Wednesday 2 December 2015

“Autism treatments proposed by clinical studies and human genetics are complementary” & the NSAID Ponstan as a Novel Autism Therapy

Today’s post was not my idea at all, it was the author of one of the papers who has drawn my attention to the subject.

Genetic studies are complicated and are not the sort of thing I would have chosen to read, let alone write about, before starting this blog. 

The optimal time to initiate pharmacological 
intervention in Autism?

However, much of the complex subject matter has now already been covered, step by step, in earlier posts. Regular readers should not feel put off.

It is perhaps easier to think about ion channel dysfunctions, or channelopathies.  Some of the key genetic dysfunctions produce these channelopathies.  There are many posts in this blog about channelopathies, partly because many therapies already exist to treat them.

Then we have the complex signaling pathways which are often the subject of cancer research, but we have seen that certain ones like RAS and PTEN are key to conditions like some autism and some MR/ID.

So it is not a big leap therefore to consider the findings of a statistical reassessment of the existing genome-wide association studies (GWAS).  As is often the case in medical science, it is the acronyms/abbreviations, like GWAS, that make it look more complex than it really is.

If you only ever read one paper about the genetics of autism, I suggest you make it this one.

Fortunately, the conclusion from the genetic study really fits nicely with the clinical studies reviewed on this blog and even my own first-hand experience of investigating and treating my n=1 case of autism.

Knut, the Biometrician

It was Knut who left a brief comment on this blog and, after a little digging, I was very surprised how much a statistician/biometrician could figure out about autism, from re-analyzing the existing genome-wide association studies (GWAS).

I think the Simons Foundation could save themselves a decade or two by giving him a call.

The Research

For those wanting the science-lite version, there is a short article reviewing the research in lay terms:-

Biostatistics provides clues to understanding autism: an interview with Dr Knut M. Wittkowski

“Hence, modulation of ion channels in children at the age of about 12 months, when the first symptoms of autism can be detected, may prevent progression to the more severe end of the spectrum.” .

The actual research paper is here:-

You may find it heavy going and I have highlighted some key parts.

A novel computational biostatistics approach implies impaired dephosphorylationof growth factor receptors as associated with severity of autism

“Despite evidence for a likely involvement of de novo and environmental or epigenetic risk factors, including maternal antibodies or stress during pregnancy  and paternal age, we contend that coding variations contribute substantially to the heritability of ASD and can be successfully detected and assembled into connected pathways with GWAS—if the experimental design, the primary outcome, the statistical methods used, and the decision rules applied were better targeted toward the particulars of non-randomized studies of common diseases.”

The data comes from the Autism Genome Project (AGP), and there are two sets of data AGPI and AGPPII.

The third data set is for Childhood Absence Epilepsy (CAE)

What I would call Classic Autism, others call severe autism or autistic disorder; Knut calls it Strict Definition Autism (SDA).  HFA is high functioning autism, much of which is Asperger’s Syndrome.

“Study design We aimed at risk factors specific to strict definition autism (SDA) by comparing case subpopulations meeting the definition of SDA and milder cases with ASD (excluding SDA), for which we here use the term ‘highfunctioning autism’ (HFA). To reduce variance, we included only subjects of European ancestry genotyped on the more frequently used platform in either stage. In AGP II, we also excluded female cases because of confounding between chip platform and disease severity. The total number of subjects included (m: male/f: female) was 547/98 (SDA) and 358/68 (HFA) in AGP I and 375 (SDA) and 201 (HFA) in AGP II.

Overall, the results (see Supplementary Figure 1 for a Manhattan plot) are highly consistent with previously proposed aspects of the etiology of ASD. The clusters of genes implicated in both of the independent stages (Figure 2a/b) consistently overlap with our published CAE results (Figure 2c), confirming the involvement of ion channels (top right) and signaling downstream of RAS (bottom left), with two noticeable additional gene clusters in ASD. Both stages implicate several genes involved in deactivation of growth factor (GF) receptors (Figure 2a/b, top left) as ASD-specific risk factors and chloride (Cl − ) signaling, either through Ca2+ activated Cl− channels

Click to enlarge the figure 

A new term is PTPR (protein tyrosine phosphatases receptor), just to confuse us it is also called RPTP.

Receptor Protein Tyrosine Phosphatases in Nervous System Development


For example, the receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ) are expressed primarily in the nervous system and mediate cell adhesion and signaling events during development.

In an earlier post I highlighted the numerous dysfunctions in growth factors (GF) in autism.  Knut is highlighting here the effect of PTPR on growth factors.  Later it is suggested that this cascade of GF dysfunctions could be halted, pharmacologically if it was identified very early.  But, as Courchesne from UC San Diego noted, by the time people have been identified as having autism, around three years old, the accelerated brain growth has already run its course.

You would need to intervene around one year old.

