Autism Research Connections #2: A Conversation with Dr. Robert L. Hendren

Dr. Robert L. Hendren was interviewed by Seth Bittker on March 26, 2016 on autism, methyl-B12, Omega-3s, Vitamin D, over-the-counter therapies, pharmacological therapies, and the shift in the treatment paradigm for autism.  The first part of the interview focuses on Dr. Hendren’s recent methyl-B12 double blinded trial for autism. © 2016

Robert Hendren.jpg

A podcast of the interview is available here.  A transcript of the interview appears below.

SB: This is Autism Connections #2.  It is March 26, 2016.  I am Seth Bittker, your host.  Our guest today is Dr. Robert L. Hendren.  Dr. Hendren is the Director of Child and Adolescent Psychiatry unit at University of California San Francisco.

In addition to autism, Dr. Hendren specializes in the diagnosis and treatment of a number of other neurodevelopmental disorders such as pervasive developmental disorder, bipolar, schizophrenia spectrum and impulse control disorders. In his research, Dr. Hendren studies pharmacology and nutrition in treatment of autism.  He has been involved in a number of placebo controlled trials in autism including those on omega-3 supplementation.  He has also published reviews on biomarkers for autism and complementary and alternative treatments for autism.  In addition Dr. Hendren is the lead author of a remarkable paper that was published just last month – that is February 2016 – in the Journal of Child and Adolescent Psychopharmacology.  The paper is “Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism”.  Dr. Hendren thank you for being with us on Autism Research Connections.

RH: Thank you for inviting me.  It is a pleasure to talk with you and to talk with your audience about ways that we hope that we can improve childrens’ resilience to help them push back against autism and other neurodevelopmental disorders.

SB: This is great.  I think we are going to learn a lot.  Prior to – or maybe before we get into your methyl-B12 research I just wanted to give our audience some background.  Back in the early 2000s Dr. Jill James and some other researchers noticed that those with autism typically had a higher ratio of S-adenosyl homocysteine to S-adenosyl methionine than controls.  In addition they noticed that those with autism typically had higher ratios of oxidized to reduced glutathione than controls.  These are issues in the methionine cycle and more broadly issues of insufficient methylation.  These researchers hypothesized if they gave their patients betaine, folinic acid, and methyl-B12, this would address these issue.  In fact they noticed when they gave their patients these supplements they seemed to get somewhat better behaviorally and they could measure that the biochemistry became slightly more normal.  This was not a placebo controlled trial though.  In any case they published these results in a remarkable paper in 2004 where Dr. James was the lead author.  Since that time these compounds and especially methyl-B12 have been compounds of interest in autism, and a number of practitioners and parents have been providing methyl-B12 to their patients and children.

If you flash forward to 2010, Dr. Kiah Bertoglio published a paper on a double blinded cross over trial with methyl B12 in autism.  Dr. Hendren, who is our guest today, was a coauthor on this paper. In this trial they did not find efficacy with statistical significance but they did find some interesting things in subgroups.

If we flash forward again to last month, Dr. Hendren’s double blinded trial of methyl-B12, and Dr. Hendren found that methyl-B12 outscored the placebo with statistical significance based on a Clinical Global Impressions Improvement index.  In other words Dr. Hendren established efficacy for methyl-B12 in autism.  He also showed that improvements in this index were correlated to improvements in biochemistry.  So congratulations on this remarkable work Dr. Hendren.  What aspects of it would you like to highlight to our audience?

RH: Well I will tell you a little bit of a story about how I got into that I think says something about what I think is especially interesting.  When I first became the executive director of the MIND Institute at UC Davis parents encouraged me to leave no stone unturned about how kids with autism could be helped and to keep an open mind but to do good science.  So I called together a group of people that were doing kind of alternative or complementary type treatments and asked them what should be the first trial that I do?  What one do they think is most promising and they said methyl-B12.  I have to say I was skeptical at the beginning.  I was mostly used to more traditional medicine and yet thought this was fine.  We would try to see if it made some difference.  I had known and really liked Jill James and so Jill was willing to do the labs, and so we started a trial.  The first trial that you mentioned that Kiah Bertoglio and I did, didn’t show efficacy but we only had thirty kids in it.  I think so many of these nutraceuticals or nutritional type trials are things that don’t show dramatic improvement right away – they show slow steady improvement over time, and its hard then to do a double blind placebo controlled trial in that amount of time because you have to hold everything else constant but we did the thirty kids and we found a subgroup that seems to be helpful and we applied to Autism Speaks for funding and they funded us to do fifty.  So since then I have moved to the University of California San Francisco and we did the trial with fifty kids and we found significance.  So I think the biggest difference was that we had twenty more kids.  We saw a trend towards improvement in the first trial but we needed more in order to reach that significance, and I think it says in one way that in the first trial we saw improvement in oxidative stress biomarkers and the second one it was methylation biomarkers and those are related as you pointed out, but it says that this is a way to approach autism that will hopefully make the body healthier, make it more resilient, take away some of the products that might be – the metabolic products that might be causing difficulties and methyl-B12 is one that does that and I think there are others that as we get more sophisticated and thoughtful in what we are doing that we can find that can help kids in this gene environment interaction to push back on the environment and become healthier.

SB: Its outstanding work and we are so glad that you – as you said you were so open minded and you explored this.  One question that I did have on the research: if you dig into your most recent paper – I mean you did definitely get statistically significant improvement the Clinical Global Impressions Improvement index and I believe that you had set that as your primary… reference…

RH: Endpoint.

SB: Endpoint.  Primary endpoint.  Thank you, but then there were some other measures such as an Aberrant Behavior Checklist and the Social Responsiveness Scale where it was more of a mixed picture and I wondered if you could comment on that?

