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Friday, 8 March 2013

Epiphany - Applied Neurological Analysis


For 5 years I have been learning and applying ABA (Applied Behavioural Analysis) to treat autism. This is a very time consuming, although highly fruitful process. Continued gradual improvement has been the result.

Then in December 2012 came my epiphany.


I read a very interesting clinical trial - A randomised controlled trial of bumetanide in the treatment of autism inchildren. This turned out to be a transformative moment for my son.

I thoroughly checked the possible side effects, acquired bumetanide, and made my own trial not telling anybody. Almost immediately the positive effects began to show and I kept getting unprompted feedback from school, relatives and even the special piano teacher. "What has happened to Monty ?" they were all asking and then they started telling me all the great things he was doing.

Then I looked into the history of the controlled trial. It all started when Lemmonier asked a colleague why is was that Valium works in reverse in kids with autism. This really shocked me. Is it really true that there are well established blatant biological abnormalities in autism ?  If so, maybe there are more ?

I started looking in the research and there are lots of such abnormalities, several waiting to be thoroughly investigated.

So I termed my new project ANA (Applied Neurological Analysis). I am going through 40 years of research (via Google Scholar) looking for anything that looks odd to me, albeit not a neurobiologist.


I already came up with some great stuff. I am looking for things that have either been proved in a randomised controlled clinical trial, or where just the trial needs to be done.

There is a remarkable amount of relevant research already out there, particularly if you include associated disorders such as epilepsy.




 

63 comments:

  1. It is interesting to note Bumetanide is working very well with Monty.
    You said 'almost immediately the positive effects began to show'
    but the French authors say it take weeks for it to take effects, and also no effects on some people

    ReplyDelete
    Replies
    1. The French authors cannot observe each child closely on an hourly basis. They assessed each child at certain milestones during the trial process.

      Many drugs are supposed to work "a bit" or after "a few weeks". I concluded that if a drug really works, it works fast and in a serious way, otherwise I put the small possible changes down to the placebo effect and wishful thinking.

      I would suggest trialing bumetanide for 2 weeks, but if you look closely and objectively you should see changed much faster. I would always rely on feedback from others (teachers etc) who are not aware of the trial.

      It would only work in people who had an elevated level of chloride (Cl-)in their brains. If the level of Cl- was normal, then the neurotransmitter GABA would already be functioning properly. The level of electrolytes is contolled by various hormones, I propose that during puberty in some children the hormonal changes that occur make by chance result in Cl- levels falling to where they should be.

      Delete
  2. Is it possible that if he does not urinate more after taking Bumetanide, then the effect of this drug on Autism will also be less. I started the trial last Friday, RR does not seems to urinate more after taking Bumetanide (0.5 mg twice a day).

    the French authors says(Several qualitative comments of the parents attest to its positive effects, including a greater presence of the child, facilitated visual communication and social exchanges. In keeping with this, at the end of the wash-out period, almost all the parents demanded to shift (continue) to bumetanide treatment.).
    This seems to suggest Bumetanide is effective in large % which may not be reflected in CARS

    ReplyDelete
    Replies
    1. What should matter is the dose mg/KG. If the does not urinate more that would imply that the diuretic effect is small, I would have thought. I give 1mg all in one go before breakfast, the diuretic effect starts within 20 min utes and is substantial. Perhaps your dosage is too weak, since you have split it in two ? Some children are on higher doses than 1mg/day since lower doses showed no effect.

      Delete
  3. I am trialing with Folinic acid, L-carnitine, and now Bumetanide. so you are trialing with NAC, + Statin + Bumetanide ?

    ReplyDelete
    Replies
    1. Correct, but I also add B vitamins (required for NAC to produce GSH) and I added extra potassium/magnesium to replace what is lost due to the diuretic effect of the bumetanide. In summer I have now added an antihistamine (see my recent posts) since I found out that histamine affects behaviour.

      Delete
  4. these are Dr Ben-Air replied to my email:

    with some there is more urination including nin classrooms and hey go more often to the toilet but with others this is very limited

    yes they must take ir for long time and the efefcts are not seen before some weeks

    ReplyDelete
    Replies
    1. It is nice that he replied. 90+% of researchers do not reply to emails from parents.

      Delete
  5. though I have seen immediate positive effect, I am still hopeful

    ReplyDelete
    Replies
    1. Try 7 days on a slightly larger dose (all in go, not split) and see if anything changes. If there is no change, then stop the trial.

