Wednesday, 30 August 2017

Acid-sensing Ion Channels (ASICs) and Autism – Acid in the Brain

Acid sensing ion channels (ASICs) are another emerging area of science where much remains known.  It would seem that ASICs have evolved for a good reason, when pH levels fall they trigger a reaction to compensate.  (The lower the pH the higher is the acidity)  In some cases, like seizures, this seems to work, but in other cases the reaction produced actually makes a bad situation worse.

Research is ongoing to find inhibitors of ASICs to treat specific conditions raging from MS (Multiple Sclerosis), Parkinson’s and Huntington’s to depression and anxiety. Perhaps autism should be added to the list.
NSAIDs like ibuprofen are inhibitors of ASICs.
The complicated-looking chart below explains the mechanism.  The ASIC is on the left, also present is a voltage-gated calcium channel (VGCC) and an NMDA receptor. We already know that VGCCs can play a key role in autism and mast cell degranulation. Similarly we know that in autism there is very often either too much or too little NMDA signaling. Here we have all three together.

The role of ASICs is to sense reduced levels of extracellular pH (i.e. acidity outside the cell) and result in a response from the neuron. Under increased acidic conditions, a proton (H+) binds to the channel in the extracellular region, activating the ion channel and opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions.

All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization.

Voltage-gated Ca2+ channels are then activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released.

NMDA receptors are also activated and this results in more influx of calcium into the cell.

This calcium inflow then triggers further reactions via CaMKII (calmodulin-dependent protein kinase II).

The overall effect is likely to damage the cell.

There is also an important effect on dendritic spines:-

“ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca2+]i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures”

In general the research is looking to inhibit ASICs to improve a variety of neurological conditions.

Acid in the Brain

ASICs only become activated when there is acidity (low pH).  When the pH is more than 6.9 they do nothing at all.
Unfortunately, in many neurological disorders pH is found to be abnormally low and that includes autism.
ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca2+permeability and an inward flow of Ca2+. ASIC1a channels additionally facilitate the activation of voltage-gated Ca2+ channels and NMDA receptor channels upon initial depolarization, contributing to the major increase in intracellular calcium that results in cell death.
However in the case of epilepsy, ASIC1a channels can be helpful.  Seizures cause increased, uncontrolled neuronal activity in the brain that releases large quantities of acidic vesicles. ASIC1a channels open in response and have shown to protect against seizures by reducing their progression. Studies researching this phenomenon have found that deleting the ASIC1a gene resulted in amplified seizure activity. 

Changes in the brain pH level have been considered an artifact, therefore substantial effort has been made to match the tissue pH among study participants and to control the effect of pH on molecular changes in the postmortem brain. However, given that decreased brain pH is a pathophysiological trait of psychiatric disorders, these efforts could have unwittingly obscured the specific pathophysiological signatures that are potentially associated with changes in pH, such as neuronal hyper-excitation and inflammation, both of which have been implicated in the etiology of psychiatric disorders. Therefore, the present study highlighting that decreased brain pH is a shared endophenotype of psychiatric disorders has significant implications on the entire field of studies on the pathophysiology of mental disorders.

This research raises new questions about changes in brain pH. For example, what are the mechanisms through which lactate is increased and pH is decreased? Are specific brain regions responsible for the decrease in pH? Is there functional significance to the decrease in brain pH observed in psychiatric disorders, and if so, is it a cause or result of the onset of the disorder?. Further studies are needed to address these issues.

The following paper is mainly by Japanese researchers and is very thorough; it will likely make you consider brain acidosis as almost inevitable in your case of autism. 

Lower pH is a well-replicated finding in the post-mortem brains of patients with schizophrenia and bipolar disorder. Interpretation of the data, however, is controversial as to whether this finding  reflects a primary feature of the diseases or is a result of confounding factors such as medication, post-mortem interval, and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models, which can be studied without confounds inherent in human studies.  In the present study, we first confirmed that the brains of patients with schizophrenia and bipolar  disorder exhibit lower pH values by conducting a meta-analysis of existing datasets. We then  utilized neurodevelopmental mouse models of psychiatric disorders in order to test the hypothesis  that lower brain pH exists in these brains compared to controls due to the underlying pathophysiology of the disorders. We measured pH, lactate levels, and related metabolite levels in brain homogenates from three mouse models of schizophrenia (Schnurri-2 KO, forebrain-specific  calcineurin KO, and neurogranin KO mice) and one of bipolar disorder (Camk2a HKO mice), and  one of autism spectrum disorders (Chd8 HKO mice). All mice were drug-naïve with the same post-mortem interval and agonal state at death. Upon post-mortem examination, we observed  significantly lower pH and higher lactate levels in the brains of model mice relative to controls. There was a significant negative correlation between pH and lactate levels. These results suggest that lower pH associated with increased lactate levels is a pathophysiology of such diseases rather than mere artefacts.
A number of postmortem studies have indicated that pH is lower in the brains of patients with schizophrenia and bipolar disorder. Lower brain pH has also been observed in patients with ASD. In general, pH balance is considered critical for maintaining optimal health, and low pH has been associated with a number of somatic disorders. Therefore, it is reasonable to assume that lower pH may exert a negative impact on brain function and play a key role in the pathogenesis of various psychiatric disorders.            

