Numerous reports have recently appeared in both the lay and medical press questioning the value of vitamin E supplementation and suggesting that there are risks associated with its use even at doses previously thought to have been “safe”. What do we do with the hundreds of studies and extensive clinical research that has been published in the medical literature suggesting benefit in cardiovascular disease, alzheimers, diabetes and other degenerative diseases? A search of the National Library of Medicine yields over 25,000 citations, many funded or sponsored by the National Institutes of Health (NIH) and other prestigious medical and scientific organizations.
This month, the authors of an article in Health News (Health News. 2005 Apr;11(4):12-3) headlined this statement: “High doses of vitamin E may increase risk of death. Talk to your doctor before taking supplements containing more than 200 IUs.” Discussing these questions with your doctor is very important. The purpose of this article is to provide you with a tool, a resource that you can print out and discuss with your physician.
Negative Clinical Studies:
Increased cancer recurrence in patients with head and neck cancer:
Bairati and co-workers (J Natl Cancer Inst. 2005 Apr 6;97(7):481-8.) found in a multicenter, double-blind, placebo-controlled, randomized chemoprevention trial among 540 patients with head and neck cancer treated by radiation therapy that supplementation with alpha-tocopherol (400 IU/day) produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival.
No increase in cancer risk, but increased risk of Heart Failure in patients with established vascular disease or diabetes:
The HOPE Trial Investigators (JAMA. 2005 Mar 16;293(11):1338-47) evaluated whether long-term supplementation with vitamin E (Daily dose of natural source of 400 IU of vitamin E or matching placebo) decreases the risk of cancer, cancer death, and major cardiovascular events. The Hope vitamin E trial was a randomized, double-blind, placebo-controlled international trial of patients at least 55 years old with vascular disease or diabetes mellitus (9541 patients, in 174 centers) with a median duration of follow-up of 7.0 years.
The investigators examined cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death), heart failure, unstable angina, and need for cardiac revascularization.
Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, 11.6% in the vitamin E group vs 12.3% in the placebo group developed cancer (a non-significant reduction for vitamin E); for cancer deaths, 3.3% in the vitamin E group vs 3.7% in placebo (also not significant) and for major cardiovascular events, 21.5% vs 20.6%, respectively (not significant). Of concern, was that patients in the vitamin E group had a significantly higher risk of heart failure and hospitalization for heart failure. The authors concluded that in patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.
Increased all-cause mortality:
A meta-analysis of randomized, 19 controlled clinical trials (135,967 participants) evaluating the dose-response relationship between vitamin E supplementation and total mortality (Ann Intern Med. 2005 Jan 4;142(1):37-46. Epub 2004 Nov 10.)
Published by Miller and associates at the Johns Hopkins School of Medicine, found High-dosage (greater than or equal to 400 IU/d) vitamin E supplements may increase all-cause mortality by 5% and should be avoided.
Neutral Clinical Studies:
Risk of Coronary heart disease (CHD) in Smokers not effected:
The effect of vitamin E on coronary heart disease (CHD) was evaluated in the alpha-tocopherol, beta-carotene cancer prevention (ATBC) study (Eur Heart J. 2004 Jul;25(13):1171-8.). 29,133 male smokers, aged 50-69 years were randomized to receive alpha-tocopherol 50 mg, or beta-carotene 20 mg, or both, or placebo daily for 5-8 years. The risk for a first-ever major coronary event was insignificantly reduced by 5% among alpha-tocopherol recipients compared with non-recipients, and the risk for non-fatal MI was insignificantly reduced by 4%. The authors did not advocate the use of vitamin E supplements due to the weak findings.
Cardiovascular mortality and all cause Mortality not effected:
In a meta analysis of eighty-four trials (J Gen Intern Med. 2004 Apr;19(4):380-9.) examining outcomes of all-cause mortality, cardiovascular mortality, fatal or nonfatal myocardial infarction vitamin E was not found to have neither positive nor adverse effects. Shekelle and colleagues found that the use of vitamin E supplements insignificantly reduced the risk of all cause mortality by 4%, insignificantly reduced cardiovascular mortality by 3% and trended toward but did not achieve a significant reduction in nonfatal myocardial infarction, reducing the latter by 28%.
Positive Clinical Studies:
Reduced Risk of Congestive Heart Failure and Myocardial Infarction
In two large clinical studies conducted by Stampfer et al470 and Rimm et al,471 vitamin E supplements were associated with a reduced risk of congestive heart failure. In an analysis of almost 45,000 men in the Health Professional Follow-up Study database by Ascherio and associates,823 the use of vitamin E, or multi-vitamin supplements, was associated with a significantly decreased risk of myocardial infarction. These results suggest that higher supplemental doses of vitamin E may be beneficial in patients with CAD, especially those on diets high in polyunsaturated fatty acids.
Reduction in Risk for Cardiovascular Disease and Myocardial Infarction (Heart Attack):
The Nurses’ Health Study, a study of 121,700 women between the ages of 34 and 59 which was conducted by Manson and co-workers,69,805 used food frequency questionnaires to demonstrate a relationship between dietary intakes of foods rich in vitamin E and beta carotene, and the reduction in the risk of cardiovascular disease.

