Abstract
This is a review of recent human clinical trials evaluating quercetin supplementation at doses of 1,000 mg/day. A recent study suggests supplementation with quercetin combined with fish oil and green tea extracts yields greater effect than quercetin alone. Some studies on athletic performance suggest moderate effect in trained athletes and more significant effect in untrained individuals. Both animal and human data suggest quercetin stimulates mitochondrial biogenesis. The scientific literature provides compelling clinical information about this interesting flavonol.
Introduction
A series of interesting and closely related studies published over the last year describe the effects of quercetin on endurance athletes and their performance. These studies provide knowledge that should inform our practices and should change the way we dose quercetin and broaden the range of situations in which we consider using this supplement.
Epidemiological studies suggest that quercetin should be of benefit in preventing a range of different diseases. Although some mouse studies bear these predictions out, human trials have demonstrated little benefit. Individuals who participate in extreme endurance sports produce distinct inflammatory and oxidative stresses in their bodies as well as disruptions in immune function. Studying the effect of quercetin on these athletes provides a means to test quercetin’s long-term predicted effects over the short term and to experiment with varying methods of dosing, compounding, and combinations with other nutrients to enhance quercetin’s effectiveness.
Quercetin is classified as a flavonol, 1 of the 5 subgroups of flavonoid compounds. Flavonoids in turn are a subgroup of the polyphenolic subgroup of the phenolic organic compounds found in plants. Food sources of quercetin include elderberries (42 mg/100 grams), red onions (33 mg/100 grams), hot peppers (15 mg/100 grams), apples (4.7 mg/100 grams), and kale (7.7 mg/100 grams). Capers contain far greater amounts (180 mg/100 grams) but are rarely consumed in significant quantity. The 1,000 mg/day dose of quercetin used in these recent trials far exceeds the amount of quercetin that would be easily consumed via diet.
In vitro animal and human epidemiologic studies suggest a long list of desirable effects result from consuming quercetin in the diet. These include antioxidative,1 anti-inflammatory,2 antibacterial,3 immunomodulatory,4 anticarcinogenic,5 and cardioprotective actions.6 High quercetin intake via diet is associated with decreased rates of colorectal,7 kidney,8 pancreatic,9 prostate,10,11 and lung cancer;12,13 cardiovascular14 disease; and diabetes.15
Many of these protective effects are hypothetically considered to be a result of quercetin’s antioxidative and anti-inflammatory actions. The extreme exercise engaged in by certain athletes, because it causes oxidative damage and inflammatory reactions, has been used to test quercetin’s potential protective effects. Extreme exercise in theory mimics the effect of aging, trauma, and surgery. A treatment that benefits these athletes might also prevent or help treat diseases and morbidity caused by oxidative damage and inflammation.
Literature Review
Measurements of long-term supplementation with quercetin yield a wide variance in absorption rates. A 12-week study of 1,000 subjects who received either placebo or 500 mg or 1,000 mg of quercetin per day yielded a range of unpredictable responses in plasma levels.16 A study of ileostomy patients given single 100 mg doses of quercetin found a mean absorption rate of 24%. Another study found a 52% absorption when the quercetin was administered as a serving of fried onions.17 Polymorphisms in intestinal enzymes, transporters, and liver enzymes, and effects of coadministered foods (dietary compounds), may explain some of these variances.
Many of these recent studies on quercetin, including the one highlighted above, have been conducted by researchers at Appalachian State University in Boone, North Carolina. In one of their earlier quercetin studies published in 2008, the researchers gave trained cyclists either 1,000 mg/day daily doses of quercetin or placebo for 5 weeks. After 3 weeks of normal training during the winter season, these athletes rode intensely (3 hours per day at 57% wattsmax) for 3 days in a row and were tested for multiple measures of inflammation, oxidative stress, and immune function and monitored for incidence of upper respiratory tract infection (URTI). Quercetin supplementation increased plasma quercetin levels and reduced incidence of URTI during the 2-week period following the 3-day burst of extreme exertion but had no effect on laboratory measurements of immune dysfunction, inflammation, or oxidative stress. Although, “F2-isoprostanes, nitrite, ferric-reducing ability of plasma, trolox equivalent antioxidant capacity, and C-reactive protein were significantly elevated as a result of exercise,” no difference was seen between those taking quercetin and those not taking it.18
The Boone researchers conducted a second parallel study of the same duration but, rather than cyclists, used ultra-marathon runners who competed in the 160-kilometer Western States Endurance Run (WSER). Subjects took 1,000 mg of quercetin or placebo each day for 3 weeks prior to the race. Quercetin supplementation again had no effect on inflammation, immune dysfunction, or oxidative stress in serum samples from the runners after completing the race. URTI rates did appear lower in the following weeks in those who took quercetin but not to the point of statistical significance. Combining data from this WSER study with data from their earlier cyclist study did yield a statistically significant reduction in post exertion illness; URTI rates were two-thirds lower in the quercetin group than in the placebo group.19 Yet the lack of measurable effects in serum testing suggests the parameters being measured may not accurately predict the benefit of supplementation.
