Clinical Trial of Mega-dose Folinic Acid in Autism

The common form of Leucovorin Calcium is for injection, but it exists in 

tablet form. Maybe another opportunity for intra-nasal delivery?

As pointed out by Tyler, Richard Frye has published his trial on the effect of mega-dose folinic acid in children with autism and language impairment.

FRAA (folate receptor-αautoantibody) status was predictive of response to treatment.  This means that people who are FRAA positive are likely to really benefit from folinic acid treatment.

There are different types of folinic acid.  Dr Frye uses Calcium Leucovorin (Calcium Folinate), which is used in chemotherapy.  It is given by intramuscular injection or orally.

Dr Frye uses the oral form.

Folinic acid should be distinguished from folic acid (vitamin B₉). However, folinic acid is a vitamer for folic acid, and has the full vitamin activity of this vitamin.

The dose is huge by normal standards of vitamin B₉.  It was 2 mg/ kg per day (maximum 50 mg per day) in two equally divided doses with half of the target dose given during the first 2 weeks. 

Biomarkers

Two folate-related biomarkers were investigated. FRAA titers, both blocking and binding, were analyzed. Plasma free reduced-to-oxidized glutathione redox ratio was determined. Folate-related vitamins and minerals were measured. Serum total folate and vitamin B₁₂ were measured 

Of 93 children with ASD, 60% and 44% were positive for blocking and binding FRAAs, respectively.

  

Folinic acid improves verbal communication in children with autismand language impairment: a randomized double-blind placebo-controlled trial

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4  months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg⁻¹ per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-αautoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen’s d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen’s d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD 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.

Separate analyses were conducted for each biomarker of folate metabolism (Table 2A). In general, improvement in verbal communication was significantly greater in participants on folinic acid as compared with those on placebo for participants with abnormal folate metabolism (i.e., FRAA positive, low glutathione redox ratio). For participants with biomarkers indicating more normal folate metabolism (i.e., FRAA negative, high glutathione redox ratio) improvement in verbal communication was not significantly different between groups.

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.⁶¹ Other factors such as genetic polymorphisms in folate-related genes or mitochondrial dysfunction may be important in determining treatment response but were not examined in this study. When methylcobalamin was combined with folinic acid, improvement in communication as well as glutathione redox status was found.⁴⁸ Indeed, future studies will be needed to define factors that predict response to treatment, investigate optimal dosing and help understand whether other compounds could work synergistically with folinic acid.

Conclusion

This study, and previous ones, suggest that > 50% of people tested have what Frye is calling positive Folate Receptor Antibody Status.  This combined with oxidative stress, as measured by low glutathione redox ratio, looks a like a good predictor of who will benefit from Calcium Folinate.

Clearly using tablets, as opposed to the usual injections, means that less of the folinic acid actually reaches the brain.  As was discussed in an earlier post, there are other forms of folate, like Metafolin, that are OTC.

Can Metafolin perform the same function as  Calcium Leucovorin?

It would be useful to know how much Metafolin = 2 mg/ kg of Calcium Leucovorin.  

The only way to find out would be to ask someone taking Calcium Leucovorin.

According to the producer, Merck,

“Metafolin® is a proprietary ingredient directly usable by the human organism, involved in lowering homocysteine blood levels, and the only form of folate able to cross the blood-brain barrier. In addition, Metafolin® does not mask a vitamin B₁₂-deficiency and presents no risk of an accumulation of unmodified folic acid in the body.”

I suppose readers will now want to measure Folate Receptor Antibody (FRA) status and look for Calcium Leucovorin.  Our regular reader Roger may want to give his insights; perhaps he wants to see if Metafolin can do the job of Calcium Leucovorin?

Any side effects, Roger, after long term use of Calcium Leucovorin?