By Brenda Baletti, Ph.D.

Synthetic folic acid — a widely celebrated supplement and food additive — may cause unintended neurological and immunological harm, especially in genetically susceptible individuals, according to Dr. Tim Kelly and Dr. Clare Craig.

In an interview with medical commentator John Campbell, Ph.D., physicians Kelly and Craig said there isn’t good evidence that folic acid — a lab-made, oxidized compound often labeled as vitamin B9 — can replace the body’s levels of folate, found naturally in proteins, fruits and vegetables.

Folate is essential for DNA and RNA synthesis and methylation, a vital biochemical process. Folate deficiency in pregnancy increases the risk of neural tube defects, which are birth defects of the brain, spine or spinal cord.

Public health officials have long promoted the addition of synthetic folic acid to food and maternal health supplements to maintain healthy levels.

However, according to Kelly and Craig, the body doesn’t process synthetic folate in the same way it processes natural folates.

Developing brains rely on folate moving across the placenta and entering the cerebrospinal fluid via folate receptor alpha (FRα). Folic acid binds to FRα more tightly than natural folates, so it can “gum up” the receptor and block natural folate from reaching the fetal or infant brain — even when maternal blood shows high folic acid levels, Kelly and Craig said.

Infants may also accumulate high levels of unprocessed folic acid in their bodies, which can trigger the creation of autoantibodies — malfunctioning immune cells that attack healthy cells.

“When you have foreign things in the body, it can confuse the immune system and lead to an autoimmune attack,” Craig said. And with “something synthetic like folic acid, that could absolutely happen.”

Autoantibodies found in many children with autism

Citing studies that found FRα autoantibodies in many children with autism, they hypothesized that the prolonged binding of synthetic folic acid to the receptor could trigger autoimmune reactions that disrupt folate delivery to the brain.

Kelly noted that genetics plays a role in how people metabolize folate, so different people have different capacities to process it. “But public health interventions are uniform,” he said.

For babies or children unable to effectively process folate due to genetic factors, policies that expose them to large doses of folic acid can sharply reduce the amount of folate available to their brains.

Kelly said the discussion is delicate because research has shown that folic acid prevents neural tube defects. However, Kelly and Craig argued that those studies were limited and failed to examine the harms linked to folic acid, including fetal death, and the increased likelihood of multiple births.

Early safety and efficacy evaluations of folic acid relied on data from a rat study and a flawed human trial that overlooked confounding factors and reported higher rates of adverse events in the folic acid group.

Recommended dose of folic acid increased in 1990s, after study by food industry

The U.S. began adding folic acid to flour in 1998, according to Craig.

She described it as a “neutraceutical,” a biological therapy made by the pharmaceutical industry and added to food. Manufacturers include it in enriched bread, flours, pasta, rice and cereals, exposing people to levels of folic acid far beyond the daily recommended dose, she said.

Kelly and Craig questioned whether supplementing folates is necessary at all.

Craig said people can easily get their required folates by eating fruits, vegetables and protein. “One cup of orange juice will give you enough to replace your daily [folate] losses,” she added.

Kelly said manufacturers add folic acid to foods partly because it has a long shelf life, while natural folates are more fragile.

U.S. health agencies increased their daily recommended dose of folate in the late ’90s based on a study sponsored by the food industry, Craig said.

But now, observational data — such as the plateau in infant-mortality declines after the U.S. began fortifying wheat with folic acid, and the rise in conditions like eczema, asthma and middle ear infections — raise serious concerns about supplementation that merit fresh scrutiny.

“We’re giving huge doses of folic acid to virtually the entire population based on essentially no evidence and thinking, ‘Oh, it’s probably all right. It’s probably good for you,’” Campbell said. “It just seems arrogant. It seems presumptuous. It seems that the burden of proof … should be on the person carrying out the intervention.”

Regulators must ‘seriously review folic acid supplementation’

Kelly and Craig recently published a preprint paper on their research and are working on more studies. They said researchers have previously accepted this public health intervention without question, but it urgently requires more investigation.

“So, basically, what are we asking for? We’re asking for regulators around the world to seriously review folic acid supplementation,” Campbell said.

The researchers called for cross-sectional and longitudinal studies to examine the effects of autoantibodies across more conditions and emphasized the need for better diagnostic testing to determine when folate supplementation is necessary, enabling a more personalized approach.

They also said that when supplementation is necessary, using food-based or natural forms would likely be more effective than administering folic acid to the entire population.

Watch the interview here: 

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