The data were not what the researchers had expected and prompted re-evaluation about half-life, absorption, and bioavailability of quercetin. In these two studies, the last dose of quercetin had been taken 10–24 hours before the exercise bout, a length of time that might have exceeded quercetin half-life, which may be as short as 3.5 hours.20
In rat studies, omega-3 fats, vitamin C, vitamin E, and green tea extracts have a synergistic effect on quercetin’s action.21,22,23 The Boone researchers used this information to design their next trials.
In July 2009, the Boone group described a trial utilizing a combination of quercetin, green tea, and fish oil. Quercetin (1,000 mg/day), with or without the addition of epicallocatechin 3–gallate (EGCG; 120 mg), isoquercetin (400 mg), and EPA-DHA (400 mg), was administered to a group of cyclists who went through the same 3-hour, 3-day period of extreme exertion. This time the treatment period lasted only 2 weeks. In this trial, the last dose was taken only 1 hour before the start of the heavy exertion. This trial yielded far better results: the mixture reduced post-exercise measures of inflammation, oxidative stress, and immune disruption. Plasma quercetin levels of those who took the supplement combination were almost twice as high as in those who took quercetin alone.24 This suggests that improved absorption was at least partly responsible for this improved effect.
Regular bouts of endurance exercise can increase mitochondrial density in muscle tissue by 50% in a period of weeks.25 In animals, similar increases in mitochondrial density can be triggered by caloric restriction, as well as by certain plant polyphenols, including isoflavones from soy, resveratrol, and EGCG. 26,27,28 Quercetin has a similar effect, at least in mice.
In April 2009, Davis et al from the University of South Carolina reported that feeding mice 25 mg/kg of quercetin for a week almost doubled their muscle mitochondrial DNA. Feeding the mice even half that dose of quercetin increased their SIRT1 mRNA by 200% and increased their treadmill running time by 37%; however, repeating these experiments on humans yielded mixed results.29
In December 2009 researchers had a study published looking for a similar effect in humans. Dumke and colleagues at the University of Montana recruited 40 cyclists, gave them either 1,000 mg/day of quercetin or placebo for 3 weeks, and then tested muscle biopsies from the riders. The researchers could not find any difference between those taking quercetin and those taking placebo in muscle efficiency, muscle mRNA expression, or other measurements.30
Yet a study in 2006 had shown benefit. In this earlier paper researchers from Pepperdine University recruited 11 elite cyclists and fed them a mixture of antioxidant vitamins and green tea extract either with or without quercetin for 3 weeks. Those who received the mixture plus the quercetin improved their times on a 30-kilometer time trial by 1.7% more than those who didn’t receive the quercetin.31
Of note, the Boone group’s 2009 study using athletes showed that quercetin, EGCG, and fish oil taken together decreased inflammatory markers, but did not produce changes indicative of increased mitochondria growth.32
In the most recent study, published in February 2010, the Boone group used quercetin alone, but not in athletes. Instead they conducted their trial with untrained individuals. Even without the addition of green tea and fish oil, they reported a distinct benefit. In this study, 26 adult males took quercetin (1,000 mg/day) or a placebo. They were given 12-minute time trials on treadmills. Those taking quercetin went almost 3% farther during their 2nd time trial, while those taking placebo actually went about 1% less than their initial distance on their 2nd attempt. Increases from 16% to 25% in the measured levels of mitochondrial RNA and DNA suggest that muscle cells were building new mitochondria, but these numbers did not reach statistical significance.33
Not all studies of untrained subjects have shown benefit in exercise performance. An October 2009 paper reported the work of Cureton et al from the University of Georgia who randomly gave 30 untrained individuals either 1,000 mg/day quercetin or placebo mixed with PowerAde® for time periods that ranged between 9 to 16 days. This study was funded by the Coca Cola Company, the makers of PowerAde.34 Performance was tested via cycling tests and indirect muscle oxidative capacity testing and showed no improvement in either of these parameters. There appear to be valid reasons to critique this study, so its inability to show benefit may have an explanation.
Discussion
Despite all of its promised potential, quercetin has not shown the striking effects in human clinical trials that were predicted from the in vitro or animal studies; at best, the human trials have shown only modest effect at lowering inflammation, and other studies have demonstrated no effect.
