Outrage of the Month: The FDA, Autism, Leucovorin and Cerebral Folate Deficiency
Health Letter, December 2025
By Robert Steinbrook, M.D.
Director, Public Citizen's Health Research Group
If you’re not outraged, you’re not paying attention!
Read what Public Citizen has to say about the biggest blunders and outrageous offenses in the world of public health, published monthly in Health Letter.
In a highly unusual action with little precedent, the Food and Drug Administration (FDA) in September 2025 initiated the approval of leucovorin calcium tablets (previously marketed as WELLCOVORIN and generics) for patients with cerebral folate deficiency, a rare neurological condition that affects the transport of folate into the brain and has autism-like features. Folate is an essential B vitamin that the body needs to make DNA and RNA.
Remarkably, the initiative came from the FDA, not from GSK, the company that marketed Wellcovorin after its first approval in 1983. Although GSK has not marketed leucovorin since the 1990s, when generic versions became available, the company’s agreement to update the prescribing information will allow manufacturers of generic leucovorin to do so as well.
The FDA’s action is part of a broader narrative about the Trump Administration’s focus on autism. The highly publicized announcement allowed officials to tout “bold action opening the door to the first FDA-recognized treatment for autism,” despite the relevance of the initiative to few patients, the lack of convincing evidence that the drug is safe and effective for cerebral folate deficiency, and the extraordinary procedures to facilitate the approval.
Leucovorin is typically prescribed to counteract the toxic effects of methotrexate, a drug with various uses, including treating some types of arthritis, ectopic pregnancies, and leukemia in combination with other chemotherapy. Leucovorin is also prescribed to treat inadvertent overdoses of drugs that block the actions of folic acid, including methotrexate and some other drugs used to treat cancer and infectious diseases.
People with cerebral folate deficiency may have developmental delays that are characterized by autism symptoms, such as difficulties with social communications, sensory processing and repetitive behaviors, as well as problems with movement and coordination.
Cerebral folate deficiency is a rare disease. Although the true prevalence is unknown, the genetic form may affect one in a million people worldwide. By comparison, in 2022 the prevalence of autism spectrum disorder was far greater: one in 31 children aged 8 years in the United States.
The evidence to support the FDA’s initiative is “published case reports [that] provided patient-level data on over 40 patients” with the genetic form of the disease, and the agency’s “systematic analysis of literature published between 2009-2024,” not the robust clinical trials that are typically required to support an additional label indication for an already approved drug.
Typically, companies file extensive clinical data with the FDA to support label updates. In the leucovorin case, GSK will submit the label update at the FDA’s request and has disclaimed any involvement beyond that. Emma Walmsley, GSK’s chief executive, said the company is responding to “an administrative request,” adding “[W]e have no commercial interest, we have no scientific research, and we’re not pursuing it.”
As of early December 2025, the FDA’s analysis of the leucovorin data had not been published and the drug label had not been updated. Although it is scientifically plausible that leucovorin has a role in treating some people with confirmed genetic cerebral folate deficiency, whether the drug in fact has a role is not known.
Instead of initiating the approval of leucovorin, the FDA should have called on the National Institutes of Health or another research funder to sponsor robust clinical trials. Such trials would establish whether the drug is safe and effective and, if it is, the dose of the drug and how frequently it should be taken. Moreover, instead of speculating whether leucovorin might have a role in treating the autoimmune form of cerebral folate deficiency, the FDA should have called for patients with this form of the disease to be enrolled in the clinical trials.