The Antioxidant Sky Is Not Falling
6 March 2007
by Peter C. Everett, M.D.
Between February 28 and March 1, 2007, nearly every major news outlet in
the English-speaking world presented an alarmist headline on the safety
of antioxidant vitamins. "Antioxidants Don't Help You Live Longer" was
the FOX News headline for an AP story that began, "Antioxidant vitamins
taken by tens of millions of people around the world won't lead to a longer
Even more arresting, "Vitamins 'could shorten lifespan'," wrote
the BBC. The source was the March 1 issue of JAMA which presented a combined
analysis of a large number of clinical trials of antioxidant vitamins that
calls into question the safety and benefit of supplements broadly categorized
The meta-analysis behind the headlines, authored by Bjelakovic et al. raises
some important issues about the safety and efficacy of vitamins. But it
is vitally important to understand what the study does and does not say,
and more generally to recognize how the impulse by the news media to sensationalize
a story resulted in delivering the wrong message to millions of people.
The review of the literature asked the simple question, "Does antioxidant
supplementation impact mortality, and if so, how?"
"Antioxidant supplementation" was broadly defined and included
vitamins A, C, E, beta-carotene and the mineral selenium alone or in any
of many combinations. The analysis identified 815 trials involving antioxidant
supplementation, but included only 68 of them.
Most of the excluded trials were eliminated from analysis because nobody
died in either the treatment or control groups, and thus could not contribute
to the specific question of mortality. Most of the rest were excluded for
methodological reasons. Therefore, the analysis represented only a tiny
subset of the overall clinical trial experience with antioxidant supplementation.
Aggregate analysis of the 68 included trials showed no significant harm
or benefit, but when analyzed for protection from bias, the 47 trials identified
as having a low risk of bias showed a small but statistically significant
increase (about 5 percent) in mortality among groups treated with antioxidants.
The study did not attempt to investigate the causes of death. When subgroups
were analyzed, it appeared that the risk of death was mostly associated
with high doses of vitamins A, E, or beta-carotene, while vitamin C had
no effect and selenium appeared to be beneficial.
These arcane methodological details are crucial for understanding how very
narrow these results are, and how non-representative they are of the way
supplements are typically used.
The first thing to realize about the limitations of this analysis, is that
it does not address the long-term use of balanced multivitamin combinations
by essentially healthy, young or middle-aged people who are hoping to avoid
age-related diseases. Of the 47 "low bias risk" trials from which
the study's main conclusions were drawn, 70% of them were "secondary
That means that they involved mostly elderly people in whom a lifetime
of oxidative and other degenerative processes had already resulted in disease,
and the trial investigated whether a short course of antioxidants, averaging
less than three years, could slow, stop, or prevent recurrence of their
While it would be nice if a short course of vitamins for less than 3 years
could stop or reverse a lifetime of degeneration, this in no way resembles
the rationale for taking vitamins by the vast majority of people. Most people
die from heart disease or cancer , whose latency periods are a decade
The second limitation has to do with the study's overly broad definition
of what constitutes an "antioxidant" regimen, and the inclusion
of combinations that are likely to be pro-oxidant. Different antioxidants
work in different parts of the body, and work with each other to remove
radicals from where they can cause harm.
In general terms, the fat-soluble antioxidants (A & E), gather free
radicals from the cellular membranes. In doing so, they become potentially
harmful radical molecules themselves.
The water-soluble antioxidants, like vitamin C, gather free radicals in
the watery environment within and between cells. They also regenerate oxidized
vitamins A and E in the membranes so that they can go back and continue
to protect the cellular membrane and its protein machinery.
It has been known for years now that high doses of vitamin E and beta-carotene
when taken alone can be harmful [2, 3, 5], and it is easy to see how by
imagining a bucket brigade. Imagine a flood in your bathroom. You set up
a bucket brigade, with someone in the bathroom handing buckets to someone
in the living room, who then throws the water safely out the front door.
