Leucovorin: a Path to Hope in Autism?

By Alain Greige
MD/PhD Candidate - Cowan Lab
SGA Academics Vice President
Department of Neuroscience
Medical University of South Carolina

In September 2025, the FDA updated the leucovorin tablet label to include its use for symptoms linked to cerebral folate deficiency in autism. Although the supporting data is still preliminary and not yet conclusive, this marks an encouraging step forward for families exploring new treatment options!

You might be wondering how leucovorin fits into the picture with autism. While the exact link isn't crystal clear yet and researchers are still digging deeper, some studies suggest it could help, especially for children with autism who also have low folate levels in their brains. I’ll try to explain this as simply as possible.

To understand this connection, we need to talk about folate first. Folate, or vitamin B9, is an essential nutrient that helps our cells make DNA, proteins, and other important molecules needed for growth and repair. We usually get it from foods like leafy greens, beans, and fortified cereals, or from supplements as folic acid. After being absorbed in the gut, folate circulates in the blood, but reaching the brain is a more selective process. The brain, one of our most important organs, is protected by a barrier made of tightly connected cells, forming what is known as the blood-brain barrier. You can think of it as a filter that allows only specific “trusted” nutrients to pass through while blocking toxins and harmful substances. Folate normally crosses this barrier through a special receptor that acts like a docking site or a lock that opens the door for it.

Leucovorin & Autism

In many children with autism, however, the immune system mistakenly produces autoantibodies that attack the folate receptor, preventing folate from entering the brain efficiently. Studies have shown that this problem occurs in about 70% of children on the autism spectrum. Even if folate levels in the blood are normal, folate levels in the brain may still be insufficient, a condition known as cerebral folate deficiency. This shortage can contribute to developmental delays, seizures, or autism-related symptoms such as difficulty with communication, social interaction, and repetitive behaviors.

That’s where leucovorin, also called folinic acid, comes in. Unlike regular folic acid, leucovorin is already in an active form that does not depend on the damaged folate receptor to enter the brain. It uses a different transport route across the blood-brain barrier, bypassing the blockage and restoring folate levels where they are needed most. In other words, because folinic acid uses a different receptor to enter the brain, it can avoid folate receptor autoantibodies and reach the brain. Once inside, folinic acid supports normal cellular functions and helps reduce the effects of folate deficiency. Clinical studies and real-world reports have shown improvements in verbal communication, social interaction, attention, irritability, and movement in many of these children after folinic acid supplementation.

Leucovorin isn’t a universal treatment for autism. It tends to help most when folate transport is disrupted by specific autoantibodies. Autism itself can have many different causes, ranging from genetic to environmental. For instance, in MEF2C haploinsufficiency, symptoms stem from a gene mutation resulting in insufficient MEF2C protein levels rather than a direct folate issue. Still, supporting brain metabolism with folate may offer some benefit, especially if a folate deficiency also exists in the brain. It’s important to note that the information in this post is for educational purposes only and should not be taken as medical advice. If you’re considering leucovorin for yourself or your child, it’s best to consult with your healthcare provider, who can help assess potential risks and benefits based on your medical history.

References: 
Frye, R E et al. “Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial.” Molecular psychiatry vol. 23,2 (2018): 247-256. doi:10.1038/mp.2016.168

Renard, Emeline et al. “Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial.” Biochimie vol. 173 (2020): 57-61. doi:10.1016/j.biochi.2020.04.019

Rossignol, Daniel A, and Richard E Frye. “Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.” Journal of personalized medicine vol. 11,11 1141. 3 Nov. 2021, doi:10.3390/jpm11111141

U.S. Food and Drug Administration. “FDA Takes Action to Make a Treatment Available for Autism Symptoms.” FDA, 22 Sept. 2025, https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms