On March 23, Dr. Zev Zelenko wrote an open letter "to medical professionals all around the world" about his treatment for COVID-19 using hydroxychloroquine, azithromycin, and zinc sulfate. Days before, he had addressed a YouTube video to President Trump about his success, which went viral and got picked up by many political commentators. This Wednesday Trump said at a briefing "you should add zinc" to any COVID-19 treatment, which has zinc all over the news right now.

I count myself among the advocates for zinc, and my protocol in The Food and Supplement Guide for the Coronavirus, supplies 46-78 milligrams of zinc per day, depending on how it's implemented, with an extra 36 milligrams of zinc around each potential exposure to the virus, and then additional zinc added for anyone experiencing any symptoms of cold, flu, or COVID-19. Someone who uses a typical zinc supplement and the recommended zinc lozenges, and goes out to the store once a day, would wind up getting 114 milligrams of zinc.

On the lower end, functional medicine mogul Dr. Mark Hyman recommends 20 milligrams per day of zinc. On the higher end, Zelenko's protocol includes 240 milligrams per day.

These are all significantly higher than the RDA of 11 mg/d for adult men and 8 mg/d for adult women. However, there is more than a ten-fold spread between these recommendations.

In this update, I'll be covering two questions:
  • How likely is zinc to help prevent or treat COVID-19?
  • If it is effective, what is the best dose to take?
Could Zinc Prevent or Treat COVID-19?

Zelenko's rationale for zinc was as follows "We know that hydroxychloroquine helps Zinc enter the cell. We know that Zinc slows viral replication within the cell."

Actually, we know neither of these things. As I pointed out in past updates, hydroxychloroquine and chloroquine have not been shown to bring zinc into cells at concentrations anywhere near as low those required to stop the replication of SARS-CoV-2, the virus that causes COVID-19. Moreover, at the high concentrations needed to bring zinc into the cell, they keep it stuck in locations of the cell that would be irrelevant to slowing viral replication. Further, there is as yet no direct evidence that zinc slows the replication of the virus.

Here is what we do know.

Zinc directly inhibits two enzymes essential to the replication of SARS-CoV, the coronavirus that causes SARS. These include papain-like protease 2 (PLP2) and the 3CL protease. The sequences and structures of these enzymes are similar to the corresponding enzymes of SARS-CoV-2 (documented here, and here). These are enzymes known as "cysteine proteases," which use sulfur from the amino acid cysteine to carry out their work. Zinc binds to the cysteine to inhibit them. This particular aspect of the enzymes is completely the same between SARS-CoV and SARS-CoV-2. Therefore, zinc almost certainly inhibits the enzymes within SARS-CoV-2.

Does that mean it slows viral replication?

It means it could.

One of the main determinants is what concentration of zinc will be available to inhibit the enzymes, and what concentration would be required to do so.

The studies looking at the inhibitory effect of zinc on these enzymes use ionic zinc, which is freely available and not bound to anything else. They also use purified enzymes. They show that zinc inhibits these enzymes by 50% when its concentration is one micromole per liter, a measure of how many atoms or molecules are present in a liter, abbreviated here as uM.

In a living organism, however, the enzymes are not purified, nor is the zinc mostly ionic. The enzymes are found embedded in the membrane of the cell's primary protein-producing factory, known as the endoplasmic reticulum. The part of the enzymes that are inhibited by zinc face the cytosol, which is the main compartment of the cell. While the concentration of zinc required to inhibit the enzymes in their purified state is 1 uM, I suspect it is lower when they are embedded in the membrane because the membrane will help hold them in place and orient them toward the zinc. My suspicion is it might cut the concentration required in half, to 0.5 uM (which is 500 nanomolar, or nM).

Is there enough zinc in the cytosol to inhibit these enzymes?

The answer depends on how we think about it. On the one hand, the total cytosolic zinc is hundreds of micromolar, which is hundreds of times higher than what is needed to inhibit the enzymes. On the other hand, only hundreds of picomolar of zinc are ionized in the cell at any given moment. That's about 1,000 times lower than what is needed to inhibit these enzymes. Still, about 30 times as much zinc as is ionized in any given instant is loosely bound to proteins, and will very rapidly free itself to replenish ionic zinc pools. Even larger amounts of zinc can be freed over the course of hours or days by degrading the zinc storage proteins within the cell and not replacing them. So, in theory, there are hundreds of micromolar zinc available that could be freed to inhibit the viral replication enzymes, but will they?

That really depends on whether cellular zinc proteins have all they need:
  • The highest-priority zinc proteins will bind zinc at low picomolar concentrations. They will never give up their zinc except in extreme deficiency.
  • The lowest-priority zinc proteins will bind zinc at nanomolar concentrations. They only get zinc when the cell is replete.
  • The viral replication proteins are inhibited at 1 micromolar, perhaps lower within the cell. Whatever the true inhibitory concentration is, it is certainly larger than needed to satisfy essential zinc-binding proteins, and it will only be available to inhibit viral replication when provided over and above what is needed for adequate nutritional status.
Therefore, our best chance to leverage the antiviral properties of zinc is to raise the cytosolic concentrations of zinc to the maximum possible safe level.