A recent analysis of the same data by Stampfer et al470 revealed that the protective effect of vitamin E was attributable to supplemental vitamin E at pharmacological levels exceeding 100 IU per day. Since dietary intakes of alpha tocopherol in the United States typically range from 4 to 16 IU per day, the former level of intake would be extremely difficult to achieve from diet alone.804 Those women who took 100 mg. vitamin E supplements (in addition to 15mg of beta carotene daily) experienced a 36% reduction in myocardial infarction, and women with the highest dietary vitamin E intake, and who consumed vitamin E supplements daily for two years, had a 41% reduction in risk (multivariant risk 0.59).
The Health Professionals Follow-up Study,471 involving 51,529 male health professionals, demonstrated similar cardiovascular benefits of a diet rich in antioxidants. As in the Nurses’ Health Study, these male participants’ antioxidant vitamin intake was assessed by a dietary questionnaire, and coronary heart disease was assessed by medical record review. After controlling for age and coronary risk factors, higher dietary vitamin E intake levels were associated with a significantly lower risk for CAD. For men consuming more than 60 IU (an amount usually requiring vitamin supplementation), the risk of myocardial infarction or cardiac death was 36% less (multivariant risk 0.64) than in those men consuming 7.5 I.U. per day. CAD risk was lowest for the men with the highest dietary vitamin E intake who additionally took at least 100 IU of vitamin E supplements daily for two years.
Low serum Vitamin E may be a greater risk factor for myocardial infarction than either high blood pressure or elevated serum cholesterol alone, according to research sponsored by the World Health Organization, and reported by Gey et al67 in the Multinational Monitoring Project of Trends and Determinants of Cardiovascular Disease (MONICA) study. In the MONICA study, Gey and co-workers67 compared plasma antioxidant levels among 16 different groups of 100 men each from regions with a six-fold difference in CAD mortality and reported a strong inverse correlation (p=0.002) between plasma vitamin E and mortality from ischemic heart disease which was independent of lipid levels.
This inverse relationship for CAD mortality was strongest for vitamin E. Low serum vitamin E alone was an accurate predictor for fatal myocardial infarction in 60% of cases studied. Death from Acute Myocardial Infarction was accurately predicted in 80% of patients with both low serum vitamin E and elevated serum cholesterol; and fatal outcomes were accurately predicted in 90% of patients with low serum levels of both vitamin E and A in conjunction with high serum cholesterol, and elevated blood pressure. These findings were consistent with earlier scholarship published by Gey.580
Restenosis:
Cavarocchi and associates681 found that pretreatment of coronary bypass patients with 2,000 IU of vitamin E significantly inhibited the generation of destructive oxygen free radicals during surgery, and DeMaio and co-workers583 found that vitamin E supplementation reduced the incidence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA).
Angina:
Rimersma and co-workers469,643 found an inverse relationship between the risk of angina pectoris and vitamin E levels. Individuals with serum vitamin E levels in the lowest quintile (28.2 µM/L). Similarly, Byers870 reported that an increased dietary intake of vitamin E reduced death from myocardial infarction.
CAD:
A prospective study of antioxidant vitamins and the incidence of CAD in women, which was conducted by Manson et al,805 used food frequency questionnaires to estimate dietary intake of vitamin E, and found that the incidence of CAD was lowest among women with the highest intake of alpha tocopherol.
Reduced Risk of Cancer:
An inverse relationship between serum vitamin E levels and cancer has been found in seven epidemiologic studies,580,669,670,679,685,686,687 and vitamin E supplementation has been shown to suppress indexes of lipid peroxidation in the blood of both smokers and non-smokers, without effecting plasma lipoprotein concentrations.899 Because low density lipoprotein is one of the main transports for vitamin E and cholesterol in the blood stream, pharmacologic and certain dietary interventions resulting in reductions in LDL and serum cholesterol may reduce serum vitamin E in individuals whose diets are not supplemented.488,490 Hypolipidemic drug therapy may act as a vitamin E antagonist and reduce serum vitamin E.844
ALS:
Regular use of vitamin E supplements was associated with up to a 62% lower risk of dying of ALS in a study of 957,740 individuals 30 years of age or older participating in the American Cancer Society’s Cancer Prevention Study II. (Ann Neurol. 2005 Jan;57(1):104-10.)
The Balanced Approach:
Perhaps a reasonable approach would be a three-tiered effort:

To moderately increase vitamin E levels with healthy dietary sources of the vitamin (which may allow for an equivalent level of 15-45 IUs per day from optimizing diet)
The addition of MODERATE levels of supplementation with NATURAL (d-isomer) mixed tocopherols (which are closer to the mix seen in diet) and
Use of minimum levels of vitamin E that have shown beneficial effect (100 IU or greater) and not exceeding levels which have been associated with risk (greater than 400 IU) and certainly not greater than 1,600 IUs where increased risk seems to be more clearly defined in some studies.

This is in line with recent recommendations made this month by Hancock and co-workers who analyzed a large database of numerous clinical studies, (Am J Clin Nutr. 2005 Apr;81(4):736-45) and writing for the Council for Responsible Nutrition (CRN) in Washington, DC declared:
“… dietary supplements of vitamins E and C are safe for the general population…. Many clinical trials with these vitamins have involved subjects with various diseases, and no consistent pattern of adverse effects has occurred at any intake… Thus, we conclude from clinical trial evidence that vitamin E supplements appear safe for most adults in amounts less than or equal to 1,600 IU ….” Additionally, this is in agreement with recommendations of Denton Harmon, M.D. Ph.D., the father of the Free-Radical Theory of Aging (D. Harmon, J. Gerontol. 11, 298-300 (1956).) who recommends 400 IU of vitamin E daily (Life Extension Magazine, Interview, January 1998).
DISCUSSION: What is Vitamin E?
Vitamin E is a fat-soluble antioxidant vitamin that is involved in the metabolism of all cells. Vitamin E protects vitamin A and essential fatty acids from oxidation in the body cells and prevents breakdown of body tissues. Vitamin E is widely accepted to be the primary physiological antioxidant in man. 472,488,844,845,846

Vitamin E exists in eight different forms, each with its own biological activity and functional use in the body(Traber MG and Packer L. Vitamin E: Beyond antioxidant function. Am J Clin Nutr 1995;62:1501S-9S). Alpha-tocopherol is the name of the most active form of vitamin E in humans. It is also a powerful biological antioxidant (Traber MG. Vitamin E. In: Shils ME, Olson JA, Shike M, Ross AC, ed. Modern Nutrition in Health and Disease. 10th ed. Baltimore: Williams & Wilkins, 1999:347-62). Vitamin E in supplements is usually sold as alpha-tocopheryl acetate, a form that protects its ability to function as an antioxidant. The synthetic form is labeled “D, L” while the natural form is labeled “D”. The synthetic form is only half as active as the natural form (U.S. Department of Agriculture, Agricultural Research Service. 2004. USDA National Nutrient Database for Standard Reference, Release 16-1).

