AAP Declines to Recommend Leucovorin for Autism, Citing Limited Evidence

The American Academy of Pediatrics (AAP) has issued interim guidance stating it does not recommend the routine use of leucovorin for children with autism spectrum disorder (ASD), citing insufficient evidence to support its widespread application. This announcement comes amidst recent developments in the pharmaceutical industry regarding potential treatments for autism and related conditions.

AAP's Stance on Leucovorin for Autism

The AAP's decision, released on Friday, emphasizes the need for large clinical trials to determine leucovorin's efficacy and safety profile for the broader autism population. While acknowledging that small studies have shown "potential benefit in carefully selected cases," the organization maintains that the current evidence base remains too limited to support broad recommendations.

This guidance follows the Department of Health and Human Services' (HHS) September 22 announcement positioning leucovorin as a treatment for cerebral folate deficiency (CFD), a condition present in some children with ASD. The HHS stated that the move would "authorize treatment for children with ASD" and allow state Medicaid programs to cover the drug for autism indications.

Leucovorin and Cerebral Folate Deficiency

Leucovorin, also known as folinic acid, is being investigated for its potential to bypass defective folate transport systems in some children with autism. According to an HHS fact sheet, folate receptor alpha (FRα) autoantibodies in certain autistic children block the transport of folate—a B vitamin—into the brain, leading to CFD. Leucovorin is thought to deliver folate directly to the brain, potentially addressing this deficiency.

The FDA's decision to work with GSK on relabeling the previously discontinued leucovorin product Wellcovorin for CFD treatment was based on a "systematic analysis of literature published between 2009-2024, including published case reports with patient-level information, as well as mechanistic data."

Controversy Surrounding Autism Treatments

The leucovorin discussion is part of a larger controversy surrounding potential autism treatments and causes. The AAP has previously criticized the Trump administration for linking autism to childhood vaccines and the use of acetaminophen during pregnancy without sufficient evidence.

Following a September 22 White House press conference on autism, AAP President Susan Kressly, M.D., stated that the event was "filled with dangerous claims and misleading information that sends a confusing message to parents and expecting parents and does a disservice to autistic individuals."

The debate extends to Tylenol (acetaminophen), with President Donald Trump advising against its use during the press conference. However, U.S. Health Secretary Robert R. Kennedy Jr. later clarified that while there is suggestive evidence, it is not sufficient to definitively link Tylenol to autism.

Kenvue, the maker of Tylenol, has pushed back against these claims, urging the FDA not to change the label of the popular pain medication. Meanwhile, Texas Attorney General Ken Paxton has filed a lawsuit against the Johnson & Johnson consumer health spinoff, alleging deceptive marketing practices regarding Tylenol's use during pregnancy.

As the pharmaceutical industry continues to grapple with these complex issues, the AAP emphasizes that future guidance needs "to be grounded in both scientific rigor and respect for neurodiversity."