What are the risks of treating a child with autism with folinic acid (leucovorin)?

Risks of Treating a Child with Autism with Folinic Acid/Leucovorin

The primary risks of treating a child with autism with folinic acid (leucovorin) include bone marrow suppression (neutropenia, anemia, and thrombocytopenia), which requires regular blood count monitoring, though this risk is generally low when used as a standalone treatment rather than in combination with pyrimethamine. 1

Safety Profile of Folinic Acid in Autism

• Folinic acid is generally well-tolerated in children with autism spectrum disorder (ASD), with minimal reported adverse effects in recent clinical trials 2, 3
• When used in the treatment of congenital toxoplasmosis (which requires higher doses and combination therapy), leucovorin is specifically administered to minimize the hematologic toxicity of pyrimethamine 1
• Recent randomized controlled trials have not reported significant adverse reactions in children with ASD receiving folinic acid at doses of 2 mg/kg/day (maximum 50 mg/day) 2, 3

Potential Adverse Effects to Monitor

• Bone marrow suppression is the primary concern when leucovorin is used with pyrimethamine, but is less common when used alone 1
• Complete blood count monitoring should be performed:
  • Weekly when used with daily pyrimethamine
  • Monthly when used with less frequent pyrimethamine dosing 1
• Because of the long half-life of pyrimethamine when used in combination therapy, leucovorin should be continued for 1 week after pyrimethamine discontinuation 1

Clinical Considerations for Use in Autism

• Folinic acid treatment appears most beneficial for children with ASD who have:
  • Folate receptor alpha autoantibodies (FRAAs), present in 58-76% of children with ASD 4, 5
  • Soluble folate binding proteins (sFBPs), which are associated with more severe ASD symptoms 6, 5
• The efficacy of folinic acid may be influenced by folate metabolism gene polymorphisms:
  • Children with MTHFR A1298C or MTRR A66G mutations may show greater improvements in various developmental domains 3
  • Certain genotype combinations (e.g., MTHFR C677T and A1298C) may respond better to folinic acid treatment 3

Dosing and Administration Considerations

• Clinical trials have typically used folinic acid at doses of 2 mg/kg/day (maximum 50 mg/day), divided into two daily doses 2, 3
• Treatment duration in studies has ranged from 12 to 24 weeks, with improvements in ASD symptoms observed during this timeframe 2, 3
• Folinic acid is administered orally in these studies, making it convenient for outpatient management 2

Monitoring Recommendations

• While serious adverse effects are uncommon in ASD treatment, regular clinical follow-up is prudent 2, 3
• Consider baseline and periodic complete blood count monitoring, particularly if higher doses are used or if combined with other medications 1
• Regular assessment of ASD symptoms using standardized tools (e.g., Childhood Autism Rating Scale, Social Responsiveness Scale) helps evaluate treatment response 2, 5

Clinical Pitfalls and Caveats

• Folinic acid treatment for ASD is considered complementary/alternative medicine and is not part of standard ASD treatment guidelines 1
• Current evidence for efficacy comes primarily from small clinical trials rather than large-scale studies 4, 2
• The U.S. Preventive Services Task Force notes that complementary and alternative medicine approaches for ASD have less robust evidence compared to behavioral interventions 1
• Testing for folate receptor autoantibodies or gene polymorphisms may help identify children most likely to benefit from treatment 5