Norwegian Cod Liver Oil 2200 mg by NSI - Nutraceutical Sciences Institute

POSSIBLY INEFFECTIVE

• Coronavirus disease 2019 (COVID-19). Oral cod liver oil does not seem to be beneficial for COVID-19 prevention. Details: A large clinical trial in adults shows that taking cod liver oil 5 mL daily for up to 6 months in winter does not prevent any or serious COVID-19 infection compared with placebo. Each 5 mL of cod liver oil provided vitamin D3 400 IU, eicosapentaenoic acid (EPA) 0.4 grams, and docosahexaenoic acid (DHA) 0.5 grams (110378).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). It is unclear if oral cod liver oil prevents AMD. Details: A population study from Iceland suggests that taking oral cod liver oil supplements daily is not associated with a reduced risk of developing AMD over a 5-year period when compared to not taking cod liver oil (94753). However, since dietary fish intake is relatively high in this population, additional cod liver oil supplementation may not have been beneficial.
• Allergic rhinitis (hay fever). It is unclear if oral cod liver oil during pregnancy prevents allergic rhinitis in the child. In addition, it is unclear if oral cod liver oil during childhood prevents allergic rhinitis. Details: Population research from Norway found that taking cod liver oil at least once weekly during pregnancy or breast-feeding is not associated with a reduced risk of allergic rhinitis in the child. Also, consumption of cod liver oil at least once weekly at 2 years of age is not associated with a reduced risk of allergic rhinitis at age 6 years (101989). Since the participants in this study normally consumed high amounts of oily fish and cod liver oil, it is unclear if cod liver oil would be beneficial in populations with normally low intake.
• Arrhythmia. It is unclear if oral cod liver oil is beneficial for ventricular premature complexes (VPCs). Details: Preliminary clinical research shows that taking cod liver oil (Möller Tran) 15 mL orally daily for 16 weeks might reduce VPCs in people with moderate to low-grade ventricular arrhythmias and no significant heart failure. Approximately 44% of patients treated with cod liver oil achieved a clinically relevant reduction in VPCs, compared to only 15% taking placebo (7360). However, it is not clear if this reduction in VPCs correlates with a reduction in the risk of cardiovascular-related mortality. Other clinical research shows that taking cod liver oil 20 mL orally daily for 6 weeks does not reduce the number of ventricular extrasystoles or other arrhythmias in men with arrhythmias following myocardial infarction (MI) (94759).
• Asthma. It is unclear if oral cod liver oil during pregnancy or while breast-feeding prevents asthma in the child. In addition, it is unclear if oral cod liver oil during childhood prevents asthma. Details: Population research has found that taking cod liver oil 1-3 times weekly during pregnancy is associated with a 43% reduced risk of asthma in the child at 6 years of age. However, taking cod liver oil at least 4 times weekly during pregnancy, or taking it while breast-feeding, is not associated with a reduced risk of asthma in the child at 6 years of age. Also, consumption of cod liver oil at least once weekly at 2 years of age is not associated with a reduced risk of asthma at age 6 years (101989). Since the participants in this study normally consumed high amounts of oily fish and cod liver oil, it is unclear if cod liver oil would be more beneficial in populations with normally low intake.
• Atopic dermatitis (eczema). It is unclear if oral cod liver oil during pregnancy or while breast-feeding prevents eczema in the child. In addition, it is unclear if oral cod liver oil during childhood prevents eczema. Details: Population research has found that taking cod liver oil at least once weekly during pregnancy or breast-feeding is not associated with a reduced risk of eczema in the child. Also, consumption of cod liver oil at least once weekly at 2 years of age is not associated with a reduced risk of eczema at age 6 years (101989). However, in the infant, taking cod liver oil at least 4 times a week at one year of age is associated with a 29% reduced prevalence of eczema (101989).
• Burns. Although there has been interest in using topical cod liver oil for burns, there is insufficient reliable information about the clinical effects of cod liver oil for this condition.
• Coronary heart disease (CHD). Although there has been interest in using oral cod liver oil for CHD, there is insufficient reliable information about the clinical effects of cod liver oil for this condition.
• Depression. It is unclear if oral cod liver oil prevents depressive symptoms. Details: Evidence from a large population study including Norwegian adults aged 40-49 and 70-74 years shows that taking cod liver oil orally daily is associated with a 29% lower odds of depressive symptoms when compared with not taking cod liver oil (15648).
• Diabetes. It is unclear if oral cod liver oil is beneficial in gestational or type 1 diabetes. Details: In women with gestational diabetes, clinical research shows that taking cod liver oil 500 mg daily for 4 weeks, starting at 24-28 weeks gestation, does not improve levels of glycated hemoglobin (HbA1c), fasting blood glucose, insulin resistance, or plasma lipids when compared with placebo. However, taking cod liver oil for 12-16 weeks reduces HbA1c by 8.4%, fasting blood glucose by 41%, and insulin resistance by 43%, when compared with baseline. These differences were statistically significant when compared with placebo. Taking cod liver oil also resulted in a 17.5% reduction in perinatal complications, especially postpartum infections and Caesarian section (101988). Preliminary clinical research in patients with type 1 diabetes and elevated cholesterol levels shows that taking cod liver oil (Eskisol emulsion, Pharma-Vinci A/s) 21 mL orally daily for 8 weeks does not lower total cholesterol or LDL cholesterol levels, or affect insulin requirement, HbA1c, or blood glucose levels. There was a small effect on high-density lipoprotein (HDL) cholesterol and systolic and diastolic blood pressure (3399).
• Diabetic nephropathy. Although there has been interest in using oral cod liver oil for diabetic nephropathy, there is insufficient reliable information about the clinical effects of cod liver oil for this condition.
• Diaper rash. Although there has been interest in using topical cod liver oil for diaper rash, there is insufficient reliable information about the clinical effects of cod liver oil for this condition.
• Exercise-induced muscle damage. Although there has been interest in using oral cod liver oil for exercise-induced muscle damage, there is insufficient reliable evidence about the clinical effects of cod liver oil for this purpose.
• Familial hypercholesterolemia. It is unclear if oral cod liver oil is beneficial in familial hypercholesterolemia. Details: Preliminary clinical research shows that taking cod liver oil does not lower total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride levels, or increase high-density lipoprotein (HDL) cholesterol levels, in patients with familial type IIa hypercholesteremia when compared to baseline (10083).
• Glaucoma. Although there has been interest in using oral cod liver oil for glaucoma, there is insufficient reliable information about the clinical effects of cod liver oil for this condition.
• Hemorrhoids. Although there has been interest in using topical cod liver oil for hemorrhoids, there is insufficient reliable information about the clinical effects of cod liver oil for this condition.
• Hypercholesterolemia. It is unclear if oral cod liver oil is beneficial for lowering lipid levels; the available research is conflicting. Details: Preliminary clinical research shows that taking cod liver oil (Eskisol emulsion, Pharma-Vinci A/s) 21 mL orally daily for 8 weeks does not lower total cholesterol or low-density lipoprotein (LDL) cholesterol levels in patients with type 1 diabetes and elevated cholesterol levels. However, it appears to increase high-density lipoprotein (HDL) cholesterol levels by 5 mg/dL when compared to baseline (3399). Other clinical research in men with a history of myocardial infarction shows that taking an Icelandic cod liver oil 20 mL orally daily for 6 weeks appears to decrease triglycerides by 18 mg/dL when compared to baseline, with no improvement in LDL cholesterol levels (94758). A large, single-blind clinical study of patients with hypercholesterolemia shows that taking oral cod liver oil 415 mg daily in conjunction with oral rosuvastatin 10 mg daily for 30 days further reduces total cholesterol and LDL cholesterol levels when compared with rosuvastatin monotherapy (107491). It is unclear if this effect is due to cod liver oil, rosuvastatin, or the combination.
• Hypertension. It is unclear if oral cod liver oil is beneficial for lowering blood pressure. Details: In adults with type 1 diabetes, albuminuria, and mild hypertension, taking cod liver oil (Eskisol emulsion, Pharma-Vinci A/s) 21 mL orally daily for 8 weeks can reduce systolic blood pressure by 7 mmHg and diastolic blood pressure by 5 mmHg when compared to baseline (3399). A small clinical study in healthy men shows that taking cod liver oil (British Cod Liver Oils, Hull, UK) 5 mL orally four times daily with meals for 6 weeks can reduce systolic blood pressure by 13 mmHg and diastolic blood pressure by 12 mmHg when compared to baseline (4026). However, the validity of these findings is limited by the lack of comparator groups.
• Hypertriglyceridemia. It is unclear if oral cod liver oil is beneficial for lowering triglyceride levels. Details: Clinical research in men with a history of myocardial infarction shows that taking cod liver oil 20 mL orally daily for 6 weeks appears to decrease triglycerides by 18 mg/dL when compared to baseline, with no improvement in LDL cholesterol levels (94758). The clinical significance of these changes in patients with hypertriglyceridemia are unclear.
• Inflammatory bowel disease (IBD). It is unclear if oral cod liver oil is beneficial in IBD. Details: Preliminary clinical research shows that taking cod liver oil (Möller Axellus AS) 10 mL orally three times daily before meals for 14 days reduces joint pain intensity in adults with arthralgias associated with Crohn disease or ulcerative colitis when compared to baseline (94754). The validity of this finding is limited by the lack of a comparator group.
• Myocardial infarction (MI). It is unclear if oral cod liver oil is beneficial for preventing MI. Details: A large, non-blinded clinical study in patients at moderate to high risk for a cardiovascular event shows that taking oral cod liver oil 415 mg daily for up to 12 months does not affect the overall incidence of MI or the incidence of fatal or non-fatal MI when compared with no supplementation (107490). It is unclear if cod liver oil supplementation has any effect on modifiable risk factors such as hypertension and hypercholesteremia, which may impact the long-term incidence of MI.
• Osteoarthritis. It is unclear if oral cod liver oil is beneficial when used with nonsteroidal anti-inflammatory drugs (NSAIDs). Details: Preliminary clinical research shows that taking cod liver oil 10 mL orally daily for 24 weeks, in combination with NSAIDs, does not decrease pain or inflammation when compared with NSAID treatment alone (3398).
• Otitis media. It is unclear if oral cod liver oil prevents otitis media in children. Details: Preliminary clinical research shows that taking cod liver oil 5 mL orally daily, in combination with a children's multivitamin-mineral preparation containing selenium, can reduce the number of days of antibiotic therapy in an otitis media (OM) season in young children aged 0.8-4.4 years. The mean percentage of days on antibiotics in the OM season decreased by 12% when compared with the previous year's OM season, when no supplements were used (10151).
• Respiratory tract infections. It is unclear if oral cod liver oil prevents respiratory tract infections. Details: A large clinical trial in adults shows that taking cod liver oil 5 mL daily for up to 6 months in winter does not prevent acute respiratory infections compared with placebo. Each 5 mL of cod liver oil provided vitamin D3 400 IU, eicosapentaenoic acid (EPA) 0.4 grams, and docosahexaenoic acid (DHA) 0.5 grams (110378). However, preliminary clinical research shows that giving children a specific cod liver oil product (Carlson for Kids cod liver oil lemon flavor, Carlson Labs) along with a multivitamin (Carlson for Kids Scooter Rabbit Chewable Vitamins and Minerals, Carlson Labs) for about 5 months decreases the number of doctor's office visits for respiratory tract infections when compared with no supplementation. Children aged 1-5 years received 1 teaspoon of cod liver oil and half a multivitamin tablet daily; children aged 0.5-1 year received half doses (94756).
• Rheumatoid arthritis (RA). It is unclear if oral cod liver oil is beneficial in RA. Details: A preliminary, uncontrolled study suggests that taking a specific cod liver oil product (Seven Seas Neutrataste, Seven Seas Ltd.) 1 gram daily for 3 months might decrease pain, morning stiffness, and swelling in people with symptoms suggestive of RA who have not received any prior treatment (94757). Other clinical research shows that taking cod liver oil and fish oil (Seven Seas Marine Oil, Seven Seas Ltd.) 10 grams daily for 36 weeks can reduce NSAID use in patients with RA. About 4-fold more patients taking cod liver oil and fish oil can reduce NSAID intake by at least 30% when compared with placebo (65855). It is unclear if this effect is due to cod liver oil, fish oil, or the combination.
• Vitamin D deficiency. It is unclear if oral cod liver oil is beneficial as a vitamin D supplement. Details: Cod liver oil is sometimes used as a source of vitamin D. Evidence from population research shows that increased daily intake of cod liver oil supplements is associated with higher serum levels of vitamin D (94760). Also, a population study of postmenopausal women in northern Scotland shows that those taking a daily cod liver oil supplement are less likely to be vitamin D deficient during the winter and spring than those not taking a supplement (94761). However, preliminary clinical research shows that taking a low dose of cod liver oil (Möller Axellus AS) orally to provide 200 IU of vitamin D daily for 8 weeks during the winter does not maintain serum vitamin D at typical summer levels (94755).
• Wound healing. Although there has been interest in using topical cod liver oil for wound healing, there is insufficient reliable information about the clinical effects of cod liver oil for this condition. More evidence is needed to rate cod liver oil for these uses.

