Leucovorin might help some kids with autism, but it’s no silver bullet

introduction

A controversial White House press conference on 22 September 2025 saw U.S. President Donald Trump making several inaccurate and misleading health claims. For instance, he incorrectly claimed that hepatitis B could only be transmitted sexually, so babies didn’t need the vaccine. He also claimed that acetaminophen (also known as paracetamol) increased the risk of autism spectrum disorder in children, and called on pregnant women to “fight like hell” to avoid taking it, even though scientific evidence hasn’t established a causal relationship between acetaminophen and autism risk.

Professional medical associations in the U.S., including the American Academy of Pediatricians and the American College of Obstetrics and Gynecology, as well as those abroad decried Trump’s claims and warned about the harm that such claims could cause.

But the sensational health claims didn’t stop with Trump, whose remarks were followed by an announcement from U.S. health secretary Robert F. Kennedy Jr., who declared leucovorin “an exciting therapy that may benefit large numbers of children who suffer from autism”.

Reflecting Secretary Kennedy’s announcement, the U.S. Food and Drug Administration (FDA) moved to begin approving leucovorin to treat a condition called cerebral folate deficiency (CFD), adding it would work with the pharmaceutical company GlaxoSmithKline on relabeling leucovorin for the new approval. FDA Commissioner Marty Makary’s remarks in the announcement implied that the approval allowed leucovorin to be used as a treatment for autism as well. (The approval has since been granted.)

The move by U.S. officials to portray leucovorin as a groundbreaking therapy for autism has drawn criticism from some experts who found the decision to be hasty. In this Insight, we help readers understand the basis for the idea of leucovorin as an autism treatment and the current scientific evidence on how effective it is.

What is leucovorin?

Leucovorin is a form of folate (vitamin B12) known as folinic acid. Folate is an essential part of cell division and renewal in the body, since it’s needed to make DNA and RNA for new cells. Lack of folate (folate deficiency) leads to a variety of medical problems, including fatigue, mouth ulcers, and vision problems. In pregnancy, folate deficiency raises the risk of severe birth defects known as neural tube defects in the unborn child.

The human body cannot produce its own folate, so it needs to be obtained through our diet. Foods naturally rich in folate include leafy green vegetables, beans, peas, and nuts. In many countries, including the U.S. and Canada, certain foods like bread and cereal are fortified with folic acid to increase our intake of this essential vitamin^[1].

On the flip side, folate’s importance to cell division makes it valuable to cancer cells, which grow and divide uncontrollably. For this reason, some chemotherapeutic drugs used to treat cancer, like methotrexate, target the ability of cells to use folate. However, such drugs tend to affect healthy cells as well as cancer cells, causing a range of side effects including hair loss, nausea, and vomiting.

Prior to September 2025, leucovorin had already been an FDA-approved drug, indicated for mitigating side effects from high-dose methotrexate, treating certain forms of cancer when combined with a chemotherapeutic drug called 5-fluorouracil, and treating a form of anemia linked to folate deficiency.

What’s the connection between autism and cerebral folate deficiency?

The FDA’s recent announcement expands leucovorin’s approved uses to include treating a condition known as cerebral folate deficiency (CFD). This is a neurological disorder stemming from insufficient folate levels in the brain as a result of impaired folate metabolism. 

One common cause of CFD is autoantibodies (antibodies produced against the body’s own cells and proteins) that bind to a protein called folate receptor alpha, which helps transport folate to the brain. Autoantibody binding interferes with the receptor’s ability to bring folate into the brain.

Children with CFD typically exhibit normal development until around the age of two, when they begin to lose mental and motor skills (developmental regression). Some symptoms of CFD include speech difficulties and autism-like features.

Some studies have found that leucovorin, when given orally, increases folate levels in the brain and improves CFD symptoms. This is possible because unlike other folates, leucovorin can enter the brain without the help of folate receptor alpha.

The hypothesis that leucovorin’s benefits in children with CFD could be replicated in children with autism is based on several observations. Firstly, as we mentioned earlier, CFD and autism have several symptoms in common, and secondly, the age at which regression occurs is also similar in both conditions.

