Part III: Clinical Evidence, Perspective, and Concluding Remarks
Prior to COVID
Like all other drugs, most compounds tend to have a spotty record when it comes to effectiveness in human trials.
Take this excerpt from Li et. al. 2016(emphasis mine):
In a randomized, double-blinded, placebo-controlled trial, 1002 subjects took 500 or 1000 mg/day quercetin or a placebo for 12 weeks. For the group as a whole, quercetin supplementation had no significant influence on rates of upper respiratory tract infections (URTI) compared to placebo. In a subgroup of subjects age 40 or older who self-rated themselves as physically fit, 1000 mg/day quercetin resulted in a statistically significant reduction in total sick days and symptom severity associated with URTI [72]. Female subjects were supplemented with 500 or 1000 mg/day quercetin or placebo for 12 weeks. While quercetin supplementation significantly increased plasma quercetin levels, it had no influence on measure of immune function [73]. Quercetin (100 mg/day) did not alter exercise-induced changes in several measures of immune function following three days of intense exercise in trained athletes, but it significantly reduced URTI incidence (1 of 20 subjects in active versus 9 of 20 in placebo group) during the two-week post-exercise period [74]. A similar lack of effect on strenuous exercise-induced immune system perturbation was found in subjects who took 1000 mg/day of quercetin for three weeks before, during, and continuing for two weeks after the 160-km Western States Endurance Run. In this study, however, there were no differences in the post-race illness rates between quercetin and placebo groups [75].
There are a few things to note here. The studies indicated here did not use a metal complex or any other supplements. They also noted some studies that suggest Quercetin may effect exercise-induced immune changes. Although a weird topic, there's some speculation to the idea of a post-exercise period where immune function is compromised, and that people who exercise heavily are more likely to become ill within this time frame. I don't know much about the topic, but it seems like something that many researchers are looking into.
Another study, a double blind, randomized control trial conducted by Heinz et. al. 2010 wanted to see if supplementation with Quercetin, Vit. C, and Niacin over a 12-week period would reduce the average number of Upper-Respiratory Tract Infection (URTI) days.
Unfortunately, this study suggested that the average number of URTI days did not decrease with Quercetin supplementation.
Taken from Heinz et. al. 2010. Supplementation with a cocktail of OTC compounds, including different Quercetin levels, did not significantly reduce URTI days, severity, or symptoms.
However, the researchers did note that Quercetin seemed to be effective in groups who rated themselves in the top half of fitness levels. Again, it seems like there is some evidence of a "post-exercise" immune effect, and that Quercetin seems to help reduce URTI days in those groups. Strangely enough, the researchers also indicated that greater fitness levels correlated with reduced URTI days in general, without Quercetin supplementation.
Taken from Heinz et. al. 2010. People over the age of 40 who considered themselves as highly athletic had lower incidences of URTI days and URTI severity when supplemented with Quercetin.
So far, these studies point to something interesting. It seems that there may be a dichotomy between incidences of URTI rates and URTI symptom days. This would point to the idea that prophylactic flavanoid consumption may help to reduce the chances of getting sick, while flavanoids may not help reduce duration and severity of illness when already sick.
A meta-analysis conducted by Somerville et. al. 2016, suggested that flavanoid consumption correlated with reduced rates of URTI infection but did not correlate with reduced infection days.
Taken from Somerville et. al. 2016. Quercetin/flavanoid supplementation reduced incidences of URTI infection.
Taken from Somerville et. al. 2016. Quercetin/flavanoid supplementation did not reduce days of infection.
Note that some of these studies had a low number of participants, and that these studies did not look at just Quercetin, but other flavanoids such as anthocyanins as well. Some of the studies also looked at athletes while others looked at college-age students.
Regardless, this indicates a possible link to Quercetin/flavanoid intake and risk of infection. Although I'll explain later, this may point to a relationship between diet and risk of infection in general, something that will be important to underscore.
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Trials Against COVID
Unfortunately, the number of studies examining Quercetin's effectiveness against COVID are limited. However, there are a few studies, and they all seem to be pretty promising.
In a study conducted by Margolin et. al. 2021 researchers examined whether an over-the-counter cocktail regimen would be effective as a prophylactic and early treatment against COVID. It's important to note that this study used many compounds including zinc, drops of Quina (Quinine), vitamin C, D3, E, and l-Lysine, although the control group seems to have been given everything besides Zinc or the ionophores (quinine and Quercetin). In that sense, the difference between the two groups would be dependent upon the administration of Zinc and ionophores.
