Are zinc supplements helpful against Covid-19? Let’s see what the research says.

[1] A 2010 peer-reviewed study showed that zinc ions “block the replication” of two types of RNA viruses, the coronavirus type and the arterivirus type, in vitro, only if a zinc ionophore is present to carry the zinc ions into the cell [1]. The study also found that zinc ions plus a zinc ionophore inhibited the RdRp (replicase enzyme) of the SARS-CoV virus (i.e. SARS-CoV-1).

[2] A 2020 article, dated as 31 Dec 2019 at EuropePMC.org, stated its conclusion as its title: “Improving the efficacy of chloroquine and hydroxychloroquine against SARS-CoV-2 may require zinc additives” [2]. The article found that both drugs chloroquine and hydroxychloroquine are zinc ionophores. Since hydroxychloroquine acts directly against SARS-CoV-2 and is a zinc ionophore, adding zinc to hydroxychloroquine might increase its effectiveness by adding the action of zinc against RdRp. The study cited Velthuis, in the body of the article, concerning zinc as an inhibitor of the RdRp of SARS-CoV-1 [2].

[3] A 2014 study, titled “Zinc ionophore activity of quercetin and epigallocatechin-gallate: From Hepa 1-6 cells to a liposome model,” found that both quercetin, a flavonoid, and EGCG, a polyphenol found in green tea, are zinc ionophores [3].

[4] An April 2020 article concluded that zinc might work against Covid-19 by several different mechanisms of action: “Zn may possess protective effect as preventive and adjuvant therapy of COVID-19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator-induced lung injury, modulation of antiviral and antibacterial immunity” [4].

[5] An article in Medical Hypotheses suggested that, since zinc is “physiologically needed for an effective antiviral response,” a Covid-19 study on treatment modalities should include one arm with “HCQ in combination with zinc” [5]. Another arm of the study would use hydroxychloroquine (HCQ) without zinc, to determine the effectiveness of adding zinc to HCQ, a zinc ionophore.

[6] An article in “Frontiers in Immunology” explained a number of ways that zinc might benefit Covid-19 patients:
“* Zinc deficiency may be common and associated with severe infection.
* Zinc helps to enhance the interferon type 1 response to the virus and participates in many regulatory pathways.
* Low levels of zinc have been associated with higher IL-6 responses.
* IL-6 plays an important role in severe lung injury due to COVID-19 infection.
* Zinc inhibits SARS-CoV RNA polymerase, and thus its replication capacity.” [6]

Higher IL-6 is bad for Covid-19 patients as it means that more cytokines will be released, making a cytokine storm more likely; and the cytokine storm is one of the main causes of death in Covid-19. Zinc suppresses this excessive IL-6 response to viral infection. Zinc also inhibits Replicase (RNA dependent RNA polymerase or RdRp), slowing viral propagation.

[7] A study of Covid-19 patients found that those treated with triple therapy — zinc, hydroxychloroquine, azithromycin — were 84% less likely to be hospitalized than untreated patients.

“In the treatment group 4 of 141 patients were hospitalized, which was significantly less than in the untreated group with 58 of 377 patients (15.4%), (fig 2.), (OR 0.16; [95% CI, 0.06 to 0.5]; p<0.001), (table 7, fig 4). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated patients." [7]

The study noted that zinc not only inhibits the replicase enzyme of SARS-CoV-2, but “In addition, zinc might inhibit the serine protease furin.” Furin has been hypothesized to have a role in SARS-CoV-2 infection by means of the ACE2 receptor.

[8] An article titled “Zinc Supplementation Prevents the Complications of COVID-19 Infection in Cancer Patients” recommends zinc for cancer patients, due to its benefits for the immune system. The study also notes: “Research indicates that the concentrations of zinc in the serum or plasma are low in people with cancer, which is consistent with several studies, which confirm that there is a strong relationship between low levels of zinc and cancer [8]”.

