Tuesday, 16 June 2015

End of School Year

As another school year comes to an end it was time for Monty, aged 11 with ASD,’s end of year grades and the parent teacher meeting.  Monty attends a small mainstream international school with his own assistant.

This year is particularly interesting because we have the same class teacher, Miss B, this year that we had three years ago (prior to starting to develop Monty’s autism Polypill).  So if anyone can judge the impact, it should be her.

In the English system Year 4, is where you find 8-9 year old typical kids and equates to 3rd grade in the US system.  Monty just finished Year 4.

After completing Year 3 first time round with Miss B three years ago, with a traumatic several months of aggression and cognitive and behavioral regression, we put Monty to start Year 2 again.  At the end of the first term in Year 2 (second time around) he started Bumetanide.

Year 1
Year 2
Year 3            Miss B
Year 2            (repeated)
Year 3            (repeated)
Year 4            Miss B again (current year now ending)
Year 5            Next school year starting Sep 2015

First time around with Miss B, Monty could not really follow any instruction from her and he was entirely dependent on his 1:1 assistant.  

At home, in the afternoons and holidays, he had learned to speak, read and write using ABA.  At school he was assessed on simple tasks like being able to change into his indoor shoes independently, or with prompting.  Academic assessment was all customized for him; no attempt was made to use the same assessments as his classmates.  Assessment was extremely basic, like adding one to a single figure number.

Some children are diagnosed very young with autism and by five years old things have changed so much that they have lost their diagnosis.  Monty is not one of those.  He was diagnosed at three and a half and continued to get more autistic.  Using PECS and ABA he gained basic speech.  With 40 hours a week of 1:1 assistance he learned to read and write, but we did not even try and teach numeracy.

We were following the standard trajectory of classic autism; no learning followed by (very) slow learning.

This distorted learning trajectory is one reason why I feel that Asperger's should remain entirely separate from classic autism; calling them both "autism" does justice to neither.  In Asperger's there is no language delay and no impaired cognitive function, resulting in quite different people, with very different issues.  I am beginning to feel that when you treat classic autism, as far as you can, the result will be something not dissimilar to Asperger's. What happens if you treat Asperger's?

After initiating pharmacological therapy, we now have had nearly three years of skill acquisition at a rate similar to a typical child, of average IQ.

So Monty finished Years 2, 3 and 4, had the same assessment as the NT classmates and is not at the bottom of the class of 12 kids, in any subject.  Monty is certainly not a “straight-As” student, like his big brother is; he is now more of a C student with some Bs.  But as I told his teacher Miss B, the great achievement is that we are even discussing the results of standard assessments at all.

Pleiotropic effects?

Sometimes drugs seem to have broader beneficial effects than intended, these get called pleiotropic effects.

It looks very likely that one or more elements in Monty’s Polypill have some pleiotropic effects, or some synergistic effects.  

There is a study showing the effect of ten months of Bumetanide treatment.

My feeling after 30 months of Bumetanide treatment is that it provides a critical step-change in cognitive function.  Following this one-time gain, things seemed to progress faster cognitively only when other elements were added.

The following papers on pleiotropic effects of drugs in the PolyPill do not refer to autism, but are interesting.eiotropic Effects


Future progress

As I told the teacher,Miss B, a good plan seems to be to just keep following the regular kids and keep going until the end of year assessment might put Monty at the bottom of the class.  Should that happen, we can just repeat that year again.

This is not the advice you will likely find anywhere else regarding educating a boy with classic autism in a mainstream classroom.  Indeed it is pretty clear that in mainstream schools “inclusion” just means a class within a class; so the child with autism and his assistant are doing one activity, while the class teacher and the other kids do something entirely different.


  1. Hi Peter,

    You might have recognized my name from some of my earlier posts, specifically on how broccoli sprouts helped to alleviate a serious aggression and SIB spell my now almost 5 year old son had late last year. For the better part of a year now, I have been relentlessly trying to find a physician willing to try Bumetanide (I am in the US). After a long campaign of email writing, phone calling, and in some cases literally handing a printout of the study to them, I have finally found a physician local to me that would like to try it. She actually seemed surprised how I came across that information.

