Saturday, 10 March 2018

A Thinking Person’s Brief Guide to Autism

I wrote this list because most people visit this blog and do not go any further into the details, either because they think this blog is nonsense, or it is just too complicated.

It certainly does sometimes get complicated, but complex subjects require detailed attention. There is little point in looking superficially.  Understanding autism science is not beyond most people’s ability, but it does take time. It will not cost you a penny. Then you can make up your own mind as what is a novel therapy and what is likely a quack therapy.

Some doctors do know best.  While your family doctor no doubt was taught autism is untreatable, some doctors who have a child with autism think differently and I do not mean MAPS/DAN doctors. Some mainstream doctors read the same research as me and successfully treat their child – an example of personalized medicine. In the ideal world they would all publish their experiences, but most keep it private.

Autism is not a biological medical diagnosis, it is just an observational diagnosis based on guidelines published in a book called the Diagnostic and Statistical Manual of Mental Disorders (DSM). These guidelines have changed substantially over time. We are currently on DSM 5; in 1987 it was DSM3 Revised. Most people diagnosed today with autism would not have been given that diagnosis under DSM 3. This is one key reason for the autism diagnosis “epidemic”, but there are other reasons.

A vast amount of scientific research already exists about autism. More is published every day and very helpful lay summaries are available for free on the internet on medical news websites and blogs like Paul Whiteley's Questioning Answers. There is also the Simon’s Foundation’s excellent website for non-scientists at

There are hundreds of different known biological causes of autism.  Scientists have already created 267 different genetic mouse models of autism and 78 types of induced autism. 192 rescue models exist, where the scientist could reverse autism in the mouse.  If you can reverse it in a mouse, perhaps you can treat it in a child? Not crazy to at least try.

Some autism/MR/ID caused by rare errors of the metabolism is treatable today, by mainstream medicine. Clinicians in Vancouver maintain a database; they focus on Mental Retardation (MR) / Intellectual Disability (ID), but many of these conditions can also be diagnosed as autism.

Science and medicine are not the same. Medicine applies drugs that are shown effective in large clinical trials on people with the same biological disorder.  This is evidence-based medicine.  Where a disorder exists with multiple causes, medicine struggles to cope. Many illnesses have multiple causes, or unknown causes, for example dementia, depression, epilepsy, multiple sclerosis etc. and even conditions outside the brain like chronic prostatitis.

Medicine has many poorly effective drugs for neurological conditions. There are drugs for dementia, ALS (motor neuron disease), Parkinson’s, Huntington’s, Schizophrenia, Bipolar etc., but they are not curative - they are better than nothing, but sometimes not by much. Drugs for autism should be seen in this perspective; generally they will be partially effective and only in specific people with the same particular biological dysfunction. Drugs for ALS, Alzheimer’s etc. currently just treat some features of the disease, they do not address the cause; some of these features are shared by others brain disorders. So using an ALS drug to treat autism or schizophrenia is not a crazy idea, if the same biological features are present.

There are numerous well-researched biological features present in some autism. Some of these same features are present in unrelated, better-researched, medical conditions where often they are treated. For example:- oxidative stress, elevated pro-inflammatory cytokines and reduced anti-inflammatory cytokines, activated microglia, disturbed growth factors (BDNF, NGF, IGF-1, VEGF etc.), numerous ion channel and transporter dysfunctions (NKCC1, KCC2, Cav1.2 etc.), NMDA hypofunction or hyperfunction, reduced estrogen and ERβ, excitatory-inhibitory imbalance, glutamate excitotoxicity, impaired autophagy, unusual myelination etc. 

Autistic brains are not just “wired up differently”. Brains are not computers and while some things are fixed as in a computer, much inside your brain is changing all time and so can potentially be modified.  You can induce even “autism” in a perfectly normal brain (with propionic acid) and then reverse it.  A slightly better analogy might be an old out-of-tune piano; tuning the strings (wires) is a complex process, but results in much improved function. Autistic brains can be tuned to improve their function and the person’s wellbeing.

Vaccines can trigger mitochondrial disease in children, which will appear as autism. This was proved by Dr Jon Poling a US neurologist trained at Johns Hopkins, who won $1.5 million in compensation for his daughter. Here interviewed on CNN:-

Vaccines caused one little girl's autism, but that does not mean they caused it in your child. How widespread this problem might be is something Dr Poling does comment on, but it is not something anybody would research.  Johns Hopkins is home to some of the best autism and mitochondrial disease researchers and clinicians. They even developed a cheap therapy to minimize the risk of possible damage from vaccinations to their young patients who already have mitochondrial disease. 

Autism does not kill you?
Vaccines save millions of lives and even Dr Poling does not suggest avoiding them. People with severe autism do have a life expectancy of less than 40 years mainly due to death from seizures, drowning and other accidents. People with the Asperger's type of milder autism have a nine times elevated risk of suicide and a disturbingly a high proportion of the tiny number of mass killers have an Asperger's/autism diagnosis (the other large group have suffered a previous head injury). So autism clearly can have troubling consequences.  Teaching anyone to shoot a gun who has a neurological disorder (autism, bipolar, schizophrenia, even ADHD, Intermittent Explosive Disorder etc), severe enough to get a medical diagnosis, is asking for trouble.

Does Autism need to be treated?
Some of the people with the newly included mild autism protest about the idea of treating autism. A significant minority of deaf people think their children born without hearing should not receive cochlear implants and so remain with them in silence, but most hearing people would likely want their child disabled by hearing loss to be treated. Medically diagnosed autism is currently based on guidelines from a book of mental disorders (DSM5). Most people probably think disorders in a psychiatrist’s manual should be treated, even if the very people with those disorders think they are just fine - they do after all have a disorder potentially clouding their judgement. If their autism is so mild and not troubling at all, then it does not warrant a medical diagnosis. You can be different without needing a medical diagnosis to support it.

Many observational diagnoses like Autism, ADHD, Bipolar and Schizophrenia are overlapping biologically
. Genetic studies have shown people can have biological elements of more than one diagnosis. So you can have autism with a little Bipolar and a touch of ADHD.  This means that some therapies trialed in Schizophrenia may show a positive effect in some autism, for example.

