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Thursday, 28 July 2016

Memantine – yet another failed Autism Trial


Memantine (Namenda/ Ebixa) is an Alzheimer’s drug that has been used off-label in autism for many years; but does it actually work?

More than a thousand people with autism have completed clinical trials and yet more trials are in progress. 

A few years ago, at the FDA’s request, the producer of the drug, Forest Laboratories, funded two clinical trials enrolling 903 children with autism.  The results were never fully published because the trials were deemed to have failed to find any positive effect and a note to reflect this is included in each pack of Namenda.

A quick look at ClinicalTrials.gov website shows yet more autism trials in the pipeline.


What is going on?

When Dr Chez made a trial in 2007 he found Memantine to be effective; he has since moved on to stem cell therapy which he also finds to be effective.

The latest study to be published includes Dr Hardan from Stanford, who published that study showing NAC to be effective in autism.  This time his study shows no positive effect.

If you look on the clinical trials site you can see some data for the primary endpoint used in the very big trial funded by Forest Laboratories.  It seems to show 517 responders.







By the time the results were reviewed in detail the conclusion drawn by Forest was “there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo”. 

In other words it does not work.

The drug itself now carries this note:-

8.4 Pediatric Use

The safety and effectiveness of memantine in pediatric patients have not been established.
Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (ASD), including autism, Asperger’s disorder, and Pervasive Development Disorder — Not Otherwise Specified (PDD-NOS). Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively.
In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158).


So if it does not work, why do researchers continue to carry out further trials, like the recent one below, including Hardan?



OBJECTIVE:

Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.

METHODS:

A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.

RESULTS:

There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.

CONCLUSIONS:

This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.
  
Dr Chez? 

So how reliable then are Dr Chez’s other findings?  He is a "big name" in autism research.

Back in 2007 Dr Chez published a very positive study on the use of Memantine in autism. 

Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observationof initial clinical response and maintenance tolerability.

 

Abstract

Autism and Pervasive Developmental Disorder Not Otherwise Specified are common developmental problems often seen by child neurologists. There are currently no cures for these lifelong and socially impairing conditions that affect core domains of human behavior such as language, social interaction, and social awareness. The etiology may be multifactorial and may include autoimmune, genetic, neuroanatomic, and possibly excessive glutaminergic mechanisms. Because memantine is a moderate affinity antagonist of the N-methylD-aspartic acid (NMDA) glutamate receptor, this drug was hypothesized to potentially modulate learning, block excessive glutamate effects that can include neuroinflammatory activity, and influence neuroglial activity in autism and Pervasive Developmental Disorder Not Otherwise Specified. Open-label add-on therapy was offered to 151 patients with prior diagnoses of autism or Pervasive Developmental Disorder Not Otherwise Specified over a 21-month period. To generate a clinician-derived Clinical Global Impression Improvement score for language, behavior, and self-stimulatory behaviors, the primary author observed the subjects and questioned their caretakers within 4 to 8 weeks of the initiation of therapy. Chronic maintenance therapy with the drug was continued if there were no negative side effects. Results showed significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree. Chronic use so far appears to have no serious side effects.


Making sense of Memantine

Personally, I think it likely that Memantine may indeed have a positive effect in some people with autism.  For most people it probably does no good, but no harm, so it is a harmless placebo that may make the parents feel better and gives the doctor something to prescribe.

Memantine and the very similar Galantamine probably do deserve a place in the long list of drugs and supplements that may be effective in some people.  But how great is that “effect”?  I suspect this is the problem; it is big enough for Dr Chez but not big enough for the others.

I suspect this will be a recurring problem in almost all future autism drug trials.  What is a responder?  How big an effect is a worthwhile effect?

I think a better approach would be to focus on the so-called responders identified by Dr Chez and others.  Document the claimed positive effects and then see if these effects continue when the responders are given a dummy placebo.

This is the approach I use in my trials; when I stop a therapy, I look to see if there is a change.  When you suspend an effective therapy things should get worse.

The hundreds or thousands of kids currently on Memantine should do the same; take a break and see if there is any change, be it positive or negative. 

Many people believe no valid treatments for autism exist and that those thinking otherwise are all deluded.

I think that many people are giving their kids drugs and supplements of no therapeutic value and in some cases are making the situation worse.

However, effective therapies do exist for many people with autism and they stand up to scrutiny.  The effect is apparent to third parties, like teachers and therapists, and when you stop the therapy the positive effect is lost and people notice, only to return when it is restarted.  Then you know it is not wishful thinking and at that point what the FDA says does not really matter and you do not need bother with what subsequent trials say.

So when a reader asked me what I thought about the recent “failed” trial of NAC, to treat social impairment in autism, I took a very relaxed view.  If they had identified 50 kids with classic autism and stereotypy and looked at whether NAC reduced this, I would take note.  They choose the wrong primary endpoint, social impairment, and wasted a lot of money.


A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder

Conclusions
The results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD
.
      
I only wait to see what happens when Ben Ari publishes the results of his large trial on Bumetanide.  Whatever data they choose to collect, is it going to convince the European Medicines Agency that it is an effective therapy?  I hope so, but nothing would surprise me.

I would love to know how Dr Chez rationalizes the fact that so many others cannot replicate his positive research findings.  But he keeps on going.

Rather off-topic, a recent comment on my post on Clonidine, informed us that this drug, often prescribed off-label in autism and ADHD, really is acting as a sedative to calm the person down. So no effect on core autism.  Sedation does have a role to play in some people’s disorders.  Very low doses of Mirtazapine (Remeron) are also sedating via its effect of central H1 receptors; it occurred to me that this might be a safe long term therapy for some "out of control" people with severe autism; likely safer than the usual antipsychotics. 







70 comments:

  1. Hi Peter,
    First, a big thanks for keeping us informed on the successes and failures of autism related drug trials and your clarity and objectivity is praiseworthy.

    My personal query is regarding interventions which claim to impart stable and permanent benefits so that testing their efficacy through temporary withdrawal might not prove anything. Ten days into homeopathic treatment, my son at the age of 3.3 years started imitating actions, then came sounds and then words. I am not hundred percent sure whether it was homeopathy or a pure coinvidence but ability to imitate was a big development which everybody noticed. Now homeopathy and Ayurveda claim to bring about constitutional changes so if the treatment had worked, changes will be permanent. If I remember correctly, even in the bumetanide trial, all gains were not lost once the treatment was stopped.

    So, it seems a placebo controlled and if possible double blind trial, is till the best bet out there.

    And lets all hope the positive effect of interventions are not all in our mind.


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    1. There are many hundreds of known causes of "autism", including even being bitten by mosquito (leading to cerebral malaria), so I am sure some must have disease changing therapies.

      For most people it seems to be a case of constant therapy being needed (bumetanide, NAC etc). As people get older often their autism moderates, I suppose often related to puberty. I think the biggest benefit for the therapies I use was in earliest childhood, so it is a case of starting sooner the better, but also better late then never.

      One-off use of steroids, for example, can trigger the onset of speech. I doubt that is coincidence, but it may just have brought forward what was going to happen a few months later anyway.

      Bumetanide will raise IQ and I have more faith in measurement of IQ than measurement of autistic traits, which is highly subjective. Even measuring IQ is challenging.

