Emerging Off-Label Use of Leucovorin Shows Promise in Helping Children with Autism Speak

When Caroline Connor first noticed her son Mason wasn't speaking by his first birthday, she became increasingly worried as the months passed without any words. Despite reassurances from their pediatrician, Mason's speech delay persisted, leading to a diagnosis of autism at age 2½. Desperate to find solutions, the Connors began researching potential treatments and discovered Dr. Richard Frye, a pediatric neurologist, who was investigating an inexpensive, off-label drug called leucovorin.

Leucovorin, derived from folic acid (vitamin B9), is currently prescribed to mitigate side effects of cancer chemotherapy and to prevent neural tube defects during pregnancy. While not a cure for autism, preliminary evidence suggests it could significantly improve speech and neurological symptoms in some children.

The FDA has recently initiated steps toward approving leucovorin for autism treatment, though rigorous large-scale clinical trials are still lacking. Dr. Frye emphasized that current studies, including three randomized controlled trials, show promising results, but more research is needed to determine optimal dosing, timing, and which subgroups of children might benefit most.

Underlying the use of leucovorin in autism is the theory of cerebral folate deficiency (CFD), a condition where children have adequate folate levels in blood but low levels in their brain. This deficiency may stem from autoantibodies against folate transporters, hindering folic acid's delivery to the brain and potentially affecting development. Leucovorin can bypass these transport issues, increasing brain folate levels and improving symptoms in affected children.

Studies have shown that about 75% of children with autism possess autoantibodies against the folate receptor alpha, which could interfere with folate transport. Testing for these autoantibodies can identify children most likely to respond to leucovorin therapy.

Mason Connor’s parents report remarkable progress after starting leucovorin at age three—his first words emerged just days later, giving them hope and a new outlook on their son's development. Currently, leucovorin is used off-label in this context, as it lacks FDA approval specifically for autism. Dr. Frye advocates for more funding and research to legitimize and optimize its use.

However, challenges remain. As a generic medication, leucovorin’s quality and supply can vary, and there's little financial incentive for companies to produce it specifically for autism treatment, complicating access. Dr. Frye is working on establishing a dedicated manufacturing process to ensure children receive a safe, effective form.

This case highlights the broader issue of off-label drug use, which accounts for an estimated 20–30% of prescriptions in the United States. Such practices often fill treatment gaps for conditions lacking approved therapies but require rigorous research and regulatory oversight to confirm safety and efficacy.

In the broader context, the work of scientists like Frye and others in the field of neurodevelopmental research underscores the potential of drug repurposing—using existing medications to treat new conditions. This approach can hasten access to effective therapies and reduce development costs, benefiting many children with autism and other neurodevelopmental disorders. As research continues, hope grows for more targeted, safe, and accessible treatments.

Source: https://medicalxpress.com/news/2025-09-drug-boy-autism-parents-experts.html