Researches have revealed that brain acidosis influences a number of brain functions, such as anxiety, mood, and cognition. Acidosis may affect the structure and function of several types of brain cells, including the electrophysiological functioning of GABAergic  neurons and morphological properties of oligodendrocytes. Alterations in these types of cells have been well-documented in the brains of patients with schizophrenia, bipolar disorder, and ASD and may underlie some of the cognitive deficits associated with these disorders. Deficits in GABAergic neurons and oligodendrocytes have been identified in the mouse models of the disorders, including Shn2 KO mice. Brain acidosis may therefore be associated with deficits in such cell types in schizophrenia, bipolar disorder, and ASD.

Interestingly, we observed that Wnt- and EGF-related pathways, which are highly implicated in somatic and brain cancers, are enriched in the genes whose expressions were altered among the  five mutant mouse strains.

These findings raise the possibility that elevated glycolysis underlies the increased lactate and pyruvate levels in the brains of the mouse models of schizophrenia, bipolar disorder, and ASD.

Dysregulation of the excitation-inhibition balance has been proposed as a candidate cause of schizophrenia, bipolar disorder, and ASD. A shift in the balance towards excitation would result in increased energy expenditure and may lead to increased glycolysis.

University of Iowa neuroscientist John Wemmie is interested in the effect of acid in the brain (not that kind of acid!). His studies suggest that increased acidity—or low pH—in the brain is linked to panic disorders, anxiety, and depression. But his work also indicates that changes in acidity are important for normal brain activity too.

“We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, associate professor of psychiatry in the UI Carver College of Medicine. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”

Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.
“Brain activity is likely different in people with brain disorders such as bipolar or depression, and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day: Could this signal be abnormal or perturbed in human psychiatric disease? And if so, might it be a target for manipulation and treatment?”

Panic attacks as a problem of pH

An easy to read article from the Scientific American

Dendritic Spines and ASICS

The present results and previous studies suggest that ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca2+]i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures (Xiong et al., 2004; Yermolaieva et al., 2004; Gao et al., 2005; Friese et al., 2007; Ziemann et al., 2008). Interestingly, one previous report suggested increased ASIC2a expression in neurons surviving ischemia, although the functional consequence of those changes are uncertain (Johnson et al., 2001). Moreover, recent studies suggest genetic associations between the ASIC2 locus and multiple sclerosis, autism and mental retardation (Bernardinelli et al., 2007; Girirajan et al., 2007; Stone et al., 2007). Thus, we speculate that ASIC1a and ASIC2, working in concert, may regulate neuronal function in a variety of disease states  

ASICs in neurologic disorders

Role of ASICs
Parkinson’s disease
Lactic acidosis occurs in the brains of patients with PD.
Amiloride helps protect against substantia nigra neuronal degeneration, inhibiting apoptosis.
Parkin gene mutations result in abnormal ASIC currents.
Huntington’s disease
ASIC1 inhibition enhances ubiquitin-proteasome system activity and reduces huntingtin-polyglutamine accumulation.
ASIC3 is involved in: 1) primary afferent gastrointestinal visceral pain, 2) chemical nociception of the upper gastrointestinal system, and 3) mechanical nociception of the colon.
Blocking neuronal ASIC1a expression in dorsal root ganglia may confer analgesia.
NSAIDs inhibit sensory neuronal ASIC expression.
Cerebral ischemia
Neuronal ASIC2 expression in the hypothalamus is upregulated after ischemia.
Blockade of ASIC1a exerts a neuroprotective effect in a middle cerebral artery occlusion model.
Most dural afferent nerves express ASICs.
Multiple sclerosis
ASIC1a is upregulated in oligodendrocytes and in axons of an acute autoimmune encephalomyelitis mouse model, as well as in brain tissue from patients with multiple sclerosis.
Blockade of ASIC1a may attenuate myelin and neuronal damage in multiple sclerosis.
Intraventricular injection of PcTX-1 increases the frequency of tonic-clonic seizures.
Low-pH stimulation increases ASIC1a inhibitory neuronal currents.
Malignant glioma
ASIC1a is widely expressed in malignant glial cells.
PcTx1 or ASIC1a knock-down inhibits cell migration and cell-cycle progression in gliomas.
Amiloride analogue benzamil also produces cell-cycle arrest in glioblastoma.