Broad evidence for involvement of PTPRs One of the most striking observations is the involvement of at least five PTPRs in ASD (Figure 2, 10 o’clock position). PTPRs (Table 1e) regulate GF signaling through reversible protein tyrosine dephosphorylation.72 PTPRT (90th/20th, 8.57) was implicated in ASD by a deletion73 (Table S2 AU018704) and a somatic mutation

It was my post pondering the reasons for the positive effect of potassium supplementation that drew Knut’s attention to this blog.  Now we move on to Knut’s ideas on potassium and chloride channels.

K+ and Cl− ion channels as drug targets

Aside from PTPRs (Figure 2, 10 o’clock) as a risk factor for protracted GF signaling, our results suggest a second functional cluster of genes, involved in Cl− transport and signaling, as specific to ASD (Table 1f). In AGP I, the CaCCs ANO4 and ANO7 scored 1st and 70th, respectively. In AGP II, the lysosome membrane H+ /Cl- exchange transporter CLCN7 scored 21st, followed by CAMK2A, which regulates ion channels, including anoctamins82 (55th), and LRRC7 (densin-180), which regulates CAMK2A83 (Figure 2a/b, 2 o’clock). The role of the anoctamins in pathophysiology is not well understood, except that CaCC activity in some neurons is predicted to be excitatory84 and to have a role in neuropathic pain or nerve regeneration. More recently, CaCCs have also been suggested as involved in ‘neurite (re)growth’. Finally, we compared the HFA and SDA cases as separate groups against all parental controls in the larger AGP I population. Overall, the level of significance is lower and the enrichment is less pronounced, especially for the SDA cases (Supplementary Figure 9), as expected when cases and some controls are related. For the HFA cases (Figure 4, and Supplementary Figure 8), however, a second anoctamin, ANO2, located on the other arm of chromosome 12, competes with ANO4 (Figure 1, left), for the most significant gene among the result. Hence, drugs targeting anoctamins might have broader benefits for the treatment of ASD than in preventing progression to more severe forms of autism. ANO2 and ANO6 are associated with panic disorder and major depressive disorder, respectively. ANO3, ANO4, ANO8 and ANO10, but not ANO1, are also expressed in neuronal tissue.86 As ‘druggable channels’, anoctamins ‘may be ideal pharmacological targets to control physiological function or to correct defects in diseases’.  Few drugs, however, target individual anoctamins or even exclusively CaCCs. Cl− channel blockers such as fenamates, for instance, may decrease neuronal excitability primarily by activating Ca2+-dependent outward rectifying K+ channels.

Here is a follow-up paper with consideration of the possible next steps.

Gene gene environment behavior development interaction at the core of autism:

Here, we combine a recent wide-locus approach with novel decision strategies fine-tuned to GWAS. With these methodological advances, mechanistically related clusters of genes and novel treatment options, including prevention of more severe forms of ASD, can now be suggested from studies of a few hundred narrowly defined cases only.
(Nonsyndromic) autism starts with largely unknown prenatal events (: age, : virus/stress ...)
• Mutations in growth factor regulators (PTPRs) lead to neuronal overgrowth (brain sizes).
• Mutations in K+/Cl− channels cause Ca2+ mediated over excitation of neurons (“intense world”).
• Stressful environments (urbanization) contribute to epistatic interaction (increasing prevalence).
• This GGE interaction causes “migraine-like” experiences during the “stranger anxiety” period where children learn verbal/social skills, leading to behavioral maladaptation (“tune-out”).
The lack of verbal/social stimuli causes “patches of disorganization” (Stoner 2014, NEJM) as a form of developmental maladaptation when underutilized brain areas are permanently “pruned”. The PTPRs point to a short window of opportunity (WoO) for pharmacological intervention:
• Treatment has to begin as early as possible, while neurons are still growing (12 months of age. Broad support for the proposed unifying etiology and the 2nd year of life as the WoO:
• Regression (“loss of language”) seen in some children >12 mos of age.
• “Patches of disorganization” in >2 yr old brains.
• Romanian orphans developed “quasi-autism” when placed into foster care at >24 mos of age. 
• Hearing impairment leading to intellectual disability when diagnosed >24 mos of age.

 A rational drug target: treating either of two epistatic risk factors suffices:
• Blocking growth factors (Gleevac, ...) is unacceptable in children merely at risk of ASD.
• Ion channel modulators have been used in small children for arthritis and seizures.