“In conclusion, with the multiple doses approved from zinc, we suggest that there be a supplement in zinc by 50 mg / day for three month with each treatment for cancer patients, in order to strengthen the immune system to prevent the serious effects of COVID19 infection.” [8]

[9] A study from New York University, Grossman School of Medicine, published in medRxiv (not peer-reviewed) compared two groups of patients, one treated with and the other without a zinc supplement. The authors “performed a retrospective observational study to compare hospital outcomes among patients who received hydroxychloroquine and azithromycin plus zinc versus hydroxychloroquine and azithromycin alone [9].”

“After adjusting for the time at which zinc sulfate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09) reduction in mortality or transfer to hospice remained significant (OR 0.449, 95% CI 0.271-0.744).” [9]

So the patients given zinc supplements with hydroxychloroquine and azithromycin, as compared to patients who received hydroxychloroquine and azithromycin but not zinc, were 53% more likely to be discharged home, and 55% less likely to either die or be transferred to a hospice (usually meaning that the patient was not expected to live) [9].

“As a result of in vitro evidence suggesting zinc sulfate may be efficacious against COVID-19, our hospitals began using zinc sulfate as add-on therapy to hydroxychloroquine and azithromycin. [9]” The involved hospitals did not wait for an RCT or even a clinical study. They began using zinc based on in vitro evidence (lab studies). And this decision was borne out in the results of this study, adding zinc to their protocol saved lives. Half as many patients died from Covid-19 under the new treatment regimen.

[10] A study in rats found that zinc deficiency makes the injury of lungs from mechanical ventilation worse: “Zinc deficiency primes the lung for ventilator-induced injury [10].” The hope, which is certainly not yet proven, is that zinc supplementation will reduce lung injury for Covid-19 patients who need mechanical ventilation. However, this study was in 2017, before Covid-19 began. So the study authors are concerned with mechanical ventilation in general, not specifically for Covid-19: “Mechanical ventilation (MV) is often lifesaving but can also exacerbate lung injury [10].”

[12] Dr. Paul Marik, who developed the MATH+ Protocol for treating Covid-19, was interviewed by Dr. Mobeen Syed, on his YouTube channel (DrBeen Medical Lectures) about Covid-19. There, Dr. Marik stated that hydroxychloroquine should be taken with zinc, beginning as early as possible (as soon as symptoms occur). It takes 4 or 5 days to reach proper levels in the lungs.

Dr. Marik on hydroxychloroquine: “I think it has a role early…. I think it has to be taken with zinc. I think that zinc and hydroxychloroquine go hand in hand…. The zinc makes it a much more potent drug….” [12] He also stated that in some studies the dose of hydroxychloroquine is too high. When using hydroxychloroquine, he recommended early use with zinc at low levels (200 mg twice a day).

Discussion

The first point is that zinc ions cannot enter a cell unless another compound, called a zinc ionophore, carries it across the lipid bilayer. Zinc ionophores include: hydroxychloroquine, chloroquine, doxycycline, quercetin, and EGCG (found in green tea extract). Once zinc is inside a cell, if that cell is also infected with SARS-CoV-2 (the Coronavirus), researchers believe it can bind to and inhibit the RdRp enzyme (“replicase”). That enzyme makes copies of the viral RNA. So the goal is to bring zinc into the cell, and have it bind to replicase so as to prevent viral replication. This would keep the virus from making copies of itself and thereby slow the progress of the Covid-19 disease. However, this type of inhibition, if it occurs, is never 100%, so the effect it limited. It is not a cure. The mechanism of action whereby zinc binds replicase is not proven, but is deduced from in vitro studies of SARS-CoV-1 (the SARS virus), and from the effectiveness of zinc supplements in clinical studies.

The second point is that zinc strengthens the immune system in various ways and may therefore help the body fight off any viral infection. “Zinc is vital for normal development and function of cells mediating innate immunity, NK cells and neutrophils [8].” The immune system has two “arms”, the innate arm which is the first responder against viral and bacterial infection, and the acquired arm, which “learns” which viral and bacterial proteins are foreign, and seeks to neutralize them.