One logical question is whether the brain ASIC connection with autism connects to the common  gastrointestinal problems, some of which relate to acidity and are often treated with H2 antihistamines and proton pump inhibitors (PPIs).

Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders.

It looks like it is still early days in the research into ASICs and GI problems. Best look again in decade or two.  

Too Much Lactic Acid – Lactic Acidosis 
One theory is that panic attacks are cause by too much lactic acid.
In earlier posts of mitochondrial disease and OXPHOS, we saw that when the mitochondria have too little oxygen they can continue to produce ATP, but lactate accumulates and this leads to lactic acidosis.
So people with mitochondrial disease might have some degree of lactic acidosis that would reduce extracellular pH and activate ASICs.
So perhaps along with those prone to panic attacks, people with regressive autism and high lactate might benefit from an ASIC inhibitor?
Aerobic exercise is suggested to reduce excess lactate, although extreme exercise like running a marathon will actually make more.  Moderate exercise has the added advantage of stimulating the production of more mitochondria.
So moderate exercise for panic disorders and regressive autism (mitochondrial disease).   Moderate exercise is then an indirect ASIC inhibitor, because it should increase pH (less acidic). 

ASICs in panic and anxiety?

Acid sensing ion channels (ASICs) generate H+-gated Na+ currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1−/− mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO2 inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Recent genome-wide studies have associated SNPs near ASIC2 with autism (Stone et al., 2007), panic disorder (Gregersen et al., 2012), response to lithium treatment in bipolar disorder (Squassina et al., 2011) and citalopram treatment in depressive disorder (Hunter et al., 2013), and have implicated a copy number variant of ASIC2 with dyslexia (Veerappa et al., 2013). However, little is currently understood about whether ASIC2 is required for normal behavior.

The goals of this study were to better understand the role of ASIC2 in brain function. Thus our first aim was to localize ASIC2 subunits. Because ASIC2 subunits multimerize with ASIC1 subunits, we hypothesized that the distribution of the two subunits would show substantial overlap. In addition, given that ASIC channels in central neurons missing ASIC2 have altered trafficking and biophysical properties, we hypothesized that disrupting expression of ASIC2 would impact behavior. Therefore, we asked if mice missing ASIC2 would have altered behavioral phenotypes, and whether disrupting both ASIC1 and ASIC2 would have the same or greater behavioral effects than disrupting either gene alone. Because we found that ASIC2, like ASIC1, was highly expressed in brain regions that coordinate responses to threatening events, we focused on tests that evaluate defensive behaviors and reactions to stressful and aversive stimuli.
These results suggest that ASIC channels can influence synaptic transmission. We speculate that pH falls to the greatest extent with intense synaptic activity; the mechanism might involve release of the acidic contents of synaptic vesicles, transport of HCO3 or H+ across neuronal or glial cell membranes, and/or metabolism. The reduced pH could activate ASIC channels leading to an increased [Ca2+]i (Xiong et al., 2004; Yermolaieva et al., 2004; Zha et al., 2006). In this scenario, the main function of ASIC channels would be to enhance synaptic transmission in response to intense activity. This would explain the pattern of abnormal behavior in ASIC null mice when the stimulus is very aversive.

Translating ASIC research into therapy
As you may have noticed in the first chart in this post, there already exist ways to inhibit ASICs, ranging from a diuretic called Amiloride to NSAIDs, like ibuprofen.  The process of translating science into medicine has already begun in multiple sclerosis, as you can see in the following study:-

Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis. 

Agmatine and Spermine
In the graphic at the start of this post you might have noticed Agmatine and Spermine.  While ASICs are acid sensing and so activated by protons, they appear to be also activated by other substances.
The arginine metabolite agmatine may be an endogenous non-proton ligand for ASIC3 channels.
Extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction.
However, other research shows spermine promotes autophagy and has been shown to ameliorate ischemia/reperfusion injury  (IRI) and suggests its use in children to prevent IRI .  
So nothing is clear cut.
It looks like spermine, spermidine and agmatine all promote autophagy.            
Agmatine gets converted to a polyamine called putrescene.