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    2. Hi,

      This is not related to the current topic in discussion but
      I would be grateful if anyone could throw light on two issues that have preoccupied my mind for quite a while now

      Is there a trade-off between development of speech and other skills in autistic indivifuals? My son's therapist as well as the counsellor of the mainstream school he attends suggested so, and therefore we are putting off rigorous speech therapy. Indeed, my son picked up writing his alphabet and numbers by the age of 3.8 and to my pleasant surprise seemed to be enjoying it, learning to print quite a few letters on his own. By this time he had started imitating speech sounds so we started with little exercises where he would he would label simple objects. But as this slow but steady development took off simultaneously my son just lost interest, not the ability,in writing and every other exercise requiring sustained focus.

      I would also appreciate if anybody could give me their opinion on another of my son's behaviour which might give a clue to his apparent loss of interest in performing tasks as his speech is developing. It might seem odd but when my son tries to focus hard on any atttempt of his, speech, writing, reading, identifying or actions, he starts feeling uncomfortable in his nether areas, getting an irritating erection which prevents him from focussing on the task. Both his doctor as well therapist have not been able to provide any helpful solution to this problem. I feel hyperexcitability and too intense a focus probably overstimulates certain neurological pathways.. much like quite a few neurotypicals including myself and my husband will get a pleasantly overactive digestive system when really mentally stimulated
      ..doing some academic work or reading something exciting.

      My son does not have much stereotypical behaviour, is highly flexible, enjoys variety of foods and is a happy, affectionate child skipping and hopping his way through life.

      If anybody has any suggestions or idea about what's going on and how to resolve it, a major roadblock will be removed. Yes, I have considered the possibility of performamce anxiety too.











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    3. I agree, Kritika. My son hated speech therapy and any attempts were met with crying and running away! It really irritated him that we were constantly trying to get him to do something he couldn't, because of his speech apraxia. I don't doubt that it could very well be that mechanism you described--an overstimulation in one area leading to a change in behavior. Then again, when we make things into a game with something he likes, he makes much more attempt at speech. My son is also hyperlexic, he enjoys reading and attempts to write but is frustrated by that too...again, from the motor apraxia. ESL for kids videos on youtube has become the best way to teach since he enjoys it and it's visual.
      MKate

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    4. Hi Mkate,

      You are right, the learning videos are an excellent tool.. the anxiety that comes from interaction with a judgemental adult and the pressure to perform at their dictats is absent. However, we have try and widen up their abilities.

      Interestingly, both myself and my husband are similar to my son in this..we will spend hours trying to figure out things on our own.. searching, reading, thinking than take help although after becoming a mother my attitude has changed..look at the number of queries I put up.


      Mkate, my son is so like me. In fact I was a very sensory seeking and sensitive child, and could spend hours gazing at glass paperweights trying to imagine the world inside, or would collect scraps of cloth peices of different texture, satin, silk.. feeling them and looking at the vivid patterns.
      And then all the smelling, sniffing and tasting behaviour..emotionally hypersensitive ..in short almost an autistic but not quite.

      I strongly feel that the psychological component of any interaction with a child is very important..we underestimate their emotional perceptiivity and resulting vulnerability. But if you observe deeply, even the severely affected developmentally delayed individuals can sniff out a patronizing, phoney and uncomfortable person.

      So happy to know your son is responding well to bumetanide.. touch wood!

      Wishing your son health and progress

      Regards




      So happy to know that your son seems to be responding well to bumetanide.

      All



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    5. Mkate, Peter..what would be your views on reflex integration techniques which supposedely help indivifuals with autism and related disorders. Under this premise, a retention of primitive reflexes late into childhood might create problems with focus, learning and language. You tube videos are abundant although just the thought of getting my mercurial four and a half year old to trace an eight gets my adrenalin, or whatever the stress hormone is called, flowing and flooding.

      I would appreciate any feedback on this..anybody else who tried it?


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  2. My son began Memantine in 2011 and I just recently weaned him off of it in May. When we first started using it my son was 7 years old and had terrible GI problems alternating between severe constipation and diarrhea. He was having accidents constantly and was literally in the pike position when trying to have a bowel movement it hurt so bad. It was horrible. Interestingly when we started the Memeantine he was able to go to the bathroom and not only that, became the most "regular" kid ever. He would go every day after he got home from school no problem. After years on the drug however, I have become concerned as to what this drug's effect could be on my son after all of these years. I wanted to see what his baseline looked like without drugs. I weaned him off of the Memantine and Prozac and surprisingly I have seen no change in his behavior or his GI. I am so thrilled that he is no worse without the drugs. After he was off the above mentioned drugs for several weeks, I began the BioGaia Gastrus and now the PharmaNAC. The PharmaNAC has had a significant effect on his verbal stimming (repeating his schedule and tv talk). --Christine

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  3. One more thing to add, the NAC has had a side effect for my son of decreased appetite. I am a little bit concerned about this as my 11 1/2 year old son is only 75 lbs, so he cant afford to lose any weight. I will try to lessen the dose and see if that helps. I will let you know. -- Christine

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  4. Last time I checked, autism is a lot more than just the SRS, especially if you factor in autism with intellectual disability, ADHD like comorbidities, OCD like symtpoms/stereotypies, etc.

    The problem with many of these studies is the researchers almost never have enough money. Testing for more than just social responsiveness takes more time, and more time means more money to pay therapists, postdocs, etc. to run the studies. When more money is spent to ask more questions and to probe more behaviors in a study, then you will have less money for recruiting research subjects so that the study is adequately powered. Unfortunately, when a study comes up saying "NAC does not modify an autistic subject's rating on the SRS", does not mean that NAC does not help with other symptoms of autism including self-injurious behavior, attention, and hyperactivity. Unfortunately, we human beings are far more attuned to negative news than positive news so a negative result in a study often gets extrapolated and exaggerated to other domains. For example, with a particular vitamin the press may lead with the headline "Vitamin C is useless in preventing cancer" because it was found in a pilot study to not improve a particular type of cancer.

    With respect to memantine and autism, I think its best potential is in the striatum of the brain in attenuating repetitive behaviors/stereotypies because even though 95% of the cells are GABAergic, they are driven by glutamatergic input. I don't think it will do much for social responsiveness as the issue there is more a function of connectivity between various areas of the brain forming what are often called "social networks". In fact, sometimes various nodes in these "social networks" such as the amygdala can be hyperactive, in which case more glutamatergic signalling can make things worse with respect to anxiety and fear.

    Of course in these discussions dosage is a super-important consideration, so I have not read these specific studies cited, but I would not be surprised if the dosage and schedule of memantine varies greatly between the various studies.

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    1. It would be rather sad if after the involvement of the FDA, funding from Forest for trials on a thousand kids, they had not resolved whether memantine is beneficial in some people with autism. If that were the case, it does not bode well for future trials of any other drug.

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    2. A simple, elegant additional step in all these drug trials is to compile data on metabolic, immunological and other profiles of the test population or at least carry out these on the responders even if they make up only five percent of the total recruitments. Probably this might give the team carrying out the trial a more scientifically rigorous explanation about the mechanism behind the drug response and better result reproducibility which is a condition every scientific experiment/trial has to fulfil.

      Or are they already carrying out these steps and not able to find any correlation between biomarkers and drug efficacy in which case future of potential drug treatment for autism seems disapponting and discouraging.

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  5. I can tell you that in our experience on Memantine, dosing was an issue. Each and every time we tried to increase the dose (he was on 2ml -- the liquid) he became quite activated. We would try to ride it out as we assumed his body needed to adjust. But to no avail. He remained more hyperactive and we were never able to get over the 2ml dose. I was afraid to discontinue as it was the only thing that seemed to help his GI issues. Like I mentioned before, we just recently decided after years on it to wean and see if his GI issues came back and they haven't. What does that say? I'm not sure. Dosing in a trial isn't adjusted if one child becomes activated at the given dose. I have found that regardless of the drug or supplement, my son is sensitive to these interventions and another kid may be fine with a higher dose. Autism is so complicated and a whole body disorder. Each person is different and the people doing these studies are unable to know exactly what issues each participant is coming to them with. --Christine

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    1. I would never have guessed that you used Memantine to improve GI issues. In studies Memantine usually produces GI problems in a small proportion of cases. If people with autism are as different as this then big studies are not going to get far, better lots of detailed case reports of what worked in individual people.