Clinical trials in Autism have all ultimately failed. All of the many clinical trials in autism to date have been viewed as failures and part of the reason is that there is more than one autism. There is no easy way to tell which person has which type, so trials include many people who are bound not to be responders.

People treating autism are all quacks? There undoubtedly are many people making money out of the families affected by autism and where money is involved, you will always find quack therapies of one kind or another.

Personalized medicine is one way forward. In cancer care personalized medicine is already being used, where drugs are tailored to exactly what is wrong in a specific person.  With hundreds of different variants of autism personalized medicine would be the ideal solution, but it is many decades away for most people.

Autism clusters and nexus where multiple dysfunctions converge.  The realistic way to treat autism in the 2020s will be to group people into similar clusters, not perfect matches, and treat by cluster.  This is possible because it seems that multiple different dysfunctions converge at a manageable number of so-called nexus. This means that rather than several hundred unique therapies you have just a few tens of therapies. Each person is then matched with their Polypill of a handful of those few tens of therapies.

Autism is a condition of opposites. In autism very often both extremes of the same condition exist, making the average meaningless. On a simple level the research finds many big heads, but also a fair number of tiny heads. There is very high cholesterol and very low cholesterol. There are very high levels of a particular growth factor and then some with virtually none.   So do not expect what works for someone else’s autism, to necessarily work for your child’s autism.

Many drugs have multiple modes of action. Lay people assume that drugs do just one thing, be it lower blood pressure, lower cholesterol or act as a diuretic.  This is not the case; most common drugs have multiple effects. For example many antibiotics have completely unrelated anti-inflammatory effects. A diuretic that affects one ion channel in your kidneys can also affect a related one in your brain, so yes a diuretic can treat some people’s autism, it is not crazy.

Many existing drugs can be repurposed. Many drugs already exist that can potentially be repurposed to treat neurological conditions. Big drug firms like to develop new drugs because their patents allow them to charge very high prices. Existing drugs are often now cheap generics, with well-known safety profiles, that can potentially be used off-label in personalized medicine, based on intelligent use of the vast wealth of autism research.

Off-label prescribing used to be widespread; it is when a drug is used for an application other than that for which it has been officially approved. For example, the diuretic Spironolactone is widely used off-label to treat acne in females.  Modern doctors are less willing to prescribe off-label either because they insist on strictly following the rules, or do not want to take a risk of being blamed for an adverse reaction.  Treating autism will inevitably require off-label prescribing.

Personalized therapy for the few? Hopefully the mainstream doctors who currently successfully treat their own children will persuade more of their peers to try and treat others. Until then, or until a drug like Bumetanide finally passes its stage 3 clinical trials for autism, I do not think much will change.  A small number of parents do read the research and persuade their physician to help them and others evidently self-treat. For those who are truly motivated there are options, which is what really matters.


  1. Sadly, the medical profession does not realize how easily their jobs will be replaced due to their own rigidity , whether their rigidity is driven for legal reasons or their own intellectual laziness (doctors exist to earn not learn). Amazon, JP Morgan, and Berkshire Hathaway (a holding company of many insurance companies including GEICO), are forming their own health care company for their own businesses to help keep costs down. Initially, the new health care company will merely work to get around the corruption in American health care which is costly to everyone, and especially businesses, but soon I suspect they will replace doctors with AI faster than most people realize because even the primitive AI we have now (by human intelligence standards) may not be very good at recommending solutions to complex cognitive problems like say autism, but the AI of today does excel very well at solving easily classifiable problems, i.e. the kind a doctor does in a 300 dollar 15 minute visit. Maybe once there is mass unemployment of doctors in the not too distant future and the health care bubble bursts, doctors will be more serious about treating complex conditions like autism that actually require diversity of thought because their services will no longer be needed for what they do today. Then and only then will they stop throwing their hands up in the air when they see a child with moderate to severe autism and say the only thing they are willing to do is give the parent a list of phone numbers for speech and behavioral therapists.

  2. For people interested in gut health, a new study shows that many symptoms of type 2 diabetes can be reversed, simply by adding soluble fiber from diverse sources into the diet:

    Press Release:


    With respect to autism, I see all kinds of interventions involving antibiotics and avoiding a lot of foods that some believe cause gut issues in their child, but I rarely hear of parents doing the basics with regards to gut health and that involves dietary fiber (which is very hard to get enough of through diet alone, and especially for picky eaters). If you go to the supplemental materials for this study you can find the long list of fiber sources in the gruel the researchers prepared.

    Also, this study is far from the first study that suggests that soluble fiber prevents a lot of negative health outcomes from a typical western diet high in sugar and saturated fat, but it does reinforce how a very cheap and very important, yet often neglected intervention can help the body and brain by maintaining gut integrity and promoting a healthy gut flora.

    Currently, the combination I use is to get two bags of equal weight of Bob's Red Mill Potato Starch (contains resistant starch) and Barley Flour (contains beta-glucans) and shake it up together. For whatever reason doing this solves the problem of barley flour on its own being too grainy for adding to a shake, smoothie, or even peanut butter as well as the problem of potato starch clumping together when exposed to moisture. The inulin you can mix in with this potato starch/barley flour mix or else add it in separately (inulin will clump with moisture as well so using a shaker to diffuse it in liquid is a good idea as well).

    This is what works for me and is very economical and goes a long way to keeping the kids healthy and less likely to come down with the flu or some other malady that racks up medical bills from visiting the doctor. Great for adults too for the same reasons, but for anyone having gastrointestinal issues, supplementing soluble fiber is about the best thing you can do especially from a cost/benefit ratio, especially when it comes to keeping the quantity of undesirable bacterial species low as this particular study demonstrates.

    1. In cases of SIBO or history of SIBO, inulin is the toughest on the gut. Studies show effectiveness with hydrolyzed guar gum or GOS. Best to avoid inulin initially if you suspect SIBO.

