One of the recurrent themes of science-based medicine is that any medical intervention that can plausibly cause physiological benefit can also plausibly cause physiological harm.  There is no such thing as “it can’t hurt.” Sometimes the risk may be minuscule – but we should never assume that it is zero. Being “natural” or “holistic” or being blessed with some other alleged marketable virtue does not affect the risk vs benefit calculation of an intervention.

Vitamins are an excellent example. There is widespread sentiment that vitamins are harmless, and that supplementing with vitamins is therefore a no risk-possible benefit scenario. It is certainly reasonable to conclude from the evidence that vitamins (at usual supplemental levels) are low risk, compared to many other types of medical interventions. High doses, or megadoses, of vitamins, however, risk toxicity and this risk increases with the dose.

But even at sub-toxic doses vitamins should not be assumed to be risk free. This is especially true when we take a public health perspective – what is the net effect of large scale supplementation on the population? A new meta-analysis looking at the net effects of Vitamin E supplementation on stroke risk reinforces this caution.

Vitamin E has received a lot of attention recently because of its antioxidant effects. Oxidative stress plays a role in tissue damage, aging, and various disease processes, and so supplementing with anti-oxidants seems like an obvious treatment to mitigate this damage. However, biology is complex, and oxygen free radicals also play a role in cell signaling, for example, so that exogenously suppressing them may have negative unintended consequences.

For example, the emerging research regarding Vitamin E and heart disease is mixed and complex. Vitamin E supplements actually seem to increase total mortality and heart failure. However, observational studies show a decreased risk of cardiac disease in those who take Vitamin E. The difference may be that foods rich in Vitamin E come with a health benefit (which may be from the foods that are not eaten with such a diet), but vitamin pills do not convey this benefit. There may also be a difference between primary prevention (in those without prior cardiac events) where there is a net benefit and secondary prevention (in those who have suffered a cardiac event) where there is net risk. There may be subpopulations, like diabetics, who benefit more.

The bottom line at this time is that eating a healthful diet rich in fruits and vegetables is consistently associated with decreased risk of various diseases, including heart disease. However taking vitamin E supplements may not have this same benefit, and in fact may come with a net risk of increased heart disease and mortality.

What about stroke risk? While there are differences, stroke is also a vascular disease, like myocardial infarction, and the risk factors tend to be similar. In the new meta-analysis the researchers found:

In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.

Again we see a bottom line caution against supplementing with vitamin E. It is important to note that even a small increase in net stroke incidence has a huge effect on the general population. Stroke is a debilitating disease, potentially fatal, and a huge financial burden on the health care system. Even small percentage increases therefore have a huge societal effect. A 22% increased in hemorrhagic stroke is a very large clinical effect.

Conclusion

The research on vitamins in general and vitamin E in particular is messy and complicated. My overall impression of this research is that there is no consistent signal of net benefit for routine supplementation. There are many specific conditions in which specific supplementation is of benefit, but not routine supplementation for general health.

At the same time there is a consistent signal of benefit to having a healthful diet, the primary feature of which is to have a diet rich in fruits and vegetables. So in the end, after decades of research, what your mother always told you turns out to be the best advice – eat your vegetables.