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  6. Hi Peter,

    Have you ever considered that if you go back in time and restart bumetanide treatment on your son, you might not get the same magnitude of improvements im his autistic symptoms as you got this time. I am having this uneasy suspicion that trials concluding efficacy or otherwise of drugs, especially on core autistic traits will not only be unable to reproduce their results in different test populations but also the same test population in a repeat trial.
    I fervently hope it is not so, but what if the variables determining autistic symptoms are themselves not stable and subject to so much fluctuation over time that predicticting drug suitability even for autism subtypes becomes a very very difficult task.

    And what about the loss of gains reported every time and which happen so rapidly after the initial bloom that it is unlikely that it was due to emergence of a new pathophysiological condition and if these new anomalies are really popping up so fast they might render all treatment less effective.

    I was reading comments to your excellent posts on bumetanide, looking for feedback from parents and two of the reports caught my interest. In their positive response assessment of clonazepam and bumetanide, these parents have mentioned development and effective use of olfactory sense, which if I remember correctly is the first to develop and last to switch off with death. Now, my son has been displaying the same behaviour, smelling the new food items before tasting them, sniffing his hand after being licked by the family dog and adoringly even smelling flowers sometimes. More curiously he even tries to take in my smell often as if he is just forming a sensory picture of mum, for the past few months. There are of course numerous other improvements, he got potty trained the first day I tried. These developments, in areas of adaptive living, life skills and maturation of sensory awareness will be maintained. It's the positive changes in the core domain of autism, language and social awareness which seem to be the most unstable. And if you remember, we have not done any drug therapy as yet except for homeopathy, which assuming is as good as a placebo effect, all these changes seem to be brought about by normal growth processes or the other non drug interventions. Homeopathy however claims to give you slow gentle improvements interspersed with some light bulb moments. Again, improvements were happening even before he was diagnosed at 2.8 so I would never know.

    I am not advocating homeopathy here but trying to get over a predicament I face as I arrange for some drug based interventions for my son.

    1. In light of the development trajectory of my child, what am I supposed to accept as a significant improvement..the rapidity of response or the areas of impairment it seems to be imparting benefit to.

    2. How will I segregate the benefits attributed to maturation process and those the intervention..if I get a steady improvements but not the lot of big vows should I accept the therapy as good or as ineffective as homeopathy.

    I know it's complex and subjective but I need some clarity and an experienced advise as I am feeling quite direction less here even before setting out.
    Sorry for the rambling mail..

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    1. I have stopped all of the therapies including Bumetanide to verify that they work. There is a post about the last time I did this. I use an online maths tutoring program and so far we have done about 400 exercises. When we stopped bumetanide he could no longer complete previously mastered excercises and was hopeless at trying the next more complex ones. It was glaringly obviously, he became dumber. Once he started the pills again, after a week or so everything went to back to normal. With bumetanide the effect wears off over a few days. The other drugs lose effect much faster.

      Many common therapies have very marginal benefits and I assume that is why after decades they are not mainstream. These tend to give the idea of treating autism a bad name.

      For 30-50% of people with classic autism, bumetanide makes such a difference almost everyone will notice. It is not a cure, it just reduces the severity of the autism.

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    2. Peter, thanks for the prompt response.

      Yes, I remember the latitude/longitude post and the dictation/mental maths and piano performance one and how withholding the drug led to loss of initiative and cognition. Commendable for your son to have come so far.

      So it's an improvement in cognition that bumetanide might bring about in responders..and that's I feel an umbrella trait that should have a beneficial cascading impacts on other deficits. You have been reiterating this fact.

      Thanks

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    3. One thing I do with my son who has some speech but not conversational speech in that he can say "I want X and I want Y" or simple commands like "stop" or "go away", is what I call the "ABC song test" which I use mostly as a gauge for acute interventions.

      The ABC song is about the only song he can do from beginning to end, including the last part which goes "Now I know my ABC's, next time won't you sing with me".

      So what I do is ask him to do the song and then pay attention to several aspects of his performance:

      (1) Speed - If he is singing very slow with significant pauses, it suggests impaired brain rhythms due to malfunctioning fast-spiking parvalbumin interneurons which are necessary for gating brain rhythms. The mGluR5 receptor for driving PVIN's seems to be malfunctioning in many models of autism, so if you don't have well functioning PVIN's you don't have any rhythm and optimal speech requires functional brain rhythms for phonemes to build up into syllables and syllables to build up into words.

      (2) Attention - If he starts and stops, it suggests he can't focus and is being distracted by something in the environment he can't filter out. Neurologically, if there is hyperactivity in the brain, then there will be too much noise which will boost the signal of too many sensory inputs at a time causing distraction. Or an alternative hypothesis is that they can't make sense of their environment because the excess noise in the brain prevents any discrimination of environmental stimuli leading to hypoactive sensory processing. Either way, antioxidants like NAC (among other interventions I employ) I feel attenuate the attention issue and my son is not as attentive on the ABC song test when not on NAC.

      (3) Tone - If there is flat effect, it could mean the amygdala is not functioning well for any number of reasons (a leaky blood brain barrier from oxidative stress in the body renders the amygdala and hippocampus the most vulnerable to hyperactivity). The amygdala does many things and it is still a very big gray area in terms of its function, but one thing it has been linked to is proper affect in tone of speech, as being part of the limbic system, without that emotional input, one's speech can sound robotic. If the amygdala is working better, then you will have more natural sounding speech in the ABC song.


      Anyways, your child may have some other song he/she can sing instead of the ABC song if there is enough speech in your child's repertoire to do so, but for me it is usually a good proxy for if my son is going to have a good speech session with his therapist or even a good day at school. Hope this helps.

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    4. Hi Tyler,

      My son at 4.6 is nowhere close to reciting entire poems/songs but does remember them and excitedly will struggle to join in with the words especially while watching the musical videos. ABC song obviously tops the autism chart and he learnt to speak the letters and even write some of them by closely watching the videos. Now he has graduated to more mature choices..he will fill in Lou or darling when you sing skip to my Lou, for instance.

      As I mentioned earloer, we are not doing formal speech therapy sessions with him but gently pushing him with the labelling, manding and intraverbsls..the fill ins. He is a kinesthetic learner so songs with a good beat and movement will energize him to open his mouth..I like to ?? Move it he will fill in.

      My son has always used his speech meaningfully, even if it was three words at one year which gradually disappeared almost completely to start reappearing at around 3.5 although random words and phrases popped up even during the dark phase and mama was the one he maintained.

      At present we are in the process of teaching him to join two or three words..basically memorizing scripts but sometime he surprises us by coming out with appropriate untaught phrase. Two days back I asked him name the school he goes to expecting a one word answer. Instead, I got, " I m go t Ami" and a second time after ten minutes " me go ami" amity being the name of his school. That was it.. I did not get this answer again.

      Tyler, you have lucidly explained the links between aberrations in speech and neurological causes. What to do about it. My son still has lot of speech sounds missing, and like most autistic kids, lacks attention, a sense of rhythm, tempo and I can't even dream of musical notes for at least a few years to come. About prosody and voice inflection..I am not really sure as we are still not hearing lot of phrases and he is really at a fledgling stage where even producing the correct sound seems to be an issue.