    2. Never read that before but it does make sense since different species of bacteria prefer different types of soluble fiber and too much food for the little bugs in your gut will cause them to increase their numbers significantly if not regulated by the immune system and other competing bacteria in the microflora. Personally, I have never had any of the symptoms of SIBO even after accidentally ingesting a lot more inulin than I intended (same with kids). Too much soluble fiber of any kind will make you have a lot of gas though, but from the research I have seen, even a little gas is not a bad side effect compared to the benefits of keeping the gut microflora healthy and the intestinal epithelium functioning properly. But yah overall I agree, any gut intervention that causes the runs is not working as intended and means you need to try something else.

    3. Yes, agree. My son tested positive for SIBO via hydrogen/methane breath test. it was obvious cause:effect for us: he would eat foods high in inulin, and then have horrible gut pain. Xifaxan worked gloriously the first course and then later not as effective. But back then, it was recommended to avoid prebiotics and high fiber “high residue foods” during flares. Just recently learned about the guar gum and GOS treatment being effective. He still has flare ups, and I have to make sure to give only low FODMAPs foods to get him back on track. Will be nice if the gos gets rid of it for good. Reading GOS with dark chocolate is even more effective. About to test it.

    4. Tanya,

      What is GOS? Could not find it on the net.

    5. Hi Kritika, it is galactooligosaccharide. Here is a little description from a product called Bimuno - I plan on testing this one:

      Types of prebiotics
      Prebiotics that currently fulfil all three class criteria are:

      Fructo-oligosaccharides (FOS)
      Galacto-oligosaccharides (GOS)
      Prebiotics are either 1st generation or 2nd generation. FOS, GOS (except B-GOS®) and lactulose prebiotics are classed as 1st generation. There is only one 2nd generation prebiotic; this is referred to as a B-GOS® and is commercially available under the brand name Bimuno®.

      1st generation prebiotics are selective at the genus level. In other words they are fermented at the family group level (e.g. by bifidobacteria or lactobacillus level) and produce a prebiotic effect – increasing the number and activity of the beneficial bacteria – or a bifidogenic effect – increasing the number and strength of the bifidobacteria.

      2nd generation prebiotics are tailor made to offer selectivity at species level (e.g. by Bifidobacterium bifidum) and also offer added functionality i.e. anti-adhesive or anti-pathogenic properties.

      The development of 2nd generation prebiotics resulted from research into GOS structures that could potentially offer protection of the gut from infection and inflammation. It had previously been suggested that such novel GOS structures could simulate receptor sites causing a ‘decoy’ for the pathogen (E.coli and Salmonella species) not to colonise the gut wall9.

    6. Dear Tanya,

      Thanks as always for that very useful information. I think SIBO and its relation to IBS might be very relevant to us. I have a very sensitive gi system, and a sudden drop in temp or change in climatic conditions will trigger indigestion and nausea. Every year I get atleast two major gi episodes..and I am anemic and am.positive suffer from b vitamin deficiency too. My father had similar issues and during his later years developed diverticulitis and had several episodes of fainting with vomiting and diarrhea. My son had two episodes of extreme nausea and involuntary vomiting when I was trialling all those stupid supplements and probiotics. I think probiotics given long term can be dangerous for some like my son as they can proliferate unchecked due to some other issues.

      Bimuno I have heard of, guar gum I read can be tricky as it might get stuck simetimes. How about rifaximin. It is one of the least risky antibiotic. I think I should trial it on myself and if I get a good response, add it in my potential arsenal along with amoxcillin and cefixime,for my son. By the way I do really well digestively after a short course of amoxicilln+clauvinic acid. Does GOS have any potential risks if I use it for my son?


    7. Kritika, rifaximin/rifamycin also seems to have potent non-antibiotic effects.

      Anti-inflammatory and immunomodulatory activities of rifamycin SV.

    8. From what I am reading, GOS is the gentlest one for SIBO/IBS. The guar gum in the studies is partially hydrolyzed so maybe that makes the difference?

    9. And yes - rifaximin/xifaxan was the only antibiotic I ever tried for my son that I saw obvious benefit. But the second time around, not as marked. Probably because of other things we were doing at the time that got in the way - like trying supposedly “safe” probiotics for SIBO. Who knows. It is hard to get rx for xifaxan at least in the US because it is expensive - but our insurance paid for it, so we got lucky there. Maybe it isn’t a problem to get in India though. Best wishes Kritika

    10. Tanya, Peter,

      Since infections and inflammations can trigger elevation in glutamate levels and decrease in GLT 1, and excess glutamate levels can have multiple health impacts including gut health, particularly in a glutamate sensitive infividual like my son, antibiotic's positive impact on some autism through glutamate control might not be independent of its antimicrobial effect, I was thinking. I cant be certain if its the chicken or egg that is our problem and moreover, if they are even related in our case, unless diagnostic tests completely rule out some kind of microbial imbalance. The problem is that its easy to convince a doctor to write tests in case of an acute episode; a seemingly thriving healthy autistic child only has a neurological issue and as we all know, as far as considered, the buck stops at the brain.

      One more thing Tanya, my sons belly remains slightly bloated, even though he has regular, healthy motions, mostly twice a day.

      Thanks for all the information.

    11. Tanya,

      If you happen to read this, could you send me the link to the study where it was found GOS along with dark chocolate us very effective for gi health. It seems very useful for my son as he does well on chocolates. If things turn out well, this could be an intervention worth sticking to long term. B-GOS seems to have wonderful psychological impacts, lead to good sleep and most importantly with anti pathogenic properties.
      Please do share your experience with it too.


    12. Hi Kritika, I will be sure to share.. And B-GOS has been shown help with anxiety and lower stress hormones:
      Here is the study on chocolate:

    13. Thanks Tanya,

      Yes I did read about b-gos' positive effects on anxiety, sleep, OCD, waking cortisol levels and selective preference for noticing and remembering positive experiences as compared to negative ones. What a list! And earlier doctors were prescribing a combination of GOS and MOS to get maximum gi benefits which b-gos confers as a single intervention.

      Bimuno is expensive but if it works for either or both of us, it will be great. Thanks for the chocolate study...will go through it.

      Love to Jake. Hope the Picasso in him is still going strong. Isnt that great!

