Dr Frye and his various research are no stranger to this blog; ranging from mitochondrial dysfunction linked to cases of autism (see here), through to tetrahydrobiopterin (BH4) and autism (see here), and folate receptor autoantibodies and autism (see here). Indeed that last link on folate receptor autoantibodies brings into view a potential reason why folinic acid was included in their recent study. That and the inclusion of Jill James on the authorship list and her previous studies looking at combined methylcobalamin and folinic acid supplementation for autism** (open-access) discussed as part of a previous post (see here).
The crux of this study was the suggestion that in the great and complex pathway which links the recycling of homocysteine (the big 'H') and the folate cycle, there is potentially enough going on in cases of autism to interfere with (a) the process of methylation (see here) and (b) that most useful of compounds, glutathione (see here), well reduced glutathione anyway. I'm also inclined to point readers the way of the very thorough analysis of glutathione and autism produced by Main and colleagues*** (open-access) a while back (see here) just in case you think I'm talking biochemical mumbo-jumbo.
Readers might already have seen mention of the words 'open trial' at the top of this post. This indicating that the latest study from Frye and colleagues was a case of following 37 children who fitted the entrance criteria - including "abnormal methylation capacity (SAM/SAH < 3.0) and glutathione redox metabolism (GSH/GSSG < 6.0)" - and seeing how they went over the course of a "sterile subcutaneous injection of methylcobalamin in the fatty tissue of the buttocks" every 3 days combined with oral delivery of folinic acid twice daily mixed with food. For those wincing or furrowing their brows about those injections of methylcobalamin with children with autism, I'll just say that the issue of drug delivery has been talked about in a previous post and this study was passed through an ethics committee "at the University of Arkansas for Medical Sciences".
The results are interesting. Quite a few behavioural changes were documented according to use of the VABS. This bearing in mind that (a) there was no control or placebo group and (b) VABS is a parent-report schedule which in this case merely looked at unblinded pre- and post-intervention scores. Nonetheless, the intervention resulted in "significant increases in VABS scores for all domains, including daily living, social, and communication skills, with an average effect size of 0.59, which is in the medium-to-large range." The authors even went as far to say that the VABS changes indicated something like an average 7.7 month gain over the 3 month period of study.
All well and good with that open-trial caveat well and truly in place. It is however the details regarding the biochemical measure of glutathione measurement that I was more interested in. Indeed, if I had to suggest one improvement to this paper, it would have been to include a simple table showing glutathione measures - GSH/GSSG - at baseline compared with at 3 months. Instead, the glutathione results are all bundled up with the VABS results as per the example of figure 3 showing: "the change in the glutathione redox status (reduced-to-oxidized glutathione ratio) and change in subscales of the Vineland Adaptive Behavior Scale (VABS) subscales".
What I did manage to glean is that: "the overall glutathione redox status was not related to VABS subscales, indicating that overall development did not appear to be related to overall glutathione redox status". Fair enough, a possible selection issue based on the group eventually included for study. It was the change in glutathione redox status after intervention which seemed to tie into the VABS results reported. Still, I would have liked to have the biochemical data presented as a stand-alone table.
I'm trying not to be overly-critical of this paper and results contained within. As with many other researchers, I'm guilty of the odd open-trial forming part of my CV (see here). Whilst useful as a starting point for looking at a particular intervention or trying to get others to do a more methodologically-sound study, one has to be quite cautious of such work and the myriad of biases that they contain.
I do get the impression that outside of just a more methodologically-sound trial, a lot more questions need to be asked about this intervention regime before it can be considered as something more mainstream. Outside of the 2 children who dropped out of the study because "parents were uncomfortable giving the methylcobalamin injections", there's also a question of what such an intervention is actually doing. I note the authors when discussing the previous James trial**, are quoted as saying: "The fact that the treatment [methylcobalamin and folinic acid] improved but did not normalize methionine, SAM and glutathione concentrations may reflect ongoing metabolic compensation for incompletely resolved oxidative stress". This may very well be true, but could also indicate that intervention was also working on other biological systems too.
That also mention is made of the Hardan trial of N-acetlycysteine (NAC) for autism (see here) and NAC being a direct glutathione precursor, suggests to me that when it comes to glutathione production, the shortest point might be A to B bearing in mind what results have been obtained from direct glutathione supplementation**** (open-access).
To close, the Clash have a question for you.... (it's the indecisions which bug me).
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* Frye RE. et al. Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status. Autism Res Treat. 2013: 609705.
** James SJ. et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009 January; 89(1): 425–430.
*** Main PA. et al. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr Metab (Lond). 2012 Apr 24;9:35.
**** Kern JK. et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011 Dec;17(12):CR677-82.
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Richard Frye, Stepan Melnyk, George Fuchs, Tyra Reid, Stefanie Jernigan, Oleksandra Pavliv, Amanda Hubanks, David W. Gaylor, Laura Walters, S. Jill James (2013). Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status Autism Research and Treatment DOI: 10.1155/2013/609705
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