For athletes, antioxidant pills may not help performance

In the fickle world of sports nutrition fads, few trends have shown the staying power of antioxidants. For more than three decades, athletes have remained devoted fans of supplements; the American College of Sports Medicine estimates that around half of elite athletes take vitamins in hopes of keeping their bodies fit and boosting endurance.

The idea makes intuitive sense: Energy consumption within a cell leaves a trail of spent oxygen molecules that can damage tissues and contribute to fatigue. Although the body has internal garbage collectors to clean up the waste products of metabolism, the demands of strenuous physical activity overwhelm the system. Cells need a boost. Food can supply antioxidants naturally — some of the best known are vitamins C and E — but why rely on vegetables when pills or sports drinks can deliver hundreds of times the vitamin E that comes in a serving of spinach?

That line of thinking helped drive U.S. sales of vitamin and dietary supplements to almost $25 billion in 2014, according to the market research firm Euromonitor International. Of those, vitamin C was the second most popular supplement after multivitamins, accounting for $1.1 billion in sales, which are rising.

“It’s that American mentality,” says Jay Williams, a professor in the department of human nutrition, foods and exercise at Virginia Tech in Blacksburg. “If some is good, more is better.”

Except when it might be worse. In a scientific reboot, many newer, more rigorous studies are contradicting decades of previous thinking, finding little support for — if not outright harm from — antioxidant supplements for athletes. Although antioxidants obtained from food appear to do a body good, the colossal doses in supplements may disrupt a cell’s built-in system for coping with oxidative stress. And it appears that muscles under exertion may need a certain level of oxidative beating to adapt and strengthen over time. If the recent research holds up, it means one of the very things athletes commonly do to help their bodies could not only waste money but may even undermine the benefit from those hours of dedication.

One group of European researchers went so far as to call antioxidant pills “worse than useless” in a 2012 letter to the American Journal of Physiology–Endocrinology and Metabolism. The bottom line of a 2011 study: “In certain situations, loading the cell with high doses of antioxidants leads to a blunting of the positive effects of exercise training.”

At best, overall results have been neutral. A recent meta-analysis of studies published in September in Applied Physiology, Nutrition, and Metabolism concluded that vitamin E supplements did not protect against oxidation or muscle damage. Writing in February 2014 in the Journal of the International Society of Sports Nutrition, researchers from Brazil tallied the results of 12 studies comparing the performance and physiology of athletes who took antioxidants with those who took a placebo instead. The team found “no consistent evidence suggesting that supplementation reduces oxidative stress and ensures better results in exercise.”

The report also notes that the topic has been challenging to study because there are no uniform standards for doses or research design. But there’s enough concern that many prominent scientists in the field are warning athletes not to be too enamored with vitamin and dietary supplements. “There are papers on both sides of the fence,” says Scott Powers, a physiologist at the University of Florida in Gainesville. “But my work in animal models suggests that there is a risk.”

Radical, man

Oxidation is a chemical reaction that occurs when a molecule loses at least one electron. It happens throughout nature and can include many different elements, but commonly involves oxygen (thus the name). Oxidation is why a freshly cut apple turns brown and the Statue of Liberty’s copper skin has aged to green. In living cells, oxidation occurs in the mitochondria, the combustion engines of the body. In the process of liberating the energy locked in sugar and other molecules, electrons from oxygen get out of balance. The result is a free radical, a molecule so unstable it will react indiscriminately with nearby molecules to scavenge an electron to stabilize itself. Sometimes during the chemical frenzy, the electron gets snatched from molecules that make up DNA or cell membranes and other structures, potentially harming them. The higher the cell’s energy demand, the more free radicals appear.

While experts in the 1960s had theorized about protection from vitamins, the beginning of the golden era of antioxidants is often traced to an experiment published in 1978 from the University of California, Davis. Researchers asked 10 volunteers to ride an exercise bike for one hour. In part of the experiment, the scientists captured exhaled breath from the cyclists and measured levels of pentane. That compound is a marker of what would come to be called “oxidative stress,” which occurs when free radicals are grabbing electrons faster than cells can neutralize the radicals. When the study participants started breathing harder, levels of pentane, and therefore oxidative stress, rose.

