Where is the safety trial on folic acid?

Dr Clare Craig

Key points • At least thirty randomised trials involving 82,334 people have tested whether folic acid prevents heart disease and stroke. No trial has been designed to test whether it causes harm. • The safety evidence that has been demonstrated has been found by accident. • A company that sells a medicine is legally required to monitor its safety and to pay for that monitoring. Folic acid in flour is not treated as the drug that it is and no monitoring of safety has been planned. • SACN made its support for fortification conditional on monitoring. The regulations do not require any safety monitoring.

There have been two randomised trials which have produced a signal of harm from folic acid. Neither was designed to measure harm.

The first was the Aspirin/Folate Polyp Prevention Study which gave 1,021 people 1 mg of folic acid a day or a placebo. All of them had already had a bowel polyp removed. The trial was testing whether folic acid stops polyps coming back. Advanced polyps appeared in 11.6 percent of those on folic acid compared to 6.9 percent in the placebo group. For three or more polyps the difference was 9.9 percent compared to 4.3 percent. They also found more cancers elsewhere in the body. A later analysis of the same men found prostate cancer at 2.6 times the placebo rate. The researchers ended their 2007 paper by understandably calling for safety trials to establish whether folic acid increases bowel cancer. That work has never been done.

The second is the Aberdeen trial between June 1966 and June 1967, which enrolled 2,928 pregnant women who were given 5 mg of folic acid a day, 0.2 mg or a placebo. The study aimed to measure whether low folate causes birth defects, anaemia and placental abruption. Cancer was not an endpoint. Thirty-five years later a different team linked the women’s records to Scottish registries and found cancer deaths 70 percent higher and breast cancer deaths twice as high in the 5 mg group, with 112 and 31 deaths respectively. A further follow up to 2013 did not find the same concerning increase. This is the only randomised data in the world that examined folic acid effects after decades but it was not designed to do that.

Both trials used higher doses of folic acid than the fortification level. It is widely accepted that different drug doses result in different benefits. The same is true for safety. For folic acid specifically, cancer risk is not evident above 1mg a day but at fortification doses there is a clear signal. 

What gets funded

A study design that starts with a hypothesis of benefit is easier to fund. Funders are more attracted to research that would produce a positive and applicable outcome, even if reducing harm because of negative outcomes is clearly of great importance to the public.  For example, seeing as high homocysteine is related to heart disease stroke and folic acid lowers homocysteine a hypothesis could be presented that folic acid could prevent heart disease strokes. Studies to answer that exact question were funded in seven countries. Thirty trials and 82,334 people have now tested folic acid for benefits in heart disease and stroke. 

Manufacturers may support such studies in addition to other sources. CSPPT – Chinese Stroke Primary Prevention Trial, which produced the strongest evidence that folic acid might prevent stroke, gave 20,702 Chinese adults a single tablet combining enalapril with 0.8 mg of folic acid, or enalapril alone. It was sponsored by the manufacturer of that tablet, Shenzhen AUSA Pharmed.

By contrast, a hypothesis that starts in a negative way is less likely to be funded. Any researchers saying folic acid is synthetic, that the enzyme which converts it works slowly and gets overwhelmed, that unconverted folic acid circulates in the blood, that cancerous cell division might be amplified by it and that we should count cancers for twenty years to see what happens are going to struggle relatively to get funding. Cancer is slow and the effect is likely to be small. The situation is not helped by the fact that folic acid is treated as if it was folate and therefore a vitamin and therefore safe. Nor is it helped by the fact eighty countries already add it to their food. It is not just manufacturers who fail to fund such studies.

Folic acid is a drug

Companies that market medicines have a legal obligation to carry out safety monitoring, called pharmacovigilance. They must collect reports of side effects and submit reports at set intervals to the regulator.

Folic acid tablets are a licensed medicine in the United Kingdom so all that applies. However, folic acid when added to flour under the Bread and Flour Regulations is being treated as a food ingredient. The route of ingestion is what determines this distinction not the dose. There is no system for tracing food safety in the same way and there is no big company with a folic acid patent who could be held to account.

There is money available

The Global Alliance for Improved Nutrition was launched in 2002 with more than $70 million over five years. $50 million was from the Gates Foundation. The Food Fortification Initiative started the same year and is based at Emory University. It campaigns for vitamins and minerals to be added to milled wheat, maize and rice. The International Association of Operative Millers is one of its leading supporters. In 2023 the Gates Foundation gave the Food Fortification Initiative $300,000 to review the evidence on the impact of fortification across ten foods.

Campaigns  staffed and funded by people who think it is heroic to add things to food are not going to fund research to establish the negative effects of folic acid. No organisation exists with a purpose to establish the negative impacts of folic acid at fortification levels.

The ethics problem

If a safety trial was proposed and funded it would run into a problem with the ethics committee. Given that SACN has recommended fortification and the government tells every woman who might become pregnant to take folic acid, an ethics committee would claim that further research, even much needed safety research, was unethical. Once authorities declare something safe it becomes “unethical” to question it.

There has never been a single trial of the effects of folic acid on children and yet no ethics committee is pointing this out and saying that mandating it in flour is unethical.

Timing is also a problem. Cancer takes decades to appear but research grants run for three to five years. The measurements used in the funded benefit trials are for outcomes that are quick: blood results, polyps, memory tests and brain scans. Slow harms do not fit into the funding cycle.

Monitoring instead

The plan is to monitor. If that were really the only option then the most ethical way to do that would be a standard design called a stepped wedge. The rollout begins in a particular region and the order in which regions receive it is randomised. Given the fact that it is being put into staple food and that our food provision is not regionalised this becomes impossible in practice. 

That leaves monitoring a population after a uniform rollout as the only measure. SACN in 2009 estimated that the monitoring data available had a 13 percent chance of detecting a 10 percent rise in bowel cancer. A study with 13 percent power would miss a real effect seven times out of eight. That is not good enough. Worse, the Bread and Flour (Amendment) Regulations 2024 did not require safety monitoring at all.

In 2017 a Cochrane review tested whether any more trials were needed on cardiovascular deaths or deaths from any cause and concluded that enough had been done. The trials they considered were short with follow up for adverse events from 3.4 years to 7.3 years. Cancer takes far longer than that to appear. They also did not separate the evidence at fortification doses.

Eighty thousand people across seven different countries have been randomised over twenty-five years, at public expense, to find out whether folic acid prevents heart attacks, strokes, dementia, deafness, fractures, depression and polyps. That effort proves a safety trial could be done.

Now that folic acid is already in a huge variety of food ahead of the December 2026 mandate it is too late to do the safety trials. There is no clean placebo group to compare.