Vitamins: Just Because Less is Bad, More is Not Better

Vitamin and supplement enthusiasts may have been disappointed by a recent barrage of large prospective randomised controlled studies (the supposedly highest level of evidence) that failed to find benefits for various vitamins and other nutrients that were associated with ‘benefits’ in association studies.

Examples include ‘negative’ studies on vitamin E, B vitamins and fish oil.

Now, a thoughtful commentary by Martha Morris and Christine Tangney from Rush University, Chicago, published in JAMA raises an important design flaw that may explain why these studies found no effect.

Thus, as the authors point out:

“A basic principle of nutrition is that most nutrients have a nonlinear, inverted U-shaped association with optimum physiological function. Very low nutrient levels in diet or tissues result in poor function or even death. As the nutrient level increases, function also increases. Optimal functioning occurs over a fairly wide range of nutrient levels but at some point, higher levels become toxic and result in suboptimum function.”

Thus, while one could expect to see ‘positive’ effects in people who are deficient in that nutrient, no effect in people who have an adequate intake, or even ‘toxic’ effects in people who are already at a high level of intake.

Unfortunately, as the authors point out:

“Nutrient levels are rarely considered in trial inclusion criteria. Further, trial volunteers are typically healthy behavior–seeking individuals and are unlikely to have low nutrient intake. More probably, intake levels are already at the level for optimal functioning and further supplementation provides no additional benefit.”

Thus, for example, a large fish oil study only excluded participants, who ate more than three fish meals a week, when an adequate supply of fish oil can be had with one fish meal a week.

Obviously, when everyone is already eating enough fish, it becomes difficult, if not impossible to demonstrate any beneficial effect of fish oil supplements. All the study can show is, that in people who are not ‘fish-deprived’, adding a few capsules of extra fish oil doesn’t do much (or, as in the case with vitamin E, can even be harmful).

This, interestingly, is the case with many ‘nutrient’ studies, which rarely recruit participants based on the presence of any measured or presumed deficiencies. Indeed, in most western countries (and especially among the folks who volunteer for such studies), the presence of meaningful nutrient deficiencies is probably quite rare.

Regular readers may recall a previous post on the effect of dairy calcium supplementation on body weight, which was found to have a positive effect only on the subset of very low-calcium consumers (initial calcium intake < or =600 mg/d), with no effect on the majority of the participants.

These findings have two important implications:

1) Positive associations found in epidemiological studies that are not replicated in randomised controlled trials do not necessarily rule out positive effects for individuals, who are actually deficient in the nutrient of interest (unless of course the study specifically recruits people likely to have meaningful deficiencies).

2) In the absence of an actual deficiency, adding additional vitamins or supplements may have no effect and can, in some cases, be harmful.

This, of course is not what makers of vitamins and health supplements worry about – there will likely always be enough folks out there, who will continue to believe that if less is bad, more is definitely better.

Edmonton, Alberta

Morris MC, & Tangney CC (2011). A potential design flaw of randomized trials of vitamin supplements. JAMA : the journal of the American Medical Association, 305 (13), 1348-9 PMID: 21467288