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Richard Frye MD, PhD is the Director of Autism Research at Arkansas Children's Hospital Research Institute.  He is also a practicing pediatric neurologist who sees patients at the Arkansas Children’s Autism Multi-specialty clinic. 


Dr. Frye & his group recently published the results of a multi-year study that demonstrated that Folinic Acid improved speech and language and other symptoms in children with autism.

N of One: Autism Research Foundation has worked closely with Dr. Frye for years and collaborated with him to co-sponsor the first-ever Conference on Autism and the Microbiome in 2014.  We recently caught up with Dr. Frye to discuss his latest research.

N1:  Good morning Dr. Frye and thanks for joining us. Can you give a short synopsis of the Folinic Acid Trial you just completed?

RF: The trial was a double-blind placebo-controlled trial to determine if folinic acid, a special type of folate, could improve core and associated symptoms of autism. It was "blinded" so neither the parents nor the study staff running the trial were aware of which children in the study were receiving a capsule of folinic acid or a placebo.

Before the children received the folinic acid or the placebo the severity of their symptoms related to autism were evaluated. From of our previous work, we believed that folinic acid would have the greatest impact on verbal communication, so we recruited children into the trial who had language impairment and measured verbal communication skills in great detail using well validated standardized tests before any treatment. After 12 weeks of treatment with either folinic acid or placebo we repeated those same evaluations in exactly the same way to determine if there was any change.

N1:  What did you see?

RF: We found that the children that received folinic acid demonstrated significantly greater improvement in verbal communication and other behaviors such as daily living skills, irritability, stereotyped behavior and hyperactivity compared to the children that received the placebo. The results demonstrated a significant clinical benefit in these children, but my collaborators and I caution that the results need to be replicated in a larger study before we start drawing conclusions.

N1:  What’s significant about these results?

RF:  Well first, this treatment addresses core symptoms of autism not just behaviors or medical issues associated with autism. Second, this treatment addresses a key abnormality that might be a root biological mechanism that may promote the development of autism symptoms. This means that this treatment may be fixing the underlying biology which, in turn, may be driving autism symptoms to improve. This would, indeed, be considered a significant medical breakthrough in this field. Third, we obtained these results with folinic acid, a vitamin that is a very well tolerated and considered a safe treatment. Folinic acid has been in clinical use in pediatric oncology since the 1950’s to rescue the body from the ill effects of a chemotherapy agent known as methotrexate. So the treatment we are giving has been studied for quite some time and the safety profile is well known. This is in contrast to many common treatments used for children with autism with less well-known safety profiles, which are less well studied, and can lead to adverse effects which can sometimes be serious.

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N1: What is Folinic Acid?

RF:  Folinic acid is a type of folate, also known as vitamin B9. Folates are a general type of vitamin and are necessary for many basic systems in our body to work. Most of us are familiar with folic acid, which is the oxidized form of folate used in prenatal vitamins and is also put in our foods and over the counter vitamins. The folinic acid that we used in this study is a reduced [the opposite of oxidized] type of folate which is similar to natural folates found in food but can get into the brain via a different channel than the more common folic acids and can also work around other biological “roadblocks” which have been found in children with autism.

N1: What led you to try Folinic Acid?

RF: There's a disorder called cerebral folate deficiency (CFD) that was discovered a little over 10 years ago. As more and more cases were described with this disorder, it was clear that many cases had symptoms consistent with autism. This disorder (CFD) was caused, in some cases, by Folate Receptor Alpha Autoantibodies (FRAAs) which were blocking the transportation of folate into the brain.

This discovery of CFD led a colleague and me to test children with autism to see if they also had FRAAs in their blood.  We found that there was a very high prevalence of FRAAs in the blood of children with autism and that some had low levels of folate in their central nervous system, just like the kids with CFD. So it made me question whether folinic acid could also be helpful for certain children with autism that also have FRAAs.

Our initial trials suggested that folinic acid was indeed helpful for some children. This paved the way for my team at Arkansas Children’s Hospital to do what's called a randomized double blind placebo controlled trial.  This type of trial is considered the "gold standard" in medicine.  We were very careful in the design of the trial and not all children with autism were eligible, only a particular subgroup that met criteria for entry. This is an important thing to remember, as these findings were on a very carefully selected patient population and we can’t yet generalize these findings to ASD in general, so it gives us an idea of which subgroups of children with ASD have the best chance to respond to folinic acid.

N1:  You went to some unusual steps to make sure that no one could tell if they were getting the drug or the placebo.  Can you describe those and tell us why?

