressure ulcers and other wounds shows that applying a homeopathic powder (RGN107) containing calendula 0.1% and arnica 0.01% to wounds for 4 weeks is rated by the patients and caregivers to be acceptable for controlling pain, odor, and exudate when compared with baseline (96647). The validity of this finding is limited by the lack of a control group.
• Radiation dermatitis. It is unclear if topical calendula reduces radiation dermatitis symptoms. Details: A meta-analysis of three preliminary clinical trials in patients with breast cancer shows that topical calendula does not affect the development of radiation dermatitis or the incidence of moderate to severe symptoms when compared to control (110325). In addition, a meta-analysis of two studies (39503,93560) shows that topical calendula does not reduce the incidence of treatment interruptions due to severe symptoms of radiation dermatitis (110325). In one of the included studies, a specific calendula petroleum jelly ointment (Pommade au Calendula par Digestion, Boiron Ltd.) used twice daily during radiation therapy was found to reduce acute radiation dermatitis occurrence when compared with topical trolamine (Biafine) (39503). However, it is unclear if the benefit was due to calendula or petroleum jelly. Another clinical study used a specific calendula 10% cream in wool fat and sesame oil (Calendula Weleda, Weleda AG) twice daily during radiation therapy. This product was found to be no better than aqueous petroleum jelly cream (Essex, Schering-Plough) for reducing acute skin reactions and dermatitis symptoms of pain, burning, itching, pulling, and tenderness (93560).
• Vaginal atrophy. Topical calendula has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in menopausal patients with vaginal atrophy shows that use of a specific vaginal gel containing calendula, Lactobacillus sporogenes, isoflavones, and lactic acid (Estromineral Gel, Rottapharm-Madaus) daily for 4 weeks reduces vaginal itching, burning, dryness, and painful intercourse when compared with no topical treatment. Both groups also received oral isoflavones (39534). It is unclear if these effects are due to calendula, other ingredients, or the combination.
• Vaginal candidiasis. One small clinical study suggest that topical calendula is not beneficial for the treatment of vaginal candidiasis. Details: Preliminary clinical research shows that applying 5 grams of calendula 1% cream intravaginally once daily for 7 days effectively treats vaginal candidiasis in 34% fewer patients when compared with using clotrimazole 1% cream (93559).
• Venous leg ulcers. It is unclear if topical calendula is beneficial for improving venous leg ulcers. Details: Preliminary clinical research shows that applying a calendula 7.5% ointment twice daily for 3 weeks to venous leg ulcers accelerates healing when compared with applying saline solution dressing (39509).
• Wound healing. It is unclear if topical calendula is beneficial for improving the healing of small wounds. Details: Two small clinical trials in postpartum patients show that applying calendula ointment (formulation unspecified) to the episiotomy wound every 8 hours for 5-10 days modestly reduces pain, and seems to speed up the resolution of redness, edema, and ecchymosis, when compared with standard care, such as application of betadine solution (93550,105087). Another small clinical study in adults with wounds smaller than 10 cm² on the hands and fingers shows that applying calendula flower extract 2% to the wound twice daily may modestly improve healing and epithelialization time when compared with mineral oil (107806). More evidence is needed to rate calendula for these uses.

(Read more about CALENDULA)

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

LIKELY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about GLYCEROL)

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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There is insufficient reliable information available about the effectiveness of holly.

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LIKELY SAFE ...when the flower preparations are used orally or topically and appropriately (4,19779,36931,39503,93552,93557,96647,105088).

PREGNANCY: LIKELY UNSAFE
when used orally; contraindicated due to spermatocide, antiblastocyst, and abortifacient effects. There is insufficient reliable information available about the safety of calendula when used topically during pregnancy (4).

LACTATION:
Insufficient reliable information available; avoid using.

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

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

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

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

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

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

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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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UNSAFE ...when the berries are ingested. Eating berries can be fatal (18). There is insufficient reliable information available about the safety of holly leaves.

CHILDREN: UNSAFE
when the berries are ingested. Eating berries can be fatal (6).

PREGNANCY AND LACTATION: UNSAFE
when berries are ingested (6). There is insufficient reliable information available about the safety of holly leaves; avoid using.

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CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, calendula might have additive effects when used with CNS depressants, although this appears to be unlikely.  Details Although some animal research has suggested that a saponoside constituent in calendula may have sedative effects (39545,39547), calendula has been used for over 30 years without reports of sedation in humans (105088).

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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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General ...Orally and topically, calendula is generally well tolerated.
Serious Adverse Effects (Rare):
All ROAs: Allergic reactions.

Dermatologic ...Topically, a preparation containing calendula powder 0. 1% resulted in inflammation around the wound to which it was applied (96647). Burning sensation, itching, redness, and scaling were reported rarely in patients applying a combination of calendula, licorice, and snail secretion filtrate to the face. The specific role of calendula is unclear (110322).

Immunologic ...Orally, calendula can cause allergic reactions. Topically, calendula can cause eczematous allergic reactions. Calendula-specific patch testing is recommended prior to usage to determine allergenic potential. Testing is particularly necessary in individuals sensitive to the Asteraceae/Compositae family (10691,11458,96647). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs. A preparation containing calendula powder 0.1% resulted in hives in a patient with a ragweed allergy (96647). Despite the widespread use of calendula and the occurrence of allergies to other family members, there has been only one report of anaphylaxis (11152).

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

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

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

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

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

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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, ingestion of holly leaf can cause GI irritation, diarrhea, nausea, and vomiting (6,18). Holly leaf spines may tear or puncture skin or mucous membranes (6). Ingestion of as few as 2 holly berries can cause vomiting and diarrhea in small children (6). Ingestion of more than 5 holly berries can cause nausea, vomiting, and diarrhea (6,18). Ingestion of 20-30 holly berries can cause death (18).

Gastrointestinal ...Orally, ingestion of holly leaf can cause GI irritation, diarrhea, nausea, and vomiting (6,18). Holly leaf spines may tear or puncture skin or mucous membranes (6). Ingestion of as few as 2 holly berries can cause vomiting and diarrhea in small children (6). Ingestion of more than 5 holly berries can cause nausea, vomiting, and diarrhea (6,18).

Neurologic/CNS ...Orally, ingestion of more than 5 holly berries can cause stupor (6,18).

Other ...Orally, ingestion of 20-30 holly berries can cause death (18).

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