That will not be achieved with hydroxyhloroquine or chloroquine. As noted above, they trap zinc in other locations of the cell that are irrelevant to viral replication. As I will discuss below, the best chance of achieving this is with appropriately dosed zinc supplements.

Clinical Evidence Supporting the Antiviral Activity of Zinc

At this time, there is no clear clinical evidence that zinc has a specific application for COVID-19. Zelenko's protocol may work, but it hasn't been tested in a randomized controlled trial, and if we assume it works, we still don't know which component works best, if they are all needed in combination, or whether the doses chosen are best.

The clearest clinical evidence that zinc has antiviral properties in humans comes from the use of zinc lozenges to treat the common cold (reviewed here, here, and here.) These trials show that ≥75 mg/d zinc is necessary to have a useful effect. They supply the zinc using lozenges, and the zinc is in a form such as zinc acetate, zinc gluconate, or zinc gluconate glycine. Zinc acetate resulted in an average reduction of the duration of colds by 42%, while other forms of zinc resulted in an average reduction of 20%.

The rationale for zinc in the common cold is quite different from the rationale in COVID-19.

For the common cold, the primary mechanism of zinc is to prevent rhinoviruses from docking to their cellular receptor, ICAM-1. Since cold viruses infect the nose and throat, lozenges are used to increase the delivery to those tissues. This requires zinc to ionize outside of the relevant cells, and zinc acetate ionizes to a greater extent than other forms of zinc, which is why it is roughly twice as effective as other forms.

Since SARS-CoV-2 appears to start in the nose and throat, it does make sense to use zinc acetate lozenges to deliver zinc to those tissues. However, since the worst consequences occur in the lungs, it is also important to deliver zinc systemically so that the lung tissue becomes similarly enriched. This will only be achievable with high-dose oral zinc supplements that are swallowed, taken consistently over time prior to exposure to the virus.

What Is the Maximum Amount of Zinc We Can Get Into Our Bodies?

Our best chance at leveraging the antiviral activity of zinc systemically is to use the maximally useful, safe dose of zinc. When I say "maximally useful," I mean zinc that actually gets incorporated into our tissues instead of our feces or urine.

So let's look at what that dose is.

When a single dose of zinc is taken, the amount absorbed increases with increasing doses from 2 to 15 milligrams, but then we hit the law of diminishing returns. At 15 milligrams, 9.5 milligrams are absorbed. At 20 milligrams, 11 milligrams are absorbed. At 30 milligrams, 11.2 milligrams are absorbed. That's right, of the 10 milligrams added as we go from 20 to 30, only 0.2 milligrams are absorbed. Mathematical modeling from this study suggests that it is impossible to absorb more than 13 milligrams of zinc in one sitting, no matter how high the dose.

A single dose of zinc is not actually the best way to understand this. When our intake of zinc increases, even from a single dose, within hours or possibly up to several days, we will lower the amount of zinc we can absorb from food or supplements. Studies that look at total zinc from food and supplements spread throughout the day over the course of several weeks suggest that maximal daily zinc absorption is 5-7 mg.

Those studies, however, only used intakes up to 18 milligrams zinc. A much longer study added 100 mg/d zinc sulfate against a background diet of 10 mg/d from food over the course an average of 307 days. This dose more than doubled the total zinc absorbed from 4.5 to 10.5 mg/d, and it increased total body stores of zinc by 37%.

This latter study was conducted in people who had smell and taste dysfunction. They had lower than average body stores of zinc, so they may have been better primed to soak up enough zinc to boost their total body stores than someone with very good zinc status.

It is also notable that 110 mg/d carried out over the better part of a year produces a daily zinc absorption that is roughly equivalent to what is absorbed from a single dose of 20 mg. Unfortunately, it didn't clarify whether the zinc was taken all at once or spread throughout the day.

Unfortunately, there is no clear data showing what happens to total zinc stores using doses between 20 mg and 110 mg over weeks, months, or a year. It is clear that 20 mg is insufficient to maximize zinc absorption over days or weeks, because 20 mg/d zinc intakes only produce 5-7 mg/d that are absorbed. Presumably, at least 40 mg/d would be needed to result in the absorption of 10 mg/d. While it is not clear that 110 mg/d is needed, it is true that the only study showing a way to get the average daily absorption as high as 10.5 mg/d over the long term used that dose.