RH: That’s a great question and its one that people have brought up in our study.  The CGI – the Clinical Global Impressions scale is based on usually a physician but a clinician gathering all the information they can.  Seeing the child – talking to the parents – and then as a blinded rater – someone that doesn’t know whether they are on active or a placebo – giving an impression of improvement or worsening in their condition.  It is a general impression and isn’t based on particular items in a scale.  It in most studies has been shown to be in most studies the single best predictor – that kind of – somehow the physician’s impression and feel of the kid or the person in the study is a better predictor of someone improving than any kind of blood or rating scale measure that we can use.  So in this trial the two [other] measures we used were the Aberrant Behavior Checklist and the Social Communication Questionnaire and neither of those seemed to capture whatever the improvement was in these kids, but the impression – and I was the one that did all the ratings – was that the child had improved, and I would say the parents had that impression too.  They could get this feel of the kid that doesn’t fully get captured on a rating scale, and there were things on the blood test that showed changes, but I think it is more as they say in advertisements all the time, “Je ne sais quoi.”  There is something that is there.  I guess the thing that impressed me was that when I saw these kids improve it was like a veil had been lifted a little or their eyes seemed cleaner or clearer or they seemed more connected and that is something that doesn’t get captured well on a ratings scale other than the CGI.

SB: Very interesting.  Very interesting, and you must be a great observer.  Did you see cases where you would see a sudden improvement and then a drop off or it wasn’t like well you could see that given when you were doing these two before and end – after points?

RH: I think when we saw somebody seem to improve and then drop off – we didn’t know whether they were on active or placebo – but I think that happens more with the placebo group.  I didn’t find any kids that were as we look back over the records that we then learned were on methyl-B12 and they showed an initial improvement and then it dropped off.  A real rapid response too is often something that is associated with a placebo response. The methyl-B12 -sometimes people noted improvements within a few days, but it wasn’t usually something you would see the next day.  That was more because the way we were giving this was with subcutaneous injections that you know it’s pretty dramatic for the parents to do that, and I think they really hoped and wanted to think that their child was doing better.

SB: That makes total sense.  So I understand research is one thing and clinical practice is another.  What do you think the take away is from this research for physicians who are out there that have autism patients?

RH: Well I think our study needs to be replicated before we could say that this would be a general recommendation that people ought to put into their practice on a regular basis.  I think there are a lot of physicians I know who are comfortable making it part of their practice.  Then I would say it is important to make sure that you find a good lab that makes your syringes and makes up the methyl-B12.  Our pharmacy at first UC Davis and then at UCSF really wanted to be sure that the lab was making the mixture in a consistent way and that it was sterile and the first lab that we found they didn’t approve and then we found one that they did.  So I think that part’s important – finding a good lab if someone feels comfortable doing it.  When people finished our trial in order for them to continue to get the methyl-B12, they went back to their primary care physicians and I sent them our protocol and sent them our first paper and most of them were willing to prescribe it.  I think as a kind of general thing for people that don’t have any familiarity with it, it might be something that they hesitate using regularly, but I hope that we can do another trial, or get funded to do another trial, or somebody that else does another trial that shows benefit, and then it becomes something that is used regularly.  I also think it may help some kids and not others.  So I think there needs to be some abnormality in oxidative stress or something along in that pathway and if we can find a better biomarker of that that was easy to use, it would help us know to target those kids.

SB: That brings up a great point.  I mean your paper it seemed to highlight that those that had high levels of S-adenosyl homocysteine or at least the ratio of S-adenosyl homocysteine to S-adenosyl methionine was high – I believe it indicated – or maybe it was the same ratio but for the glutathione – the reduced to oxidized glutathione actually improved – I think that was what is was.  Should people be looking at some of these markers and if a physician is considering using this and they look at some of the markers and then they make a judgement based on the markers as to whether it makes sense to use it or this is just too preliminary?

RH: I think if someone’s knowledgeable in the area they might find it helpful.  Jill and I talked a lot about – you know homocysteine is not that hard to get.  People could look at it and say is that a marker, but I don’t think she found it in all of her patients.  But it kind of makes sense that homocysteine could be. It is a marker that is used in other disorders of oxidative stress.  Maybe that one would be helpful.  I think we need more study to really be able to say what biomarker would be most useful.

SB: OK.  Very fair.  I know you have also done some trials of omega-3s in autism.  What can you tell us about omega-3 supplementation in autism?

RH: It makes a slow steady difference.  Our study again was limited by the length of time that we could do it.  I think we have done three now.  They have all shown trends toward significance, but they never fully reach significance in part because we just didn’t have long enough that we could keep using them.  I think it makes sense that Omega-3s and they have been helpful in other disorders as well in other disorders ADHD and bipolar disorder and even schizophrenia.  It helps with neuron growth and if that’s the case then it seems like it would be good for kids with autism as well.  There was one positive study in autism done by Amminger, and I think based on all of that there is enough evidence to say that we routinely ought to give kids with autism Omega-3s usually around a gram.  Some of the studies used more than a gram, but when you just go to the health food store and buy a bottle of Omega-3 or fish oil, you will find that it has a lot less than a gram, so you need to find either a better concentration or give multiple pills.

SB: That makes a lot of sense.  So again would you look at some sort say fatty acid panel, or you would say this kid has autism, I think we should do a trial of Omega-3s?

RH: For the kids that I see in the clinic, I suggest to the parents that they give them a gram of Omega-3s, and I don’t base that on any laboratory tests.

SB: Interesting.  That makes a lot of sense.  If it works, it works.

RH: Yeah and there is no real harm in it and it seems like people are using it for lots of things.  So might as well use it this way.

SB: That makes a lot of sense.  I also understand that you have done some work around oral vitamin D supplementation in autism.  Have you found anything there you can tell us about?

