Leucovorin Rebranded as Autism Treatment Triggers Debate

The Trump administration on Sept. 22 announced what it described as an exciting treatment for a subset of autism: leucovorin, a decades-old medication used to counteract chemotherapy-related folate depletion. Officials said the drug could be re-labeled to treat cerebral folate deficiency (CFD), a condition in which low folate in the brain may accompany autism-like symptoms. While supporters frame the move as a potential disease-modifying option for certain patients, several medical experts cautioned that the scientific evidence is not yet robust enough for broad use, and that CFD and autism are not identical conditions.

Leucovorin is a form of folinic acid, a synthetic version of folate (vitamin B9). Folate supports DNA production and cell growth; women planning or undergoing pregnancy are advised to take folic acid to reduce neural tube defects. In CFD, some individuals have unusually low brain folate despite normal folate levels elsewhere in the body. Researchers have linked CFD to antibodies that bind brain folate receptors, which can block folate transport into brain cells. In 2005, a U.S.-European study associated these antibodies with CFD and related neurological symptoms, reporting that folinic acid improved symptoms in affected children. In 2013, Richard Frye published a small study indicating that a sizable share of children with autism also exhibited brain folate deficiency, and that those with lower folate receptor function could show notable improvements with leucovorin. Five years later, Frye's randomized trial found benefits for children receiving leucovorin compared with placebo. He told TIME that leucovorin represents a major step toward addressing core biological deficits in some children, adding that it is not a cure but can substantially improve function for many.

The latest push to reposition leucovorin comes with FDA involvement. Dr. Marty Makary, then the agency’s commissioner, stated at the press conference that the FDA had begun the process to approve off-label use of the drug to treat CFD, while the agency’s official position described the potential indication as CFD rather than autism itself. He argued that changing the label could help doctors treat hundreds of thousands of children, a claim that drew both support and skepticism from the medical community. The FDA stressed that CFD can resemble autism or produce developmental delays, but is not synonymous with autism; many people with CFD have autism, but not all who have autism have CFD.

Even as officials highlighted potential benefits, several experts urged caution. Alycia Halladay, chief science officer at the Autism Research Foundation, said leucovorin remains premature as a treatment for autism. She pointed to limited safety data in children, the absence of large-scale trials, and reports that some children may become hyperactive on the drug. Halladay urged that more robust evidence and long-term data are needed before widespread use is considered. She also warned that publicity around leucovorin could divert scarce research funding away from more thoroughly studied interventions.

The American Academy of Pediatrics echoed concerns about oversimplifying autism treatment. The organization noted that autism is complex and highly variable, with no single cause or medication capable of addressing all needs. It urged individualized care plans that combine developmental, behavioral, educational, and social-relational strategies, recognizing that pharmacologic approaches are only one piece of a broader treatment landscape.

Supporters of leucovorin argue that the drug could fill an unmet need given the relative scarcity of proven, disease-modifying options for autism. Frye has said that, in his view, leucovorin should not be a first-line therapy but could be considered after foundational therapies, such as speech and occupational therapy, and after addressing sleep, gut health, and behavioral issues. He is pursuing development of a child-friendly, oral form of leucovorin that is colorless, tasteless, and odorless to facilitate administration.

The story is also framed by the drug’s history. Brand-name leucovorin, once marketed by GlaxoSmithKline in the early 1980s, was withdrawn from marketing in 1999. Generic versions later appeared, and some clinicians began prescribing leucovorin off-label for CFD-related concerns. The current initiative involves coordinating with GSK to reintroduce the drug under a new CFD indication while continuing to rely on evidence from small studies and ongoing research. Critics warn that marketing a repurposed drug for autism without broader proof could mislead families and clinicians while drawing attention away from therapies with stronger scientific backing.

Experts cautioned that more data are needed to determine safety, dosing, and duration for children with CFD or autism-related symptoms. For now, clinicians are advised to monitor emerging findings while continuing to emphasize proven therapies and individualized care plans. As the medical community weighs the potential of leucovorin, families are left to navigate a landscape in which a long-standing drug is being reimagined as a treatment for brain-based symptoms associated with autism, even as consensus on its effectiveness remains unsettled.

If validated by further trials, leucovorin could become one piece of a nuanced, multi-pronged approach to managing CFD in some autistic children. Until then, researchers and clinicians stress the importance of rigorous study designs, transparent safety reporting, and careful patient selection to ensure that any new use of the drug rests on solid evidence rather than hope.