Do Zinc and Vitamin C Reduce COVID Symptoms?

F. Perry Wilson, MD, MSCE


February 17, 2021

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This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson of the Yale School of Medicine.

Wouldn't it be nice if there was a treatment for COVID-19 that was safe, effective, cheap, and out of the control of faceless pharma executives beholden more to shareholders than to patients? The dream of such a magic bullet has led to a number of similar claims that a given drug — or supplement, in some cases — has dramatic effects against COVID-19. We saw it first with hydroxychloroquine, but similar hype surrounded vitamin D, ivermectin, melatonin, vitamin C, and, of course, zinc.

What made the claims so compelling were two things. One was a dose of biologic plausibility. Biologists could argue that there was some underlying reason why a given vitamin would help, usually citing beneficial effects on immune function or a reduction in inflammatory cytokines. But more than that, these drugs had something of an underdog story. These unassuming agents that were with us for decades or longer could become our most powerful ally against this scourge of a virus. Preliminary data were often breathlessly hyped, but, as I pointed out in regard to vitamin D, we'd been burned before. Many of us wanted to see the randomized trials before we committed to any of these potential cures.

This week, we got one such trial, appearing in JAMA Network Open, looking at the ability of zinc and vitamin C — alone or in combination — to shorten symptoms of COVID-19 in outpatients.

This was a 2 x 2 factorial design, as you can see here. Patients were randomized to usual care or to one of the three treatment arms in a roughly equal fashion.


These were outpatients, so we weren't going to see a ton of hard outcomes. Rather, the researchers used a rank-based symptom scoring method. Each day, participants were asked about four symptoms, which they rated on a scale from 0 to 3, giving a symptom score range of 0-12. The primary outcome was the time to halving of the symptom score; in other words, if you start at a 4, the time it takes to get to 2; or if you start at 10, the time it takes to get to 5. This is a bit of a weird outcome, since it assumes some mathematical equivalence where I don't think any exists, but I suppose it's as good as we can get.

Here are the symptoms over time for the entire study cohort. You can see a general waning of moderate symptoms (in yellow) in favor of mild symptoms (in green).

Thomas S, et al. JAMA Netw Open. 2021;4:e210369. doi:10.1001/jamanetworkopen.2021.0369

But when you stratify by treatment, the time to 50% symptom reduction was basically the same across the board: about 5.5 to 6.5 days, depending.

Thomas S, et al. JAMA Netw Open. 2021;4:e210369. doi:10.1001/jamanetworkopen.2021.0369

No individual symptom resolved quicker with zinc, vitamin C, or the combo. Basically, the population looked like we've come to expect: a few days of fever, with lingering cough and fatigue.

Hospitalization rate didn't significantly differ, though it was slightly higher in the supplement groups. And there were thankfully only three deaths — one in the vitamin C group and two in the combo group.


In terms of side effects, there was nothing crazy. But obviously, the authors saw more in the treatment groups than in the usual-care group, mostly GI stuff.


Now, zinc apologists will no doubt note the lack of a zinc ionophore (like chloroquine or pyrithione) as a reason this didn't work. And again, I remind everyone that biologic plausibility is not the end of medical research but the beginning; it's the minimum bar to pass to ethically conduct a definitive trial, not an end in itself. I'll be happy to do a readout of any impending hydroxychloroquine-zinc combo randomized trials that emerge.

More broadly, I think we need to just accept the fact that it's pretty unlikely that a cure for COVID is sitting in our closets. Lots of chemicals have activity against pathogens in test tubes, just like lots of stuff works in vitro against cancer. But this trial reminds us that, more often than not, biologically promising agents don't survive the rigors of real-world testing. Keep hope, but bring data.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at

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