What are we to make of the recent warnings about antioxidant supplements?

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Last week’s big ‘nutritional news’ was that taking certain nutritional supplements increases risk of death. Apparently. News headlines throughout the UK were awash with the reports of a study which found that the taking of ‘antioxidant’ nutrients (namely beta-carotene, vitamin A and vitamin E) in supplement form is associated with a statistically significant increase in risk of dying [1]. The increased risk for vitamin A, beta-carotene and vitamin E was found to be 16, 7 and 4 per cent respectively. I suppose it comes as no surprise that I’ve had a number for emails from ‘concerned’ readers who want my take on this research. So here it is:

The study in question was what is called a ‘meta-analysis’, where similar studies are lumped together and analysed in an effort to assess the broad effects of a treatment. 67 studies were used in the original analysis. These trials were ‘randomised’ trials, in which individuals were allocated (randomly, of course) to receive either the nutritional supplement or placebo. These studies were designed to be ‘double-blind’, which means efforts were made to ensure that neither the study participants nor the investigators knew who was taking what until the end of the study.

When all relevant studies were included in the analysis, neither vitamin A, beta-carotene nor vitamin E were associated with either an increased or decreased risk of death. Plus, studies involving selenium showed that taking this nutrient was associated with a 10 per cent reduced risk of death.

Not content with leaving it there, however, the authors of this study went on to do some further analysis of the data. Specifically, they culled about a third of the studies if there was evidence of ‘bias’. For example, if there was evidence that the double-blind nature of the study was compromised, it was excluded.

It was on the basis of this more focused analysis that the results showing increased mortality came to the fore.

I can understand the authors of this study wanted to use the very best ‘methodology’ to assess the available data. However, it needs to be borne in mind the 67 studies analysed by the authors represented only a small part of several hundred studies available for analysis. It turns out that many studies were not deemed suitable for inclusion in the meta-analysis because no-one died during the course of the study. I can see no good reason to exclude such studies. One thing is for sure: their presence in the overall analysis would have diluted its ‘negative’ findings, and may have negated them altogether. It seems that while the authors of this review were concerned about ‘bias’ regarding the methodology of the studies they analysed, their methodology for picking studies was somewhat biased from the start.

Another thing to bear in mind is that the studies analysed in this review were of relatively high doses of nutrients, and in the main, far higher than the sorts of dosages found, say, in a multivitamin and mineral preparation.

Another potential deficiency of this analysis is that it focused on studies in which nutrients had been used in their ‘synthetic’ form ” i.e. a form not found naturally in food and some supplements. Using beta-carotene as an example, we know that the synthetic form of this nutrient consists of only one type of molecule, known as ‘all trans beta-carotene’. On the other hand, natural beta-carotene (found in food) is made of a mix of two molecules”‘all trans beta-carotene’ and ‘9-cis beta-carotene’. These differences may have important implications for health: Studies in animals [2] and humans [3] have shown that the natural form of beta-carotene has antioxidant activity that the synthetic form does not. Also, one trial found that natural beta-carotene caused precancerous lesions in the stomach to revert to normal, while synthetic beta-carotene did not [4].

Another deficiency of the analysis is that it included a bit of a hotchpotch of studies. Ideally, meta-analyses should include studies that have, say, similar ‘protocol’ such as duration of treatment and treatment dosage. However, the studies included were widely different in terms of these things. For example, vitamin E dosages ranged from between 10 and 5000 international units (that’s a 500-fold difference), and study periods ranged from four weeks to 14 years.

No piece of science is perfect, but some research is more perfect than others. My opinion is this review’s weaknesses and limitations mean that it’s hard to draw any conclusions from it. The ‘selective’ approach to selecting studies, the very variable ‘protocols’ of the studies, and the fact that the focus was on high doses of ‘synthetic’ nutrients, means that this review has little or no relevance to individuals taking, say, a multivitamin and mineral each day as ‘nutritional insurance’.

This is not the first time this group of authors have produced work of dubious relevant. Actually, just last year they published an almost identical review in the Journal of the American Medical Association. It seems, actually, that their latest meta-analysis is basically a re-hash of their earlier work.

This group is also responsible for a similar study published in the Lancet in 2004 [5]. This review analysed data from 14 separate studies, and assessed the relationship between antioxidant supplementation and cancer in the gut. Here again, the conclusion was that nutrients have the capacity to enhance risk of death. Yet, an editorial that accompanied this review concluded that, for a variety of reasons including inappropriate statistical analysis, it provided no convincing evidence of hazard (for more on this issue, click here). Is it me, or is there a pattern developing here?


1. Bjelakovic G, et al. Antioxidant supplements for the prevention of mortality in healthy participants and patients with various disease (Review). The Cochrane Library 2008 Issue 2.

2. Bitterman N, et al. Beta-carotene and CNS oxygen toxicity in rats. J Appl Physiol 1994;76:1073″6.

3. Ben-Amotz A, et al. Bioavailability of a natural isomer mixture compared with synthetic all-trans beta-carotene in human serum. Am J Clin Nutr 1996;63:729″34.

4. Yeum KJ, et al. Beta-carotene intervention trial in premalignant gastric lesions. J Am Coll Nutr 1995;14:536.

5. Bjelakovic G, et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004;364(9441):1219-28.

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