      Delete
  6. RR is 4 years old. I thought 1mg/day would be enough.
    also Dr Ben-Air replied ' but with others this is very limited '

    ReplyDelete
  7. also Dr Ben-Ari replied:
    yes they must take ir for long time and the efefcts are not seen before some weeks.
    I think he must have evidence to say this. - I think if the effects are immediate, then he would know-, I think the parents would told him to large extent.
    by the way, How is Monty, I guess he is close to 'normal' now.

    ReplyDelete
  8. How do you monitor the blood K+ level of Monty if he urinate more?
    monthly?
    you know it will be nice if 0.5 mg twice a day (which is recommend in Ben-Ari's paper) can produce the effect without causing electrolytes problems (-too much urinate also is a problem during the class)
    but you are right, I can try 7 days on a slightly larger dose (all in go, not split= 1mg once daily for a 18kg boy) and see if anything changes.

    ReplyDelete
    Replies
    1. After a few weeks any change in electrolytes should have energed. Then do a blood test and see how the results look. If they are totally OK, then no need to check too often. You may find taking a blood sample is not an easy process. It is wise to add extra potassium to the diet just in case (banana, orange juice). Ben-Ari does not mention the other electrolytes, but bumetanide will also reduce calcium, so you should make sure you have plenty milk products in the diet.

      Delete
  9. you said < Some children are on higher doses than 1mg/day since lower doses showed no effect >, are you aware of Dr Ben-Air's trial or you heard from others? I am keen to pursue this, as there is no other effective methods around. We are also doing ABA, but as you know the effect is slow and time/money consuming.

    ReplyDelete
    Replies
    1. You will probably need to continue ABA for years to come. If you buy books and use free training videos on Youtube you can do it yourself. It then is not money consuming, but it certainly will be time consuming.

      While all drug treatments are disputed by some/many; there is solid evidence behind ABA being effective in all cases of autism, if correctly implemented, of course.

      Delete
  10. I have feedback from other people who have read my blog and tried bumetanide. I have no contact with Dr Ben-Ari

    ReplyDelete
  11. If you read my blog (a long slog), you will find that autism is caused by brain damage. You can make its symptoms much better, but it cannot be made to go away. If you expect to reach "normal" you will most likely end up very disappointed. If you target gradual improvement, then you can achieve "success".

    ReplyDelete
  12. I guess early intervention can normalize parts of the brain damage. this is the theory behind ABA. I used the word 'close to normal' as some of the high functional ASD can be close to normal or recover.

    So you got feedback from others, is that " no more urination = no effect " ? Must more urination -> effect?

    also is that effects of Bumetanide 'symptomatic' only?

    ReplyDelete
  13. Early intervention works because of the neuroplasticity of the brain. Even though the brain is damaged in certain important areas, it is able "re-wire/re-program" itself to use to better use what is there. The brain becomes less plastic with age, so your ABA with a 4 year old will have much more long term effect than with a 14 year old.

    The drug interventions make it easier for the ABA to work. If it reduces stimming and absence periods, the child will naturally be better able to learn.

    What surprised me in my 8 months of research, is just how different we all are. Many drugs are ineffective in a substantial proportion of people. It might be that bumetanide does not "work" in your child. In the absence of urination I would think the drug is not effective. There are other loop diuretics, but they would have to be NKCC1 blockers. But no doubt Ben-Ari should know best.

    ReplyDelete
  14. Dr Ben-Ari replied yesterday:
    we have occasionnaly increased to 2mg daily ((bumetanide))

    1 twice a day

    but of course all this depends on many factors and I cannot make more suggestions as the drug is not yet approved for that usage and we are going to make a european phase 2 trial to compare vaious dosages

    best

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  15. I also hope that the drug interventions make it easier for the ABA to work. I think I will need to increase the bumetanide dosage a little.

    ReplyDelete
  16. I feel that we lack a good ABA consultant for our boy.
    Do you have a ABA consultant for Monty ? i.e. He provides advices and monitor the progress and you act as a therapist ?

    ReplyDelete
  17. We have an ABA consultant and in our case we trained our own therapists (including one parent). You will find it very hard work and so it helps to have some helpers. They could be relatives, friends, students etc. It does not have to cost a fortune. Without a good consultant, you may be doing it wrong. If ABA appears not to work the chances are it is not being implemented correctly. Depending on where you live, finding a good ABA consultant can be very hard. If you live in the US or Australia it is much easier than if you live in most of Europe.

    ReplyDelete
  18. I tested Bumetanide 1.5 mg daily for 1.5 months, did not see effect, so I stopped the trials

    ReplyDelete
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    1. This comment has been removed by the author.