Personally, I expect polyamines will generally be found beneficial in autism, but there will always be exceptions.  

There is a case to be made for the use of the diuretic amiloride to treat MS and indeed panic disorders.
Will amiloride help autism? You would not want to use it if there is comorbid epilepsy, since ASICs are “seizure protective”. 
If your genetic testing showed an anomaly with the ASIC2 gene, which is known to occur in both autism and MR/ID, then amiloride would seem a logical therapy.
I think we should not be surprised if people with neurological conditions have lower pH brains than NT people, just like we should expect them to show signs of oxidative stress.
If you do indeed happen to have a rather acidic brain, as seems to be quite often the case, damping down the response from ASICs might make things better or worse, or in indeed a mixture of the two. You would hope, at least in some people, that ASICs provide some beneficial response on sensing low pH.
It would be useful if a researcher did a trial of amiloride in different types of autism, then we might have some useful data. You would think the Japanese researchers would be the ones to do this.
One good thing about amiloride is that it increases the level of potassium in your blood and there even is a combined bumetanide/amiloride pill.  Bumetanide has the side effect of lowering potassium.
Many people with autism find NSAIDs beneficial, either long term or for flare-ups. NSAIDs have many beneficial effects; just how important is ASIC inhibition is an open question.
Is the anxiety that many people with autism seem to suffer, sometimes related to ASICs?  Perhaps it is just a minor panic disorder and it relates to ASIC1 and ASIC2.  I think there are numerous different dysfunctions that produce what we might term “anxiety”, among the long list one day you may well find ASICs.
Science has a long way to go before there is a complete understanding of this subject.
Moderate exercise again appears as a simple therapy with countless biological benefits, in this case reducing lactate and thus reducing acidity (increasing pH).


  1. The problems with NSAID's is that they also inhibit cox-2, having too little cox-2 is just as bad as having too much with regards to emotional problems.

    Too little cox-2 will decrease prostaglandins (not all prostaglandins are bad, in fact some are anti-inflammatory - see the study of arachidonic acid being used against social isolation in ASD).

    Too much cox-2 is very obviously bad though, inflammation will be over the top.

    As with everything, balance is key.

    A good way to test how someone response to changes in blood lactic acid/lactate would be to give someone a decent amount of sodium bicarbonate.
    Sodium bicarbonate for example is able to decrease blood acidity and decrease endorphins in response to exercise.

    Personally I have found out through the years I respond horrible to intense exercise (suspect serotonin/lactate/creatine kinase induced fatigue, that lasts atleast 3 full days after exercising).

    Cardio at a low to medium pace however I find very beneficial (2 times a week).

    Pretty much all my blood tests show elevated LDH and CK.

  2. I discussed in depth a long time ago on this blog about polyamines, and in particular spermidine. The four main polyamines are putrescine, spermidine, spermine, and cadaverine. Their names owe to the context in which they were discovered not which cells they are in as they are integral to all cells.

    From my recollection supplemental spermine and putrescine reduce autophagy while spermidine enhances autophagy as well as helps reduce gene expression by keeping heterochromatin packed tightly which reduces aberrant gene expression and limits the activity of transposons which are now thought to be one of the major drivers of the aging process.

    Putrescine, spermidine, and spermine all are interchangeable with the right enzymes while cadaverine is kind of a different topic as its concentration is highest in dead cells.

    High natural sources of putrescine can be found in grapefruit juice and orange juice. Spermidine is highest in its most practical form in uncooked wheat germ. To get a dose of spermidine to significantly raise spermidine levels in the body requires at least a cup of wheat germ a day for an average sized man when basing measurements done on other animals. Young people have higher levels of spermidine while older people have lower levels.

    Last but not least some cancers will cleave spermidine from neighboring cells since they seem unable to make their own, though higher than normal levels of spermidine are associated with decreased rates of cancer and enhanced longevity, at least in mice and rats so far.

    1. Could also take citrulline/ornithine to raise polyamines, they also help detoxify ammonia, but they bring problems of their own: raised urea levels in blood tests.

      Citrulline and ornithine helps me alot, especially citrulline, but I have high urea levels at baseline so I try to minimize my use.

  3. Hi everyone,

    Absolutely fascinating new paper on the connection between ASD and mitochondrial dysfunction:

    There seem to be so many clues to this giant puzzle, and with so many relevant papers and new tools in the world of biology, hopefully it won't take long for treatments that are really impactful for our kids.