Thirdly, some studies reported finding higher levels of autoantibodies against the folate receptor protein in certain children with autism. These children also tended to have lower brain folate levels—just like children with CFD.

These parallels between CFD and autism are among the key reasons why some researchers posit that certain children with autism could benefit from leucovorin, in the same way that children with CFD do. 

What’s the evidence for leucovorin’s effectiveness in treating autism?

Even before the White House announcement, some parents had already claimed leucovorin improved their child’s autism symptoms (see examples on TikTok here and here). As anecdotes, however, they don’t constitute reliable scientific evidence.

The FDA’s decision is based on more solid ground: its announcement cites “a systematic analysis of literature published between 2009-2024, including published case reports with patient-level information, as well as mechanistic data”.

So just how strong is said literature?

We can start with a 2021 review of the published scientific literature on this subject. This review reported that leucovorin treatment was associated with improvements in various autism-related symptoms, including those related to communication and behavior.

What’s more, the drug appeared to be fairly safe at the doses employed in these studies (doses typically ranged from 0.5 to 2.5 mg/kg of body weight/day), although some studies reported adverse events, such as increased agitation, aggression, and headaches, in a small proportion of the treatment groups.

However, the existing evidence base came with important limitations. For example, of the 20 studies reviewed, nine lacked a control group, while four were case reports or series (essentially anecdotal reports). The authors also noted that the only two blinded, placebo-controlled clinical trials were fairly small: one included 48 children^[2], while the other included 19, far from the thousands needed to generalize results to the broader population of children with autism.

In addition, the review authors noted that several studies included groups receiving leucovorin in addition to other treatments and interventions. This can make it difficult to determine how much any observed improvement was due to leucovorin alone.

They concluded that leucovorin “has significant promise”, but that more studies would help to “confirm and expand” on their findings. Such studies duly appeared in the years following the review.

In 2024, a randomized controlled trial looked at whether leucovorin treatment over 24 weeks improved symptoms in children with autism^[3]. The trial, which was conducted in India, enrolled 80 children: 40 were assigned to the placebo group and 40 were assigned to receive leucovorin. Both the placebo and treatment groups “received standard care (ABA [Applied behavior analysis] and sensory integration therapy)” during the study.

At the end of the 24 weeks, the researchers reported that the leucovorin-treated group experienced significant improvements in behavioral symptoms linked to autism.

And in 2025, a randomized controlled trial in China was published, looking at whether leucovorin treatment over 12 weeks improved symptoms in children with autism^[4]. 80 children were enrolled in the study, of whom 30 were assigned to the placebo group and 50 to the leucovorin group. Like the study in India, both groups received standard interventions for children diagnosed with autism.

Both the placebo and treatment groups showed improvements in most measures at the end of the 12 weeks. But the leucovorin group showed more improvement than the placebo group specifically in a trait known as social reciprocity which is, put simply, the ability to engage in social interactions in a give-and-take manner, something that people with autism tend to find difficulty in sustaining.

In summary, these research findings suggest that leucovorin holds promise for addressing certain autism-related symptoms. However, the sample sizes in these studies are relatively small, making it difficult to generalize to the broader population.

It’s also important to note that the trials in India and China found improvements following leucovorin treatment tended to be the most significant in a specific subset of children. For the trial in India, the most marked improvement was observed in children with high levels of autoantibodies against folate receptor alpha. And for the trial in China, the same was seen particularly in children with genetic traits that potentially impair folate metabolism.

In other words, these findings suggest leucovorin may not be equally beneficial for every child who’s on the spectrum—a detail glossed over by the White House announcement, made all the more curious given the White House press secretary’s remark that the administration “does not believe popping more pills is always the answer for better health”.

How did experts react to FDA approval of leucovorin?

In general, experts agree that current studies are encouraging and that further research on leucovorin’s potential benefits for children with autism is worthwhile. However, some expressed concern with how the approval was communicated by U.S. officials.