      Any novel insights?






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  7. Hello peter,

    Could you please suggest the b vit combination, strength wise required while on nac.

    I was exploring the option of trying cerefolin but felt it's better to isolate the impact of nac first so fluimucil 600 seems to be a safe initial step.

    1. My problem is I am not able to find a combination formula with methylcobalamin, folic acid and pyridoxine; the ones out there have cyanocobalamin.
    2. Combination formulas with methylcobalamin have ALA as well which will confound the effect of nac alone if any.

    3. If I decide to give the vitamins seperately, what is a sensible dose of b6 and b9. You have already posted that 1000mcg seems to be a good starter dose for b12.

    Genetically, vit b12 deficiencies and anemia run in in our families and my son is mildly anemic so supplementation with b vitamins will be necessary..probably after assessing effect of nac for a week, I start him off on the vitamins.

    Sourcing bumetanide is becoming a little problematic..the sites offering the drug without prescription look a bit shady..worried about quality control...have not dealt with any before do no idea.

    Biogaia protectis is available but actually I wanted to start with bumetanide first..and ho step wise giving around one month for each intervention so to rule out background fluctuations on my son's behaviour.

    Should I start with what is available or should I try harder for bumetanide which I am sure will not be impossible to procure.











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    1. I would start with Biogaia because you will know in one day whether he is a responder. Some people even respond on low doses.

      I do not use any B vitamins at all. Large doses of biotin seem helpful but only for a few days and then it makes things worse. For other people certain B vitamins can help a lot, you just need to try them.

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    2. Hi Peter,
      I am very much in the same situation as Kritika, wanting to start NAC with my 3 year old as well as the biogaia, and if possible, bumetanide. With the biogaia, my son is sensitve, possibly allergic to dairy, should I even attempt this one? Have never seen much improvement from probiotic but would love to see if this leads to a response, just not a bad one! Also, may I ask where are you able to get bumetanide? Do you have an rx? In the US, the internet is becoming many autism parents only method to find these drugs, often from sketchy websites indeed. Any response would be much appreciated...cannot thank you enough for all the information you have researched and provided. You are giving so parents a light in the dark, myself especially. Best to you and your family!

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    3. There are Biogaia drops for babies, five drops is the same as one tablet of Protectis. I do not see the harm in a quick trial. I get bumetanide from my local pharmacy, without rx, even though it is an rx medication. It all depends in which country you live.

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    4. Hi MKate, I asked Biogaia manufacturer about milk protein content and they claim that it is not detectable in final products. One of their product is prepared without use of milk at all. I don't have references at hand at the moment, but I think it was Biogaia Protectis drops. There is a study linked on their website which suggests that L. reuteri may be even helpful for children allergic to dairy exposed to milk products.

      My both kids are allergic to milk protein and both on Biogaia now. In my son with autism Biogaia Gastrus had clear effect on allergy/mast cell activation symptoms.

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    5. Thank you Peter and Agnieszka, that's great to hear, we will give the drops a try. Haven't done probiotics continuously since he was a baby. Even the Klaire Labs probio made him a bit zany, most likely from a dairy component. This evening he took almost a half of a PharmaNAC pomegranate tablet mixed into fruit punch, and I am keeping my fingers crossed that good things happen in the next few days.
      Peter-Not going to find anything like bumetanide OTC in the US, best bet is to get an open minded autism friendly Dr. to prescribe, and those guys are worth their weight in gold when/if you find them.

      Thanks again to you both!

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    6. Hello peter,

      Apologies for being so persistent but in your posts on nac you emphasized on the need to replenish b vit when dosing your child with nac, though it seems from your last comment, probably you do observe vit deletion in your son who has been on nac for quite a while now.

      Then, elsewhere,there were recommendations for supplementation with vit c to avoid kidney stones and with taurine when on long term nac use. What do you think..it seems I will end up giving a hundred vitamins minerals and amino acids to my son. Please give your views.

      Another issue that I wanted some understanding on was my son's negative response to cetrazine, chlorpheniramine and other common anti histamines. They seem to make him really uncomfortable and interestingly I really seem to share my biology with him so the same holds true for me (in fact I could well act as a proxy for my son while trialling drugs). So right now I manage his colds and coughs with cams and they work. But does his bad reaction to the common antihistamines throw light on his immunological profile? I have long buried my biochemistry books and selected ecology as a subject for my doctorate so it was good riddance. Honestly I wonder and really almost rever how you and other enlightened parents are taking out time to research and brainstorm to find suitable treatments for or your kids. I have my hand fulls with a child on an explorative mission.


      And right now he is going through that bright phase, as if on an oxytocin surge. Aware, really tuned in and getting over another of his fears..nasal drops. In fact he fished out the drops along with the dropper, brought it to me and gestured that he be tried..I obliged with water and then just a little bit of nasivion after which he smiled and said no.



      Delete
  8. Sorry, I meant you do not see vitamin depletion in you son so it seems.

    ReplyDelete
    Replies
    1. Kritika, in some people a lack of B12 means that the benefits of NAC are missed. A good example is an older person taking drugs to lower stomach acidity, this can lead to a lack of B12 being absorbed.

      In my son NAC appeared to stop working and a lack of B12 was a plausible cause, but it was not the problem. His allergy related flare-up in summer masked all the benefit of his drugs. Now that the allergy is 90% suppressed, NAC works just fine in the summer.

      Our daily regime is NAC, Atorvastatin, Verapamil, Bumetanide, broccoli powder, potassium, low dose clonazepam and for allergy the biogaia and azelastine nasal spray. That may sound a lot, but it is quite simple to administer, gives no side effects and works very well.

      Sometimes I add CoQ10 since the statin depletes this and sometimes cinnamon which gives a marginal cognitive benefit.

      My son eats a very wide variety of fruit and vegetables and so we do not use multivitamins.

      High dose vitamins like biotin, B12,E, K etc do not seem to have any sustained long term benefit in our case.

      Delete
    2. Hello peter,

      My concerns regarding supplementation with b vitamins while on nac were based on the likelihood of a deficiency which might aggravated as we are on a vegetarian diet although my son eats a wholesome diet ..eggs, dairy products nuts fruits and vegetables. But yes, i think one cannot be spoon fed here and I will have to take decisions on my own as and when required.

      I have already placed an order for biogaia protectis which is not yet available in india and it was not cheap by any count as 60 tabs cost me around 95 euros and this was the only denomination that is currently imported to India by Amazon.

      My child's autism seems to fit the intense world theory and i feel there is too much of neuronal firing going on or hyperexcitability characterizes his neurological processes..a head on the larger size but within the normal range which thankfully seems to have become more proportionate, that is where I thought bumetanide might play a role so will definitely get my hands on it be it through fair or foul means.

      I was also concerned about issues of immunity. Just before conception, I suffered a bad case of gasteroentitis which troubled me for such a long time that my family thought its the super bug and I kept on self medicating myself with norflox and metrogyl. Taking the risk of sounding politically incorrect, although i really wanted the baby I just felt that there is a disconnect..he is not responding to my voice songs..just a healthy independent being in my womb. I am sure sensitive mothers will feel the difference even when the child is in the womb. And as he grew and everybody admired his gregarious nature I thought how unselective he is in throwing away his affection. And when I finally brought that up with his paed..his neediness but lack of love, the brilliant young neonatal surgeon trained in usa, looked at me as if I need to see a shrink.