(Read more about COD LIVER OIL)

EFFECTIVE

• Ataxia with vitamin E deficiency (AVED). Oral vitamin E is effective for treating vitamin E deficiency due to the genetic disorder AVED. Details: This genetic disorder occurs when the gene that produces alpha-tocopherol transfer protein (alpha-TTP) is defective. This causes severe vitamin E deficiency. Symptoms such as cerebellar ataxia, dysarthria, absence of deep tendon reflexes, and sensory loss usually appear between 4 and 18 years of age. Vitamin E supplements are used in the treatment of AVED (13498,101437,101438).
• Vitamin E deficiency. Oral vitamin E is effective for preventing or treating vitamin E deficiency and associated conditions. Details: Taking vitamin E orally is effective for preventing and treating vitamin E deficiency (4844). However, vitamin E deficiency is rare in humans. It most commonly occurs in people with malabsorption disorders such as abetalipoproteinemia; cystic fibrosis; gastrectomy; hepatic-biliary tract disease including chronic cholestasis, hepatic cirrhosis, biliary atresia, and obstructive jaundice; in infants receiving formula with insufficient vitamin E; intestinal diseases including celiac and tropical sprue; and regional enteritis (4844,104411).

POSSIBLY EFFECTIVE

• Alzheimer disease. Oral vitamin E might slow functional decline in some patients with this condition. However, it does not seem to prevent Alzheimer disease onset. Details: A clinical study in patients with moderate Alzheimer disease shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 2000 IU daily for 2 years might be similar to selegiline (Eldepryl), and superior to placebo, for slowing cognitive decline. Benefit was only apparent when outcomes were adjusted for baseline Mini-Mental State Examination (MMSE) scores. This study is limited by attrition bias, or incomplete outcome reporting (4635,97070). Another clinical study in patients with mild-to-moderate Alzheimer disease shows that taking all-rac-alpha-tocopherol 2000 IU daily reduces the annual rate of decline in activities of daily living by 19% when compared with placebo. This translates to a delay in disease progression of 6.2 months. This is comparable to the effect of acetylcholinesterase inhibitors (e.g., rivastigmine) in this population. Despite these positive findings, the World Health Organization (WHO) recommends against the use of vitamin E for the management of dementia due to the increased risk for adverse effects with the extended use of high-dose vitamin E (104823). Interestingly, the combination of vitamin E and memantine (Namenda) 20 mg per day is not superior to placebo in this population. Researchers speculate that this lack of effectiveness may be due to an interaction between vitamin E and memantine, but this proposed interaction has not been validated in research (19060,97070). Vitamin E supplementation doesn't seem to prevent Alzheimer disease or slow progression of mild cognitive impairment. Patients with mild cognitive impairment who take vitamin E 2000 IU daily for 3 years progress to Alzheimer disease at the same rate as those who take placebo (13060,97070). Furthermore, although population research has found that greater intake of foods high in vitamin E is associated with a lower risk of developing Alzheimer disease (34597,90082), taking vitamin E supplements does not seem to help. Evidence from a large clinical study that was later converted into an observational study shows that taking vitamin E 400 IU orally daily does not prevent Alzheimer disease when compared with placebo in cognitively intact men (93570). However, this study is limited by the fact that the participants were well-educated and were assessed for dementia in their 60s; the prevalence of dementia is typically low in this age group (93571).
• Beta-thalassemia. Oral vitamin E seems to be beneficial for children with this condition. Details: A small clinical study in children with beta-thalassemia and low vitamin E plasma concentrations shows that taking vitamin E orally seems to correct erythrocyte membrane abnormalities when compared with control (4642). Another small clinical trial in children 5-18 years of age with beta-thalassemia shows that taking an age-based dose of vitamin E (alpha-tocopherol) 200-600 mg daily for 4 weeks seems to increase haptoglobin levels, suggesting reduced hemolysis, when compared with placebo (104412).
• Dysmenorrhea. Oral vitamin E seems to reduce pain in adults with dysmenorrhea. Details: Small clinical studies in younger adults with primary dysmenorrhea show that taking vitamin E 200-500 IU daily, starting 2 days before menstruation and continuing through the first 3 days of bleeding for 2-4 cycles, decreases the severity and duration of pain and reduces blood loss when compared with placebo (10361,14432,99367). One study also shows that taking vitamin E 200 IU with fish oil provides better pain relief when compared with taking either vitamin E or omega-3 fatty acids alone (99367). A meta-analysis of 8 small clinical studies, including those described above, in individuals with dysmenorrhea shows that taking vitamin E reduces the severity of pain when compared with placebo (112170).
• Exercise-induced muscle damage. Oral vitamin E seems to modestly reduce exercise-induced muscle damage. Details: A meta-analysis of 17 very small clinical studies in trained and untrained adults shows that taking vitamin E 300-1200 IU daily for up to 12 weeks reduces markers of exercise-induced muscle damage, including creatine kinase and lactate dehydrogenase, when compared with placebo. Vitamin E appears to be most beneficial in athletes and at doses under 500 IU daily (112160). However, a small clinical study in endurance-trained runners, not included in the analysis above, shows that taking vitamin E (as alpha-tocopherol) 235 mg and vitamin C 1000 mg 2 hours prior to an exercise protocol does not reduce delayed onset muscle soreness or improve markers of exercise-induced muscle damage when compared with placebo (109961).
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Oral vitamin E seems to be beneficial in patients with G6PD deficiency. Details: Individual clinical studies evaluating the use of vitamin E in patients with G6PD deficiency show mixed results (4682,4683,4684). However, a meta-analysis of 6 small clinical studies in patients with G6PD deficiency shows that taking vitamin E improves hemoglobin levels and reduces reticulocyte levels when compared with placebo in the setting of both acute and chronic hemolysis (112164).
• Intracranial hemorrhage. Oral vitamin E might reduce the risk of intracranial hemorrhage in premature infants. Details: Clinical research shows that giving premature neonates vitamin E orally might reduce the risk of intracranial hemorrhage when compared with control (4655,85074).
• Intraventricular hemorrhage. Oral vitamin E might reduce the risk of intraventricular hemorrhage in premature infants. Intravenous vitamin E does not provide this benefit. Details: A meta-analysis of the available clinical research shows that oral, but not intravenous, administration of vitamin E can reduce the risk for intraventricular hemorrhage in premature neonates when compared with control. However, it might not reduce the risk for severe (grade III-IV) intraventricular hemorrhage. Additionally, high serum levels of vitamin E have been associated with an increased risk for sepsis in premature infants (85062).
• Nitrate tolerance. Oral vitamin E might reduce tolerance to nitrates. Details: Nitrate tolerance might involve increased vascular superoxide anion production, and antioxidants may help prevent this (4705). Clinical research in patients with ischemic heart disease shows that taking vitamin E 447-894 IU daily can help prevent nitrate tolerance when compared with placebo (4705,11543).
• Nonalcoholic steatohepatitis (NASH). Oral vitamin E seems to improve outcomes in patients with NASH. Details: Clinical studies and meta-analyses in adults with NASH shows that taking vitamin E 800 IU daily for up to 24 months improves liver enzymes, hepatic fibrosis, steatosis, and lobular inflammation (14005,17517,97077,104413). Taking vitamin E 400-1200 IU in children with NASH also seems to improve liver enzyme levels after 4-10 months of treatment (89). Furthermore, a small study in patients with NASH shows that taking vitamin E 800 IU daily for 1 year seems to improve liver histology to a similar degree as taking telmisartan 40 mg daily (104405). In fact, practice guidelines by the American Association for the Study of Liver Diseases (AASLD) recommend taking vitamin E 800 IU daily as a first-line therapy in non-diabetic adults with biopsy-proven NASH. However, vitamin E isn't recommended in NASH patients with diabetes, cirrhosis, or cryptogenic cirrhosis (98130).
• Premenstrual syndrome (PMS). Oral vitamin E seems to improve PMS symptoms. Details: Clinical research in adults with PMS shows that taking vitamin E 400-600 IU daily for 3 cycles reduce subjective reports of symptoms, including anxiety, craving, and depression, when compared with placebo (4719,4720). Another small clinical study in Japanese patients with PMS shows that taking vitamin E, as gamma-tocopherol 180 mg, twice daily for 7 days during the luteal phase of 2 consecutive cycles reduces fatigue, irritability, and leg swelling when compared with placebo (112337).
• Tardive dyskinesia. Oral vitamin E might attenuate worsening of tardive dyskinesia in patients taking antipsychotic medications. Details: Small clinical studies suggest that taking vitamin E orally improves Abnormal Involuntary Movement Scale (AIMS) scores in patients with tardive dyskinesia. It seems to be more effective in higher doses and in people who have had tardive dyskinesia for less than 5 years (3942,3943,3944,3945,3946,3948,85323). Both RRR-alpha-tocopherol (natural vitamin E) and unspecified forms were used in clinical trials. However, some conflicting findings have been reported. A meta-analysis suggests that vitamin E does not improve symptoms of tardive dyskinesia when compared with placebo; however, taking vitamin E seems to prevent the deterioration of symptoms when compared with placebo (97079).