    If you have any insights on the paper linked above, please share.

    Have a great night!


  4. Off blogpost topic, but nevertheless on topic.

    I just learned that there is a condition called "Auditory processing disorder" in children. (mentioned here:

    First, this made me happy because it sounded like a real diagnose that would fit my daughter and probably many other children with ASD with receptive language issues. Deconstructing "autism" into a range of several other diagnoses would be a nice divide-and-conquer strategy. Maybe someone already had put together the facts on ion channels and cochlea dysfunctions and I actually could show it to our doctor? So I read on:

    "APD is not the result of higher-order, more global deficit such as autism"
    So having autism, you can't have this disorder. Period. I suppose it is clinically impossible.
    "APD cannot be diagnosed from a symptoms checklist (..) A multidisciplinary team approach is critical (..) none of the test tools used by these professionals are diagnostic tools for APD."
    So, a disease without common symptoms. And a lot of people involved in diagnosing, almost none of them competent for the assignment.
    "There are many types of auditory processing deficits (..) because each child is an individual"
    Ah, so this is actually not one disease but thousands?

    And so on. As expected, there were no existing medical interventions, just a lot of proposed therapy time:
    "Children with APD can learn to become active participants in their own listening, learning, and communication success rather than hapless (and helpless) victims."

    Yes, I got a bit angry reading this for several obvious reasons. How is it possible to call something like this a disease or diagnose at all? What authority or scientifical data do you really need to create a new diagnose and get it in the standard manual?

    This got me thinking.

    What would happen if, say, a leading autism expert/blogger with the help of some committed researchers/parents published a series of newly found diagnoses: "Comorbid with, but not to be confused with autism". Complete descriptions with disease name, symptoms, ethiology, genetic associations and treatments.

    “Montys hypokalemic sensory overload syndrome” anyone? Then just print out the PDF and bring it to your local pediatrician.


    1. Ling, on the one hand there are forgotten pieces of science, like hypokalemic sensory overload, that are sitting there waiting to be applied, but on the other hand many features of autism are far beyond the scope of today's science.

      When you do not understand the science, like speech therapists, all you can have is therapy. In some cases therapy can be highly beneficial.

      Observational diagnoses are always of limited value, with arbitrary exclusions. Kanner thought you could not have autism, if you had epilepsy.

      Here is a more scientific review of auditory processing and autism, but it does not have any practical answers for you.

      Auditory Processing in Autism Spectrum Disorder: A Review of the Literature

      Pediatricians usually see their job as applying generally endorsed medicine, which in some countries is prescribed in great detail, as in the UK by NICE. Going beyond these guidelines is generally not approved of, and so off-label prescribing is often unavailable.

      A small number of doctors, like AJs new doctor, are open to experimental therapies, but quite often just to "their" experimental therapies.

      It would help if more clinicians published case histories about specific autism interventions. That is a very realistic expectation.

      Personally, I do not expect to change the world of autism, but I am content that at least in one tiny part of the internet there is a logical process underway of trying to translate science into therapy and try and explain why some stumbled-upon therapies might actually be effective.

    2. Your blog is a lot about sharing new insights from science and finding practical ways to apply these in vivo. The ultimate goal is, if I guess it right, to help other people suffering from ASD in one way or another. Many of us readers would be in a much darker situation if it wasn't for you Peter, and indeed Monty. Even though I am only at the beginning of this journey, I feel tremendously thankful for what I have learnt. There is no way I'll ever be able to pay it back, other than eventually passing on the knowledge to those in need.

      As a working mother to two small children, I have very little spare time left. I have struggled to work my way through the PolyPill blog, reading medical reports on neurological issues late evenings or on the tube. Since this new hobby is nothing I am used to do, it has taken some time. My estimate is that I will finish within 6 months. After that, I'll probably need to re-read most parts; there is just too much good information in here.
      Unfortunately I know many other ASD parents in greater need than me, who would not be able accomplish this. Not because of commitment issues, but because they have their hands full.

      Would it be possible to simplify the science even more, in some handy format for them? Absolutely.

      But then again, it is not enough to be educated yourself. Your doctor or pediatrician has to be motivated too. I really believe that most doctors truly want to help people, but throwing the autism diagnose at them will make many shy away. Treating autism is just too big, too hard. It is like asking someone to cure cancer without telling which cancer it is. You have to be an expert on neurology, metabolism, allergies, immunology, genetics and blood at the same time to know where to start.
      Getting someone to prescribe verapamil for autism is just not going to happen. But for calcium ion channel dysfunction? More probable.