    So I will be picking up our prescription today, and we will be starting it tomorrow morning. Now, I have seen you post in various places throughout your blog about dosing strategies. What dosing strategy have you found to be the most effective? Granted, what works in one person may not work in another, but I would appreciate any feedback you could offer on getting started. In other words, knowing what you know now about Bumetanide, if you were starting it tomorrow, what would you do?

    Our prescription calls for .5mg twice a day. So we will start with .5 in the morning and .5 in the afternoon. He is approximately 48 lbs (21 kg). Giving it at bedtime seems like a waste. Also, how long did it take before you started seeing the positive effects in Monty? Was it a slow gradual improvement, or a sudden burst of improvement. Again, every child may respond differently. Lastly, my son is fed through a G-Tube, so we will have to crush up the tablet and dissolve it in water to get it through the tube. I don't think that is an issue at all, but I thought worth mentioning.

    1. I found small does had no effect, so better 1mg once a day than sptlitting it into two doses. You should add potassium and monitor levels in the blood, hopefully the doctor knows this. It takes weeks to lower the chloride level, in our case it was at least two weeks, but much longer in some. The researchers suggest giving it two months before assuming it does not work. So it is a gradual change, that you cannot miss when it happens. There are various effects, but it is like the fog lifting and the child being present. You should see a measurable cognitive improvement.

      We now use 1mg twice a day and this is now the standard dose used by the researchers. We add 250mg of potassium twice a day.

      Crushing the tablet is no problem.

      Best not to look too hard for changes, ideally other people should notice and so I suggest not telling therapists/teachers. Wait for them to tell you of improvements. Then you know it is real.

      Good to hear that perseverence paid off.

  2. Hi Peter,

    It’s always great to read about your son’s achievements. Congratulations for Monty!

    I’ve read the paper about NAC pleiotropic effects highlighted in this post, very interesting. They write about decrease in NAC plasma level during prolonged treatments as described in other NAC pharmacodynamics study. Could that explain some cases when NAC stops working (if not for allergic/inflammatory exacerbation)? They report using NAC three consecutive days a week to allow the wash-out period and avoid this phenomenon.
    They also suggest beneficial effects of NAC, melatonin and selenomethionine synergism. I don’t know the last one, but melatonin effects in my son seem to exceed the additional hour of sleep that he gained with it. Involvement of mTOR has also been suggested for melatonin:
    However the doses and timing of melatonin treatment in this study is something that cannot be followed easily in autistic children. I wonder what do you think about melatonin for non sleep-related issues in autism?

    1. Melatonin seems to have very many effects, not least on oxidative stress.

      Melatonin as a natural ally against oxidative stress: a physicochemical examination

      Protective effects of melatonin in reducing oxidative stress and in
      preserving the fluidity of biological membranes: a review

      There was also an interesting genetic study into the genes:-

      Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients

      What dose of Melatonin do you give? People seem to use 1 -3 mg.

      Melatonin is used as an anti-aging therapy and given that oxidative stress rises in older age and plays a role in many age-related diseases, this looks like a logical preventative therapy.

      Monty sleeps quite well, so we never tried Melatonin. It might be worthwhile to see the effect of a short trial. It is clear that oxidative stress is ever-present in most people's autism, but different people respond differently to the various possible therapies. Some people really respond to Carnosine, better than NAC.

    2. Thanks for references, all new to me. I started with 1 mg for jet-lag on holidays long before other treatments. It did help with falling asleep, though it was not a huge problem before. Surprisingly we noticed better mood and behavioral improvement, so we continued back home and I increased the dose to average 3-5 mg.

      Two months ago I started 10 mg - this dose was found effective for cluster headaches in adults. Three days later Mateusz asked me “for a pill for head”. Such request happened for the first time in his life and he still hardly communicates any pain so this was quite shocking. He still has strange periodic episodes of distress, but they changed, look now more like periodic weakness than headaches, that’s why I tried to give him K+ in a way hypoKPP is treated. There are some concerns about long term melatonin treatment, with nasty things like precocious puberty reported in animals, but on much higher doses. I remember that up to 12 mg was studied for sleep in children with developmental disorders without side-effects and also looked for case reports of adverse events, but did not find any.

