I’ve previously written about the ability of vitamin C and vitamin D to protect against respiratory infections. Vitamin C has been found to shorten the duration of respiratory infections slightly, although it needs to be taken continuously throughout the year in order for there to be any benefit. Vitamin D has been found to shorten the frequency of respiratory infections, by a small amount in people who are not deficient, and by large amount in people who are deficient. I figure that it’s time to look at the third nutrient that is frequently touted as being protective against respiratory infections, zinc.
A systematic review was published in the Open Respiratory Medicine Journal back in 2011 that looked at the use of zinc lozenges in people with upper respiratory tract infections. 2011 may seem like a long time ago, but virtually of the studies on this subject were carried out in the 1980’s and 1990’s, so that isn’t a problem. Interest in zinc has waned, at least until covid-19 got people talking about it again.
The logic behind lozenges (i.e. tablets you suck on), rather than tablets you swallow, is that the zinc is released in the oral cavity, which should result in much higher local concentrations in the place where you want it most, the upper respiratory tract.
13 double-blind placebo-controlled trials were identified, with a total of 1,402 participants. The dose of zinc used varied enormously, from 30 mg per day to 207 mg per day, so the systematic review analyzed those giving a high dose (75 mg or higher) and those giving a low dose (less than 75 mg) separately, to see whether there was an effect of dose size on the results.
So, what were the results?
In the five trials using low doses, there was no difference between the treatment group and the control group on the duration of symptoms. In the eight trials using high doses, however, there was a big difference. All eight showed a reduction in symptom duration, and the overall average reduction was 32%. If an average cold lasts ten days, that would mean a shortening of symptom duration of around three days, which isn’t bad at all.
So, case closed, right? Zinc lozenges, when dosed at 75 mg or higher per day, shorten the duration of upper respiratory infections. Well… there is a big problem here, and that is that all but one of these trials was carried out before the birth of clinicaltrials.gov, and the one that was carried out later, was never registered there.
For those who are unaware, clinicaltrials.gov is a website that was set up in the year 2000, after it became clear that lots of trials were disappearing off the face of the earth after being completed, and that this was seriously skewing the evidence base. The problem is known as “publication bias”. Studies that show benefit are much more likely to get published, partly because they get more media attention, which means that scientific journals (which to a large extent depend on advertising for their income) are much more likely to want to publish them, and partly because most studies are financed by people with a vested interest in the result. If a company that makes zinc lozenges finances a trial that is supposed to show that the lozenges shorten the duration of respiratory infections, and the trial doesn’t show any benefit, then the company is probably going to do its best to bury that trial.
The main purpose of clinicaltrials.gov is to make it harder for people to “disappear” trials that show unwanted results, by asking them to register the trial there before they start recruiting participants. Since the systematic review we’re discussing here is based on studies that were conducted in the pre-clinicaltrials.gov era, it is perfectly possible that there were another 50 trials that were conducted on zinc lozenges, but that were hidden away and never published, because they failed to show benefit. It’s impossible to know.
Perhaps as a result of this, the author of the systematic review has carried out a new double-blind randomized controlled trial, that was published in BMJ Open in January 2020. This trial was pre-registered at clinicaltrials.gov.
It recruited workers over the age of 18 who reported having at least one cold per winter, on average. 252 people were recruited, and randomized to either placebo lozenges or zinc lozenges (containing 13 mg of zinc). The participants were instructed to start taking one lozenge every two hours in the event that they developed symptoms of a respiratory infection. This would result in a daily dose of 78 mg of zinc.
Of the 252 participants, 87 went on to develop an upper respiratory tract infection during the study period. of these, 42 participants were in the placebo group and 45 were in the zinc group. On average, treatment with the lozenges started within four hours of the beginning of symptoms of a respiratory infection. The participants consumed an average of five lozenges per day, not the planned six, so the actual average dose was 65 mg.
What were the results?
Unfortunately, the participants in the zinc group recovered a little bit more slowly than the participants in the placebo group, although the difference was not statistically significant. However, the fact that there wasn’t even a hint of a benefit to zinc is disappointing.
This trial was most definitely designed to succeed. The lead author is a strong proponent of the beneficial health effects of vitamin and mineral supplements, and has written multiple opinion pieces arguing for the benefits of zinc in treating respiratory infections. So the fact that the trial failed to find any sign of benefit suggests strongly that there is no benefit, and that the beneficial effect seen in the systematic review was due to publication bias.
There are of course other possible explanations. One is that the dose given in the study was simply too low to have an effect. Maybe 65 mg per day simply isn’t enough to see any benefit. There is also the fact that the study was quite small, with only a little over 40 people in each treatment group, which means that there is some scope for random chance to mess up the results. However, a reduction in symptom duration of around 30%, as found in the systematic review, should be noticeable even with this relatively small number of participants.
A third hypothesis, suggested by the authors, is that maybe the zinc lozenges dissolved too quickly in the mouth. In this study, the lozenges took an average of eight minutes to dissolve. The studies in the systematic review that showed a beneficial effect were mostly using lozenges that took from 15 to 30 minutes to dissolve completely.
It is worth noting that the participants in the zinc group experienced far more side effects than the participants in the placebo group (63% vs 31%). The side effects took the form of odd oral sensations, such as a dry or aching mouth, and an affected sense of taste. So even if the zinc lozenges do in fact shorten the duration of upper respiratory tract infections by 30%, as the systematic review implies, it is not clear whether that benefit is big enough to outweigh the negative side effects.
So, what can we conclude from all this?
It’s still uncertain whether zinc lozenges have any role to play in the treatment of upper respiratory tract infections. The studies that do show a benefit with high doses were largely carried out before the existence of clinicaltrials.gov, and none were registered before commencing recruitment, so there is significant risk of publication bias. The one newer trial that was properly registered beforehand failed to find any benefit. And although it is unclear whether zinc lozenges are helpful, they do definitely cause mild but annoying side effects in a significant proportion of those taking them.