“Adequate zinc intake is essential in maintaining the integrity of the immune system, specifically for normal development and function of cells that mediate both innate (neutrophils, macrophages, and natural killer cells) and adaptive (B-lymphocytes and T-lymphocytes) immune responses.” [11]

The third and final point is that zinc supplementation, in two recent studies, improved the outcomes for Covid-19 patients [7, 9]. In one study, patients with mild to moderate Covid-19 were 84% less likely to need hospitalization when given triple therapy: zinc, hydroxychloroquine, azithromycin [7]. In the other study, patients given triple therapy, including zinc, as compared to those who received hydroxychloroquine and azithromycin only, were 53% more likely to be discharged home, and 55% less likely to either die or be transferred to a hospice [9].

You may have read about the importance of having an RCT (randomized controlled trial) before using a treatment. Notice that the group of hospitals in the latter study [9] began adding zinc supplementation to their treatment of Covid-19 patients based on in vitro evidence only. They performed the study later, and discovered that they were saving lives by this decision: patients were 55% less likely to die or be sent to a hospice (where they would likely die). When you have information that saves lives, you use it. Zinc supplementation is well-known to be a safe intervention, and it is an essential micronutrient. So it made sense for the hospital group to give zinc to their patients, and this decision paid off in lives saved.

Ronald L. Conte Jr.
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

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1. Te Velthuis, Aartjan JW, et al. “Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture.” PLoS pathogens 6.11 (2010): e1001176.
https://tinyurl.com/y7uv5mf2

2. Shittu, Mujeeb Olushola, and Olufemi Ifeoluwa Afolami. “Improving the efficacy of chloroquine and hydroxychloroquine against SARS-CoV-2 may require zinc additives-A better synergy for future COVID-19 clinical trials.” Infez Med 28.2 (2020): 192-197.
https://tinyurl.com/ycpchd4t

3. Dabbagh-Bazarbachi, Husam, et al. “Zinc ionophore activity of quercetin and epigallocatechin-gallate: From Hepa 1-6 cells to a liposome model.” Journal of agricultural and food chemistry 62.32 (2014): 8085-8093.
https://pubs.acs.org/doi/abs/10.1021/jf5014633

4. Skalny, Anatoly V., et al. “Zinc and respiratory tract infections: Perspectives for COVID‑19.” International Journal of Molecular Medicine 46.1 (2020): 17-26.
https://www.spandidos-publications.com/10.3892/ijmm.2020.4575

5. Derwand, R., and M. Scholz. “Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win todays battle against COVID-19?.” Medical Hypotheses (2020): 109815.
https://www.sciencedirect.com/science/article/pii/S0306987720306435

6. Mayor-Ibarguren, Ander, and Ángel Robles-Marhuenda. “A Hypothesis for the Possible Role of Zinc in the Immunological Pathways Related to COVID-19 Infection.” Frontiers in Immunology 11 (2020): 1736.
https://www.frontiersin.org/articles/10.3389/fimmu.2020.01736/full

7. Scholz, Martin, Roland Derwand, and Vladimir Zelenko. “COVID-19 Outpatients–Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study.” (2020). Received by Preprints.org 30 June 2020.
https://www.preprints.org/manuscript/202007.0025/download/final_file

8. Derouiche, Samir. “Zinc Supplementation Prevents the Complications of COVID-19 Infection in Cancer Patients.” Asian Pacific Journal of Cancer Care 5.S1 (2020): 137-141.
http://www.waocp.com/journal/index.php/apjcc/article/view/399

9. Carlucci P, Ahuja T, Petrilli CM, Rajagopalan H, Jones S, Rahimian J. “Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patents.” medRxiv (2020).
https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v1

10. Boudreault, Francis, et al. “Zinc deficiency primes the lung for ventilator-induced injury.” JCI insight 2.11 (2017).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453708/

11. Higdon, Jane. “Linus Pauling Institute Micronutrient Information Center.” Oregon State University (2005).
https://lpi.oregonstate.edu/mic/minerals/zinc

12. Dr. Paul Marik, interviewed by Dr. Mobeen Syed at DrBeen Medical Lectures on YouTube, 7/15/2020; 1 hour and 5 minute mark, approximately.