A majority of Americans take one or more supplements on a daily basis. But do these vitamins and minerals help or harm? Yo-yo media coverage has left many people -- including people with HIV -- confused and troubled. Some advocates assert that the very structure of the studies with negative findings about the popular products is flawed.
Dire headlines like "Study: Multivitamins Should Be Avoided" and "Should We Toss Our Vitamin Pills?" were based on an editorial in the Annals of Internal Medicine, titled "Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements." The editorial was based on a meta-analysis (which is an interpretation of data combined from selected studies) of the potential for vitamin and mineral pills to prevent cardiovascular disease and cancer, plus two new studies on whether multivitamins/minerals can prevent cognitive decline and serious heart problems. The editorial concluded, "Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided." But a co-author of one of the studies cited by Annals, John Michael Gaziano, M.D., associate editor of the Journal of the AMA, told USA Today, "It drives me crazy that they say 'enough is enough,' when there's only been one large study of (standard) multivitamins and it's ours ... I'd say the case is not closed."
Other critics say the Annals findings contradict decades of solid research showing benefits for the same nutrients. Lark Lands, Ph.D., a nutrition and treatment expert on HIV, hepatitis, cancer and diabetes interviewed by TheBody.com, says, "Multiple studies with findings that strongly contradict those of the negative studies have been published." Lands adds that there is particularly strong evidence of supplements' value for people with HIV.
Two trials included in the meta-analysis actually found cancer prevention benefits. One, the largest and longest ever done on multivitamins/minerals (involving 14,000 male doctors followed for 11 years) found a statistically significant 8% reduction in cancer cases, concluding, "These data provide support for the potential use of multivitamin supplements in the prevention of cancer in middle-aged and older men." The study also found that multivitamin/mineral-takers had a 39% reduction in fatal heart attack risk.
The second study followed 13,000 adults taking only five antioxidants (not a full multivitamin) for over seven years. It found reductions among men (but not women) of 31% in cancer incidence and 37% in deaths. Yet the meta-analysis authors dismissed such results.
Critics Say Nutrient Trial Methods Are Fundamentally Flawed
Critics say that randomized clinical trials (RCTs), considered "the gold standard" for drug research, have fatal flaws in both theory and practice when applied to nutrients. In an interview, Balz Frei, Ph.D., a biochemist and director of the Linus Pauling Institute at Oregon State University, argues, "The way we do trials now is heavily stacked against showing an effect of micronutrients." At least nine persistent problems with nutrient RCTs have been identified:
1. Randomized design doesn't work well for nutrients.
An RCT requires half of the study group to take the treatment and the other half to take a placebo (inactive pill). If the treated group then shows significantly better outcomes than the placebo group, the conclusion is that it's beneficial. But as Frei explains, in RCTs of supplements, "these are essential nutrients -- you always have them in your body, or you'd be very sick or would have died. You've been exposed for a lifetime, so researchers never have a true placebo group." As a result, he argues, "only if you have low levels to begin with will you be able to increase them substantially with supplements" and thus show benefit, if there is any. But Frei notes, it would be unethical to deliberately deprive anyone of known necessary levels of nutrients, or even to provide placebos to those with dangerously low levels.
Jeffrey Blumberg, Ph.D., chief of the Antioxidants Research Lab at Tufts University and an acknowledged expert on nutrition research, says in an interview, "Nutrient studies rarely look at baseline levels of the vitamin being studied and they don't ask about dietary intake. If I don't know the baseline, I've made it impossible to see the difference in outcomes." The few studies that do measure nutrient levels prove the point. A 2011 article on flaws in vitamin RCTs cited two placebo-controlled studies of vitamins (E and B complex) for the prevention of cognitive decline. Both found no overall benefit, yet significant benefit for subgroups with lower beginning nutrient intake.
Frei also notes that nutrient studies rarely include tests to distinguish those at risk for the condition studied. He compared this to testing a drug for hypertension without first measuring participants' blood pressure.
Many nutrition experts emphasize the importance of reviewing other data available on nutrients. Blumberg says, "Whoever thought that everything important we need to know uses only one experimental approach? Basic research, laboratory, animal, observational studies -- we can't know anything from those? Only from RCTs? I do RCTs, but even the best are extremely limited. Observational studies [where people report their nutrient intake, but are not given supplements] have limitations, absolutely, but they're a really good research approach for nutrition."
2. Many studies are skewed to people with higher nutrient levels.
The Annals editorial writers claimed that "supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful." (They reserved judgment on vitamin D, about which there are many favorable studies.)
In a later letter to that journal, Frei, Blumberg and two other scientists responded, "They ignored decades of nutrition research and diet monitoring of the U.S. population to reach this misleading conclusion" and cite survey data showing that "most persons in the United States are not 'well-nourished'" and fail to obtain federally recommended minimum nutrient levels. They noted even higher rates of nutritional shortfalls "among subpopulations with increased micronutrient needs, including older adults, African Americans, and obese persons," adding that a 3-cent-a-day, high-quality multivitamin/mineral tablet can "fill many of these nutritional gaps effectively, safely, and at low cost." (Other scientists also penned letters to the Annals in response to the editorial.)
Frei adds that these groups are rarely included in nutrient studies, although "low socioeconomic status [poverty] is the best predictor of low nutrient levels." By contrast, he observes, "most large clinical studies of vitamins have been done with groups such as doctors and nurses who are educated, informed, able to afford healthy food, and routinely have better dietary standards than the public as a whole."
Blumberg notes a related problem: "If you look at nutrient studies that have failed to show benefit, many people in the placebo group were taking those supplements anyway [against the rules]." He cites a large study of vitamin D and calcium for hip fracture prevention in women in which the placebo group had twice the recommended daily intake of calcium. The result? No significant benefit was found for the "treated" group, because the trial ended up only comparing high with very high calcium levels.
