Potential autism breakthrough as three-year-old boy’s symptoms are reversed using cheap drug
Old Drug Offers New Hope for Children with Autism
Caroline Connor first noticed something unusual about her son Mason around his first birthday: he wasn’t speaking. Their pediatrician wasn’t concerned, but the speech delay persisted. By age 2½, Mason was diagnosed with autism.
Determined to help, the Connors began researching treatments on their own. “That’s when my husband Joe found Dr. Frye through a research study he was conducting,” Caroline said.
Richard Frye, a pediatric neurologist, is exploring ways to help children with autism using an existing drug called leucovorin. A form of folic acid, leucovorin is inexpensive and typically used to counter side effects of chemotherapy. It is also recommended for pregnant women to prevent neural tube defects, which affect the brain and spinal cord.
Leucovorin is not a cure for autism, but Frye says it may have significant benefits for some children. “It could really have a substantial impact on a very good percentage of children with autism,” he noted.
This week, the FDA began reviewing leucovorin for use in autism, despite the absence of large phase 3 trials. Frye explained, “We have preliminary evidence that leucovorin helps, but normally the FDA would want several large, randomized clinical trials. Right now, we only have phase 2B studies, and more research is needed to answer questions about dosing, timing, and which children benefit most.”
The theory is that some children have difficulty transporting folic acid into the brain, potentially contributing to neurological challenges. Leucovorin bypasses this blockage and has been shown in three randomized trials to improve speech in some children with autism. Frye cited five controlled studies with positive results, though doses and populations varied.
Despite decades of research, Frye said he was disappointed his group wasn’t consulted for upcoming trials or funded by the National Institutes of Health’s Autism Data Science Initiative.
Understanding Cerebral Folate Deficiency
Cerebral folate deficiency (CFD) occurs when folate levels in the brain are low, even if blood levels are normal. It was first identified by physician-researcher Vincent Ramaekers, who, along with Edward Quadros, found that autoantibodies against the folate receptor (FR⍺) may block folic acid transport to the brain, contributing to autism in some cases.
Research shows that over 75% of children with autism have FR⍺ autoantibodies, compared with 10–15% of neurotypical children. There is evidence of a genetic predisposition, and while environmental and immune factors may play a role, vaccines have no connection to the condition.
The brain can use a backup transporter, the reduced folate carrier (RFC), which is less efficient but can transport leucovorin into the brain. Studies led by Frye and others found that about one-third of children with CFD saw improvements in speech and behavior after leucovorin treatment. Tests like the folate receptor autoantibody test (FRAT) can help identify children most likely to respond.
Mild Side Effects, Big Impact
Side effects of leucovorin are generally mild, with some children experiencing temporary hyperactivity. Mason Connor’s parents say he spoke his first words just three days after starting leucovorin at age 3.
Currently, doctors can prescribe leucovorin for autism only off-label. Frye welcomes the FDA’s interest but warns that guidance for proper use is still needed. He also highlighted challenges: “Leucovorin is an old, cheap drug, so there’s no financial incentive for companies to invest in it. Supply and quality can also vary.”
Frye is working to create a reliable source of leucovorin for children with autism.
Unlocking Hidden Cures
Off-label prescribing is common, accounting for an estimated 20–30% of prescriptions in the U.S., especially for rare or untreated conditions. Nonprofit Every Cure uses AI to identify drugs that could help patients, including leucovorin. David Fajgenbaum, the organization’s co-founder, said, “It’s heartbreaking to think about drugs being on the shelf while someone suffers from a disease.”
Now 5 years old, Mason will start mainstream kindergarten this fall, his development aided by an old drug offering new possibilities.
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