      In short, I am convinced his autism had developed in utero, possibly due to the prior prolonged stomach infection I had. Does this have any implications on his immunological status? Do you suggest some basic tests to be carried out? We have not been suggested any as my child is thriving well physically but I was wondering if examination of his immunological profile might give us a better insight. I do understand that probiotics like l.reuteri might have a positive modulatory effect on the immune system.

















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    3. There are lots of tests you can take, but they do not seem to help many people. The best option seems to be informed trial and error to narrow down your son's sub-type.

      If your son has an over activated immune system that might be reflected in rarely getting sick.

      There is a mouse model called Maternal Immune Activation, many substances are trialled on these models, so you could look up what works in this mouse model. Humans are not mice, but it is not a bad place to start from.

      Delete
    4. Hi,

      Just to let you know my son is a again in that improvement phase accompanied by frequent and copious amounts of urination. He is connected, running to give my husband a hug when he is back from office, giving me long sustained eye contact and staring at me lovingly at night like young neurotypical kids do. On the language front he asked me to act out a rhyme and tried to speak the words which is very difficult for him right now.

      What do you think is going on? I am having a suspicion that probably his therapy center is giving him something..are there late acting diuretics..today was a Sunday so nothing could have been given to him today and he went four times in the past hour and also drank a lot of water.

      Could it be the other way round..because he urinating so frequently due to natural reasons he has somehow flushed out toxins or chloride. Is it a plausible explanation? Really intrigued!



      Delete
  9. Hi Peter,

    As I mentioned earlier, my sons episodic increase in frequency of urination is accompanied by an increase in relatedness and cognition. It's not the whole time but say one or two hours in day once in two months and it happens usually in late evening. We have had a urine routine and microscopy done and it's clear.

    I looked up causes of polyuria and dismissed that line of inquiry as my son is happy comfortable and healthy. He has been displaying behaviours appropriate to his physiology type and sensory needs which prevent him from going over the top with autistic behaviours like meltdowns, rigidity and stereotypy. I choose to believe his body has some kind of internal wisdom that helps him acheive homeostasis specific to his constitution.

    My specific query related to this is

    1. Has there been any research comparing bumetanide with other diuretics in relationship to amelioration of autistic traits?

    2. Is there any evidence to suggest that the mechanism of bumetsnide action is indeed the one responsible for its observed benefits?

    3. Is it possible that in some subtypes of autism, a malfunctioning excretory system which is controlled by the pituitary and hypothalamus, leads to inefficient flushing out of toxins or diluted or

    4. auyistic kids are more sensitive to even small quantities of toxins or hypertension so that in these individuals a diuretic (which may include simple mild herbal formulations ) may have a supportive role aiding the excretory process

    5. Will simply increasing water consumption in some kids help alleviate some symptoms of autism ?

    Actually the last question was the one I hoped could work for my child but I know it could not be that simple.

    Please give your views


    ReplyDelete
    Replies
    1. Rather surprisingly it has been known for some time that certain diuretics help some psychiatric conditions, there is a paper I mentioned somewhere in this blog by a psychiatrist who wrote about this.

      I have some posts where I proposed that Diamox should produce a similar effect to Bumetanide, it does seem to help some people.

      If you read the posts about Ben Ari and NKCC1 you will see how he has tried to explain why bumetanide helps certain types of autism. Bumetanide also affects NKCC2 and that is why it is a diuretic. So it is coincidental that these drugs happen to be diuretics, you could make a molecule that had the autism effect without the diuresis.

      Some other diuretics will affect ion channels in the brain and so in people with ion channel/transporter dysfunctions they may stumble upon a diuretic that makes their neurological problem less severe.

      I doubt just drinking more will help, some herbal diuretics may be chance have effects on ion transporters. They might have a good effect or a bad effect.

      Delete
    2. Hello Peter,
      Actually this is what I wanted to know..whether the effect of diuretics is mediated via its role in regulating ion channels which in the case of bumetanide reverses the action of gaba from excitory to inhibitory

      Or the diuretic action of these drugs could also have a remedial influence on some individuals probably by lowering blood pressure which even at levels deemed normal for neurotypicals, disrupt functioning in a hypersensitive autistic individual.

      Thanks

      Delete
    3. Hello Peter,

      Further elaborating on my previous post about hypertension and role of diureyics, I was wondering about a common anti inflammatory and blood thinning drug..disprin. In India, till about ten years ago, we were popping it for headaches and fevers. But then we had the massive dengue episodes where the common old nsaid could be fatal and slowly disprin became a much shunned drug and paracetamol took over. Apparently disprin was also linked to gastrointestinal issues.

      I was wondering if giving just a tiny bit of disprin might have some benefits although it's risky and not prescribed for kids. I would probably not take that kind of risk but was just exploring the idea. It suited me really well and my biological profile (and sometimes I feel the mental profile as well) is quite similar to my son.

      Your opinion would be valuable


      Delete
    4. Hi Kritika,

      One of the first things when we started Bumetanide for my daughter was an increase in social engagement - giving lots of hugs, talking to family on the phone etc. Immediately after was improvement in language, all within a few days.

      Maybe there is something he eats occasionally that is causing the urination and the improvement? In our case, vegetables like asparagus and onions cause an increase, though nothing like what you describe. But then, overall, my daughter does not have much diuresis even from bumetanide. And none from Diamox.

      Oh, my daughter drinks a lot of water, but that doesn't do anything particularly noticeable.

      Delete
    5. Hi RG,
      Thanks for your inputs..I was pretty much thinking on the same lines
      Actually I am thinking on multiple lines simultaneously but I was trying to look at the diet part which is quite constant over a longer time scale..I mean we keep on rotating his diet and my son keeps on varying his permissible helpings of chocolate and savoury munchies on a day to day basis but on a monthly or bimonthly scale it's quite static. Probably I have to observe more keenly. Probably I am reading too much into it.

      Wanted to start on bumetanide but difficult to procure and wanted to start first with biogaa which I should receive in few days time. Also have arranged for nac, potassium supplement and b12 but I was interested in what gains biogaia gives us.

      Thanks and wishes for daughter.

      Delete
  10. Hi Peter,
    Quick question regarding bumetanide and forgive me if this has been referenced or discussed already--But, is it the release of extra fluid from the brain that is improving cognition, since the drug is an anti-edemic?

    ReplyDelete
    Replies
    1. Bumetanide's mechanism is quite complex but fully understood. It corrects an ion channel dysfunction common in autism that causes neurons to remain immature; this makes the key neurotransmitter GABA work in reverse. Bumetanide slows the inflow of chloride ions into the cells and after a matter of weeks the level approaches where it should be. At that point GABA becomes inhibitory rather than excitatory.

      Delete
    2. Hello Peter, Mkate,

      Peter, what is your opinion on a very important point that Mkate raised..does bumetanide decrease fluid accumulation in the brain. In fact diamox is prescribed for treating intra cranial hypertension which has implications on the functioning of the optic nerve.

      Now we all know the critical role the optic nerve plays in the development and functioning of optimum vision, problems with which has a wide range of impacts over language, movement and cognition. Regular as my son is in his daily motions, a little disturbance causes odd visual behaviours in him like looking through corner of eyes which is resolved once his stomach is clear. So we can only imagine what behaviours hypertension might be producing.


      So I come back to my question
      ..can diuretics have beneficial effects on some autism types not only through incidental regulation of ion channels (which is just s hypothesis) but also through the effects they were meant for i e.,controlling hypertension even if that induces only a little sense of physical well being by a little reduction in say the debilitating headache.