      Case studies are one good way to get things going in the right direction. They are directed at researchers and the medical industry.
      But there also need to be available "tools" for patients and their doctors. Defining diagnoses that make up parts of autism is just one idea. Maybe it is naive, but putting a name on things used to be very powerful.

      I haven't found anyone yet who was that found of autism as a concept. So why not divide it until it isn't needed anymore? There is a graveyard for old diagnoses, I'm sure there is a vacant place close to "hysteria" and "wandering womb" that would fit.


    3. Ling,

      You put your thoughts out very eloquently and I agree with you to a large extent. Doctors do want to help but an autism diagnosis is too vague a medical terminology. Both my sons regular paediatrician and paediatric neurologist do not use that unhelpful term when addressing issues.

      Yes, it would be great if we could devide autism into narrower and narrower 'medical types'....however absence of 'explicit medical issues' in many autisms, unlike cancer, where encountering a health concern, say, a lump or a cough or weight loss or persistent fever or digestive issues that gets you started on the process leading to a diagnosis, would make it that much more difficult. Also, autism is usually multifactorial.

      A detailed review and compilation of exhisting research, supported by individual case studies which hopefully can throw light on at least some of the linkages between symptoms and possible medical causes, howsoever crude....a decision tree of sorts, will allow a parent or a doctor to make a start. Exhisting compilations I feel are too vague and generalized in their approach. I hope someone like Peter, can pretty soon come up with some kind of guide/manual, well researched and replete with case studies which might arm a parent and a willing doctor with the basic aresenal, even a sling counts, as they go about trying to defeat this Goliath. It might just result in a shift in discourse and help give a dignified burial to 'autism', its soul resting peacefully alongside 'hysteria' and 'wandering womb'. Peter, too many expectations from to lighten up heres Ogden Nash for you

      If wishes were horses, beggars would ride

      If turnips were watches, I'd were one by my side. And

      If Peter slogs hard, he can really come up with an autism medical guide.

    4. Ling, dividing autism into sub-types is the only way to go. The US medical profession however is going in the other direction with everything as "autism", in their DSM book.

      I think Asperger's is a really good term, it tells you a great deal about the type of autism, but in the US they have got rid of it. So now you have some people (with Asperger's) saying that autism is not a disability, but a great asset.

  5. Peter and all, off topic for this post but just wanted to mention to you - re: my question on a thread several weeks ago about excessive thirst (and excessive urination resulting) - you mentioned this as a common behavior for those with dev. delay, polydipsia - just now learning this can be a sign of fatty acid deficiency. Makes sense as this is common for those with autism and adhd.

    1. Tanya, yes it looks like lack of omega-3 can indeed cause polydipsia. It can also contribute to other behavioural issues. Omega-3 is good for you, as to how many people are deficient we do not know.

      Clinical trials of omega-3 in autism are not convincing, but that does not mean that a minority do not benefit. Trials are not going to pick up when there are 15% responders, it gets lost in inevitable weaknesses of the trial process.

    2. I think with autism, things tried once before with seemingly no benefit are worth another chance. Even the simple "autism 101" supplements. When my son was first diagnosed, we tried the cod liver oil protocol, and another time just fish oils but I couldn't see any difference then. Why does it fail? Maybe there weren't co-factors in place or sufficient antioxidants? Or not the right amount of EPA and DHA.
      Ling, if you see this: I read your comments on Ponstan and the asthma side effects (my son also had asthma) - have you tried and a complete omega fish oil? It might cover all the things you found helped by ponstan and help with asthma.

    3. Dear Tanya,

      Since you have seen good results with omegas, would you have any information on vayarin, prescription grade omega conjugated with phospholipids I think and said to work for focus and attention.

      Cod liver oil, barleans omega swirl and Nordic naturals dha did not work for my son.

    4. Hi Kritika, I don't have any experience with vayarin - sorry. I am using the Complete Omega product by Nordic Naturals with a higher EPA to DHA ratio. You might find some help on this website:

  6. Hi Peter, Tyler, and community,

    I would greatly appreciate your input on the following paper:

    While this isn't the full paper, it basically implicates overhydration of the brain as a potential cause of ASD, and suggests that osmolytes glutamine and taurine released prior to and during a fever as the reason why some kids improve dramatically during a fever. They draw water away from brain myelin and astrocytes.

    Assuming this hypothesis is correct, Sustamine (as it is more stable than free form Glutamine) and Taurine would be obvious supplements - are there any osmolytes that you think would be helpful?

