Vitamin E

Common Name(s): Alpha-tocopherol, Vitamin E

Medically reviewed by Drugs.com. Last updated on Nov 21, 2022.

Clinical Overview

Use

There is limited evidence supporting a role for vitamin E supplementation in treating or preventing cancer, CNS diseases (eg, Parkinson disease, epilepsy, Down syndrome), liver diseases, macular degeneration and cataracts, menopause, osteoporosis, rheumatoid arthritis, and osteoarthritis; data are often insufficient or conflicting. Various guidelines state that results data regarding the use of vitamin E in cardiovascular disease and in diabetes are conflicting. Evidence of potential harm with supplementation exists and must be considered and balanced with potential therapeutic benefits.

Dosing

The recommended daily allowance (RDA) for vitamin E (natural form) in adults is 15 mg (22.4 units). Currently, vitamin E is most commonly dosed in international units, which measure biological activity instead of quantity. However, by 2021 under the FDA's new labeling regulations for dietary supplements, vitamin E will be dosed in milligrams only. Most supplements contain only alpha-tocopherol, although some "mixed" products containing other tocopherols and tocotrienols are available. Synthetic supplements of vitamin E (all rac-alpha-tocopherol labeled as "DL-" or "dl-alpha-tocopherol") are only half as active as the same amount (by weight in mg) of the natural form (RRR-alpha-tocopherol, labeled as "D-" or "d-alpha-tocopherol").

To convert from mg to units:

• 1 mg of alpha-tocopherol=1.49 units of the natural form or 2.22 units of the synthetic form

To convert from units to mg:

• 1 unit of the natural form=0.67 mg of alpha-tocopherol

• 1 unit of the synthetic form=0.45 mg of alpha-tocopherol

Vitamin E doses up to 1,000 mg/day (1,500 units/day of natural or 1,100 units/day of synthetic) in adults appear to be safe. However, this is based on limited data and evidence from small studies of individuals receiving at least 2,000 units/day for a few weeks or months.

Contraindications

Use should be avoided in patients with bleeding disorders due to increased bleeding risks associated with vitamin E.

Pregnancy/Lactation

Studies have demonstrated that vitamin E supplementation does not reduce the risk for pre-eclampsia, still birth, neonatal death, preterm birth, or intrauterine growth restriction. However, a Cochrane review suggests a possible association between vitamin E and reduced risk for placental abruption; further studies are needed. These findings, coupled with the conflicting evidence regarding a relationship between vitamin E supplementation and mortality risk in the literature will need to be considered when determining whether to supplement with vitamin E beyond the recommended daily intake during pregnancy.

Interactions

See Drug Interactions section.

Adverse Reactions

Low-dose vitamin E supplementation (150 mg/day) does not appear to be associated with any serious adverse reactions. High levels of vitamin E can adversely affect the absorption of vitamins A and K. Long-term use of high doses may cause nausea, diarrhea, blurred vision, and prolonged bleeding time. Topical vitamin E may cause contact dermatitis, itching, and rash.

Toxicology

Vitamin E is a known antioxidant. However, studies have shown that vitamin E may be pro-oxidant in certain circumstances, causing oxidation and consequent damage to cells. Conflicting data exist regarding vitamin E supplementation and increased mortality. An increase in the risk for prostate cancer has been suggested in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

Source

Vitamin E can be found naturally in foods such as nuts, seeds, vegetable oils, and green leafy vegetables, or can be synthetically produced. It addition, vitamin E can be added to food, such as fortified cereals, and is available as a dietary supplement.NIH 2018 Alpha-tocopherol is the only form recognized as meeting human requirements and is the most abundant form found in human plasma. In the American diet, the most common form of vitamin E is gamma-tocopherol, present in foods such as soybean, canola, and vegetable oils.El Hadi 2018, NIH 2018

History

Vitamin E was discovered in 1922 by Dr. Herbert Evans and his assistant Katherine Bishop when they observed in utero deaths of pups in pregnant rats receiving a special semipurified diet. When the diet was changed to lettuce and wheat germ, the rats delivered healthy pups. Recognizing that something was lacking in the diet, they termed the missing compound "Factor X," which would later become known as vitamin E.ANA 2018, Evans 1922 A pure fraction was chemically identified in 1938 and named "tocopherol" after the Greek words tocos meaning "child birth," pheros meaning "to bear," and ol meaning "alcohol."Marelli 2018 Henry Mattill and Harold Saft Olcott were instrumental in discovering vitamin E's antioxidant properties.Niki 2012 In the 1980s and 1990s, the various forms of vitamin E were noted to act as signaling and gene regulation compounds.Galli 2017

Chemistry

Vitamin E is a generic term for a group of 8 compounds, including 4 tocopherol and 4 tocotrienol derivatives. Tocopherols and tocotrienols occur in alpha, beta, gamma, and delta isomers in naturally occurring vitamin E, based on the methyl and hydroxyl substitutions in their phenolic rings. Vitamin E contains a chromanol double ring with a hydroxyl group (to reduce free radicals) and a hydrophobic side chain (to penetrate membranes).El Hadi 2018, Galli 2017, Guralp 2014, Mathur 2015, NIH 2018, Peh 2016 The difference between tocopherol and tocotrienol molecular structures involves the phytyl tail they all have; tocotrienols have 3 double bonds in this tail while tocopherols do not.ANA 2018, Mathur 2015

Vitamin E is fat-soluble, with perhaps the most important chemical characteristic being its antioxidant property. Alpha-tocopherol in supplements is typically esterified to preserve its shelf life.NIH 2018 Tocotrienols are poorly water soluble, possess low chemical stability, and are quickly metabolized.Savitskava 2016

Uses and Pharmacology

Note: When information regarding the specific vitamin E form (natural vs synthetic) used in a clinical study is available, the form is noted in the following data.

Vitamin E has been extensively studied for several decades; a large number of clinical trials and animal experiments have been conducted. Vitamin E exerts its antioxidant effects through inhibiting production of reactive oxygen species formed from fat oxidation. Additionally, it is involved in cell signaling and regulation of gene expression. Alpha-tocopherol blocks protein kinase C (PKC) activity, impacting the proliferation and differentiation of cells in smooth muscle, platelets, and monocytes.(Dennehy 2010, NIH 2018) Tocotrienols are associated with more powerful antioxidant activity and anti-inflammatory properties compared to alpha-tocopherol.(Peh 2016) This is due to tocotrienols being more uniformly distributed across the lipid membrane, the presence of double bonds on its isoprenoid side chain leading to more free radical interaction, and higher efficiency of redox cycling.(Chin 2018) Vitamin E also enhances the release of prostacyclin, promoting vasodilation and reducing platelet aggregation.(Dennehy 2010) It has been suggested to exert pro-oxidant effects in the absence of co-antioxidants such as vitamin C and in cases of a constant low-level flux of free radicals.(El Hadi 2018)

Conflicting findings regarding associations between vitamin E supplementation and increased mortality risk and cancer risk (ie, prostate cancer) warrant judicious use of vitamin E.

