Your immune system is your first line of defense against all disease, especially infectious disease, and there are many different ways to boost your immune system and improve its function. One nutrient that plays a very important role in your immune system’s ability to ward off viral infections is zinc.
Zinc gluconate,1 zinc acetate2 and zinc sulphate3 have all been shown to reduce the severity and duration of viral infections such as the common cold. Zinc also appears to be the key ingredient in treatment protocols using hydroxychloroquine (HCQ).
The reason for this is because HCQ is a zinc ionophore (zinc transport molecule),4,5 meaning it’s a drug that improves your cells’ uptake of zinc. Once inside your cells, zinc prevents viral replication.6 This is also why zinc and zinc ionophores need to be taken very early in the illness, or as a prophylactic.
The problem is that zinc is largely insoluble and cannot easily enter through the fatty wall of your cells. Getting all the way into the cell is crucial, as this is where the viral replication occurs. This is why zinc ionophores are so important.
Aside from hydroxychloroquine, other natural, and safer, zinc ionophores include quercetin and epigallocatechin-gallate (EGCG). If given early, zinc along with a zinc ionophore should, at least theoretically, help lower the viral load and prevent the immune system from becoming overloaded.
Zinc Is Crucial for Healthy Immune Function
Zinc is crucial for healthy immune function7 — like vitamin D, it actually helps regulate your immune function8 — and a combination of zinc with a zinc ionophore was in 2010 shown to inhibit SARS coronavirus in vitro. In cell culture, it also blocked viral replication within minutes.9
Importantly, zinc deficiency has been shown to impair immune function.10 As noted in a 2013 paper on zinc deficiency:11
“Zinc is a second messenger of immune cells, and intracellular free zinc in these cells participate in signaling events. Zinc … is very effective in decreasing the incidence of infection in the elderly. Zinc not only modulates cell-mediated immunity but is also an antioxidant and anti-inflammatory agent.”
Similarly, the September 2020 paper in Medical Hypotheses, “Does Zinc Supplementation Enhance the Clinical Efficacy of Chloroquine / Hydroxychloroquine to Win Todays Battle Against COVID-19?” points out that:12
“Besides direct antiviral effects, CQ/HCQ [chloroquine and hydroxychloroquine] specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication.
As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.”
Low Zinc Levels Increase COVID-19 Death Risk
Preliminary data also suggest people with low zinc levels are more likely to die from COVID-19 than those with higher levels. The research13,14,15,16,17 was presented at the European Society of Clinical Microbiology and Infectious Disease (ESCMID) Conference on Coronavirus Disease,18 held online September 23 through September 25, 2020, and posted19 on the preprint server medRxiv October 11, 2020.
In the video above, Dr. John Campbell reviews this and other zinc research. As noted by the authors of this study,20 “Zinc balances immune responses and also has a proven direct antiviral action against some viruses.” As mentioned, zinc’s primary antiviral action is to impair viral replication inside the cell.
To evaluate the importance of plasma zinc levels on COVID-19 outcomes, the researchers did a retrospective analysis of 249 COVID-19 patients admitted to a hospital in Barcelona, Spain, between Mach 15 and April 30, 2020, for whom fasting plasma zinc levels were recorded. The average patient age was 63.
Patients who had low zinc levels upon admission were found to have higher levels of inflammation during the course of their illness, and they were also more likely to die from complications related to COVID-19. As reported by Medical Xpress:21
“Mean baseline zinc levels among the 249 patients were 61 mcg/dl. Among those who died, the zinc levels at baseline were significantly lower at 43 mcg/dl vs 63.1 mcg/dl in survivors.
Higher zinc levels were associated with lower maximum levels of interleukin-6 (proteins that indicate systemic inflammation) during the period of active infection.
After adjusting by age, sex, severity and receiving hydroxychloroquine, statistical analysis showed each unit increase of plasma zinc at admission to hospital was associated with a 7% reduced risk of in-hospital mortality.