    Also, I wonder again if the reason why a drug like Bumetanide is helpful isn't at least partially due to its diuretic activity lowering water levels in the body (and therefore the brain)?

    Any input anyone has would be very helpful - it's a fascinating hypothesis, and potentially actionable with osmolytes.



    1. AJ, in this post Peter Good talks about his use of various supplements:

      Older adults take diuretics to lose fluids, but children with autism on bumetanide should be compensating for fluid loss by drinking more; if not they will get side effects from dehydration.

      My son is drinking 3 liters a day of water, by his choice, when on bumetanide. Without bumetanide he drinks much less, but has "more autism".

      Peter Good may be right in some cases, perhaps in the people with autism and MR/ID who drink vast amounts of fluid (polydipsia), or those with a truly bizarre response to fever.

      Diuretics all affect electrolytes in one way or another and this will affect many types of ion channel. So in some people with autism, diuretics other than bumetanide may improve autism via other channelopathies.

      I would suggest you discuss this with your new doctor.

    2. Hi Peter, Thank you very much for your insights and for providing the link!


  7. Hi Peter,
    Is there any email address to contact you directly?I posted a comment yesterday.Not sure if you got it or not

    1. SB, the idea of the discussion in the comments section is that it is public and people can learn from the experience's of others. I am not a doctor and so I am not giving medical advice.

      If you share your question, nobody will know who you are (just don't mention your doctor's name) and other people may give you useful advice, some of whom are doctors.

      This way I think you will gain most.

  8. Hi Peter, my son made a marked allergic reaction to influenza virus, yesterday,large spots began to appear all over his body.In the emergency we did blood and urine tests, and they told me that it was feverish urticaria.They indicated clorfeniramine. Is clear that influenza virus worsens allergy and asthma in my son,but that is new. What does this horrible reaction tell about his immune system?What could I do? Valentina

    1. Valentina, the flu virus has triggered the release of histamine which has caused the spots/hives to appear. The flu virus and others are known to have this effect in some people.

      As he recovers from the flu, the spots should go away, but ask your doctor about whether any treatment is needed.

      All this event tells you is that your son is allergic to this particular virus. It is a known reaction and I do not think you need to worry further.

      I think if you have autism and asthma, you will inevitably be more prone to other allergies.

  9. Hi All,
    I would like to get suggestion from you.

    My son has done all the biomeds and therapies but still no improvement.He is cognitively very challenged.He is like a 2 year old.He cannot learn anything.His autism symptoms are less compared to cognitive challenges.He is currently under the supervision of a renowned pediatric neurologist

    These are the things I tried
    HBOT(hard chanber)
    Multiple vitamins
    Auditor Integration therapy
    Meccil from your polypill for 1.5 months
    Durex(forgot the name,that was also from your website)

    The neurologist has put him on Namenda ,L-Carnonine.Namenda 5 mg ,L-Carnosine 500 mg everyday.The next appointment is in March 2018.I am not seeing any improvement.He has been on the treatment for 5+ months
    He does not have seizure as per his 24 hr EEG

    Anything you think that could potentially help him with cognition and understanding.He cannot recollect letters,numbers anything.Memory is the main issue.No SIB,no tantrum,very pleasant behavior.

    Please advise

    1. SB, is it early onset autism or regressive autism? If he has mitochondrial disease none of the above would help.

      If had mitochondrial disease you might also notice a lack of stamina / exercise endurance.

      Does he have other comorbid conditions like allergy, asthma, GI problems etc.

      How verbal is he?

  10. Hi Peter,
    It is early onset autism.He never met the developmental milestones like pointing,learning naturally.He is very active.He was given ADHD medicine(ritalin or something) by his pediatrician which did not work.
    He has very low attention span.
    He does not have asthma.He poops once in 3 days.It is regular poop and hot hard.He speaks single words.Cannot generalize.Like he knows his particular bottle which I use so that he does not spill water and say if I show him another bottle and ask what it is,he cannot say that it a bottle.The 2-3 word sentences which he says are from rote memory and many times it is not in context.No original sentence.
    Please let me know what you think might help him.He does ABS 24 hrs a week,speech therapy and OT.
    Once thing I want to mention that though he likes to climb ,jump all the time,sometimes he just wants to lay down especially when he is expected to sit down .He lies down on the floor,coach.Not sure if it is mitochondia.

    1. SB, what about physically? Is he big/small? Big head or small head? Was he big/small at birth? Any unusual physical features (eg facial, feet, hands etc), was his Agar score 7 or above?

