Autism Research Article Review: Efficacy of Methylcobalamin and Folinic Acid Treatment on Glutathione Redox Status in Children with Autism

Previous research has shown that autistic children are deficient in several metabolites that play key roles in methylation and detoxification.  What role do methylcobalamin (a form of vitamin B12) and folinic acid supplementation play in assisting in the production of these key metabolites?  This research study focuses on the effect that methylcobalamin and folinic acid have on the production of the “active” forms of glutathione and SAM in autistic children.

Autism Research Article Title:

Efficacy of Methylcobalamin and Folinic Acid Treatment on Glutathione Redox Status in Children with Autism by S Jill James, Stepan Melnyk, George Fuchs, et. al.


Study Using Methylcobalamin (Vitamin B12) and Folinic Acid Shows Benefit in Glutathione Synthesis
Supplementation with Folinic Acid and Methylcobalamin (Vitamin B12) in Autistic Children Resulted in an Increased Level of Glutathione

Am J Clin Nutr 2009;89:425-30

JAN 2009

Study Purpose:
  • To determine whether or not methylcobalamin (a form of vitamin B12) injections and folinic acid supplementation would improve the potential capacity for methylation and detoxification/antioxidant pathways in autistic children
Background Info:
  • Previous studies have demonstrated that autistic children have metabolic deficiencies compared to non-autistic children
  • Ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) has been shown to be significantly lower in autistic children
  • SAM:SAH ratio is an indicator of the body’s methylation capacity (the higher the ratio the greater the methylation capacity)
  • Ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) has also been shown to be significantly lower in autistic children
  • GSH:GSSG ration is an indicator of the body’s detoxification and antioxidant capacity (the higher the ratio the greater the detoxification and antioxidant capacity)
Study Design:
  • Open-label study design
  • 40 children in study group and 42 children in control group
  • Study group received 75 mcg/kg of methylcobalamin (vitamin B12) twice a week and 400 mcg of folinic acid twice daily
  • Study covered a 3 month period
  • Baseline and post-treatment lab work performed to obtain objective values of metabolite changes during study period
Inclusion Criteria:
Exclusion Criteria:
  • Asperger’s disorder
  • Pervasive developmental disorder, not otherwise specified (PDD-NOS)
  • Chronic seizures
  • Other genetic disorders comorbid with autism
  • Recent infection
  • High-dose vitamin or mineral supplementation
Study Results:
  • No significant changes in methionine, SAM, SAH, and SAM:SAH between baseline and post-treatment metabolite levels
  • Significant changes in homocysteine, cysteine, cysteinylglycine, tGSH, fGSH, GSSG, tGSH:GSSG, and fGSH:GSSG (all levels increased significantly except for GSSG, which showed a significant decrease).
  • Significant improvements in GSH, GSSG, and GSH:GSSG after 3 month treatment period still did not bring levels in autistic children to the levels of the control group

Methylcobalamin/Folinic Acid Benefits:

  • Decreased autistic behaviors as measured by the Vineland Adaptive Behavior Scales (although this observation is susceptible to bias as this was an open-label study)
  • Significant improvements in many metabolites measured in study (see results section)
  • Potential increased antioxidant and detoxification capacity in children with autism

Methylcobalamin/Folinic Acid Side Effects:

  • 20% (8 children) experienced increased hyperactivity (80% reported no change in hyperactivity)
  • 10% (4 children) experienced  hyperactivity that was decreased when folinic acid dose was lowered to 400 mcg once daily
  • 2 children experienced sleep issues
  • 1 child experienced increased impulsiveness
  • 1 child experienced irritability
Study Strengths:
  • Methods put in place to ensure accurate measurement of metabolites from lab work
  • 78% of parents stated that they would like to continue methylcobalamin and folinic acid supplementation after the trial ended
  • Study allowed parents to administer methylcobalamin (vitamin B12) injections, thus reflecting discrepancies that might occur in the “real world” outside of a clinical trial setting
Study Weaknesses:
  • Open-label study as opposed to a double-blind, placebo controlled trial
  • Small number of participants
  • The study group originally had 48 children but 8 of these children dropped out of the study (a 16.6% dropout ratio)
  • Of the 8 children that dropped out, 4 were lost to follow-up and 4 voluntarily dropped out
  • Of the 4 voluntary dropouts, 2 stopped due to the parents not feeling comfortable with the methylcobalamin (vitamin B12) injections while the other 2 stopped due to increased hyperactivity
  • The 2 children that dropped out due to increased hyperactivity were not included in the analysis (i.e. were not part of the 8 children that experienced increased hyperactivity as stated in the methylcobalamin/folinic acid side effects section above)
  • Study design did not allow ability to distinguish if significant changes in metabolites that occured were due to the methylcobalamin, the folinic acid, or both
  • The study showed that methylcobalamin and folinic acid supplemenation improved the “active” form of glutathione, thereby possibly increasing the body’s detoxification and antioxidant capacity
  • The study did not show that folinic acid and methylcobalamin supplementation improved level of the “active” form of SAM
  • The lack of significant difference in SAM level at baseline and post-treatment may be a reflection of the oxidative stress the bodies of the autistic children in the study were experiencing rather than the inability of methycobalamin and folinic acid to significantly increase the level of SAM (the production of GSH may be favored over the production of SAM when the body is experiencing a lot of oxidative stress)


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