It was back in the early 1990s when I first reviewed the evidence for zinc for respiratory tract infections. That particular journal club during my residency is somehow still occupying space in my mind – I even remember prepping my presentation with overhead projector slides (That should give you an idea of how long ago this was). At the time, the buzz was that zinc tablets or lozenges could shorten the duration of a cold. Even then, there were studies that dated back into the 1980s. Unlike a lot of dietary supplements, enthusiasm has never completely disappeared over the following decades, as there has been a slow trickle of weakly positive, poorly controlled studies.

In 2020 with the appearance of COVID-19, there was renewed interest in zinc to prevent infections or potentially lessen their severity. Given colds can be caused by coronaviruses and there was somewhat positive (if conflicting) evidence for zinc in colds, this was perhaps not unreasonable – especially before the availability of vaccines.

Since the 1990s the evidence for zinc has remained weak and not particularly convincing. Now there is a newer study published in The BMJ from the NICM Health Research Institute at Western Sydney University. This institute is “Australia’s leader in integrative and complementary medicine research and policy” with funding from different levels of the Australian government and also individuals and industry. The authors include a general practitioner, naturopaths, and academics with backgrounds in natural and “integrative” medicine. Some of the authors report payments related to complementary and alternative medicines. However, this particular paper was not commissioned, sponsored or funded by any one organization.

Why zinc?

Zinc is a trace mineral with functions throughout the body. Zinc deficiency is a significant issue worldwide, where access to a healthy diet and adequate calories is a problem. In some countries, foods may be fortified with zinc, such as breakfast cereals. Where regular diets include zinc-containing foods (e.g., meat, shellfish, chicken, nuts, lentils) like many in the USA, zinc deficiency is less common, but still possible. Severe deficiencies in these countries are more common where there are chronic diseases that cause reduced absorption (e.g., inflammatory bowel diseases) or as a consequence of gastrointestinal tract surgery. Some medications can increase the body’s loss of zinc as well (e.g., diuretics).

A severe zinc deficiency is most commonly associated with impaired growth, but the effects also include immune system dysfunction. Being deficient in zinc could conceivably affect your susceptibility or response to colds viruses including coronaviruses. Zinc could also have direct anti-viral effects. The signals of benefit that have appeared in research studying zinc supplementation and the common cold has led to continued questions about whether or not zinc can meaningfully affect your susceptibility to, or response to, a viral respiratory infection.

The evidence for zinc to prevent or treat the common cold

There is evidence to demonstrate that zinc-containing nasal sprays may be harmful as they can cause temporary and in rare cases permanent loss of smell. Other formulations that have been well studied are lozenges and tablets. One systematic review, published in 2011, identified 13 placebo-controlled trials with wide variation in doses. Low doses (<75mg/day) were found to be ineffective and trials with higher doses were founds to reduce the duration of colds (by 42%), but not their incidence. Another systematic review included 17 trials that compared zinc to placebo or no treatment. This analysis found that zinc reduced the duration of cold symptoms (by an average of 1.65 days) but the results varied widely across the trials. This review noted that adverse events (taste, nausea) were more common in the zinc group. Finally a Cochrane review from 2013 was withdrawn in 2015, citing concerns with the data analysis. It remains withdrawn as of the last update in 2016.

The new systematic review

This is not a new trial. It is an analysis of previously-published randomized controlled trials. The authors stated that their review conforms with Cochrane guidance on how systematic reviews should be conducted. I admit that I am not an expert in systematic review methodology, so I have taken their approach at face value. Some of our experts in the comments may have additional observations about the methods.

The authors started with a comprehensive database search to identify any relevant trials. Eligible for inclusion were any randomized or quasi-randomized clinical trials. Trials needed to be specific to adults. Any type of zinc product or route of administration could be included. Any type of control group was acceptable. English and Chinese databases were searched through August 2020, including searches for RCTs that studied zinc’s effects against SARS-CoV-2. These searches included preprint databases. The search and extraction method followed standard rapid review extraction methods, where data on each trial was verified by a second reviewer. Risks of bias of each trial were also assessed with a Cochrane tool.

From 1,360 articles and trials screened, 28 RCTs with 5,446 participants met the inclusion criteria. Three trials were published in Chinese only. 95 RCTs evaluating zinc in pediatric populations were excluded, as were seven RCTs studying zinc in COVID-19, as those results were still pending.

Participants in the trial were generally healthy, with symptoms consistent with mild to moderate respiratory tract infections. The average age was 37. The median sample size for prevention studies was 53 and for treatment studies, 78. Most of the trials (19) were conducted in the USA with 5 in Europe, 3 in China, and 1 in Australia.