Here is a response to Knut’s first paper from a professor at the UCLA medical school who suggests the combination of the specific NSAID and bumetanide. 
The professor would better understand the mechanism of action of bumetanide in autism if he read Ben Ari’s research more thoroughly, or even this blog.
The article by Wittkowski et al.1 reports results of human genetic studies that suggest that a nonsteroidal anti-inflammatory drug (NSAID) given for a few months from the time of the first symptoms might help some children who are at risk of developing more severe forms of atrial septal defect.
While the authors mention the recent article by Lemonnier et al.,2 which reported that a clinical study of the diuretic Bumetanide was partially effective in children with milder forms of autism, they seem to have overlooked that these two treatments may well be complementary, leading to sequential interventions, each targeting specific risks related to well-defined stages in the development of brain and social interactions.
Since abnormal brain development in autistic disorder goes through different stages from infancy to childhood, targeting different developmental stages with different treatment interventions may well be necessary to foster continued normalization of brain growth.
Bumetanide is known to block inward chloride transporters, yet the relation of this mechanism to the etiology of autism is unknown. Wittkowski et al. identified mutations in calcium-activated (outward) chloride channels as associated with autistic disorder, suggesting loss-of-function mutations in anoctamins as one of the risk factors for autism. This provides a testable hypothesis for the mechanism by which Bumetanide alleviates symptoms of autism. For example, mouse models could test whether Bumetanide ameliorates a stress-induced phenotype caused by a knockout/down in ANO2 and/or ANO4.
A second cluster of genes identified receptor protein tyrosine phosphatases, which downregulate growth factors. These findings support the notion that successful treatment should start as early as possible,3 while neuronal development still takes place.
The rationale for combining these two treatments rests on the fact that Bumetanide is contraindicated in infancy because it is known to interfere with neuronal development when used long term. In contrast, the NSAID proposed in the second study has been given for decades to children with juvenile idiopathic arthritis from 6 months of age on, with no adverse effects on brain development. It is known to modulate chloride channels (see above) as well as potassium channels.4
In conclusion, I wish to extend their hypothesis based on the synergy of the two treatment approaches: (1) early treatment with NSAID can reduce early maladaptive behaviors that cause abnormal pruning of neurons in the cortical areas; (2) these children could subsequently benefit from Bumetanide, which would compensate for the primary ion channel defect, but could not reverse the secondary effect of abnormal pruning.
This hypothesis allows for a novel two-way interaction between behavior and molecular events. Traditionally, one assumes that molecular events determine behavior. The new hypothesis, based on human genetics, also allows for symptoms (such as the absence of social interactions, delayed speech onset and language development) during certain sensitive periods to change molecular events (pruning of neurons in areas required for normal development).

Therapeutic implications from the genetic analysis

Some of the therapies that Knut is proposing, based on the genetic analysis, have already been reviewed in this blog.  Some have not.  A few therapeutic ideas in this blog actually target genes Knut has identified, but not highlighted a therapy.

I will just review the drugs and genes that the above study highlights.


Low dose clonazepam fits in this category.  We have the work of Professor Catterall to support its use.  At higher doses, benzodiazepines have different effects but use is associated with various troubling side effects.


Bumetanide is at the core of my suggested therapy for classic autism or what Knut calls SDA (strict definition autism).  We have Ben-Ari to thank for this

Fenamates (ANO 2/4/7 & KCNMA1)

Here Knut is trying to target the ion channels expressed by the genes ANO 2/4/7 & KCNMA1. 

·        ANO 2/4/7 are calcium activated chloride channels. (CACCs)

·        KCNMA1 is a calcium activated potassium channel.  KCNMA1 encodes the ion channel KCa1.1, otherwise known as BK (big potassium).  This was the subject of post that I never got round to publishing.
Fenamates are an important group of clinically used non-steroidal anti-inflammatory drugs (NSAIDs), but they have other effects beyond being anti-inflammatory.  They act as CaCC inhibitors and also stimulate BKCa channel activity.

Fenamates stimulate BKCachannel osteoblast-like MG-63 cells activity in the human.

 The fenamates can stimulate BKCa channel activity in a manner that seems to be independent of the action of these drugs on the prostaglandin pathway”

Molecular and functional significance of Ca2+-activated Cl− channels in pulmonary arterial smooth muscle

Of this “first generation” of CaCC inhibitors, NFA (a fenamate called niflumic acid)  is the most potent blocker of these channels and the compound most frequently used to investigate the physiological role of CaCCs”

Choice of Fenamate
There are several fenamate-type NSAIDs, but one is a very well used generic drug, Mefenamic acid known as Ponstan, Ponalar, Ponstyl, Ponstel and other generic names.  It is even available as a syrup for children.
 It is not available in all countries.


Gabapentin is used primarily to treat seizures and neuropathic pain. It is also commonly prescribed for many off-label uses, such as treatment of anxiety disorders, insomnia, and bipolar disorder.

Some people with autism are prescribed Gabapentin.  Some people suffer side effects and others do not.

If you have a dysfunction of voltage operated calcium channels, Gabapentin should help.


This is all about modifying NMDA receptors.  Memantine is but one method.


Minocycline is an antibiotic with several little known extra properties.  In autism, we looked at its ability to reduce microglial activation and so improve autism.  A clinical trial showed that it did not help autism.

Minocycline also affects MMP-9.  MMP-9 is an enzyme found to be associated with numerous pathological processes, including cancer, immunologic and cardiovascular diseases.

High MMP-9 activity levels in fragile X syndrome are lowered by minocycline.

