"Folinic acid improves communication in childhood autism"

A quote to begin: "... in this small trial of children with non-syndromic ASD [autism spectrum disorder] 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 [folate receptor-α autoantibody]."

Those were the findings reported by Richard Frye and colleagues [1] (open-access) continuing a research theme from this group looking at how folinic acid - a reduced form or vitamer of folate - may "markedly" improve symptoms in some children diagnosed with ASD (see here). Some media reporting about these latest results are available (see here for example) but if you're sticking with my interpretation there are a few important points to note.

So:

• This was a gold-standard "double-blind, randomized placebo-controlled" study meaning that as well as pitting folinic acid against a placebo, both researchers and participants were blind to 'who got what' during the 12 weeks of study. The aim was to compare a "target dose" of folinic acid "(2 mg kg−1 per day)" with said placebo formulation. It also appears that the authors went to some lengths to ensure that folinic acid and placebo capsules were "indistinguishable by sight and feel" as well as odour and taste.
• Participants (~7 years old) (N=48) were allocated to the folinic acid (n=23) or placebo group (n=25). All had a diagnosis of ASD and importantly, "Reconfirmation of the diagnosis using the lifetime version of the Autism Diagnostic Interview-Revised by an independent research reliable rater was requested from all participants." Participants were also required to have "documentation of language impairment" accompanying their autism as well as being free from current antipsychotic medication use alongside various other inclusion/exclusion criteria.
• "Verbal communication was the primary outcome" we are told, offering a rather refreshing prospect insofar as the focus being on symptoms rather than syndromes. That's not to say that various behavioural schemes pertinent to the presentation of autism and other general 'adaptive behaviours' weren't also included, but this was a study looking specifically at what happened to verbal communication.
• Results: well, first and foremost folinic acid seemed to be pretty safe and well tolerated as we are told that "no serious adverse effects" were recorded for the folinic acid group when blinding was broken. First, do no harm and all that. As per the opening sentence of this post, there were some significant group improvements noted for the group taking folinic acid in relation to verbal communication ("an important core ASD symptom") compared with the placebo group.
• Going back to the whole 'positive for FRAAs' there were also some results to be seen. "This study suggests that FRAAs predict response to high-dose folinic acid treatment. This is consistent with the notion that children with ASD and FRAAs may represent a distinct subgroup." Without turning this post into some grand explanation of what FRAAs are (bearing in mind I'm barely getting my head around this myself), this ties into other findings (see here) and how these autoantibodies work to impair folate transport and 'block' or 'bind' to the folate receptor. One explanation is that folinic acid is able to 'bypass the FRα [folate receptor-α] when it is blocked and/or dysfunctional' particularly at higher doses. The use of the term "distinct subgroup" when it comes to autism is music to many ears in these days of the more plural 'autisms' and recognition that certain inborn errors of metabolism seem to be associated with 'some types' of autism [2] (more on this paper to come soon).

Of course there is more to do in this area as the authors themselves identify the small participant numbers as one limitation and the future requirement to "determine the optimal folinic acid dose". Although no adverse effects were reported during the 12-week period, I'd also suggest that longer-term follow-up is needed to make sure that this effect extends a little longer too. Given the folate connection evident in this line of research, I'd for example, also be interested to see a little more work done on whether everyone's favourite scrabble gene - methylenetetrahydrofolate reductase (MTHFR) - potentially linked to some autism (see here) might also be an important player with regards to folinic acid use and response. Finally, minus any sweeping generalisations, the idea that FRAAs might also extend across labels to schizophrenia (see here) for example, is also potentially worthy of further investigation insofar as the 'links' that still remain when it comes to the autism and schizophrenia spectrums (see here) (remembering too the important work of Mildred Creak).

Having said all that, these are important results as they stand. Not least because under rigorous methodological conditions, folinic acid has seemingly passed yet another scientific hurdle with regards to its potential relevance to at least some autism. We will no doubt see more on this topic in the peer-reviewed literature in times to come...

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[1] Frye RE. et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular Psychiatry. 2016. Oct 18.

[2] Simons A. et al. Can psychiatric childhood disorders be due to inborn errors of metabolism? European Child & Adolescent Psychiatry. 2016. Sept 30.

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Frye, R., Slattery, J., Delhey, L., Furgerson, B., Strickland, T., Tippett, M., Sailey, A., Wynne, R., Rose, S., Melnyk, S., Jill James, S., Sequeira, J., & Quadros, E. (2016). Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial Molecular Psychiatry DOI: 10.1038/mp.2016.168