    14. Actually, there is GOS in the ingredients of the most common baby milk formula in my country, so it is probably one of the more safe interventions. Interestingly enough, there is also MFGM, phospholipids, gangliosides, choline, omega-3, taurine, L-carnitine and a long list of vitamins and trace minerals too.
      Maybe baby formula is the new PolyPill? ;-)


    15. Ling, I did indeed think of suggesting baby formula to you. I will write a post about MFGM. In your case you could also add soy milk. A PolyMilk therapy.

    16. I'd love to read about the PolyMilk therapy...
      It fits perfectly into the range of some memorable crazy/brilliant themed posts on your blog. :-)

      If you consider extending the MFGM post with anything about phospholipids you might want to add an illustration like this one where sphingomyelin and phosphatidylserine (both in buttermilk) figure close to other memory enhancing supplements and acetylcholine:

      On a side note, in Glass syndrome the formation of acetylcholine seems impaired somehow (no 1 in the figure):
      "Knockdown of endogenous Satb2 (..) prevents the upregulation of choline acetyltransferase (Chat) and vesicular acetylcholine transporter (Vacht)"


  3. Peter, this blogpost was probably the most political one you have ever written... You have my vote.


    1. Ling, there is so much ill-informed nonsense written about autism and yet there is a lot of solid science just sitting there for anyone to consult and then make well-informed opinions. So I decided to have one post and fixed page/tab to encourage people to collect some facts and then reconsider their views on (not) treating autism.

  4. And let's not forget visual cues as a diagnostics tool:


  5. I'm trying a trial of bumetanide on my 11 year old son. For 1 month, he had 0.5 mg bid (no improvement). After 10 days, we had a physical done and his potassium levels were fine (even on the high side). Also, he didn't have any increase in urination. Now, we just increased the dose to 1 mg bid and he still doesn't have frequent urination. (I tried 1 mg myself several times and I urinated 4-5 times within 2 hours of taking it.) Does that mean we don't have to worry about low potassium? Or can diuresis (frequent urination) and hypokalemia happen independently? We've been giving him bananas and potatoes (one baked potato with skin has 900 mg of potassium) and also sprinkle a little bit of "low-salt" (potassium chloride) on his food. I'm worried that we might be giving him too much K now if he doesn't really need it. Our plan is to continue with 1mg bid for another 4-6 weeks...hopefully, he's a responder.

    1. Some people taking bumetanide have big problems with hypokalemia, some have none at all, while most people are in the middle. So you can have extra diuresis without any great loss of potassium. If you have no extra urination it might be that the drug is not being absorbed and metabolized sufficiently. The very similar drug furosemide loses it bioavailability when taken with food. Are you giving bumetanide with food, if so try it 30 minutes before eating.

      Adding potassium via diet, as opposed to a pill, is extremely safe, because the potassium is very slowly absorbed. There are plenty of 11 year olds in warm countries eating 3 bananas a day (2.5g of K+); what might well cause a problem is a pill with 2.5g of potassium.

      If he does not metabolize bumetanide very well, it might be that 2mg once a day will be more effective than 1mg twice a day. Only a tiny amount crosses into the brain, which is why I give my son 2mg once a day to maximize its impact.

    2. Thanks- Peter. We are giving him the pill w/ water only-we had to teach him how to swallow a pill first. (Thankfully, the bumetanide (miccil) is tiny as far as pills go.) We'll try increasing the amount of time between the pill and any food he eats.

    3. In the studies I have read, bumetanide mixed in liquid drinks will have an above 80% absorption rate, whereas the case for its cousin furosamide the absorption rate is much lower.

    4. Bumetanide is probably best taken then on an empty stomach with water only. There was a lot of press years ago that taking pills with Juice (esp. orange and grapefruit) reduces the effectiveness of medication. In a few cases, it could also enhance the effect.

    5. Actually, the studies I have read said it can be taken with food without compromising absorbability, unlike many medications. Also, you don't want to take many medications with grapefruit juice not because it reduces the effectiveness of the medication but because a particular compound in grapefruit juice inhibits an enzyme called CYP3A4 which is necessary to break down many foreign substances (including drugs) and this property could lead to an overdose of some drugs as they are not cleared from the body in the usual amount of time causing the user to buildup medication in their blood. As far as orange juice goes, there is only one type of orange that significantly inhibits CYP3A4, plus I think limes as well.

      Nevertheless, I don't have these papers on Bumetanide absorbability bookmarked so you are just going to have to take my word for it or look it up yourself.

    6. We finished our 3 month-trial of bumetanide today (1 month on 0.5 mg/bid and 2 months on 1 mg/bid). Our son (11 years old) gradually became "more present"/attentive with improved cognition- e.g., his basic arithmetic improved and he can now identify the day of the week on the calendar. It's not a dramatic improvement but still a noticeable one. However, there was no improvement with his stimming(running/jumping around) or with his obsessive thoughts/interests. Also, there were some adverse effects such as reduced appetite/weight loss and thirst (he drank a lot of water)- and he finally did start peeing more often (either due to the increased dose or because we increased the time before eating food). Also, we didn't check his potassium levels again- I don't think we can justify another physical so soon. We plan to stop now in order to determine if the improvement/adverse effects were actually due to bumetanide or were just coincidence.

      My question: how often should blood be checked for those on bumetanide (long-term), if we decide to go back on. Is simply eating potassium-rich foods and using potassium chloride salt enough? Also, do improvements continue with time or level off? Thanks, Peter for your blog. We would have never tried this on our own without it.

    7. A small proportion of people are known to lose potassium easily and so they need to monitor potassium more closely, but for most people if they add potassium through diet every day and add a supplement they seem fine. So if when you do test potassium, you find it is always in a narrow range, you will know which group you are in.

      If I did a blood draw for some reason, I would check potassium, but I do not make a blood draw just for potassium.

      If there is a lot of diuresis you have a good indication that your dosage is right. I found 2mg once a day more effective than 1mg twice a day and also less disruptive.

      I would say that bumetanide increases the rate of learning/skill acquisition. So if after 3 months you see a gain in skills, you can expect much more after 5 years.

      Bumetanide alone is not a total fix for autism, you will need other things that vary depending on the person. Cautious trial and error seems the way to go.