 “ The results of this study suggest that, in humans, activity levels of MMP-9 are lowered by minocycline and that, in some cases, changes in MMP-9 activity are positively associated with improvement based on clinical measures.

So if you are treating a case of Fragile-X, or partial "Fragile-X-like" autism, better take note.


Rapamycin and mTOR was the subject of the following post:

mTOR – Indirect inhibition, the Holy Grail for Life Extension and Perhaps Some Autism

Both too much and too little mTOR can occur in autism.


My conclusion is probably different to yours.

For me, it seems that all the pieces really are fitting together and so this blog on the cause and treatment of classic autism will eventually cover the current scientific knowledge, in its entirety.  No complex areas are off limits, because in the end they are not as complex as they seem, when you lift the veil of jargon and acronyms.

From the all-important therapeutic perspective, new insights from today’s post are:-

·        Those with a dysfunction of voltage operated calcium channels might want to give Gabapentin (Neurontin) a try.

·        The fenamate-type NSAID mefenamic acid,  widely known as Ponstan, really should be tested, either at home, or in a clinical trial.

This statistical analysis is based on “all autism”, so any one person would be highly unlikely to have all the mentioned dysfunctions.  These are the most common genetic dysfunctions and many can both hypo and hyper, as in the case of NMDA dysfunctions and indeed mTOR. 

In Knut’s chart, I would add a green line pointing to RAS and PTEN with the word Atorvastatin.  Baclofen would point to the growth factors.  Verapamil would point in multiple places.

The motto of University of Tübingen, where Knut originally comes from, is Attempto !  The Latin for "I dare".

This might be a useful motto for readers of this blog, and also a good tittle for a book on treating autism.


  1. Thank you Knut and Peter. If you have an adolescent (boy) who benefits from ibuprofen and naproxen, how would you know if the additional benefits of Ponstan would help? What benefits? It seems that the benefits you are talking about would mostly accrue to younger children (pruning, etc)?

    1. Ponstan should have similar effects to your current NSAIDS plus some extra ones. If you already use NSAIDS it is well worth a little trial.

      Some people, like Courchesne, think that by age 3 the game is all over, but it clearly is not. The ion channel KCa1.1 is important and drugs that affect growth factors, like Arbaclofen, can affect behavior in adolescents.

      So I cannot tell you for sure what the extra effect would be, but it seems worth finding out.

      The very early intervention is supposed to halt the progression of the autism, but that does not mean there cannot be improvement using it later.

    2. Thank you Peter. Does Ponstan require an RX? It seems that way in the US
      To clarify, would Ponstan combine selected benefits of ibuprofen and arbaclofen?

      I am hoping you are considering writing a book :)

    3. One of the effects of Arbaclofen and baclofen is on growth factors, nobody knows which effect is the therapeutic one in some autism. Ponstan does require a prescription but is widely prescribed for types of pain relief. You might find it easier to get it precribed for yourself. If it does not work, no harm has been done.

      I think a blog is better than a book because of the links and comments.

    4. Hi peter,

      I really like your very scientific forum here.

      I just found some more info linked to GABA from Harvard

      My son is 4 years old and has autism and he does talk since half a year.

      The most common behaviour I see is lining up things
      with usually the same toys and wanting things the same. Tantrums occur often when things change.
      He has periods on the day that it is almost non existing and sometimes it is very bad. We stopped milk half a year ago which improved things a bit.
      He was born at 32 weeks at 2 kg with few complications but he did have severe stomach cramps in the first half year and constipation from 2 years till 3.5 year.
      Since half a year I use many of the DAN adviced supplements. It seems to help a bit but I am not sure as it could be natural change. Last week I had the first appointment with a DAN doctor who is doing some tests on urine, stool and hair.
      Before the test results she already put him on
      Beta 1,3 glucan and Citramesia.

      I wonder if anybody recognizes a strange skin behaviour while he does not have any skin allergies.
      There is a sudden appear of temporarily red spots/red skin on his eyebrow and
      forehead while he has a tantrum. The spots initially look like they have been there for days but after the tantrum is gone they just disappear after 10 minutes. I really wonder what that could be and if that is an indication of something that needs attention. I asked his doctor but he did not have any idea.

      Does anybody know where to buy Bumetanide or Clonazepam without doctor prescription?
      I am in Europe.
      I would like to test these and feedback the results.

    5. You can get bumetanide without prescription in some countries, for example Spain. Clonazepam is a substance some people abuse, and so will not be easy to obtain without a helpful doctor.

    6. Thanks for your response.
      Which of the 2 would you rate safer for a 4 years old boy?

    7. I think both are safe, but the one with the clinical trials to support it, is Bumetanide. This drug is used in 3 week old babies.

