Leucovorin is a biologically active form of folic acid. It was approved by the U.S. Food and Drug Administration in March 2026 for the treatment of cerebral folate deficiency, a rare condition seen in both children and adults. People with this condition often have developmental delays and other neurological complications.

Because cerebral folate deficiency is rare, between January 2023 and January 2025 rates of leucovorin prescribing were 34 prescriptions for every 100,000 outpatient visits. Rates began climbing in early 2025, increasing by more than ten-fold to 335 prescriptions for every 100,000 visits by August.

The impetus for this increase was a national news segment that aired in February 2025. It reported a child with autism spectrum disorder (ASD) had dramatic improvements in language after being treated with leucovorin.

The evidence for leucovorin use in treating ASD is limited to children with ASD and cerebral folate deficiency.

Leucovorin prescribing was further fueled in September 2025 when President Trump and Health and Human Services Secretary Kennedy promoted leucovorin as a treatment for speech-related deficits associated with ASD.

By November of 2025, prescribing rates had climbed to more than 835 prescriptions for every 100,000 outpatient visits.

To better understand this increase in leucovorin prescriptions for children with ASD, researchers from the University of California at San Diego analyzed data from almost 840,000 children seen at over 43,000 hospitals and clinics across the U.S.

The analysis included records from children with autism who were younger than 18 years old when they were prescribed leucovorin.

The timing was striking, Joshua Rothman, the first author on the study, said. Prior to the events in February and September of last year, he was rarely asked about leucovorin. Since then, more parents have asked him to prescribe it for their children with ASD. Colleagues at UC San Diego and other providers across the country have also been asked about leucovorin, he added.

“It shows you how rapidly clinical practice can shift when a treatment captures public attention,” Rothman told TheDoctor.

When parents ask him about leucovorin, Rothman, a clinical assistant professor of pediatrics at UC San Diego School of Medicine, does his best to explain that evidence for its use in treating ASD is limited. In small studies, children with ASD and cerebral folate deficiency showed improvement in verbal communication skills following treatment with leucovorin, so it is sometimes prescribed for off-label use in children with ASD. But no large-scale studies have been done that provide strong evidence for recommending leucovorin to all children with ASD.

In small studies, children with ASD and cerebral folate deficiency showed improvement in verbal communication skills following treatment with leucovorin.

The side-effect profile for leucovorin is generally safe, but since it has not been studied in children with ASD over a long period of time, there may be a risk of severe side effects. This makes large-scale, long-term studies an important next step. “Rare side effects that are more severe would be unknown until a study like that is done,” he explained. Going forward, researchers could determine if those taking leucovorin really see benefits versus those who are not taking it, and if the side effects they report are rare or more common.

The rise in requests for leucovorin for children with ASD gives researchers an opportunity to see how children on the drug do over time. “This would not be a randomized, controlled trial, but it would still give us a lot of information,” Rothman said. “Our goal as a scientific community is to do rigorous testing, so that families are confident the treatments we recommend are safe and effective.”

The study is published in JAMA Network Open.