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

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.

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

  1. Neil 21 April 2008 at 8:39 am #

    Meta Analysis = Making a strong chain by combining weak links.

    quoted from Prof John Brignell


  2. Jenny Ruhl 21 April 2008 at 11:06 am #

    There is another possibility which is worth considering, and it is that because supplements are full of vitamins etc that come from poorly regulated Chinese factories they may be contaminated with toxins from polluted Chinese water and with industrial chemicals used in the manufacturing process.

    Over the decades I’ve been observing health, I’ve noticed a very high incidence of cancer among the people in my community who are most vocal advocates of herbs and supplements.

    Given how often lab analysis in the U.S. finds that the capsules don’t contain what they say they do, but instead contain lead and other contaminants, it is quite possible this is true.

    Getting nutrients from food (locally grown if possible) is far safer.

  3. Dr John Briffa 21 April 2008 at 12:02 pm #

    I’m not sure about this, and not just because your observation re cancer rates in proponents of herb/supplements is anecdotal: the supplements used in these sorts of studies tend to be ‘high-quality’ and ‘pharmaceutical grade’ i.e. it’s unlikely that they’ll have any old ingredients and contaminants in them.

  4. Terry 25 April 2008 at 8:03 am #

    Thanks for taking the time to expose this charlatan study for what it is – a shameless piece of medical establishment propaganda.

  5. Leigh Turner 25 April 2008 at 8:21 am #

    I am a nutritional therapy student and wonder where are our professionals when it comes to standing up and being counted. CAM is constantly attacked and yes we survive it and always will because it works, whether we can explain it or not. However, there is evidence out there to support the use of vitamins and to disclaim the findings of the most recent attack, so why is our counter-claim not being brought to public awareness in a similar way. I just find it odd that no one is prepared to even plant the seeds of doubt for a lot of frightened public. Dont ya just wanna?

  6. Peter Killingback 25 April 2008 at 8:25 am #

    What concerns me is that with the high profile that this study has gained, it will be used by the Government as support for the European Union moves to outlaw ANY higher dose (whatever that means) supplements. It is well known that the pharmaceutical industry wants to eliminate the massive range of supplements available – their markets for very expensive, and often with obscured visibility of untoward side effects, are being challenged. Wouldn’t it be interesting to know what organisations financed this work?

  7. Liz 25 April 2008 at 8:48 am #

    This meta analysis seems to be a case of making a complex topic simple for the sake of headlines (which I suppose I am doing also in this post!).

    I teach my students that all antioxidants work together ” stuffing someone full of vitamins E without ensuring they have enough selenium or glutathione, for example, is not science, although “good science” tells us we can only test one variable at a time.

    The comment about forms of beta-carotene is also most apt. For example I also tell my students that 17-β-oestradiol is much more oestrogenic than 17-α-oestradiol – the only difference between them is a slight change in orientation of one hydroxyl group but the body responds very differently. So it would be important to test the biological molecules in the right proportions and not synthetic products.

    Nice comment from Neil!

  8. Ann Eastman 25 April 2008 at 9:42 am #

    Could you publish a check-list of the vitamin and mineral names that one should be looking for on labels to ensure that ingredients are derived from natural sources? That would be extremely helpful. The labels are a minefield – even for people like me who are not horteculturally challenged!

    Incidentally, my family and I have been taking vitamin C ever since reading the Linus Pauling studies – about 35 years . Despite all the negative comments from experts saying it does not work to prevent and abort colds and flu; it DEFINIETELY DOES! However, it is effective only but if derived from fruit and vegetable sources — especially acerola cherries.

  9. Jenny Ruhl 25 April 2008 at 12:02 pm #

    Dr. Briffa,

    Some of the studies provide the supplements, but quite a few others I have seen are retrospective studies where the subjects report on their level of intake of supplements they purchased on their own.

    The other issue which needs to be considered is when a supplement in food is a different isomer from the one supplemented–which is common, or when it is part of a family of related molecules where supplementing with only one suppresses the uptake of others.

    It is my understanding that supplementing with gamma tocopherol, for example (Vitamin E) suppresses the uptake of alpha tocopherol.

    Dr. Davis of the Heart Scan Blog has pointed out that supplementing calcium without adequate vitamin D appears to cause calcium plaque to form in the arteries, but this is speculation. We only know that the calcium supplementation pushed on women for the past decades is giving them higher levels of calcium plaque, probably because the calcium is part of a more complex system.

    The complexity of how nutrients interact and the poor quality of most nutritional studies (many of which are not reproducible) suggests to me that we all do better getting “supplementation” from the food sources our bodies evolved to use.

  10. Sally 25 April 2008 at 7:09 pm #

    I share Peter’s concerns and suspect that we’ll be seeing more such reports in order to prime the general public to accept the new EU directives without challenge. For further details on this, please see the Alliance for Natural Health website: http://www.alliance-natural-health.org/.

  11. Dr Andrew Morrice 25 April 2008 at 8:38 pm #

    Very very interesting stuff.

    It appears that the same tactics are being used against nutritional approaches as we are currently experiencing in the onslaught on homeopathy.

    In the case of the homeopathy, a very shady “meta-analysis” by Shand et al instigated an ongoing and still accelerating attack on homeopathy and CAM in general. The meta-analysis as originally designed showed homeopathy and conventional medicine working equally well. But then the authors went on to re-analyse a subset of data (they didn’t even say which trials they used!) to show that homeopathy is “no better than placebo”. Now they are calling for the closure of all NHS homeopathy services. Yes, indeed, there is a pattern here!

    Be prepared for an escalating rhetoric portraying nutritional therapy as useless, harmful and the province of quacks and cranks. Studies such as the one John analyses here will be continually reported as “showing that antioxidant supplements are harmful”. The aim will be to make them unavailable to buy.

    The advantage that nutritional therapy has is that it has more plausibility within the bio-chemical paradigm – the bile and venom directed against homeopathy has to be experienced to be beleived.

    Get your rebuttals out early, clearly and repeatedly is my advice.

  12. Maria 29 April 2008 at 4:40 pm #

    Dear John
    I would like to comment on Patrick Holford who seems to be the voice of Nutritional Therapists. I didn’t have any feelings for or against Holford until I heard him deliver the argument against this study on BBC Five Live. His lack of a well thought out argument made him appear unable to critically evaluate this piece of research. This inability enabled Bjelakovic to showcase his academic superiority. It was extremely embarrassing and I wish the BBC researchers would trawl around to find more academically savvy representatives for our profession.

    I appreciate your clarification on the subject and wish that you had had the opportunity to confront Bjelakovic while millions were listening.


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