The Efficacy of High-Dose Folinic Acid for Autism Spectrum Disorder: A Double-Blind Placebo Controlled Study

Background: Autism spectrum disorder (ASD) is associated with several abnormalities of folate metabolism. Previous open-label studies have demonstrated that treatment with a high-dose reduced folate, folinic acid, at pharmacological doses, can improve language and behavior in ASD children. Folinic acid is believe to provide benefits since, as compared to other forms of folate, it can more readily enter the folate cycle and can be readily transported through the reduced folate carrier into the brain if folate receptor alpha autoantibodies are present. Previous research suggests that up to 75% of children with ASD have the presence of at least one of the two folate receptor alpha autoantibodies.

Objectives: To determine if high-dose folinic acid can improve language (primary outcome) and behavior (secondary outcome) in ASD children in a randomized double-blind placebo controlled trial.

Methods: Thirty-eight children with ASD (verified by the Autism Diagnostic Interview – Revised) and language impairment, without severe irritability (<=25 on the aberrant behavior checklist irritability score) who met inclusion and exclusion criteria were randomized to receive high-dose folinic acid (2mg/kg/day; maximum 50mg/day) in two divided daily doses or indistinguishable placebo capsules for 12-weeks. The dose was titrated up over 2 weeks to the target dose. At the beginning and end of the 12-week treatment period language and behavior were assessed. Language was assessed using the appropriate instrument given the child’s age and language ability (preschool language scales or clinical evaluation of language fundamentals). Adaptive behavior was assessed using the Vineland adaptive behavior scale. Core and associated behavior was assessed using a combination of parental questionnaires (aberrant behavior checklist, social responsiveness scale) and clinician observation (Ohio autism clinic impression scale).

Results: Thirty-six children completed the study: one on active treatment could not comply with the treatment regimen because of an unforeseen family emergency and one on placebo was withdrawn from the study due to an adverse event that was unrelated to the study medication. Language scores increased significantly in the participants on folinic acid, whereas it remained unchanged for the participants receiving placebo (p<0.005) demonstrating that folinic acid significantly improved language (primary outcome). Raw scores for stereotyped behavior on the aberrant behavior checklist decreased significantly (p<0.02) for the group of participants receiving folinic acid as compared to the participants receiving placebo (secondary outcome). Several other measures of behavior on the Ohio autism clinic impression scale demonstrated borderline significant trends towards improvement for the participants on folinic acid treatment as compared to the participants receiving placebo. The treatment was well-tolerated without any participants dropping out for any adverse events.

Conclusions: This double-blind placebo controlled study demonstrated the efficacy of high-dose folinic acid, a well-tolerated and safe treatment, for treating core and associated ASD symptoms, thereby confirming our previous open-label studies. Larger randomized multisite controlled trials are needed to confirm these preliminary findings.