Mortality risk

Clinical data

Conflicting data exist regarding the relationship between vitamin E supplementation and mortality risk. One study found the pooled all-cause mortality risk difference with high-dose vitamin E (ie, doses more than 400 units/day) to be 39 per 10,000 persons (95% CI, 3 to 74; P=0.035). However, different findings were noted with low-dose vitamin E, with a risk difference of −16 per 10,000 persons (95% CI, −41 to 10; P>0.2).(Miller 2005) Around the time this study was published, results from the Women's Health Study, in which natural-source vitamin E supplementation was given as 600 units every other day, were also published. The investigators found that while vitamin E had no significant impact on the incidences of myocardial infarction, stroke, or total mortality, there was a 24% risk reduction in cardiovascular mortality (relative risk [RR], 0.76; 95% CI, 0.59 to 0.98; P=0.03).(Lee 2005) More recently, a Cochrane meta-analysis of all randomized clinical trials evaluating the effect of antioxidant supplements on primary and secondary disease prevention found that antioxidants had no significant effect on all-cause mortality (78 trials; RR, 1.02; 95% CI, 0.98 to 1.05); however, there was a significant increase in mortality in a fixed-effect model (RR, 1.03; 95% CI, 1.01 to 1.05). Supplementation with vitamin E alone in trials with a low risk of bias showed increased mortality (46 trials; RR, 1.03; 95% CI, 1 to 1.05).(Bjelakovic 2012) Another meta-analysis that included 57 trials of 246,371 subjects and 29,295 all-cause deaths found no effect on all-cause mortality with vitamin E (overall RR, 1; 95% CI, 0.98 to 1.02).(Abner 2011)

Amyotrophic lateral sclerosis/Motor neuron disease

Clinical data

A 2017 Cochrane review found that vitamin E was associated with little to no effect on cramps associated with amyotrophic lateral sclerosis/motor neuron disease (low-quality evidence).(Ng 2017)

Asthma

Clinical data

The updated British guideline on the management of asthma (2019) indicates that no intervention studies are available to make any recommendations on maternal dietary supplementation with vitamin E as an asthma prevention strategy. Additionally, results from intervention studies suggest that vitamin E supplementation is not associated with clinical benefits in people with asthma.(SIGN 2019)

Atopic eczema/dermatitis

Clinical data

A 2012 Cochrane review identified 2 randomized clinical trials evaluating vitamin E for atopic eczema/dermatitis that met criteria for analysis. A reduction in lichenification and dryness was noted with vitamin E monotherapy (600 units of alpha-tocopherol) in 52 adults and children older than 13 years. Additionally, vitamin D (cholecalciferol 1,600 units) and vitamin E combination therapy resulted in a difference in severity scores at the end of a 60-day treatment period, as well as improvements in pruritus and erythema compared with placebo. Vitamin D supplementation alone did not provide significant benefit over placebo in any of the measured outcomes. No differences in mean disease severity scores were observed in 60 adults treated with vitamin E plus selenium.(Bath-Hextall 2012)

In another study, vitamin E 400 units/day for 4 weeks was associated with improvements in itching and extent of lesions in patients with mild to moderate atopic dermatitis compared with placebo. Vitamin E supplementation did not impact sleeplessness.(Jaffary 2015)

Cancer

Vitamin E has been investigated for its cytotoxic effects. It can decrease the free radical levels in tumor cells, cause cell cycle arrest, and ultimately inhibit proliferation, promote apoptosis, suppress angiogenesis, and increase immune system functioning to eliminate tumor cells.(Savitskaya 2016) The anticancer effects of tocotrienol are independent of its antioxidant effects. Delta- and gamma-tocotrienol, 2 isomers with less antioxidant properties, have greater anticancer effects. Decreasing the methyl groups on the chromanol head leads to increased antiproliferative potency of tocotrienol (delta-tocotrienol>gamma-tocotrienol>beta-tocotrienol>alpha-tocotrienol). Tocotrienol has also been investigated for its anti-angiogenic and proapoptotic effects.(Chin 2016, Marelli 2018) RRR-alpha-tocopheryl succinate, also known as vitamin E succinate, has been investigated as a promising chemotherapeutic compound because it is able to selectively induce apoptosis (through the mitochondrial pathway) and inhibit proliferation in tumor cells while sparing normal cells and tissues.(Savitskaya 2016)

Animal and in vitro data

Animal studies have suggested that delta-tocotrienol and gamma-tocotrienol accumulate in tumors.(Chin 2016) Delta-tocotrienol was found to inhibit pancreatic ductal adenocarcinoma (PDAC) stem-like cells as well as the growth and metastasis of gemcitabine-resistant PDAC human stem-like cells.(Husain 2017)

Clinical data

Despite epidemiological studies suggesting favorable outcomes with vitamin E supplementation in reducing the risk of cancer and death from cancer, meta-analyses of clinical trials(Albanes 2000, Blanke 2001, Cascinu 2000, Mooney 2005, Rautalahti 1999, Virtamo 2000) demonstrate no beneficial effect and suggest evidence for harm.(ADA 2014, Bjelakovic 2012, Bjelakovic 2004, Miller 2005, Senior 2005, Slatore 2008, Vitamin E 1994)

In the SELECT study, synthetic vitamin E 400 units/day increased the risk for prostate cancer (HR, 1.17; 99% CI, 1.004 to 1.36; P=0.008).(Klein 2011) However, in the Women's Health Study, natural vitamin E 600 units on alternate days did not increase the risk of cancer or death from cancer, nor did it increase total mortality.(Buring 2006)

Topical vitamin E has demonstrated improvement in oral mucositis caused by chemotherapy/radiation.(Chaitanya 2017) Mucositis associated with chemotherapy may be alleviated with topical vitamin E through its ability to regulate Nrf2 activation. Topical vitamin E is preferred over oral administration based on clinical findings.(Thomsen 2018) A meta-analysis that included 6 clinical trials involving 353 patients found that, in general, vitamin E was not associated with reducing the incidence of chemotherapy-induced peripheral neuropathy (RR, 0.55; 95% CI, 0.29 to 1.05; P=0.07). However, it significantly prevented cisplatin-induced neurotoxicity (RR, 0.31; 95% CI, 0.17 to 0.58; P=0.0002).(Huang 2016) The American Society of Clinical Oncology (ASCO) guideline update for prevention and management of chemotherapy-induced peripheral neuropathy (2020) recommends that clinicians not offer vitamin E for the prevention of chemotherapy-induced peripheral neuropathy in adults with cancer undergoing treatment with neurotoxic agents (Intermediate; Moderate).(Loprinzi 2020)

Cardiovascular disease

Vitamin E's potential benefits in cardiovascular disease span beyond its antioxidant effects. Anti-inflammatory and antiplatelet effects have been suggested; antiplatelet effects are the result of vitamin E's inhibition of PKC. Additionally, both alpha- and gamma-tocopherol enhance endothelial nitric oxide synthase to increase nitric oxide levels. Tocotrienol, but not tocopherol, may be an inhibitor of the mevalonate pathway, specifically through inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, thereby impacting cholesterol production.(Chin 2018, Rashidi 2017) Gamma-tocotrienol has been associated with stimulating the degradation of apolipoprotein. Both delta- and gamma-tocotrienol influence gene expression involved in lipid homeostasis.(Chin 2016) Alpha-tocopherol reduces lipid peroxidation, inhibits platelet aggregation, and modulates inflammation via inhibition of 5-lipoxygenase. It also enhances nitric oxide production.(Mathur 2015)

Animal data

In a study of pregnant mice exposed to high-dose formaldehyde, vitamin E 0.1 mcg reversed apoptosis in cardiomyocytes of maternal mice and the offspring.(Wu 2017) In another murine study, the combination of vitamin E and omega-3 polyunsaturated fatty acids reduced fine particulate matter–induced cardiovascular injury and decreased production of inflammatory cytokines (eg, tumor necrosis factor alpha [TNF-alpha], interleukin [IL]-1beta, IL-6). Antioxidant activity was also increased with these agents.(Du 2017)

Supplementation with pure tocotrienol produced lipid-lowering effects in rabbits with established (ie, 8 weeks) atherosclerosis but not in those with early (ie, 2 weeks) atherosclerosis. Tocotrienol treatment also reduced expression of adhesion molecules and IL-6 expression in both groups.(Rahman 2016) In a study of obese rats, alpha-tocopherol and alpha-, gamma- and delta-tocotrienol reduced inflammatory cell infiltration and improved contractility; however, only delta- and gamma-tocotrienol improved heart structure and normalized blood pressure.(Wong 2017)

Clinical data

Data regarding the use of vitamin E for cardiovascular disease outcomes and related mortality are conflicting. Older epidemiological studies have suggested an association between vitamin E intake and reduced coronary heart disease and associated death.(Kushi 1996, Rimm 1993, Stampfer 1993) In a study of men and women with hypercholesterolemia, supplementation with tocotrienols from 3 different sources and dosed at 200 mg/day did not have any effects on cardiovascular disease risk factors.(Mustad 2002) In smokers 50 years of age or older, ultrasound showed no effect on atherosclerosis after 5 years of natural vitamin E supplementation.(Magliano 2006) In the Women's Antioxidant and Cardiovascular Study, no impact from supplementation (natural vitamin E 600 units every other day) on total mortality was observed in women at high risk for cardiovascular events, but a marginal effect was reported in women with a previous cardiovascular event.(Cook 2007) A null effect was documented in another study evaluating vitamin E supplementation, with increased mortality in certain disease groups and a reduced risk in others.(Hayden 2007)

Results from the Women's Health Study showed that supplementation with natural vitamin E 600 units every other day had no significant impact on the incidences of myocardial infarction, stroke, or total mortality; however, there was a 24% risk reduction in cardiovascular mortality (RR, 0.76; 95% CI, 0.59 to 0.98; P=0.03).(Lee 2005)

A 2015 meta-analysis evaluated the effects of vitamin E alone and in combination with vitamin C on endothelial function. The investigators reviewed 27 trials (N=742) evaluating vitamin E alone and found a significant improvement in endothelial function with vitamin E (standardized mean difference [SMD], 0.48; 95% CI, 0.23 to 0.72; P=0.0001). However, there was significant heterogeneity among the trials. A subgroup analysis revealed beneficial effects of vitamin E in participants who had lower baseline vitamin E concentrations (ie, less than 20 mcM). A negative correlation between baseline vitamin E concentration and vitamin E supplementation on endothelial function was demonstrated. The combination of vitamin E and vitamin C was not associated with an improvement in endothelial function (SMD, 0.12; 95% CI, −0.18 to 0.42; P=0.428).(Ashor 2015)

In a randomized, double-blind, placebo-controlled study of 39,815 initially healthy women at least 45 years of age and who were enrolled in the Women's Health Study, the impact of natural vitamin E 600 units every other day on heart failure risk was evaluated. During a median of 10.2 years, 220 heart failure events occurred. When adjusting for aspirin use, beta-carotene administration, and age, vitamin E did not significantly affect the risk for heart failure (HR, 0.93; 95% CI, 0.71 to 1.21; P=0.59). The authors concluded that vitamin E did not impact the overall risk of heart failure in a generally healthy population of women.(Chae 2012) In a large study including 23,099 Japanese men and 35,597 Japanese women, gender-specific effects on heart failure–associated mortality were evaluated based on dietary intake of vitamins A, D, E, and K. A reduced risk of heart failure mortality was noted in women but not men with dietary intake of vitamin E.(Eshak 2018)

Vitamin E has been investigated for a role in prevention of atrial fibrillation, potentially due to its anticoagulant effects (ability to lower activation of vitamin K–dependent clotting factors) and due to its antiatherosclerotic properties. Data suggest that low serum vitamin E levels are related to the recurrence of atrial fibrillation. Conflicting results exist for vitamin E in the setting of postoperative atrial fibrillation.(Orenes-Piñero 2015)

Given the conflicting results regarding the effects of vitamin E on cardiovascular outcomes and associated mortality, the American Heart Association does not support the routine use of antioxidants in individuals with cardiovascular disease.(Kris-Etherton 2004) Additionally, the American College of Cardiology Foundation/American Heart Association guideline for the management of peripheral artery disease (2005/2011) states that vitamin E is not recommended for treatment of patients with intermittent claudication (level C evidence).(Anderson 2013)

CNS effects

Neurodegeneration/Alzheimer disease/Mild cognitive impairment

Oxidative stress is linked to Alzheimer disease and other states of cognitive impairment, and vitamin E has been studied for its antioxidant activity in these populations. Specifically, amyloid-beta plaques, hallmarks of Alzheimer disease, cause oxidative stress, resulting in the production of reactive oxygen species and associated lipid peroxidation.(Gugliandolo 2017) Tocotrienol is believed to exert neuroprotective effects through scavenging free radicals, reducing the generation of free radicals, and improving mitochondrial function. Because high cholesterol has been implicated in Alzheimer disease, tocotrienol may be beneficial due to its effects on cholesterol production.(Chin 2018)

Animal and in vitro data

In vitro data have demonstrated that vitamin E prevents amyloid-beta–induced oxidation, generation of reactive oxygen species, and neurotoxicity. Additionally, animal studies evaluating alpha-tocopherol have shown beneficial effects such as reductions in memory, cognitive deficits, and oxidative stress.(Gugliandolo 2017) A tocotrienol-rich fraction dosed at 60 mg/kg/day for 10 days inhibited the formation of amyloid-beta fibrils and amyloid-beta oligomers in vitro and improved cognitive function in an amyloid-beta PPswe/PS1dE9 double transgenic Alzheimer disease mouse model.(Ibrahim 2017) In rats, vitamin E administration ameliorated the effects of long-term lead exposure on animal behavior, based on analysis using a passive avoidance learning and memory task test; effects may be due to vitamin E's antioxidant effects.(Khodamoradi 2015)

Clinical data

In a 2017 Cochrane review, the authors concluded that vitamin E supplementation did not prevent progression to dementia in patients with mild cognitive impairment, nor did it improve cognitive function in patients with mild cognitive impairment or in those with Alzheimer disease. One study showed vitamin E supplementation may be beneficial in slowing functional decline in patients with Alzheimer disease. Additionally, supplementation with vitamin E did not appear to result in increased mortality or adverse effects.(Farina 2017)

The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADViSE) primary prevention trial enrolled 3,786 of the 7,450 men from the parent prostate cancer prevention study (SELECT). Depending on the particular analysis, hazard ratios for dementia incidence over a 7-year period ranged from 0.8 to 0.97 for vitamin E alone and 0.97 to 1.18 for the combination of selenium plus vitamin E.(Kryscio 2017)