Similarly, the fat-soluble antioxidants can hand radicals to the water-soluble
antioxidants. If you add workers to the bathroom, incoming buckets will
overwhelm the person in the living room, and the living room, where the
furnishings are far less water-resistant, will flood.
Since it is the protein machinery of the cellular membrane that is most
in need of protection, a relative excess of fat-soluble antioxidants can
accumulate radicals in the membrane if they are unable to pass their radicals
to the water-soluble antioxidants.
Bjelakovic et al. acknowledge this type of potential problem with their
study noting, "We have compared antioxidants with different properties,
given at different doses and duration, singly or combined. We are aware
of the potential risks in assessing the effects of different types of antioxidants...
It has been suggested that antioxidant supplements may show interdependency
and may have effects only if given in combination."
The third limitation is that this study says nothing about food sources
of antioxidant vitamins, and does nothing to refute the abundant epidemiologic
evidence that consumption of antioxidant rich foods are associated with
improved health, including a lower incidence of cardiovascular disease,
neurodegenerative disease, and several major cancers.
The reasons why the data for individual supplements do not appear to agree
with the data for foods are not known, but one suspected reason is that
foods naturally contain balanced combinations of antioxidants that work
together, avoiding the problems of relative excess.
Indeed, even in the Finnish trial, which showed more lung cancer in asbestos-exposed
heavy smokers who took vitamin E and beta-carotene, the participants in
the placebo group with the highest blood levels of these vitamins from their
diets had the lowest incidence of lung cancer.
Despite these limitations, there is useful information to be gained from
this study. We now have more evidence that high dose supplementation of
vitamins A, E and beta-carotene from non-food sources should probably be
avoided in the absence of a condition-specific indication for them, where
high-dose is approximately 400IU of vitamin E, 20mg of beta-carotene, or
15,000IU of vitamin A.
Those who wish to supplement with antioxidants because they are either
not able or not inclined to consume enough antioxidant-rich foods would
be wise to purchase combinations that do a reasonable job of approximating
the mixture found in an antioxidant-rich diet, for which there is a wealth
of evidence of benefit, and avoid single-substance formulations, with the
possible exceptions of vitamin C and selenium.
About the author:
Peter C. Everett, M.D. is a resident in internal
medicine with a longstanding interest in dietary supplements
and health optimization. Prior to his medical training, he participated
in the successful effort to pass the Dietary Supplement Health
and Education Act of 1994. Subsequently he assisted in the founding
of the Dietary Supplement Quality Initiative. His research interests
include the anti-cancer potential of curcumin.
1. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality
in Randomized Trials of Antioxidant Supplements for Primary and
Secondary Prevention: Systematic Review and Meta-analysis. JAMA.
2007 Feb 28;297(8):842-57.
2. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar
high-dosage vitamin E supplementation may increase all-cause mortality.
Ann Intern Med. 2005 Jan 4; 142(1): 37-46.
3. Omenn GS, Goodman
GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens
FL, Valanis B, Williams JH, Barnhart S, Hammar S. Effects
of a combination of beta carotene and vitamin A on lung cancer
and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1150-5.
4. Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL Jr, Omenn
GS, Valanis B, Williams JH Jr. The
Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular
disease mortality during 6-year follow-up after stopping beta-carotene and
retinol supplements. J Natl Cancer
Inst. 2004 Dec 1;96(23):1743-50.
5. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The
effect of vitamin E and beta carotene on the incidence of lung
cancer and other cancers in male smokers. (1994) N.
Engl. J. Med. 330, 1029–1035.
6. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ,
Albanes D, Taylor PR, Albert P; ATBC Study Group. Incidence
of cancer and mortality following alpha-tocopherol and beta-carotene
supplementation: a postintervention follow-up. JAMA. 2003
7. Sies H, Stahl W, Sundquist AR. Antioxidant
functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. Ann
N Y Acad Sci. 1992 Sep
8. Center for Disease Control, National Center for Health Statistics, NCHC
- FASTSTATS - Leading Causes of Death.
Referenced on March 2, 2007.