      Delete
    2. You gave it a solid trial. In your type of autism there is no defect with GABA caused by NKCC1 transporter malfunction. I would not be put off, it is highly likely that some of the other treatments will apply to your type of autism. Have you tried NAC ?

      Delete
  19. Peter, have you heard of CM-AT (Curemark)? which has completed phase III clinical trials, and is seeking FDA approval

    ReplyDelete
    Replies
    1. CM-AT sounds very interesting, they have been fast-tracked by the FDA and they have just raised $18.5 million. One of problems I have read about is the lack of an enzyme called D2 in the brain, this results in a lack of T3 hormone in the brain and causes central hypothyroidism. If Curemark have found the reason that these enzymes are lacking and have a treatment, that would be great.

      http://www.google.com/patents/US20120207740

      This is a patent filed by the founder of Curemark, Joan Fallon.

      It appears to be mainly about Secretin, which I was looking at myself the other day. There has long been talk about Secretin as a therapy for autism. It looks like CM-AT is a combination that includes Secretin.

      Delete
    2. It looks like CM-AT contains pancreatin, which is a combination of enzymes given when the pancreas is not working properly. This is available as a drug called Creon and also as a supplement. Creon 10,000 looks similar to what was used in the trials in the patent. You have it 3 x day with meals. Lots of research showed that Secretin does not actually work.

      Delete
  20. yes the case of CM-AT is intriguing.
    It has completed phase III clinical trials, and is seeking FDA approval, but there is no reports on efficacy, even in the form of abstract. There is no update of its website.
    I am also doubtful that it will have a huge effect.
    For NAC, the problem is that I only find one paper in PubMed
    (Harden et al Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/j.biopsych.2012.01.014. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. )

    Hope there will be some disease modification drugs for ASD. - Dr. Mike's Psychiatry Blog – In my boy’s case, ABA is too slow, the effect is not great. (but yes ABA taught him some skills, -but not a breakthrough in cognitive level-)

    ReplyDelete
  21. Since NAC is available OTC there is no financial interest for anyone to research it. NAC is known to be a highly effective anti-oxidant. Numerous studies in autism show low GSH, which means oxidative stress. So I think it is clearly worth $10 to give it a try for seven days.

    ReplyDelete
  22. there is one case report:
    Ahmad Ghanizadeh Nima Derakhshan N-acetylcysteine for treatment of autism, a case report J Res Med Sci. 2012 October; 17(10): 985–987.
    I just ordered NAC.

    ReplyDelete
  23. I looked at this patent:
    http://www.google.com/patents/US20120207740
    the efficacy is not impressive

    ReplyDelete
  24. You are very knowledge, impressed me very much.
    I was trained in medicine, in this > 8 months now, still do not know where to go.

    ReplyDelete
  25. You are very knowledgeable.
    I will also start statin if you believe statin helps.

    ReplyDelete
  26. Only oil-soluble statins can cross the blood brain barrier. The choice is Atorvastatin, Lovastatin and Simvastatin. They are all slightly different. I use Atorvastatin 10 mg, and within 24 hours could see an effect. I am going to see going to try Simvastatin and see if there is any difference. If you see no effect after a few days, then stop. There is now plenty of statin research ongoing (Fragile X, SLOS and in Manchester - SimvAstatin in Neurofibromatosis Type 1-Autism (SANTA))

    ReplyDelete
  27. Hi Peter, what is your view on using baclofen?
    It looks Arbaclofen worked wonderfully at least for some children.

    ReplyDelete
    Replies
    1. I suggest you read the article below and then read up on possible side effects of baclofen. If you do make a short trial, do let me know the result.

      http://healthland.time.com/2010/12/01/how-a-new-version-of-an-old-drug-may-someday-help-treat-autism-and-addiction-too/