RH: We had a hard time enrolling in that trial.  So many parents felt they don’t want to come into a double blind trial when they can just go out and buy it.  We said that we are using really high doses and we are monitoring it carefully.  So this might be a reason to come in.  We had about ten people sign up.  A number actually dropped out.  We had four that actually completed and we are just writing that up.  It is not going to be anything that is profound other than saying that people could tolerate very high doses and there was a slight trend in this small number of cases to looking towards improvement.  The person that has really been a great proponent of that is Dr. John Cannell at the Vitamin D Council.  You can look at his website and he has lots of anecdotes and testimony and case studies of vitamin D benefiting kids with autism.  There have been studies indicating that about 30% of American kids in general have low vitamin D and about 50% of kids on the spectrum have low vitamin D.  So I think all of that makes it another one of those things that I routinely suggest to parents that they give their kids a couple thousand IU of vitamin D3.  Sometimes I get a vitamin D level and I think it is the right thing to do, but sometimes if I’m not drawing blood for anything else I might just suggest that they go ahead with vitamin D.

SB: Thank you for that summary and the results you have gotten so far.  I would like to ask a few more questions or at least one more question about vitamin D, but before I do so I should acknowledge to you as well as my audience that I am a little bit of skeptic on the practice of providing large doses of vitamin D to those with autism, and I have some biases on this issue and my questions probably reflect that.  That being said when you give the large doses of vitamin D, do you see negative reactions or in general it’s positive or neutral?

RH: It is generally positive or neutral.  I think what you are referring to and there are a few thoughtful papers suggesting that perhaps really large doses of vitamin D could make autism worse or even lead to autism.  That is an interesting theory, and it certainly has made me cautious about supplementing at really high doses for long periods of time.  I worry too that if parents are [giving] vitamin D that has A with it – which often comes in fish oil or others – that you can get toxic on vitamin A since it is a fat soluble vitamin.  I have seen one kid that really kind of wrecked his liver and got his abdomen all swollen up with too much.  It wasn’t my patient, but I saw him in the hospital.

SB: Oh my goodness.

RH: I think people have to be cautious especially with the fat soluble vitamins, and saying well if a little bit is good, then maybe I can give him a whole bunch and that really ought to be good.  I think for the water soluble vitamins it mostly just makes expensive urine to give such high doses, but giving them at a good dose – and I think that the vitamin D idea makes some sense to me and the way that it could push toward health.  In our study we started at 6000 IUs and then gradually went down.  When I see patients in practice I usually just go with 2000.  I know in groups where I have asked physicians how much do they take, a lot of physicians raised their hand at 5000 IU and say that they take that much every day and think that it is helpful.

SB: Wow.  OK.  I know that you have also done a review paper and research on biomarkers in autism.  Do you have a couple that you find to be most useful?

RH: I wish that I did.  In the review there was not a kind of really strong conclusion about things that we might use.  We are just writing up a study that we did of four practices of integrative medicine docs who see kids with autism, and we couldn’t get any agreement about [inaudible] and tried to reach consensus about what labs other than just the routine labs what labs should we be doing.  There are obviously the kind of routine ones like a metabolic panel and a CBC and I think if there is any concern it is worth getting iron.  There have been a number of studies saying that ferritin is sometimes low in these kids.  It’s also good to think about lead screening.  There has been some concern about that as well.  And a D3 level that I mentioned previously.  The ones that are kind of in the maybe they are worth getting kind of category or maybe if you see something of concern.  Some people get serum amino [acids] or urine organic acids and wonder about that and helping to screen for mitochondrial dysfunction.  Some people also routinely get lactate and pyruvate to help with that kind of screening.  The ones that become a little less clear are things like even B12.  In our study the kids mostly had fairly normal B12 levels.  It is mostly that the B12 doesn’t get where it is needed or the methylation isn’t occurring there.  Others sometimes get zinc / copper ratios.  Some look at selenium.  Some look at magnesium, but it’s not part of anything that I think would say that these could be routinely used.  We are doing another study now at a school for autism in the Bay area – the Oak Hill School.  We have implemented an outcome study there, and now we are doing a trial of something that seemed innocuous that the family would feel OK about and that is with this sulforaphane you know the concentrated broccoli sprout extract that had one very positive study from a very good group, and it was thought to help with oxidative stress.  So we are doing a trial at the school where we do before and after urinary metabolomics – a way of seeing clusters of metabolic by-products that could cluster in areas like oxidative stress or mitochondrial function or free fatty acids and so we had twenty of the parents sign up which we think is great.  The kids are giving the urine before and after.  We hope that that could eventually become a kind of biomarker panel that might help us screen and then better target our metabolic interventions to help the kids be more resilient and healthier.  We will see whether that pans out or not.  We have a meeting at a place called the Think Tank that occurs a couple of times a year, and I’m presenting some of this there, and I’m hoping that I can get some consensus at some point from all the different practitioners doing these about what things do they get routinely, but I haven’t found it so far.

SB: That’s great and that is interesting news about your sulforaphane follow-up trial.  I think that the way you did your methyl B12 research, and it sounds like you are doing something similar with your sulforaphane research where you look at behavior before – maybe some metabolic markers before – then you do the trial.  Then afterwards you look at the same thing.  That is very powerful.  I’m looking forward to seeing what you produce on that.

I wondered when a child comes into your clinic and you can see the parents have brought him in.  He or she has the classic signs of autism, are there particular labs you normally order at that point or how do approach these things?

RH: So for the labs that I order, it is usually just those routine ones – the metabolic panel, CBC, D3, and if I think it is indicated the ferritin and those are the only ones I order regularly.  I’m wondering about starting to order more regularly the serum amino acid and urinary organic acid, and lactate and pyruvate.

SB: So metabolic panel.  This may be my ignorance.  What are typical things that are in the metabolic panel?

RH: That is the regular things like sodium, chloride, glucose.  You know whenever you go on your yearly test.  It is just kind of a general view of your body’s health but not metabolic in the way that we have been talking about in this conversation.

SB: I see. Makes sense.  Thank you for clarifying that.  So aside from the supplements you mentioned earlier, are there other over-the-counter supplements you find useful in treating these patients with autism?