3. Many participants don't adhere to treatments in nutrient trials.
A major study cited by the Annals editorial reported that 46% of the treated and placebo groups stopped taking their pills, and 17% of all participants withdrew from the study -- a non-adherence problem seen in many such studies. Lands comments, "If this was a drug trial, they wouldn't even think it was acceptable to analyze what they had left." Even the study's authors wrote that these problems "limit[ed] the ability to draw firm conclusions."
4. Dosages are too low to have an effect.
According to Lands, many nutrient studies use much lower dosages than those found effective in improving various body functions or reducing disease risk in previous research. She says this problem affected several of the multivitamin/mineral studies cited by the Annals editorial. Referring to low dosages of vitamin C, B12 and selenium included in the mega-trial of older male physicians, Lands says, "It's ridiculous to even hypothesize that those kind of doses would deliver any observable effect on health." Even the researchers themselves acknowledged, "Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin."
5. Trials are often not long enough.
Many nutrition experts have observed that cancer and cardiovascular disease are complex conditions that take many years to develop, so nutrient trials need to be very lengthy (and thus expensive) if they are to show risk reduction. As noted by the Annals authors, "Most of the included vitamin trials provided less than a decade of follow-up, and vitamin effects on [cardiovascular disease] and cancer may take longer to manifest." Notably, the two long-term studies mentioned earlier found lowered cancer risks in older men.
6. Ineffective or harmful forms of nutrients are used.
Lands says most studies' use of synthetic vitamins is "a very important flaw." She notes, "It is well known that the synthetic forms of some micronutrients may not have the same effect in the body as the natural form." The Annals editorial repeated the frequent claim that vitamin E and beta-carotene "increase mortality." But as to vitamin E, dissenters asserted that the meta-analysis on which this conclusion was based "has been refuted by several more comprehensive meta-analyses."
According to Lands, the cheap, commonly studied version of vitamin E (a petroleum-based product) "may actually interfere with some of the beneficial effects of natural vitamin E." She also faults the usual use of only one form, rather than all eight, of the vitamin, which may reduce blood levels of other forms, one of which, research suggests, may be particularly important for protection against cancer.
Similarly, Lands notes that beta-carotene trials use a synthetic version that researchers found may speed the progression of pre-existing lung cancer (not causing it, as often misreported) in continuing smokers.
7. Single-nutrient studies are much less likely to show benefit.
Lands says, "A huge flaw of most vitamin/mineral trials assessing health protectiveness is that only one or two nutrients are studied. But in nature, multiple micronutrients work together in countless ways." Blumberg adds that such trials "don't ensure intake of other essential nutrients needed for the test nutrient to manifest its own potential benefit."
The meta-analysis discussed earlier was largely based on studies of one or two nutrients -- yet found significantly reduced risk of cataracts. Even the authors acknowledged that a possible reason they found no benefit might be that "physiologic systems affected by vitamins ... are so complex that the effects of supplementing with only one or two components is generally ineffective." They also wrote that "the best support for benefit of supplementation came from two multivitamin trials that used physiologic doses of a wider variety of agents."
8. Meta-analyses magnify problematic studies and dilute strong ones.
Blumberg warns that "if enough trials are poorly done, a meta-analysis can mask successful outcomes." He adds, "The easiest way to dismiss positive findings is to do a meta-analysis." Lands says nutrient meta-analyses tend to repeatedly recycle flawed RCTs and, further skewing the picture, "often combine data from studies which used widely varying doses of different forms of nutrients in very different populations."
9. Many medical researchers have little nutrition knowledge and a pro-drug bias.
Frei says, "The doctors who conduct these trials, and the peer reviewers for journals, generally don't understand the fundamentals of nutrition and jump to unjustified conclusions." Part of the problem, he notes, is that "nutrition education in medical schools is basically nonexistent." In addition, as Marcia Angell, M.D., a Harvard senior lecturer, observed in her final issue as editor-in-chief of the New England Journal of Medicine, "The ties between clinical researchers and [the drug] industry include not only grant support, but also a host of other financial arrangements ... Academic medical institutions are themselves growing increasingly beholden to industry." The result, she later wrote, is that "doctors and their patients come to believe that for every ailment and discontent there is a drug, even when changes in lifestyle would be more effective."
As more eye-poppingly priced drugs are marketed for cancer, cardiovascular disease and other killers, their manufacturers may view supplements as potentially strong competitors. Interestingly, a 2011 study concluded that "in major medical journals, more pharmaceutical advertising is associated with publishing fewer articles about dietary supplements and having more negative conclusions about [supplement] safety."
Postscript: Thinking Critically About Nutrient Studies
Lands says, "Too often, researchers have limited their conclusions to a certain group, but the media story gives the impression that the findings apply to one and all. If you care about the truth, look at the study itself, rather than only a reporter's version of it." Good starting points: PubMed for the study texts and a search for articles on possible study flaws.
Bottom line? "Next time you see a blaring headline about the dangers of this or that nutrient," Lands suggests, "remember that most studies claiming negative results have been strongly criticized by experts for deep flaws. And know that the vast majority of evidence from years of research not only confirms supplements' safety but also their considerable benefits to health."
This is the first of a two-part series examining the questions surrounding vitamins, minerals and disease prevention; the second will address research on supplements for people with HIV/AIDS.
Bob Lederer, M.P.H., is a longtime health journalist, co-host of "Health Action" on WBAI-FM in New York City, former ACT UP organizer, and writer for The Supplement_, newsletter of the the nonprofit New York Buyers Club, which offers nutrient information and access to discounted products, especially for people with HIV and hepatitis C._