The researchers found that people who received Zinc and both ionophores had fewer incidences of COVID as compared to the control group over the 20 week study.
Taken from Margolin et. al. 2021. Zinc and Zinc Ionophore supplementation helped to reduce incidences of COVID infection. Remember that this was a combination study, so Quercetin was not looked at in isolation.
Although this didn't test Quercetin in isolation, the study does suggest that over-the-counter, easily accessible compounds may be extremely beneficial in fighting against COVID, especially when taken as a prophylactic.
Another study (Pierro et. al. 2021) examined whether a 30 day randomized, controlled, on-label administration of Quercetin as an adjuvant would have an effect on reducing COVID severity in people who tested positive but did not have severe symptoms. In this study, standard care therapy (e.g. analgesics, anti-fevers, oral steroids, antibiotics) was used in both groups while the therapy group also received 200 mg twice daily of Quercetin (400 mg/day). As can be seen, it looks like Quercetin greatly reduced hospitalization rates as well as days of hospitalization.
Taken from Pierro et. al. 2021. Compared to standard care, Quercetin led to reduced hospitalization rates and days of hospitalization.
As of now, these were the only clinical trials I came across. However, it still indicates Quercetin may be very beneficial in fighting COVID.
This creates an interesting scenario as it pertains to Quercetin, one that we can dive into a little bit further. Because unlike many of the other drugs we have looked at, Quercetin doesn't have decades, but millennia of history with us as a species, and one that we may tend to overlook in our age of modernity.
Quercetin: How Eating Well can make you Feel Well
The discussion surrounding COVID therapeutics has been dominated by novel compounds that have hardly been around for many years. Pfizer's PAXLOVID and Merck's Molnupiravir have hardly been through human testing, with a clinical testing history of only over a year (drugs like Molnupiravir were previously tested and scrapped, so they haven't been through decades of trials). Ivermectin and Hydroxychloroquine have had decades of clinical use, and even their record against COVID and as general therapeutics continue to come under scrutiny.
So what do you say to a compound that we have had millennia of evolutionary history with, that plays a pivotal role in our diets, and is abundant in many foods that are vital to our health and well-being?
Quercetin, as well as the entire class of flavanoids, are compounds that we have had an extremely long history with. They contribute to the colorful nature of many different fruits and vegetables, so it wouldn't be hard to argue that this has contributed in some manner to our evolutionary lineage; those who were able to discern colorful foods, or even understand that different colored foods may contain different nutrients, would be far more adapted to searching for diverse foods. By doing so, they're more likely to obtain competent, diverse forms of nutrients that would help to fight off different pathogens and diseases.
And it works the other way as well. Fruits and vegetables that begin to turn bad tend to turn brown, an indication that free radical formation may be occurring due to the breakdown of the plant's polyphenols. We all know how rotten fruits tend to taste off, and it could be a sign of evolutionary adaptation to avoid brown hues from plants as it may indicate rotting, possibly sickening foods.
Quercetin is no exception, and as we have outlined above the great number of benefits that these compounds contribute to humans cannot be overstated. When discussing proper nutrition, it seems that we focus entirely on essential vitamins and minerals and making sure we get enough of those nutrients, while other compounds such as Quercetin may be given the label of "pseudoscience", "hogwash", "fad" supplements that are just wasteful with no real benefit.
But many of our distant relatives have had a history with these compounds, and if we did not require such a large quantity of fruits and vegetables in our daily diets we may not have evolved to require it now. Colorful vegetation is a well known invitation to be eaten by animals, and even bees have evolved to understand the role different colored flowers play. It wouldn't be hard to argue the same occurring with us, where our ancestors, in the search for nutrients, come across colorful vegetation and decide to try eating them. Now, they certainly wouldn't know that the vegetation contained Quercetin or other flavanoids or anthocyanins, as it would most likely be a secondary benefit. They most likely would have fed off of these vegetations as a source of energy, with many of the antioxidant, antimicrobial properties coming second. Nevertheless, there's no doubt that our distant ancestors' ability to source diverse vegetation (well, at least the ones that don't lead to being poisoned) have contributed to our survivability as a species.