RF:  It is really important to make sure that no one can tell the difference between the capsules that contain folinic acid and those that contain the placebo. In order to control for this important variable, I asked the manufacturer do their best at matching the capsules. As an additional step that is unique to this trial, we also had different groups of people (scientists, technicians, etc) see if they could tell the capsules apart -- they couldn't.  I credit my staff for coming up with this idea, as I’ve never seen this done before in a clinical trial and in the end it gave us even more confidence that the trial was truly blinded.

N1: What are some side effects that people may see with FA?

RF: Overall the folinic acid was well tolerated and we didn't see any significant differences in reported adverse effects between the group of children that received folinic acid and the group that received the placebo.  In our previous study we did observe that a few patients that were concurrently taking antipsychotic medication appeared to become more irritable on folinic acid so we made the decision to exclude children taking antipsychotic medication. We also excluded highly irritable children from this trial just to be on the safe-side. Although our previous observations were based on only a few patients, further research will be needed to see if patients concurrently taking antipsychotic medications become irritable on folinic acid in general.

In addition, in both my clinical practice and this trial, we start children at half of the target dose for two weeks because we find that some children may show increased hyperactivity when starting the medication. However, this usually ends up being temporary and resolves in a few weeks.  Interestingly, the study found that, overall, attention and hyperactivity seemed to improve as compared to baseline after 12 weeks of folinic acid treatment.

In the clinic I also find that some children taking commercial, non-compounded, forms of folinic acid can sometimes experience stomach upset, hyperactivity, or irritability. It’s my personal belief that this may be due to a reaction or sensitivity to the additives or fillers in those non-compounded brands of medication, although we will need to study this in greater detail. In our first study, we used a commercial brand of folinic acid which was in tablet form and not a compounded capsule.  We saw more irritability in that first trial than in this one (as explained above). This is the reason why our current study used a compounded formulation of folinic acid without additives.

N1: You say that the biology you are addressing is low levels of folate in the brain, but the only way to test that for sure is with a lumbar puncture, a painful, invasive and expensive procedure.  Do you think it’s necessary to test for this in advance or is a trial of Leucovorin [Folinic Acid] a simpler approach?

RF:  This is one of the reasons I am so excited about the FRAA biomarker. Our study demonstrated that this biomarker could help predict who will respond to treatment, making the diagnostic lumbar puncture not necessary, at least in most cases. My team and I are excited about launching other larger studies where we can study additional biomarkers in order to make the prediction better. It’s my personal belief, as a doctor and practicing physician, that there will be some complicated cases where some physicians, including myself, may believe that a lumbar puncture will be necessary, but hopefully we can try and minimize the number of children that require this procedure.

N1: How do you get tested for FRAA?  Is it a test that any doctor can order?

RF:  FRAA’s can currently be tested through commercial labs such as Iliad Neurosciences using their FRAT™ test

N1: Have you seen improvements in children with autism who didn't have FRAAs?


RF:  Absolutely. A predictive marker just means that it can identify the children that are statistically more likely to respond. But we also see kids negative for FRAA's improve with folinic acid treatment. There are many biological, scientific, and medical reasons why a child may respond to folinic acid in the absence of FRAA’s. For each patient it is best to discuss the benefits and risks of folinic acid treatment with a physician with a good understanding of the science and the medical literature in order to make a determination if a child that is negative for FRAA’s may benefit from a therapeutic trial of folinic acid.

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N1: At N of One we like to emphasize research that takes "n=1's" or case reports and uses them to "connect the dots" or guide research.  Were there any "n=1" moments for you in this research?

Yes, there were.  We made the connection between Cerebral Folate Deficiency [CFD], FRAAs and autism in large part because of the experience with a single patient.  About 7 years ago I saw a patient in my autism clinic with a variety of symptoms that also appeared to fit the profile of CFD.  Testing did indeed show low levels of cerebral folate and when we treated him with folinic acid we saw great gains in many of his autism symptoms.  It was that experience that led us to start asking broader questions and investigate whether CFD and FRAAs may be factors in other autism patients.

N1: Anything Else you'd like to Add?

RF:  On a personal level, I’d like to thank John Rodakis and the N of One: Autism Research Foundation for their efforts in supporting medical research on autism and their advocacy and mission to get the message out to a wider audience particularly for parents in need of this information that have children that need help. It’s this sort of grassroots effort that goes a long way and it’s my pleasure to be able to take the time to have this interview.

You can read the full publication: here

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The views and opinions in these interviews are not necessarily those of N of One: Autism Research Foundation and should not be construed as medical advice or recommendations.  Be aware that reatments that may help one child may have adverse effects in another.  Before beginning any type of treatment regimen, natural or conventional, it is advisable to seek the advice of a licensed healthcare professional.

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