  2. We had a real-life hard lesson in this, and witnessed things going in the opposite direction: At the age of 2.5 our son was on the 'moderate' centre of the autism spectrum, displaying some basic interaction and communication skills, as well as short-lived hard-earned moments of interest and engagment with the world around him ...while at the same time suffering severe anxiety, tantrums, demands, defiance - those beauties that are not strictly part of 'autism' dx but give it a lovely familiar flavour :(

    Cut the long story short: on doc's advice we started him on calcium supplements one winter day, but by mistake and as luck would have it gave double the daily dose for several days in a row. As second stroke of luck this was given alongside cod liver oil/Vitamin D (us being totally unaware of it increasing ca absorption ...).

    The result was that our son underwent an almost instantenous transformation from a moderately-autistic into one totally-unreachable-impossible-to-engage-not-recognising-its-parents-any-longer VERY severely affected child. He was just GONE. Another weird thing was that his severe oppositional-irritable-fussy behaviours and manic fears were also completely GONE. For the first time in his life was not screaming, pulling, stimming, demanding about anything or anxious about anything or irritable about anything or obsessing-compulsing about anything. All he did was sit there and look past us, past everything. GONE.

    Another funny thing, something that I sometimes notice in photos of other severely affected children, is that during this period he assumed an odd body shape, with hands bent at ellbows and wrists, held insect-like very close to his chest.

    After about 3-4 days we started suspecting that this bizarre transformation could in some way be linked to this new supplement regime, and stopped giving him calcium. The next day he started looking at us again when we called his name, and on the second calcium-free day he was back to his baseline moderately-impaired, tantrumy, demanding, screaming old self. Happy ending.

  3. As my son is 22, is it futile to think of reversing any of this classic autism, with Ponstan or anything else? We have seen reduction of rages with NAC (but not the stimming unfortunately), and Pantogam + clonazepam. Quercitin at 500-100 mg /day started to clear up his blistered-looking skin but it really upped his stimming and loss of sleep.
    I am so thankful for this blog.

    1. I think you should think of it as "treating" classic autism. Then every step is a success.

      Did you try bumetanide and atorvastatin ? This can make a big cognitive improvement which then helps everything.

      I have not tried Ponstan, but certain types of Monty's rages go away with Ibuprofen. So NSAIDs really are worth investigating.

      Monty's rages to date either respond to Verapamil or to Ibuprofen/Sytrinol. Both also prevent the rages from happening.

      You just need to figure out what is triggering your son's rages, it will vary from person to person, but there is always a reason.

      If NAC did not cure our stimming I would try 6g a day of Inositol. It is cheap, safe and does halt certain people's compulsive behaviors. It does not taste bad, I am informed. Certainly worth $13 to find out.

  4. Thank you, Peter. I did try bumetanide but only a few days. I wonder if I should stick with it for a good 2-4 weeks. I would love to get back the memory and learning trajectory we were on before the "double tap" at age 5. I would love to try the statin and have not.
    Again, thanks for your input.

    1. Nancy, you need to use Bumetanide 1mg twice a day for a good four weeks.

      If he is a responder,the statin works almost immediately, but you may need a few days to convince yourself.

      If your son has allergies and if he has skin problems this sounds highly likely, he may have the same mast cell type of problem that many readers have identified. You can try various anti-histamines, but our big success is Verapamil. Other things are cromolyn sodium or even basic thinks like Zyrtec and Claritin.

  5. Peter -- on Wikipedia, I noticed that

    Anthranilic acid derivatives (Fenamates)
    The following NSAIDs are derived from fenamic acid. which is a derivative of anthranilic acid which in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin.[64]:235[65]:17

    Mefenamic acid
    Meclofenamic acid
    Flufenamic acid
    Tolfenamic acid

    So would aspirin work similarily to a fenamate like Ponstan (if you also took ibuprofen)? Also, in the U.S. there has been some press about aspirin and its salicyclic partially helping with Alzeimers. Is any of this related? Thanks for this thoughtful post.

    1. Some people with autism do take low dose aspirin.

      I think to be sure of maximizing the chance of getting the specific benefit that Knut proposes, Mefenamic acid (Ponstan) is likely the best choice.

  6. Hello Peter, Ponstan takes me back almost two decades, when my son was a little baby. We used Ponstan syrup up until he was 14 years of age but of course only in times of inflammation.
    Ponstan was very effective and although the doctor had told us to use it in turns with Panadol, we saw that Panadol didn't work for him.
    I know that in your post you make a point of other effects beyond the anti-inflammatory properties of Ponstan, but I suppose everything is connected.
    Thanks to your posts I've learned about Ibuprofen (600 mg) and it works indeed. I suspect that it clears the mind out of intrusive thoughts and thus helps with stimming. Today I'll try Ponstan (500 mg).
    Thank you very much

