Leucovorin is Not FDA-Approved for Autism Spectrum Disorder
Leucovorin (folinic acid) is not FDA-approved for the treatment of Autism Spectrum Disorder (ASD), despite some emerging research showing potential benefits in specific subgroups of children with ASD.
Current Status of Leucovorin for ASD
Leucovorin is currently only FDA-approved for specific indications unrelated to ASD, including:
- As rescue therapy after high-dose methotrexate treatment
- For treatment of certain toxoplasmosis infections 1
- For treatment of folate deficiency states
Research on Leucovorin in ASD
Recent research has investigated leucovorin's potential benefits in ASD, particularly in children with:
- Cerebral folate deficiency (CFD) 2
- Presence of folate receptor alpha autoantibodies (FRAAs) 3, 4
- Presence of soluble folate binding proteins (sFBPs) 5
Key Research Findings:
A 2021 meta-analysis found that children with ASD were 19 times more likely to be positive for folate receptor alpha autoantibodies compared to typically developing children 2
Treatment with leucovorin has shown improvements in:
The most common adverse effects reported were generally mild:
- Aggression (9.5%)
- Excitement or agitation (11.7%)
- Headache (4.9%)
- Insomnia (8.5%)
- Increased tantrums (6.2%) 2
Regulatory Considerations
The FDA approval process requires substantial evidence from multiple large-scale, well-controlled clinical trials demonstrating both efficacy and safety 6. Currently, leucovorin lacks this level of evidence for ASD treatment.
Similar to other medications like methotrexate, which remains unapproved by the FDA for certain indications despite widespread off-label use, leucovorin's use in ASD remains off-label 6.
Clinical Implications
Despite not being FDA-approved for ASD, some clinicians may consider leucovorin as an off-label treatment option in specific cases:
- Children with confirmed cerebral folate deficiency
- Children who test positive for folate receptor alpha autoantibodies
- Children with documented abnormalities in folate metabolism
Conclusion
While emerging research suggests potential benefits of leucovorin in specific subgroups of children with ASD, particularly those with folate metabolism abnormalities, it has not received FDA approval for this indication. The American Academy of Child and Adolescent Psychiatry practice parameters for ASD do not include leucovorin among recommended pharmacological interventions 1.
Clinicians considering leucovorin for ASD should be aware of its off-label status and the need for appropriate biomarker testing to identify patients who might benefit from this approach.