    8. Thanks, Peter. His IQ is only 50 so even a minor cognitive boost could improve his quality of life a lot as you say in your current post.

  6. Hi everyone,

    There was a very interesting paper released today called

    "Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition"

    The paper can be found here:

    The abstract notes the following:

    "Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations".

    Check out the stories about this paper on Medical Xpress and Daily Mail, as they shed more light on the paper:

    I just saw this so will dig deeper into it - it seems like this is relevant to those with Shank3 deficiency (haploinsufficiency). The drug used is a potent Class I HDAC inhibitor, and it looks like the intended target is HDAC2. I wonder if any natural treatments or substances we can get a hold of (Istodax, the trade name of the drug used, is likely difficult to access) that would have similar effects.

    I don't know what percentage of the ASD population this would be relevant to, but very very interesting (especially if one knows that they have a Shank3 issue)

    I'll do more research and will post anything of interest I find.

    Hope the community finds this to be of value.


    1. Hi everyone,

      Well that didn't take me long - and the result was interesting because what I came up with something that had just popped up for me in another search last week!


      So just a week or so ago, Palmatine showed up on my radar because of the following paper on P2X7 inhibition (due to Naviaux research):

      And as I was looking for an HDAC2 inhibitor I found:

      So it inhibits P2X7 and is a specific HDAC2 inhibitor.

      The following paper provides info on some common supplement sources as HDAC inhibitors, but I am very intrigued by Palmatine:

      Now time to search for the best sources of Palmatine - I believe when I was looking in the past few weeks, it was mostly via Chinese medicine.

      If anyone finds a good source of Palmatine in the meantime while I'm looking, would you kindly share?


    2. Yes there are plenty of HDAC2 inhibitors around, though the cancer drugs used are very potent and very expensive.

      Short Chain Fatty Acids fermented in the gut via the ingestion of dietary fiber are effective HDAC inhibitors, as is sodium butyrate which Peter has discussed at length in the past.

      HDAC2 is also effectively inhibited by valproate which of course has many other functional properties and side effects.

  7. Peter,
    We are giving 1 mg bumetanide to my 4 year old 13 kg grandson for 28 days. No effect so far. One year before we gave .5 mg for 32 days with had no effect. We are thinking about increasing the dose to 2 mg. Low dose clonazepam also had no effect. This gives any clues to the type of autism ha has? He is comparatively small for his age with comparatively small head.

    1. Salempeacock, I think you need to make a list of all the interventions your grandson has tried and tick which ones had a benefit. I think you found leucoverin had a benefit, for example. Then you need to note any comorbid features, details of the birth (his percentile for height weight, APGAR score etc), details of parents (age at birth, gestational diabetes, allergies, IBS/IBD etc). Is his autism stable or does it vary in severity? Try and build a comprehensive picture.

      With all this data go and talk to people like his autism doctor in the US and see how this fits in with other people being treated.

      For example some people with autism at birth are very big, but by the age of 3 they are very small for their age. This is a defining characteristic. But your grandson may have always been small, it seems to be a relevant difference.

      Is mitochondrial disease suspected? Does the child show poor exercise endurance?

      When you look at family history, comorbidities etc, I do see similarities with my son and some of the others who respond to the same therapy.

      If you treat hundreds of kids with autism, I would think the doctor should see where you Grandson might fit in.

      For example it looks like people with diagnosed mitochondrial disease do not respond to any of the same drugs as my son, other than treatments for oxidative stress. They do not respond to bumetanide/low dose clonazepam because GABAa receptors likely work just fine.

      Ideally you want to find an older child who shares many features with your grandson and see what worked for him.

    2. Also personal observations by a parent are always going to be affected by confirmation bias. One thing I do to see if it isn't just myself wearing rose colored glasses when evaluating a particular intervention is to ask teachers and therapists specifics but not let them know there is anything special going on so that they are at least blinded from the intervention. This method is far from perfect as teachers and therapists sometimes will tell you what you want to hear and not what you need to hear but I feel it is still more practical than giving IQ tests every other day. Independent cognitive testing can help give some answers as well if done routinely as we all know how much variance there can be with autism when it comes to factor that are not always easy to control such as sleep duration and a one off test won't be of much use.

  8. Hi Peter,

    We just started L-Methionine 3 days ago and we've had no negative issues, and a couple of times my daughter has said something marginally more complex than usual (which may just be due to natural improvement).

    I know you've mentioned that Johns Hopkins (I believe it was them) had used L-Methionine to improve speech, and I've looked to see what dosage they used and I can't seem to find this. I'm using .25 Teaspoons (i.e. 0.75 grams) X 2, but I don't know if I'm using an effective dose relative to what is providing results at Johns Hopkins.

    Thanks very much in advance for any info you can provide Peter!


    1. AJ, the problem is that none of the therapies used/developed by certain very smart clinicians get published. So there are just unpublished reports and personal communications. I think this should not remain secret/confidential, because kids lives are actually more important.

      The following relates to treating children with mitochondrial dysfunction, which may not be your daughter

      " For reasons that are not clear, supplemental methionine has more of an effect on language development than any of the other mitochondrial treatments we use. I usually start L-methionine at 50 mg/kg/d and then measure the plasma amino acid levels after 2 to 3 weeks and make adjustments, as needed, to keep the level of methionine (in a 4 - 5 hour fasting sample) near the upper limit of normal."

    2. Hi Peter,

      This is great info actually, because according to Dr. Goldenthal's results, my daughter's mitochondrial test results came up on the low end, and her Complex I levels were particularly low (below the control range).

      I'm going to run a Great Plains Labs Amino Acids test shortly, which will hopefully help me gauge if I need to give her more L-Methionine than I'm currently giving her.

      Thanks Peter!


    3. P.S.

      Just to also note, I already had my daughter on a mitochondrial cocktail at the time of testing, including Acetyl-L-Carnitine and R-Lipoic Acid, which surprised Dr. G because he said he would have expected her results to be better given that she was on a mito cocktail.


    4. AJ, I have done that combo before with my son and it definitely did not cause any problems, but anecdotally it did not lead to any noticeable improvements. They are both poorly assimilated in oral form so maybe that was where I erred. I still give alcar, but only because we overpurchased it a long time ago.