  7. Hi, I just received Ponstan in the mail and was wondering if there are further insights from readers?

  8. Hi Peter,

    I have tried Bumetanide and Clonazepam on my son and I found both of them working just like you described in your table - clonazepam after 3 days and Bumetanide after two weeks - the fog has lifted.
    I also trialed Pantogam + Carnosin, Piracetam and Galantamine, but no visible effect from either one of them.
    I am considering trying Mefenamic Acid or Atorvastatin next. Which one would you recommend trying first?
    Also, we are in the middle of the homeopathic allergy treatment, so I would prefer using the drugs that do not affect his response to the homeopathy. I know that Atorvastatin suppresses cytokines, which would affect the body's response to homeopathic remedy histaminum that he is taking. I am taking it as well, and I notice a huge effect on me after each dose. I feel like I am coming down with a flu, but it only lasts one day. I had a bad inflammatory response to the flu shot in the third trimester of my pregnancy, which triggered my son's autism. I guess this homeopathic remedy causes my body to process the flu virus from the vaccine, 4 years after I had it. I do not see the same response in my son, unfortunately. But I would like to postpone any of the allergy drugs for now, waiting for the end of the detox, in a month from now.
    Also, I read about mefenamic acid usage online and they have a warning of not using it for more than 7 days in a row. How do you feel about long-term usage of this drug?

    How much of mefenamic acid would you give to a kid who is almost 4?

    Thank you for your blog, it helps a lot. But my son is almost 4 and he is still completely non-verbal and I am starting to feel pretty desperate, knowing that some areas of his brain might be irreversibly pruned. I am trying every possible drug to initiate speech, but so far all my efforts are not successful.
    Which one should I try next? I am trying to avoid the allergy drugs right now, because of the homeopathic treatments.

    Thank you,


    1. Polly, Ponstan (mefenamic acid) is widely used by children in many countries. One reader of this blog from Greece found it always worked differently (better) than other NSAIDs when her son was young. The dosage used in those countries is 100mg in 2 to 4 year olds. All NSAIDs can cause GI side effects. Trying it for a few days falls within the normal usage.

      If you continue use of Bumetanide and Low dose Clonazepam, there should be a continued cognitive improvement. As long as you combine this with lots of therapy to encourage communication (like PECS), you will maximize your chances of speech developing.

      I would now focus on the communication therapy, rather than more pills.

    2. Thank you for your reply, Peter. I do not think therapy makes any difference in autism. I read lots of stories of non-verbal kids receiving 40 hours a week ABA therapy for decades and remaining severe and non-verbal. We tried to introduce PECS 1.5 years ago and it only made the matters worse. I am not going to stress him out like that again, because stress is one of the triggers of autistic symptoms. Your son and other kids started talking in spite of the stress of ABA, not thanks to it. They were ready to start talking at that point and that would have happened regardless of the therapy. My son is more damaged than most kids, because the assault on his brain happened earlier than in most kids, even before he was born.
      He is communicating by bringing me objects - his bottle, TV remote, shoes, etc. I do not see how it would make any difference if he brings me a picture of a remote, or of a bottle or of the shoes? He is very smart and loves learning, for example he likes to show me the animals on the wall of his room, he wants me to ask him which animal is where. After 5 weeks of ABA therapy 1.5 years ago, he completely lost interest in learning new things, and became resistant and psychotic. I think ABA therapy does not make any difference in less damaged kids, they improve on their own, but it affects severe kids, like my son, in a very negative way and makes them even more severe.
      All of the progress so far has come from one supplement or the other, and none from the communication therapies. I just need to continue looking for the appropriate supplements to address his particular issues.

      Thanks to clonazepam, his mood has improved and there is no more electrical activity during his sleep. I hope that by giving him this drug in low doses it will prevent him from developing real siuzures in the future. That was a very good addition to his supplements. Thank you for that! Bumetanide has lifted the fog, he responds to the same requests much faster, like to turn on the coffee machine, to flush the toilet, to show me letter A. Before he was taking a long time before responding, and now he does it right away. It happened 2 weeks into giving him Bumetanide. I do not see any other changes lately, even though I continue with both of these drugs. I tried other drugs that are supposed to help with speech, like Galantamind and Piracetam, but there was no changes in speech. Perhaps he is one of those kids that I read about, who never start talking, even on lots of ABA. Perhaps the damage to that part of his brain that is responsible for speech is irreversible :( I will continue with my low stress, minimum interaction approach for now. It works the best for him, because any interaction, like with the strangers on the street, causes an intense stress and increased stimming in him. I do not see any upside in the forced socialization, but lots of regression. I am not sure what I am going to do when it's time to enroll him in school, because he is nowhere near ready to attend any schools and he does the best when he is left alone and not bothered. Leaving him alone triggers his own initiation of communication. Any forced form of communication, like ABA, ends in a disaster and results in him completely shutting down and regressing. I wish there was another way to treat his condition, but so far the only thing that worked is to address it medically, with drugs and supplements.

    3. Polly, interventions can be made to be fun and not stressful. It all depends on who is the therapist. It can be a parent.

      Maybe look at the Hanen Program.

      PECS is actually really clever and much more than just handing over a picture of what you want. The training course lasts two days. Kids LOVE it. It shows the child that communication is worthwhile and hence in his interest. Once there is active communication, speech often then follows.