      Delete
  28. Hi Peter,
    Thank you for your very informative blog and the link to the French paper. This is most interesting indeed.
    I have a son with autism who is nearly 3 years, also doing ABA (I got the link to your site from Dana who is one of our tutors). I personally feel too scared to try the bumetanide without medical monitoring of the electrolyte levels, as I think occasionally the electrolyte imbalances could be so severe to be life threatening and this may not show up in a small-scale trial. However,
    I'm also a medical herbalist in the UK, and I'm wondering whether I could use this information to find a herbal treatment. Here are some interesting things I wanted to share:
    -My son has sometimes got disturbed sleep patterns and we have tried different herbal medicines. I found that valerian did not work at all. Herbalists have known for a long time that some people react paradoxically to valerian, and I think this may be similar to the observations with valium you mention. We found that passionflower works beautifully though, which is thought to boost GABA levels in the brain. I also found that sometimes he is particularly verbal and attentive when he has had passionflower before bedtime. Perhaps it is the GABA connection, I'm going to do some more research and experimentation with herbs that affect GABA.
    -We have been trialling a mushroom powder for two weeks, and during those two weeks he has made amazing progress in his ABA targets, not sure if it is related. This is a culinary mushroom called Lions Mane (Hericium erinaceus). I doubt there are any trials published, but I came across this at a recent conference. A few herbalists have treated cases of Multiple Sclerosis with great success with this mushroom. It has been found that it has substances that cross the blood brain barrier and stimulate nerve growth factor, so I thought this could be useful in autism to give the brain some stimulus to rebuild and reconnect. Dose is about 3g per day dried mushroom which can be mixed into food.
    -The most important thing we are doing is a dietary approach called the GAPS protocol that aims to correct the underlying root cause of autism. This is a long and convoluted story, so I'll just post the link to Dr. Natasha Campbell-Mcbride's website, who developed this protocol through recovering her own son from autism. The great thing is that in conjunction with ABA this actually offers hope for complete, or at least substantial, recovery which does not depend on continued drug intake to maintain. The website is www.gaps.me if you want to read about this.

    Wishing you all the best of luck with Monty!

    Sabine

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    Replies
    1. Hi Sabine,

      Thanks for all your comments.

      The thing with autism, the more you research it in depth, is that saying your child has autism is like saying your child has spots. Spots could mean chickenpox, an insect bite or many other things.

      I expect your child had a "Multidisciplinary Assessment" and you were told he/she fits the behavioural diagnosis of ASD. Very wisely you started an ABA programme with an excellent tutor.

      Beyond that, I expect you have no idea what kind of spots your child has, and why they are there. Some autistic behaviours result from things that are easy to fix, like food allergies. The kind of autism that is researched mainly by mainstream science is the severe type. This is characterized by brain damage, visible on physical brain samples that have been analyzed by world leading neuroscientists and alsoshows up on brain scans. Your child is very young and hopefully you have a mild case of “autistic behaviours” rather than a nastier type of autism.

      If the GAPS diet, or any other diet helps, great, just don’t stop the ABA sessions.

      Delete
  29. Also wanted to add that while Fragile X is the most common *genetic* cause of autism, however the vast majority of cases are not genetic, and overall Fragile X accounts for only 5% of cases of autism. Unless your child has tested positive for Fragile X I would not use statins. Statins work by blocking cholesterol production in the liver and cholesterol is crucially important for the developing brain, memory formation and cell regeneration. Another effect of statins is that they suppress the immune system. As many autistic children have high levels of inflammation (an immune-process), including in the brain, this may explain why you see an immediate effect. I'm not convinced that the draw-backs of statins are worth it though, they also increase the risk of cancer and infection long-term.

    All the best!
    Sabine

    ReplyDelete
    Replies
    1. Sabine: Statin is also tried on ASD, not only for Fragile X.
      maybe the gain can out-weight the drawbacks.
      regards. Yi


      Neurofibromatosis Type 1 and Autism Spectrum Disorder
      Research in NF1 knock-out mice has shown us that use of statins can rescue the cognitive and behavioural difficulties associated with NF1. Internationally two trials using statins (one using Simvastatin in the Netherlands and other using Lovastatin in the States) in children with NF1 have been carried out and have reported modest improvement in verbal and non-verbal memory. A functional MRI scan of children with NF1 suggests that statins can normalise resting state functional connectivity in the Default Network region of the brain.
      The aim of this proposed study is to ascertain whether Simvastatin can rescue the ASD phenotype in children with NF1 and ASD.
      Nature of the trial
      The SimvAstatin in Neurofibromatosis Type 1-Autism (SANTA) trial is a single site, triple-blind (clinician/patient/assessor) phase II randomised controlled trial of simvastatin versus placebo. This is a feasibility study which will further inform larger studies. Participants (children aged 5-8 years inclusive) will be identified and recruited from the NF1 clinics in Manchester, Leeds, Liverpool and Newcastle and through advertisements via the Neuro Foundation, the Children with Tumours and NF wellbeing research group newsletters.
      Participants will be screened for autism spectrum disorder through the use of postal screening questionnaire. Those meeting the screening criteria will be invited for detailed ASD assessments. Children diagnosed with ASD on these detailed assessments will be invited to participate in the study.
      The study will be carried out in Wellcome Trust Children's Clinical Research Facility (WTCCRF) at Central Manchester Children's Hospital.