The next part of the study is what helped launch a worldwide sports nutrition craze and a multibillion-dollar industry. After the volunteers took vitamin E for two weeks and then got back on the bikes, oxidative stress seemed to plummet. The study appeared in the Journal of Applied Physiology. Many more like it would follow.  Athletes took note, chief among them Kenneth Cooper, the renowned physician and former U.S. Air Force flight surgeon who coined the term “aerobics” and inspired generations of people to exercise their way to better health. His 1994 book, The Antioxidant Revolution, promoted megadoses of antioxidant vitamins, especially for elite athletes, who consume the most oxygen.

“Starting in the 1970s and ’80s, all that was written about free radicals is that these are damaging molecules,” Powers says. If free radicals are dangerous, the thinking went, neutralizing them would do nothing but good. Research at the time was relatively consistent with this idea, both in animal and human studies.

As investigations have probed deeper, using ever more sophisticated measures of oxidative stress and its role in the body, the shiny reputation of antioxidants has begun to tarnish. Steven McAnulty and colleagues performed one of the earliest experiments to question whether the theoretical benefits of antioxidants were real.

In the early 2000s, McAnulty, of Appalachian State University in Boone, N.C., recruited 38 athletes training for an Ironman triathlon, which requires a two-mile swim, a 26-mile run and a 112-mile bike ride. Two months before the race, the researchers gave 19 of the athletes 800 international units of vitamin E every day, more than 35 times the recommended daily amount. Before and just after the event, the scientists measured the compound isoprostane in blood and urine samples as a newly established, state-of-the-art marker of oxidative stress. Instead of a protective effect, they found that the amount of oxidative stress in the group taking the antioxidant was higher — twice as high, in fact — compared with athletes who were taking a placebo.

“We were pretty floored,” McAnulty says. In a similar experiment with ultramarathon runners, he found that giving them 1,500 milligrams of vitamin C daily for a week before the race did not make any difference in measures of oxidative stress. Both papers were published more than a decade ago, the Ironman study in the journal Medicine & Science in Sports & Exercise and the study of ultra-marathoners in the European Journal of Applied Physiology.

But experiments like these, questioning the conventional wisdom of antioxidants, got little notice until 2009, when the New York Times wrote about a report in the Proceedings of the National Academy of Sciences. A team of researchers from two German universities and Harvard Medical School measured how taking vitamin E and C supplements affected insulin sensitivity, and by implication diabetes risk, in a group of 40 healthy young men. Half of the participants were fit, while the other half did not regularly exercise. All were randomly assigned to take either antioxidant supplements or a placebo as they went through a four-week period of exercise training.

At the end of the study, the men who had taken the antioxidants did not see a boost in insulin sensitivity,  which usually occurs under the demands of exercise. It’s one reason why exercise is viewed as an important part of diabetes prevention and management. “Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans,” the researchers reported.

At the time, skeptics rightly pointed out that this was only one study. But the bad news kept coming. The same year as the PNAS paper, researchers in Australia reported experiments in Cell Metabolism involving mice genetically unable to produce a key enzyme involved in the elimination of free radicals, the very function championed with antioxidants. When the mice unprotected from free radicals were fed a high-fat diet, they did not develop insulin resistance, which is normally a consequence of eating poorly. Free radicals, it seemed, were offering some protection against diabetes. Researchers at the time increasingly noted a paradox — namely, that high doses of antioxidants were not only allowing free radical damage, but in certain cases, promoting it.

A power boost

More recent research has carried these concerns further, suggesting that muscles in training perform best when they have to cope with blasts of free radicals. Prolonged oxidative stress might damage cells and contribute to aging and chronic disease, but the brief bursts that come from physical activity could perhaps sharpen internal mechanisms that mop up free radicals and build muscle endurance.

