Quercetin and Zinc Ionophore Activity: Studies and Review 2021

By Dr Frank Yap, MD - March 19, 2021

Zinc is a mineral element needed to regulate adaptive immune cells' functions. Higher level of intracellular zinc showed to increase intracellular pH; which affect on RNA-dependent RNA polymerase and decrease replication mechanism of RNA viruses. Therefore, drugs that described as zinc ionophores could be used with zinc supplement to act as antiviral against many RNA viruses including SARS-CoV-2. Quercetin is natural compound act as zinc ionophore to cause zinc influx intracellular.

Quercetin is a safe natural anti-oxidant and anti-inflammatory polyphenolic compound that found in various natural sources include onion, red grapes, honey and citrus fruits. It was shown that quercetin has the ability to chelate zinc ions and act as zinc ionophore. Therefore, quercetin could have antiviral activity against many RNA viruses . Quercetin, a flavonoid found in fruits and vegetables, has unique biological properties that may improve mental/physical performance and reduce infection risk.

As of March 2021, there are more than 70 types of supplements that are being tested for COVID-19. You can review the details of these trials on clinicaltrials.gov. There are more than 120 trials testing the various nutrients and dietary supplements including vitamin D, vitamin C, zinc and quercetin. Vitamin D remains the most tested vitamin followed by vitamin C, for COVID-19.

The lung injury in COVID-19 patients is associated with ROS (reactive oxygen species) released by white cells in the blood, and thus the use of antioxidants is necessary for the management of COVID-19.

Do take note that for optimal effectiveness, each supplement should not be considered as a single intervention as most of the supplements are given as part of a combination protocol. Further, each nutrient will also have influence on another nutrient. For example, vitamin C and zinc need to be given together with copper. Also, vitamin D3 is synergistic with vitamin K2 and magnesium.

Hydroxychloroquine, Quercetin and EGCG (EpiGalloCatechin Gallate) are all zinc ionophores. Meaning they all transport zinc into the cells. We will dive deeper into the science and here below is a compilation of Quercetin and Zinc related studies:

Quercetin and COVID-19

Quercetin was initially found to provide broad-spectrum protection against SARS coronavirus in the aftermath of the SARS epidemic that broke out across 26 countries in 2003.

Quercetin acts as a zinc ionophore (PubMed 2014), the same mechanism of action that hydroxychloroquine has via helping zinc pass the cell wall where it might halt viral replication.

This zinc ionophore activity of quercetin facilitates the transport of zinc across the cell membrane. It is known that zinc will slow down the replication of coronavirus through inhibition of enzyme RNA polymerase (PubMed 2010). The COVID-19 is an RNA (RiboNucleicAcid) virus and requires the RNA polymerase to replicate. Do take note that the study publication was a 2010 publication and is referring to a different coronavirus as compared to the latest coronavirus (COVID-19); though both are from the same family of coronaviruses.

Quercetin, Zinc and Vitamin C

Incidentally, ascorbic acid (vitamin C) and the bioflavonoid quercetin (originally labeled vitamin P) were both discovered by the same scientist — Nobel prize winner Albert Szent-Györgyi. Quercetin and vitamin C also act as an antiviral drug, effectively inactivating viruses.

There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy.

For prevention, the Front Line COVID-19 Critical Care Working Group, FLCCC recommends (updated January 12, 2021):

Vitamin D3 — 1000–3000 IU/day. Note RDA (Recommended Daily Allowance) is 800–1000 IU/day. The safe upper-dose daily limit is likely < 4000 IU/day. Vitamin D deficiency has been associated with an increased risk of acquiring COVID-19 and from dying from the disease. Vitamin D supplementation may therefore prove to be an effective and cheap intervention to lessen the impact of this disease, particularly in vulnerable populations, i.e. the elderly, those of color and obese. (Amazon)
Vitamin C - 1,000 mg BID (twice daily)
Quercetin 250 mg daily. It is likely that vitamin C and quercetin have synergistic prophylactic benefit. Quercetin should be used with caution in patients with hypothyroidism and TSH levels should be monitored. (Amazon)
Melatonin: 6 mg before bedtime (causes drowsiness). (Amazon)
Zinc: 50 mg/day (elemental zinc). Zinc lozenges are preferred. (Amazon)
Ivermectin for prophylaxis in high-risk individuals (> 60 years with co-morbidities, morbid obesity, long term care facilities, etc). 0.2 mg/kg Day 1, Day 3 and then followed by biweekly dosing (one dose every two weeks). (also see ClinTrials.gov NCT04425850). NB. Ivermectin has a number of potentially serious drug-drug interactions. Please check for potential drug interaction at Ivermectin Drug Interactions - Drugs.com. The most important drug interactions occur with cyclosporin, tacrolimus, anti-retroviral drugs, and certain anti-fungal drugs.