Having a plasma zinc level lower than 50 mcg/dl at admission was associated with a 2.3 times increased risk of in-hospital death compared with those patients with a plasma zinc level of 50 mcg/dl or higher.”
Zinc Deficiency Linked to Poor COVID-19 Outcomes
Another paper22 reviewed by Campbell was published in the November 2020 issue of the International Journal of Infectious Diseases. Here, they found that people admitted to the hospital with COVID-19 related symptoms were more likely to be deficient in zinc than healthy controls. The median zinc level among hospitalized COVID-19 patients was 74.5 mcg/dl, compared to 105.8 mcg/dl in the control group. As reported by the authors:23
“Amongst the COVID-19 patients, 27 (57.4%) were found to be zinc deficient. These patients were found to have higher rates of complications, acute respiratory distress syndrome (18.5% vs 0%), corticosteroid therapy, prolonged hospital stay, and increased mortality (18.5% vs 0%). The odds ratio (OR) of developing complications was 5.54 for zinc deficient COVID-19 patients.”
Importantly, while 70.4% of zinc deficient patients developed complications, only 30% of those with sufficient levels developed complications. As noted by Campbell, here we see that healthy controls had far higher zinc levels than patients with milder illness in the Spanish study.
The hospitalized patients also had higher levels on average. This raises the question as to whether the Spanish cutoff level of 50 mcg/dl might be too low still. He points out that “normal” levels of zinc are between 72 mcg/dl and 144 mcg/dl. This seems to support the findings of the Spanish study, seeing how all of the patients were on the low side.
Zinc Is a Key Component of MATH+ Protocol
Among the most effective treatment protocols for COVID-19 is the MATH+ Protocol,24 developed by the Front Line COVID-19 Critical Care Working Group25 (FLCCC).
In the interview above, Dr. Paul Marik explains how the COVID-19 critical care protocol grew out of his sepsis treatment (a core ingredient of which is vitamin C), as he and other doctors noticed there were many similarities between sepsis and severe COVID-19 infection, in particular the out-of-control inflammatory cascade.
There are also distinct differences between the two conditions, and to address those, Marik and nine other physicians founded the FLCCC and began developing a modified protocol specifically for COVID-19.
Zinc is one of the central components of this protocol. As of its July 2020 update, the protocol also includes the use of quercetin to facilitate zinc uptake. There are now MATH+ protocols26 for prophylaxis, mild symptoms that can be treated at home, and a full clinical in-hospital critical care protocol.
The group has issued several updates since April 2020, so be sure to download the latest versions from the Eastern Virginia Medical School COVID Care for Clinicians site.27
Natural Zinc Transporters — Quercetin and EGCG
As mentioned, quercetin28 and EGCG are natural zinc ionophores that can do the same job as HCQ. According to a study29 published in 2014, many of the biological actions of quercetin and EGCG actually appear to be related to their ability to increase cellular zinc uptake. As explained by the authors:30
“Labile zinc, a tiny fraction of total intracellular zinc that is loosely bound to proteins and easily interchangeable, modulates the activity of numerous signaling and metabolic pathways. Dietary plant polyphenols such as the flavonoids quercetin (QCT) and epigallocatechin-gallate act as antioxidants and as signaling molecules.
Remarkably, the activities of numerous enzymes that are targeted by polyphenols are dependent on zinc. We have previously shown that these polyphenols chelate zinc cations and hypothesized that these flavonoids might be also acting as zinc ionophores, transporting zinc cations through the plasma membrane.
To prove this hypothesis, herein, we have demonstrated the capacity of QCT and epigallocatechin-gallate to rapidly increase labile zinc in mouse hepatocarcinoma Hepa 1-6 cells as well as, for the first time, in liposomes … The ionophore activity of dietary polyphenols may underlay the raising of labile zinc levels triggered in cells by polyphenols and thus many of their biological actions.”