POSSIBLY INEFFECTIVE

• Age-related macular degeneration (AMD). Oral vitamin E does not seem to slow AMD progression. Details: Results from clinical trials and meta-analyses of clinical trials show that vitamin E when taken alone or in combination with other antioxidants does not prevent the development (4667,7303,7304,34625) or progression of AMD (34633). In contrast, taking vitamin E 400 IU orally with elemental zinc 80 mg, vitamin C 500 mg, and beta-carotene 15 mg daily does seem to be beneficial. When taken for 5 years, this combination reduces visual acuity loss and reduces the risk of progression of AMD by 25% in patients with advanced AMD (7303,11326). A 10-year follow-up on this study confirmed these findings (90069). It is not known if this combination is beneficial for people with less advanced macular disease or for preventing AMD. Additionally, it is not clear if this benefit is due to vitamin E, the other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Oral vitamin E does not seem to slow ALS progression. Details: Clinical research in patients with ALS shows that taking alpha-tocopherol 1490 IU daily for up to 12 months in addition to riluzole does not influence survival or motor function when compared with riluzole alone. However, these patients seem to be less likely to progress to a more severe disease state from a milder disease state (83180). Additionally, a large population study has found that dietary intake of vitamin E is not associated with risk of developing ALS (90087).
• Angina. Oral vitamin E does not seem to reduce angina symptoms. Details: Clinical research shows that taking vitamin E orally may have some effect on endothelial dysfunction, but does not improve angina in nonsmokers or smokers, when compared with placebo (3896,4634,4649,4650,4651,4652).
• Atherosclerosis. Oral vitamin E does not seem to reduce atherosclerosis progression. Details: Taking RRR-alpha-tocopherol (natural vitamin E) orally does not appear to have any effect on atherosclerosis progression or mortality in patients with atherosclerosis when compared with placebo (3899,3936). However, there is preliminary evidence that a combination of vitamin E and vitamin C might help prevent the progression of atherosclerosis in men, particularly smokers and cardiac transplant patients (1918).
• Atopic dermatitis (eczema). Oral vitamin E does not seem to reduce eczema symptoms. Details: Clinical research shows that taking vitamin E 600 IU in combination with selenium daily for 12 weeks does not improve symptoms of atopic eczema when compared with placebo or selenium alone (74456). Also, while some clinical research shows that taking 600 IU of all-rac-alpha-tocopherol (synthetic vitamin E) daily for 60 days with vitamin D 1600 IU improves overall atopic dermatitis symptoms, pruritus, and erythema when compared with placebo, taking vitamin E alone does not seem to have this effect. However, vitamin E alone does improve hard, leathery skin symptoms and dryness when compared with placebo (84491).
• Breast cancer-related hot flashes. Oral vitamin E does not seem to reduce hot flashes related to breast cancer. Details: Clinical research shows that taking vitamin E 800 IU daily for 4 weeks does not reduce hot flashes in females who have had breast cancer when compared with placebo (454).
• Bronchopulmonary dysplasia. Oral vitamin E does not seem to reduce the risk for bronchopulmonary dysplasia in premature infants. Details: Clinical research in premature infants weighing less than 1500 grams at birth shows that taking vitamin E orally does not prevent bronchopulmonary dysplasia when compared with placebo (4657,85062).
• Cataracts. Oral vitamin E does not seem to reduce cataract risk. Details: Some population research has found that dietary and supplemental vitamin E intake is associated with a reduced risk of developing age-related cataracts (4208,4663,4665,4759). However, other population research has not found this association (2395,4664,92902). Additionally, higher quality evidence from clinical trials and a meta-analysis consistently shows that vitamin E, taken alone or with other vitamins, does not prevent the progression of age-related cataracts or decrease vision loss when compared with control (4666,7304,34626).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin E does not seem to reduce peripheral neuropathy due to chemotherapy. Details: Although some small, low-quality clinical studies and a meta-analysis of these studies suggest that vitamin E 600 mg daily for 3 months might be beneficial for preventing chemotherapy-induced peripheral neuropathy induced by cisplatin, carboplatin, or oxaliplatin when compared with placebo (10366,85117,90072), these studies have found no effect with lower doses of vitamin E or in those receiving paclitaxel chemotherapy (107862). In addition to the low methodological quality of the studies, the validity of these finding is limited by high heterogeneity, as the studies included patients with several different cancer types. Also, a large, high-quality clinical study shows that taking vitamin E 400 mg daily is not beneficial for preventing peripheral neuropathy induced by taxanes or platinum analogues when compared with placebo (101457). The American Society of Clinical Oncology does not recommend the use of vitamin E for the prevention or management of chemotherapy-induced peripheral neuropathy (101434).
• Colorectal cancer. Oral vitamin E does not seem to reduce colorectal cancer risk. Details: Some population research has found that intake of vitamin E and multivitamins is associated with a reduced risk of colorectal cancer (1047). Some preliminary clinical research also shows that taking vitamin E orally in combination with other vitamins might have a protective effect in patients with a history of colorectal adenomas (3954,3956,92903). However, higher quality evidence from larger clinical trials and meta-analyses of clinical research consistently show that taking vitamin E supplements alone, or in combination with other vitamins, does not prevent colorectal cancer incidence or recurrence when compared with control (3953,3955,3957,12185,13036,13131,34594,90361). Despite this conflicting research, the US Food and Drug Administration (FDA) approved a qualified health claim in 2009 regarding vitamin E and colorectal cancer risk. However, the FDA has determined that it is highly unlikely that vitamin E supplements reduce the risk of colorectal cancer (102332).
• Congestive heart failure (CHF). Oral vitamin E does not seem to reduce CHF symptoms or prevent CHF development. Details: Clinical research in adults with New York Heart Association (NYHA) functional class III or IV heart failure shows that taking vitamin E (RRR- α tocopherol) 500 IU orally daily for 12 weeks does not improve prognostic or functional indices of CHF or quality of life measurements when compared with placebo (3906). Additionally, population research shows that taking vitamin E 600 IU every other day does not affect the risk of developing heart failure in healthy females 45 years or older when compared with placebo (90068).
• Head and neck cancer. Oral vitamin E does not seem to reduce the risk of head and neck cancer recurrence. In fact, it might increase recurrence risk. Details: A large clinical trial in patients with stage I or II head and neck cancer shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily, during radiation therapy and for 3 years after the end of radiation therapy, does not reduce the risk of recurrence of the first tumor or development of a second primary tumor when compared with placebo. In fact, there is some concern that patients taking vitamin E seem to have an increased risk of tumor recurrence or a second primary tumor when compared with patients taking placebo (13055). Advise patients with head and neck cancer to avoid taking vitamin E supplements in doses of 400 IU/day or more.
• Hypertension. Oral vitamin E does not seem to reduce blood pressure. Details: A clinical study in patients with hypertension who are receiving conventional treatment shows that taking vitamin E 300 mg daily orally for 3-4 years does not lower blood pressure when compared with control (5210).
• Intrauterine growth restriction (IUGR). Oral vitamin E during pregnancy does not seem to reduce IUGR risk. Details: A meta-analysis of clinical research shows that taking vitamin E along with other ingredients throughout pregnancy does not reduce the risk for IUGR when compared with placebo (97075).
• Liver disease. Oral vitamin E does not seem to reduce liver disease-associated mortality. Details: A meta-analysis of clinical research shows that taking vitamin E does not reduce all-cause-or liver related-mortality or morbidity in patients with liver diseases, including autoimmune liver diseases, viral hepatitis, alcoholic liver disease, or cirrhosis (34608). Additional clinical research in male smokers over 50 years old shows that taking vitamin E 75 IU orally, alone or with beta-carotene 20 mg orally, daily for 5-8 years does not reduce the risk of mortality due to chronic liver disease when compared with placebo (91383).
• Oral leukoplakia. Oral vitamin E does not seem to reduce the risk for oral leukoplakia in male smokers. Details: Although there is some conflicting evidence (3951,4708), the largest randomized controlled trial indicates that supplementation with all-rac-alpha-tocopherol (synthetic vitamin E) 55.6 IU daily for 5-7 years has no effect on the incidence of oral lesions in male cigarette smokers when compared with placebo (3951).
• Osteoarthritis. Oral vitamin E does not seem to be beneficial for osteoarthritis treatment or prevention. Details: Taking vitamin E 500 IU daily for 6 months does not seem to decrease symptoms of pain or stiffness in patients with osteoarthritis when compared with placebo (5264). Additional clinical research show that taking vitamin E 500 IU daily for up to 2 years does not slow cartilage loss when compared with placebo (13066). Population research has shown that taking vitamin E supplements does not reduce the risk of developing osteoarthritis or slow the progression of existing osteoarthritis (5881).
• Pancreatic cancer. Oral vitamin E does not seem to reduce pancreatic cancer risk. Details: Taking vitamin E supplements alone or in combination with other antioxidants such as beta-carotene and vitamin C does not reduce the risk of developing pancreatic cancer (12185,85147). Taking all-rac-alpha-tocopherol (synthetic vitamin E) 55.6 IU daily for 5 to 8 years also does not seem to reduce the incidence of or mortality from carcinoma of the pancreas in male smokers (3961).
• Parkinson disease. Oral vitamin E does not seem to reduce Parkinson disease symptoms or progression, although the risk of developing the disease may decrease with increased dietary vitamin E intake. Details: Observational research has found that dietary vitamin E intake might be associated with a decreased occurrence of Parkinson disease (4712). A meta-analysis of 12 studies evaluating the risk of developing Parkinson disease has found that the highest daily intake of vitamin E is associated with a 20% lower risk than those with the lowest intake (107858). However, clinical research in patients with stage I or II Parkinson disease shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 2000 IU daily for up to 24 months doesn't seem to have any benefit when compared with baseline or control (4709,4710,4711,85318).
• Pharyngeal cancer. It is unclear if oral vitamin E reduces the risk of developing cancer of the pharynx. Details: A sub-group analysis of a large-scale clinical trial (The HOPE Trial) in patients with diabetes or cardiovascular disease suggests that taking RRR-alpha-tocopherol (natural vitamin E) 400 IU daily for about 7 years is not linked with a reduced risk of developing oral or pharyngeal cancer when compared with placebo (13036).
• Pre-eclampsia. Oral vitamin E does not seem to reduce pre-eclampsia risk. Details: The majority of clinical research shows that taking a combination of vitamins E and C, at the same doses, does not reduce the risk of pre-eclampsia in low-, moderate-, or high-risk patients, when compared with placebo or no treatment. Also, the risk of gestational hypertension might increase in some cases, although results are inconsistent (83312,83356,83383,83472,83474,97075,97059). Other researchers using vitamin E in combination with vitamin C and allopurinol beginning at 24-32 weeks gestation found the combination similar to placebo (4718). However, some clinical research suggests that taking a combination of vitamin E 400 IU and vitamin C 1000 mg daily reduces the risk of proteinuric hypertension in high-risk patients when started in weeks 16-22 of pregnancy (3236).
• Preterm labor. Oral vitamin E does not seem to reduce risk for premature labor. Details: A meta-analysis of clinical research shows that taking vitamin E along with other ingredients throughout pregnancy does not reduce the risk for preterm labor when compared with placebo (97075).
• Prostate cancer. Oral vitamin E does not seem to reduce the risk of prostate cancer. Details: A meta-analysis of over 30 large clinical trials and observational studies shows that neither dietary nor supplemental vitamin E reduces the risk of prostate cancer when compared with a control (112159). However, individual study results are mixed. Population research on the use of dietary or supplemental vitamin E intake for prostate cancer risk reduction is conflicting (12872,14124,12873,15607). Although one large-scale study in smokers found that taking 55.6 IU daily of all-rac-alpha-tocopherol (synthetic vitamin E) reduced the risk of prostate cancer and mortality (3959,11303), most large-scale randomized, controlled trials show that vitamin E is not beneficial. A sub-group analysis of a large-scale clinical study (The HOPE trial) in patients with diabetes or cardiovascular disease suggests that taking 400 IU of RRR-alpha-tocopherol (natural vitamin E) daily for about 7 years is not linked with a decreased risk of developing prostate cancer when compared with placebo (13036). Another large scale study (Physician's Health Study II) shows that taking vitamin E 400 IU every other day for an average of 8 years does not reduce the risk of prostate cancer when compared with placebo (16708,90097). Similarly, another large clinical study (The SU.VI.MAX study) shows that a combination of vitamin E (alpha-tocopherol) 44.7 IU, vitamin C 120 mg, beta-carotene 6 mg, selenium 100 mcg, and zinc 20 mg daily for an average of 8 years does not reduce the risk of prostate cancer overall when compared with placebo (14135). A fourth large-scale clinical trial (The SELECT trial) in men over the age of 50 years shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily, alone or in combination with selenium 200 mcg daily, for an average of about 5.5 years does not reduce prostate cancer risk when compared with placebo (16707). Also, an extension of this initial study found that taking vitamin E alone was associated with a 17% increased of developing prostate cancer (17688).
• Respiratory tract infections. Oral vitamin E does not seem to reduce respiratory infections in most patients. However, there's some evidence that it might reduce incidence of the common cold in patients living in long-term care facilities. Details: Taking oral vitamin E 298 IU daily, alone or in supplemental multivitamin form, does not appear to decrease the incidence, duration, or severity of upper or lower respiratory infections in elderly persons when compared with placebo (10788,12094). However, some research shows that taking vitamin E reduces the incidence of the common cold in elderly long-term care patients when compared with placebo (12094). More evidence is needed to determine how effective vitamin E might be for reducing the incidence of the common cold.
• Retinitis pigmentosa. Oral vitamin E does not seem to reduce retinitis pigmentosa and related visual decline. Details: Taking all-rac-alpha-tocopherol (synthetic vitamin E) orally does not appear to slow visual decline is people with retinitis pigmentosa and has been associated with more rapid loss of visual acuity, although the validity of the study with these findings has been questioned (83,84,85,86,87,88).
• Scarring. Topical vitamin E does not seem to improve scar appearance. Details: Some clinical research shows that applying ointment containing vitamin E topically does not reduce surgical wound scarring when compared with a placebo ointment (4721,4722).
• Stillbirth. Oral vitamin E does not seem to reduce risk of a stillborn baby. Details: A meta-analysis of clinical research shows that taking vitamin E along with other ingredients during pregnancy does not reduce the risk for stillbirth when compared with placebo (97075).

