The Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder

Background: Treatments targeting metabolic abnormalities in children with autism are limited. Previously we reported that a simple, safe and well-tolerated nutritional treatment with methylcobalamin and folinic acid significantly improved glutathione metabolism in children with autistic disorder who had evidence of low glutathione and methylation status.

Objectives: To determine whether treatment with methylcobalamin and folinic acid could improve adaptive behaviors in children with autism and abnormal glutathione and methylation metabolism and to determine whether such changes are related to alterations in glutathione metabolism.

Methods: Thirty-seven children diagnosed with autistic disorder (Diagnostic Statistical Manual Version 4 Text Revision and Childhood Autism Rating Scale) and abnormal glutathione metabolism (reduced-to-oxidized glutathione ratio < 6.0) and methylation metabolism (S-adenosylmethionine to S-adenosylhomocysteine ratio < 3.0) were treated with twice weekly 75µg/Kg methylcobalamin and twice daily 400µg folinic acid for 3 months in an open-label trial. The Vineland Adaptive Behavior Scale (VABS) and glutathione redox metabolites were measured at baseline and at the end of the treatment period.

Results: Over the treatment period, all VABS subscales significantly improved with most subscales demonstrating a medium-to-large effect size (average effect size of 0.59). Effect size for specific subscales were as follows: receptive (d=0.59), expressive (d=0.97) and written (d=0.56) communication skills, personal (d=0.65), domestic (d=0.37) and community (d=0.52) daily living skills and interpersonal (d=0.43), play-leisure (d=0.59) and coping (d=0.66) social skills. The average improvement in age-equivalent performance was 7.7 months over the three month treatment period, with many subscales, particularly those with larger effect sizes, demonstrating large gains during the three-month intervention. This was particularly true for the communication domain where skills improved between 6.0 and 8.3 months, on average, and in the social skills domain where skills improved between 5.4 and 12.0 months, on average, over the three-month treatment period. The significant  improvement in glutathione redox status was positively associated with an improvement in expressive communication, personal and domestic daily living skills and interpersonal, play-leisure and coping social skills. Age, gender and history of regression did not influence treatment response. The treatment was well-tolerated with no serious adverse effects although 14% of parents reported symptoms of moderate hyperactivity. Among the four children who dropped out of the study: two children dropped out because the parents were uncomfortable giving the methylcobalamin injections and 2 children dropped out because of hyperactivity and reduced sleep. Four families reported hyperactivity which resolved with decreasing the folinic acid dose to 400µg per day.

Conclusions: The significant adaptive behavioral improvements were observed and the positive relationship between behavior improvements and glutathione redox status suggests that nutritional interventions targeting redox metabolism may benefit some children with autism.  Larger double-blind placebo controlled studies are needed to demonstrate the efficacy of this well-tolerated and safe treatment.