      For last few weeks I’ve been also trying Clonazepam, so it may be responsible for some effects also. I haven’t tried Carnosine, have you used it?

  3. I tried Carnosine briefly in place of one 600mg of NAC and saw no change.

    However, other readers of this blog have found that Carnosine+NAC is better than NAC alone. It is worth trying, because there are good reasons why Carnosine+NAC should be better.

    I am no expert on cluster headaches, but it looks like mast cells and histamine do play a big part.

    "•Histamine and nitroglycerine are also provokers of attacks in chronic CH and during cluster periods in episodic CH."

    Given your son's mast cell issues, this does look like one of the triggers. If you knew where the mast cell degranulation was taking place, you might be able to reduce it.

  4. Melatonin may also have pleiotropic effects and seems to affect mast cells: “mast cell activation seem to be partially inhibited by incubation with melatonin”.

    I don’t know if my son has (or - hopefully - had) cluster headaches, but you are right with histamine, it has been confirmed by a lab test. I am pretty sure it’s a kind of mast cell degranulation triggered “trigeminal autonomic cephalalgia”. However it does not explain all issues: my son has other symptoms at time of these “episodes” and some are immediately relieved by liquid K+ “shots”. This would not help for mast cells, would it? You once wrote that it would be good if Ben-Ari talked to Catterall about GABA E/I balance and I think here Theoharides could talk to Gargus. To make it more complicated, during such a “week with headaches” my son’s autism core symptoms diminish: no stimming and speaks better - like in fever effect. And he has unusually high ketone bodies in urine then.

    These “episodes” happen every few weeks, so when I try something new it takes a whole month to see if it prevents them. It seems better now on melatonin 10 mg, more K+ supplementation and clonazepam.

    1. It is all very complicated, but the GABA A receptor is made up of subunits; these may include 6 α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6) and 3 β subunits(GABRB1, GABRB2, GABRB3)

      Research has linked GABRA5 and GABRA3 to migraine headaches. Other research has linked GABRA5 and GABRA3 to autism and bipolar.

      GABRB3 is linked to autism, epilepsy and migraine.

      GABRA5 is the target of Roche’s new drug to improved cognitive function in Down Sydrome. RG1662, is a selective GABAA α5 Receptor Negative Allosteric Modulator.

      Roche expect to improve the E/I imbalance with RG1662.

      Catterall’s research using low dose Clonazepam was targeting GABRA2 and GABRA3.

      So it is entirely plausible that the right dose of Clonazepam may both help your son’s headaches and improve his autism (via an increase in inhibitory GABA signaling).

      Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice

      RG1662, a Selective GABAA α5 Receptor Negative Allosteric Modulator, Increases Gamma Power in Young Adults with Down Syndrome.

      A Study of RG1662 in Adults and Adolescents With Down Syndrome

    2. I’ve chosen Clonazepam to reduce E/I imbalance and also address Nav channels, both I think are associated with what I can see in my son. But it seems not to be so simple and I will look into this further, thanks for elaborating the details.

      Finding the right dose of Clonazepam is not that easy, all above 3 ml per day (using 0,5mg/100 ml) seems to make him prone to anxiety, so it's different that in your son or what Maja wrote here.

      OT: I would think my son has a rare medical problem, but last year he was the same kid, it was just called “mood disorder” then. There are many people with severe autism and mood disorder and now I know from other parents that headache is very common in those autistic children, who are able to tell about it. Also discussed with the other reader of your blog here, that her child seems to have some similar symptoms with “afebrile fever effect”.

    3. I understood Maja is using 5ml a day, which is half my dose. I also noted in one post that I found that anxiety followed at a dose slightly above the effective one. I think Maja's daughter is likely a similar size to Monty, so you cannot figure out the dose just based on KG. It may be that your son has a different sub unit dysfunction, but since there is an effect from this tiny dose, it is not clear. It would be useful to know the effect on typical children, I suspect there would be no effect. So the increase in anxiety
      may just confirm you are on the right track, but need a lower dose.

