Is leukovorin effective in treating Autism Spectrum Disorder (ASD)?

Leukovorin (Folinic Acid) in Autism Spectrum Disorder

Leukovorin (folinic acid) is not recommended as a standard treatment for Autism Spectrum Disorder (ASD) as it is considered a complementary/alternative medicine approach without sufficient evidence to support its routine use for core ASD symptoms. 1

Understanding the Evidence for Leukovorin in ASD

• Leukovorin is being investigated for treating folate metabolism abnormalities in children with ASD, particularly those with cerebral folate deficiency (CFD) 2
• Folate receptor alpha autoantibodies (FRAAs) have been identified in 58-76% of children with ASD, which may block folate transport to the brain 2
• A meta-analysis found that children with ASD were 19.03-fold more likely to be positive for FRAAs compared to typically developing children 3
• While some studies suggest improvements in communication and core ASD symptoms with leukovorin treatment, these findings have not been incorporated into major clinical practice guidelines 3, 1

Current ASD Treatment Guidelines

• The American Academy of Child and Adolescent Psychiatry (AACAP) practice parameters do not include leukovorin among recommended treatments for ASD 4
• Evidence-based structured educational and behavioral interventions remain the foundation of ASD treatment 4
• Pharmacotherapy in ASD should target specific symptoms or comorbid conditions rather than core features 4
• The British Association for Psychopharmacology does not recommend routine use of any pharmacological treatment for core symptoms of ASD 5

Potential Benefits of Leukovorin in Specific ASD Subgroups

• For individuals with ASD and confirmed cerebral folate deficiency, meta-analysis found improvements with leukovorin in:
  • Overall ASD symptoms (67%) 3
  • Communication (with medium-to-large effect sizes) 3
  • Irritability (58%) 3
  • Associated behaviors including attention and stereotypy 3

Safety Considerations

• The primary risks of leukovorin treatment include potential bone marrow suppression (neutropenia, anemia, and thrombocytopenia), though this risk is generally low when used alone 1
• Common adverse effects reported include:
  • Aggression (9.5%) 3
  • Excitement or agitation (11.7%) 3
  • Headache (4.9%) 3
  • Insomnia (8.5%) 3
  • Increased tantrums (6.2%) 3
• Complete blood count monitoring should be considered, particularly with higher doses 1

Clinical Decision-Making Algorithm

1. First, ensure proper diagnosis of ASD using standardized criteria 4
2. Implement evidence-based behavioral and educational interventions as first-line treatment 4
3. Consider testing for cerebral folate deficiency and folate receptor alpha autoantibodies only in specific clinical scenarios:
   • Children with ASD who have neurological symptoms (ataxia, movement disorders) 3
   • Those with treatment-resistant epilepsy 3
   • Those with signs of metabolic disorders 3
4. If CFD is confirmed, a trial of leukovorin might be considered under specialist supervision with appropriate monitoring 1, 3
5. Monitor response using validated assessment tools for ASD symptoms 4

Important Caveats

• Leukovorin should not replace established evidence-based interventions for ASD 4
• The AACAP recommends clinicians specifically inquire about and discuss complementary/alternative treatments with parents, recognizing their motivation to seek all possible treatments 4
• Many complementary approaches have limited empirical support but are commonly pursued by families 4
• Families should be guided toward the growing body of work on evidence-based treatments in autism 4

While some promising research exists on leukovorin for specific subgroups of children with ASD, current clinical guidelines do not support its routine use as a standard treatment for ASD core symptoms.