      I am curious about this because then a lot of mild OTC drugs like asprin might have some potential benefits for my son.





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    3. Kritika, most drugs have multiple effects. For example diamox also makes your blood more acidic, resulting in it being able to carry more oxygen to the brain. So in some people this effect might itself make them a responder.

      Low dose aspirin may very well help people with inflammatory sub-types of autism, just like ibuprofen does. The problem is that many people with autism have GI problems and so may be prone to side effects.

      Bumetanide is a sold as a drug to treat hypertension. It reduces the volume of fluid in your body and so reduces blood pressure. People taking it for autism need to drink extra water since they do not have excess fluid in their body.

      Delete
  11. Thanks Peter,

    That did clear up some of my confusion. In fact, diamox does seem worth a trial , specifically in light of mild visual integration problems that my son suffers from.

    Peter, right now I am having a hard time deciding upon which impairment to focus on which will direct the choice of drugs. And some problems might not be perceptible like minor allergies, indigestion but influencing issues like focus and attention apart from the big threes, cognition, language and socialization. But I guess that is where the challenge of treating autism lies.

    Regards

    ReplyDelete
    Replies
    1. Hi Kritika,

      Peter started with Bumetanide. I, after reading Peter, started with Verapamil because the top problems were seizures, allergy induced behaviors and anxiety. It was brilliant for us. My daughter now takes only half the original dose because I think the rest of the stack, especially Sytrinol and low dose clonazepam, has ameliorated the condition. The same is true for magnesium as well, we need only about 1/2 to 1/3 of what was needed before.

      The second addition was Bumetanide, our happy pill. It literally lifts the fog off, I can see it in her face.

      Identify your burning problem and pick the starting point. If your son has allergies at all, that should be where you start, since it can mask the positive effects of all the other meds/supplements.

      Delete
    2. Hello RG,

      Thanks for the helpful message. Alas, I wish I knew what my burning problem was. You know, autism and it's implications on focus, language, central coherence and theory of mind. That is my problem. If my son had any visible symptom of allergy, or gastric troubles or seizures it would have been easier although not more pleasant to address. Better the devil you know. He does not even have tantrums, rigidity or stereotypy.

      So right now my concerns center on cognition and speech..

      . improvements there would have overarching benefits on his functionality. That is why I was so interested in bumetanide. Actually the trade off between possible ill effects of long term drug use and the uncertainty and subjectivity of benefits that I am seeking especially when my child is not particularly incapacitated makes it s particularly difficult call. So my son is not really physically ill, not really intellectuslly disabled, is toilet potty trained, can write his numbers and alphabet, is very affectionate and happy and active.
      This is what makes me jittery about trying out pharmacological interventions.

      Right now sticking to my plan of trialling biogaia, nac, probably pptassium, and then look for bumetanide in that order.

      Regards






      Delete
    3. Kritika, have you seen this post:

      http://epiphanyasd.blogspot.rs/2015/12/autism-treatments-proposed-by-clinical.html

      It talks about early intervention preventing further damage.

      My daughter started out very similar to your description of your son. In autism, the wedge between our children and their nt peers keeps widening over time. Now, there is a chasm between my daughter and her nt cousins. Complications can stack up over time, Peter talks about secondary hits frequently. My daughter was an amiable girl with no behavior issues whatsoever, until November 2013. The hit was allergies, which she had not had at all until then, and it also worsened her seizures. Btw, I did not even know that it was allergies.

      Maybe Peter can help out here, he had a very nice graph about two years ago, on developmental trajectory and prognosis for Monty, and what he hoped to avert with meds and supps. You may be successful in preventing future hits and deterioration and your trajectory may be that of a narrowing gap with nts. Proactive rather than reactive.

      Sorry if I am coming off a bit strong, I don't mean to be offensive, just the thought of a wholly different life for my family if we had known then what we do now.

      Delete
    4. Hi Kritika,

      As you mentioned effects of long term drug use for autism I would like to add that Bumetanide has been used for ASD in France not only in children included into clinical trials. The longest period of safe use of Bumetanide for autism I am aware of is currently 8 years. Apparently there are no adverse events related to the long period of treatment.

      While this is personal communication I've got from a doctor involved in Bumetanide clinical trials and it has not been published in papers, I think it's good to know this when making a decision about treatment. I also think safety is very important.

      Delete
    5. Hi Angeiszka,

      Thank you so much for the information on safety of bumetanide when used over extended period of time. Yes, the drug indeed seems extremely safe and the cognition enhancing effects it seems to impart on responders may have such a wide range of impacts, not in the least those averting further deterioration.


      In fact, the second hit, which you, rg and Peter faced is most unfortunate and it's scary because it seems so frequent especially in kids who seemed to be doing well. It should not be this way.

      Angeiszka, the therapy center I go to, there is a boy around 19, a beautiful singer and though he can speak he chooses not to, sometimes communicating his feelings through a song. He has an above average IQ but torn by sensory issues. His mother is an intelligent but boisterous women and she goes on and on about food, gadgets, beauty treatments..everything except autism. One day when we were together she started talking. Her son had at the age of seven was doing so well on therapies that she thought the autism story is over and there is a mathematics prodigy in the making. Then his teacher left and the second regression came, probably aggravated by the marital conflict at home. And the boy was gone forever. His mother tells me that he has such a strong visual memory that he can just scan a page and he will remember it but can she make him into s doctor. So when other mothers are discussing their kids, she sits quietly scanning her cellphone. It's too painful.

      I will do everything to make sure this does not happen to my son..and with the support and information I am finding on this blog I am sure we should be able to control the things that are within our capacities.


      Sometimes, in the mornings when I am lovingly stroking my son and he smiles and lazily puts an arm around me..I wonder..I think you will understand. So we put the emotions aside and roll our sleeves and it's just another day.

      I really admire all of you..probably you have no idea what a precious contribution you are making..making complex information coherent and accessible to so many.

      Best wishes for your son












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    6. Thank you Kritika and I also wish you all best with improving health of your son.

      Unfortunately I can find too many familiar details in the story you quoted. These include stuttering in my son, possibly triggered by a sudden decision of the school to change his long-term 1:1 teacher in the middle of the year.
      By chance I've recently found a paper which may be relevant:
      http://www.ncbi.nlm.nih.gov/pubmed/27077366

      What they found in rats is that chronic unpredictable mild stress "induced a long-lasting increase in expression levels of cation chloride co-transporter NKCC1 in the PVN, but a transient decrease in expression levels of KCC2" (PVN=hypothalamic paraventricular nucleus)
      This paper is not about autism and rats don’t have their favourite teachers, but I imagine that it might as well be relevant to a child with autism, especially with NKCC1 overexpression. They mention Bumetanide in the paper.

      I think that psychological stress management is another topic too rarely thought about in regard to children/adults with autism especially that it probably can manifest as atypical as other health issues in ASD and have serious biological impact.

      Delete
  12. Hello RG,

    Thanks for the drilling. Yes, you have made your point and i have internalized the philosophy of perceiving autism syndrome as a cumulative outcome of numerous pathologies. And many of the the pathologies may be treatable and some measures if taken at the right time may even preempt development of new morbidities.

    I have been reading Peters past blogs again and yes, had seen the projected development trajectory of an autistic kid, on this case Monty, under ideal pharmacological support. Actually, I am almost a fan of Peter's .

    As far as narrowing the gap between asd and nt kids is concerned, we started off with a non nt kid so I think it's unfair to a parent or a child to be pressurized to chase a nt outcome. Societal pressure to conform can be extremely damaging to even nt individuals leave alone the different among us. So I delicately trudge the line between the neurotribes movement and going all out to whack autism out of our kids. I think most of us parents are like that, struggling hard to make our kids as functional as possible. We owe that to our progenies.

