The March label left out autism, the largest trial was retracted, and the Medicaid pathway HHS described depended on an autism label that was never issued.
Key Takeaways
- What HHS announced: On September 22, 2025, HHS said the FDA would update leucovorin’s label and that state Medicaid programs would be able to cover the drug for autism once the label was updated for that use.
- What the FDA approved: On March 10, 2026, the FDA approved Wellcovorin only for cerebral folate transport deficiency in patients with a confirmed FOLR1 gene variant, a rare genetic condition. Autism is not on the label.
- What happened to the evidence and prescribing: The largest randomized trial of leucovorin in autism was retracted in January, while a Michigan Medicine-led study found pediatric dispensing rose sharply through 2025.
- What it means for autism providers: Families are asking clinicians about a drug professional groups say needs more study, and CMS says Medicaid coverage for autism turns on state policy, with no federal guidance or mandate requiring it.
A year ago, federal health officials presented leucovorin as a new option for children with autism. On September 22, 2025, the Department of Health and Human Services (HHS) announced that the Food and Drug Administration (FDA) would update the drug’s label for cerebral folate deficiency, a condition HHS said has been associated with autism, and that “following the label update for ASD, state Medicaid programs will be able to cover leucovorin for the indication of ASD.”
The label update that arrived in March did not include autism. The FDA approved Wellcovorin (leucovorin calcium) tablets on March 10, 2026, for cerebral folate transport deficiency in adults and children with a confirmed variant in the folate receptor 1 gene, known as FOLR1. In the meantime, the largest randomized trial of leucovorin in autistic children was retracted, and a national prescription analysis found that dispensing of the drug to children rose sharply through 2025. A Spokesperson for the Centers for Medicare & Medicaid Services (CMS) told Acuity the agency has issued no guidance requiring states to cover the drug for autism.
For autism service providers, the gap between the announcement and the approval shows up in intake conversations, in family questions about treatment plans, and in what Medicaid will and will not pay for.
What HHS Said About Leucovorin for Autism and Medicaid Coverage
The September announcement framed leucovorin as a potential treatment for speech-related deficits associated with autism spectrum disorder. HHS said the FDA was publishing a Federal Register notice outlining a label update for leucovorin for cerebral folate deficiency, and it described Medicaid coverage for autism as following from a label update for that indication, “in partnership with the Centers for Medicare & Medicaid Services.”
The same release included a caution. HHS wrote that leucovorin “is not a cure for ASD” and may improve speech-related deficits for only a subset of children with autism. GlaxoSmithKline, which marketed Wellcovorin from 1983 to 1997, said the same day that it would submit a label update at the FDA’s request.
What the FDA Approved: Leucovorin for Cerebral Folate Transport Deficiency
The FDA’s March approval is narrow. The updated label covers cerebral folate transport deficiency in patients with a confirmed FOLR1 variant, a rare genetic condition that the agency said often brings severe developmental delays, movement disorders and seizures. The FDA said the approval rested on a systematic review of published literature, including case reports with patient-level information, and on mechanistic data rather than a randomized trial.
FDA Commissioner Marty Makary said the action “may benefit some individuals with FOLR1-related cerebral folate transport deficiency who have developmental delays with autistic features.” According to CNBC, FDA officials said the agency did not have sufficient data to establish efficacy for autism more broadly, and that it remains open to companies studying leucovorin in the autism population.
The distinction matters for the Medicaid pathway HHS described. That pathway was tied to a label update for autism, and the label the FDA approved names a genetically confirmed condition instead.
Leucovorin Autism Research After the Largest Trial Was Retracted
The research base was thin before the approval and thinner after it. In late January, the European Journal of Pediatrics retracted a 2024 randomized, placebo-controlled trial of oral folinic acid in children with autism, the largest such trial published. According to the journal’s notice, as reported by The Transmitter, a review confirmed concerns about the data and statistical analysis and could not replicate the reported results from the dataset the authors provided.
The American Academy of Pediatrics, in guidance for prescribing clinicians, notes that some studies suggest potential benefit in autistic children with cerebral folate deficiency but that the overall quality of evidence is limited and the findings may not apply to all autistic children. It recommends shared decision-making that reviews that evidence with families.
New trials are underway. A multicenter, placebo-controlled Phase 2 trial sponsored by Shaare Zedek Medical Center in Israel registered in 2026, and a U.S. trial of leucovorin for social and language deficits in young autistic children is recruiting at SUNY Downstate. A draft of the federal autism research plan the Interagency Autism Coordinating Committee adopted on August 27 proposed a multicenter leucovorin trial, and the Health Resources and Services Administration responded that its research program lacks the resources to fund one, as Acuity reported in its coverage of the 2026 to 2028 IACC strategic plan.
Pediatric Leucovorin Prescriptions Rose Sharply in 2025
Prescribing moved faster than the evidence. A Michigan Medicine-led study published in August in The New England Journal of Medicine analyzed a national database covering nearly all prescriptions filled at U.S. retail pharmacies. It counted 150,026 leucovorin prescriptions dispensed to 47,394 children in 2025, and found that the weekly number of children with a filled prescription rose from 734 at the start of the year to 5,858 at the end.
The number of children with a filled prescription rose 46 percent from the week before the September press conference to the week of it, from 4.6 to 6.7 per 100,000, according to the study. Dispensing to children was already rising before the briefing, a trend the researchers said may have been driven by national news coverage featuring patient stories. The largest increases came among children ages 6 to 11 and in the southern United States, and adult dispensing did not spike.
“This increase is concerning because the effectiveness and long-term safety of leucovorin for children with autism is uncertain,” said Kao-Ping Chua, the study’s lead author and a Pediatrician and Researcher at University of Michigan Health C.S. Mott Children’s Hospital, in the university’s release. He said the rise could create false hope for families and displace evidence-based therapies. Some families have described improvements in language and social skills after their children started the drug, CNBC reported. In announcing the label update a year ago, Makary said “a growing body of evidence suggests that some children suffering from autism are folate deficient within the brain.”
Leucovorin Medicaid Coverage and What It Means for Autism Providers
Leucovorin is an old generic drug that state Medicaid programs already cover for its long-standing uses, such as countering the toxic effects of methotrexate. Under the federal Medicaid drug rebate statute, section 1927 of the Social Security Act, states may limit coverage of outpatient drugs to medically accepted indications, meaning uses approved by the FDA or supported by recognized drug compendia, and may require prior authorization. With autism absent from the label, whether a Medicaid program pays for a leucovorin prescription written for an autistic child depends on how that state and its managed care plans apply those rules.
CMS has not stepped in to change that. The agency has not issued guidance or a broad mandate requiring states to cover leucovorin for autism, the CMS Spokesperson said, and coverage depends on state-level policy, medical-necessity criteria and the drug’s specific FDA indications. CMS did not address Acuity’s questions about leucovorin’s labeling, federal research on the drug or the recent rise in pediatric prescribing.
For ABA and other autism service organizations, the drug has become part of the conversation even though it is not part of the service. Families may arrive at intake already taking leucovorin, or ask whether it should change a treatment plan, while their clinicians weigh evidence the American Academy of Pediatrics describes as limited. The question of what counts as evidence-based autism care runs through Medicaid policy this year, from the CMS ABA toolkit’s push to tie coverage to a confirmed diagnosis to the debate over what the evidence supports on ABA dosage and the push by providers to publish outcomes data at scale, including benchmarks on treatment intensity.
What would change the picture is new data. A randomized trial with a confirmed result in autistic children, or an FDA label that names autism, would reopen the coverage question HHS raised a year ago. Neither has arrived yet.