The most common zinc formulations studied were lozenges (45-300mg) , but nasal spray and nasal gels (0.9-2.6mg) were also studied. For prevention, the daily dose was 15mg or 45mg daily for 7 or 12 months, respectively.

The authors note that most of the outcomes reported had at last some concerns about the overall risk of bias. There were substantial differences in the trial in terms of design, drug formulation, population etc., which challenged overall observations. Here are the results for prevention of respiratory tract infection:

Figure 2

If we ignore the nasal spray studies (which showed efficacy, but use a route of administration that can cause significant adverse effects) there is a single trial showing efficacy at 45mg per day, and one that does not at 15mg per day. For prevention of infection from direct inoculation of the cold virus, zinc does not appear to be effective.

Here are the results for treatment, where symptoms of colds were studied:

Figure 3

Even ignoring the topical trials, here the results for treatment (Day 3 symptom severity score) look slightly more impressive and consistent, recognizing there are substantial bias concerns in these trials. And here are the duration of infection results:

Figure 4

Again, modest but suggestive evidence in favour of zinc. Finally, here are the adverse effects:

Figure 5
It’s clear that zinc has side effects, with most trials reporting more side effects in the treatment group compared to placebo.

Overall the results were summarized by the authors as follows (bolding is mine):

  • Compared with placebo, oral or intranasal zinc prevented 5 RTIs per 100 person-months (95% CI 1 to 8, numbers needed to treat (NNT)=20, moderate-certainty/quality).
  • Sublingual zinc did not prevent clinical colds following human rhinovirus inoculations (relative risk, RR 0.96, 95% CI 0.77 to 1.21, moderate-certainty/quality).
  • On average, symptoms resolved 2 days earlier with sublingual or intranasal zinc compared with placebo (95% CI 0.61 to 3.50, very low-certainty/quality) and 19 more adults per 100 were likely to remain symptomatic on day 7 without zinc (95% CI 2 to 38, NNT=5, low-certainty/quality).
  • There were clinically significant reductions in day 3 symptom severity scores (mean difference, MD −1.20 points, 95% CI −0.66 to −1.74, low-certainty/quality), but not average daily symptom severity scores (standardised MD −0.15, 95% CI −0.43 to 0.13, low-certainty/quality).
  • Non-serious adverse events (AEs) (eg, nausea, mouth/nasal irritation) were higher (RR 1.41, 95% CI 1.17 to 1.69, NNHarm=7, moderate-certainty/quality). Compared with active controls, there were no differences in illness duration or AEs (low-certainty/quality). No serious AEs were reported in the 25 RCTs that monitored them (low-certainty/quality).

Zinc is no panacea

Despite multiple trials over the past 40 years, there remains limited evidence to demonstrate that zinc offer meaningful benefits to prevent or treat respiratory tract infections. While there is some evidence it may prevent infections and shorten their duration, the effects are modest. The authors describe zinc as “a viable ‘natural’ alternative”, but “viable” is doing some heavy lifting in that sentence. Zinc products do have side effects that may be noticeable, and the topical nasal spray formulation is associated with rare but sometimes permanent disturbances in the ability to smell, which seems like a poor trade-off for a product that, at best, may provide a slight benefit.

Author

  • Scott Gavura, BScPhm, MBA, RPh is committed to improving the way medications are used, and examining the profession of pharmacy through the lens of science-based medicine. He has a professional interest is improving the cost-effective use of drugs at the population level. Scott holds a Bachelor of Science in Pharmacy degree, and a Master of Business Administration degree from the University of Toronto, and has completed a Accredited Canadian Hospital Pharmacy Residency Program. His professional background includes pharmacy work in both community and hospital settings. He is a registered pharmacist in Ontario, Canada. Scott has no conflicts of interest to disclose. Disclaimer: All views expressed by Scott are his personal views alone, and do not represent the opinions of any current or former employers, or any organizations that he may be affiliated with. All information is provided for discussion purposes only, and should not be used as a replacement for consultation with a licensed and accredited health professional.

Posted by Scott Gavura

Scott Gavura, BScPhm, MBA, RPh is committed to improving the way medications are used, and examining the profession of pharmacy through the lens of science-based medicine. He has a professional interest is improving the cost-effective use of drugs at the population level. Scott holds a Bachelor of Science in Pharmacy degree, and a Master of Business Administration degree from the University of Toronto, and has completed a Accredited Canadian Hospital Pharmacy Residency Program. His professional background includes pharmacy work in both community and hospital settings. He is a registered pharmacist in Ontario, Canada. Scott has no conflicts of interest to disclose. Disclaimer: All views expressed by Scott are his personal views alone, and do not represent the opinions of any current or former employers, or any organizations that he may be affiliated with. All information is provided for discussion purposes only, and should not be used as a replacement for consultation with a licensed and accredited health professional.