RH: Yeah I think melatonin is really helpful.  I think people often give it to their kids for sleep, but it may even boost immune function.  So for parents that are so inclined, I say it seems worth just giving your kid melatonin.  There is concern – a small concern – about giving high doses for long periods of time.  I have never seen that kind of borne out, but I do use melatonin regularly for kids that have sleep difficulties.  If they have a lot of GI disturbance, I suggest probiotics and pancreatic digestive enzymes.  For a while every time I would see a kid that had GI issues, and I would send them to the GI specialist, they would always do that – put them on probiotics and pancreatic digestive enzymes.  And I thought well I could do that first and if that helps then maybe they don’t have to go to the GI specialist.  But we were part of a study done by Curemark of pancreatic digestive enzymes where they used fecal chymotrypsin as a biomarker, and while the results of that trial have not been released, they are coming back and doing it again this time without fecal chymotrypsin biomarker and that was at the recommendation of the FDA.  So it would suggest – I’m just kind of guessing – that it showed some benefit since they are going through this again and the FDA is continuing to monitor that with them.  The probiotic study that was done at Caltech with the mouse model of autism that reversed with probiotics I think has made people think about how that might be helpful even in even more of a routine way than just for those kids that have GI difficulties.  As I had mentioned I do the D3 and the Omega-3.  Those in general are the things that I think there is enough evidence that I use routinely.

SB: That’s terrific background and you have sort of given us a scoop there on these trials of the pancreatic enzymes.  It does seem like there is a lot of interesting research around the microbiome – a lot of indications that the microbiome is involved.  The one trial I saw on probiotics in autism the results were… disappointing.  Do you have any thoughts are we giving the wrong probiotics in general?  Is there an effect there that is not being picked up?  Any thoughts on that?

RH: I think that is a good point.  There are a whole bunch of these little things that they put into the probiotic.  The one in the mouse model that showed benefit was B Fragilis.  I don’t know whether there is anything special about B Fragilis, but it is the one that they used and reversed the mouse model.  I think it is thoughtful kind of way that these things might get formulated and used.  That Curemark study – the thoughtful lady that led it and puts together the things in the digestive enzymes.  They are not just the things you buy off the shelf.  She kind of put it together and then patented it.  I think if we could just find better biomarkers, we could begin to start to personalize the treatment for these kids and find ways to show benefits.  The other thing that happens I think in these studies, is that if we don’t screen with the biomarker, and we take all kids with autism, they may not have an active process going on at the time, and so the intervention that we use doesn’t help, and then we wind up with a negative study and we say well this doesn’t work.  It’s more like saying well – I think we are increasingly referring to the autisms, or you’ve seen one kid with autism, you have seen one kid with autism.  So each child kind of has a unique way that they have autism.  I think if we could do a better job of identifying that, I think we could better target our treatments.

SB: Those are great points.  Dr. Hendren excluding your own research, what other autism research that has been published in the last year or so you thought this is really exciting – this is really important?

RH: Well it’s been a little over a year, but Antonio Hardin’s NAC paper is exciting, and I find a number of kids that I see if they have skin picking or OCD type things or they are irritable, I find that NAC is helpful.  I think there another study that will be out soon that is negative for NAC with autism. So it’s not a panacea or it’s not something that we can say it will do great for everybody.  I think the work that comes out of your first interviewee – Richard Frye’s lab – I think is interesting and promising.  The things that he and Dan Rossignol do together and the reviews and things that are moving things forward like the cerebral folate deficiency.  Also looking at folinic acid.  I think those are interesting thoughtful studies, and I think those groups are moving the field forward.

SB: That’s really interesting.  I appreciate you bringing up NAC.  The Hardin study I think showed improvement in irritability.  I understand that part of that study showed a lot of GI issues.  There are other issues with NAC.  What do you think we are doing when we give NAC to a kid biochemically?  Any thoughts on that?

RH: I think it seems to be helpful for oxidative stress as well.  So I think that’s one of the strong ideas of what the mechanism of its benefit is.

SB: Makes total sense.  We talked about your research, about this research that is going on.  Is there research that has not been done yet that is really important that should be done?  Is there something out there that you think – gosh – people should be doing this now?

RH: Well I think looking for biomarkers and I think doing more with metabolomics.  It may or may not work, but we are excited about trying to do that.  It would help us make better cocktails that would kind of fit with particular kids.  So I think that.  I am not thinking right now of anything that is really promising and someone hasn’t been doing the studies of.  I’m not sure what that would be.  Everybody has their favorite.  Nothing comes to mind.  When I talked about being about the MIND Institute, and I asked the group what things should we study?  What they wanted me to do a study of chelation, and I said no, I’m not going to start there.  That is just too controversial and too difficult to know whether you are doing a good trial.  I have had some parents tell me that it helped them.  I think there is an exciting potential in using transcranial magnetic stimulation – TMS – that maybe is showing some benefits.  I have heard real mixed reviews on stem cells, but I have had some people tell me that they thought their kid got quite a bit better.  So there is some research beginning to look at those things, but I think all of it reflects that we are changing our paradigm.  We are not thinking just as neurotransmitters or brain regions and then trying to use conventional medications like anti-psychotics or SSRIs or other things to help people do better because we are only helping their behavior and we are not fixing the metabolic process, but now I think we are moving in the direction that cancer research is and vascular research and the practice of those that are increasingly looking at metabolic processes and ways that they can target those, and I think we will learn a lot from them, and a lot in that way as we move forward in understanding the metabolic process of autism.

SB: That is terrific, and I realized I wanted to ask you one question that I had really neglected, which is that we have talked a lot about over-the-counter supplements for autism.  We really didn’t talk so far about pharmaceuticals with autism, and I know you are an expert on that too.  I understand that there are a lot of…a lot of… side-effects and issues with some of the traditional anti-psychotic medications and things given with autism.  Are there certain pharmaceuticals that you think – wow – we are just underutilizing this – this should be given more to certain kids with autism?