LIKELY INEFFECTIVE

• Breast cancer. Oral vitamin E does not reduce breast cancer risk. Details: Some evidence suggests that higher serum levels of vitamin E might be associated with a reduced risk of breast cancer (10132). However, increasing vitamin E intake from the diet or supplements does not seem to reduce the risk of developing breast cancer (4658,4659,85147,112334). Also, a large-scale randomized trial in patients with diabetes or cardiovascular disease shows that patients who take 400 IU of RRR-alpha-tocopherol (natural vitamin E) daily do not have a reduced risk of developing breast cancer (13036). In other large-scale studies, females who take RRR-alpha-tocopherol (natural vitamin E) 600 IU every other day for up to 10 years also do not have a lower risk of developing breast cancer (13131,34580).
• Cancer. Oral vitamin E does not reduce the risk of cancer in most patients. Details: Some research suggests that a combination of vitamin E 44.7 IU daily with vitamin C, beta-carotene, selenium, and zinc does not lower the overall risk of cancer, although it might reduce the risk of cancer when only males are evaluated (14109). However, clinical research from a large scale study (Physician's Health Study II) shows that taking vitamin E 400 IU every other day for an average of 8 years does not reduce the overall risk of cancer in males when compared with placebo (16708,90097). Also, clinical research published in a meta-analysis shows that taking vitamin E does not reduce the overall risk of cancer (85147). In 2003, the US Food and Drug Administration (FDA) approved a qualified health claim regarding antioxidant vitamins, such as vitamin E and overall cancer risk. However, the FDA has determined that the evidence is limited and inconclusive (102334). The US Preventive Services Task Force (USPSTF) states that there is no net benefit to supplementation with vitamin E for the prevention of cancer in general and therefore recommends against its use (108641,112166).
• Cardiovascular disease (CVD). Most evidence shows that oral vitamin E does not reduce the risk for CVD events or complications. Details: Most clinical research in various populations shows that taking vitamin E supplements orally is not effective for preventing heart disease or adverse cardiovascular outcomes such as myocardial infarction (MI), stroke, hospitalizations for unstable angina, morbidity, or cardiovascular death (12492,12493,13036,14108,66140,83050,85084,85224). The US Preventive Services Task Force (USPSTF) states that there is no net benefit to supplementation with vitamin E for the prevention of CVD in general and therefore recommends against its use (108641,112166). With few exceptions (3357,3936), large-scale controlled clinical trials show that vitamin E supplements offer no benefit for primary prevention in healthy or high-risk patients (3907,3935,3937,13036,13131), or for secondary prevention of heart disease and cardiovascular events such as MI, stroke, and death (3896,3899,13036). While one analysis of clinical research found that in mostly healthy patients 70 years or younger without CVD, vitamin E supplementation reduces the risk of cardiovascular mortality, the authors performed more than 20 statistical tests and did not adjust for multiple comparisons. Therefore, it possible that the positive effect was due to chance. This analysis was also limited because it excluded adults older than 70 years of age and adults that are more likely to suffer an exacerbation from a chronic condition. Furthermore, the analysis showed that vitamin E supplementation does not reduce the risk of all-cause mortality or the risk of CVD compared with placebo or no intervention (97078). There's additional conflicting evidence. One large-scale trial shows that healthy females who take RRR-alpha-tocopherol (natural vitamin E) 600 IU every other day for up to 10 years also do not have a lower risk of major cardiovascular events but might have a 24% lower risk of cardiovascular death when compared with placebo (13131). This finding is contradictory to previous findings. One notable limitation of this trial is a lack of systematic assessment of the use of statins or other cardiovascular therapies by the participants throughout the 10-year period. Meta-analyses of clinical trials involving patients with type 2 diabetes and the haptoglobin 2-2 genotype show that taking vitamin E, up to 600 IU daily for up to 8 years, reduces the incidence of non-fatal myocardial infarction and death due to CVD (85179,85221). Because these meta-analyses included only specific patients, the generalizability of the results is questionable. There is debate about whether some forms of vitamin E might work differently than others. Some people suggest that RRR-alpha-tocopherol (natural vitamin E) is more effective than all-rac-alpha-tocopherol (synthetic vitamin E). This has not been verified by studies. A meta-analysis of vitamin E studies indicates that there is no significant difference in cardiovascular outcomes based on the form of vitamin E used (13132). The FDA has refused to allow labeling claims for vitamin E supplements for prevention of CVD (3939). A Science Advisory from the American Heart Association also states that the evidence doesn't justify use of antioxidants such as vitamin E for reducing the risk of CVD (12142). Advise patients not to rely on vitamin E supplements for preventing heart disease.
• Fetal and premature infant mortality. Oral vitamin E does not seem to reduce death in preterm infants. Details: Meta-analyses of clinical research show that taking vitamin E throughout pregnancy does not affect morbidity or mortality in preterm infants when compared with placebo (85074,97075).
• Fibrocystic breast disease. Oral vitamin E does not improve fibrocystic breast disease in most patients. Details: Clinical research shows that taking alpha-tocopherol 150 IU, 300 IU, or 600 IU daily for 2-3 months does not improve subjective or objective measures of fibrocystic breast disease when compared with placebo (4660,4661,4662).
• Lung cancer. Oral vitamin E does not seem to reduce lung cancer risk. Details: Taking all-rac-alpha-tocopherol (synthetic vitamin E) 55.6 IU daily for 5-8 years is not associated with a lower risk of developing lung cancer for male smokers (3949). A sub-group analysis of a large scale clinical trial in patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily for about 7 years do not have a lower risk of developing lung cancer when compared with placebo (13036). In another large-scale study, females who take RRR-alpha-tocopherol (natural vitamin E) 600 IU every other day for up to 10 years also do not have a lower risk of developing lung cancer (13131). Meta-analyses of clinical research suggest taking vitamin E as alpha-tocopherol for up to approximately 10 years does not prevent lung cancer or reduce the incidence of lung cancer mortality when compared with placebo (34632,85147).
• Overall mortality. Oral vitamin E does not seem to reduce the risk of mortality from all causes. Details: Although some population research suggests that increased dietary vitamin E intake is associated with reduced overall mortality (98260), most meta-analyses of clinical research in adults show that taking vitamin E supplements for at least 1 year does not affect all-cause mortality (34622,85164,85200). Furthermore, when only high quality clinical trials were analyzed, mortality was increased by 3% in adults taking vitamin E when compared with control (34622).
• Prematurity. Oral vitamin E does not seem to reduce the risk of premature birth and complications. Details: Clinical research shows that vitamin E does not improve blood parameters or prevent the development of anemia in premature infants (4648,10362). One clinical study in premature infants weighing less than 1500 grams at birth shows that giving vitamin E 25 IU daily for six weeks does not improve hemoglobin concentration, reticulocyte counts, or platelet counts when compared with placebo (4648). Another clinical study in premature infants weighing less than 1250 grams at birth shows that giving vitamin E 50 IU daily for eight weeks does not increase the response to erythropoietin and iron when compared with placebo (10362).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Topical vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in Asian females aged 30-65 years shows that applying a specific liquid product, (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing vitamin E 1%, vitamin C 20%, and red raspberry leaf cell culture extract 0.0005%, to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Anemia of chronic disease. Small clinical studies suggest that oral vitamin E might improve response to anemia treatment in patients on chronic hemodialysis. Details: Two small studies in adults and children on chronic hemodialysis have shown improved response to erythropoietin with vitamin E supplementation (4640,4647). In one study, children given vitamin E 22.4 IU/kg in combination with erythropoietin had significantly increased hemoglobin and hematocrit levels after 2 weeks of combination treatment, compared with eight and five weeks in patients receiving erythropoietin alone (4640). In a study of adults, concurrent supplementation with vitamin E 745 IU daily allowed dose reductions of erythropoietin from an average of 93 U/kg/week to 74 U/kg/week with the same resultant hemoglobin levels (4647).
• Anthracycline cardiotoxicity. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with breast cancer receiving doxorubicin and cyclophosphamide chemotherapy shows that taking vitamin E 600 mg three times daily and L-carnitine 3000 mg by intravenous infusion on day 1 followed by 300 mg by mouth four times daily thereafter for 3 weeks reduced the risk of cardiovascular events by 63% and improved laboratory markers of cardiotoxicity when compared with chemotherapy alone (112338). It is unclear if these findings are due to vitamin E, L-carnitine, or the combination.
• Anxiety. It is unclear if oral vitamin E is beneficial in patients with anxiety. Details: A meta-analysis of 5 mostly small clinical studies in patients without anxiety shows that taking vitamin E 200-400 IU daily for up to 10 weeks does not improve anxiety symptom scores when compared with placebo (112158). It is unclear if these findings can be generalized to patients with anxiety disorders.
• Asthma. It is unclear if oral vitamin E is beneficial for asthma treatment or prevention. Details: There is inconsistent evidence about the role of vitamin E in asthma. Some population research has found that increased dietary intake of vitamin E is associated with a lower risk of asthma; however taking vitamin E supplements are not associated with decreased risk (6058,15006). Low vitamin E intake also appears to be associated with an increased risk of asthma (315,401,422). A small clinical study in children with asthma suggests that adding vitamin E 74.5 IU by mouth daily to fluticasone treatment for 8 weeks may decrease cough, wheezing, and dyspnea when compared with baseline (90077). This study was limited because it did not compare the vitamin E intervention to the control group.
• Atopic disease. It is unclear if oral vitamin E reduces the risk of atopic disease in infants. Details: Population research has found that increased maternal vitamin E intake isn't associated with decreased odds of developing eczema, food allergy, wheeze, allergic sensitization, or any allergic disease in infants (90098).
• Bladder cancer. It is unclear if oral vitamin E reduces bladder cancer risk. Details: A meta-analysis of clinical research shows that the highest intake of vitamin E is associated with a reduced risk for bladder cancer when compared to the lowest intake in patients followed for more than 10 years. This benefit was not seen in those followed for less than 10 years. This effect appears to be dose-dependent, although it is not clear how much vitamin E intake is required to reduce bladder cancer risk. Additionally, it is not clear whether this benefit differs for dietary or supplemental intake of vitamin E (101435). In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding vitamin E and bladder cancer risk. However, the FDA has determined that it is highly unlikely that vitamin E supplements reduce the risk of bladder cancer (102332). Some population research also shows that regular use of vitamin E supplements for more than 10 years is associated with a reduced risk of bladder cancer mortality; however, use for less than 10 years is not associated with reduced mortality (9839).
• Burns. It is unclear if topical vitamin E is beneficial for healing of burn wounds. Details: A small clinical study in patients with moderate and deep burn wounds (25% to 67%) shows that applying a specific alpha-tocopherol product (Filme Olio) daily seems to reduce infection and improve healing when compared with usual treatment (104407).
• Chemotherapy-related infection. It is unclear if oral vitamin E is beneficial in patients with infection due to chemotherapy. Details: Observational research suggests that greater dietary intake of vitamin E may lower the incidence of infection in children undergoing chemotherapy for lymphoblastic leukemia (11997).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral vitamin E for CFS, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
• Cisplatin-associated ototoxicity. It is unclear if oral vitamin E is beneficial for preventing ototoxicity due to cisplatin. Details: A small clinical study in patients receiving cisplatin for solid tumors shows that taking a specific vitamin E supplement (Rigentex, Bracco) as alpha-tocopherol 400 IU daily for 3 months attenuates hearing loss when compared with placebo (97082).
• Colistin-induced nephrotoxicity. It is unclear if oral vitamin E is beneficial for preventing nephrotoxicity due to colistin. Details: A small clinical study in patients receiving colistin therapy shows that taking vitamin E (alpha-tocopherol) 400 IU orally daily for the duration of colistin therapy does not reduce the incidence or duration of acute kidney injury when compared with colistin alone (107867).
• Contrast induced nephropathy. It is unclear if oral or intravenous vitamin E is beneficial in patients with nephropathy due to contrast dye. Details: A small clinical study in patients receiving elective computer-assisted tomography with nonionic radiocontrast agents shows that receiving vitamin E 3218 IU emulsion in 0.45% saline intravenously infused at the rate of 1 mL/kg/hr over 24 hours does not decrease the risk of contrast agent-induced nephropathy when compared with normal saline alone (90081). However, oral vitamin E may modestly reduce the risk of contrast induced nephropathy. A clinical trial shows that taking vitamin E as alpha-tocopherol 522 IU or gamma-tocopherol 447 IU orally daily, starting 5 days prior to the procedure and continuing 2 days post-procedure, results in a 9% to 10% lower incidence of contrast induced acute kidney injury when compared with standard treatment with normal saline (90096). Another clinical study shows that taking a single dose of vitamin E 1490 IU orally before elective coronary angiography reduces the risk of contrast induced kidney injury by 7% when compared with placebo (97074).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral vitamin E is beneficial for recovery after CABG. Details: When taking vitamin E orally with vitamin C and allopurinol two days prior to CABG and one day postoperatively, patients had fewer perioperative infarctions and lower creatine kinase-MB release (4699); however, this benefit was not found when using vitamin E alone or in combination with vitamin C without allopurinol (4697,4698).