For starters, the White House’s very public announcement hailed leucovorin as a treatment for autism, without making it clear that the FDA approval was narrower in scope, citing only CFD. As explained earlier, while some children with autism exhibit low brain folate levels—a hallmark of CFD—not every child with autism can automatically be assumed to have the same condition.

In theory, this hurdle could be overcome if testing was systematically done for every child with autism. But establishing a CFD diagnosis requires subjecting these children to a risky and expensive procedure known as a spinal tap, Aaron Kesselheim, a professor of medicine at Harvard Medical School, told the New York Times—not a procedure to be done lightly.

The even bigger stumbling block at the moment is that we still have a long way to go when it comes to establishing leucovorin’s effectiveness—promising early studies notwithstanding.

Adam Guastella, a professor at the University of Sydney who specializes in neurodevelopmental conditions, told the Australian Science Media Centre that the evidence for using leucovorin as a treatment for autism is “not at the quality that is needed for widespread use.”

Speaking to Science Media Centre U.K., Monique Botha, an associate professor in social and developmental psychology at Durham University, said that “more evidence is needed” and called the evidence currently available “exceptionally tentative”. She also stressed that while medications could help to adjust behavior or reduce distressing symptoms, “there is no medication or treatment that actively cures or erases autism”, adding: 

“Autism is a lifelong heritable disability […] autistic people are exceptionally heterogenous so any treatment or medication for specific traits is likely to work for very specific presentations of autistic traits, in very particular context. Sweeping statements about cures or treatments do not tend be accurate, helpful, or ethical.”

In his comments to the Australian Science Media Centre, Andrew Whitehouse, a professor of autism research at The Kids Research Institute Australia found that “the enthusiasm [for leucovorin] far outstrips the scientific evidence”.

“The field lacks large, multisite, rigorously controlled trials that could confirm whether benefits are real, reproducible, and meaningful in everyday life,” he said, stressing that “[f]amilies and clinicians should be cautious, and also know that there are already many support programs with strong scientific backing that reliably support development in autistic children”.

The scientific uncertainty surrounding leucovorin has dominated mainstream discourse about the FDA’s new approval, for good reason. But something less talked about is how the language used by U.S. officials to discuss autism and its treatment add to the stigma already experienced by people on the spectrum.

Andrew Cashin, a researcher in autism and intellectual disability at Southern Cross University, remarked that U.S. officials’ description of autism as an “epidemic” and designation of autism as part of “an explosion in childhood disease” shifted the narrative about autism, changing it from “a neurotype that forms part of human diversity to one of chronic disease and/or disability”.

By framing autism as a “disease and disability that needs treatment”, the language detracted from the importance of support systems and adjustments needed for the “wellbeing and functioning” of people on the spectrum, he said.

Dawn Adams, an autism researcher and professor at Griffiths University, expressed the same view. “When we frame [autism] as a condition that needs ‘fixing’, we risk adding to the stigma autistic people already face,” she cautioned, adding:

“What really makes a difference for autistic people is the right supports: inclusive classrooms, workplaces that adapt to needs, communities that understand communication and sensory differences, and policies shaped by good-quality research. These are the things that help autistic people thrive and the things that governments have the opportunity to create.

Autistic people don’t need treatments or cures. They need a world that accepts and values them for who they are.”

Summary

There are published studies showing that leucovorin could help manage certain autism-related symptoms in a subset of children. However, the evidence to date comes from studies with small sample sizes, which limits our ability to generalize to the broader population of children with autism. Continued research should help scientists find out more about leucovorin’s effectiveness and in whom such treatment would be beneficial.

In the meantime, experts caution against viewing leucovorin as a one-size-fits-all solution for autism. They stress that support systems and other existing interventions remain essential in enhancing quality of life and empowering people with autism to live up to their full potential.

References

• 1 – Quinn et al. (2024) Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review. eClinicalMedicine.
• 2 – Frye et al. (2016) Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular Psychiatry.
• 3 – Panda et al. (2024) Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. European Journal of Pediatrics.
• 4 – Zhang et al. (2025) Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms. Nutrients.