RH: I think that about some of the nutraceuticals, but I think the one that has been kind of a surprise to me was propranolol.  It has been around for a long time.   I have used it for many many years.  I kind of quit using it because I didn’t think it was really helpful, and then the group at the Thompson Center in Columbia Missouri has had a series of studies showing propranolol benefiting some kids.  I think some of the literature around that suggests that kids that have an autonomic over-reactivity – they get flushed and red and sweaty and there is something in the autonomic nervous system that is driving their meltdown or their falling apart and maybe propranolol works for that.  So I have been using it more and I find a few kids do better.  So I guess it is a little bit underutilized but it is not for everybody.  I think people keep trying to find ways to have anti-psychotic medications have less side effects, but that hasn’t totally worked.  Like Risperdal and Abilify cause a lot of weight gain and they worry about increasing glucose and then the risk of type 2 diabetes.  So Latuda has come along – lurasidone.  It was thought that it didn’t increase glucose.  It didn’t increase blood lipids.  The trial of that for autism was negative.  I still have some kids on it, but I find that other kids get a kind of inner restlessness that makes them uncomfortable.  So while we are moving ahead in some ways, we haven’t really figured out a way to have some of those medications that help.  They don’t help reverse the disease process.  They help for kids that have major behavior problems and the parents can’t go out, and they can’t take their kid anyplace, and they are worried about their siblings, and they are thinking of an out-of-home placement, and then this medicine can make a world of difference even though it has a lot of risks.

SB: Thank you for that excellent overview of what is available in term of the pharmaceuticals for autism.  Is there anything else that you would like our audience to know about the research you are doing or other thoughts on autism?

RH: I think the thing that is pushing me – or driving me – or that I find most exciting in this new approach – not necessarily a new approach – but it is a shift in the paradigm is that it is kind of saying is this is whole body disorder – that you can treat the immune system or you can treat the GI tract and it effects the person’s socialization and the way their brain works.  All of these are things that say if we can find ways to help the body to be as resilient as possible, then I think these kids are more able to take advantage of education, speech and language, behavioral programs, interacting with other kids – all of those things – and that is what we are trying to do in this school – the Oak Hill School that I had mentioned.  It is a two part thing: it is getting their bodies as healthy as possible and everything working as well and then having an excellent program for them to be in.  I think that approach is going to move the field forward.

SB: That makes total sense.  Dr. Hendren thank you so much for being with us on Autism Research Connections.

RH: Mr. Bittker it was a pleasure.

Autism Research Connections #1: A Conversation with Dr. Richard E. Frye

Dr. Richard E. Frye was interviewed by Seth Bittker on March 15, 2016 on autism, mitochondrial dysfunction, autoimmunity of the folate receptor, over-the-counter therapies, folinic acid, the microbiome, and other advances in autism research and treatment. © 2016

Dr Frye

A podcast of the interview is available here. A transcript of the interview appears below.

SB: This is Autism Research Connections #1.  This is Seth Bittker, and our guest today is Dr. Richard Frye.  Dr. Frye is Director of Autism Research, Director of the Autism Multispecialty Clinic, Co-Director of the Neurometabolic Clinic, Associate Professor of Pediatrics of Child and Behavioral Neurology at Arkansas Children’s Hospital Research Institute as well as University of Arkansas Medical School.  Dr. Frye has written extensively on mitochondrial dysfunction in autism, autoimmunity of the folate receptor in autism, methylcobalamin and folinic acid in autism, the microbiome, as well as numerous other papers on autism.  Dr. Frye, thank you for being with us today.

RF: Sure it is my pleasure.

SB: Dr. Frye I wonder if you could introduce us to what is mitochondrial dysfunction?

RF: Well we should start out with what is the mitochondria.  So our cells which make up our body have different pieces in them that do different functions, and the mitochondria is the part of the cell that is best known for making all the energy in the cell, and it is a very unique part of the cell.  First of all you don’t just have one mitochondria for every cell.  You can have anywhere from hundreds to tens of thousands per cell in any cell in your body depending on how much energy that cell needs, and what we have found out that sometimes this powerhouse is not working the way it should.  And so you can imagine if you are living in a city and the power and you have a blackout, there are so many things that are going to happen, and things won’t work.  What we find is that mitochondrial problems or what we call mitochondrial dysfunction seems to be pretty prevalent in autism.  Now the idea that the mitochondria doesn’t work and diseases associated with the mitochondria really are pretty new on the playing field of medicine.   Really the first well known or well characterized disorders are really just in the 1980s that described diseases of mitochondrial disease, and for a long time we believed mitochondrial disease occurred when the mitochondria was very dysfunctional, that is just like if you were living in a city and there was a blackout and you had absolutely no power.  So many of the early mitochondrial diseases were described where the mitochondria was not working at all.  So the cells were not working in the body and the body became sick and many of the organs did not work, but what we are starting to find out and we think we see this in autism is that sometimes this powerhouse of the cell, the mitochondria, it’s not that it doesn’t work at all, but it doesn’t work up to the potential that is needed for the body to work optimally.  So you can think of this as if you are kind of in the city you have a brown out where the power goes down a bit, maybe you can’t use your air conditioner, but the lights are still on.  And what we find is that this is analogous to what we see in many children with autism is that this powerhouse of the cell isn’t working up to the capacity that is needed, and this is very important during development – during that time at which we see the onset of autism because the body is growing.  When the body is growing, it needs lots of energy to grow.  It needs lots of building blocks, and if it doesn’t have the resources that it needs, it is going to stall, and we believe that is what happens is that brain development stalls and doesn’t complete through the steps that it needs to fully develop and we end up with the characteristics of autism.  So that is just in a nutshell you know mitochondria and why we think they are important in autism.

SB: That is a wonderful – or very revealing picture there that you have sketched for us.  So when you suspect mitochondrial dysfunction what are the lab tests that you would typically order?