    4. Yes, I give her 5ml of solution. Tried with less and more - no effect. First two weeks was truly amazing, after that she has maintained a stable good level till today. Tried to pull off Rivotril - just to see: less spontain, less friendly, more in fog...
      But, those two weeks... Self Confident, with great interest in everything around her, from birds, wind, to people in the street. Learning much easier; without fear of noise; trying to communicate with other kids using WORDS, trying to explain herself... Something of that is here now, but in that intensity - not.
      From the other hand, she was excited, prone to be dramatic if she doesn't achieve her expectations. I had the impression that her wish to talk and communicate was much bigger of her ability, so, it made her frustrate.
      In the word - excited, not anxious...

    5. Hi Maja and Peter, thank you both for reply!

      I started with 3,5 ml a day for my son (7yo, 23 kg). In our daily notes we write if he says something exceptional and since the 4th day on Clonazepam my husband, who was unaware of new treatment, wrote several things. I can now see the same kind of affection as on low dose Valproate, other people noticed this as well. So I think it’s associated with Clonazepam. He got anxious when I increased the dose.

      I can also see like Maja that he is trying to use words to tell us something. He told me what he is afraid of and he was not able to communicate such things - feelings - in the past. He is excited for sure. He is less indifferent and this means many things: yesterday he used one of the longest sentences ever to tell his speech therapist that he is not going to sit nicely at the table any more ;-) But also noticed me among many parents watching their class performance at school and smiled to me - such thing happened for the first time in his life. All these and more happened in the last month on Clonazepam, so it is possible that such dose is enough for my son (?). He also responded to Bumetanide 2x0,5mg, which is rather low dose.

      Periodic “migraine-like” attacks are the challenge now and hyperactivity. I thought the latter could be related to Clonazepam, but it started before it, in late April. Can hyperactivity be associated with more antioxidant treatments he gets now? Or is he prone to “summer-rage”, but earlier it was not seen in all his behaviors?

      It’s great to read about your daughter Maja and her best two weeks on Clonazepam. I think that if a child is able to get better at times, then it means that it may be possible to find why and try to achieve the same for a longer time. Could you share also your other treatments?

      I didn’t think about Clonazepam in so much detailed way as Peter explained here (subunit specificity), but now I wonder if genetic testing could be helpful to point the targets for treatment? I don’t mean things like whole exome sequencing which probably gives too much data to interpret them (or maybe I’m wrong), but if one knows that there’s something about “GABRA-X”, but not sure about what subunit and there are new specific treatments in the pipeline. And we talk about things that influence such important things in the child… What do you think? OK genetics is “dark art” for me and this comment too long as usual. Thank you!

    6. I have seen no negative effects of NAC, even at high doses.

      A large group of researchers, like those funded by the Simons Foundation, very much believe that genetics is the key to treat autism. In the long term (50 years), I am sure they are right.

      What really matter is gene expression. The people with Down Syndrome may have no relevant genetic disorders, other than over-expression of up to 500 genes. So the genes were fine, just 50% too many copies. I imagine many things can cause over/under expression of a perfectly functional gene.

      So you would have to go to proteomics, which in effect measures gene expression. This is possible today, for example here:-

      Interaction Proteomics of Autism Spectrum Disorder- and Intellectual Disability-Associated Proteins Identifies a Novel Hap1-Tsc1 Signaling Link that Controls Neuronal mTORC1 Signaling and Pyramidal Neuron Morphogenesis

      It is all so complicated that you are currently better off with the “trial and error” approach; even if you are very clever in 2015, I doubt you can be clever enough.

      As in my recent post on NMDAR function, you are either going to be hypo, hyper, or just fine. There will one day be a clever test, but you can find out what you need to know by first trying an NMDAR agonist and then an NMDAR antagonist. This would be fast, cheap and safe, but also falls into “trial and error”.

