Is leucovorin (folinic acid) effective in treating autism?

Leucovorin for Autism Spectrum Disorder: Current Evidence

Leucovorin (folinic acid) is not recommended as a standard treatment for autism spectrum disorder according to current clinical guidelines, as it lacks sufficient evidence for efficacy and safety in this population. 1, 2

Current Guideline Recommendations

• The American Academy of Child and Adolescent Psychiatry's practice parameters do not include leucovorin among recommended pharmacological interventions for core autism symptoms 1, 2
• Current guidelines emphasize that most alternative or complementary treatments for autism have limited empirical support, and clinicians should be prepared to discuss their risks and potential benefits with families 1
• Some alternative treatments have been repeatedly shown not to work or lack randomized controlled evidence to support their use in autism 1

Evidence for Leucovorin in Autism

• Recent research suggests a potential role for leucovorin in a subset of children with autism who have folate metabolism abnormalities 3, 4
• Studies have identified folate receptor alpha autoantibodies (FRAAs) in 58-76% of children with autism, which may interfere with folate transport to the brain 3, 5
• A meta-analysis found that children with autism were 19 times more likely to be positive for FRAAs compared to typically developing children 4
• Some studies report improvements in communication and core autism symptoms with leucovorin treatment, particularly in FRAA-positive children 4, 6

Potential Benefits and Limitations

• In children with autism and cerebral folate deficiency, leucovorin treatment has been associated with improvements in:

  • Overall autism symptoms (67% of cases) 4
  • Communication skills (with medium-to-large effect sizes) 4
  • Irritability (58% of cases) 4, 6
  • Stereotypical behavior 4, 5

• However, these findings are limited by:

  • Small sample sizes in many studies 3
  • Heterogeneity across studies 4
  • Limited long-term safety data 7
  • Lack of inclusion in major treatment guidelines 1, 2

Safety Considerations

• When used alone (not in combination with pyrimethamine), leucovorin generally has a favorable safety profile 2, 7
• Reported adverse effects in autism studies were generally mild but included:
  • Aggression (9.5%) 4
  • Excitement or agitation (11.7%) 4
  • Headache (4.9%) 4
  • Insomnia (8.5%) 4
  • Increased tantrums (6.2%) 4

Clinical Approach

• Behavioral interventions remain the first-line approach for autism spectrum disorder 2, 7
• Testing for folate metabolism abnormalities (including FRAAs) is not routinely performed in standard autism care 2
• Leucovorin treatment should be considered an alternative/complementary approach that is not part of standard treatment guidelines 7
• If considering leucovorin, clinicians should:
  • Discuss with families that this is considered an alternative treatment 1
  • Consider testing for folate receptor autoantibodies or other folate metabolism abnormalities 6
  • Monitor for potential adverse effects 7, 4
  • Evaluate treatment response using standardized assessments 8, 6

Conclusion

While some emerging research suggests potential benefits of leucovorin for a subset of children with autism who have folate metabolism abnormalities, current clinical guidelines do not recommend it as a standard treatment. More robust clinical trials are needed before leucovorin can be recommended as part of routine care for autism spectrum disorder.