In a significant announcement on Monday, Dr. Marty Makary, the commissioner of the Food and Drug Administration (FDA), revealed that the agency would be updating the label for a relatively lesser-known medication. This change aims to make the drug accessible for children with autism.
The medicine in question is leucovorin, also known as folinic acid. It’s a modified version of vitamin B9, or folate, which is naturally abundant in foods like beans, leafy greens, eggs, beets, and citrus fruits.
Folate plays a vital role in our bodies, essential for red blood cell production and overall cell growth. Its importance is particularly highlighted during early pregnancy, where adequate folate intake can significantly reduce the risk of severe birth defects affecting a baby’s brain or spine. Research consistently points to how folate levels can influence various aspects of our health, and scientists are actively investigating its connections to conditions such as depression, dementia, heart disease, and autism.
Interestingly, some individuals produce antibodies that disrupt the normal transport of folate within the body. Smaller studies suggest that a notable percentage of people with autism—potentially up to 75 percent in some cases—might possess these specific antibodies.
According to a Federal Register notice issued by the FDA, the agency is now officially approving leucovorin tablets for individuals suffering from “cerebral folate deficiency.” This decision comes after a thorough review of studies conducted between 2009 and 2024, which indicated that the medication can “improve certain symptoms.” While acknowledging the need for further research, the FDA highlighted one particular study involving 40 participants on the medication and 40 on a placebo. The results showed that those receiving leucovorin experienced “substantial improvement” in their deficiency symptoms.
For approximately two decades, this medicine has been used ‘off-label’ to treat individuals diagnosed with cerebral folate deficiency.
Typically, symptoms of cerebral folate deficiency begin to manifest around the age of two. Children may start to exhibit speech difficulties, intellectual disabilities, and, in some instances, seizures. Tremors and challenges with muscle control can also be part of the clinical picture.
Edward V. Quadros, a research professor at SUNY Downstate Health Sciences University and a leading expert in folate metabolism, explains that leucovorin is specially formulated to circumvent certain obstacles that prevent folate from effectively reaching the brain.
Dr. Richard E. Frye, an autism researcher, has observed significant improvements in receptive language among some children with autism who were given folinic acid in studies. He noted advancements in their ability to comprehend spoken or written words, as well as in their expressive language—the capacity to articulate thoughts and emotions. These improvements were particularly evident in children who had antibodies blocking folate transport to the brain.
However, it’s important to note that for some children involved in Dr. Frye’s studies, leucovorin showed no discernible effect.
“It is not a cure, but it substantially improves the function of many children,” Dr. Frye affirmed.
Dr. Alycia Halladay, chief science officer of the Autism Science Foundation, emphasized that larger, placebo-controlled studies are essential to precisely determine who would benefit most from this medication and at what optimal dosage.
Both she and other experts caution against viewing leucovorin as a definitive cure or a preventative measure for autism at this early stage.
“Given the limited funding available, there are much higher priority items than this,” Dr. Halladay stated, underscoring that “The data just are not there” to support such broad claims.
Currently, leucovorin holds FDA approval for other uses, including mitigating the harmful side effects of chemotherapy drugs like methotrexate, and as a component in treating colorectal cancer when combined with fluorouracil. It is also prescribed for megaloblastic anemia, a condition often caused by insufficient folic acid.
Leucovorin can be administered in various forms: orally as a pill, through injection, or intravenously. It can also be custom-compounded into a liquid medicine, though this specialized preparation is typically not covered by insurance.
According to Dr. Quadros, the side effects of leucovorin are generally minimal, primarily because it is derived from a water-soluble vitamin that is largely expelled from the body within 24 hours.
However, one analysis did identify some adverse effects, which included aggression, agitation, headaches, insomnia, and an increase in tantrums.
Christina Jewett contributed to this report.