The Vitamin E and Memantine in Alzheimer's Disease trial assessed the effects of synthetic alpha-tocopherol (2,000 units/day), memantine (20 mg/day), or a combination of the two compared with placebo on mild to moderate Alzheimer disease progression in patients taking an acetylcholinesterase inhibitor. A slower rate of decline was noted in patients receiving alpha-tocopherol over a mean period of 2.27 years compared with placebo. This translated to a delay in symptoms by 19% (approximately 6.2 months) in those receiving alpha-tocopherol. This effect was not noted in patients in the memantine group or memantine plus alpha-tocopherol combination group. The authors stated the lack of response with memantine was consistent with previous studies showing negative findings in mild dementia. However, it is unclear why the alpha-tocopherol plus memantine combination group did not demonstrate some level of benefit consistent with the alpha-tocopherol alone group. An increased rate of mortality associated with vitamin E was not observed.(Dysken 2014) In a 2015 meta-analysis, high vitamin E or vitamin C intake was found to attenuate the risk for Alzheimer disease by about 26% (grade I evidence); however, no effect was noted with the combination of vitamins E and C (RR, 0.82; 95% CI, 0.6 to 1.04).(Xu 2015) A 2017 review of 5,269 subjects from the Canadian Study of Health and Aging found an age-adjusted risk reduction of 32% (HR, 0.68; 95% CI, 0.5 to 0.92) in those receiving vitamin E supplements for cognitive impairment with no dementia; a risk reduction of 46% (HR, 0.54; 95% CI, 0.34 to 0.85) for Alzheimer disease; and a risk reduction of 47% (HR, 0.53; 95% CI, 0.36 to 0.78) for all-cause dementia.(Basambombo 2017)

A 2018 systematic review (3 trials; N=12,830) found moderate-strength evidence suggesting that vitamin E was no different than placebo in preventing cognitive decline, as measured by brief cognitive performance tests, a multidomain neuropsychological performance test, and memory tests.(Butler 2018)

Several guidelines have been published regarding vitamin E use in Alzheimer disease and dementia. The European Federation of Neurological Societies guidelines on the management of Alzheimer disease (2010) state there is insufficient evidence to support the use of vitamin E for primary prevention of dementia and it should not be used in treatment of patients with mild cognitive impairment. Additionally, the guidelines state that vitamin E should not be used in the treatment of Alzheimer disease (level A recommendation).(Hort 2010) The British Association for Psychopharmacology (BAP) consensus statement on clinical practice with anti-dementia drugs (2016) states that type IA evidence shows vitamin E is not effective in reducing the risk of developing Alzheimer disease and that supplementation is not recommended for prevention or treatment of Alzheimer disease.(O'Brien 2017) The American Academy of Neurology (AAN) practice parameter for the management of mild cognitive dementia states vitamin E is possibly ineffective in preventing the progression to Alzheimer disease in patients with mild cognitive impairment, and efficacy of the combination of vitamin E and vitamin C in patients with mild cognitive impairment is uncertain.(Petersen 2018) The American Psychiatric Association (APA) guideline watch for the treatment of patients with Alzheimer disease and other dementias (2014) did not find enough definitive new evidence to change the 2007 guideline recommendation stating alternative agents, including vitamin E, are generally not recommended due to uncertain efficacy and safety.(Rabins 2014)

Recognizing differences in findings from clinical trials, consideration should be given to the formulations of vitamin E studied. A combination of tocopherols and not a specific tocopherol such as alpha-tocopherol (most commonly studied) may exert a larger neuroprotective effect in patients with Alzheimer disease.(Gugliandolo 2017) Additionally, in light of the variable conclusions, it might be important to better understand a patient's vitamin E levels and oxidative stress patterns to help guide treatment decisions.(Cervantes 2017)

Down syndrome

Because oxidative stress is implicated in the pathogenesis of Down syndrome, the antioxidant effects of vitamin E supplementation have been evaluated.(Shichiri 2011)

Animal data

In a mouse model of Down syndrome, long-term supplementation with alpha-tocopherol was associated with improvements in cognitive deficits and reduction of lipid peroxidation.(Shichiri 2011)

Clinical data

Supplementation with vitamin E 1,000 units twice daily for 3 years did not slow progression of cognitive deterioration in aging patients (ie, 50 years and older) with Down syndrome.(Sano 2016) In children and teenagers with Down syndrome, vitamin E 400 mg plus vitamin C 500 mg daily for 6 months reduced oxidative stress.(Parisotto 2014) These participants were further studied, with antioxidant effects still noted up to 1 year after discontinuation of antioxidant therapy.(Parisotto 2015)

In a randomized, double-blind, placebo-controlled, 2-year trial of 53 patients with Down syndrome and Alzheimer disease–type dementia, the effects of a combination of alpha-tocopherol 900 units, alpha lipoic acid (ALA) 600 mg, and ascorbic acid 200 mg did not improve cognitive function or stabilize cognitive decline. No serious adverse effects were noted.(Lott 2011)

In a randomized controlled trial (N=93), supplementation with alpha-tocopherol 400 units/day for 4 months significantly decreased urinary concentrations of the oxidative stress biomarker 8=hydroxyl-2'-deoxyguanosine (8OHdG) in children with Down syndrome compared with placebo (P<0.01). Because Down syndrome children have higher baseline levels of oxidative stress than their siblings, the authors suggested that alpha-tocopherol supplementation may reduce oxidative stress at the DNA level.(Nachvak 2014)

Epilepsy

Animal data

In a rat model of kainite-induced status epilepticus, a diet enriched with natural alpha-tocopherol for 2 weeks was associated with anti-inflammatory and neuroprotective effects.(Betti 2011)

Clinical data

A Cochrane review of trials from 1966 through 2006 discusses poor trial methodology and did not show sufficient evidence to support routine use of vitamin E in the management of epilepsy.(Ranganathan 2005) However, a more recent study demonstrated that vitamin E 400 units/day for 6 months in patients with epilepsy and receiving long-term antiepileptic drug therapy was associated with a significant reduction in the frequency of seizures (P<0.001) and improved electroencephalogram findings (P=0.001).(Mehvari 2016)

Parkinson disease

Animal data

In a study of rotenone-induced Parkinson disease in rats, coadministration of intramuscular vitamin E (every other day) ameliorated changes in total locomotor activity and catalepsy and decreased lipid peroxidation following 35 days of treatment.(Sharma 2013)

Clinical data

In a population-based cohort study conducted in Sweden, dietary intake of vitamin E was evaluated in 84,774 patients. After a mean follow-up of 14.9 years, 1,329 cases of Parkinson disease were identified. The findings suggested that dietary intake of vitamin E was associated with a lower risk of developing Parkinson disease in women but not men (HR, 0.87; 95% CI, 0.79 to 0.96; P_trend=0.02). The gender differences might be explained by antioxidant (ie, protective) effects of estrogen in women.(Yang 2017)

In a study of patients with Parkinson disease, a combination of vitamin E 400 units plus 1,000 mg of omega-3 fatty acids for 12 weeks resulted in improvements in Unified Parkinson Disease Rating Stage, high-sensitivity C-reactive protein, total antioxidant capacity, and glutathione concentrations, as well as markers of insulin metabolism.(Taghizadeh 2017)

Tardive dyskinesia

Animal data

In a study of rats with haloperidol-induced tardive dyskinesia, vitamin E 20 mg/kg/day given orally for 5 weeks was associated with improvements in measures of tardive dyskinesia.(Shi 2016)

Clinical data

A 2018 Cochrane systematic review analyzed the effects of vitamin E in 13 clinical trials enrolling 478 participants experiencing antipsychotic-induced tardive dyskinesia. Results suggest that supplementation with vitamin E may protect against deterioration of tardive dyskinesia in this population, because those receiving placebo experienced more deterioration; however, there is no clear evidence that vitamin E improves symptoms of tardive dyskinesia once the condition is established.(Soares-Weiser 2018)