    Once again, thanks for helping me idenntify and assess my objective and option.

    Will keep you informed about the developments.




    ReplyDelete
  13. Hi Peter,

    It has been a good month with my son displaying lot of self regulatory behaviour and joint attention. He is trying to imitate my teeth brushing strokes, reaching the molars and learnt to make the smooching sound. I feel as his propioceptive sensory processing will improve we should see positive changes in many spheres. Yesterday he completed seven pages of dot to dot joining activities, although there were minor errors, with a 'bring them on' attitude. And today as he brought out his book, with one half of a particular page torn and hanging precariously, i waited for the little devil to rip it off as he usually does. Instead he delicately located the relevant page and arranged the errant portion neatly smoothing it out with his hands. These may be minor episodes but point to some sort of appropriate response.

    I am posting today to

    1. Get your opinion on use of spironolactone which seems to have positive effects on range of issues associated with autism although it's influence on androgens seem to be a bit worrying. In fact, diamox, spironolactone and furosemide are readily available in India and any local chemist would easily get you these drugs..if not my hypertensive parents are there. Grandfather's medical cabinet! Why did Ben-ari have to choose bumetanide!! To tell you the truth, I am not convinced about the safety profile of diamox and spironolactone. So
    2. What are your views on intermittent use of these diuretics either in combination or rotation..say twice a week. We can cover the rest of the week with a little potassium magnesium supplement which also seems to impart certain benefits and of course we will have a daily dose of antioxidant if my son responds well. Can these interventions have some beneficial effects on his sensory processing problems? Our therapist feels that the child has a high IQ and any pharmacological support addressing focus, sensory integration and cognition will have huge outcomes.

    3. It seems drinking lots of water may after all have some benefits..regulating vadopressin. In some autistic individuals vasopressin levels are elevated and lowering it's levels has resulted in improved learning, better social behaviour and reduced threat perception in rats. In fact Roche is manufacturing a vasopressin blocker for use on autistic adults. Probably you have already written about it. But for me it translates into encouraging my son to drink plenty of water.


    Still waiting for my biogaia..should arrive around 24th..seems like forever.

    Regards







    ReplyDelete
    Replies
    1. Kritika, unfortunately nothing is simple with autism. There are currently clinical trials for vasopressin underway, Roche are trying to reduce its effect while at Stanford, Hardan is trying to increase its effect. So perhaps some people are hyper, some hypo and some just fine with their natural vasopressin levels.

      Spironolactone is interesting and because it is a potassium sparing diuretic, it is often combined with bumetanide, since then you do not need to supplement potassium. In theory spironolactone could have other autism benefits, it had no effect in our case.

      For bumetanide to be effective it has to be taken continuously, otherwise the level of chloride will rise back up.

      Diamox has more than one potential benefit, but these will only be effective if you continue to take it.

      Adding Diamox to bumetanide makes some sense, but cycling between them does not.

      In our case it is very simple, bumetanide plus a potassium supplement.

      Furosemide does the good thing that bumetanide does but has another effect that will counter the good effect. So it may give a net benefit, but bumetanide is by far the best choice.

      Delete
    2. Hi Peter, out of interest could you briefly describe the counter effect of furosemide? We found it did not work for Morgan, & so I assumed no loop diuretics would be effective. However to my surprise, it appears that bumetanide (in Miccil) is starting to have a real effect. No "wow!" expressions from his teachers (who naturally have not been told about it), but quite alot of very happy expressions on their faces & positive reports about learning at the end of the day. Still experimenting to find out whether it really is the Miccil at this stage, but looking good so far. Alexandria

      Delete
    3. Alexandria, in some autism neurons remain "immature" because the level of the chloride ion is too high inside cells. In immature neurons the neurotransmitter GABA is in effect working in reverse and neurons fire too much, leading to impaired cognition and other negative effects.

      The level of chloride inside cells is determined by how much flows in through transporters (NKCC1) and out through other transporters (KCC2).

      We want less chloride to enter so we want to block NKCC1, but we could also encourage more to leave, so open KCC2.

      Bumetanide blocks NKCC1 and does not affect KCC2.

      Furosemide blocks NKCC1 (good effect) but also inhibits KCC2 (bad effect). The question is whether the net effect is good or bad. Morgan has now answered this question. Or perhaps the effect on chloride was positive but just too small to do any good.

      So it looks like Miccil (Mexican Bumetanide) is going to be a good long term choice for Morgan.

      Delete
  14. Hi Peter,
    So, as you expected Baclofen did not work for my 11 year old son with classic autism. What it did do is cause bowel problems -- he had several accidents on even the lowest dose. It was a real hit to his self esteem. He kept saying "I'm sorry" and "be happy". We weren't upset, but he felt upset. My son's doctor had mentioned Bumetanide as a drug to trial. I am going to ask him to write a script this week. Can you tell me how quickly Bumetanide shows results for people who respond? Is it a few days or does it need to build up in the system? Also, if my son doesn't respond will he need to be weaned or can you stop abruptly?
    One last question: Does it have any effect on anxiety?
    THANK YOU SO MUCH! Christine

    ReplyDelete
    Replies
    1. In my son it took 10 days to lower the chloride level in his neurons sufficiently for GABA to switch to inhibitory. The researchers say to try for two months.
      If you give him 1mg twice a day, I think he should start showing increased awareness and improved cognition within 3 weeks. If you give him 1mg once a day it may take longer.

      You can stop it abruptly, no problem. If he is a responder you will see his cognitive function gradually reducing over the next few days, back to where it was originally.

      Anxiety seems to mean different things to different people. You could make a strong case that bumetanide should help with some types of anxiety, since it is reducing excitation and random neuron firing.

      In our case the effect was him becoming "present", actually listening and therefore able to learn. In the very short term his school teacher found him all of a sudden to be "joyful".

      If your son is a responder you cannot miss the effect.

      Delete
    2. Thank you so much for your thoughtful answer! I am crossing my fingers that he is a responder.
      --Christine

      Delete
  15. Hi Peter and Angeiszka,

    In a normal healthy body, homeostasis is essential for optimum growth and development. In autism, it just seems the opposite.

    In other words, strategies that keep on challenging the system and do not let homeostasis (or probably that is an incorrect word) , rather biochemical complacence from setting in, seem to prod and push the system to inch forward. Every comorbidity in isolation does not cause autism, but if unfortunately one happens to be autistic, then each tiny blow makes one more so. Therefore part from obvioisly treating the critical and apparent pathologies like allergies, seizures and gastric upsets which require consistent medical care, what is your opinion on consciously keep varying drug regimes targeting core autistic symptoms (the meaning of which i am no longer sure of) so that feedback mechanisms do not get a chance to bring down the system to the default mode.




    ReplyDelete
    Replies
    1. Fortunately many interventions do not seem to be affected by feedback mechanisms, so there is no need to vary them. It is important to check whether an intervention really does continue to work; the only way to do this is to stop from time to time.

      A comorbidity may give the impression that the intervention has "stopped working", but it is the consequence of the comorbidity that masks/blocks the therapeutic effect. So in our case the allergy makes it seem that bumetanide, NAC etc no longer works, but removing/controlling the allergy makes everything go back to normal.

      Some interventions seem to work for a very short time before feedback loops seem to counter them. These you could uses in cycles if they work for longer than a day or two.

