By Chris Masterjohn, PhD
At the beginning of the COVID-19 pandemic, we already knew that vitamin D helps reduce the risk of respiratory infections, especially when given to people who are deficient.1 We also knew that it helps us make antimicrobial peptides, and that it simultaneously boosts our immune system’s ability to fight viruses and bacteria while dampening the excessive or dysfunctional activities of our immune system that can lead to autoimmune disease.2
Nevertheless, it didn’t automatically follow from this that vitamin D would reduce the risk of COVID-19. Viruses regularly hijack good things within our bodies to use them against us. It is therefore entirely possible a virus could hijack things made with the help of vitamin D and use those things against us.
One of the very first things we learned about SARS-CoV-2, the virus that causes COVID-19, is that it enters human cells by binding to a human protein known as ACE2.3 From the perspective of human physiology, ACE2 is an enzyme that supports healthy blood pressure, cardiovascular function, and respiratory function.4 From the perspective of the virus, ACE2 is a “receptor” that it can use as an easily opened door, allowing it to enter our cells. This is a great example of the virus hijacking something that is very health-promoting in order to cause disease.
Binding to ACE2 is a property that SARS-CoV-2 shares with only two other coronaviruses — the first SARS virus5 and human coronavirus NL63,6 a virus that mainly infects children and immunocompromised people7 — but not with the coronaviruses8,9 or rhinoviruses10 that cause the common cold, and not with the viruses that cause the flu.11 Animal studies prior to the pandemic had generally shown that vitamin D increases the amount of ACE2 on the cell surface,12–14 (note 2) raising the concern that vitamin D could make it easier for the virus to enter our cells. Moreover, since most viruses that cause respiratory infections do not use ACE2 to get into cells, this raised the possibility that the existing research showing vitamin D protects against respiratory infections may not apply to COVID-19.
Because of this, my initial response to the ACE2 research in March of 2020 was to urge caution against supplementing with vitamin D. I wrote that we should continue to get sunshine and eat vitamin D-rich foods, such as fatty fish, but should avoid supplementing or at least limit supplements to 1700 IU per day.
Others, such as Dr. Rhonda Patrick of Found my Fitness, argued in April of 2020 that vitamin D’s ability to raise ACE2 might actually make COVID-19 less severe, since ACE2 protects against lung damage. My response to this was to point out that a moderate increase in ACE2 might offer moderate protection against lung injury, but since viruses grow exponentially, the same moderate increase in ACE2 might lead to an exponential increase in viral load.
Dr. Patrick also pointed out circumstantial evidence that poor vitamin D status contributed to severity: COVID-19 hospitalization rates were higher in obese people, African Americans, Somali immigrants in Sweden, and older people, all of whom have lower vitamin D status. While vitamin D is a plausible way to tie these together, I pointed out that other factors, such as hypertension, could explain the cluster just as well. Thus, the circumstantial evidence at that time was relatively easy to dismiss.
Things slowly began to change toward the end of April, 2020. At a country level, COVID-19 mortality was associated with northern latitudes where it is more difficult to get vitamin D from the sun.15 On April 23 and April 29, the first two studies emerged from South and Southeast Asia tying low vitamin D status in individual COVID-19 patients to more severe disease and greater mortality.16,17
Additional ways that vitamin D could protect against the disease were also becoming more clear over time. Low lymphocytes, high neutrophils, and high levels of interleukin-6 emerged as key predictors of poor outcomes,18–24 and existing research suggested vitamin D had the potential to help with all three.25–29
As more and more research emerged, in a series of posts, I slowly began to change my mind and become convinced that vitamin D is effective against COVID-19, possibly dramatically so.
Unfortunately, the first three studies directly tying the vitamin D status of individual patients to COVID-19 outcomes, all from South or Southeast Asia and all originally published between April 23 and May 5, 2020, have since been retracted, with no explanation why.16,17,30 In fact, there is reason to doubt that the authors of the second paper, which came out of Indonesia, even exist. In July of 2020, a group of Indonesian physicians and medical professors claimed to look everywhere within the Indonesian medical system without ever finding these authors.31 They lamented that this potentially fraudulent paper created an “infodemic” of “misinformation” about the supposedly helpful effects of vitamin D that had spread like wildfire on Twitter and Reddit.
Fast forward to August of 2021,(note 3) and these retracted papers are just three drops in what is quickly becoming an ocean of legitimate research. There are now 98 observational studies,32–129 6 published randomized controlled trials,130–135 and dozens more randomized controlled trials that are registered and are either not yet started, underway, or completed but not yet published.
Let us now take a look at what that research has found, starting with the observational studies.