• Critical illness (trauma). An analysis of several small clinical studies suggests that oral or intravenous vitamin E is not beneficial in patients admitted to the intensive care unit (ICU). Details: A meta-analysis of 5 small clinical studies in patients admitted to the ICU shows that administration of oral or intravenous vitamin E 400-3000 IU daily for up to 4 weeks does not decrease the length of hospital or ICU stay or reduce the risk of mortality when compared with control (112335). The validity of these findings is limited by a high degree of heterogeneity among the studies, which included differences in vitamin E dosing, duration of therapy, and reasons for ICU admission.
• Dementia. It is unclear if oral vitamin E is beneficial for dementia prevention; the available research is conflicting. Details: A longitudinal cohort study in Japanese adults aged 40 years or older at baseline who were followed for a median of about 20 years, shows that total daily dietary intake of vitamin E is inversely associated with the risk of developing dementia, with a hazard ratio of about 0.8 for the highest compared with lowest quartiles of intake (107857). In a longitudinal cohort study of males aged 71-93 years, consuming supplemental vitamin E and vitamin C decreased the risk of developing vascular and mixed or other dementias; however, there was no protective effect for Alzheimer dementia (4636). Evidence from clinical research that evolved into an observational study shows that taking vitamin E 400 IU daily does not decrease the incidence of dementia in males 60 years or older (93570). However, the results from this study are limited by selection bias due to the high education levels and relatively young age of the participants, limitations with case ascertainment, and problems with follow-up (93570,93571). Also, these studies did not distinguish between different forms of vitamin E (4636,93570).
• Depression. It is unclear if oral vitamin E is beneficial in patients with depression. Details: A meta-analysis of 7 mostly small clinical studies in patients without major depressive disorder shows that taking vitamin E 400-2000 IU daily for up to 6 months modestly improves depression symptom scores when compared with placebo (112158). It is unclear if these findings can be generalized to patients with depression.
• Developmental coordination disorder (DCD). Oral vitamin E has only been evaluated in combination with other ingredients for DCD; its effect when used alone is unclear. Details: A small clinical study in children with developmental coordination disorder (DCD), also known as dyspraxia, shows that taking vitamin E orally, in combination with evening primrose oil, thyme oil, and fish oils, for 4 months seems to improve movement when compared with control (5708). The effects of vitamin E alone on DCD are unclear.
• Diabetes. It is unclear if oral vitamin E is beneficial for the treatment or prevention of diabetes. Details: Population research has found that higher vitamin E dietary intake is associated with a lower risk of developing type 2 diabetes (14004). However, individual clinical studies in patients with existing diabetes show mixed results (13496,13497,90095,90099,98259). A meta-analysis of 36 small clinical studies in patients with diabetes suggests that vitamin E may slightly improve some measures of glycemic control. In patients with type 2 diabetes, vitamin E seems to reduce glycated hemoglobin (HbA1c) by around 0.2% and improve insulin resistance, but not fasting blood glucose, when compared with placebo. In patients with type 1 diabetes, vitamin E seems to reduce HbA1c by around 0.8%, but does not improve fasting blood glucose, when compared with placebo (112161). The validity of this analysis is limited by a high degree of heterogeneity across the studies, including differences in vitamin E dose, treatment duration, concomitant medications, patient populations, and study designs.
• Diabetic foot ulcers. Oral vitamin E has only been evaluated in combination with other ingredients for diabetic foot ulcers; its effect when used alone is unclear. Details: A small clinical study in adults with a grade 3 diabetic foot ulcer shows that taking vitamin E 400 IU and magnesium oxide 250 mg daily for 12 weeks reduces ulcer length, width, and depth when compared with placebo (101436). A small clinical study in adults with non-healing diabetic foot ulcers being treated with a platelet-rich plasma fibrin glue dressing shows that taking vitamin E 200 IU and vitamin C 12.5 mg orally twice daily for 8 weeks increases the rate of ulcer healing when compared with placebo. In those receiving vitamins, 46% of wounds closed completely, compared with 17% of those receiving placebo (107870). It is not clear if the effects seen in these studies are due to vitamin E, the other nutrients, or the combinations.
• Diabetic nephropathy. It is unclear if oral vitamin E is beneficial in patients with diabetes and impaired kidney function. Details: A meta-analysis of clinical research in adults with diabetic nephropathy shows that taking vitamin E 600-1200 mg daily, alone or with other antioxidants, modestly reduces urinary albumin excretion when compared with placebo or no treatment, but seems to have no effect on glomerular filtration rate (GFR) (97069). A small clinical study in patients with diabetic nephropathy shows that taking a specific tocotrienol-rich vitamin E supplement (Tocovid SupraBio, Hovid Nutriworld) 200 mg twice daily for 12 weeks seems to modestly reduce serum creatinine, with a corresponding increase in GFR, when compared with placebo. According to a sub-group analysis, these improvements remain statistically significant in patients with low tocopherol levels (less than 42 mcmol/L) at baseline, but not in those with higher levels at baseline (103010). Another small clinical study shows that taking this same supplement regimen for 12 months reduces serum creatinine levels and improves GFR at 8 months, but not 12 months, when compared with placebo. In a subgroup analysis of patients with stage 3 chronic kidney disease, these benefits persisted at 12 months when compared with placebo (107390).
• Diabetic neuropathy. It is unclear if oral vitamin E is beneficial for improving diabetic neuropathy symptoms. Details: A small clinical trial in patients with uncontrolled type 2 diabetes and neuropathy shows that taking a specific vitamin E supplement (Evion) 400 IU daily for 12 weeks modestly decreases neuropathic pain scores when compared to baseline (90091). Another very small clinical trial shows that taking vitamin E 1341 IU daily for 6 months improves nerve conduction in diabetic neuropathy when compared with placebo (4724).
• Down syndrome. Oral vitamin E does not seem to slow cognitive decline in patients with this condition. Details: A clinical study in patients over 50 years old with Down syndrome shows that taking vitamin E 1000 IU twice daily for 3 years does not slow cognitive decline when compared with placebo (97076).
• Endometriosis. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with endometriosis and pelvic pain shows that taking vitamin E 800 IU and vitamin C 1000 mg daily for 8 weeks improves dysmenorrhea, dyspareunia, and chronic pelvic pain scores when compared with placebo (106622).
• Extravasation. Topical vitamin E has only been evaluated in combination with dimethylsulfoxide (DMSO); its effect when used alone is unclear. Details: A very small clinical study in patients receiving chemotherapy shows that applying vitamin E topically, in combination with DMSO, seems to prevent skin ulceration after chemotherapy extravasation (4668).
• Gastric cancer. It is unclear if oral vitamin E is beneficial for preventing gastric cancer or reducing associated mortality. Details: Population studies have found that increasing dietary vitamin E intake by 22.4 IU daily is associated with a 21% decreased risk of gastric cancer (3360,90083). However, clinical trials have not found that vitamin E supplements reduce gastric cancer risk (3960,4676,4677,12185). Studies evaluating vitamin E in combination with other supplements have been inconsistent. In one large-scale clinical trial a specific combination of vitamin E 100 IU with selenium 37.5 mcg and vitamin C 250 mg twice daily for about 7 years did not reduce risk of gastric cancer in patients from Shandong Province in China where there is a very high prevalence of gastric cancer (14447,90085). In another large-scale clinical study of 29,584 people in China, the combination of oral vitamin E, beta-carotene, and selenium over 5 years did reduce total mortality, total cancer mortality, and stomach cancer mortality (4679). A meta-analysis of clinical research shows that taking vitamin E plus beta-carotene with or without vitamin C does not reduce gastric cancer incidence (12185).
• Glomerulosclerosis. It is unclear if oral vitamin E reduces proteinuria due to glomerulosclerosis in children. Details: A very small clinical study in children with focal segmental glomerulosclerosis who are refractory to standard medical management shows that taking vitamin E 200 IU daily orally might reduce proteinuria when compared with baseline (4675). The validity of this finding is limited by a lack of control group.
• Granuloma annulare. Although there is interest in using topical vitamin E for granuloma annulare, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
• Helicobacter pylori. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in patients with Helicobacter pylori dyspepsia without ulcers shows that taking vitamin E 200 IU and vitamin C 500 mg by mouth twice daily for 30 days in addition to standard triple therapy increases eradication rates by 37% when compared with triple therapy alone (90094). It is not clear if this benefit is due to vitamin E, vitamin C, or the combination.
• Huntington disease. It is unclear if oral vitamin E improves Huntington disease symptoms. Details: A small clinical study shows that taking RRR-alpha-tocopherol (natural vitamin E) might improve symptoms in patients with early Huntington disease, but this benefit is not seen in patients with more advanced disease when compared with placebo (4686).
• IgA nephropathy. It is unclear if oral vitamin E is beneficial for IgA nephropathy in children. Details: A small clinical study in children with IgA nephropathy shows that taking vitamin E (400 IU for those weighing less than 30 kg; 800 IU for those weighing more than 30 kg) improves urinary protein to creatinine ratio, but not glomerular filtration rate, creatinine clearance, or hematuria, when compared with placebo (85063).
• Infertility. It is unclear if oral vitamin E improves pregnancy rates in females with infertility of unknown cause. Details: A small clinical study in females experiencing implantation failure shows that taking vitamin E 400 IU daily for 12 weeks improves endometrial thickness when compared with placebo (99852). Vitamin E has also been studied in combination with selenium. In a small clinical study in patients with premature ovarian insufficiency (POI), taking vitamin E 400 IU with selenium 200 mcg orally daily for 90 days increases anti-Mullerian hormone index, antral follicle count, and mean ovarian volume after 12 months of follow-up when compared with placebo (107866). It is unclear if these improvements correlate to higher pregnancy or live birth rates.
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin E for IBD, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
• Insomnia. It is unclear if oral vitamin E is beneficial in patients with insomnia. Details: A moderate-sized clinical study in postmenopausal patients with chronic insomnia shows that taking vitamin E 400 IU daily for 1 month improves sleep quality ratings and reduces the need for sedative medications when compared with placebo (112163).
• Intermittent claudication. It is unclear if oral vitamin E improves intermittent claudication symptoms. Details: A large clinical study in male smokers with intermittent claudication shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 50 mg orally daily for about 3.7 years does not appear to have any effect when used alone or in combination with beta-carotene for treating symptoms or disease progression when compared with placebo (4732). However, according to poor-quality clinical research included in a meta-analysis, taking vitamin E 447-2384 IU daily for up to 18 months appears to reduce symptoms of intermittent claudication (85023).
• Lice. Topical synthetic vitamin E might be beneficial for head lice eradication. Details: A small clinical study in children and adults with head lice shows that topical application of a specific tocopheryl acetate 20% spray (LiceKO, Panin SRL) once, and then again 7 days later, is more effective for eliminating lice when compared with permethrin 1% cream rinse (90067).
• Male infertility. An analysis of several small, low-quality clinical studies suggests that oral vitamin E might improve pregnancy rates and measures of sperm health in males with infertility. Details: Several small clinical studies in males with infertility show conflicting results (3583,4695,107865). However, a meta-analysis of 7 small, low-quality clinical trials shows that taking vitamin E 300-600 IU for 12-48 weeks increases pregnancy rates by 86% and modestly improves sperm count, concentration, motility, and vitality, but does not seem to increase semen volume, when compared with a control (109461). Vitamin E has also been used in combination with other nutrients with unclear results. Small studies show that taking vitamin E 800 mg daily with vitamin C 1000 mg daily for 8 weeks doesn't seem to improve sperm functionality (4696), while vitamin E 400 IU plus selenium 200 mcg daily for at least 100 days improves sperm functionality, but not fertilization rates, when compared with baseline (3585). In another small clinical study in infertile males undergoing varicocelectomy, taking vitamin E 400 IU, selenium 200 mcg, and folic acid 5 mg daily for 6 months improved sperm count and motility when compared with control (102968). Another small clinical study shows that taking vitamin E 100 mg and coenzyme Q10 10 mg three times daily for 3 months modestly increases levels of testosterone and improves progressive sperm motility and morphology when compared to baseline. However, taking an L-carnitine nutrient complex 15 grams twice daily was more effective for increasing testosterone and improving sperm parameters (109390). However, it is unclear if any of these combination therapies increases live birth rates.
• Melanoma. It is unclear if oral vitamin E is beneficial for reducing melanoma risk. Details: A sub-group analysis of a large-scale clinical trial in patients with diabetes or cardiovascular disease suggests that taking RRR-alpha-tocopherol (natural vitamin E) 400 IU daily for about 7 years is not linked with a reduced risk of developing melanoma when compared with placebo (13036).
• Menopausal symptoms. It is unclear if oral vitamin E is beneficial for reducing menopausal symptoms such as hot flashes. Details: A small clinical study in postmenopausal patients shows that taking vitamin E 200 IU twice daily for 8 weeks reduces hot flashes, but does not affect other menopausal symptoms or anxiety, when compared with placebo. The improvement in hot flashes was no longer present 4 weeks after the intervention (102969). However, a meta-analysis of 3 small clinical studies in postmenopausal patients, including the study above, shows that taking vitamin E 400 IU daily for 8 weeks does not reduce hot flash frequency when compared with placebo (111460).
• Methotrexate toxicity. It is unclear if oral vitamin E reduces the risk of liver toxicity due to methotrexate. Details: An observational study in patients taking methotrexate for rheumatoid arthritis has found that taking vitamin E 400 mg twice daily for 3 months is associated with reductions in serum glutamic pyruvic transaminase (SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) levels when compared with no supplementation. This suggests a reduction in liver injury in the treatment group (104414).