The American Academy of Neurology guidelines for the treatment of tardive syndromes (2013), including tardive dyskinesia, concludes that data are conflicting and insufficient to determine the efficacy of vitamin E in the management of tardive dyskinesia syndrome.(Bhidayasiri 2013)

Diabetes mellitus

Animal data

In a study of diabetic rats, vitamin E given for 6 weeks was associated with reduced myocardial damage, blood glucose, and lipid peroxidation, as well as improved serum lipids and enhanced antioxidant capacity.(Abdel-Raheem 2015) Another study in fructose-induced metabolic syndrome in rats found that vitamin E (100 mg/kg/day for 6 weeks) alone or in combination with liraglutide (0.3 mg/kg/day for 6 weeks) exerted beneficial effects on visceral fat index, liver function tests, fasting blood glucose, and cholesterol parameters.(Geddawy 2017)

Clinical data

Conflicting data exist regarding use of vitamin E in patients with or at risk for diabetes. A number of older clinical trials found no effect of vitamin E on outcomes.(Engelen 2005, Fardoun 2007, Giannini 2007, Liu 2006, McQueen 2005)

A meta-analysis of randomized controlled clinical trials found that vitamin E supplementation improved blood glucose and hemoglobin A_1c (HbA_1c), as well as enhanced antioxidant capacity in patients with type 2 diabetes.(Balbi 2018)

The effect of mixed tocotrienols (200 mg twice daily for 1 year) on patient-reported neuropathy Total Symptom Score (TSS) (TSS components being lancinating pain, burning pain, paresthesia, and asleep numbness) was evaluated in the Vitamin E in Neuroprotection Study (VENUS), a parallel, double-blind, placebo-controlled study in patients with diabetes and neuropathy. After 12 months, there was no significant difference in TSS between the mixed tocotrienols and placebo groups (−0.3; 95% CI, −1.16 to 0.56; P=0.49). In a post hoc subgroup analysis, patients with HbA_1c greater than 8% who received mixed tocotrienols experienced a significant reduction in lancinating pain (P=0.03); further exploration is warranted in this population.(Hor 2018)

Similarly, in a review of clinical trials involving patients with type 2 diabetes (N=418), vitamin E supplementation did not improve glycemic control in the full set of patients. However, in subsets of patients with HbA_1c of 8% or greater or with low baseline serum vitamin E levels, vitamin E was associated with improved glycemic control. The pooled mean difference in HbA_1c changes, which was the same for both subsets, was −0.58% (95% CI, −0.83% to −0.34%; P<0.00001).(Suksomboon 2011)

In a randomized, double-blind, placebo-controlled clinical trial, the effects of high-dose vitamin E supplementation versus placebo were assessed in 60 patients with diabetic nephropathy. Supplementation with vitamin E 1,200 units/day for 12 weeks was associated with a reduction in markers of renal injury and inflammation: urine protein and protein-to-creatinine ratio, serum TNF-alpha, matrix metalloproteinase 2 (MMP-2) and MMP-9, and insulin concentrations.(Khatami 2016)

In a randomized, double-blind, placebo-controlled trial of 60 women with gestational diabetes, the combination of vitamin E 400 units/day and magnesium oxide 250 mg/day for 6 weeks was associated with reductions in fasting blood glucose, serum insulin levels, and homeostasis model of assessment-insulin resistance compared with placebo. Additionally, all lipid parameters were improved with combination therapy, except for high-density lipoprotein (HDL) cholesterol levels.(Maktabi 2018)

The American Diabetes Association updated guidelines on the standards of medical care in diabetes (2021) recommends individualized medical nutrition therapy programs as needed to achieve treatment goals for all people with type 1 or 2 diabetes, prediabetes, and gestational diabetes (level A). However, they advise against routine use of dietary supplementation with antioxidants, including vitamin E, for glycemic control based on no clear evidence that it can improve outcomes as well as concern regarding long-term safety.(ADA 2021)

Dysmenorrhea

Clinical data

A 2016 Cochrane systematic review and meta-analysis of dietary supplements for dysmenorrhea identified only low- or very–low-quality studies with very small sample sizes. Vitamin E supplementation did not demonstrate efficacy for the treatment of primary dysmenorrhea compared with placebo or no treatment (2 randomized clinical trials; n=135); no difference was observed for vitamin E compared to fennel (1 randomized clinical trial; n=42), and data were unsuitable for analysis in the studies that compared vitamin E with vitamin B₁ and vitamin E plus fennel with ibuprofen.(Pattanittum 2016) However, in a randomized, double-blind clinical trial, vitamin E (200 units/day for 8 weeks) was effective in relieving menstrual pain compared with placebo in patients between 18 and 25 years of age. The combination of vitamin E and omega-3 fatty acids (ie, EPA 180 mg, DHA 120 mg) was more effective than any other treatment groups (P<0.05).(Sadeghi 2018)

Liver diseases

The imbalance between oxidative stress and diminished antioxidant activity is purported to be a cause of liver disease. Antioxidants such as vitamin E have been evaluated in diseases of the liver. (Bjelakovic 2011) In patients with nonalcoholic steatohepatitis (NASH), vitamin E is important for mitigating hepatocyte damage through reducing the circulation of malondialdehyde and transforming growth factor alpha-1.(Tang 2017)

Animal data

In a study of mice undergoing partial hepatectomy, vitamin E supplementation (approximately 20 mg/day) reduced thiobarbituric acid reactive substances level (a measure of oxidative stress), as well as nonalcoholic fatty liver disease (NAFLD) activity scores at day 7 following hepatectomy.(Karimian 2015)

In rats subjected to partial hepatectomy and exposed to alcohol, which inhibits liver regeneration, a group receiving intraperitoneal doses of vitamin C 250 mg/kg/day and vitamin E 250 mg/kg/day for 5 weeks demonstrated lowered serum malondialdehyde levels and protective effects on liver function (eg, lowered ALT serum concentrations). The investigators suggested that vitamins C and E may have promoted liver regeneration.(Okamura 2018)

Clinical data

In a Cochrane review, 15 trials of vitamin E dosed alone and in combination with other supplements (vitamin E doses ranging from 30 to 1,000 units) were reviewed. The authors found no evidence to support or refute the use of vitamin E in patients with conditions of the liver, such as alcoholic or autoimmune liver diseases, hepatitis B or C, or cirrhosis. Additionally, the data reviewed showed a nonsignificant trend towards elevated liver function tests with vitamin E (RR, 2.27; 95% CI, 0.48 to 10.67).(Bjelakovic 2011) A 2019 systematic review and meta-analysis of 9 randomized, placebo-controlled trials (N=889) that assessed vitamin E in NAFLD provided both a qualitative and quantitative synthesis of trial data in adult and pediatric patients with primary NAFLD. Compared to placebo, pooled data from 4 pediatric and 1 low-quality adult study showed no significant effect of vitamin E on any of the 6 parameters assessed (ALT, AST, body mass index [BMI], ballooning, fibrosis, or histology). Based on data reported in tables, qualitative improvements were reported for ALT in all trials but were only significantly better than placebo in 3 of the 5 adult trials and in none of those conducted in children. Outcome measures for AST, BMI, and steatosis scores were mixed, as were those for the other outcomes. Dosing ranged from 80 to 1,000 units once daily for adults and 222 to 888 units once daily for children.(Amanullah 2019)