Epidemiology Regarding Vitamin E:
Pacht and colleagues498 found deficient levels of vitamin E in chronic cigarette smokers. Similarly, Riemersma and associates469 found low vitamin E levels among angina patients who were smokers, and Brown et al899 found that smokers sustained an increased free radical load (characterized by increased indices of lipid peroxidation) because of their exposure to large quantities of reactive free radicals in the gas and tar phases of cigarette smoke. The researchers determined that this increased lipid peroxidation was reduced in vitro following vitamin E supplementation. These findings are in accordance with other clinical research which suggests that smoking reduces plasma vitamin E levels, and increases oxidative stress. 590,591

Excessive alcohol consumption may have an adverse effect on serum antioxidant levels which is independent of nutritional status. Excessive consumption of alcohol has been associated with low serum vitamin E levels,499,889 malondialdehyde (MDA) markers of oxidative stress and free radical activity.889 Numerous studies have shown that alcoholics have lower serum beta carotene,901 alpha tocopherol,889 selenium,889 and ascorbic acid889 concentrations than control subjects who drink moderately.

Supporting the hypothesis that heme iron acts as a pro-oxidant in vivo, and validating previous clinical research, Ascherio et al823 found that a high intake of antioxidant vitamin E may prevent the adverse cardiovascular effects of excess heme iron consumption,830,831,832,833 and concluded that oxidative stress resulting from smoking837 and hyperglycemia associated with diabetes834,835,836 may enhance it.

Nutritional recommendations:
According to many nutritionists who have evaluated this data, 150 to 200 IUs a day is probably beneficial and safe for most individuals wanting to supplement their diet. That is more than three times what people can get from a healthy diet (good sources include: nuts, cooking oil, sweet potatoes, mayonnaise, wheat-germ oil, fish, eggs, fortified cereals) and low-dose multivitamins. Almonds may help to increase vitamin E in the blood and reduce lipid levels (J Am Diet Assoc. 2005 Mar;105(3):449-54). Kiwi fruit contain high amounts of vitamin E and may be cardioprotective (Platelets. 2004 Aug;15(5):287-92).

Good Sources of Vitamin E

Food Serving Size Milligrams % RDA

Egg, whole, fresh 1 large 0.88 5.8

Almond oil 1 tablespoon 5.3 35.3

Corn oil 1 tablespoon 1.9 12.6

Corn oil (Mazola) 1 tablespoon 3 5

Cottonseed oil 1 tablespoon 4.8 32

Olive oil 1 tablespoon 1.6 10.6

Palm oil 1 tablespoon 2.6 17.3

Peanut oil 1 tablespoon 1.6 10.6

Safflower oil 1 tablespoon 4.6 30.6

Soybean oil 1 tablespoon 1.5 10

Sunflower oil 1 tablespoon 6.1 40.6

Vegetable-oil spray 2.5 second spray 0.51 3.4

Wheat-germ oil 1 tablespoon 20.3 135.3

Tomato juice 6 fluid ounces 0.4 2.6

Apple with skin 1 medium 0.81 5.4

Mango, raw 1 medium 2.32 15.4

Macaroni pasta, enriched 1 cup 1.03 6.8

Spaghetti pasta, enriched 1 cup 1.03 6.8

Almonds, dried 1 ounce 6.72 44.8

Hazelnuts, dried 1 ounce 6.7 44.6

Peanut butter (Skippy) 1 tablespoon 3 5

Peanuts, dried 1 ounce 2.56 17

Pistachio nuts, dried 1 ounce 1.46 9.7

Walnuts, English 1 ounce 0.73 4.8

Margarine (Mazola) 1 tablespoon 8 53.3

Margarine (Parkay, diet) 1 tablespoon 0.4 2.6

Mayonnaise (Hellmann’s) 1 tablespoon 11 73.3

Miracle Whip (Kraft) 1 tablespoon 0.5 3.3

Avocado, raw 1 medium 2.32 15.4

Asparagus, frozen 4 spears 1.15 7.6

Spinach, raw 1/2 cup 0.53 3.5

Sweet potato 1 medium 5.93 39.5

Tomato, red, raw 1 tomato 0.42 2.8

Turnip greens, raw 1/2 cup chopped 0.63 4.2
Source: Ohio State University Extension Fact Sheet
Web MD Interview of Dr. Petrosino Regarding Vitamin E (Sept. 26, 2000)
Vitamin E safety is posted in its entirety (with annotated footnotes) on http://www.nutritionadvisor.com
Other Reviews on nutritional Supplements by Dr. Petrosino