• Muscular dystrophy. Small clinical studies suggest that oral vitamin E may not improve muscular dystrophy symptoms or progression. Details: Small clinical studies in patients with myotonic or Duchenne muscular dystrophy show that taking vitamin E along with penicillamine or selenium doesn't appear to slow disease progression or improve symptoms when compared with placebo (4703,4704).
• Nocturnal leg cramps. It is unclear if oral vitamin E reduces leg cramps in veterans or in patients on hemodialysis. Details: A small clinical study in adults undergoing hemodialysis shows that taking vitamin E 400 IU at bedtime for 2 months seems to reduce the frequency of nocturnal leg cramps when compared with placebo (4701). However, another small clinical study in male veterans shows that taking vitamin E 800 IU at bedtime for 4 weeks does not reduce cramp frequency or severity or reduce sleep disturbances when compared with placebo (4702).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin E is beneficial in adults or children with NAFLD. Details: One meta-analysis of studies assessing both NAFLD patients and patients in whom NAFLD progressed to nonalcoholic steatohepatitis (NASH) shows that taking vitamin E 100-800 IU daily for 1-24 months improves liver enzyme levels, hepatic steatosis, and lobular inflammation when compared with control. However, taking vitamin E does not appear to improve hepatic fibrosis in these patients (97077). Methodological limitations such as publication bias and unclear calculations limit the reliability of these results. Another meta-analysis of 8 small clinical trials in adults with NAFLD shows that taking vitamin E 400-800 IU daily for up to 24 weeks improves liver enzyme levels when compared with placebo (112336). Vitamin E has also been evaluated in children with NAFLD. A meta-analysis of studies in this population shows that taking vitamin E 15-900 IU daily for up to 24 months reduces total and low-density lipoprotein (LDL) cholesterol levels, but does not affect liver enzyme levels, measures of insulin resistance, body mass index (BMI), ballooning degeneration of the liver, or liver fibrosis when compared with placebo (107861). Until additional data showing its benefit becomes available, practice guidelines by the American Association for the Study of Liver Diseases (AASLD) state that vitamin E is not recommended in patients with NAFLD without liver biopsy (98130).
• Obesity. It is unclear if oral vitamin E is beneficial for improving weight loss. Details: A meta-analysis of 24 small clinical studies shows that taking oral vitamin E, 67-900 mg daily does not affect weight, body mass index (BMI), or waist circumference in adults with obesity. In fact, in people with a normal BMI, vitamin E seems to increase body weight (107859).
• Oral mucositis. It is unclear if oral or topical vitamin E is beneficial in patients with oral mucositis from chemotherapy or radiotherapy. Details: Vitamin E has been evaluated in both chemotherapy- and radiation-induced mucositis. A small clinical study in children with chemotherapy-induced oral mucositis shows that a specific vitamin E product (Evion Paediatric Drops, Merck Limited) 200 IU applied topically in three divided doses daily for 1 week improves healing, pain, and the ability to eat when compared with placebo (94585). However, another small clinical study in patients receiving radiotherapy for head and neck cancer shows that taking vitamin E 1000 mg once daily with pentoxifylline 400 mg twice daily does not reduce the incidence or severity of oral mucositis and dysphagia when compared with control (102972).
• Osteopenia. It is unclear if oral vitamin E helps slow the progression of osteopenia. Details: A small clinical study in postmenopausal adults with osteopenia who are taking calcium and vitamin D supplements shows that taking vitamin E (mixed tocopherols) 400 IU daily for 12 weeks prevents the increase in serum C-terminal telopeptide, a marker of bone resorption, seen with placebo over that same time period (107868).
• Osteoporosis. It is unclear if oral vitamin E helps to reduce complications of osteoporosis such as fractures. Details: Observational research has found that vitamin E supplementation is associated with a 22% lower risk of hip fracture and a 14% lower risk of all fractures in elderly females with osteoporosis (90086). Additional observational research has found that higher dietary vitamin E intake is also associated with a 34% reduced risk of fractures in adults at risk for osteoporosis (104415).
• Peyronie disease. It is unclear if oral vitamin E reduces Peyronie disease symptoms. Details: A small clinical study in patients with Peyronie disease shows that taking vitamin E 894 IU daily in addition to conservative treatment for 6 months does not improve pain, but may reduce plaque, when compared with using conservative treatment alone. Conservative treatment included verapamil 10 mg biweekly injection and iontophoresis, blueberries 160 mg orally daily, propolis 600 mg orally daily, and topical diclofenac 4% twice daily (90090). It is not clear if this effect is due to vitamin E, the other interventions, or the combination.
• Photoreactive keratectomy. Oral vitamin E has only been evaluated for recovery after photoreactive keratectomy in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients undergoing laser surgery for myopia shows that taking vitamin A (retinol palmitate) 50,000-75,000 units with vitamin E (alpha-tocopheryl nicotinate) 343 IU daily seems to accelerate re-epithelialization, reduce haze formation, and improve visual acuity when compared with placebo (348).
• Physical performance. It is unclear if oral vitamin E improves physical performance in the elderly. Details: Population research has found that increasing intake of dietary vitamin E is associated with increased physical performance and muscle strength in elderly people (14006).
• Polycystic ovary syndrome (PCOS). Analyses of small clinical studies suggest that oral vitamin E may modestly reduce lipid levels in patients with PCOS. It is unclear if vitamin E can improve glycemic control, body weight, hormone levels, or symptoms of PCOS. Details: Meta-analyses of several small clinical studies in patients with PCOS show that taking vitamin E, alone or in combination with coenzyme Q10, fish oil, magnesium, or vitamin D, reduces total cholesterol by 9-18 mg/dL, low-density lipoprotein (LDL) cholesterol by 7-16 mg/dL, and triglycerides by 13-21 mg/dL when compared with placebo. However, vitamin E does not appear to increase high-density lipoprotein (HDL) cholesterol, reduce body weight, or improve hirsutism. The effects of vitamin E on glycemic indices and levels of testosterone, estradiol, and sex hormone binding globulin are unclear; individual meta-analyses show mixed results (112167,112168,112169). The validity of these findings is limited by a high degree of heterogeneity across the included studies, which varied in vitamin E dosing, treatment duration, and concomitant supplements used.
• Premature rupture of membranes (PROM). Oral vitamin E does not seem to prevent PROM, although it's unclear if it might prevent premature delivery due to PROM. Details: Vitamin E has been evaluated for the prevention and management of PROM. A meta-analysis of clinical research shows that taking vitamin E with other ingredients throughout pregnancy does not affect the risk of developing PROM when compared with placebo (97075). However, a clinical study in patients with PROM shows that taking vitamin E (RRR-alpha-tocopherol acetate) 400 IU and vitamin C 1000 mg daily, starting within 1 hour of membrane rupture and continuing for an unspecified amount of time, seems to hold back premature delivery by about 5 days when compared with placebo. However, maternal or neonatal outcomes did not seem to be affected (90078). It is not clear if this effect is due to vitamin E, vitamin C, or the combination.
• Radiation-induced sialadenitis. It is unclear if oral vitamin E is effective for the prevention or treatment of radiation-induced sialadenitis. Details: A small clinical study in patients undergoing radiation therapy for thyroid cancer shows that taking vitamin E 200 mg daily for 5 weeks, starting 1 week before radiotherapy, improves several measures of parotid and submandibular salivary gland function when compared to baseline, suggesting that vitamin E might prevent radiation-induced sialadenitis and its associated complications (112332). The validity of these findings is limited by a lack of control group.
• Radiation dermatitis. It is unclear if topical vitamin E is effective for the prevention or treatment of radiation dermatitis. Details: A small clinical study in patients undergoing radiation therapy for breast cancer shows that applying a cream containing nanoparticles of vitamin E 2%, three times daily and after each radiation session until 2 weeks after radiation therapy is complete, does not reduce the severity of radiation dermatitis or improve quality of life when compared with a placebo cream. However, in patients that did not receive a boosted radiation dose, this vitamin E cream seems to slightly delay the onset of dermatitis when compared with placebo (112333).
• Radiation fibrosis. It is unclear if topical vitamin E reduces radiation fibrosis symptoms. Details: Clinical research shows that taking vitamin E 1000 IU orally with pentoxifylline 800 mg daily seems to reverse radiation fibrosis (4672,4673). Regression of radiation fibrosis becomes significant after three months of treatment and continues to improve thereafter. After 12 months of treatment, mean surface area of fibrosis can decrease by 66% (4672). It is unclear if the benefit is due to vitamin E, pentoxifylline, or the combination. One very small study suggests that vitamin E alone does not seem to be effective when compared with placebo (10363).
• Renal cell carcinoma. It is unclear if oral vitamin E reduces renal cell carcinoma risk. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding vitamin E and renal cell carcinoma risk. This qualified health claim was based on one weak and limited study. The FDA has determined that it is highly uncertain that vitamin E supplements reduce the risk of renal cell carcinoma (102332).
• Restless legs syndrome (RLS). Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in hemodialysis patients shows that taking vitamin E 596 IU, vitamin C 200 mg, or a combination of both daily for 8 weeks modestly reduces severity of restless legs syndrome when compared with placebo (90093).
• Retinopathy of prematurity. It is unclear whether oral or parenteral vitamin E reduces the risk for retinopathy in prematurity (ROP). Details: A clinical study in very low birth weight infants with respiratory distress syndrome suggests that giving vitamin E 12.5 IU twice daily from 72 hours after birth through 28 days of age might reduce the incidence of stage 1 ROP when compared with placebo. However, the difference reached significance in the per-protocol analysis, but not in the intention-to-treat analysis (107864). Also, a meta-analysis that did not include this more recent study shows that administering oral, intravenous, or intramuscular vitamin E daily does not reduce the risk for ROP. Additionally, high levels of vitamin E and large intravenous doses of vitamin E have been associated with an increased risk for sepsis in premature infants (85062).
• Rheumatoid arthritis (RA). It is unclear if oral vitamin E is beneficial in patients with RA. Details: A small clinical study in adults with RA shows that taking vitamin E 600 mg twice daily in conjunction with standard therapy for 12 weeks is superior to standard therapy alone for reducing pain, but not inflammation (4723). However, other studies show mixed results. A meta-analysis of 7 small clinical studies in patients with RA shows that taking vitamin E up to 1200 IU daily for up to 12 weeks does not reduce pain, tenderness, swelling, or morning stiffness when compared with control (112330).
• Schizophrenia. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking vitamin E (RRR-alpha-tocopherol) 135.8 IU and a specific ascorbic acid supplement (CellaVie) 250 mg with or without ethyl eicosapentaenoate 500 mg daily for 16 weeks does not improve negative or positive symptoms of schizophrenia when compared with placebo (89234).
• Sickle cell disease. Although there is interest in using oral vitamin E for sickle cell disease, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
• Stretch marks (striae gravidarum). Topical vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that using a moisturizer containing vitamin E, rosehip oil, hydroxyprolisilane C, and gotu kola triterpenes at least twice daily on affected areas does not decrease incidence of new stretch marks, but does decrease the severity of new stretch marks by about 30%, when compared with control cream in pregnant patients (90076). It is not clear if this effect is due to vitamin E, other ingredients, or the combination.
• Stroke. It is unclear if oral vitamin E is beneficial for reducing stroke risk. Details: A trial-sequential meta-analysis of 12 clinical trials with 148,000 patients shows that vitamin E does not seem to reduce the risk of total stroke when compared with placebo. However, in a subgroup analysis, vitamin E was associated with an 8% lower risk of ischemic stroke and a trend to an increased risk of hemorrhagic stroke when compared with placebo. Based on subgroup analyses, there was no difference on risk based on vitamin E dosage, use of synthetic versus natural vitamin E, and whether prevention was primary or secondary (104408). This analysis was limited due to high heterogeneity, small study size, and insufficient power to detect differences between treatments. Older meta-analyses also found mixed results of using vitamin E 74.5-1192 IU daily alone or in combination for up to 10 years. However, there was a similar sub-group analysis finding that vitamin E might reduce the risk of ischemic stroke, but it might also increase the risk of hemorrhagic stroke (14621,85201). Some clinical research shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) might reduce the risk of ischemic stroke in male smokers with hypertension and diabetes (3359).
• Sunburn. Topical vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Oral vitamin E alone does not seem to prevent sunburn. Details: Two small, double-blind, placebo-controlled studies suggest that taking high dose oral RRR-alpha-tocopherol (natural vitamin E) up to 2 grams daily in combination with vitamin C 3 grams protects against skin inflammation after exposure to ultraviolet (UV) radiation. However, taking vitamin E alone does not seem to be beneficial when compared with control (4715,4716). This combination was also tried topically. In one study, topically applied vitamin E in combination with topical vitamin C and melatonin provided modest photoprotective effect when used prior to UV exposure, but had no effect when used during or after UV exposure (4713,4714).
• Uveitis. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking vitamin E 149 IU twice daily with vitamin C 500 mg daily for 8 weeks improves visual acuity in patients with acute anterior uveitis, but does not seem to decrease inflammation measured by laser flare, when compared with placebo (4730). It is not clear if this effect is due to vitamin E, vitamin C, or the combination.
• Vaginal atrophy. It is unclear if a vitamin E suppository is beneficial in patients with vaginal atrophy. Details: A small clinical study in females with breast cancer and tamoxifen-induced vaginal atrophy shows that intravaginal administration of a vitamin E 1 mg suppository nightly before bed for 8 weeks improves self-reported symptoms of vaginal atrophy, decreases vaginal pH, and improves vaginal estrogenization, as measured by the Vaginal Maturation Index, when compared with placebo (99773). More evidence is needed to rate vitamin E for these uses.