For early outpatient protocol (COVID-19 positive), the Front Line COVID-19 Critical Care Working Group, FLCCC recommends (updated January 12, 2021):

Vitamin D3 — 4000 IU/day. (Amazon)
Vitamin C - 2,000 mg BID (twice daily)
Quercetin 250 mg twice a day.
Melatonin: 10 mg before bedtime (causes drowsiness).
Zinc: 100 mg/day. Zinc lozenges are preferred. (Amazon)
Ivermectin 0.2 mg/kg per dose. One dose daily - minimum 2 days, maximum 5 days.
FLCCC also recommend monitoring your oxygen saturation with a pulse oximeter and to go to
the hospital if you get below 94%.
Aspirin 325 m/day unless contraindicated.

The medical evidence to support each drug and nutrient can be found under “Medical Evidence” on the FLCCC’s website.

Related: Best Pulse Oximeter 2021

Quercetin: Anti-viral Significance

A review published in The Sage Journal (Dec 2020), summarizes the antiviral significance of quercetin and proposes a possible strategy for the effective utilization of natural polyphenols in our daily diet for the prevention of viral infection.

Quercetin: AAPS (Association of American Physicians and Surgeons) Guidelines

The AAPS recommends the following outpatient treatment protocol for COVID-19:

Quercetin oral 500 mg twice a day.
Vitamin C 3000 mg
Vitamin D3 5000 IU
Zinc sulphate 220 mg

Please take note the above dosages are relatively high and is meant for 'treatment'. If you wish to continue taking these nutrients for health maintenance, you'll need to go back to the usual 'RDA or RDI' dosages after you recover.

A word about quercetin: Some physicians are recommending this supplement to reduce viral illnesses because quercetin acts as a zinc ionophore to improve zinc uptake into cells. It is much less potent than HCQ (hydroxychloroquine) as a zinc transporter, and it does not reach high concentrations in lung cells that HCQ does. Quercetin may help reduce risk of viral illness if you are basically healthy. But it is not potent enough to replace HCQ for treatment of COVID once you have symptoms, and it does not adequately get into lung tissue unless you take massive doses (3-5 grams a day), which cause significant GI (gastrointestinal) side effects such as diarrhea.

Best Quercetin Zinc Supplement:

Nature's Bounty Immune 24 Hour + > Check Price on Amazon (Vitamin D, C, Zinc and other nutrients)
Now Foods Quercetin with Bromelain > Check Price on Amazon (#1 in Bromelain Supplements)

Related: Best Quercetin Supplement 2021

Zinc and COVID-19

Foods that are high in zinc include oysters, crab, lobster, mussels, red meat, and poultry. Cereals are often fortified with zinc. Most multivitamin and nutritional supplements contain zinc.

Zinc has been shown in a lab study to inhibit regular coronavirus (not the current SARS-CoV-2) in a 2010 publication.

As of February 2021, there are more than 45 studies that have been launched to investigate the benefits of Zinc against COVID-19. You can review the status of these trials on clinicaltrials.gov.

A retrospective observational study (Carlucci P, Sep 2020) compared zinc supplementation to no zinc supplementation in hospitalized patients with COVID-19 who received hydroxychloroquine and azithromycin from March 2 to April 5, 2020. A total of 932 patients were included in this analysis; 411 patients received zinc, and 521 did not. After adjusting for the time at which zinc sulphate was added to the protocol, an increased frequency of being discharged home and reduction in mortality or transfer to hospice among patients who did not require ICU level of care remained significant. This study provides the first in vivo evidence that zinc sulphate may play a role in therapeutic management for COVID-19.

A study in Spain (Gonzalez, The Lancet preprint, Oct 2020) among people hospitalised with COVID-19 found that having very low blood levels of zinc was associated with more severe disease and higher mortality rates.

Taking zinc long term is typically safe for healthy adults, as long as the daily dose is under the set upper limit of 40 mg of elemental zinc (PubMed ).

Be aware that typical daily doses of zinc provided by zinc lozenges generally exceed tolerable upper limits for zinc, and for this reason, they should not be used for longer than about a week.