      Delete
  30. Thanks, Sabine,

    for the sharing.

    Smelling lemons, listening to classical music and intense sensory exercises produced improvements in autism symptoms in children after just six months, scientists have found.
    The research, which appears in the online edition of Behavioral Neuroscience, shows that inexpensive, at-home exercises can reduce the severe symptoms of autism more than traditional autism therapy.
    Autism (now known officially as Autism Spectrum Disorder) affects 1 out of every 88 children in the U.S., and about four times as many boys as girls. It is a complex brain disorder marked by difficulties relating to other people, having typical emotional responses and listening. Its cause remains unknown.
    Cynthia Woo and Michael Leon, researchers at the University of California, Irvine, found that the sensory therapy, known as environmental enrichment, resulted in improvement in autism symptoms in boys in the study, who were aged 3 to 12 years.
    For six months, the children took part in traditional autism therapy, but one group received extra enrichment exercises. This enrichment consistent of having parents having the boys smell lemon, apple, lavender, and vanilla, and listening to music. The parents and children also conducted exercises involving touch, temperature, sight and motion.
    At the end of the six month study, nearly half of the children showed significant behavior improvement, while only 7 percent of the standard-care only group showed any improvement. The boys in the enrichment group also made gains in cognitive function, and parents even noticed a difference in their children.
    Enrichment has worked in animal testing, where these environments can reduce the symptoms of a number of behavioral disorders, including autism. But what’s important about this study (besides the ease of getting to results) is that the children were older than most autism patients. Usually, effective autism therapy must start at a very early age. In this case, the average age of the improved children was 6.6 years.
    Sources: UC Irvine, Autism Speaks
    Woo, C., & Leon, M. (2013). Environmental Enrichment as an Effective Treatment for Autism: A Randomized Controlled Trial. Behavioral Neuroscience DOI: 10.1037/a0033010

    -Yi

    ReplyDelete
  31. I am little doubtful that a dietary approach called the GAPS protocol can offer hope for complete, or at least substantial, recovery which does not depend on continued drug intake to maintain.

    ReplyDelete
  32. Hi Peter,
    Will you still be commmited to Statin with this recent report ?

    patients with neurofi bromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial: Lancet Neurol 2013; 12: 1076–83

    Findings We randomly assigned 84 children to a treatment group (43 to simvastatin, 41 to placebo) between March 9, 2010, and March 6, 2012. We did not assess outcomes in two patients in the placebo group because they needed additional drug therapy. Simvastatin for 12 months had no eff ect on full-scale intelligence (treatment eff ect compared with placebo –1•3 IQ points [95% CI –3•8 to 1•3]; p=0•33), attention problems (–1•6 T-score points [–4•3 to 1•0]; p=0•23), and internalising behavioural problems (–0•1 T-score points [–3•3 to 3•1]; p=0•96). 38 (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events, which were serious in two and four patients, respectively. Interpretation 12 month simvastatin treatment did not ameliorate cognitive defi cits or behavioural problems in children with neurofi bromatosis type 1. The use of 20–40 mg simvastatin per day for cognitive enhancement in children with neurofi bromatosis type 1 is not recommended.

    ReplyDelete
    Replies
    1. Neurofibromatosis type I (NF-1) is a tumor disorder that is caused by the mutation of a gene on chromosome 17 that is responsible for control of cell division. NF-1 causes tumors along the nervous system. NF-1 often comes with scoliosis (curvature of the spine), learning difficulties, eye problems, and epilepsy.

      Fortunately, my son does not have the above disorder. He has a moderate case of early onset "classic" autism. His phenotype can be further narrowed , since he has NKCC1 transporter dysfunction, elevated serotonin, elevated IGF-1 and elevated thyroid hormones.

      In his case, Atorvastatin made an impact ,noticed by all his care givers within 24 hours.

      The trial you referred to used levels of statin, rising to 40mg, that I would regard as dangerous and continued for 12 months, which I consider absurd. If they could not see a benefit after a month, why continue? In the US the FDA limits statins to 8 year olds and older, with a limit of 20mg.

      Note that in the study (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events. So almost on the patients on the PLACEBO reported adverse effects.

      I my trial, the first 10mg produced an effect. This was entirely unexpected and quite shocking.

