What is the role of Leucovorin (folinic acid) in treating autism?

Role of Leucovorin (Folinic Acid) in Treating Autism Spectrum Disorder

Leucovorin (folinic acid) may benefit some children with autism spectrum disorder who have folate metabolism abnormalities, particularly those with folate receptor alpha autoantibodies, but it is not considered a standard treatment for ASD in current clinical guidelines.

Evidence for Folate Metabolism Abnormalities in ASD

• Folate receptor alpha autoantibodies (FRAAs) have been identified in 58-76% of children with ASD, which can interfere with folate transport into the brain 1
• Cerebral folate deficiency (CFD) has been associated with ASD, with a pooled prevalence of CFD in ASD of approximately 38% across studies 2
• Higher FRAA serum titers have been found to correlate with lower cerebrospinal fluid 5-methyltetrahydrofolate concentrations, indicating reduced folate transport to the brain 2, 3
• Children with ASD are approximately 19 times more likely to be positive for FRAAs compared to typically developing children 2

Clinical Evidence for Leucovorin Treatment in ASD

• Several studies, including placebo-controlled trials, suggest that leucovorin can improve particular symptoms in children with ASD, especially those positive for folate receptor alpha autoantibodies 1, 2

• Improvements have been reported in:

  • Communication (medium-to-large effect sizes) 2
  • Core ASD symptoms 2, 4
  • Associated behaviors such as attention and stereotypy 2
  • Irritability 2, 4

• A 2013 study found that approximately one-third of FRAA-positive children with ASD showed moderate to significant improvement with leucovorin treatment (2 mg/kg/day; maximum 50 mg/day) over a 4-month period 3

• Recent research (2024) indicates that higher binding FRAA titers are associated with greater treatment response to leucovorin 4

Safety Profile and Monitoring

• Leucovorin is generally well-tolerated when used as a standalone treatment for ASD 5

• The most common adverse effects reported across studies include:

  • Aggression (9.5%) 2
  • Excitement or agitation (11.7%) 2
  • Headache (4.9%) 2
  • Insomnia (8.5%) 2
  • Increased tantrums (6.2%) 2

• When used in higher doses or in combination with other medications like pyrimethamine, monitoring of complete blood counts is recommended due to potential bone marrow suppression 5

Current Guideline Perspectives

• The American Academy of Child and Adolescent Psychiatry (AACAP) practice parameters for ASD do not include leucovorin among standard treatments for core ASD symptoms 6
• Leucovorin is considered a complementary/alternative treatment approach for ASD 6
• AACAP guidelines note that clinicians should specifically inquire about the use of alternative/complementary treatments and be prepared to discuss their risks and potential benefits 6
• Most complementary treatments for ASD have limited empirical support, though they generally have little risk 6

Clinical Approach to Leucovorin Treatment

• Testing for folate receptor alpha autoantibodies or soluble folate binding proteins may help identify children with ASD who might benefit from leucovorin treatment 4
• Dosing used in studies typically ranges from 2 mg/kg/day (maximum 50 mg/day) 3
• Treatment response should be monitored using standardized assessments of core ASD symptoms and associated behaviors 4
• Consider baseline and periodic complete blood count monitoring, particularly with higher doses 5

Limitations and Considerations

• Leucovorin treatment for ASD is not part of standard ASD treatment guidelines 6, 5
• Evidence for leucovorin in ASD, while promising, is still evolving and requires further research 1, 2
• The U.S. Preventive Services Task Force notes that complementary approaches for ASD have less robust evidence compared to behavioral interventions 5
• Families should be counseled that behavioral interventions remain the cornerstone of ASD treatment 6