Study Results Link Folic Acid Supplements to Higher Rates of COVID-19 Infections, Mortality

Findings have implications for patients who take supplementary folate to prevent complications of other pharmacological therapies.

Individuals in the United Kingdom taking folic acid were 1.5 times more likely to contract COVID-19 and 2.6 times more likely to die from the disease, according to the results of a study from UC Davis Health and the University of Alabama in Birmingham.

The findings, published in BMJ Open, found that having a prescription for the antifolate drug, methotrexate, mitigated the negative impact of folic acid on COVID-19 when taken together.

“We examined whether COVID-19 diagnosis and death were related to the large doses of folic acid, 5 times the safe upper limit, prescribed to patients for a variety of medically approved indications. We found that the risk of becoming infected and dying from COVID-19 was significantly greater in the group treated with folic acid,” Ralph Green, a distinguished professor in the UC Davis Department of Pathology and Laboratory Medicine, said in a statement.

Folic acid is a synthetic form of vitamin B9, where low levels are associated with health conditions, such as an increased risk of birth defects, heart disease, and stroke, according to the statement.

Folic acid is prescribed for various issues, including high-risk pregnancies, individuals receiving anti-seizure medications, and sickle cell disease. It is also known to offset adverse events for individuals taking methotrexate.

Methotrexate treats certain types of autoimmune diseases and cancers, but it also interferes with folate, which cancer cells require for proliferation.

Investigators analyzed folic acid and methotrexate prescription data between 2019 and 2021 in 380,380 individuals from the UK BioBank, a major biomedical database that contains health information from approximately half a million individuals.

They found that 26,033 individuals were diagnosed with COVID-19, and 820 had died from it. Individuals with a methotrexate prescription were diagnosed with COVID-19 at a similar rate to the general population.

However, investigators found that individuals with a folic acid prescription were diagnosed at a higher rate at 5.99% and had a much higher COVID-19 mortality rate at 15.97% than the general population.

“Our findings could have implications for patients who take supplementary folate to prevent complications of other pharmacological therapies,” Angelo Gaffo, MD, an associate professor of medicine in the Division of Rheumatology at the University of Alabama at Birmingham, said in a statement.

“Although taking folate in these cases is clearly indicated, clinicians should be cautious about excessive folate intake,” he said. “Of course, our results will require replication.”

Investigators did note limitations of the study, which included that the findings were limited to individuals aged 45 years and older who are predominantly from white European ethnicities.

Another limitation included that the study did not observe the serum folate levels of the individuals, and investigators said further studies are needed to explore the impact of folate status and folic acid intake on the susceptibility to COVID-19 infection and related mortality.

Investigators also noted that it is important to avoid extremely high doses of folic acid unless medically indicated.


High folic acid supplementation associated with higher rates of COVID-19 infections and mortality, study finds. News release. Science Daily. August 31, 2022. Accessed September 2, 2022.