      Nicotanimide Riboside in my opinion is overall the best intervention for mitochondrial health in an environment where cells are constantly stressed as is the case with autism because cofactors for producing NAD+ will be exhausted which especially includes vitamin b6. There are also exotic options like MitoQ and other related compounds that are supposed to be targeted directly at the mitochondrion, rather than work indirectly but I don't think they are generally as good unless you know for certain there is a specific hiccup in the electron transport chain.

    5. Hi Tyler,

      Thanks so much for your input!

      Yes, you are right insofar as I didn't see any improvement with the ALCAR and R-Lipoic specifically, but continue to use them due to the Mito issue Dr. Goldenthal noted. I wonder if using bioperine to those two would enhance oral absorption.

      As far Niagen, I actually started using this after reading your comments a while back, and continue to use it.

      Also, I was using 50mgs/day of Ubiquinol prior to Dr. G's comment and upped it to 100mgs/day. However, I wasn't aware of the MitoQ you had mentioned, so I just read up on it and it is very interesting - Thanks so much for sharing this!

      I will very likely look at add this to my treatment protocol given the potential mito issue with my daughter. Interestingly, I saw somewhere that it gets into mitochondria 800 - 1,200 times more than standard CoQ10.

      I don't know if you've read this in my posts or not, but I'm waiting for a genetic test on my daughter which includes mitochondrial genes and hopefully we'll have a better idea of what we're dealing with (if anything shows up). Given that my daughter was on the low end of the items Dr. G tested for, and in fact low in Complex I, I'm very interested to see if the mito issues are genetic. I think it'll be another 3-4 weeks for the result.

      Thanks so much again for sharing this info Tyler, this was really helpful!


    6. Hi Peter, AJ and Tyler,
      My grandson is skinny and has no muscles. But his motor co-ordination is good and is highly energetic and is on the hyper side.
      We were giving mitospectra for more than a year but saw no specific improvement and stopped it.
      As per Dr.Goldanthal’s buccal swab test his complex I range was above normal and that excluded complex I mito disorder but he said that he didn’t understand why it is elevated. His level is 12 whereas the control range is
      3.5 - 10.5. His complex I/IV ratio is also higher than the control range.
      More or less at the same time his blood plasma test revealed the following.
      Low free carnitine 14 UMOL/L Normal 25-55
      AST (SGOT) 52 normal <40
      Lactic acid 22. Normal <19mg/dL
      Dr.Rossignol suggested it may be due to poor mito function and to start Acetyl L Carnitine and Ubiquinol along with B6. We are giving this since last October but haven’t seen any improvement. His core deficits are language comprehension and social interaction.
      What do the test results signify? We haven’t tried Nicotinamide ribocide so far. Maybe we should try it?
      Also his creatinine level is very very low. Dr.Rossignol ignores it every time we raise this issue. We are also thinking about adding creatine supplement.

    7. Peter et al,
      My grandson’s plasma Methionine level is 19. Reference range is 14-50 UMOL/L. Will Methionine supplement give improvement in language? Some parents say SAMe is more beneficial though it costs more. Anybody tried Methionine or SAMe?

    8. Salempeacock, there are a number of known creatine deficiency syndromes. They can appear as autism.

      I would think if you contacted a specialist at a large children's hospital they could investigate his creatine deficiency. Without enough creatine your brain does not work properly.

      I would not ask an autism doctor about this, but a specialist in metabolic disorders.

  9. Hello, all. My son with regressive autism has improved from sulforaphane. And from risperidona it was bad. In what direction I should think? Thank you.

    1. What product and method of administration did you use for the sulforaphane?


    2. BroccoMax

    3. Read this post on regressive autism:-

    4. Thank You, Peter. I read this post. My son has autism + ADHD. He is very energetic and athletic. From supplements of carnitine son was bad. Aggression and istence. Nothing good.

    5. Ideally you would go and see an expert, like those at Johns Hopkins and rule out mitochondrial disease. They are the ones saying that regressive autism is almost always caused by some kind of mitochondrial disorder.

      You do need to be sure what you describe as regressive autism is the same condition the Johns Hopkins people are considering. They are talking about fundamental loss of important skills like speech or toileting, from a starting point of no autism. Much autism appears to get worse between 2 and 3 years of age, but this is not what they are talking about.

      There are different types of mitochondrial disorder, the most common is caused by an insufficiency of Complex 1. This is the target of most mitochondrial therapies, but there can be problems with any of the other enzyme complexes. They all end up causing reduced ATP (energy) production.

      While it is may be possible to have organ-specific mitochondrial disease (ie just the brain), very often people with mitochondrial disease appear to have poor exercise endurance. This makes sense. Having mitochondrial disease and being hyperactive/athletic would seem strange, but strange does happen.

    6. Thank You, Peter. The regression was strong. Son lost speech, he was talking 50 words, understanding speech, game activities, eye contact, sleep, and began to frequently urinate. But he has a good physical endurance. He never tires and strong muscles.

    7. Peter, speaking of regressions, while researching lithium, I came across a case history of “shankopathies” in autism responsible for serious regressions of two adolescents with autism - which was completely reversed with lithium treatment. So it seems not just mito issues responsible for “regressions”. I had never heard of shankopathies before.

    8. I would now try bumetanide, it should take a couple of weeks to show any effect, but best to make a 4 week trial to be sure. You need to add back potassium and fluids due to the diuresis that bumetanide will cause.

  10. Hi everyone,

    Another interesting paper on ASD just came out recently. It can be found at:

    The significance statement and abstract are as follows:

    Defects in the neurogenesis of the dentate gyrus (DG) seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Our study reveals that deletion of the Liver X receptor β (LXRβ) in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and reduced neurogenesis. Behavioral analysis of LXRβ-deficient mice showed autistic-like behaviors, including social interaction deficits and repetitive behavior. These findings provide evidence that early changes in DG neurogenesis is possibly associated with the genesis of autism-related behaviors in LXRβ-deficient mice.
    The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor β (LXRβ) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRβ in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRβ-null mice. In addition, LXRβ deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRβ in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRβ-deficient mice.