    7. Agnieszka, it is such a good sighn that your son noticed you among many parents and smiled...
      We are giving the same dose of Clonazepam (my child is ten, weight 35 kg). That is the only medicine that has "survived" two weeks trial (only lost intensity after 2 weeks). I`ve read somewhere from another parent that it seems like our kids are programed to switch "safe mode" each time they progres.
      Sorry, there is one drug that works all the time: Verapamil. Unfortunately, my child has developed rare nus effects: gingival hyperplasia et galactorrhea (autism is making fun with me...). Verapamil was my guarantee that she will behave nicely at the school. Without it, stomach ache has come back. Now I give her Verapamil only when I expect stressful events, like test in school (she refuses to do it) ...
      I am literally Peter`s follower... Expensive medical testing doesn't seems to do any god - today's science interpretation is foggy, and it is not guarantee for so many things. He is the first one who has the guts to try (and tell the others) all the safe stuff that can help his child.
      This is my list:
      • Morning: 2 caps of Carnosine (by Dr Kutcher - Carnosine Extra); 100 mg ALA; 1 caps of Krill oil
      • After snack: 1 caps of broccoli (Super Spruit); 10mg Zn
      • Lunch time: vitamins (50mg B1, 1 tablet of Beviplex® (contains very small doses of all B vitamins), 600 mcg of Biotin, vit C)
      • After snack: probiotik ( Flobian® (Lactobacillus plantarum 299v) + Simethicone gtt (Espumisan® - to reduce bloating); 1 caps of Carnosine.
      • Dinner time: Clonazepam; 150mg of tangeretine (Sytrinol - NOW); 2 caps of Krill oil
      • Sleeping time: Mg glycinat 360mg

      My child has four indicators (measure of therapeutic benefit) :
      - psychogenic divergent strabismus (occasional)
      - dandruff (cradle cap),
      - scripting (most of the time she uses it appropriately as she grows, but she lives in parallel imaginary world)
      - digestive signs: stomach ache (gases) and aphthous stomatitis

      Her sensitivity to sounds, hyperacusis (like Superman...) is not good indicator because it doesn`t shows regularity in the time of occurrence or intensity.

      So sorry for the long post,
      P.s. Next step is Yurinex …

    8. Maja, thank you for details, I learn here new things everyday.

      That’s a pity with Verapamil side effects, I wonder if there’s anything that could replace Verapamil in terms of its GI activity, but with no risk or less risk for these adverse events.

      Peter, this proteomics study shows clearly that you are both right with your opinion on sophisticated testing vs. “trial and error” approach. Still, it would be good to have some clinical clues and perhaps NMDAR treatment is a good example. A psychiatrist involved in a multicenter memantine trial told me once that despite this trial failed, he saw improvement in some children and when asked about good outcome indicators he said that kids with intellectual disability benefited most. It’s just the opinion of one researcher, but with more data it might be possible to find something. But I don’t know if they tried.

      I was thinking about hyperactivity and antioxidants as dr Kelley wrote “An occasional immediate sign of the effectiveness of carnitine in children with more severe, non-AMD complex I deficiencies is hyperactivity (...) hyperactivity stems from increased cerebral energy availability and, therefore, that long-term benefit from carnitine supplementation can be anticipated.” This is about carnitine, but I wonder if this can happen if you improve mitochondrial function with other treatments. Your new blog entry is very interesting and I will have to rethink what the effects of melatonin really mean for my son.

    9. It would be very useful to match each possible drug with the likely effect, but it seems that the results can vary widely by each person. I found it strange that the best responders to bumetanide are supposedly the people with less severe autism. It looks to me that bumetanide's main effect is actually on cognition, so I would expect it to work best on people with more severe autism.

  5. Have you been following the Suramin research at all? Thoughts? Maybe a blog post about it? Dr. Naviaux seems on the right track. Clinical trial in humans just to see what it does and if they're on the right track, even though he says it can't be given long term to humans. Works on two different mouse models.

    1. Yes, I have followed Dr Naviaux and there will be a post on Suramin. The strange thing is just how many therapies work in 2+ mouse models. Some of these are easier to implement. It appears that you can make the NMDAR receptor work better and rescue some autism deficits by moving zinc from a presynaptic terminal to postsynaptic sites in the brain using a drug called Clioquinol. It works on mice. Those researchers do not have Dr. Naviaux's PR skills.

  6. Also, have you ever heard of a CBS gene mutation? I contacted someone at Arizona State regarding their polypill (for lack of a better word, I'll plagiarize you). Anytime my son gets ANYTHING with B-12 in it, he gets off the charts aggressive. So, I asked them because that's what their polypill has in it, and they suggested he may have a CBS mutation. It sounds like it creates problems with breaking down protein and ammonia gets built up in their systems, resulting in high levels of homocysteine. He DOES have the MTHFR gene C677T mutation, and the CBS gene is part of the MTHFR (I have not had time to refresh my genetics classes, so I'm sorry my genetic references are clumsy). I am trying to decide what I think of this, and whether getting him into the CM-AT clinical trial would actually BE addressing a CBS mutation, because that's what it is supposed to do. Does a CBS mutation cause low levels of chymotrypsin or am I just really that stupid?

