Double-Blind Placebo-Controlled Trial of Methyl B12 Injections for Children with Autism

Background: Despite the fact that remarkable clinical improvements with few side effects have been reported with subcutaneous methyl B12 injections in children with autism, this remains an understudied biomedical treatment.  Children with autism have been shown to exhibit markers of oxidative stress, which may be improved by methyl B12. We recently published a double-blind, placebo cross-over pilot study evaluating the effectiveness of methyl B12 for treating symptoms in 30 individuals with autism. One-third demonstrated clinical improvement but there were no statistically significant differences between active and placebo arms in behavioral measures or glutathione redox status (a potential biomarker for oxidative stress and treatment response) (Bertloglio et al, 2011). However, the responders exhibited significantly increases in concentrations of glutathione (GSH) and redox ratio of reduced-to-oxidized glutathione (GSH/GSSG) over the treatment period.  

Objectives: We hypothesized that there is a subset of children with autism who behaviorally benefit from methyl-B12 injections because of an improvement in redox metabolism. To investigate this, we conducted a new randomized controlled trial of efficacy of injectable methyl B12 and examined measures of oxidative stress as potential biomarkers for treatment response. He we report a preliminary analysis of the first 32 of 50 children.  

Methods: We conducted an eight-week, double-blind, placebo-controlled clinical trial of every 3-day injectable methyl B12 (75 mcg/kg)  in children ages three to seven years with autism. Behavioral assessments and blood samples are obtained at baseline and weeks 8, 16 and 4 weeks post treatment. Independent-samples t-tests were were used for group comparisons. A subgroup of responders were indentified (independent of treatment) as subjects that showed improvement of at least a 2 points on the CGI to ‘much improved’ or ‘very much improved’ and 2 other behavioral measures (5 point improvement on the EVT, PPVT, ABC, MCDI, or SRS).  

Results: We have enrolled 37 children; 32 have finished the double-blind phase and 22 have finished the open-label phase. MB12 treatment resulted in a .59-point greater average improvement on the CGI and a 9.4-point greater average improvement in ABC total scores. However, these differences were not statistically significant between groups. A subgroup of 9 responders (27%) were identified. There were no statistically significant differences in behavior measurements or glutathione endpoints between responders in the treatment and placebo groups. Pre-treatment levels of total GSH were found to be significantly higher in responders compared to non-responders (p=.01). Among subjects in the treatment group, pre-treatment levels of total GSH (p=.0006) and free GSH (p=.03) were found to be significantly higher in responders versus non-responders. There was no significant difference in any glutathione measurement between the responders and non-responders in the placebo group.

Conclusions: Initial levels of pre-treatment glutathione measurements, particularly total GSH and/or free GSH, may be a predictive biomarker of which children will demonstrate positive clinical response to subcutaneous methyl B12 treatment. Trends for significant improvement in behavioral measurements in the methyl B12 treatment group as compared to the placebo group may be significant with additional subjects