Excessive doses may interfere with copper absorption, which could negatively affect your immune system as it can cause copper deficiencies, blood disorders, impair the absorption of antibiotics and potentially permanent nerve damage or loss of smell.

The ideal dose for prevention while the COVID-19 risk is high is 40-100 mg/d, a portion of which comes from zinc lozenges to spread the zinc through the tissues of the nose, mouth and throat. It should be accompanied by at least 1 mg copper from food and supplements for every 15 mg zinc.

Do take note that you should keep the dosage back to within 40 mg/d once the exposure risk is back to normal.

Zinc Sulphate is also part of Dr. Vladimir Zelenko anti-coronavirus experimental protocol. Please take note that the protocol is experimental and has not been 100% proven. Do discuss with your doctor before taking the medication as per the protocol. You can check out his publication in the International Journal of Antimicrobial Agents.

Based on the statement released on 2 October by the U.S. president’s physician, zinc is also part of the treatment given to the US President. According to the president's physician, "Trump has been taking zinc, vitamin D, famotidine, melatonin and a daily aspirin.”

Editor's note: Hydroxychloroquine is a zinc ionophore. If increased intracellular Zn ion concentration is required to disrupt viral replication, perhaps using multiple zinc ionophores would increase that concentration thus decreasing viral replication further. Other OTC (over the counter) zinc ionophores include quercetin (QCT) and epigallocatechin-gallate (EGCG – green tea extract).

Related: Best Zinc Supplement 2021

Bromelain and Quercetin

The major benefit of Quercetin and bromelain is they both fight inflammation. Quercetin is not soluble in water, however, so it is a poorly absorbed nutrient. Bromelain, a protein-digesting enzyme extracted from pineapples, increases the absorption of quercetin, as does vitamin C. Therefore quercetin is typically sold blended with one or both additives (PubChem).

Bromelain, Quercetin, Zinc and Vitamin C

A case series of 22 patients, published in Medrxiv revealed that quercetin 800 mg once daily with bromelain 165 mg, in addition to zinc acetate 50 mg and vitamin C 1 g supplements are safe with COVID-19 patients who were on multiple therapies including antivirals and antibacterial medications. The effectiveness of quercetin, bromelain, zinc and ascorbic acid combination was not clear in this study, because of lacking placebo or comparable group.

Quercetin, EGCG, Hesperidin, Naringin and COVID 19

A molecular docking and pharmacological study, published in Heliyon, March 2021; highlighted that flavonoids such as hesperidin, naringin, and ECGC were found to be efficient towards the viral spike protein, whereas quercetin was demonstrated to efficiently block the human ACE-2 receptor.

Conclusion

Do take note that the dosages for micronutrients or vitamins are higher for treatment as opposed to maintenance or preventive. This is probably due to higher demand of the body or the deficiency of the micronutrients are worse during a complicated viral infection. However, for prevention or maintenance, the dosages for most of the micronutrients are much lower.

The risk for hospitalisations, ventilation, and death from COVID-19 are all elevated in people with preexisting conditions, especially high blood pressure and diabetes. Take steps to control hypertension and blood sugar fluctuations with diabetes, as these conditions are associated with more severe disease if infected. This may also help you maintain a healthy weight, which is important because obesity has been associated with an increased risk of requiring intubation or dying among people hospitalized with COVID-19, particularly those under 65 years of age. Risk was 60% greater among those with severe obesity (BMI > 34.9 kg/m2) compared to patients of normal weight (BMI of 18.5 to 24.9 kg/m2) (Anderson, Annals Int Med 2020).

Viral infections like the COVID-19 also put added stress on your body, which can affect your blood pressure, heart rate, and overall heart function. That can raise your probability of having a heart attack or stroke. Therefore, make sure your blood pressure is well controlled during this pandemic.

Aside from supplements, there are other ways that may help improve immune response and to prevent you from catching the coronavirus.

Wear protective face mask. This is to protect not only yourself but others.
Abundant evidence suggests that eating whole in fruits, vegetables and whole grains—all rich in networks of naturally occurring antioxidants and their helper molecules—provides protection against free radicals.
Getting Enough Sleep
Avoid Sugar, red meat and processed foods.
Don't smoke.
Take steps to avoid infection, such as washing your hands frequently, using hand sanitizer and cooking meats thoroughly.
Try to minimize stress.
Drink enough water to keep your body hydrated.
Avoid excess alcohol.
Avoid crowded areas.
Regular physical activity (outdoor activities may not be allowed in countries with 'lock-down').
Consult your nearest local healthcare provider if you have any doubt.

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