    1. It would make sense to be tested for CBS mutation.

      There are 150 known mutations. If your son has one, there are known therapies; but first best to confirm if he has one.

  7. Peter, I need help, he has lymphopenia, no ion channel dysfunction, no cases of lymphopenia and autism have been reported yet. If someone knows something i would aprecitate.valentina

    1. "The most common cause of temporary lymphocytopenia/lymphopenia is a recent infection, such as the common cold."

      Best to wait a couple of weeks and do the test again.

    2. It is not temporary, it is more complicated, the great fall of lynfocites started in 2011, and has been falling until now, he has lost 2.3 million lynfocites since november 2014, in 8 months, now he has total.I think it is very dangerous, because his defenses are as if someone with vih. In this context, i think he needs an intensive treatment with probiotics, antibacterials and antifungus.could he have pandas?

    3. Hi Valentina,
      I read your earlier comments and see that our kids may have more in common than I thought. My son has also upgaze previously suspected of seizures, but it turned out not to be epileptic event, ruled out by Video-EEG. I suspect other reasons. He usually has low white blood cell count as well. Low white blood cells can be associated with Valproate use, but it’s rare for lymphocytes and depends when did your son start Valproate. 2,6 is not that bad though. If you want you can e-mail me, I can share my experience, although even after several months I haven’t explained all in my son.

    4. Hi Agnieszka, good that you wrote me, about my son´¨s blood results, 2 important things, first lymphopenia and second, sodium valproat is covering epilepsy but not mood, as it is considered a mood regulator, it has lost its function in this aspect. I realized that the upgaze wasnt an epileptic event with the days, its a kind of tic or stereotipi that appeared with his last strep thorat, i want to know your opinion about this.I sent the blood results to my argentinian neurologist and he told me to ask an interconsult with an hematologist,to find out the reaal cause of the event and treatment. and he also told me that valproat can cause lymphopenia in 10% of cases.I think this is becuase valproat causes viral infections.Also think that he has already an immune system dysfunction and valproat is fanning the flames, but its my opinion.How can i get your e mail?, I go to see de neuroligst on monday 6 july.Valentina

    5. Valentina, my e-mail is: my name.last name at gmail. I have movies of the upgaze in my son, so you can compare. If this happened during strep infection in your son I would at first think PANDAS, but I was told by a specialist that any tic may aggravate during infection.
      There is also a condition called “paroxysmal tonic upward gaze”. It’s been associated with calcium channelopathy:
      They say: “Later publications demonstrated that a similar clinical picture may arise from structural brain lesions, channelopathies, neurotransmitter disorders, and epileptic seizures.”
      I think that in my son it’s been related to oxidative stress that depletes a molecule called BH4 which is involved in neurotransmitter (dopamine) synthesis. BH4 was described by Peter:
      But it’s my own idea and not supported at all by medical papers. And seems like this resolved with melatonin treatment.
      I think that in your situation there are some important question: has your son been diagnosed with epilepsy or does he have abnormal EEG, but no seizures? And what are benefits of valproate for your son?

  8. Hi Peter. We are on day 15 of 1mg Bumetanide. I understand that you give Monty 2mg a day. Did it take going to the 2mg dose before you saw any positive effects?

  9. We had positive effects with 1mg once a day. The researchers did find that it takes longer for the effect to appear in some people, they suggest keeping going for two months. I would suggest going to 1mg twice a day and try for a longer period.

  10. Did you learn this through your direct contact with the researchers, or is this published somewhere?


    1. It is from feedback to me and another parent from the researchers.

  11. My son is also taking Clonidine for hyperactivity. I am wondering about the possibility that it is increasing his chloride uptake, cancelling out the chloride blocking of Bumetanide. I can't find any direct literature about if Clonidine increases Chloride levels. Could you reach out to the Bumetanide researchers about this possibility?


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