Yoshi Rothman, MD, urges caution as leucovorin use rises in autism care

Prescriptions for leucovorin among children with autism spectrum disorder (ASD) rose sharply in 2025 following national media attention and a White House announcement promoting the therapy, according to a recent study published in JAMA Network Open. Now, lead investigator Yoshi Rothman, MD, is urging pediatricians to approach off-label use cautiously while advocating for larger clinical trials.¹

The study, conducted using Epic Cosmos electronic health record data from more than 300 million patient records nationwide, found leucovorin prescribing rates increased more than 24-fold among children with ASD between January 2023 and November 2025. Investigators reported that prescribing trends began rising after a February 2025 television news segment discussing leucovorin use in autism and accelerated following a September 2025 White House announcement promoting the drug for speech-related deficits associated with ASD.²

Why are leucovorin prescriptions increasing in children with autism?

In an interview with Contemporary Pediatrics, Rothman, assistant professor of pediatrics at the University of California, San Diego School of Medicine, emphasized that leucovorin does have a role in treating rare neurologic disorders associated with folate deficiency in the brain.

“I want to be very clear that there are some specific conditions that have documented low rates of folate in the brain that will respond to leucovorin or folinic acid, and those are very rare conditions, and they tend to manifest with similar symptoms as those with autism spectrum disorder, especially in the first year of life,” Rothman said.

He noted that some of these disorders may later present with seizures or other neurologic findings that help clinicians identify appropriate candidates for treatment.

“Patients who have a documented condition that will respond to folinic acid or leukovorin should be prescribed that treatment,” Rothman said.

What evidence supports leucovorin use in autism spectrum disorder?

However, he cautioned that most children with ASD do not have these rare disorders and that evidence supporting broader leucovorin use in autism remains limited. According to the study authors, prior small clinical trials have suggested possible improvement in verbal communication among some children with autism and folate deficiency, but large randomized clinical trials confirming safety and efficacy are lacking.

“Even though there are small scale studies that suggest that there could be some improvements from Leucovorin for kids with autism,” Rothman said, “we want to make sure that before we're recommending something like leukovorin to all patients with autism, that we have more studies that can look further into not just the safety, but also confirming that it's effective and doing what it's purported to do.”

Rothman added that long-term follow-up data are also needed before clinicians can broadly recommend the therapy to families.

“At this point, we don't have those large-scale studies and the long-term follow-up that we need to make these recommendations to most families of children with autism spectrum disorder,” he said.

How should pediatricians counsel families about off-label leucovorin use?

Although Rothman described leucovorin’s established safety profile in other indications as relatively reassuring, he said uncertainties remain when the therapy is used in children with ASD.

“Leucovorin in itself doesn't have a very concerning side effect profile for the things that it has been studied for, and it is an active form of a vitamin,” Rothman said. “But we just don't know for certain, especially in this patient population.”

Rothman encouraged pediatricians to have transparent discussions with families about the limitations of current evidence and the unknown risk of rare adverse events.

“The best approach is to acknowledge the limited information, the limited evidence that we do have, and partner with families, and really go through what we know and what we don't know about the medication,” he said.

For families who still wish to pursue off-label treatment, Rothman suggested documenting shared decision-making with informed consent discussions similar to other off-label prescribing situations.

Could larger clinical trials clarify leucovorin’s role in ASD?

The increase in prescribing rates, Rothman said, may also justify investment in larger studies evaluating outcomes and safety in children with ASD.

“It's really important that we do consider pursuing a larger-scale trial just because we want to make sure that we have the rigorous evidence to make these recommendations,” Rothman said.

He added that researchers could evaluate outcomes among children already receiving leucovorin or conduct randomized controlled trials with long-term monitoring for efficacy and adverse effects.

Rothman also acknowledged the challenges many families face when searching for therapies that may help children with severe autism.

“Families of children with autism, especially those who have severe autism, are always searching for anything that's going to help their child,” Rothman said. “As long as we can remind families that that's how we feel and partner with them, hopefully we can build those therapeutic relationships.”

References

1. Rothman JM, Kwan B, Longhurst CA, Jena AB. Rates of leucovorin prescriptions for children with autism. JAMA Netw Open. 2026;9(5):e2613286. doi:10.1001/jamanetworkopen.2026.13286

2. HHS. President Trump, Secretary Kennedy Announce Bold Actions to Tackle Autism Epidemic. HHS. September 22, 2025. Accessed May 20, 2026. https://www.hhs.gov/press-room/hhs-trump-kennedy-autism-initiatives-leucovorin-tylenol-research-2025.html