Aside from increasing zinc uptake, both quercetin and EGCG also inhibit 3CL protease31 — an enzyme used by SARS coronaviruses to infect healthy cells.32 As explained in a 2020 paper33 in Nature, 3CL protease “is essential for processing the polyproteins that are translated from the viral RNA.”
And, according to another 2020 study,34 the ability of quercetin, EGCG and certain other flavonoids to inhibit SARS coronaviruses “is presumed to be directly linked to suppress the activity of SARS-CoV 3CLpro in some cases.”
Niacin (vitamin B3) and selenium also improve the absorption and bioavailability of zinc. For example, a study35 published in 1991 demonstrated that when young women were on a vitamin B6-deficient diet, their serum zinc declined, suggesting B6 deficiency affected zinc metabolism such that “absorbed zinc was not available for utilization.”
A more in-depth exploration and explanation of both niacin and selenium’s relationship to zinc is provided in the 2008 paper, “Zinc, Metallothioneins and Longevity: Interrelationships With Niacin and Selenium.”36
More Support for Quercetin
Support for the use of quercetin against COVID-19 has also been reported by the Green Stars Project.37 Using the supercomputer SUMMIT, Oak Ridge National Lab researchers looked for molecules capable of inhibiting the COVID-19 spike protein from interacting with human cells. Quercetin is fifth on that list.38
Quercetin is also a potent antiviral in general. As detailed in “Quercetin Lowers Your Risk for Viral Illnesses,” mechanisms of action that can make it useful against COVID-19 include:
Inhibiting virus’ ability to infect cells39
Inhibiting replication of already infected cells
Reducing infected cells’ resistance to treatment with antiviral medication
Inhibiting lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) production in macrophages.40 TNF-α is a cytokine involved in systemic inflammation, secreted by activated macrophages, a type of immune cell that digests foreign substances, microbes and other harmful or damaged components
Inhibiting release of proinflammatory cytokines and histamine by modulating calcium influx into the cell41
Stabilizing mast cells42
Regulating the basic functional properties of immune cells43
Down-regulating or suppressing inflammatory pathways and functions44
Zinc-to-Copper Ratio Can Impact Immune Function
When it comes to zinc supplementation, more is not necessarily better. In fact, it can frequently backfire is you do not also maintain a healthy zinc-to-copper ratio. As explained by Chris Masterjohn, who has a Ph.D. in nutritional sciences,45 in an article46 and series of Twitter posts:47
“In one study, 300mg/day of zinc as two divided doses of 150 mg zinc sulfate decreased important markers of immune function, such as the ability of immune cells known as polymorphonuclear leukocytes to migrate toward and consume bacteria.
The most concerning effect in the context of COVID-19 is that it lowered the lymphocyte stimulation index 3 fold. This is a measure of the ability of T cells to increase their numbers in response to a perceived threat. The reason this is so concerning in the context of COVID-19 is that poor outcomes are associated with low lymphocytes …
The negative effect on lymphocyte proliferation found with 300 mg/day and the apparent safety in this regard of 150 mg/d suggests that the potential for hurting the immune system may begin somewhere between 150-300 mg/d …
It is quite possible that the harmful effect of 300 mg/d zinc on the lymphocyte stimulation index is mediated mostly or completely by induction of copper deficiency …
The negative effect of zinc on copper status has been shown with as little as 60 mg/d zinc. This intake lowers the activity of superoxide dismutase, an enzyme important to antioxidant defense and immune function that depends both on zinc and copper …
A study done with relatively low intakes of zinc suggested that acceptable ratios of zinc to copper range from 2:1 to 15:1 in favor of zinc. Copper appears safe to consume up to a maximum of 10 mg/d.
Notably, the maximum amount of zinc one could consume while staying in the acceptable range of zinc-to-copper ratios and also staying within the upper limit for copper is 150 mg/d.”
