Observational studies that measure dietary intake and/or serum concentration, and experimental studies that ideally are randomized clinical trials (RCTs), are two means of examining the effects or lack thereof of a proposed intervention on human health. Healthcare outcomes may be expected to be in accord between reviews of observational and experimental studies. If there is a lack of agreement, then factors other than design need to be considered. In observational studies on vitamin E, an inverse correlation between dietary intake and risk of a disease, or serum concentration and risk of a disease, may be considered suggestive, but any conclusions also should rest on randomized clinical trials of sufficient size and duration to measure clinically significant results. One concern with correlations is that other nutrients and non-nutrient compounds (such as polyphenols) may be higher in the same diets that are higher in vitamin E. Another concern for the relevance of RCTs described below is that while observational studies are comparing disease risk between low and high dietary intake of naturally occurring vitamin E from food (when worldwide, the adult median dietary intake is 6.2 mg/d for d-α-tocopherol; 10.2 mg/day when all of the<unk>  and<unk> otrienol isomers are included), the prospective RCTs often used 400 IU/day of synthetic dl-α-tocopherol as the test product, equivalent to 268 mg of α-tocopherol equivalents. Supplement popularity over time In the US, the popularity for vitamin E as a dietary supplement may have peaked around 2000. The Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) tracked dietary supplement use by people over the age of 40 during years 1986–2006. For women, user prevalence was 16.1% in 1986, 46.2% in 1998, 44.3% in 2002, but had decreased to 19.8% in 2006. Similarly, for men, prevalence for same years was 18.9%, 52.0%, 49.4%, and 24.5%. The authors theorized that declining use in these health science aware populations may have due to publications of studies that showed either no benefits or negative consequences from vitamin E supplements. There is other evidence for declining use of vitamin E. Within the U.S. military services, vitamin prescriptions written for active, reserve and retired military, and their dependents, were tracked over years 2007–2011. Vitamin E prescriptions decreased by 53% while vitamin C remained constant and vitamin D increased by 454%. A report on vitamin E sales volume in the USA documented a 50% decrease between 2000 and 2006, with a significant cause attributed to a well-publicized meta-analysis that had concluded that high-dosage vitamin E increased all-cause mortality. Age-related macular degeneration A Cochrane review published in 2017 on antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration (AMD) identified only one vitamin E clinical trial. That trial compared 500 IU/day of α-tocopherol to placebo for four years and reported no effect on the progression of AMD in people already diagnosed with the condition. Another Cochrane review, same year, same authors, reviewed the literature on α-tocopherol preventing the development of AMD. This review identified four trials, duration 4–10 years, and reported no change to risk of developing AMD. A large clinical trial known as AREDS compared β-carotene (15 mg), vitamin C (500 mg), and α-tocopherol (400 IU) to placebo for up to ten years, with a conclusion that the anti-oxidant combination significantly slowed progression. However, because there was no group in the trial receiving only vitamin E, no conclusions could be drawn as to the contribution of the vitamin to the effect. Complementary and alternative medicine Proponents of megavitamin therapy and orthomolecular medicine advocate natural<unk> s. Meanwhile, clinical trials have largely concentrated on use of either a synthetic, all-racemic d-α-tocopheryl acetate or synthetic dl-α-tocopheryl acetate. Antioxidant theory<unk>  is described as functioning as an antioxidant. A dose-ranging trial was conducted in people with chronic oxidative stress attributed to elevated serum cholesterol. Plasma F2-isoprostane concentration was selected as a biomarker of free radical-mediated lipid peroxidation. Only the two highest doses - 1600 and 3200 IU/day - significantly lowered F2-isoprostane. Alzheimer's disease Alzheimer's disease (AD) and vascular dementia are common causes of decline of brain functions that occur with age. AD is a chronic neurodegenerative disease that worsens over time. The disease process is associated with plaques and tangles in the brain. Vascular dementia may be caused by ischemic or hemorrhagic infarcts affecting multiple brain areas, including the anterior cerebral artery territory, the parietal lobes, or the cingulate gyrus. Both types of dementia may be present. Vitamin E status (and that of other antioxidant nutrients) is conjectured