      Ultimately some children need help to be drawn out of their isolation, because it may otherwise not happen. This can be an fun uplifting experience, it does not have to be a stressful experience, like a visit to the dentist.

      It would be great if there was a pill for this.

    4. Peter, I am happy for you that PECS was fun for your son. My son absolutely hated it. Besides, ABA therapists warned us beforehand that PECS do not facilitate speech, but they do provide the kid with the way of communication once he is ready for it. They told me he is non-verbal and he will never talk, because he did not talk before the regression, like other kids did. There is no upside for me in ABA therapy. He found his own way of communication now that he is ready for it. PECS do not promote speech. Academically he is very smart and does not need any training. He needs help with things like food, he never ate food on his own, not even with his hands. And ABA can not help with that, the same way as it can not help with recognizing emotions, promoting initiative and things like that. He hates touching any type of food and seems to be disgusted by it. He does not chew on his own.His highest point in his development was between 12-18 months old when he would grab a piece of bread and nibble on it. He has not done that in two years, but just recently he started doing it! It coincided with starting him on Diamox and Mefenamic acid. I am not sure which one of the two helped. I will stop the Mefenamic acid after 7 days on it and will see if these changes stay.
      So far, drugs have been very helpful with his issues. I do not see how any form of therapy would help with appetite, mood, initiative, etc. Leaving him alone promotes initiative. The other thing that helps is keeping the interactions to the minimum, especially contacts with other kids. That helps with his self-esteem and builds up his confidence, because he does not compare himself to the normal kids and it does not make him feel inadequate. Because the autism, at least some forms of it, can be cured. But the neurotic disorders created by forced socialization and by comparing oneself to the normal kids are not curable. I do not want to add to his problems. I will stick with something that worked so far - plenty of alone time for him and the supplements/drugs that work.

      Thank you very much for this blog! Finally I am starting to see that his condition is not permanent and there are drugs that can improve it. He is finally returning to the highest point of his development that was at 12-18 months old. For most kids eating with hand was a regression. Sadly, for my son the same thing is a sign of progress. His appetite is improving, he is starting to request food, he is not afraid to touch it anymore. Those are the things that even OT could not help him with. In fact, all of the therapies we attempted had brought zero improvements in any areas. Supplements brought some improvements, but not as much as the drugs you listed in your pill for autism. I feel fortunate I found your blog. Because the real autism, like in my son, is very rare. Most sites share info on treating regressive autism and it has nothing to do with the true autism my son has.

      Peter, have you ever tried Diamox on your son? I think it's helping my son, from what I've seen in the 5 days I am giving it to him. I am wondering can it be given on a permanent basis or I should take breaks, like with HBOT?

      Best regards,


  9. Regarding the mention of Gleevac in this post as a (not recommended) way to block growth factors for ASD kids.
    I just learned that Gleevac/imatinib sometimes are used for systemic mastocytosis. Can someone explain the link?


    1. Oh, now I see that Gleevac/Imatinib is used as a chemotherapy for chronic myeloid leukemia too. It is probably used then for many different conditions. Just thought that the connection with autism and mastocytosis and leukemia could have something to tell. It is easy to see patterns everywhere. :-)

  10. As a comment to genetics vs other contributing factors in autism:

    Some of you might have noticed that calcium-dependent chloride channels (anoctamins) were genetically significant in autism, as per Knut Wittkowskis paper:

    "For the HFA [High functioning autism] cases, however, a second anoctamin, ANO2, located on the other arm of chromosome 12, competes with ANO4, for the most significant gene among the result"

    This might still be relevant in autism even without that genetic dysfunction, especially if we are talking about autism related to autoimmunity. Compare with the results in the MS study below:

    Anoctamin 2 identified as an autoimmune target in multiple sclerosis (2016)
    "Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS"

    This is just one example, I am sure there are other antibodies involved in some autisms. Btw, soes anyone know if there exists antigene/antibody test panels?


  11. I have a son of 5 years (Autism) recently diagnosed with him channelopathy KCNQ3 (son of epileptic seizures does not have and never had, only the EEG record presents a continuous electrical discharge during sleep.) We have received Gabapentin treatment for a while, a dose of 200 mg for the night to be increased (there are studies in which it presents that opens kcnq3 channels). My question is whether you can take Bumetanide with Gabapentin? The son has stories of a paradoxical reaction to Benzodiazepines. Bumetanide acts on GABAA (chlorine, pore) and Gabapentin on GABAB which is coupled to the G protein (the kcnq3 mutation is bound to the protein). Mr write about NSAID (Mefenamic acid) and Bumetanide as a treatment for genetic autism associated with canalopathy. In our case, would it make sense to introduce both at once or would it be safe? Sam Meclofenate also opens the KCNQ3 channels, but I decided to introduce GBP from the disturbing EEG. I am asking for help, please.

    1. Your gene encodes the Kv7.3 ion channel, which is important in the regulation of neuronal excitability and dysfunction can be associated with epilepsy, aggression, absence seizures and issues with vision.