Another factor to keep in mind is that certain additives can inhibit zinc absorption, which is the complete opposite of what you’re looking for. For instance, research has shown citric acid, glycine, mannitol and sorbitol can reduce zinc absorption,48 so zinc lozenges containing these ingredients may be less useful.
How Much Zinc Do You Need?
That said, the recommended dietary allowance for zinc in the U.S is 11 mg for adult men and 8 mg for adult women, with slightly higher doses recommended for pregnant and breastfeeding women.49
As a prophylactic against COVID-19 and other viral infections, Masterjohn recommends taking 7 mg to 15 mg of zinc four times a day, ideally on an empty stomach, or with a phytate-free food. He also recommends getting at least 1 mg of copper from food and supplements for every 15 mg of zinc you take.
Last but not least, remember there are many food sources of zinc, so a supplement may not be necessary. I eat about three-quarters of a pound of ground bison or lamb a day, which provides 20 mg of zinc. I personally don’t take any zinc supplement other than what I get from my food, which is likely in an optimal form to maximize absorption.
Sources and References
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- 2 JRSM Open, 2017;8(5):20542704
- 3 Acta Paediatrica 2006; 95(10):1175-81
- 4 PLOS ONE 2014; 9(10): e109180
- 5, 6 Preprints April 6, 2020 DOI: 10.20944/preprints202004.0124.v1
- 7 NIH Zinc Fact Sheet for Consumers
- 8, 22 International Journal of Infectious Diseases November 2020; 100: 343–349
- 9 PLOS Pathogens November 4, 2010 DOI: 10.1371/journal.ppat.1001176
- 10 NIH Zinc Fact Sheet, Zinc Deficiency
- 11 Advances in Nutrition 2013 Mar; 4(2): 176–190
- 12 Medical Hypotheses September 2020; 142: 109815
- 13, 19 MedRxiv October 11, 2020 DOI: 10.1101/2020.10.07.20208645
- 14 Univadis, ECCVID 2020 Conference Report, September 23, 2020
- 15, 21 Medical Xpress September 23, 2020
- 16 US News September 23, 2020
- 17 Yahoo! Life September 25, 2020
- 18 ESCMID Conference
- 20 MedRxiv October 11, 2020 DOI: 10.1101/2020.10.07.20208645, Abstract
- 23 International Journal of Infectious Diseases November 2020; 100: 343–349, Results
- 24 Covid.us.org MATH+ Protocol
- 25 covid19criticalcare.com
- 26, 27 Eastern Virginia Medical School COVID Care Protocol for Clinicians
- 28 Journal of Agricultural and Food Chemistry 2014, 62, 32, 8085-8093
- 29, 30 Journal of Agricultural Food Chemistry August 13, 2014; 62(32): 8085-8093
- 31, 34 Journal of Enzyme Inhibition and Medicinal Chemistry 2020; 35(1): 145–151
- 32 Science March 20, 2020; eabb3405
- 33 Nature June 24, 2020; 11 Article Number 3202
- 35 American Journal of Clinical Nutrition December 1991; 54(6): 1059-1064
- 36 Curr. Pharm. Des. 2008; 14(26): 2719-2732
- 37 Greenstarsproject.org March 27, 2020
- 38 ChemRxiv.org March 11, 2020 (PDF full study), Table 3
- 39 Viruses 2016 Jan; 8(1): 6
- 40, 43, 44 Nutrients 2016 Mar; 8(3): 167, 5.1.2 Mechanism of Action
- 41, 42 Nutrients 2016 Mar; 8(3): 167, Table 1: Mast cell
- 45 Chrismasterjohnphd.com
- 46 Chrismasterjohnphd.com Best Dose of Zinc for COVID-19 Prevention
- 47 Twitter, Chris Masterjohn April 10, 2020
- 48 Cochrane Database Syst Rev. 2015 Apr; 2015(4): CD001364
- 49 NIH Zinc Fact Sheet