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LIKELY SAFE ...when used orally and appropriately. In clinical studies of cod liver oil in adults, a dose of 10 mL daily has been used safely for up to 24 weeks (3398), a dose of 15 mL daily has been used safely for 16 weeks (7360), and doses of 20 mL to 30 mL daily have been used with apparent safety for between 2 weeks and 8 weeks (3399,4026,10083,94758,94759,94754). Cod liver oil is a source of vitamins A and D. Dose amounts should not exceed the recommended dietary allowances (RDAs) of these vitamins. For vitamin A, the RDAs are 900 mcg (3000 units of retinol) daily for men and 700 mcg (2333 units of retinol) daily for women (7135). For vitamin D the RDAs are 15 mcg (600 units) daily for all adults up to 70 years of age, and 20 mcg (800 units) daily for older adults (91703).

POSSIBLY UNSAFE ...when used orally in excessive doses. Avoid doses of cod liver oil that contain more than the Tolerable Upper Intake levels (ULs) of vitamins A and D. For vitamin A the ULs are 3000 mcg (10,000 units of retinol) daily for adults and 2800 mcg (9333 units of retinol) daily for teenagers aged 14 years to 18 years (7135). For vitamin D, the UL is 100 mcg (4000 units) daily for everyone 9 years of age and older (91703). There is also concern that higher doses might increase bleeding risk. Cod liver oil in doses of 20-40 mL daily has been associated with prolonged bleeding time and reduced platelet aggregation in healthy volunteers (4025,4026,10083,91701,91702). There is insufficient reliable information available about the safety of cod liver oil when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses providing no more than the recommended dietary allowances (RDAs) of vitamins A and D. For vitamin A, the RDAs are 400 mcg (1333 units of retinol) daily up to age 6 months, 500 mcg (1667 units of retinol) daily for ages 6 months to 12 months, 300 mcg (1000 units of retinol) daily for ages 1 year to 3 years, 400 mcg (1333 units of retinol) daily for ages 4 years to 8 years, and 600 mcg (2000 units of retinol) daily for ages 9 years to 13 years (7135). For vitamin D, the RDAs are 10 mcg (400 units) daily for infants up to 12 months of age, and 15 mcg (600 units) daily for ages 1 year to 13 years (91703). In clinical studies, children aged 6 months to 1 year have safely received cod liver oil 2.5 mL daily for 5 months, and children aged 1 year to 5 years have safely received 5 mL daily for 5 months (94756).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. Avoid doses of cod liver oil that contain more than the Tolerable Upper Intake levels (ULs) of vitamins A and D. For vitamin A, the ULs are 600 mcg (2000 units of retinol) daily for infants and children up to 3 years of age, 900 mcg (3000 units of retinol) daily for ages 4 years to 8 years, and 1700 mcg (5667 units of retinol) daily for ages 9 years to 13 years (7135). For vitamin D, the ULs are 25 mcg (1000 units) daily for infants up to 6 months, 38 mcg (1500 units) daily for ages 7 months to 12 months, 63 mcg (2500 units) daily for ages 1 year to 3 years, 75 mcg (3000 units) daily for ages 4 years to 8 years, and 100 mcg (4000 units) daily for ages 9 years and above (91703).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately in doses providing no more than the recommended dietary allowances (RDAs) of vitamins A and D. For vitamin A, the RDAs are 770 mcg (2567 units of retinol) daily for pregnant women over 18 years of age, and 750 mcg (2500 units of retinol) daily for pregnant teenagers 14 years to 18 years of age (7135). For vitamin D, the RDA is 15 mcg (600 units) daily for pregnant women of all ages (91703). In clinical research, cod liver oil (Peter Möller, Oslo, Norway) 10 mL orally daily (providing vitamin A 1170 mcg and vitamin D 10 mcg daily) has been used safely from week 17 of pregnancy until delivery, and continuing for 3 months during lactation (94763).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. Avoid doses of cod liver oil which contain more than the Tolerable Upper Intake levels (ULs) of vitamins A and D. For vitamin A, the ULs are 3000 mcg (10,000 units of retinol) daily for pregnant women over 18 years of age, and 2800 mcg (9333 units of retinol) daily for pregnant teenagers aged 14 years to 18 years (7135). For vitamin D, the UL is 100 mcg (4000 units) daily for pregnant women of all ages (91703).

LACTATION: POSSIBLY SAFE
when used orally and appropriately in doses providing no more than the recommended dietary allowances (RDAs) of vitamins A and D. For vitamin A, the RDAs are 1300 mcg (4333 units of retinol) daily for lactating women over 18 years of age, and 1200 mcg (4000 units of retinol) daily for pregnant teenagers aged 14 years to 18 years (7135). For vitamin D, the RDA is 15 mcg (600 units) daily for lactating women of all ages (91703). An Icelandic cod liver oil, 10 mL daily, has been used safely for 4 months during lactation (94764).

LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Avoid doses of cod liver oil which contain more than the Tolerable Upper Intake levels (ULs) of vitamins A and D. For vitamin A, the ULs are 3000 mcg (10,000 units of retinol) daily for lactating women over 18 years of age, and 2800 mcg (9333 units of retinol) daily for lactating teenagers aged 14 years to 18 years (7135). For vitamin D, the UL is 100 mcg (4000 units) daily for lactating women of all ages (91703).

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LIKELY SAFE ...when used orally or topically and appropriately. Vitamin E is generally considered safe, even at doses exceeding the recommended dietary allowance (RDA); however, adverse effects are more likely to occur with higher doses. The tolerable upper intake level (UL) in healthy people is 1000 mg daily, equivalent to 1100 IU of synthetic vitamin E (all-rac-alpha-tocopherol) or 1500 IU of natural vitamin E (RRR-alpha-tocopherol) (4668,4681,4713,4714,4844,89234,90067,90069,90072,19206)(63244,97075). Although there is some concern that taking vitamin E in doses of 400 IU (form unspecified) per day or higher might increase the risk of adverse outcomes and mortality from all causes (12212,13036,15305,16709,83339), most of this evidence comes from studies that included middle-aged or older patients with chronic diseases or patients from developing countries in which nutritional deficiencies are prevalent.

POSSIBLY UNSAFE ...when used orally in high doses. Repeated doses exceeding the tolerable upper intake level (UL) of 1000 mg daily are associated with significant side effects in otherwise healthy people (4844). ...when used intravenously in large doses. Large repeated intravenous doses of all-rac-alpha-tocopherol (synthetic vitamin E) were associated with decreased activity of clotting factors and bleeding in one report (3074). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults who use e-cigarette, or vaping, products, which often contain vitamin E acetate. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Vitamin E acetate has been detected in most bronchoalveolar lavage samples taken from patients with EVALI. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. While this association shows a correlation between vitamin E acetate inhalation and lung injury, a causal link has not yet been determined, and it is not clear if other toxic compounds are also involved (101061,101062,102970).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Vitamin E has been safely used in children in amounts below the tolerable upper intake level (UL). The UL for healthy children is: 200 mg in children aged 1-3 years, 300 mg in children aged 4-8 years, 600 mg in children aged 9-13 years, and 800 mg in children aged 14-18 years. A UL has not been established for infants up to 12 months of age (23388).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL due to increased risk of adverse effects (23388). ...when alpha-tocopherol is used intravenously in large doses in premature infants. Large intravenous doses of vitamin E are associated with an increased risk of necrotizing enterocolitis and sepsis in this population (85062,85083). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adolescents and teenagers who use e-cigarette, or vaping, products. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Constituents in E-cigarette or vaping products with the potential to cause lung injury or impaired lung function include lipids, such as vitamin E acetate. Vitamin E acetate has been detected in all bronchoalveolar lavage samples taken from patients with EVALI. No other ingredient, including THC or nicotine, was found in all samples, and other ingredients, including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable This shows that vitamin E acetate is at the primary site of lung injury. A causal link has not yet been described and it is not clear if other compounds are also involved (101061,101062).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately. The tolerable upper intake level (UL) during pregnancy is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older. However, maternal supplementation is not generally recommended unless dietary vitamin E falls below the RDA (4260). No serious adverse effects were reported with oral intake of 400 IU per day starting at weeks 9-22 of pregnancy in healthy patients or those at high risk for pre-eclampsia (3236,97075), or with 600-900 IU daily during the last two months of pregnancy (4260). However, some preliminary evidence suggests that taking vitamin E supplements might be harmful when taken in early pregnancy. A case-control study found that taking a vitamin E supplement during the first 8 weeks of pregnancy is associated with a 1.7-9-fold increase in odds of congenital heart defects (16823). However, the exact amount of vitamin E consumed during pregnancy in this study is unclear. Until more is known, advise patients to avoid taking a vitamin E supplement in early pregnancy unless needed for an appropriate medical indication.

LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL). The UL during lactation is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older (4844).

LACTATION: POSSIBLY UNSAFE
when used orally in amounts that exceed the UL due to increased risk of adverse effects (4844).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, cod liver oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details High doses of cod liver oil, 20-40 mL daily, have been associated with prolonged bleeding time and reduced platelet aggregation in healthy volunteers (4025,4026,10083,91701,91702).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking cod liver oil with antidiabetes drugs might increase the risk of hypoglycemia.  Details Some clinical research shows that cod liver oil may lower blood glucose levels in women with gestational diabetes who are already taking antidiabetes drugs when used for at least 12 weeks. However, it does not appear to have any effect on blood glucose when used for shorter durations (101988). Until more is known, use caution.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking cod liver oil with antihypertensive drugs might increase the risk of hypotension.  Details Cod liver oil can lower blood pressure and might have additive effects in patients treated with antihypertensives (1001,1020,3399); use with caution.

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ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of alkylating agents.  Details There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Concomitant use of vitamin E and anticoagulant or antiplatelet agents might increase the risk of bleeding.  Details Vitamin E seems to inhibit of platelet aggregation and antagonize the effects of vitamin K-dependent clotting factors (4733,4844,11580,11582,11583,11584,11586,112162). These effects appear to be dose-dependent, and are probably only likely to be clinically significant with doses of at least 800 units daily (11582,11585). Mixed tocopherols, such as those found in food, might have a greater antiplatelet effect than alpha-tocopherol (10364). RRR alpha-tocopherol (natural vitamin E) 1000 IU daily antagonizes vitamin K-dependent clotting factors (11999). Advise patients to avoid high doses of vitamin E, especially in people with low vitamin K intake or other risk factors for bleeding.

ANTITUMOR ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of antitumor antibiotics.  Details There's concern that antioxidants could reduce the activity of antitumor antibiotic drugs such as doxorubicin, which generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B A specific form of vitamin E might increase absorption and levels of cyclosporine.  Details There is some evidence that one specific formulation of vitamin E (D-alpha-tocopheryl-polyethylene glycol-1000 succinate, TPGS, tocophersolan, Liqui-E) might increase absorption of cyclosporine. This vitamin E formulation forms micelles which seems to increase absorption of cyclosporine by 40% to 72% in some patients (624,625,10368). However, this interaction is unlikely to occur with the usual forms of vitamin E.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, vitamin E might induce metabolism of CYP3A4, possibly reducing the levels CYP3A4 substrates.  Details Vitamin E appears to bind with the nuclear receptor, pregnane X receptor (PXR), which results in increased expression of CYP3A4 (13499,13500). Although the clinical significance of this is not known, use caution when considering concomitant use of vitamin E and other drugs affected by these enzymes.

NIACIN Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = A Vitamin E might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.  Details A combination of niacin and simvastatin (Zocor) effectively raises high-density lipoprotein (HDL) cholesterol levels in people with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% (7388,11537). Vitamin E alone combined with a statin does not seem to decrease HDL levels (11286,11287). It is not known whether the adverse effect on HDL is due to one of the other antioxidants or to the combination. It also is not known whether it will occur in other patient populations.

SELUMETINIB (Koselugo) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Taking selumetinib with vitamin E can result in a total daily dose of vitamin E that exceeds safe limits and therefore might increase the risk of bleeding.  Details Selumetinib contains 48-54 IU vitamin E per capsule (102971). The increased risk of bleeding with vitamin E appears to be dose-dependent (11582,11585,34577). Be cautious when using selumetinib in combination with supplemental vitamin E, especially in patients at higher risk of bleed, such as those with chronic conditions and those taking antiplatelet drugs (102971).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using vitamin E with warfarin might increase the risk of bleeding.  Details Due to interference with production of vitamin K-dependent clotting factors, use of more than 400 IU of vitamin E daily with warfarin might increase prothrombin time (PT), INR, and the risk of bleeding, (91,92,93). At a dose of 1000 IU per day, vitamin E can antagonize vitamin K-dependent clotting factors even in people not taking warfarin (11999). Limited clinical evidence suggests that doses up to 1200 IU daily may be used safely by patients taking warfarin, but this may not be applicable in all patient populations (90).

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General ...Orally, cod liver oil is generally well tolerated. Topically, adverse effects are rare. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Flatulence, gastrointestinal upset, heartburn, and nausea.
Serious Adverse Effects (Rare):
Orally: There are rare reports of lipoid pneumonia.

Gastrointestinal ...Orally, flatulence, heartburn, nausea, and gastrointestinal upset are the most frequently reported adverse effects of cod liver oil (3398,94757). Diarrhea also been reported rarely (101990).

Hematologic ...Orally, there is a case report of melena, bleeding duodenal ulcer, and anemia in a 60 year old man who was taking cod liver oil 5 mL daily in combination with other supplements, including fish oil, flaxseed oil, chlorella, and sea buckthorn, which increased his intake of omega-3 fatty acids to more than 21 grams daily (94751).

Immunologic ...Topically, cod liver oil may cause allergic contact dermatitis. There is a case report of allergic contact dermatitis in an 80-year-old woman being treated for leg ulcers with various topical products including 40% cod liver oil ointment (Dermovitamina, Pasquale SRL). She developed severe itchy papules and vesicles requiring treatment with topical corticosteroids and antihistamines, and had a positive skin test to cod liver oil but no other ingredients in the various topical products used (94762).

Neurologic/CNS ...Orally, headache and dizziness have been reported in a single patient each after a single dose of cod liver oil (101990).

Pulmonary/Respiratory ...Data from population surveys of adults in Norway conducted in the 1990s suggests that daily consumption of cod liver oil for at least a month is associated with a 1. 6-fold increase in the odds of adult-onset asthma about 11 years later, when adjusted for several confounding factors (94752). However, the cod liver oil that was commercially available in the 1990s in Norway contained high levels of vitamin A (1000 mcg per 5 mL; equivalent to 3333 units of retinol). It is thought that accumulation of vitamin A in the lungs contributed to the development of asthma.
A case report describes a 63-year-old white woman with a history of smoking and polyarthropathy who underwent a lobectomy after identification of a mass in her lung. This was identified as lipoid pneumonia, thought to be due to her regular intake of cod liver oil capsules (3396).

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General ...Orally and topically, vitamin E is generally well-tolerated.
Serious Adverse Effects (Rare):
Orally: Bleeding, hemorrhagic stroke, cardiovascular complications.
Inhaled: Vitamin E acetate is thought to be responsible for e-cigarette, or vaping, product-use associated lung injury (EVALI).

Cardiovascular ...Some evidence suggests that taking vitamin E supplements, especially greater than or equal to 400 IU taken by mouth daily for over one year, might also increase the risk of mortality in non-healthy patients (12212,13036,15305,16709,83339). A population study shows that vitamin E use is associated with a significantly increased risk of mortality in people with a history of severe cardiovascular disease such as stroke or myocardial infarction (16709). In an analysis of clinical trials, patients who took either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) in doses of 400 IU/day or higher had an increased risk of mortality from all causes. The risk of mortality seems to increase when higher doses are used (12212). A large-scale study also suggests that patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily have an increased risk of heart failure and heart failure-related hospitalization (13036). However, in another large scale study, taking 600 IU vitamin E every other day for 10 years did not increase the risk of heart failure in healthy females over 45 years of age (90068). There is speculation that high-dose vitamin E might disrupt the normal antioxidant balance and result in pro-oxidant rather than antioxidant effects.
There is some evidence that vitamin E in combination with simvastatin (Zocor), niacin, selenium, vitamin C, and beta-carotene might lower high density lipoprotein-2 (HDL-2) by 15%. HDL-2 is considered to be the most cardioprotective component of HDL (7388). However, vitamin E and a statin alone don't seem to negatively affect HDL (11286,11287). In addition, vitamin E has been associated with increased triglycerides (85215). Although only certain isomers of vitamin E are included for determination of dietary requirements, all isomers are considered for determining safe intake levels. All the isomers are thought to potentially contribute to toxicity.

Dermatologic ...Topically, vitamin E has been associated with contact dermatitis, inflammatory reactions, and eczematous lesions (11998,85066,85285). Dermatitis, often associated with moisturizers containing vitamin E, has a scattered generalized distribution, is more common on the face than the hands, and is more common in females with a history of atopic dermatitis. In a retrospective analysis of results of patch tests for DL-alpha-tocopherol sensitivity, 0.9% of patients had a definite positive reaction, while over 50% had a weakly positive, non-vesicular erythematous reaction (107869).
Orally, vitamin E has been associated with pruritus in one clinical trial (34596).
Subcutaneously, vitamin E has been associated with reports of lipogranuloma (85188,112331). In one case, subcutaneous injection of a specific supplement (1Super Extenze), containing mineral oil and tocopherol acetate, into the penile tissue resulted in penile disfigurement due to sclerosing lipogranuloma (85188). In another case, a 50-year-old Iranian female presented with lipogranuloma of the face, characterized by severe facial erythema, edema, and tenderness, 3 months after receiving subcutaneous injections of vitamin E to the cheeks for "facial rejuvenation." The patient had noticed initial symptoms within 3 days, and her symptoms progressively worsened over time (112331).

Gastrointestinal ...Orally, vitamin E supplementation has been associated with abdominal pain, nausea, diarrhea, or flu-like symptoms (85040,85323). Intravenously, large doses of vitamin E in premature infants are associated with an increased risk of necrotizing enterocolitis and sepsis (85083,85231).

Genitourinary ...There is contradictory evidence about the effect of vitamin E on prostate cancer risk. One large-scale population study shows that males who take a multivitamin more than 7 times per week and who also take a separate vitamin E supplement have a significantly increased risk of developing prostate cancer (15607). In a large-scale clinical trial (The SELECT trial) in males over the age of 50 years, taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily increased the risk of developing prostate cancer by 17% when compared with placebo. However, the difference in prostate cancer risk between vitamin E and placebo became significant only 3 years after patients stopped taking supplementation and were followed in an unblinded fashion. Interestingly, patients taking vitamin E plus selenium did not have a significantly increased risk of prostate cancer (17688).

Hematologic ...High doses of vitamin E might increase the risk of bleeding due to antagonism of vitamin K-dependent clotting factors and platelet aggregation. Patients with vitamin K deficiencies or taking anticoagulant or antiplatelet drugs are at a greater risk for bleeding (4098,4844,11999,34596,34538,34626,34594,112162).

Neurologic/CNS ...There is concern that vitamin E might increase the risk of hemorrhagic stroke (16708,34594,34596,108641). In one clinical study, there was a higher incidence of hemorrhagic stroke in male smokers taking all-rac-alpha-tocopherol (synthetic vitamin E) for 5-8 years compared to those not taking vitamin E (3949). Other studies lasting from 1.4-4.5 years and using either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) showed no significantly increased risk for stroke (2307,3896,3936). A meta-analysis of studies shows that vitamin E in doses of 300-800 IU daily, including both natural and synthetic forms, does not significantly affect total stroke risk. However, it significantly increases the risk of hemorrhagic stroke by 22%. This means that there will be one additional hemorrhagic stroke for every 1250 patients taking vitamin E. In contrast to this finding, the analysis also found that vitamin E significantly reduces the risk of ischemic stroke by 10%. This means that one ischemic stroke will be prevented for every 476 patients taking vitamin E (14621). In patients with moderately severe Alzheimer disease, taking vitamin E 2000 IU for 2 years has been associated with a modest, but significant, increase in falls and episodes of syncope when compared to placebo (4635).

Pulmonary/Respiratory ...When inhaled, vitamin E acetate is thought to play a role in the development of e-cigarette, or vaping, product-use associated lung injury (EVALI). Although a causal link has not yet been determined, in two case series, vitamin E acetate has been found in most bronchoalveolar lavage samples taken from the primary site of lung injury in patients with EVALI, whereas no vitamin E was found in healthy control samples. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. EVALI has resulted in death in some patients (101062,102970).

Other ...In an analysis of 3 trials, taking vitamin E 400 IU with vitamin C 1000 mg daily for 14-22 weeks during gestation appears to increase the risk of gestational hypertension by 30% compared to placebo in patients at risk of pre-eclampsia. However, the risk of pre-eclampsia itself was not increased (83450).

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