Nial Wheate, Professor, School of Natural Sciences, Macquarie University, Jasmine Lee, Pharmacist and PhD Candidate, University of Sydney
The US government has announced controversial guidance on the prevention and treatment of autism in children.
New health recommendations aim to discourage pregnant women from taking the painkiller paracetamol – also known as acetaminophen and by the brand name Tylenol – to prevent autism.
The recommendations also include using the drug leucovorin to treat speech-related difficulties that children with autism sometimes experience.
So what is leucovorin and what does the science say about its ability to treat autism?
What is leucovorin?
Leucovorin is a form of folic acid, a B vitamin our bodies usually get from foods such as legumes, citrus fruits and fortified grains.
The medication is most often used in cancer treatment. It’s typically used alongside the chemotherapy drug fluorouracil, a cancer treatment that stops cancer cells from making DNA and dividing. Leucovorin enhances the effects of fluorouracil.
Leucovorin is also used to reduce the toxic side effects of methotrexate, another chemotherapy drug.
Methotrexate works by blocking the body’s use of folate, which healthy cells need to make DNA. Leucovorin provides an active form of folate that healthy cells can use to make DNA, thereby “rescuing” them while methotrexate continues to target cancer cells.
Because methotrexate is also used to treat the skin condition psoriasis, leucovorin can also be used as a rescue agent during treatment for this autoimmune condition.
Why is folate important?
Because folate is essential for making DNA and other genetic material, which cells need to grow and repair properly, it’s especially important during pregnancy.
This is because insufficient folate is linked to the development of spina bifida, a condition where a baby’s spine does not develop correctly. For this reason, women are advised to take folic acid supplements before conception and during the early months of pregnancy.
Folate is also important for supporting the production of red blood cells and overall brain function.
Why is it being considered to treat autism?
The recommendation to use leucovorin to treat autism seems to stem from a theory that low levels of folate in the brain can lead to a condition called cerebral folate deficiency.
Children with cerebral folate deficiency don’t usually display symptoms for the first two years. Then they show signs of speech difficulties, seizures and intellectual disability.
As the signs of autism are similar and it usually presents at around the same age, some people have proposed a link between cerebral folate deficiency and autism.
What does the evidence say?
So can giving children folate, in the form of leucovorin, help them to function better with autism? The evidence says maybe yes, and here’s what we know so far.
A review of the evidence in 2021 analysed the results of 21 studies that used leucovorin for autism or cerebral folate deficiency. Children who took the drug generally had improved autism symptoms. But the authors also said more studies were needed to confirm the findings.
Since then, a small 2024 study involved about 80 children aged two to ten years with autism. Half took a daily maximum dose of 50mg of folinic acid (similar to leucovorin), the other half took a placebo. Children given folinic acid showed more pronounced improvement when compared with those who took the placebo.
A similar 2025 study examined the same dose of folinic acid given to Chinese children with autism. Those given folinic acid had greater improvement in a type of social skill known as social reciprocity when compared with children given placebo.
While promising, none of these trials are at the level to change medical practice. We’d need further, larger studies before doctors can make a proper recommendation.
Like all drugs, leucovorin has side effects. The most serious or common are severe allergic reactions, seizures and fits, and nausea and vomiting.
In a nutshell
Overall, the latest health recommendations are not yet backed by sufficient evidence.
While the US Food and Drug Administration will now allow doctors to prescribe leucovorin to treat autism symptoms, the Australian government should not change its prescribing guidance.
Support for people with autism should continue to follow evidence-based best practice until the data from clinical trials of leucovorin is more robust.
Nial Wheate in the past has received funding from the ACT Cancer Council, Tenovus Scotland, Medical Research Scotland, Scottish Crucible, and the Scottish Universities Life Sciences Alliance. He is a fellow of the Royal Australian Chemical Institute. Nial is the chief scientific officer of Vaihea Skincare LLC, a director of SetDose Pty Ltd (a medical device company) and was previously a Standards Australia panel member for sunscreen agents. He is a member of the Haleon Australia Pty Ltd Pain Advisory Board. Nial regularly consults to industry on issues to do with medicine risk assessments, manufacturing, design and testing.
Jasmine Lee does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