“In order for physiological systems to adapt, they need to be overloaded,” says Arthur Weltman, who heads the exercise physiology laboratory at the University of Virginia in Charlottesville. One possible reason: Active muscles need an abundance of mitochondria to produce a lot of energy in a hurry. Powers, from Florida, published a study in 2008 suggesting that the free radical oxygen produced from exercise in rats, rather than hurting cells, triggers changes in cardiac muscle that help mitochondria stay plentiful — the very thing athletes need.

Other studies have found similar effects. A team of Spanish researchers writing in the American Journal of Clinical Nutrition conducted one of the few studies taking the same oxidative stress measures in both humans and rats given daily vitamin C supplements. In the animal studies, when muscle cells were flooded with the vitamin, mechanisms that normally stimulate mitochondria production did not engage.

Among the human volunteers, those who did not receive supplements experienced a 22 percent increase in VO₂ max, a measurement of the maximum amount of oxygen the body is using, and a key indicator of endurance. (The higher the number, the more energy you’re squeezing out of each breath.) The vitamin C group experienced an increase of about 11 percent.

Some studies even question multivitamins. Last year in the Journal of Sports Medicine and Physical Fitness, researchers from Norway found that athletes who took a mix of B vitamins, antioxidants and minerals for six weeks had significantly lower gains in VO₂ max than athletes given a placebo.

Still, taken as a whole, placebo-controlled trials of the effects of antioxidants on sports performance have produced a mixed bag of conclusions. Most studies cited in last year’s review by the Brazilian research team were equivocal, while two found an advantage in the placebo group and two an advantage in the supplement group. The authors say the lack of consistency arises from the fact that study methodology varies greatly, from sample sizes to the vitamin doses given, length of study and the underlying fitness level of the volunteers. It’s not unheard of for two sets of researchers to arrive at different conclusions with the same data (SN: 1/24/15, p. 21).

Researchers also caution that although antioxidants often get lumped together, they are in fact a heterogeneous bunch, with varying mechanisms of action inside cells. So experimental results from one supplement might not apply to another.

Even studies of antioxidants with fancy names have not gathered enough evidence to say whether they offer athletes a benefit. A study in Medicine & Science in Sports & Exercise last June reported that cyclists who took the popular dietary supplement N-acetylcysteine (which maintains levels of the antioxidant glutathione) showed improved times on sprints and better internal adaptations to oxidation. But other studies have raised concerns about the compound’s role in promoting tumor growth.

Another popular antioxidant, quercetin, has also shown unpredictable results. “We’ve published four different papers and we didn’t find meaningful effects,” says Kirk Cureton, retired head of kinesiology at the University of Georgia in Athens. A 2011 review rated the benefit of quercetin “between trivial and small.”

The Goldilocks zone

Doubts over antioxidant supplements should not be extrapolated to antioxidants found in the diet, scientists say. “The compounds are different in foods, and you’re getting normal amounts,” McAnulty says. He published a 2011 study of blueberry powder, finding reduced levels of oxidative stress after volunteers consumed it daily for six weeks. (The amount was equivalent to about a cup of blueberries; food in capsules is often used in studies to standardize the dose.) Another example: Researchers in New Zealand recently compared oxidative stress and performance of runners taking a vitamin C solution or a black currant juice drink with natural levels of antioxidants but the same number of calories. The researchers saw increased oxidative damage with vitamin C and only the black currant users dropped time.

Antioxidants from fruits and vegetables, as opposed to supplements, may keep the body in a kind of Goldilocks zone, McAnulty says, permitting enough oxidation to keep natural coping mechanisms engaged, but not so much that cells suffer harm. In the end, athletes may be better off paying attention to what goes on their plates, while scientists try to figure out whether anything in the medicine cabinet is worth the price.

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This article appeared in the March 7, 2015, issue of Science News with the headline, “Tough to swallow.“

Editor’s note: This story was updated March 12, 2015, to correct an error of chemistry in the paragraph under “Radical, man.” During chemical reactions in the mitochondria, oxygen becomes unstable not by losing an electron, but by gaining one.