Leucovorin Close-Up: A Primary Care Primer

The Trump administration's endorsement of leucovorin (folinic acid) for autism treatment, with claims it could benefit "hundreds of thousands of kids," has sparked significant debate in the medical community.

Leucovorin targets cerebral folate deficiency (CFD), where autoantibodies impair folate transport to the brain, potentially causing communication difficulties, behavioral symptoms, and "developmental delays with autistic features," according to the FDA's September 22 announcement of its plan to initiate approval.¹

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The FDA's systematic analysis of the literature on leucovorin published between 2009 and 2024 "has determined that the information supports a finding that leucovorin calcium can help individuals suffering from CFD."¹

However, researchers have pointed out that the evidence for the drug's efficacy remains limited to small clinical studies, mostly conducted outside the US, and lacks the large-scale trials needed to establish efficacy and safety in pediatric populations.² The intervention would apply only to the subset of individuals with autism who have demonstrable CFD, a small fraction, between 7% and 30%, of the autism community. This gap between policy enthusiasm and scientific evidence has left clinicians and families uncertain about patient selection, treatment expectations, and long-term safety considerations.²

What Is Leucovorin?

Leucovorin, also known as folinic acid, is a prescription drug and active form of vitamin B9 (folate) routinely used to reduce side effects of chemotherapy and to treat megaloblastic anemia. It is a synthetic molecule that bypasses the need for normal cellular metabolism to activate folate. Folate itself is crucial for cellular growth and neurological development.³

History of Use

Clinically, leucovorin has a long-established role in medicine as an “antidote” to high-dose methotrexate therapy and as adjunctive treatment in certain pediatric and adult cancers. Its investigational use for brain-related disorders, especially where folate transportation into the brain is impaired (as in CFD), has emerged only in the last 15 years, paralleling discoveries about folate metabolism in autism spectrum disorder (ASD).⁴

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How it Works in the Brain

Leucovorin directly enters cells and crosses the blood-brain barrier even when normal folate transport is blocked by autoantibodies or genetic disruption. It compensates for reduced folate carrier deficits and boosts methylation cycles that support neurotransmitter synthesis, cognitive development, and speech function. In ASD patients, up to three-quarters may have antibodies that interfere with folate transport, and leucovorin helps bypass these blocks and restore active folate to brain tissues.³

Why It’s Being Studied in Autism

Leucovorin is being repurposed in ASD after studies linked CFD and folate receptor autoantibodies (FRAAs) to certain autism profiles featuring speech and language deficits. Multiple research studies and randomized controlled trials have shown that, compared to placebo, leucovorin leads to statistically and clinically significant improvements in expressive verbal communication and social interaction in children with ASD who test positive for FRAAs. Personalizing treatment based on biomarkers such as FRAA status may identify patients most likely to benefit.^3,4

Safety for Children

Clinical studies report that leucovorin is well tolerated in children with ASD, with adverse events generally mild, including occasional hyperactivity or gastrointestinal symptoms. Serious adverse reactions are rare, and longer-term studies have not identified major safety concerns, although additional surveillance is still needed given the growing use. Leucovorin is regarded as safer than standard antipsychotics used in ASD for behavioral symptoms.^4,5

Autism Groups Weigh In

"The studies on leucovorin in autism so far have been very small, not replicated or have found inconsistent [results], and not used the same dose," Alycia Halladay, chief science officer of the Autism Science Foundation, said in a statement.⁶ She also expressed concern that social media has wrongly raised public expectations about general availability.²

"This science is still in very early stages, and more studies are necessary before a definitive conclusion can be reached. We welcome additional investigation into leucovorin, but based on existing data, the Autism Science Foundation does not recommend leucovorin as a treatment for autism.⁶

The Coalition of Autism Scientists, with a membership of more than 260 researchers, said that the suggestion that leucovorin is an effective treatment for autism will "stoke fear and falsely suggest hope when there is no simple answer.” The group explicitly withheld support for the broadened folinic acid recommendation, calling instead for rigorous, large-scale clinical trials using pre-registered protocols and appropriate biomarkers before wider adoption.⁷

References

1. FDA takes action to make a treatment available for autism symptoms. News release. FDA. September 22, 2024. Accessed September 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms

2. Ledford H. Trump team backs an unproven drug for autism — but does it work? [News] Nature. September 23, 2025. Accessed September 24, 3035. https://www.nature.com/articles/d41586-025-03103-7

3. Frye RE, Rossingol DA, Scahill L, McDougle CJ, Huberman H, Quadros EV. Treatment of folate metabolism abnormalities in autism spectrum disorder. Semin Pediatr Neurol. 2020 Jun 25;35:100835. doi: 10.1016/j.spen.2020.100835

4. Panda PK, Sharawat IK, Saha S, Gupta D, Palayllakandi A, Meena K. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. Eur J Pediatr. 2024 Nov;183(11):4827-4835. doi: 10.1007/s00431-024-05762-6

5. Frye RE, Slattery J, Delhey L, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular Psychiatry. 2018;23:247–256.

6. ASF statement on White House announcement on autism. News release. Autism Science Foundation. September 22, 2025. Accesed September 24, 2025. https://autismsciencefoundation.org/press_releases/asf-statement-wh-briefing/

7. Autism experts question HHS statements on Tylenol, leucovorin. The Transmitter. September 22, 2025. Accessed September 24, 2025.
   https://www.thetransmitter.org/spectrum/autism-experts-question-hhs-statements-on-tylenol-leucovorin/