Antioxidants: In Depth

Several decades of dietary research findings suggested that consuming greater amounts of antioxidant-rich foods might help to protect against diseases. Because of these results, there has been a lot of research on antioxidant supplements. Rigorous trials of antioxidant supplements in large numbers of people have not found that high doses of antioxidant supplements prevent disease. This section describes the preliminary research findings, the results of the clinical trials, and possible explanations for the differences in study results.

Observational and Laboratory Studies

Observational studies on the typical eating habits, lifestyles, and health histories of large groups of people have shown that those who ate more vegetables and fruits had lower risks of several diseases, including cardiovascular disease, stroke, cancer, and cataracts. Observational studies can provide ideas about possible relationships between dietary or lifestyle factors and disease risk, but they cannot show that one factor causes another because they cannot account for other factors that may be involved. For example, people who eat more antioxidant-rich foods might also be more likely to exercise and less likely to smoke. It may be that these factors, rather than antioxidants, account for their lower disease risk.

Researchers have also studied antioxidants in laboratory experiments. These experiments showed that antioxidants interacted with free radicals and stabilized them, thus preventing the free radicals from causing cell damage.

Clinical Trials of Antioxidants

Because the results of such research seemed very promising, large, long-term studies—many of which were funded by the National Institutes of Health (NIH)—were conducted to test whether antioxidant supplements, when taken for periods of at least a few years, could help prevent diseases such as cardiovascular diseases and cancer in people. In these studies, volunteers were randomly assigned to take either an antioxidant or a placebo (an identical-looking product that did not contain the antioxidant). The research was conducted in a double-blind manner (neither the study participants nor the investigators knew which product was being taken). Studies of this type—called clinical trials—are designed to provide clear answers to specific questions about how a substance affects people’s health.

Among the earliest of these studies were three large NIH-sponsored trials of high-dose supplements of beta-carotene, alone or in combination with other nutrients. These trials, completed in the mid-1990s, all showed that beta-carotene did not protect against cancer or cardiovascular disease. In one trial, beta-carotene supplements increased the risk of lung cancer in smokers, and in another trial, supplements containing both beta-carotene and vitamin A had the same effect.

More recent studies have also found that in most instances antioxidant supplements did not help to prevent disease. For example:

  • The Women’s Health Study, which included almost 40,000 healthy women at least 45 years of age, found that vitamin E supplements did not reduce the risk of heart attack, stroke, cancer, age-related macular degeneration, or cataracts. Although vitamin E supplements were associated with fewer deaths from cardiovascular causes, they did not reduce the overall death rate of study participants.
  • The Women’s Antioxidant Cardiovascular Study found no beneficial effects of vitamin C, vitamin E, or beta-carotene supplements on cardiovascular events (heart attack, stroke, or death from cardiovascular diseases) or the likelihood of developing diabetes or cancer in more than 8,000 female health professionals, aged 40 years or older, who were at high risk for cardiovascular disease. Antioxidant supplements also did not slow changes in cognitive function among women in this study who were aged 65 or older.
  • The Physicians’ Health Study II, which included more than 14,000 male physicians aged 50 or older, found that neither vitamin E nor vitamin C supplements reduced the risk of major cardiovascular events (heart attack, stroke, or death from cardiovascular disease), cancer, or cataracts. In fact, vitamin E supplements were associated with an increased risk of hemorrhagic stroke in this study.
  • The Selenium and Vitamin E Cancer Prevention Trial (SELECT)—a study of more than 35,000 men aged 50 or older—found that selenium and vitamin E supplements, taken alone or together, did not prevent prostate cancer. A 2011 updated analysis from this trial, based on a longer followup period of study participants, concluded that vitamin E supplements increased the occurrence of prostate cancer by 17 percent in men who received the vitamin E supplement alone compared with those who received placebo. There was no increase in prostate cancer when vitamin E and selenium were taken together.

Unlike the studies described above, the Age-Related Eye Disease Study (AREDS), led by the National Eye Institute and cosponsored by other components of NIH, including NCCIH, found a beneficial effect of antioxidant supplements. This study showed that a combination of antioxidants (vitamin C, vitamin E, and beta-carotene) and zinc reduced the risk of developing the advanced stage of age-related macular degeneration by 25 percent in people who had the intermediate stage of this disease or who had the advanced stage in only one eye. Antioxidant supplements used alone reduced the risk by about 17 percent. In the same study, however, antioxidants did not help to prevent cataracts or slow their progression.

  • A followup study, AREDS2, found that adding omega-3 fatty acids (fish oil) to the combination of supplements did not improve its effectiveness. However, adding lutein and zeaxanthin (two carotenoids found in the eye) improved the supplement’s effectiveness in people who were not taking beta-carotene and those who consumed only small amounts of lutein and zeaxanthin in foods.

Why Don’t Antioxidant Supplements Work?

Most clinical studies of antioxidant supplements have not found them to provide substantial health benefits. Researchers have suggested several reasons for this, including the following:

  • The beneficial health effects of a diet high in vegetables and fruits or other antioxidant-rich foods may actually be caused by other substances present in the same foods, other dietary factors, or other lifestyle choices rather than antioxidants.
  • The effects of the large doses of antioxidants used in supplementation studies may be different from those of the smaller amounts of antioxidants consumed in foods.
  • Differences in the chemical composition of antioxidants in foods versus those in supplements may influence their effects. For example, eight chemical forms of vitamin E are present in foods. Vitamin E supplements, on the other hand, typically include only one of these forms—alpha-tocopherol. Alpha-tocopherol also has been used in almost all research studies on vitamin E.
  • For some diseases, specific antioxidants might be more effective than the ones that have been tested. For example, to prevent eye diseases, antioxidants that are present in the eye, such as lutein, might be more beneficial than those that are not found in the eye, such as beta-carotene.
  • The relationship between free radicals and health may be more complex than has previously been thought. Under some circumstances, free radicals actually may be beneficial rather than harmful, and removing them may be undesirable.
  • The antioxidant supplements may not have been given for a long enough time to prevent chronic diseases, such as cardiovascular diseases or cancer, which develop over decades.
  • The participants in the clinical trials discussed above were either members of the general population or people who were at high risk for particular diseases. They were not necessarily under increased oxidative stress. Antioxidants might help to prevent diseases in people who are under increased oxidative stress even if they don’t prevent them in other people.

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