    Here is the Sciencedaily article on it:


    Also, I just ran a PubMed and found more backup for LXRB involvement in ASD:

    I'm curious to see if there are any easily accessible LXRB agonists.

    I hope this is helpful!


  11. I just came across a very fascinating read that has nothing directly to do with autism, but makes your head scratch a bit as to a possible explanation for what could be going wrong in embryonic development that has nothing to do with genes (at least directly):

    In effect, researchers discovered through a variety of experiments in tadpoles that the developing brain is very important in the development of organs and tissues throughout the body and that certain neurotransmitters such as serotonin and butyrate can be amplified via "bioelectric signals" in the sense that cells communicate with each other via ion channels, just as neurons do via electrical neural communication (gap junctions).

    The most amazing thing was that they removed the brain of a tadpole very early in development and then noticed that the rest of the body developed erratically. Furthermore, they showed that restoring this "bioelectric signalling" to the rest of the tadpole cells via gene editing of a specific ion channel (after removing the tadpole brain) prevented most of the aberrant development in the tadpoles. On top of that, they in effect poisoned the tadpoles (which causes birth defects) and these morphological defects were exacerbated by not having a brain, relative to poisoning the tadpole embryos which had a brain.

    Now very interestingly, maternal inflammation upregulates peripheral serotonin in the mother which increases brain and peripheral serotonin levels in the fetus. Poor maternal diet and a lack of fiber will yield low levels of short-chain fatty acids (such as butyrate) in the blood stream, such that development could be really thrown off course if embryos are indeed very sensitive to serotonin levels as individual serotonin molecules are shuttled around from cell to cell via bioelectrical cellular signalling. This could also be why very small levels of various toxic chemicals that do not easily break down in the blood stream whether they be natural or not could have catastrophic effects on the in utero development of the baby.

    Under these very broad ideas, one could look at various autism candidate genes and conclude many of them may only have an indirect influence in development via modifications to bioelectric signaling in the earliest stages of development, whereas the conventional wisdom today would be sending many scientists down the wrong path as they would assume that strong enough correlations in GWAS studies lead to causation. Under this assumption, autism geneticists/researchers will endlessly be chasing their own tail.

    I must be clear this is pie in the sky stuff and very bleeding edge research with no concensus yet behind it, but still very thought provoking when it comes to the larger questions of what causes autism and why have researchers been able to create many models of autism in animals and even restored functioning to some of the deficits, but do not have any good explanation for what is going on in between with respect to development. Without that key knowledge, any drug development for treating autism will be limited to the "throw enough stuff at the wall until something sticks" method.

  12. About Agmatine. Peter, aren't you concerned about Agmatine connection to schizophrenia? I don't see schizophrenia mentioned in your posts about Agmatine. There is published research about it:
    "Plasma levels of agmatine in patients with schizophrenia were significantly increased (p < 0.0001) compared to those of healthy individuals... These results support the hypothesis that an excess agmatine release is important in the development of schizophrenia. The findings also imply that the plasma agmatine level may be a potential biomarker of schizophrenia."

    1. Schizophrenia shares many similarities to autism, but also in many ways is its polar opposite. With schizophrenia, there appears to be hypoconnectivity from excessive synapse pruning that is supposed to more or less stop after puberty but in schizophrenia this process keeps going, whereas in autism you have a problem of excess dendritic growth and hyperfunctional synapses.

      Schizophrenia also has an excess of kynurenic acid as well which is a far strong NMDA antagonist than agmatine which is a moderate to mild NMDA antagonist so you can't draw too many direct conclusions from this particular study unless you can demonstrate that it is the Agmatine causing the schizophrenia symptoms, rather than Agmatine being a response to other problems going on in and around neurons.

      For example, just this week I read a compelling paper on how high blood sugar may not be a cause of Type 2 diabetes, rather a response to injury from a metabolite called methylglyoxal:

      This is just one study and it alone does not mean it is right or wrong because it has not been replicated yet, but the point is you can't make biological assumptions from one paper correlating levels of something with actually being the cause of a disease, because it could instead be a compensating factor for the disease itself.

      On top of that, considering the NMDA antagonism seems to be in overdrive for schizophrenia, you would not prescribe an NMDA antagonist for schizophrenia, but in many autisms the evidence points to a different direction.

    2. As Peter said, there are many autisms. Not all of them would benefit from NMDA antagonism. For instance, SHANK3 mutations, seen in ~1% of autism patients and often used in mouse models of autism, lead to reduced NMDA function and autistic behaviors. One can theorize that the excess glutamate, which most MAPS doctors are trying to reduce, is a brain's way to counteract the SHANK3 or other mutations leading to hypofunctional NMDA receptors. As far as autism being different from schizophrenia, most mutations leading to autism are the same as those in schizophrenia. The only two medications approved by FDA for autism (Risperidone and Abilify) are actually antipsychotic medications prescribed for schizophrenia. These are the only medications that showed clinically significant efficacy on autistic patients whereas the NMDA blocker Namenda failed to gain an FDA approval because it failed: "This trial did not demonstrate clinical efficacy of memantine in autism" (

    3. In the following study, it is suggested that schizophrenia may be treated by increasing agmatine:

      "The alteration in the levels of endogenous agmatine may contribute to the genesis of psychosis and development of drugs that enhance endogenous agmatine content may be better therapeutic approach to treat schizophrenia with low incidences of extra pyramidal side effects."

      If the thousands of body builders using agmatine developed schizophrenia I think we would know about it.

      At the dose we are using I do not think we are blocking NMDARs. At a dose 20x higher things might be different.