      This ion channel combines with either Kv7.2 or Kv7.5.

      Gabapentin activates Kv7.3.

      Many other drugs activate or inhibit Kv7.3

      Celecoxib enhances Kv7.2/7.3 and Kv7.3/7.5 currents

      14 drugs are listed as activators or inhibitors of Kv7.3 on this very long page below.

      So you have a lot of choice.

      Since your son has a paradoxical reaction to benzodiazepines, that would make him likely to respond well to bumetanide.

      You and your doctor can look up drug interactions. I looked up bumetanide and gabapentin and found no contraindication.,bumex.html

      I am not a doctor, but I could not see a reason why you could not take bumetanide with a Kv7.3 activator.

      You will inevitably have to try out different drugs and combinations to find what works best for your son.

  12. Thank you very much for your answer . I ask, because we take Gabapentin only for 2 days and the reaction is similar to Benzodiazepines, increased agitation, and I'm confused, maybe Bumetanide will work as it should.

    1. Do not be confused, just look at the other effects of Gabapentin. In my son all drugs that “increase gaba” have a negative effect and increase agitation. Find a Kv7.3 activator that does not affect GABA so directly.

    2. Also, recall that the whole point of Bumetanide in autism is that in those people GABA is working in reverse and so GABA is excitatory and not inhibitory. In such a person Gabapentin might eventually trigger epilepsy.

    3. You also need to be sure whether your son’s genetic issue requires an activator or an inhibitor of this ion channel. Both are possible and both are treatable. It is easy to get things back to front.

    4. Peter, with regard to the negative effects of "increasing GABA" drugs: do you mean the effects in your son when he was already on bumetanide? Would it mean that bumetanide is not able to reverse the paradoxical GABA function enough? So, is it better to stay away from this kind of drugs in a person who is a bumetanide responder? I guess there can be some long term effects which would not be apparent after the first few doses.

    5. Agnieszka, firstly we need to highlight that my son represents just one sub-group of autism and that bumetanide responders may include more than one sub-group.

      In my son both Picamilon and a tiny dose (< SSRI dose) of Fluoxetine produce a negative reaction with a few hours.

      One researcher did suggest a strategy of "fixing" the GABA response with bumetanide and then "increasing GABA" - in lay terms.

      I think for many people with autism, bumetanide is only a partial solution to NKCC1/KCC2 miss-expression and so some show no response and others show a positive response, but not all the potential benefit. A more potent drug is needed. Perhaps Azosemide is that drug, or else we have to wait for Ben Ari to produce his next drug. We can also use an OAT3 inhibitor to boost bumetanide levels.

      I think "partial bumetanide responders" should indeed be wary of drugs/supplements that "increase GABA" or the response to it. The effect will be apparent very quickly, so no harm done.

    6. A clever solution to discuss with your doctor might include a potassium sparing diuretic (to raise K+ levels) and bumetanide to block NKCC1. You could then see if a drug like celecoxib gave an additional benefit via Kv7.3.

      You need to be aware that you child will be specially sensitive to a drop in potassium levels caused by bumetanide. So you have to go and take blood samples to monitor K+, this is always difficult, but particularly necessary if you also have a potassium channelopathy.

  13. Once again, thank you for answering. I read a little about this Celecoxib and it is a very encouraging drug, primarily when it comes to our mutations KCNQ3. Equivalent action is to the drug Retigabine which was a drug in this canalopathy, unfortunately, was withdrawn due to serious side effects (blue skin color) This mutation is combined also with migraine or neuropathic pain, therefore, the more I would like to try this drug, because my son sometimes cries a lot of time sometimes even a few hours and it is especially in the afternoon especially. Unfortunately, I did not find any information as long as this Celecoxib can be used, only those that represent 10 weeks research. This mutation is related to the protein, and here I come to the receptor GABAb and thus Baclofen what you think about it.? GABA with us does not work as it should only bad response to Benzodiazepines or Gabapentin but whether the problem lies in the GABA B receptor or GABAb?

    1. Celecoxib is a very widely used NSAID type drug. 10% of all Americans have taken it and so of course there are reports of side effects, as there are with all blockbuster drugs.

      There are studies on the use of Celecoxib to treat schizophrenia and bipolar. There are people with autism in the US who take Celecoxib.

      Different people respond differently to individual NSAID type drugs. Some have side effects and some have none.

      The pragmatic approach would be first to see if it helps and then worry about how to safely use it long term. Ask your doctor about this. I imagine some people cycle its use to avoid side effects – so they make regular pauses.

      Baclofen at modest doses indeed help some people with mild autism, but not all of them.

      If Baclofen helps you would find out within a few days.

      I think Bumetanide is likely the GABA related drug that will help your son most, but the diuresis will disturb electrolytes and affect his potassium channelopathy.

      I suggest you continue reading up on the subject and then go back and talk to your doctor.


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