At this point all of this is highly speculate, so maybe if there were some studies that we could use to contextualize this perspective, we may gain a better perspective as to the role that a diverse plant-based diet plays in fighting diseases.
A population study by Kim et. al. 2021 examined the effects of different diets on COVID outcomes. The study looked at healthcare workers from 6 different countries (France, Germany, Italy, Spain, US, UK) and categorized them into different diet groups. From there, researchers examined if certain diets had lower rates of moderate-severe COVID infections. One thing to point out here is that the diet categories are based on self-reports and were narrowed down into 3 diet groups specifically (plant-based, plant/pescatarian, and low-carb/high-protein).
The researchers obtained 3 main results. First, workers following either plant-based or plant/pescatarian diet were less likely to suffer from moderate-severe COVID than those who didn't follow these diets (73% and 59% lower odds, respectively). Second, workers who followed a low-carb/high-protein diet had increased, nonsignifcant higher odds of moderate-severe COVID (48% greater odds) than those who did not follow this diet. Lastly, workers who followed a low-carb/high-protein diet were at nearly 3 times greater odds of moderate-severe COVID as compared to those who had plant-based or plant/pescatarian diets.
Taken from Kim et. al. 2021. Markers to the left of the divide indicate reduced odds of COVID severity, while markers to the right indicate increased odds of COVID severity, relative to other diets. "Model 1 adjusted for age, sex, race/ethnicity, and country. Model 2 additionally adjusted for specialty, smoking, and physical activity. Model 3 additionally adjusted for body mass index and presence of a medical condition."
So it seems that different diets may relate to COVID severity. This shouldn't come as a surprise since we've known of the dangers of constant consumption of highly processed foods. In this case, the lack of vital nutrients, as well as other plant-based nutrients in the case of antioxidants, may have ramifications on how our bodies deal with diseases. Again, this is not something surprising, but should still be reiterated.
As the researchers discuss (emphasis mine):
Plant-based diets or vegetarian diets are dietary patterns that are high in plant foods and low in animal products.12 13 Consistent with this definition, participants who reported that they followed plant-based diets or vegetarian diets had higher intake of plant foods (vegetables, legumes, nuts) and lower intake of poultry and red and processed meat. Plant-based diets are rich in nutrients, especially phytochemicals (polyphenols, carotenoids),13 18 with prior studies reporting higher fibre, vitamins A, C, and E, folate, and mineral (iron, potassium, magnesium) intake among those with highest versus lowest adherence to plant-based diets.12 19 Studies have reported that supplementation of some of these nutrients, specifically, vitamins A, C, D, and E, decreased the risk of respiratory infections, such as the common cold and pneumonia, and shortened the duration of these illnesses.16 20–23 These nutrients are hypothesised to support the immune system as they play important roles in the production of antibodies, proliferation of lymphocytes, and reduction of oxidative stress.16
Here, the researchers mention the importance of nutrients such as phytochemicals, something which does not get a lot of attention when it comes to talks about diet and nutrition. So the evidence from this study not only indicates the importance of having a diverse diet, but also may point to the idea that the typical modern diet, lacking many of the traditional vegetation that our ancestors ate, may be making us sick (at least from my perspective).
The standard American diet has become a form of mockery in the cultural sphere, and there's good reason for that. We're well known for our love of fast food, takeout, and frozen and highly processed foods. Add on the fact that lockdowns have lead many of us to consume even more takeout and fast food over the year and a half (remember that we've gotten fatter over the course of lockdowns). This points to a huge problem when it comes to the health of Americans. These foods raise the risk of many now prevalent diseases such as obesity, high blood pressure, high cholesterol, cancer, heart disease, and diabetes. In this case, the argument can be made that the mass consumption of these foods may increase the risk of such diseases, but what about if the lack of a vital nutrients may contribute to worse disease outcomes.
The results of the Kim et. al. 2021 study points to the idea that it may not be that a diet full of processed and red meats may be detrimental, but that diets that lack Quercetin and other polyphenols sourced from fruits and vegetables may play a huge role in the health of individuals.
Most foods such as breakfast cereals tend to be enriched with vitamins and minerals, and not plant compounds. It would make for a good argument to suggest that, due to modernity and lack of eating diversely colored foods, that it may be highly beneficial to supplement with Quercetin in a world where we are becoming devoid of consuming wholesome, in-season products.
