Is Leukovorin (folinic acid) effective for treating autism?

Leukovorin (Folinic Acid) for Autism Spectrum Disorder

Leukovorin (folinic acid) is not recommended as a standard treatment for autism spectrum disorder (ASD) according to current clinical guidelines, though it may benefit a specific subset of children with ASD who have folate metabolism abnormalities.

Evidence for Leukovorin in ASD

• The American Academy of Child and Adolescent Psychiatry practice parameters do not include leukovorin among recommended treatments for ASD, classifying it as an alternative/complementary treatment with limited empirical support 1
• Leukovorin is considered a complementary/alternative medicine approach for ASD that has less robust evidence compared to behavioral interventions 2
• Recent research suggests that leukovorin may benefit a specific subset of children with ASD who have folate metabolism abnormalities, particularly those with:
  • Folate receptor alpha autoantibodies (FRAAs), which have been found in 71% of children with ASD 3
  • Cerebral folate deficiency (CFD), which has been identified in approximately 38% of individuals with ASD 3
  • Soluble folate binding proteins (sFBPs), which are associated with more severe ASD symptoms 4

Potential Benefits in Specific Populations

• In children with ASD who are positive for folate receptor alpha autoantibodies:
  • Improvements have been observed in verbal communication, receptive and expressive language, attention, and stereotypical behavior 5
  • Approximately one-third of treated children demonstrated moderate to significant improvement in symptoms 5
• Meta-analysis found that for individuals with ASD and cerebral folate deficiency, leukovorin treatment resulted in:
  • Improvements in overall ASD symptoms (67% of cases) 3
  • Reduced irritability (58% of cases) 3
  • Improvements in core ASD symptoms with medium-to-large effect sizes 3
• Higher binding FRAA titers have been associated with greater treatment response to leukovorin 6

Safety Considerations

• The primary risks of leukovorin treatment include:
  • Bone marrow suppression (neutropenia, anemia, thrombocytopenia), though this risk is generally low when used as a standalone treatment 2
  • Adverse effects reported in studies were generally mild but included aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%) 3
• It's important to note that folic acid should not be used as a substitute for folinic acid (leukovorin) 1

Clinical Approach

• Before considering leukovorin treatment:
  • Testing for folate receptor alpha autoantibodies (FRAAs) and soluble folate binding proteins (sFBPs) should be performed to identify potential responders 6, 4
  • Baseline complete blood count should be obtained, particularly if higher doses are planned 2
• For children with positive biomarkers:
  • The typical dosage used in studies is 2 mg/kg/day (maximum 50 mg per day) of oral leukovorin calcium 5
  • Periodic monitoring of complete blood counts is recommended, especially if combined with other medications 2
  • Treatment response should be assessed using standardized measures of ASD symptoms 4

Limitations and Caveats

• Despite promising research, leukovorin is not part of standard ASD treatment guidelines 1, 2
• Most studies have been small, and larger controlled trials are needed to confirm efficacy 7
• Treatment should not replace evidence-based behavioral interventions, which remain the foundation of ASD treatment 1
• Clinicians should specifically inquire about and be prepared to discuss alternative/complementary treatments with families seeking all possible treatments for ASD 1