By Hohui “Eileen” Wang, MD | | |
During a well-child visit, a primary care provider (PCP) meets with the parents of a 4-year-old boy with autism and speech delay. The child is in speech therapy but hasn’t tried Applied Behavior Analysis (ABA). The parents ask, “We heard from another family that leucovorin is now approved for autism and helped their child talk more- can we try it too?”
The PCP pauses. While familiar with leucovorin’s use in other conditions, they recall only limited research supporting its role in autism. Still, they’ve heard this question more frequently. The PCP decides to call Cal-MAP.
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What Is Leucovorin and Why Is It Being Discussed in Autism Spectrum Disorder (ASD)?
Leucovorin (folinic acid) is an active form of folate (vitamin B9) used in conditions like methotrexate toxicity. Interest in its use in ASD began when researchers found that some children with autism have autoantibodies against the folate receptor alpha (FRAAs), which can block folate transport into the central nervous system. This can lead to low cerebrospinal fluid (CSF) folate despite normal serum levels- a condition known as cerebral folate deficiency (CFD). CFD has been linked to neurological symptoms including irritability, movement abnormalities and language impairment, which overlaps with symptoms seen in some children with ASD.
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What Does the Evidence Say?
The most commonly cited study is a randomized, double-blind, placebo-controlled trial by Frye et al. (2018) involving 48 children with ASD and language impairment. Children who are FRAA positive and received leucovorin calcium at 2 mg/kg/day (max 50 mg/day) showed improvements in verbal communication over 12 weeks compared to placebo.
However, there are important caveats:
- Only children who were FRAA positive showed significant improvement.
- FRAA testing is not an easily accessible test in clinical practice.
- The study was small, male-predominant, and short-term.
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There has been no replication in large-scale trials and long-term safety remains unclear.
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Is Leucovorin FDA-Approved for Autism?
No. Leucovorin is not FDA-approved for the treatment of autism or language delay. There is ongoing discussion about its use in cerebral folate deficiency, which can co-occur with ASD but is not the same condition.
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Clinical Considerations for PCPs
Given the current evidence, leucovorin is not recommended as a first-line treatment for ASD or language impairment. The foundation of care remains behavioral and developmental therapies- including ABA, speech, and occupational therapy, which have demonstrated effectiveness and minimal risk.
If your patients or their caregivers ask about leucovorin, a risk-benefit discussion may be helpful. Here are some points to consider in such discussions:
Potential Benefits:
- Some evidence of improved verbal communication only in FRAA-positive ASD.
- Generally tolerated in short-term use.
Risks:
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Long-term safety and effectiveness are not well studied.
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May cause hyperactivity or irritability, which sometimes requires discontinuation.
- No large trials to support use in the general ASD population.
- No guidelines on starting doses, or titration schedules.
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If You Decide to Prescribe After Shared Decision-Making
- Start low, go slow
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Some studies have used 0.5–2 mg/kg/day (max 50 mg/day)
- Monitor closely for side effects
- Discontinue if symptoms worsen
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Final Thoughts:
A PCP might consider saying to families, "This is an area of emerging research. We don't have clear evidence for broad use yet, but in some cases, it may be reasonable to consider after we weigh the potential risks and benefits together."
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References
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Frye RE, Slattery JC, Delhey LM, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018;23(2):247-256. doi:10.1038/mp.2016.168
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Hyman SL, Levy SE, Myers SM; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics. 2020;145(1):e20193447. doi:10.1542/peds.2019-3447
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Have questions about leucovorin or a specific patient case?
Connect with a child and adolescent psychiatrist, psychologist, or care coordinator today for a free consultation through Cal-MAP.org or by calling 1-800-253-2103
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Hohui “Eileen” Wang, MD is a child and adolescent psychiatrist and Clinical Associate Professor in the UCSF Department of Psychiatry and Behavioral Sciences. She provides outpatient clinical care at UCSF Benioff Children’s Hospital Oakland and the STAR center at the UCSF Pritzker Building in San Francisco. She also leads the medical student teaching clinic at UCSF Benioff Children’s Hospital Oakland. Her clinical passion lies in neurodevelopmental disorders, trauma and medical education.
She completed her undergraduate and medical degrees at National Yang-Ming University at Taipei, Taiwan, received adult psychiatry residency training at UC San Diego, and her child and adolescent psychiatry training at UCSF before becoming a faculty at UCSF.
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