I didn't come into writing this thinking much of Quercetin. Honestly, I only heard about it last year due to interviews between Dr. Drew and Dr. Zelenko, and didn't put much weight into it. As it stands, not only is Quercetin a plant-derived supplement, it's a compound that has found its way into our diets possibly since our ancestors first began to eat vegetation. Old adages, ones that we tend to brush off as nothing more than earworms, persist due to their relation to a truth. It's something that Brett Weinstein and Heather Heying refer to as being "literally false, metaphorically true"."An apple a day keeps the doctor away" stems from phrases we have come across at some point, and these phrases stick for a reason, because whether or not we know why it's good to eat an apple a day, those that tend to may have been more likely to live on and pass on these cultural catchphrases. The sayings persist because their importance persists. An apple a day may not literally keep the doctor away, but it reasons that consuming fruits daily may be vital to good health, and thus fewer doctor visits.
Quercetin comes from a class of compounds that we may have overlooked, an idea which is certainly true during our move into modernity, with a shift more towards processed foods where any color may come in the form of artificial dyes and not plant-derived polyphenols. An argument can be made that not only could Quercetin prove beneficial to our health, but an absence of it may prove detrimental in the longterm.
So to Conclude:
There's Evidence that Quercetin may work Similarly to Hydroxychloroquine
It seems that Quercetin may operate as both an immunomodulator and a Zinc ionophore. Its use as an over-the-counter anti-allergic supplement as well as its use for asthma indicates an ability to affect the production of histamine and cytokines. The evidence around being an ionophore is not as well founded, although studies do support its use as such. For an over-the-counter product that may seem very appealing to many people.
Quercetin has plenty of other Benefits
The antioxidant activities of Quercetin aligns with other polyphenols. Antioxidants are a huge buzzword in the health/fitness world, and there's good reason for that. They are some of the most well studied compounds, with possible anti-cancer, pro-heart and pro-organ benefits. Add on possible antimicrobial properties and it becomes hard to argue that this is nothing more than a possible fad supplement.
Although Limited, there is some Evidence that Quercetin may be Effective against SARS-COV2
Computer models and in vitro studies suggest that ACEII receptors and the main protease of SARS-COV2 may be good target candidates for Quercetin. However, clinical studies of prior Upper Respiratory Tract Infections show more inconsistent results. When it comes specifically to SARS-COV2, the limited number of studies suggest Quercetin may be effective, especially if used early on or as a prophylactic.
Dietary Quercetin is the main Source of Quercetin, and its Deficiency in Modern Diets may be Contributing to our Health Problems
Quercetin is primarily sourced from colorful fruits, vegetables, teas, and even some honey, all foods that many of our ancestors would have consumed on a regular basis. As we move more towards modernity and a modern American diet we may be moving away from more nutrient dense, plant-based foods. Modern "enriched" foods tend to supplement with additional vitamins and minerals, but may miss out on other plant-derived compounds that have played a substantial role in our diet. Similar to reduced sunlight exposure and the need for increased Vitamin D supplementation, we may need to look at possible supplementation of overlooked compounds such as polyphenols. Sourcing these compounds from real foods would prove the most beneficial, but in groups of people who may not have access to fresh fruits and vegetables, Quercetin and polyphenol supplementation may be useful. This would include people with alternative diets such as keto, who may avoid high carb fruits, and thus may be missing a key nutrient in their diets.
Quercetin has plenty of benefits, and for those who may be missing out on it in their diet they may want to look into sourcing it with supplementation. Don't take this as a prescription or recommendation, but an argument to examine your own health and see what you may be lacking. If you aren't someone who eats plenty of fruits and vegetables, it may be a good idea to start.
So the next time you grab an apple, reconsider peeling it, as you may be missing out on a hell of a vital compound!
Note: Citations (Part IV) will be included on a separate post, so look out for that!
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Nov 18, 2021Liked by Modern Discontent
Isn't there some evidence at this point that Sars-Cov2 isn't really a typical upper respiratory tract infection (URTI)? Many ACEII receptors are found in the intestines, as well as in the lungs. This could explain why Quercetin could possibly work better against Covid than standard URTI. I'm neither a doctor nor a chemist, just a curious and avid reader of all things Covid over the past 18 months. Thanks for your work!
1 reply by Modern Discontent
UM Ross
My wife and I have been taking quercetin supplement every other since mid 2020. I figure it can't hurt. However, I've been reading the the bio-availability of quercetin in most supplements is quite low?
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