      Delete
    2. I agree with Peter and haven't seen significant drug efficacy decrease in my son which could be attributed to feedback loops. Detailed monitoring of tx and behaviors was useful to evaluate this - I use my own scale and daily notes but there’s much more user friendly iPad app: Autism Tracker Pro. Withdrawal trials also helped.

      In my son things considered comorbid to autism (mast cell activation, periodic channelopathy) are obviously associated with autism core symptoms and I view his condition more as multisystem disorder with interrelated biological dysfunctions - some of them treatable. As you expressed doubts regarding ‘autism core symptoms’, I have similar thoughts and basically agree with the idea presented in this paper:
      http://link.springer.com/article/10.1007/s40489-016-0085-x

      On the other hand I always wondered if there can be any way to improve the efficacy of treatments used. Nat recently sent me an interesting paper: “Brief Report: Initial Trial of Alpha7-Nicotinic Receptor Stimulation in Two Adult Patients with Autism Spectrum Disorder” about experimental drug DMXB-A.

      Among other things they found that: “Constant exposure to the drug inactivates the receptor by causing it to enter a semi-stable desensitized state. Therefore, all primary biological effects are expected in a single dose trial, and none are expected to increase with increasing drug exposure”.

      http://www.ncbi.nlm.nih.gov/pubmed/27565651

      Few months ago Peter highlighted a paper about pleiotropic NAC effects, which also discussed long term efficacy: “An enhancement in NAC effect is desirable mainly in cases of prolonged treatments, where eventual side effects and a possible decrease in response could occur. Indeed, as mentioned, a decrease in NAC plasma level has been reported during prolonged treatments”

      They suggest to enhance NAC long-term effect with melatonin or selenomethionin and to give NAC on three days a week with a break to avoid blood level decrease.
      http://www.sciencedirect.com/science/article/pii/S2211766013000182

      Intermittent NAC dosing is on my ‘to do list’, but the list is quite long.

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    3. Hello Angeiszka.

      Your comments were of great help..a little scientific backing for at least entertaining the idea of intermittent or discontinuous drug therapy. Actually treatment strategeies for biological problems presenting as autism syndrome should rapidly shift to thinking on principles behind cancer treatment. Genetic predisposition and environmental insults resulting in a unique pathology treated best by individualized treatment, taking into account the evolving and shifting nature of the disease. And as we successfully treat individuals, we might start recognizing trends and patterns as we are, for at least some cancers.

      I was reading an abstract on identification of neurogenesis centres in hitherto unidentified locations in striata related to hippocampus. Neuroplasticity, neurogenesis and treatable pathologies accompanying autism should be encouraging aspects and the option of aggressively pursuing pharmacological therapies for a newly diagnosed child should be available as easily as behavioural therapies are, widening the meaning and scope of early intervention.

      I will go through the links you have provided.

      Regards

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  16. Peter, it was allergy that masked the effect of Bumetanide on the fourth day of treatment.
    There was some sneezing which I had ignored before, but then I gave 10 mg Zyrtec for two days and the allergy went away.
    Then on the sixth day I saw clear signs that it works.
    It is the effect I was anticipating to happen and could be briefly described as better focus plus less anxiety plus more sociability.

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  17. I was reading this post on the meta-studies showing the efficacy of SSRIs: http://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-to-know/ and was reminded of this post.

    If the medical community can't figure out if SSRI's "work" it is highly unlikely we will see effective ASD "treatments" any time soon given it is a disorder of heterogeneous etiology.

    Another post on the same site that was interesting was this one on Russian "elements" in pharmopsychology: http://slatestarcodex.com/2014/08/16/an-iron-curtain-has-descended-upon-psychopharmacology/

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  18. Hi Peter,

    Do you or any of your readers know how to acquire Bumetanide in Europe without prescription? I used to rely on goldpharma, but they've stopped it. Input would be much appreciated. Also, you're spot on with furosemide being a kcc2 inhibitor, and could even be contraindicated. Hope you're readers are aware of this.

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    1. One reader did receive it from the source in her comment below:-

      https://epiphanyasd.blogspot.com/2014/10/how-to-make-sulforaphane-broccoli-at.html?showComment=1474992652337#c2756594883477271608

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    2. Hi everyone!
      So, I have some first-hand experience with Namenda (Memantine HCI) that I wanted to put forth. My son has ASD; he is high-functioning at home, but more low-functioning at school. We started him on Namenda (5mg 2x a day) on the advice of Dr. Randall Kavalier in Des Moines, and right away we noticed changes. Less stimming, more eye contact, more ability to transition, fewer outbursts. We've had to increase his dose up now, twice, because he would be better for a few days, and then the symptoms would coming back. BUT, now that we believe we've got the right does (10mb 2x a day), he is doing remarkably well. This is a child who, before the Nameand, could not accomplish any of his school work; he would refuse to do anything, run away/ hide under his desk, and generally be very disruptive in class. Homework was like pulling teeth, but with minimal other distractions, he could do it. Now on the meds for a month... his work from last week just came home, and it was ALL A's and one B on his in-school assignments. Teachers reported NO disruptions or emotional outburts, no refusing to do work; a happy, inquisitive student!! I have also witnessed his incredible growth, first hand; he has Vision Therapy once a week for 45 minutes. Before Namenda, the session would be 10% work, 90% resistance. Now, on the drug, 95% of the time, he just does what's asked of him! IT'S AMAZING.
      Dr. Kavalier has treated over 3,000 patients with Namenda, and he has a 99% success rate. I think these studies are very flawed (I can't imagine 3mg on an ASD brain doing much). I also imagine there may be a financial incentive for this Dr. Chez to be switching gears and heading towards Stem Cell therapies... perhaps there's more money in it. And nobody is going to fund an FDA trial for Namenda now, it's generic! BUT, this drug IS FDA approved (for Alzheimers), it's somewhat expensive in the US but can be found for less $ elsewhere (Canada), and IT WORKS. If you're reading this thread, and you have ASD or are raising a child with ASD, you should look into it. Seriously. NIGHT AND DAY.

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    3. Cara, thank you. I have read Dr. Chaz's book and he recommends cholinesterase inhibitors and memantine for executive function. What is your son' age? Dosage is age specific no?

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    4. Galantamine (available OTC) should work very well with Namenda for certain children with ASD

      Galantamine has worked well for us, not tried Namenda as yet.

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  19. Cara, my son is also hig functioning but he is taking sodium valproate, I would like to try memantine hcl, I can get it over the counter, how old is your son? do you give him other medication with namenda? Valentina

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  20. Hi Peter, do you know if Memantine can be combined with Valproate? I don't know if memantine enhances Valproat effect or is better not to take them together. Valentina

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  21. Peter, any thought on D-serine for autism?

    I was thinking esp in those who react badly to memantine, a a trial of D-serine supplementation might be worthwhile. Also in those kids whose 'autism' symptoms overlap or show a tendency towards schizophrenia?

    Have a look at these papers:

    Supplementation with D-serine prevents the onset of cognitive deficits in adult offspring after maternal immune activation: http://www.nature.com/articles/srep37261

    D-serine improves dimensions of the sociability deficit of the genetically-inbred Balb/c mouse strain: http://www.sciencedirect.com/science/article/pii/S0361923010002583

    D-serine is described as "a full agonist for the obligatory glycine co-agonist binding site on the NMDA receptor..."



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    1. Here is a post with quite a lot on D-serine:-

      https://epiphanyasd.blogspot.com/2015/02/autism-schizophrenia-histamine.html

      In schizophrenia a dose of 60mg/kg given orally seems to be effective, at least in one study.

      You do wonder why nobody has made a human trial in autism.

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