An Effective Dosing Protocol

It seems likely that maximal zinc absorption, over the long-term, would be provided by a dose somewhere between 40 mg/d and 110 mg/d. We also know that zinc absorption is greater when the dose is spread out, and when it is not accompanied by sources of phytate, such as whole grains, nuts, seeds, and legumes. Therefore, I recommend maximizing zinc absorption as follows:
  • Since it takes food about 4-6 hours to move through the stomach and 4-6 hours to move through the small intestine, I'm assuming the short-term saturation of zinc transporters resulting from the presence of zinc in food and supplements would be more or less "reset" every five hours.
  • Aim for a total zinc intake of 40-110 mg/d, split evenly into doses that can be separated by 5 hours.
  • Consume zinc supplements away from any meals containing whole grains, nuts, seeds, or legumes, whenever possible.
The protocol I use in The Food and Supplement Guide for the Coronavirus fulfills these criteria and can be summarized as follows:
  • Consume 7-15 mg zinc four times a day, spread out as much as possible.
  • If possible, take it on an empty stomach. If that causes nausea, take it with some phytate-free food.
  • Use one zinc acetate lozenge per day, providing an additional 18 mg zinc. Before and after any deliberate potential exposures to the virus, use an additional lozenge. If a potential exposure is an accident, use a lozenge afterwards.
This provides a minimum of 46 mg/d zinc and if someone has one potential viral exposure per day it provides a maximum of 114 mg/d.

Too Much Zinc Hurts the Immune System

In one study, 300 mg/d 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 towards 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 (see here, here, here, here, and here).

While 300 mg/d zinc did not lower lymphocyte counts, the fact that it lowered their ability to multiply in a lab dish suggests that such high doses could prime a person to have a poorer ability to maintain their lymphocyte count in a disease.

There are some suggestions that lower doses don't cause this problem:
  • Radiation therapy lowers lymphocyte counts. 150 mg zinc/d does not lower them any further or hurt the ability to recover them in patients with head and neck cancer.
  • In patients with a parasitical infection known as leishmaniasis, 45 mg/d did not hurt the ability of peripheral blood mononuclear cells, a group that includes lymphocytes, to replicate in a stimulation index test.
  • In HIV-infected patients with tuberculosis, 50 mg/d did not hurt lymphocyte counts.
  • In patients with Crohn's disease, neither 60 mg/d nor 200 mg/d hurt lymphocyte counts.
The studies in HIV and Crohn's disease are not necessarily that useful to compare to the study showing 300 mg/d hurts the lymphocyte stimulation index, since all three studies showed no change in lymphocyte counts However, the study showing that 45 mg/d does not hurt a similar index in peripheral blood mononuclear cells is fairly comparable.

The radiation study, in particular, is useful. Lymphocyte counts dropped more than three-fold in response to radiation therapy, and they recovered 63% in the first month following therapy. That zinc didn't hurt the recovery in any way suggests that 150 mg/d zinc does not hurt the ability of lymphocytes to proliferate under stress.

Although there are no studies showing people are actually more likely to get sick or experience worse illnesses on high-dose zinc, the negative effect on lymphocyte proliferation found with 300 mg/d 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.

Zinc/Copper Balance Is Critical

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.

In fact, low-copper diets cause a decline in the stimulation index of peripheral blood mononuclear cells, which is a similar test.

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. The zinc lowers copper status; as a result, the enzyme has enough zinc, but not enough copper; without both, it can't function, so it's activity declines.

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.

As a result, when using zinc prophylactically for prevention of COVID-19, I suggest the following:
  • Keep non-lozenge zinc equal to or less than 150 mg/d.
  • Keep total zinc equal to or less than 150 mg/d except for short-term use of additional lozenges during illness.
  • For every 15 milligrams of zinc, obtain at least one milligram of copper from foods and supplements.
This is the rationale for including 4-8 milligrams of copper per day from food and supplements in The Food and Supplement Guide for the Coronavirus.

Other Potential Problems of High-Dose Zinc

Other adverse effects of zinc include gastrointestinal distress at 50-150 mg/d and stomach pain, nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches at 225-450 mg/d.

Zinc can interact with certain medications. It should be taken at least two hours away from the antibiotics cephalexin and penicillamine, the antiretroviral drugs atazanavir and ritonavir, tetracycline, and quinolone antibiotics.

The Bottom Line

While there are no randomized, controlled trials showing that zinc can prevent or treat COVID-19, zinc may well be able to slow replication of the virus.

The ideal dose for prevention while the COVID-19 risk is high is 40-110 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.

Zinc that is swallowed for the sake of reaching the lungs should be used preventatively rather than at the first sign of symptoms, because it takes a long time to enrich systemic stores of zinc.

I prefer to use 1-3 zinc lozenges per day preventatively so that the tissues of the nose and throat are rich in zinc as soon as they encounter the virus. Unlike swallowed zinc, however, lozenges designed to spread zinc through these tissues can be jacked up quickly in response to symptoms, because their ability to spread zinc through these tissues is not limited by intestinal zinc transporters.

Extra caution should be exercised with zinc intakes above 150 mg/d, as they carry some risk of hurting the immune system, especially when not balanced with copper.

Stay safe,