RF: Well it varies, and one of the problems that we have with mitochondrial disease and dysfunction again is it’s really the new player on the block.  So the method for diagnosing it is still not all that well developed.  So usually what we do is some of the standard labs which would be fasting labs first thing in the morning before breakfast where we look at biomarkers such as lactate or pyruvate.   We also look at amino acids and their levels in the body because many times if the mitochondria is not working there will be certain patterns of amino acid abnormalities.  We also look at fatty acid metabolism because fatty acids are also processed and burned by the mitochondria for fuel, and we look at many of these tests and we kind of put them together to see if there is a sign of mitochondrial dysfunction, and then if there is there are many other tests that really have to be done to confirm whether mitochondrial dysfunction is there or not, what is causing it, and to what extent it might be interfering with the life of the child.

SB: That is very well said.  So if you find mitochondrial dysfunction, it seems like you might provide maybe carnitine.  Are there other supplements you would consider providing  or how do you treat it?  How do you typically think about treating it?

RF: Sure.  So every child is different and different doctors that treat mitochondrial disease treat them slightly differently.  A child with autism and mitochondrial dysfunction is unique in many ways.  First of all we know that many children with autism also have what we call redox abnormalities.   That is the system that balances oxidative stress – that is toxic radicals in the body – isn’t working as well as it should be in many children with autism.  We know that when the mitochondria is not working the same thing happens.  We have this elevated level of oxidative stress.  So one of the first things that we do is try to improve the body’s  ability to make the antioxidant glutathione by giving B12 and folinic acid to help the systems that naturally make the natural antioxidants of the body – most notably glutathione.

The next thing we do to treat mitochondrial dysfunction that I find is very useful is something called CoQ10, and many people see CoQ10 for heart health – for general health as a vitamin that they can take, and CoQ10 is known as an antioxidant – is advertised as an antioxidant, but what a lot of people don’t know is that CoQ10 is actually part of the machinery of the mitochondria.  That is the final common pathway of the mitochondria that make energy called the electron transport chain – the different parts of that chain – the so called complexes – actually transfer some of their energy using CoQ10.  So CoQ10 is almost like the wires that connects some of the parts of the electron transport chain.  When there is high levels of oxidative stress, it is used as an antioxidant and can be used up, and therefore it is not available to the mitochondria for the mitochondria to function.  So that tends to be my second thing is to use CoQ10 which can act as both an antioxidant and help the mitochondria work.  Other treatments as you noted are carnitine is extremely useful.  Carnitine is important for fatty acid metabolism.  It is also important for actually removing toxic organic acids from the body and cells and eliminating them from the body.   So carnitine is definitely one of the go to vitamins.  Also many of the B-vitamins are very important.  So we supplement B-vitamins.

Another important supplement would be creatine.  Creatine is creatine monohydrate which a lot of the body builders use.  They use it because what it does is it creates phosphocreatine in the muscles which store energy.  So when the mitochondria isn’t working, what it can do is it can actually store some of this energy and you store your energy in phosphocreatine.  So creatine can go into the cells and particularly the muscles and actually store energy and so it can compensate for certain mitochondrial dysfunction.

The other thing that we find really is helpful for a lot of children with mitochondrial dysfunction is high doses of folinic acid because as you had mentioned in the beginning one of the things we do a lot of research on and have done clinical trials is central folate deficiencies – that is deficiencies in folate that seem to affect the brain but not the body, and central folate deficiencies are very important because of course folate is one of the essential vitamins.  It is important for many of the essential functions of the cell.  It ends up that your brain is protected by the blood brain barrier, and in order for many things to get across this blood brain barrier they need a special carrier to take them, and we find that this carrier that carries folate into the brain sometimes can be dysfunctional.  We find that there are these folate autoantibodies that many children with autism have that block the ability of this carrier to work, but we also know this carrier needs lots of energy, and any part of the body that needs lots of energy is going to be affected if the mitochondria is not working.  And so we find that many children have problems with cerebral folate deficiency or insufficiency and respond to high dose folinic acid.  So in a nutshell those are some of the treatments that we usually start out and use for children with mitochondrial disorders or mitochondrial dysfunction.

SB: Thank you for sketching that out, and I believe I recall that you have done some – I believe it was a double blinded trial with folinic – is that accurate or not the case?

RF: Yes.  That is definitely accurate.  You know our first study  was an open label study that was actually a large case series that I did with Dr. Rossignol where we showed that kids with the folate autoantibody seemed to respond very well to high doses of folinic acid with particularly increases in language.  So we followed that up recently – we completed a double-blinded placebo controlled study where half the children are getting placebo, half getting folinic acid and neither their doctors nor the patients know, and what we actually showed in that trial is that the kids that got folinic acid had over a three month period – demonstrated a very significant increase in language as compared to the placebo.  We also did some analysis to look to see if those kids that responded had the folate autoantibody and we found that those kiddos with autism and the folate autoantibody had a particularly large response to folinic acid.  So we think that not only is it an important treatment just in general for children with autism but particularly those that have this autoantibody that block the ability of folate to cross the blood brain barrier.

SB: Congratulations on that work.  I’m curious about the choice of folinic versus methylfolate or some other form of folate.  Do you have any thoughts on whether folinic is maybe best in some sense for a larger number of children or whether there are other forms that would be useful?

