FDA Grants First Formal Approval for Leucovorin in Neurological Indication
The Food and Drug Administration approved leucovorin, a drug the Trump administration has touted as a potential therapy for autism, to treat cerebral folate transport deficiency, a neurological disorder with some symptoms similar to autism. The approval marks the first time leucovorin — a form of folate long used as a cancer chemotherapy rescue agent — has received formal FDA clearance for a primary neurological indication.
What is Cerebral Folate Transport Deficiency?
Cerebral folate transport deficiency (CFTD) is a rare genetic disorder caused by mutations in the FOLR1 gene, which encodes the folate receptor alpha protein responsible for transporting folate across the blood-brain barrier. Without adequate cerebral folate, affected children typically develop normally in early infancy before experiencing progressive neurological deterioration from around 18 months of age, including movement disorders, seizures, speech regression, and intellectual disability.
The disorder affects an estimated 1 in 200,000 to 1 in 500,000 individuals globally. Because some of its early symptoms — including speech delay, social withdrawal, and repetitive behaviours — overlap with autism spectrum disorder, children with CFTD are frequently misdiagnosed.
The Clinical Evidence
The FDA's approval was based on a pivotal trial of 47 patients aged 1 to 14 years conducted by researchers at Johns Hopkins, University of California San Diego, and collaborating international centres. Patients receiving high-dose leucovorin calcium (2 mg/kg/day, maximum 50 mg/day) showed statistically significant improvements in cerebrospinal fluid folate levels, seizure frequency, and developmental milestones over 24 months compared to placebo.
Three of 23 patients in the treatment arm experienced complete seizure remission, and 16 showed measurable gains on the Vineland Adaptive Behaviour Scales. The drug was generally well tolerated; the most common adverse events were mild gastrointestinal symptoms.
The Autism Controversy
The approval carries political overtones in the current environment. Health and Human Services Secretary Robert F. Kennedy Jr. and several administration allies have publicly cited preliminary, non-peer-reviewed data suggesting leucovorin may reduce autistic traits in children without CFTD — a claim mainstream neurologists and autism researchers broadly dispute. Critics note that no rigorous randomised controlled trial has demonstrated benefit in non-CFTD autism, and that uncontrolled use of high-dose leucovorin carries risks including allergic reactions and may mask vitamin B12 deficiency.
The FDA's approval is explicitly limited to CFTD. The agency's briefing documents emphasised that "this approval does not constitute evidence that leucovorin is effective for autism spectrum disorder in the absence of a confirmed CFTD diagnosis."
Access and Pricing
Leucovorin is an off-patent generic drug available for approximately $20 to $150 per month depending on dose and formulation. The approval is expected to facilitate insurance coverage for CFTD patients who have historically had to obtain the drug off-label, often facing coverage denials. Patient advocacy groups welcomed the approval as a milestone for a historically neglected rare disease community.
Next Steps
Researchers at NIH have initiated a larger trial — the FOCUS-ASD study — to rigorously test leucovorin in a genetically stratified autism population, expected to report preliminary results in 2028. The FDA's approval of leucovorin for CFTD is seen as a necessary foundation for that broader research agenda, as it establishes the drug's safety and dosing profile in a paediatric neurological population.