as having a possible impact on risk of Alzheimer's disease and vascular dementia. A review of dietary intake studies reported that higher consumption of vitamin E from foods lowered the risk of developing AD by 24%. A second review examined serum vitamin E levels and reported lower serum vitamin E in AD patients compared to healthy, age-matched people. In 2017 a consensus statement from the British Association for Psychopharmacology included that until further information is available, vitamin E cannot be recommended for treatment or prevention of Alzheimer's disease. Cancer From reviews of observational studies, diets higher in vitamin E content were associated with a lower relative risk of kidney cancer, bladder cancer, and lung cancer When comparisons were made between the lowest and highest groups for dietary vitamin E consumption from food, the average reductions in relative risk were in the range of 16-19%. For all of these reviews, the authors noted that the findings needed to be confirmed by prospective studies. From randomized clinical trials (RCTs) in which α-tocopherol was administered as a dietary supplement, results differed from the dietary intake reviews. A RCT of 400 IU/day of α-tocopherol did not reduce risk of bladder cancer. In male tobacco smokers, 50 mg/day had no impact on developing lung cancer. A review of RCTs for colorectal cancer reported lack of a statistically significant reduction in risk. In male tobacco smokers, 50 mg/day reduced prostate cancer risk by 32%, but in a different trial, majority non-smokers, 400 IU/day increased risk by 17%. In women who consumed either placebo or 600 IU of natural-source vitamin E on alternate days for an average of 10.1 years there were no significant differences for breast cancer, lung cancer, or colon cancer. The U.S. Food and Drug Administration initiated a process of reviewing and approving food and dietary supplement health claims in 1993. A Qualified Health Claim issued in 2012 allows product label claims that vitamin E may reduce risk of renal, bladder, and colorectal cancers, with a stipulation that the label must include a mandatory qualifier sentence: “FDA has concluded that there is very little scientific evidence for this claim.” The European Food Safety Authority (EFSA) reviews proposed health claims for the European Union countries. As of March 2018, EFSA has not evaluated any vitamin E and cancer prevention claims. Cataracts A meta-analysis from 2015 reported that for studies that reported serum<unk> , higher serum concentration was associated with a 23% reduction in relative risk of age-related cataracts (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract - the three major classifications of age-related cataracts. However, this article and a second meta-analysis reporting on clinical trials of α-tocopherol supplementation reported no statistically significant change to risk of ARC when compared to placebo. Cardiovascular diseases Research on the effects of vitamin E on cardiovascular disease has produced conflicting results. An inverse relation has been observed between coronary heart disease and the consumption of foods high in vitamin E, and also higher serum concentration of α-tocopherol. In one of the largest observational studies, almost 90,000 healthy nurses were tracked for eight years. Compared to those in the lowest fifth for reported vitamin E consumption (from food and dietary supplements), those in the highest fifth were at a 34% lower risk of major coronary disease. Diet higher in vitamin E also may be higher in other, unidentified components that promote heart health, or people choosing such diets may be making other healthy lifestyle choices. There is some supporting evidence from randomized clinical trials (RCTs). A meta-analysis on the effects of α-tocopherol supplementation in RCTs on aspects of cardiovascular health reported that when consumed without any other antioxidant nutrient, the relative risk of heart attack was reduced by 18%. The results were not consistent for all of the individual trials incorporated into the meta-analysis. For example, the Physicians' Health Study II did not show any benefit after 400 IU every other day for eight years, for heart attack, stroke, coronary mortality, or all-cause mortality. The effects of vitamin E supplementation on incidence of stroke were summarized in 2011. There were no significant benefits for vitamin E versus placebo for risk of stroke, or for subset analysis for ischaemic stroke, haemorrhagic stroke, fatal stroke, or non-fatal stroke. In 2001 the U.S. Food and Drug Administration rejected proposed health claims for vitamin E and cardiovascular health. The U.S. National Institutes of Health also reviewed the literature and concluded there was not sufficient evidence to support
Tocopherol
Cholic acid
Folate
Lipoic acid
Pyridoxine
Pantothenic acid
Riboflavin
Niacin