    4. Just to add there is a quite a recent paper:-

      Altered brain arginine metabolism in schizophrenia

      "there is also a need to determine whether this change (elevated Agmatine) is a compensatory process to normalise the alterations in the NOS and arginase–polyamine pathways, given the role of agmatine in regulating the NO and polyamine production"

    5. The mentioned papers on possible use of agmatine to treat schizophrenia or on elevated agmatine being a compensatory action are odd ones. The widespread belief is that hypofunctional NMDA receptors is the cause of schizophrenia, not the effect. A simple google search with words "nmda" and "schizophrenia", will show you what the vast majority of research papers postulate. It has been shown that NMDA antagonists such as PCP and ketamine "transiently reproduce key symptoms of schizophrenia" ( We all know what chronic consumption of another NMDA inhibitor - alcohol - does to the brain (delirium, hallucinations, etc). Perhaps agmatine is not as strong as PCP, ketamine or alcohol, but a chronic weak inhibition of NMDA receptors may lead to the development of schizophrenia. You cannot neglect the fact that the elevated agmatine is the most reliable biomarker of schizophrenia. You can view it as a compensatory action and look for isolated papers to support your opinion if you want. But you will be fooling yourself.

    6. Agmatine is not the most reliable indicator of schizophrenia and nowhere in the paper you cited was it suggested that is the case, rather they showed a correlation between endogenous levels of Agmatine along with its polyamine metabolites. But that is schizophrenia and not autism. Furthermore, scientists don't deal with "widespread belief" or politics, but instead report findings until conclusive evidence is found to support a hypothesis which can be replicated and demonstrated. Unfortunately, for people with schizophrenia, researchers are no closer to a cure than is the case with autism because it is not well understood what causes schizophrenia even though there are many hypotheses backed up by different research, including the NMDA hypofunction hypothesis which is one of the oldest ones.

      In addition, alcohol does many things to all cells of the body and brain besides what you state as it is poisonous, especially to the brain via mechanisms that have little to nothing to do with its inhibitory functions even though NMDA antagonism with alcohol is thought to play a part in its addictive properties, as well as seizure induced NMDA hyperexcitability withdrawal symptoms after acute alcohol poisoning.

      On top of that, there are no animal models that show agmatine administration at non-ridiculous levels causes schizophrenia, rather several researchers already have investigated the matter by self-dosing themselves at much higher levels of Agmatine than has been suggested here over a period of years and had no measurable long-term effects from doing so. If they felt their lives were in danger or that they would be losing their minds, they would have never pursue such folly. Then there are those who use Agmatine for athletic reasons, and I have yet to read about anyone losing their minds from doing so as well.

      Most importantly, there is no need to use absolutist language to make your point as imperative commands such as "you cannot neglect the fact that" when what you say is not even an actual fact according to the very paper you cited, only undermines your initial concerns about people treading carefully with Agmatine or any substance they would give themselves or their children.

      I assume most people who read Peter's blog are only looking for honest discussion about ways to help their children, rather than the kind of self-defeating political discussions you commonly find among the "autism community", so if you want to comment further on this I will just let you have the last word as I have probably said too much already.

  13. Dear Peter,

    The reason I read your posts is that they promote critical thinking amongst parents by giving us scientifically based biomedical treatment options for all our children. Your new addition, Agmatine to the poly pill is a perfect example of a treatment choice.

    I also believe you are trying to facilitate real change for people with ASD, through scientific research.

    Dear, Mr Bill Gates could you please help us, it’s time. Contact Peter at this space.

    In Australia, Paediatricians can prescribe off label and they do but not for autism. No amount of imploring them to look at research will avail. They do not even try to make eye contact, let alone communicate with us or our children. Their job is to give the ASD diagnosis for the health system gravy train and prescribe behavioural modification medications.

    The ASD community needs doctors, I agree, unfortunately doctors only value other doctors opinions. Inflammatory, I know but I am from the colonies and enjoy eating lots of bananas because it is warm and beautiful where I live.

    For real change to happen, doctors must allow themselves to take on an integrated role with other therapists in the early stages of a child’s ASD Intervention. This should be taught at medical school and would improve the lives of their patients with ASD drastically.

    If my Daughter had a clef palate, asthma or a congenital heart defect, there would have been a collaborative, medically vested interest, in “fixing’ or addressing these issues early in her life.

    Instead, we shamefully hide little children with ASD away. Their sensory issues may be so complex that relationships are destroyed and one parent is left struggling, often with other children.

    How do I know this? I see it every day.

    Parents from all socioeconomic and cultural backgrounds, are looking for answers. Often it is those scary Dr Dan protocols of removing heavy metals and restrictive diets that they try. Because they are looking for guidance from doctors.

    There are desperate parents who are dose adjusting, dangerous medications for their children because their doctors will not help them. For parents with older children this is happening more and more. One friend, is so frightened that her son, with ASD, will end up in gaol that she increases his Ritalin dosage.

    These parents and their children’s lives matter but they are unsupported, patronised, clinically depressed and isolated. Most are well educated and can no longer work in their professions. They care 24/7 for their children and worry about the future.

    I do not care about the chicken and the egg scenario, between doctors and research scientists. I just want all children with ASD to be helped not hidden.

    How did the wonderful, Stephen Hawkings, live, research and enjoy his beautiful children for so long past medical expectations, off prescription, I dare suggest.


    1. Liz, you are right that doctors value each others opinions. I also value doctors' opinions, that is why I am glad that all the drug therapies in the PolyPill (even low dose clonazepam) are used by mainstream doctors treating their own children.

      Many people reading my blog think 0.03mg of clonazepam is dangerous/reckless, but fortunately mainstream doctors can see that this dose is trivial; one has used it for 2+ years already as a core therapy.

  14. Thanks Kritika ! Warm weather is here so that will be tempting little Picasso away from the canvas ha. I am so happy with his improved penmanship too. For my son, I think it’s all about the lithium. A wonder mineral

  15. Hello Peter. We have done a lot of treating our 5 year old and we believe that following your recommendations is the next part of our journey. We have so far gotten from nonverbal to verbal, from simple one word requests to simple one or two words sharing and commenting, a lot of sensory and social advancement too. My husband is coming to the Uk in May and we would like to be able to meet with you and have a productive talk where you can point us in the right direction. My email is, and we would love to hear from you. We already have a number od blood tests done, but we can do any you advise us to do so that yiu can give us quality pointers what to try.

  16. Where is it possible to get bumetanide without a prescription?

    1. People living in Latin countries (eg Mexico and Spain) just buy it in their local pharmacy without a prescription. Most North Americans seem to be buying from online pharmacies based in Mexico.


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