Leucovorin Treatment Expansion for Autism Symptoms Under FDA Review

Leucovorin, a calcium tablet approved to treat colorectal cancer and anemia, is currently undergoing FDA review to treat patients with cerebral folate deficiency (CFD)—a condition observed to cause developmental delays with autistic features.^1,2

CFD is a rare neurological condition that affects vitamin B folate—a vitamin essential for brain health—transport into the brain. Symptoms of the conditions begin to impact development in children at approximately 2 years of age. Children with these conditions begin to lose mental and motor skills, as other symptoms include intellectual disability, speech difficulties, sensory processing, and the development of recurrent seizures in nearly one-third of affected children.^1,3 The approval submission came from GSK, which is looking to update the label of the leucovorin (Wellcovorin) to indicate treatment for CFD. Leucovorin—a modified version of vitamin B9—is often referred to as folate or folic acid and has been used off-label to treat CFD for nearly 2 decades. Folate can be found naturally in foods like beans, leafy greens, eggs, beets, and citrus. It is also crucial during pregnancy to lower major risks of birth defects in a baby’s brain or spine.⁴

“We have witnessed a tragic 4-fold increase in autism over two decades,” FDA Commissioner Marty Makary, MD, MPH, said in the FDA press release. “Children are suffering and deserve access to potential treatments that have shown promise. We are using gold standard science and common sense to deliver for the American people.”

Smaller studies have shown improved verbal communications when using folic acid to treat children with non–syndromic autism spectrum disorder (ASD).⁵ The study cited in the FDA press releasealso had a small sample size, which the agency acknowledged, and noted that further research is still needed to determine the safety and efficacy of leucovorin to treat CFD.

The placebo-controlled, double-blind randomized trial consisted of 80 children aged 2 to 10 years with ASD, evenly split between the folic acid and placebo groups. The study, conducted between January 2022 and January 2024, used the Childhood Autism Rating Scale to assess child participants before and after 24 weeks of treatment. The severity of autism observed in children improved significantly in the folic acid group when compared with the placebo group [3.6 ± 0.8 vs 2.4 ± 0.7; P < .001]. Behavioral problems measured by the Child Behavior Checklist also improved more in the folic acid group when compared with the placebo group.⁶

None of the participants in either group developed any adverse events in relation to the study medication. By contrast, previous studies have shown increases in agitation, aggression, insomnia, tantrums, headaches, and gastroesophageal reflux, suggesting that some of the adverse events observed may not be related to folic acid.⁶

As the new drug application holder for leucovorin, GSK is working with the FDA in the process of extending the treated symptoms of the drug for the safe and effective use of the drug for adults and pediatric patients with CFD.¹

“This effort reflects the FDA’s commitment to identify opportunities to repurpose drugs to treat chronic diseases. The FDA remains committed to finding and treating the root causes of autism,” George Tidmarsh, MD, PhD, director of the FDA’s Center for Drug Evaluation and Research, said in the press release.

While leucovorin shows potential as a treatment for CFD and autism-related symptoms, further research is essential before FDA approval confirms its safety and effectiveness.

References

1. Commissioner of the FDA takes action to make a treatment available for autism symptoms. FDA. September 22, 2025. Accessed September 23, 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms

2. Leucovorin calcium. NCI. September 6, 2023. Accessed September 23, 2025. https://www.cancer.gov/about-cancer/treatment/drugs/leucovorincalcium

3. Cerebral folate deficiency—symptoms, causes, treatment: NORD. National Organization for Rare Disorders. January 12, 2023. Accessed September 23, 2025. https://rarediseases.org/rare-diseases/cerebral-folate-deficiency/

4. Caron C. FDA to relabel leucovorin for autism treatment. The New York Times. September 22, 2025. Accessed September 23, 2025. https://www.nytimes.com/2025/09/22/well/leucovorin-autism-fda.html

5. Frye R, Slattery J, Delhey L, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018;23:247-256. doi:10.1038/mp.2016.168

6. Panda PK, Sharawat IK, Saha S, et al. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. Eur J Pediatr. 2024;183:4827-4835. doi:10.1007/s00431-024-05762-6