      Delete
  33. Thanks, Peter, certainly you have qualified more than a doctor on ASD.
    Our boy is 4.5 years old now. He had a ‘flare up’ about one year ago (at 3.5 years old), and ASD was diagnosed. Looking back, his mild ASD symptoms were already there before this ‘flare up’. Mainly he was not social with his peers. His symptoms were initially missed because he talked and interacted with us at home appropriately according to his age. He had constipations, otherwise no development delays before the ‘flare up’. His development has been slow down since this ‘flare up’, and gap with his peers have been widening. As I mentioned, Bumetanide did not work well.
    We got NAC and will start testing today.
    I also asked to get Atorvastatin soon, would you suggest 10 mg for a 4/5 years old?

    Our boy had a ‘flare up’, apparently noted by our previous maid and also the kindergarten teacher, this may be related to the neuro-inflammation as you mentioned. If there is real neuro-inflammation, then it should be ‘to some extent’ controllable. Hope the approaches can be found.
    and works of Ricardo Dolmetsch and S Tonegawa (Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5671-6. doi: 10.1073/pnas.1219383110. ) may help patients in the not too distant future.
    -Yi

    ReplyDelete
    Replies
    1. NAC seems to work well. All the cases I know had a positive response with no side effects. This is logical, since oxidative stress is acknowledged to be at the centre of the disorder. I know of a child younger than your son with ASD, his doctor father is giving NAC with good results. He also found bumetanide to have no value. Neuroinflammation is also at the core of autism, but you can measure it. If you have access to lab testing you would be wise to run some inexpensive tests. First of all check that cholesterol is elevated and check the basic inflammatory marker CRP (C reactive protein) and if you can IL-6 (interleukin 6). Elevated CRP tells you that somewhere in the body there is inflammation, but it does not tell you where. In autism, IL-6 seems to be elevated in many cases which indicates more precisely the inflammatory process. There is a small possibility that your son’s autism is linked to a cholesterol deficiency, if that was the case, then a statin would not be a wise therapy. It is the anti-inflammatory attribute of the statin that we want. Cholesterol is itself a bio-marker of neuroinflammation. Your son is below the age at which the FDA suggest statins should be used. They are mainly concerned about obese children, with highly elevated cholesterol.
      Since your child is so young, I would start with NAC and then just rule out simple things like allergies. If you have any kind of digestive issues, that might indicate some type of food intolerance. You read about Curemark CM-AT, you may be skeptical, but the test for the biomarker is very cheap. I am also skeptical, but I am happy to pay $8 for the test.
      I am using 0.3 mg/kg of Atorvastatin and have no side effects at all. I suspect that even a lower dose would be effective. A higher dose yielded no addition benefit. It is wise to always titrate down to the minimum effective dose.

      Delete
  34. Dear Peter,
    Thanks a lot for your advice. I started NAC yesterday, will dose at 750mg twice daily (our boy is 4.5 years old). And I will report back to you in two week’s time on this.

    By the way, I was quite interested in L-Carnitine and folinic acid supplements. The scientific papers are below, and I wonder whether you have any views on them.

    David A. Geier et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit, 2011; 17(6): PI15-23.

    Sarah Farid Fahmy L-Carnitine supplementation improves the behavioral symptoms in autistic children. Research in Autism Spectrum Disorders 7 (2013) 159–166

    RE Frye et al. Cerebral folate receptor autoantibodies in autism spectrum disorder Molecular Psychiatry (2013) 18, 369–381.

    V. T. Ramaekers et al Folate Receptor Autoimmunity and Cerebral Folate Deficiency in Low-Functioning Autism with Neurological Deficits. Neuropediatrics 2007; 38: 276 – 281

    I am trying with both L-Carnitine (recommended dose) and folinic acid supplements (low dose). I do not see magnificent affect, our boy is improving, however, it is more like a natural progress instead of drug effects.

    Yi

    ReplyDelete
  35. Dear Yi

    Many researchers and parents claim positive experience with L-Carnitine and various B vitamins

    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.

    I did not see any improvement myself with L-Carnitine, whereas with NAC there was an indisputable change.

    Some children with ASD are deficient in B vitamins. If they have a good diet this should not be the case, but B vitamin supplements seem to pose no risk.

    ReplyDelete
  36. Hi Peter: this is a post on Baclofen.