RF: So theoretically the reason why we do folinic acid is that it’s a reduced form of folate.  So one of the major health advances we have made in the United States and other developed countries is fortifying our food with folic acid but one thing a lot of people don’t realize about folic acid is that folic acid is the oxidized form of folate and because it is the oxidized form it’s not readily available for your body to use.  So your body actually has to go through a number of steps to make it activated and reduce it and we know that some people particularly people with autism have a problem with the enzyme that actually reduces it.  So many times just taking folic acid will not be sufficient especially in those that have certain polymorphism in genes that are responsible for reducing folic acid.  So folinic acid is a reduced form of folate.  So it more readily goes into the biochemical pathways that are important for the body and it’s readily used by the body.  The block that we talked about in this transporter can be circumvented by using another transporter that transports folate into the brain and it’s called the reduced folate carrier and that carrier only can transport reduced folates.  It can’t transport oxidized folates.  So we use a form of reduced folate – that is folinic acid.  And we use it at high doses for a number of reasons.  One because the reduced folate carrier has a lower affinity for folate than the folate receptor alpha which is the one that is blocked.  So you need higher doses because of decreased affinity, and in addition the levels of folate in the brain are actually higher than the levels in the blood.  So that is why the folate receptor alpha –the one that is blocked – is so important under normal circumstances and why it takes energy because it actually transports folate from a lower concentration in the blood to a higher concentration in the brain.  The reduced folate carrier is not so good at doing that.  So you have to get higher levels of folate in the blood – reduced folates in the blood for it to get into the brain at adequate levels.  So why do we folinic acid or also known as leucovorin calcium?  So there are a number of reasons.  The most important one is that the studies that have looked at this disorder of problems with central folate have used folinic acid and they have actually measured the levels of folate in the brain before and after folinic acid treatment.  So we know that folinic acid works and we also know the approximate doses that it takes for it to work.  So that is important.  Now theoretically other reduced folates should work also.  So other methylfolates and such should work but we are not so confident about what the doses are that need to be used.  So if you use another type of reduced folate and it works you know that might be great, but if things aren’t working out the way that you want, you are kind of lost as far as knowing if your dosing is wrong or something else is not correct.  So personally I like to stay with something that I know more about.  The other thing about folinic acid also known as leucovorin calcium is that it has been used in oncology as rescue therapy to reduce side effects from many chemotherapy agents.  So we know the safety profile of it also.  In general folates are safe, but it gives you a little more confidence when you know that a compound has been used for many decades and people have had experience with it and there is no major side effects from it.

SB: Wow.  Thank you for that explanation.   So earlier we had spoken a little bit about mitochondrial dysfunction.  We also have the autoimmunity of the cerebral folate receptor.  When you are seeing these thing, do you have any hypothesis on is there an order in which this happens?  So in other words, do you think that you initially have some sort of mitochondrial dysfunction, then that leads to the autoimmunity or is it the autoimmunity that then leads to mitochondrial dysfunction?

RF: It is really a great question.  It is one thing that we are finding out is that a lot of kids with signs of autoimmunity with autoantibodies – not only the folate receptor autoantibodies – but other autoantibodies to the brain seem to also have mitochondrial dysfunction.  For some reason they seem to go hand in hand, and it is not exactly clear why that is, or which came first – you know which was the chicken or which was the egg?  And I think it is an important connection.  We see that the two seem to go together.  It maybe that it starts out with one or the other and it creates a viscous spiral that worsens both of them.  So for example we know that the immune system and immune cells take a tremendous amount of energy to work.  So if you have mitochondrial dysfunction, the immune cells aren’t going to be working up to their capacity, and they can end up becoming dysfunctional and creating autoantibodies.  So those autoantibodies cause inflammation which will then cause oxidative stress and more mitochondrial dysfunction.  So it can be a viscous spiral.

In the same way it may be an immune trigger.  It may be that you have a slightly weak mitochondria and some type of inflammatory event happens which just pushes things over the edge where the mitochondria can’t handle it and they become dysfunctional.  We are not sure, and it may be that there are many ways to get to the same place, and that is something that really future research has to look.   You know I don’t want to [inaudible].

SB: Very interesting.  Very interesting.  So if you also have the microbiome coming into play –and I know you have written extensively on this as well – do you see that as further something that is downstream, upstream, or again we are not really sure how exactly the order works but it something that becomes dysfunctional?

RF: Yeah.   The microbiome is just really fascinating, and the research that is coming out on the microbiome is extremely fascinating.  We know that the microbiome especially early on in life – in the first three years of life – but probably in the first month – there are critical times when the microbiome is developing and influencing the immune system and the metabolic systems.  We know that it helps program the immune system.  We know that it can also interfere with metabolic systems also.  You know there are some compelling studies that suggest that these changes in the microbiome seem to precede the onset of autism sometime suggesting that there is potentially some causative effects of the microbiome, although you can’t rule out that it is an epiphenomenon to something else.  But there is lots of data that suggests that the microbiome has some type of real key relationship to the development of autism.   You know the fact that children with autism tend to have more antibiotic use early on, which can change the microbiome.  They tend to have other changes in diet – GI problems – that may precede the onset of autism.  So I think it is really interesting, and I’m very interested to see what we find out in the near future.  You know there are great studies now that are coming out not so much on autism but in other childhood diseases that show that really modifying the microbiome particularly within in the first month of life is preventative of many particularly immune diseases and allergic diseases.  So there is a lot of data that seems to be pointing that this is really an important component and something that has really been underappreciated for a long period of time, and given the fact that it can modulate metabolic systems and can modulate the immune system, I think it is most likely a very important component to the etiology of autism, and so hopefully studies within the next five – ten years will give us those answers and will help us understand how we can change our lifestyles and our diets and such to manipulate the microbiome to make us healthier.

SB: Very interesting.  Very interesting.   So I know that in autism research recently there has been a big focus on biomarkers for autism and some of the work has gone into things like eye tracking and such.  Do you have any candidate biomarkers you would be willing to tell us about?

RF: Yeah.  I mean we work on more metabolic biomarkers – things like the folate receptor alpha.  We find that many parent and particularly mothers of children with autism that have the folate autoantibody, their mothers also have it too.  We know the same thing with many of the changes in redox metabolism that we see in children with autism, we also see them in moms.  Right now we are also developing some markers of mitochondrial function and dysfunction that seems to be very unique to autism.  We are developing those to help us not only understand how mitochondria are working or not working, but also our goal is to be able to use these tests early on in life and even prenatally to initiate treatment before autism onset occurs.

