expert opinion

Study analysis: Increased micronutrient intakes seem to be not effective in trials with participants who are already at optimum levels

May 1, 2011


Dr. Martha Clare Morris and Dr. Christine C. Tangney, Department of Internal Medicine and Department of Clinical Nutrition, Rush University Medical Center, Chicago, Illinois, USA.

“What are scientists, physicians and the general public to make of the many null findings from randomized controlled trials (RCTs) of vitamin supplements? These trials are usually conducted on the basis of positive findings from prospective epidemiological studies and laboratory evidence of biological mechanisms. Do the negative findings from the RCTs offer incontrovertible evidence that the nutrient is unrelated to disease and that the epidemiological studies are biased? An alternative explanation is that most RCTs of vitamin supplements are designed to test the hypothesis that supplementation, no matter the nutrient status, is protective. Vitamin treatment may not be effective in these trials because nutrient intakes among the participants are already at optimum levels (1).

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 can become toxic and result in suboptimal function.

Consideration of nutrient level is critically important in the assessment of the epidemiological evidence. For example, among the first three prospective epidemiological studies reporting on the association of dietary antioxidants and the risk of Alzheimer's disease, two studies found associations of high vitamin E intake from food sources and reduced disease risk (2, 3) and one found no association (4). Close examination of the reported intake levels of these study populations revealed that vitamin E intake was very low in the study with null findings (max. 4.7 mg/day), and the median intake levels of the other two trials was significantly higher (min. 10.5 mg/day). Thus, a plausible explanation for the null association is that the range of vitamin intake in this study population was below the level of protective benefit to observe an association.

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. Some RCTs examining the effect of vitamin E supplementation on cognition have suggested null results (5, 6). Of note, none of these trials targeted individuals who had low dietary intake. Analysis afterwards showed that among women whose vitamin E consumption at baseline was low (less than the median intake of 6.1 mg/day), vitamin E treatment of 435 mg every other day significantly slowed the rate of cognitive decline compared with placebo, whereas there was no effect among women whose baseline intake was already high (greater than 6.1 mg/day) (5). Analysis of the other negative study showed that trial participants were allowed to take multivitamin supplements containing nutrient concentrations that were as high as the currently recommended dietary allowance level (15 mg/day) (6).

Published and ongoing RCTs of the effect of docosahexaenoic acid, an omega-3 fatty acid in fish oil, on cognitive decline and dementia have the same design flaw. The published trials report null findings. The exclusion criteria for these trials at best omitted persons who consumed more than three fish meals per week (7, 8) This is far above the level of just one fish meal per week observed to be associated with a reduced dementia risk in the majority of prospective epidemiological studies.

In a rare example of a vitamin supplement trial that targeted individuals who were found to have insufficient folate intake, participants were randomized to receive 800 μg/day of folic acid or placebo for three years (9). During this period, folate levels among treated individuals significantly increased, and homocysteine concentrations decreased. The folic acid–treated participants had significantly slower rates of decline in cognitive function on multiple tests compared with the placebo group.

Clinical trials are both costly and important for substantiation of nutrient effects on health. The public health may be better served by initially conducting trials in individuals with insufficient intakes and, if effective, further testing the effectiveness of supplements in those with adequate intake levels.”

Chicago, USA, April 2011


  1. Morris M. C. and Tangney C. C. A potential design flaw of randomized trials of vitamin supplements. JAMA. 2011; 305(13):1348–1349.
  2. Engelhart M. J. et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002; 287(24):3223–3229.
  3. Morris M. C. et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002; 287(24):3230–3237.
  4. Luchsinger J. A. et al. Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol. 2003; 60(2):203–208.
  5. Kang J. H. et al. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med. 2006; 166(22):2462–2468.
  6. Kang J. H. et al. Vitamin E, vitamin C, beta carotene, and cognitive function among women with or at risk of cardiovascular disease: the Women’s Antioxidant and Cardiovascular Study. Circulation. 2009; 119(21):2772–2780.
  7. Quinn J. F. et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010; 304(17):1903–1911.
  8. van de Rest O. et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology. 2008; 71(6):430–438.
  9. Durga J. et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007; 369(9557):208–216.