    Julia says:
    October 9, 2012 at 7:02 am
    Trial was initiated by our DAN Gi doc, Tim Buie at MGH. He Rx Baclofen for our son’s GI issues; it is a targeted muscle relaxant that made his tummy empty sooner, so less acid. Also used for decades to treat the tight muscles of CP, so stopped our son’s toe walking and flapping (many, maybe most, of Buie’s patients have ASD). It did this by removing the URGE…no adverse consequence. AND, for two years, it made him so chill and friendly, his psych specialist said he no longer met the criterion for ASD. WOW. But after 2 years, it stopped working for the social stuff. No idea why. HIs ASD came back full on. Buie noted this sudden social cure in 20% of his ASD patients. Arbaclofen is a further refined new version of this old drug that hoped to have a higher efficacy rate. From personal experience, this drug was all good – we still take it, year 7 now – so I hope you can rest easier. It remains to be seen if the effects can be lasting. It made life so much easier for our boy!

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    Replies
    1. Hi Peter, will you be interested to look at Baclofen again? -Yi

      Delete
  37. Hi Yi, it is interesting. It seems that a small, but significant, percentage of kids with ASD respond well to both Baclofen and Arbaclofen. The parents who were in the trial for Arbaclofen, that were very upset when it was cancelled, could simply switch to Baclofen. It is odd this does not occur to them. Baclofen is probably much very cheaper, but I suppose they had Arbaclofen for free. The question is which 20% of kids with ASD benefit ? It is a GABA-B agonist. Perhaps there is a correlation, or inverse correlation with the success/failure of therapy targeting GABA-A, ie bumetanide. That would be a good question for Ben-Ari. It would help if Tim Buie tried to define the type of kids with ASD who respond well, but that might not be in his financial interest. Peter

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  38. Hi Peter,

    RE; NF1-SIMCODA, The trial you referred to used levels of statin, rising to 40mg, that I would regard as dangerous and continued for 12 months, which I consider absurd. If they could not see a benefit after a month, why continue? In the US the FDA limits statins to 8 year olds and older, with a limit of 20mg.
    In defense of the authors, I trust the dosage and duration had been very carefully considered, both by the authors (from tow university) and by the ethics committee. FDA only recommends very very safe dosage. Under close monitoring, the dosage can increased significantly. Most disease modifying effect may take time to show effect, particularly with behavioral effects measured. The study was designed to show maximum possible positive effect. However, unfortunately, positive effect was still not seen.

    Re: the parents who were in the trial for Arbaclofen, that were very upset when it was cancelled, could simply switch to Baclofen.
    From my reading in the internet, that is what they are already doing, but still they like Arbaclofen to continue. I still do not think it is a matter of money. Also Arbaclofen is supposed to work much better.
    Re: The question is which 20% of kids with ASD benefit?
    I guess ASD is of such diverse pathophysiology, and till now unless the individual patient try it, we will not know who will benefit most. This is the same even with ABA. At least in Fragile X population, Arbaclofen actually succeeded in the trial, the problem is how to define the success of a trial. Arbaclofen failed in the current FDA regulations. In the meantime, in the internet now, people are a little mixed-up with Fragile X and autism. I will think Arbaclofen will work more definitely than for ASD which is very diverse in pathophysiology. Despite this, we hope there will be some common passway we can target.

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    Replies
    1. Very thoughtful comments - Thank you.

      My experience of behaviour modifying drugs has been that they work almost immediately. When you stop using one, the beneficial effect disappears within two days. This was a surprise. I think the longer the trial goes on, and particularly if it involves parent feedback, the greater the potential placebo effect.

      I think some medical trials are extremely well constructed and professionally managed. As you may know, there are specialized companies, CROs,that run drug trials on behalf of drug firms, but this is expensive but at least you get a professional trial. In autism, the trials are very small and not outsourced.

      Some trials like on omega 3 oils are really amateur and "positive" ones cannot be replicated. If they cannot be replicated, it does not matter how fancy the University, the trial must have been flawed.

      In the study in question, 95% of the placebo group reported adverse effects. To me this tells me there was something seriously wrong with the trial.

      Statins do have side effects in adults, but on doses 20mg and less these are very rare. So I continue to think it absurd to give 40mg to a 30kg child. One of the members of the ethics committee at my local medical school thinks it is reckless to give children ANY dose of statin. This medical school is actually a hot-spot for clinical trials due to low cost. It plays host to several of the world’s largest CROs (Contract Research Organisations).

      On Arbaclofen, as I pointed out in another post, the problem seems to have been how the trial was constructed. What were the primary and secondary outcomes and how to measure them? There is a whole science about how to construct and validate clinical trials. Big Pharma knows all about this and Harvard runs a Master’s degree course in it. Fragile X and autism research tends to be amateur, as in the statin research. Step one is have an idea, or take someone else’s, then after very brief tests, fantasize about getting rich and having a biotech start up. Step two patent the idea and then rush to do-it-yourself clinical trials with 50 kids. This is not a serious approach.