SB: That is brilliant – a great future.   So I know earlier you had spoken about some of the over-the-counter therapeutics that you sometimes use.  Are there any other over-the-counter therapeutics that you feel are just underutilized in autism that you would like to mention to our audience?

RF: Yeah.   I think there is a lot of potential for a lot of different over-the-counter and other types of treatments.  The issue with a lot of them is that they really haven’t been studied in well-controlled studies to actually tell us how helpful they would be, but we know for example one of the things that has gone through some double-blinded placebo controlled studies and seems to be very helpful  for irritability is n-acetyl-cysteine which helps deplete[d] glutathione and decrease glutamate, the major excitatory neurotransmitter and something that can be purchased from suppliers and can be very helpful.  As you mentioned carnitine.  One of the other things that I use a lot of times is the Autism Nutritional Research Center’s multivitamin that Jim Adams put together, which he is showing two double-blinded placebo controlled studies  to be helpful.  Of course you know it is important when we talk about over-the-counter supplements that people understand that it is very important to get these supplements from reputable laboratories and producers as they can vary in quality quite a bit.  It is just very important that you get good quality supplements, because if they don’t work you don’t know if it is because the supplement was poor quality and if you have a poor quality supplement , it can have things in it that you didn’t expect and that is not always good.  So I think there is a lot of potential for certain over-the-counter supplements that can be useful.  I think every child is different, and it is important to understand that there is not one size fits all.  So I really encourage parents to see a physician that is knowledgeable in the use of both over-the-counter and non-over-the-counter treatments to see what would be best for a child, and really not do things so much themselves, but make sure that they have an experienced [physician] that guides them.

SB: That makes a lot of sense.  You mentioned also about the importance of using trustworthy sources.  Are there a couple of brands or names in the industry that you feel are unusually trustworthy with respect to the contents of their supplements?

RF: Yeah.  There are certain laboratories – of course the USP seal is an independent laboratory that tests supplements that can verify what is in the supplements is good, but there [are] other different pharmacies and suppliers that I think are high quality.  So I think that it is important for parents to talk to their support groups – other parents – to see what their experience is.

SB: Excellent.  Also you mentioned the potential importance of prescription pharmaceuticals in the treatment of autism.  What are some of the prescription pharmaceuticals that in your view are just underutilized in autism treatment?

RF: Yeah.  I mean I think that many of the prescription pharmaceuticals still need to really be tested on kids with autism a little bit better.   I think one of the problems is that really the only big studies that have been done have been done with antipsychotics which have significant side effects that should not be ignored.  So personally when I see a patient I try to find out what symptoms are the key symptoms to treat and then direct treatment toward that whether it be prescription or non-prescription.  I tend to try to avoid antipsychotic medications, but the studies on other prescription medications are very variable, and so I would say that it is important for anybody to see a doctor with knowledge of what has been really researched – what hasn’t been – what the best evidence is so that they get the best care for their child.   And there are a variety of different medicines that can help, and I think that it needs to be kind of customized on a case by case basis.

SB: Makes total sense.  Dr. Frye there is a lot of great autism research going on.  Is there any recently that you have thought my goodness, this is really interesting, it is something we should be watching?

RF: Oh I think there is a lot.  I think as you mentioned the microbiome research is incredible.  I think there is a lot of really great research on the immune system.  We are really finding out how the immune system and many autoantibodies seem to play into possibly not only causing autism but increasing the disability and symptoms in children of autism.  I think those are two really important areas.  Of course I am very excited about the research we have going on on metabolic systems.  I’ll tell you what I like about metabolic systems, and why I think it is so important to research and look at is that these are systems that we can change.  Although you know it’s exciting to look at the immune system, the immune system does not have any really great therapies that are extremely safe.  So until we find really good therapies, I think there is going to be limitations to what we can do to modulate the immune system.   Whereas things like the metabolic systems and the microbiome are two things that we can change pretty easily and safely and maybe have a big impact.

SB: That sounds very exciting.  With respect to the metabolic system research that you are doing – obviously don’t tell us anything you don’t want us to know – but do you feel comfortable telling us anything about that research in terms of what you are doing – what you are looking at?

RF: Well what we are looking at is how these systems may be dysfunctional and why they are and what can be done about it and what type of things can be done to support them.  What we are finding as I mentioned previously is that mitochondrial dysfunction seems to be very much linked with oxidative stress and immune dysfunction, and we are starting to learn how these are all connected and what things we can do to actually either alter these systems to normalize them or to make sure that they are working optimally so that the child and the body can work optimally.

SB: Sound great.  Dr. Frye is there anything else that you would like us to know in terms of things we should be keeping an eye on with respect to autism research?

RF: Well I think that it is very important that we focus – I think as you mentioned before that really I think the focus so far for a lot of research has not been on treatment.  I think there is a lot of treatment on the horizon – either novel treatments that we haven’t used yet or treatments that we believe that work that just have to be tested to make sure that we know how to use them.  I think that understanding what is causing autism and how metabolic and immune systems are dysfunctional are very important areas of research that we have to concentrate on, and of course really the missing piece I think is that we have not been concentrating on how environmental influences may be triggering systems to go awry and cause autism through the microbiome or other systems and what we can do to prevent that from occurring.

SB: Brilliant.  It makes a lot of sense.  So Dr. Frye, thank you so much for being with us.  This has been a truly illuminating conversation.

RF: Sure.  It’s my pleasure.

What is Autism Research Connections about?

Seth Bittker

My name is Seth Bittker.  Research shows that autism is usually fundamentally rooted in biochemistry.  Therefore, therapeutics for autism should be focused on ameliorating the negative aspects of that biochemistry.  So in my view autism biochemistry and relatedly therapeutics targeted to that biochemistry are the two areas of autism research which are likely to have the greatest impact on the lives of those with autism and their families.

Autism Research Connections is an interview series which focuses on research and researchers who are working in these promising areas to highlight their challenges, their thinking, and their successes.  I hope you find the interviews as compelling as I do.