In the Pioglitazone versus Vitamin E versus Placebo in the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, 247 patients with NASH were randomized to receive natural vitamin E 800 units/day, pioglitazone 30 mg/day, or placebo for 96 weeks. Treatment with vitamin E was associated with a significantly higher rate of improvement in NASH compared to placebo (43% vs 19%; P=0.001). Additionally, compared with placebo, vitamin E was associated with a statistically significant improvement in liver function tests (P<0.001), reduced hepatitic steatosis (P=0.005), and reduced lobular inflammation (P=0.02). However, improvements in fibrosis scores and percentage of patients experiencing resolution of NASH were not statistically significant with vitamin E.(Sanyal 2010)

In the Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) trial, 173 patients between 8 and 17 years of age with NASH were randomized to receive natural vitamin E 800 units/day, metformin 1,000 mg/day, or placebo for 96 weeks. Vitamin E was similar to placebo in reducing ALT levels. However, vitamin E was associated with significant improvements in hepatocellular ballooning scores compared with placebo. Additionally, 58% of patients receiving vitamin E (compared to 28% receiving placebo; P=0.006) experienced resolution of NASH at the completion of 96 weeks of therapy. (Lavine 2011)

The American Association for the Study of Liver Diseases guidelines (2018) suggest that natural vitamin E 800 units/day improves liver histology in nondiabetic patients with histologically proven NASH and may be considered useful in this population. The guidelines state that vitamin E should not be used to treat NASH in diabetic patients, nonalcoholic fatty liver disease without histological evidence from a biopsy, NASH cirrhosis, and cryptogenic cirrhosis.(Chalasani 2012) Clinical practice guidelines published by the European Association for the Study of the Liver, European Association for the study of Diabetes, and European Association for the Study of Obesity (2016) state that vitamin E may be used in patients with NASH for short-term treatment, although firm recommendations cannot be made (level B2 evidence). There are concerns regarding increased risk of mortality, risk of prostate cancer in patients older than 50 years, and hemorrhagic stroke with long-term vitamin E therapy.(EASL 2016, Tang 2017) Use of vitamin E should be tailored toward individuals with histologically proven NASH and potential associated adverse effects considered.(Chalasani 2012, Hung 2018)

Macular degeneration, cataracts, and visual loss

Animal data

The effects of topically applied tocotrienol on cataracts were evaluated in streptozotocin-induced diabetic rats. In rats receiving a twice-daily topical microemulsion of tocotrienol, there was a delay in cataract progression beginning from week 5 onward. This effect was noted despite persistent hyperglycemia in the rats. Tocotrienol decreased lenticular aldose reductase activity, polyol levels, and oxidative-nitrosative stress.(Abdul 2017)

Clinical data

Results from the Age-Related Eye Disease Study (AREDS) showed that high levels of antioxidants and zinc reduced the risk of advanced age-related macular degeneration (AMD) and its associated vision loss. These same nutrients had no effect on the development or progression of cataracts. The antioxidant formulation used consisted of vitamin E 400 units, vitamin C 500 mg, beta-carotene 15 mg, zinc oxide 80 mg, and cupric oxide 2 mg.(NEI 2013)

In a Cochrane review of antioxidant supplement use in patients with AMD, only 1 study evaluating use of natural vitamin E was identified. Subjects (N=1,204) were randomized to receive vitamin E or placebo, with a follow-up of 4 years. Participants were from the general population; 19% had AMD, and the number of those with late AMD was low (n=7). The estimate of the effect of vitamin E was uncertain (risk ratio, 1.36; 95% CI, 0.31 to 6.05).(Evans 2017)

In a large cohort study of apparently healthy men (N=11,267) from the SELECT study (mean follow-up of 5.6 years), eye end point data indicated that supplementation with vitamin E 400 units/day and/or selenium 200 mcg/day was not likely to have beneficial effects on age-related cataracts.(Christen 2014)

A meta-analysis of 13 observational studies (N=18,999) evaluated the association between blood levels of antioxidants and vitamins and the risk of age-related cataracts. Based on the results of 8 relevant studies with no substantial heterogeneity, vitamin E showed an inverse association with cataract risk.(Cui 2013)

Male fertility

Clinical data

A 2014 Cochrane systematic review and meta-analysis evaluating antioxidant use in male subfertility identified 2 trials (N=117) that investigated vitamin E, and although an apparent association between vitamin E and an increase in live birth rates appeared to exist (P=0.006; I²=0%), risk of bias was high. One trial (n=64) also reported a significantly lower sperm DNA fragmentation with administration of vitamin E plus vitamin C compared with placebo. Vitamin E was also one of 2 antioxidants associated with an increase in clinical pregnancy rate based on evidence from analyses of specific antioxidants.(Showell 2014)

Menopause and osteoporosis

Oxidative stress inhibits the differentiation of osteoblasts while enhancing the differentiation of osteoclasts. Therefore, effects of vitamin E and other antioxidants in osteoporosis have been evaluated.(Chin 2016)

Animal data

In a study of ovariectomized rats, both alpha-tocopherol (60 mg/kg) and tocotrienol (60 mg/kg) prevented bone loss associated with estrogen deficiency.(Muhammed 2012)

Clinical data

A vaginal suppository of vitamin E given for 12 weeks was compared with conjugated estrogens vaginal cream in postmenopausal women. Both treatments significantly improved responses on the Abbreviated Sexual Function Questionnaire (P<0.001) compared with baseline; however, there were no significant differences between treatment groups.(Golmakani 2018)

In an analysis of 2 cohort studies of 61,433 perimenopausal women and 1,138 older men over a 19-year follow-up, alpha-tocopherol supplementation was associated with reduced rates of hip fractures (HR, 0.78; 95% CI, 0.65 to 0.93) and any fracture (HR, 0.86; 95% CI, 0.78 to 0.94).(Michaelsson 2014) Additionally, the risk for hip fractures in postmenopausal women with low vitamin E intake is increased.(Guralp 2014)

Endocrine Society clinical practice guidelines for the treatment of symptoms of menopause (2015) recommend counseling patients on the lack of consistent evidence regarding benefits of complementary medicine therapies, including vitamin E, as alternative nonhormonal therapy for vasomotor symptoms (weak recommendation; low-quality evidence).(Stuenkel 2015) The North American Menopause Society position statement for nonhormonal management of menopause-associated vasomotor symptoms (2015) states that data are equivocal regarding the effectiveness of vitamin E for menopausal vasomotor symptoms (Level I).(NAMS 2015)

Pain

Clinical data

Vitamin E supplementation has been investigated for the relief of pain in various clinical scenarios, including dysmenorrhea, osteoarthritis, diabetic neuropathy, and postoperative pain, with mixed results.(Hor 2018, Pattanittum 2016, Ruiz-Tovar 2016, Sadeghi 2018, Tantavisut 2017) In a study of patients undergoing Milligan-Morgan hemorrhoidectomy, application of topical vitamin E reduced postoperative pain, length of hospitalization, and time to resume activities of daily living, and increased patient satisfaction with surgery.(Ruiz-Tovar 2016) In patients with diabetic neuropathy, those with HbA_1c greater than 8% who received mixed tocotrienols experienced a significant reduction in lancinating pain (P=0.03).(Hor 2018) Although a Cochrane review found no evidence of benefit for vitamin E supplementation in primary dysmenorrhea compared with placebo or no treatment,(Pattanittum 2016) a randomized, double-blind clinical trial, vitamin E (200 units/day for 8 weeks) was effective in relieving menstrual pain compared with placebo in patients between 18 and 25 years of age.(Sadeghi 2018) In 72 patients with late-stage knee osteoarthritis scheduled to undergo arthroplasty, vitamin E demonstrated improvements in Western Ontario and McMaster Universities Osteoarthritis Index Scores of pain, stiffness, and function.(Tantavisut 2017)

