Nearly 50,000 American children filled a prescription for leucovorin last year, a drug that has never been approved to treat autism, according to research published this week in the New England Journal of Medicine.
The study, led by researchers at University of Michigan Health C.S. Mott Children's Hospital, drew on the IQVIA Longitudinal Prescription Database, which captures the large majority of prescriptions filled in U.S. retail pharmacies. During 2025, that database recorded 150,026 leucovorin prescriptions dispensed to 47,394 children. The weekly number of children filling a leucovorin prescription rose from 734 to 5,858 between the beginning and end of the year, and much of that increase followed a September 2025 federal press conference at which officials described the drug as an effective autism treatment.
The number is striking because of what sits behind it. Leucovorin, also called folinic acid, is a decades-old reduced form of folate used mainly to mitigate the side effects of methotrexate in cancer and autoimmune disease treatment. A handful of small studies have suggested it may improve some autism symptoms in children, but large randomized clinical trials have not been completed. Tens of thousands of families made a treatment decision in a year when the evidence base did not improve.
The Week the Prescribing Curve Bent
The researchers measured a sharp, datable shift. In the week before the September 2025 press conference, 4.6 children per 100,000 aged 0 to 17 filled a leucovorin prescription. During the week of the conference, that figure reached 6.7 per 100,000, a 46 percent increase. By the end of the study period, the rate had climbed to about 8.0 per 100,000.
"This increase is concerning because the effectiveness and long-term safety of leucovorin for children with autism is uncertain," said lead author Kao-Ping Chua, a pediatrician and researcher at Mott and director of the Susan B. Meister Child Health Evaluation and Research Center, in a statement released by Michigan Medicine.
Use was already climbing before the announcement, a trend the authors link partly to national news coverage featuring individual patient stories. The largest increases were among children ages 6 to 11 and in the southern United States. Chua and colleagues also flagged the possibility that rising off-label pediatric use contributes to leucovorin shortages affecting cancer patients who depend on the drug.
Approval for a Rare Genetic Disorder, Not for Autism
The regulatory picture is narrower than the public conversation suggests, and the distinction matters for any parent weighing this.
On March 10, 2026, the FDA approved leucovorin calcium tablets, sold as Wellcovorin, for cerebral folate transport deficiency in adults and children with a confirmed variant in the folate receptor 1 gene. That is an ultra-rare genetic condition in which folate does not cross into the brain normally, and it can produce developmental delays with autistic features. It is a separate disorder with its own diagnostic criteria, and the approval does not extend to autism spectrum disorder. The agency granted it based on a systematic review of published case reports rather than a randomized trial.
Prescribing a drug outside its approved indication is legal and routine in pediatrics. What off-label status means in practice is that no regulator has reviewed evidence establishing that the drug works for that use, and no regulator has evaluated its long-term safety in that population. Physicians are permitted to make the judgment. The evidentiary backing that approval normally supplies is simply absent.
The findings build on a separate analysis published in JAMA Network Open in May 2026 by researchers at the University of California, San Diego, who used Epic Cosmos electronic health record data covering 838,801 children with autism and more than 11.9 million outpatient encounters. Prescribing held steady at roughly 34 per 100,000 encounters for about two years before rising to more than 835 per 100,000 by November 2025.
The Household Calculation Families Are Actually Making
For a parent of a nonverbal or minimally verbal child, the appeal is easy to understand and unfair to dismiss. Options are limited, waitlists for speech and behavioral therapy run long, and a low-cost generic pill with a long safety record in cancer care sounds like a reasonable thing to try.
The honest framing is that the drug's known safety profile comes from a different population, at different doses, for a different duration. Children with autism who take leucovorin for months or years are not the group in which that record was built. Some small trials reported improvements in verbal communication among children who also had folate-related abnormalities, a narrower claim than the one that circulated publicly. The evidence base also weakened rather than strengthened this year: the largest randomized trial of oral folinic acid in autistic children, which had reported significant improvement in 77 participants, was retracted by the European Journal of Pediatrics due to data inconsistencies and statistical problems. The American Academy of Pediatrics does not recommend routine use of leucovorin in children with autism.
Families who have started the drug should not stop it abruptly on their own. Parents who are considering it can ask their pediatrician or developmental specialist a set of concrete questions: whether their child has been evaluated for cerebral folate transport deficiency, what specific change would count as a response, how long a trial should run before deciding it has not worked, and what monitoring is planned. Those questions convert an open-ended experiment into something with a defined endpoint.
Cost is a live issue too. Leucovorin is generic and inexpensive in its established uses, but coverage for an off-label pediatric indication varies by plan, and some families are paying out of pocket. MedicalDaily has reported on how rising deductibles and shifting marketplace coverage are reshaping what households absorb directly.
The Trials That Would Settle It Have Not Reported
The central unknown has not moved. No large randomized controlled trial has established whether leucovorin improves outcomes for children with autism generally, and none has established what happens over years of use in a developing child.
Several trials are underway, including a National Institutes of Health-funded study of leucovorin for language impairment in children with autism spectrum disorder, which plans to enroll 134 participants across three centers. Until results are published and independently reviewed, the current evidence supports a hypothesis rather than a treatment standard.
Researchers said this pattern is what makes the prescribing data worth publishing. A single press event shifted a national prescribing curve for a pediatric population within a week, without any new trial results. That is a finding about how medical information travels, and it will apply to the next announcement as much as this one.
Parents watching this story should expect trial results and possible updated professional guidance over the coming year, and should treat any single announcement from any source as a reason to talk with their child's clinician rather than a reason to start or stop medication.
Key Questions Answered
What did the study find? A national retail pharmacy database recorded 150,026 leucovorin prescriptions dispensed to 47,394 children during 2025, with a 46 percent jump in the week of a September 2025 federal press conference.
Is leucovorin approved for autism? No. The FDA approved it in March 2026 for cerebral folate transport deficiency tied to a confirmed folate receptor 1 gene variant. Use for autism remains off-label.
Does that mean prescribing it is illegal? No. Off-label prescribing is legal and common in pediatrics. It means no regulator has verified effectiveness or long-term safety for that use.
What is the evidence so far? A small number of trials suggested possible improvements in verbal communication, mainly in children with folate-related abnormalities. The largest randomized trial was retracted, and the American Academy of Pediatrics does not recommend routine use.
Which children saw the biggest increase? Children ages 6 to 11, and children in the southern United States.
Should a parent stop the medication after reading this? No one should stop a prescribed medication without first speaking to the prescribing clinician.
When will better evidence arrive? Several trials are in progress, including an NIH-funded study of leucovorin for language impairment in autism. Results have not yet been published.