Quercetin is extensively transformed in the gastrointestinal tract and liver and, once absorbed, rapidly metabolized into glucuronides and sulfate conjugates that are excreted with the bile. Some evidence exists that quercetin metabolites accumulate in the plasma albumin and that activated macrophages at the site of inflamed arteries can deconjugate these metabolites, recreating active quercetin that in turn suppresses foam cell formation.35,36 This form of ad hoc protective action would not be measured via the common parameters by which cardiovascular risk is assessed. Measuring quercetin’s protection of vasculature structure may require histological examination of tissue rather than the simple monitoring of blood chemistry.
The prolonged and intensive physical exertion by endurance athletes and the resulting inflammation, oxidative stress, and lower immune protection leaves them at high risk of URTI.37 Athletes have been utilized as subjects in numerous clinical trials using a range of nutritional supplements including, zinc, omega-3 fats, plant sterols, antioxidants, N-acetyl-cysteine, glutamine, and others. To date, most of these trials have been disappointments. Only in recent trials have quercetin, EGCG, and omega-3 fats yielded promising results.
This information has obvious implications to our clinical practices. Dosing quercetin in combination with green tea and fish oil may increase its effectiveness.
Some of the studies about quercetin’s effect on exercise performance have paid particular attention to the effect on mitochondria and suggest a novel clinical use: increasing mitochondrial function within cells. If this proves true, then quercetin may not only be useful to increase performance, but also potentially to treat fatigue of mitochondrial origin.
For competitive athletes, even minuscule changes in performance may mean the difference between winning and losing; for researchers, however, these very small changes are difficult to perceive and prove. The effects of quercetin on performance in elite athletes were judged as modest at best. When the researchers tried a parallel clinical trial on untrained individuals, they produced more dramatic results.
We should learn a number of things from these studies and bring them to our clinical practices. It is readily apparent that we must be cautious in translating animal studies to humans.
Quercetin, like a number of other phytonutrients, appears to work better in mice than men.
Quercetin, like a number of other phytonutrients, appears to work better in mice than men. Oral supplementation of quercetin to mice produces increases in serum concentrations, albeit at much higher doses, that are not replicated in human trials. Significant results seen in animal studies do not guarantee similar action in humans.
The second lesson we should heed from these studies is that when various nutrient supplements are taken in combination, they may yield difficult-to-predict synergistic actions, the mechanics of which may not yet be understood. Specific nutrients, in this case quercetin, may prove to be more effective when taken with other specific nutrients.
Third, we should consider using quercetin in combination with EGCG and fish oil concentrates as a routine protocol. In clinical practice this is often done unintentionally; we encourage people to drink green tea instead of coffee and we suggest they eat fish or take fish oil on general principle. The enhanced absorption of quercetin resulting from combining it with green tea may work 2 ways. A January 2010 study reports red onion, an excellent source of quercetin, enhances absorption of EGCG from green tea.38
The chemical form of quercetin may also play a significant role. Though foods contain very low levels of quercetin, the structure is slightly different than that found in nutritional supplements, and we cannot rule out that absorption of quercetin from food may be far higher than from concentrates.
Conclusion
We have long considered quercetin useful in treating numerous conditions. The information contained in these studies suggests a means to enhance benefit. This research suggests also several new uses. Quercetin may be a significant tool for preventing infections in yet-undefined populations, as even when taken alone and relatively poorly absorbed, it produced significant effect at decreasing upper respiratory infections. Quercetin’s action of increasing mitochondria may warrant clinical trials to study using it for fatigue associated with cancer treatment. It may increase stamina in these patients while at the same time having anticancer action.
It is reasonable to assume that other supplements combinations may also have synergistic effects with quercetin, and that quercetin may enhance benefits derived from other flavonoids besides green tea. These findings raise the question of whether other phytonutrients with low bioavailability might be similarly enhanced when taken in combination, either in similar mixtures of green tea and fish oil or with yet-undefined combinations. This review provides the first justification published in the scientific literature for eating capers (high in quercetin) with an oily fish such as smoked salmon, ideally accompanied by red onion and a cup of green tea. If this data had originated with researchers in New York, rather than North Carolina, we might also have found a rationale for the required bagel and cream cheese to accompany them.
Acknowledgement
Much of the information in this article originates from a still-unpublished review paper written by David Nieman, PhD. Dr. Nieman has been the guiding force behind quercetin research that has emerged from the Human Performance Laboratory at
Appalachian State University in Boone, North Carolina. The paper is titled “Quercetin’s bioactive effects in human athletes.” His paper was accepted for publication February 11, 2010, and will appear in Current Topics in Nutraceutical Research, Volume 8, No. 1, later this year. A special thank you to Dr. Nieman both for sharing this paper and for tolerating my many questions.
