Leucovorin label update targets autism symptoms in cerebral folate deficiency

Key takeaways:

• The FDA said its literature review found that leucovorin calcium can treat cerebral folate deficiency.
• Experts caution that there is no strong evidence that taking folic acid during pregnancy prevents autism.

The FDA announced on Monday it has initiated the process to approve leucovorin calcium tablets for individuals with cerebral folate deficiency.

Low levels of folate in the brain have been associated with developmental delays consistent with autism spectrum disorder (ASD), such as difficulties with social-based communication, sensory processing and repetitive behaviors, seizures, and problems with movement and coordination, the FDA said in a press release.

“For too long, families have been left without answers or options as autism rates have soared,” HHS Secretary Robert F. Kennedy, Jr., said in an HHS press release issued concurrently with the FDA’s release. “Today, we are taking bold action — opening the door to the first FDA-recognized treatment pathway, informing doctors and families about potential risks, and investing in groundbreaking research.”

To expedite the label expansion process, the FDA said it will collaborate with original drug manufacturer GSK to include all necessary scientific information required for its safe and effective use for patients of all ages with CFD.

GSK has entered into a preliminary agreement to work with the FDA for this purpose, per its own company release, as the new drug application holder for the drug. The company also said it plans to submit a supplemental new drug application for leucovorin with a new label indication to treat CFD.

GSK no longer manufactures leucovorin, which the company marketed as Wellcovorin in the United States between 1983 and 1997. Leucovorin is currently available in generic formulations.

HHS said in its release that once the label update is approved, it is expected that leucovorin will be covered by Medicaid specifically for the indication of ASD. The NIH will then be expected to conduct confirmatory clinical trials examining safety and efficacy.

“There are two main things to know about folic acid and neurodevelopmental disabilities,” Benjamin J. Schindel, MD, MPH, an assistant professor at Johns Hopkins University School of Medicine and neurodevelopmental specialist at the Kennedy Krieger Institute, told Healio.

First, he said, folic acid is recommended for anyone who is or who may become pregnant because developing fetuses need it to form their brain and spinal cord.

“If a baby was not exposed to enough folic acid during fetal development, they may have conditions like spina bifida, where the spinal cord and vertebrae do not form correctly, or other conditions where the brain does not form properly,” Schindel said.

However, he said, there is no strong evidence that taking folic acid during pregnancy prevents autism or other neurodevelopmental disabilities.

“Second, there are some pretty interesting studies about leucovorin and autism, and it seems that it may be helpful for managing autism, but only in very specific cases,” he said. “One pretty rare cause of autism is from cerebral folate deficiency, when a person is not able to absorb folic acid into the brain and spinal cord.”

Schindel further noted that autism is a heterogeneous condition with various manifestations and causes and that current studies examining the connection between leucovorin and ASD are too small to draw adequate conclusions for large populations.

“My suspicion is that if more children with autism are treated with leucovorin, the results will be disappointing,” Schindel added.

Leucovorin was the subject of a systematic review and meta-analysis of research concerning patients with ASD and CFD published in the Journal of Personalized Medicine in 2021, coauthored by Daniel A. Rossignol, MD, FAAFP, FMAPS, of the Southern California-based Rossignol Medical Center and Richard E. Frye, MD, PhD, a child neurologist also affiliated with Rossignol.

For individuals with ASD and CFD, the researchers reported improvements of overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%) after leucovorin treatment.

In addition, Rossignol and Frye found, among 21 studies examining patients with ASD treated with leucovorin, the drug significantly improved communication with medium-to-large effect sizes, while also exerting positive effects on core ASD symptoms and behaviors.

The FDA additionally said in its release that it has conducted its own systematic analysis of research published between 2009 and 2024 that supports its claim that leucovorin calcium can treat those with CFD.

HHS, however, noted in its release that “leucovorin is not a cure for ASD and may only lead to improvements in speech-related deficits for a subset of children with ASD.”

The release further stated that leucovorin is required to be administered under medical supervision alongside other non-pharmacological methods such as behavioral therapy for children with the condition.

“We have witnessed a tragic four-fold increase in autism over 2 decades,” Commissioner Marty Makary, MD, MPH, said in the FDA’s 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.”

Reference:

GSK to submit label update for Wellcovorin (leucovorin) at US FDA’s request. https://www.gsk.com/en-gb/media/press-releases/gsk-to-submit-label-update-for-wellcovorin-leucovorin-at-us-fda-s-request. Published Sept. 22, 2025. Accessed Sept. 23, 2025.

President Trump, Secretary Kennedy announce bold actions to tackle autism epidemic. https://www.hhs.gov/press-room/hhs-trump-kennedy-autism-initiatives-leucovorin-tylenol-research-2025.html. Published Sept. 22, 2025. Accessed Sept. 23, 2025.

Rossignol DA, et al. J Pers Med. 2021; doi:10.3390/jpm11111141.

For more information:

Benjamin J. Schindel, MD, MPH, can be reached at psychiatry@healio.com.