      I think your points are all very valid and if we were talking about Glaxo or Pfizer and a trial with 2,000 subjects, I would be the first to shut up. We are talking about very well intentioned, often highly intelligent people, many of whom are total amateurs when it comes to clinical trials. The whole way “autism” is defined by psychiatrists is also totally amateur and unscientific. How can you compare autism statistics when you keep changing the definition?

      I hope I have not offended you. A year ago, before I started my investigation, I would have been 100% in agreement with you. It is much easier to sleep at night when you think Doctor always knows best.

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    2. One more thing, ABA is only as good as the therapist and can only work if the whole family endorse it. If the family does not endorse it and sees it like speech therapy or OT class, it will fail. The same is true with PECS, if you just stick some pictures on the fridge door and say you are doing PECS, you are likley to fail. PECS did not fail, it was neverimplemeted.

      ABA will work on your pet dog, NT kids and, yes, on your spouse. But it takes a HUGE time investment, and many people are looking for a quick fix, like a pill.

      This blog is all about pills, but at least 70% of the job will always be behavioral. Thankfully, we have widely available ABA resources, although due to a lack of good therapists in most countries, parents will have to be their own ABA consultants.

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    3. Thanks a lot. I am not offended at all.
      Being a doctor myself, I know doctors do not know a lot.
      -Yi

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  39. Another posted by: Kim No-Vac | September 19, 2012 at 04:25 AM: Our sixteen year old has been taking baclofen for the last year and a half. Absolutely has made monumental changes in anxiety and learning which was evident shortly after starting. Is he now neurotypical? No, but his (and our), quality of life is vastly improved. We cannot foresee discontinuing it except to perhaps switch to arbaclofen when it is available.
    Another post: We started out at 5 mg a day and gradually in increments of 5mg a week we moved up to our maximum dose 30mg. I started seeing improvements when he got around 15-20 mg doses.

    I guess this is the difficult part, to titrate the dosage nicely really need a specialist’s care.
    But increasingly I am thinking of giving Baclofen a try.

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    1. Given this drug is approved for use in babies for spasticity (see below), the risks involved in a brief trial, to see if your son is one of the 20% of responders, do not look so high. It is just an off-label use of a drug approved that appears already to be FDA approved for children; something Bumetanide is not.

      One piece of advice, just trial one therapy at a time. Stop all the other supplements, establish a base line of autistic behaviours, then start your trial. If you do not tell nannies/teachers etc, then you can ask them after a few days of the trial how is your son's behaviour. Then you have a much more objective measure of success.

      Spasticity

      <2 years: 10-20 mg PO divided q8hr; increase dose q3Days by 5-15 mg/day; 40 mg/day maximum

      Age 2-8 years: 20-30 mg/day PO divided q8hr; increase dose q3Days by 5-15 mg/day; 60 mg/day maximum

      >8 years: 30-40 mg/day PO divided q8hr; increase dose q3Days by 5-15 mg/day; 120 mg/day maximum

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  40. Dear Peter,
    I started Baclofen at 2.5mg x 3 /day, now it is 10mgx3 /day for three days. Still I have not seen effect for our boy. -Yi

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  41. Hi Peter,

    Thanks for your work on this blog. Pretty eye opening. What benefits did you see with your child on bumetanide? I see atleast 1 more clinical trial happened - but cant access the paper. http://www.ncbi.nlm.nih.gov/pubmed/24488662 Can you?

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    Replies
    1. That paper is just a case report on one child. It is not available for free There is now a much larger multi-centre trial being prepared in Europe, plus some further work has been done in the US. The same researcher is doing another trial with Bumetanide for use in babies as part of pan-European research into seizures. It will be 5 years before they expect to get approval for use in Autism in Europe, they gave up on approving it in the US (too expensive).

      In my son its effect was a dramatic improvement in awareness, like somebody turned on the lights. So almost everything improved, speech, social interactions, mood, cognitive performance, memory etc.

      All the drugs I now use have a marked effect. In summer Verapamil is the key one, due to the bizarre effect of his pollen allergy. NAC and micro doses of Clonazepam also have a profound effect.

      My son can now function academically in school and complete the same assessment tests as the other kids, albeit they are 2-3 years his junior.

      Without these drugs this would be impossible. When we stop the drugs he reverts back in a couple of days to how he was before. So no placebo effect.

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