Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial

Mol Psychiatry. 2018 Feb;23(2):247-256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18.

Abstract

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg-1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

Trial registration: ClinicalTrials.gov NCT01602016.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder / drug therapy
  • Autistic Disorder / drug therapy
  • Child
  • Child Development Disorders, Pervasive / drug therapy
  • Child, Preschool
  • Double-Blind Method
  • Female
  • Folate Receptor 1 / metabolism
  • Humans
  • Language Development Disorders / drug therapy
  • Language Disorders / drug therapy
  • Leucovorin / metabolism
  • Leucovorin / pharmacology*
  • Male
  • Placebo Effect
  • Receptors, Peptide / metabolism
  • Treatment Outcome
  • Verbal Behavior / drug effects*

Substances

  • Folate Receptor 1
  • Receptors, Peptide
  • glutathione receptor
  • Leucovorin

Associated data

  • ClinicalTrials.gov/NCT01602016