The updated American Academy of Neurology practice guideline summary for oral and topical treatment of painful diabetic polyneuropathy (2021) concluded that tocotrienols are possibly no more likely than placebo to improve pain (Low).(Price 2022)

Peyronie disease

Clinical data

In a study of 70 men with Peyronie disease, a combination of verapamil, propolis, blueberries, and topical diclofenac was compared with the same combination plus natural vitamin E. The addition of vitamin E was associated with significant improvements in plaque size, penile curvature (96.6% improved in the vitamin E group compared with 48.4% in the group without vitamin E [P=0.0001]), and International Index of Erectile Function scores.(Paulis 2013)

Polycystic ovarian syndrome

Clinical data

In a randomized, double-blind, placebo-controlled trial of 86 women with polycystic ovarian syndrome, the combination of vitamin E with coenzyme Q10 given for 8 weeks was associated with significant benefits on fasting blood sugar; however, this effect was not noted in the vitamin E only group. Vitamin E, both alone and in combination with coenzyme Q10, significantly reduced serum total testosterone concentrations compared with placebo (P<0.001). The combination also significantly improved sex hormone binding globulin compared to the other groups (P=0.008).(Izadi 2018)

Pregnancy, pre-eclampsia, and fetal outcomes

Clinical data

A meta-analysis of trials from 2006 found no effect of antioxidant supplementation on the rate of pre-eclampsia versus placebo.(Lui 2006) Similarly, in one clinical trial, vitamin E supplementation in pregnant women from the second trimester until delivery did not reduce the risk of pre-eclampsia, nor did it impact maternal and perinatal outcomes.(Bastani 2011) Data from a 2015 Cochrane review suggest a possible decreased risk of placental abruption in women supplemented with vitamin E in combination with other supplements (risk ratio, 0.64; 95% CI, 0.44 to 0.93); further research is needed.(Rumbold 2015)

A longitudinal study from the Danish National Birth Cohort demonstrated that maternal vitamin E intake was not associated with child asthma; however, there was a modest decrease in the risk of allergic rhinitis during the first 7 years of life in children whose mothers received vitamin E during pregnancy.(Maslova 2014)

The lack of benefit in preventing eclampsia, coupled with the conflicting evidence regarding mortality risk with vitamin E supplementation in the literature(Abner 2011, Bjelakovic 2012, Lee 2005, Miller 2005) needs to be considered when determining whether to supplement with vitamin E during pregnancy.

Preterm infants

Clinical data

The World Health Organization (WHO) recognizes the importance of vitamin E on the health and well-being of a preterm infant; however, vitamin E supplementation in preterm infants may increase the risk for life-threatening sepsis. Therefore, the WHO does not support high-dose vitamin E supplementation in this population.(WHO 2018)

Rheumatoid arthritis/Osteoarthritis

Oxidative stress resulting from imbalance of antioxidants has been implicated in causing chondrocyte damage, which can lead to impaired cartilage remodeling. Lower vitamin E doses might be beneficial in ameliorating the oxidative stress harmful to chondrocytes, while higher doses may cause oxidative damage.(Chin 2018)

Animal data

In a study of rat chondrocytes derived from articular cartilage, vitamin E prevented apoptosis and senescence of the chondrocytes, as well as preserved the proteoglycan content.(Bhatti 2013) In an osteoarthritis model in dogs, administration of vitamin E 400 units/day for 55 days was associated with increased serum and synovial fluid concentrations of vitamin E. Prostaglandin E₂ and nitrogen oxides were lower in the dogs receiving vitamin E.(Rhouma 2013)

In a study of neonatal rats with rheumatoid arthritis, a combination of glucosamine and vitamin E supplementation exerted antioxidant activity.(Dai 2018) In another rat model of rheumatoid arthritis, delta-tocotrienol 10 mg/kg daily from days 25 to 50 following induction of disease was associated with reduced paw edema.(Haleagrahara 2014)

Clinical data

The effects of vitamin E 400 units/day versus placebo for 2 months were studied in 72 patients with late-stage knee osteoarthritis scheduled to undergo arthroplasty. Vitamin E administration was associated with a reduction in malondialdehyde and increases in alpha-tocopherol levels and Trolox-equivalent antioxidant capacity compared to placebo. Vitamin E also demonstrated improvements in Western Ontario and McMaster Universities Osteoarthritis Index Scores of pain, stiffness, and function.(Tantavisut 2017)

Low-level evidence suggests efficacy of vitamin E supplementation in rheumatoid arthritis. In a randomized, double-blind study in patients with active rheumatoid arthritis, the combination of vitamin E with conjugated linoleic acid for 3 months exerted anti-inflammatory effects, as evidenced by impacts on various markers of inflammation.(Aryaeian 2014)

Scarring

Clinical data

A systematic review of the literature conducted in 2016 found insufficient evidence supporting topical vitamin E use for improvement of scar appearance. Specifically, 6 trials were evaluated, with 3 showing benefit. One of the studies involved topical treatment with vitamin E in white children and the other 2 evaluated vitamin E as part of combination therapy in adults. The 3 other trials did not demonstrate improvement with topical therapy.(Tanaydin 2016)

Vitamin E deficiency

Clinical data

A review of guidelines that addressed nutrition, physical activity, and nutrient supplementation before and after bariatric surgery identified one guideline that included recommendations for micronutrients: the American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients. Vitamin E supplementation of 15 mg/day was recommended for all post-weight loss bariatric surgery patients regardless of the type of procedure (ie, laparoscopic adjustable gastric banding, sleeve gastrectomy, Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch). Patients with a previous history of deficiency may require higher maintenance doses. Although doses are not clearly defined for repletion, higher than usual doses of 100 to 400 units/day may be required (Grade D, Level 4).(Tabesh 2019)

Dosing

The RDA for vitamin E (natural form) in adults is 15 mg (22.4 units). Currently, vitamin E is most commonly dosed in international units, which measure biological activity instead of quantity. However, by 2021 under the FDA's new labeling regulations for dietary supplements, vitamin E will be dosed in milligrams only. Most supplements contain only alpha-tocopherol, although some "mixed" products containing other tocopherols and tocotrienols are available. Synthetic supplements of vitamin E (all rac-alpha-tocopherol labeled as "DL-" or "dl-alpha-tocopherol") are only half as active as the same amount (by weight in mg) of the natural form (RRR-alpha-tocopherol, labeled as "D-" or "d-alpha-tocopherol").NIH 2018

The American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients, recommends vitamin E supplementation of 15 mg/day for all post-weight loss bariatric surgery patients regardless of the type of procedure (ie, laparoscopic adjustable gastric banding, sleeve gastrectomy, Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch). Patients with a previous history of deficiency may require higher maintenance doses. Although doses are not clearly defined for repletion, higher than usual doses of 100 to 400 units/day may be required (Grade D, Level 4).Tabesh 2019

To convert from mg to unitsNIH 2018:

• 1 mg of alpha-tocopherol=1.49 units of the natural form or 2.22 units of the synthetic form

To convert from units to mg:

• 1 unit of the natural form=0.67 mg of alpha-tocopherol

• 1 unit of the synthetic form=0.45 mg of alpha-tocopherol

Vitamin E doses up to 1,000 mg/day (1,500 units/day of natural or 1,100 units/day of synthetic) in adults appear to be safe. However, this is based on limited data and evidence from small studies of individuals receiving at least 2,000 units/day for a few weeks or months.NIH 2018 A 2016 scientific statement by the American Heart Association regarding drugs that may cause or exacerbate heart failure advises against supplementation with 400 units/day or more of natural-source vitamin E in patients with established disease, based on evidence indicating a possible increased risk of new-onset heart failure.Page 2016

Pregnancy / Lactation

Studies have demonstrated that vitamin E supplementation does not reduce the risk for pre-eclampsia, still birth, neonatal death, preterm birth, or intrauterine growth restriction. However, a Cochrane review suggests a possible association between vitamin E and reduced risk for placental abruption; further studies are needed.Bastani 2011, Rumbold 2015 These findings, coupled with the conflicting evidence regarding a relationship between vitamin E supplementation and mortality risk in the literatureAbner 2011, Bjelakovic 2012, Lee 2005, Miller 2005 need to be considered when determining whether to supplement with vitamin E beyond the recommended daily intake during pregnancy.

A longitudinal study from the Danish National Birth Cohort demonstrated that maternal vitamin E intake was not associated with child asthma; however, there was a modest decrease in the risk of allergic rhinitis during the first 7 years of life in children whose mothers received vitamin E during pregnancy.Maslova 2014

Interactions

Agents with antiplatelet properties: Vitamin E (systemic) may enhance the antiplatelet effect of agents with antiplatelet properties. Monitor therapy.(Agradi 1981, Ali 1980, Bakaltcheva 2001, Brown 1994, Calzada 1997, Celestini 2002, Chang 2000, Clarke 2006, Dereska 2006, Diez Marques 1987, Dmoszynska-Giannopoulou 1990, Ferns 2000, Ferber 1999, Fong 1976, Freedman 1996, Freedman 2001, Freedman 2000, Gisinger 1988, Gomes 1976, Huijgens 1981, Jain 1998, Jandak 1989, Jandak 1988, Kakishita 1990, Kitagawa 1989, Kockmann 1988, Korsan-Bengtsen 1974, Lake 1977, Leppala 2000, Leppala 2000, Li 2001, Liede 1998, Liu 2003, Mabile 1999, Mardla 2004, Mensink 1999, Morinobu 2002, Mower 1983, Murohara 2004, Pignatelli 1999, Rao 1981, Rao 1978, Renaud 1987, Sheu 1999, Silbert 1990, Srivastava 1986, Stampfer 1988, Steiner 1983, Steiner 1976, Steiner 1995, Szczeklik 1985, Szuwart 2000, Unchern 2003, Violi 1990, Vucinic 2010, Williams 1999, Williams 1997) Given vitamin E's ability to inhibit platelet aggregation, coadministration with antiplatelet medication increases the risk of bleeding and may increase the risk for hemorrhagic stroke.(Chin 2016, Dennehy 2010, Pastori 2013, NIH 2018)

Anticoagulants: Vitamin E (systemic) may enhance the anticoagulant effect of anticoagulants. Monitor therapy.(Booth 2004, Cook 2007, Corrigan 1974, Corrigan 1981, Ferro 1999, Kim 1996, Lee 2005, Schrogie 1975, Sesso 2008, Violi 2010, Vitamin E 1994, Yusuf 2000) Given vitamin E's ability to inhibit platelet aggregation, coadministration with anticoagulant medication increases the risk of bleeding and may increase the risk for hemorrhagic stroke.(Chin 2016, Dennehy 2010, Pastori 2013, NIH 2018)

Chemotherapy and radiation: Vitamin E might reduce the efficacy of chemotherapy or radiation through inhibition of cellular oxidative damage in cancer cells. Further research is needed to evaluate the potential risks and benefits of concurrent antioxidant supplementation with conventional therapies for cancer.(NIH 2018)

Cyclosporine: Vitamin E (systemic) may decrease the serum concentration of cyclosporine (systemic). Monitor therapy.(Blackhall 2005, de Vries 2006, Lake 2005)

Ibrutinib: Vitamin E (Systemic) may enhance the antiplatelet effect of Ibrutinib. Monitor therapy. The ibrutinib Canadian product monograph recommends avoiding this combination.(Imbruvica July 2014, Imbruvica November 2014)

Lutein: Lutein may decrease the serum concentration of vitamin E (systemic). No action needed.(Castenmiller 1999, Reboul 2007, Reboul 2007)

Orlistat: Orlistat may decrease the serum concentration of vitamins (fat soluble). Consider therapy modification. Only oral preparations of fat-soluble vitamins are expected to participate in this interaction.(Xenical May 2010) Orlistat administration may also reduce the biologic and therapeutic effect of vitamin E by decreasing GI absorption of the vitamin. In 12 healthy subjects receiving orlistat (120 mg 3 times daily for 4 days), administration of vitamin E (400 units of alpha-tocopheryl acetate) on the fourth day of orlistat treatment decreased the area under the curve and peak plasma level of vitamin E 60% and 43%, respectively, compared with placebo.(Corrigan 1974, Melia 1996)

Simvastatin, atorvastatin, and niacin: The use of vitamin E might negate the increase in HDL cholesterol that is intended with these medications.(NIH 2018, Tousoulis 2006)

Tipranavir: Tipranavir may enhance the adverse/toxic effect of vitamin E (systemic). Consider therapy modification. This interaction only applies to tipranavir oral solution.(Aptivus April 2010)

Adverse Reactions

High levels of vitamin E can adversely affect the absorption of vitamins A and K. Long-term use of high doses may cause nausea, diarrhea, blurred vision, and prolonged bleeding time.Guralp 2014, Hathcock 2004

A 2016 scientific statement by the American Heart Association regarding drugs that may cause or exacerbate heart failure advises against supplementation with 400 units/day or more of natural-source vitamin E in patients with established disease, based on evidence indicating a possible increased risk of new-onset heart failure.Page 2016

Topical vitamin E may cause contact dermatitis, itching, and rash.Tanaydin 2016

A case report described an elevation in prostate-specific antigen (PSA) level with vitamin E supplementation (doses ranging from 800 to 1,600 units/day) for the treatment of tardive dyskinesia. Due to the PSA elevation, tamsulosin was prescribed; after initiation of tamsulosin, the PSA level decreased but remained elevated. Upon discontinuation of vitamin E, the patient's PSA level normalized.Deardorff 2018

Toxicology

Vitamin E is a known antioxidant. However, studies have shown that vitamin E may be a prooxidant under certain circumstances (eg, constant low-level flux of initiator free radicals, absence of co-antioxidants such as vitamin C), causing oxidation and consequent damage to cells.El Hadi 2018 Conflicting data exist regarding an association between vitamin E supplementation and increased mortality risk.Abner 2011, Lee 2005, Miller 2005 An increase in the risk for prostate cancer has been suggested in the SELECT study.Klein 2011

Vitamin E doses up to 1,000 mg/day (1,500 units/day of natural or 1,100 units/day of synthetic) in adults appear to be safe. However, this is based on limited data and evidence from small studies of individuals receiving at least 2,000 units/day for a few weeks or months.NIH 2018

References

Disclaimer

This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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