      Do you have relatives, however distant, with autism, bipolar, schizophrenia or MR/ID or any unusual medical condition?

  11. Hi Peter,
    He is small.He weighs 37lb.He is on the 10th percentile for height and weight.His head circumference is in the normal range as per his doctor.
    He had umbilical cord wrapped at birth.I do not know of Agar score.No one told me at the time of delivery.He was not given oxygen.

    No one in my side or my husband's side has autism,bipolar or MR.Many relatives have high cholesterol,high presure.I had diebetes when I was pregnant with both boys.Older one is fine.He is the younger one

    Thank you so much for taking the time to repsond

  12. Peter,
    I forgot to add something.In the month of May,my son's doctor gave him eyedrops because he had watery eyes and she thinks that he might have some kind of allergy.Completely forgot about it.I am not ware of any food or pollen he is allergic to.Sometimes he has watery eyes which resolves on its own

    1. SB, I would check for mitochondrial disease, which itself is a subjective process. There is a new test that uses a sample from inside the cheek (buccal sample), the established tests are blood tests and muscle biopsy.

      If it is not mitochondrial disease, his smaller stature puts him in the small group of those with hypo-active pro-growth signaling pathways. In other words he would often have the opposite dysfunction of what the larger group of people with autism have, these are the ones that were born big and/or stronger.

      So the first step would be to check for mitochondrial disease/dysfunction. This is more common than was originally thought.

    2. Hi Peter,

      You noted that there is a new test that uses a cheek swab for mitochondrial disease / dysfunction - would you kindly provide a link to the lab that does this test? I'm about to get OAT / metals testing (but I don't believe they offer mitochondrial testing), and even hopefully an ASD genetics panel, but I've wanted to check on my daughter's mitochondria since many theories about ASD revolve around the mitochondria.

      Thanks in advance Peter!


    3. AJ, this is still an experimental test.

      It is Dr Michael Goldenthal who is behind the test. You can google him and find his research.

      His email is given in the first comment in the following link:

    4. Hi Peter,

      Thank you very much for the info!

      Hopefully he's open to sending the kit to Canada, and this is still available (the forum post was from 3 years ago). I would gladly pay $200 for a mitochondrial analysis.

      I will also check with the company I'm discussing an ASD DNA panel with, to see if they can fun a mitochondrial analysis using a cheek swab.

      If anything interesting happens, I will keep everyone posted.


    5. Just a note I had the cheek swab test done with Dr. G, he sent the kit to me in Canada, quite a nice guy to talk to on the phone. The test looks at activity of complex one to 4 as well as ratio of I/IV and CS. Frye and him have written a couple of papers about mito dysfunction in autism. He is going to be shutting the lab down he indicated maybe sometime this year so contact him quickly. AM

    6. Hi AM, thanks very much! I will connect with him ASAP.

      Fingers crossed he's still offering this.

      Have a wonderful day AM, and again, much appreciated!


  13. Thanks Peter.I will look into mito disfunction

  14. Very relevant science news regarding autoimmunity:
    or easier to read:


  15. Hi Tyler,in spite of my son´s allergic reaction to the flu virus,don´t think that the good effect of agamtine didn´t notice. Yesterday arrived his 3 argentinian teenage cousins,my sister´s daughters, he adores one of them and started to tell her what had happened to him,about his allergic reaction, with such a detail and fluency of speech,lifting up his pijamas to show her that now he had no spots, nowhere. Nobody had asked him anything and we fell all silent.Besides,his hand clapping was reduced by 90%. His weight is 34kg and is taking between a third and a quarter teaspoon from Bulk that is equivalent to 562 mg and 750 mg. Iam giving the full dose because i found it difficult to measure the small doses each day. Valentina

  16. Sorry, but that all sounded kind of ambiguous so I am not exactly sure what your saying. Don't worry your English grammar is much better than my Spanish or any other language for that matter.

    So to be clear, are you saying that in spite of the flu allergy symptoms, he was doing much better on agmatine around your extended family?

  17. Tyler,let´s see now if i can express myself better.I started with agmatine a week ago with very small doses as you told me, but as it was difficult to measure the small amounts each day, I reached the high dose 3 days ago. 1/3 teasppon from bulk is equivalent to 750 mg and 1/4 is 562mg. Do you think that I could give him 1/3 teaspoon? It is the standard dose indicated in the package. His weight now is 34.The results are very positive taking in consideration that the trial with agmatine coincided with his flu and allergic reaction.That is what I wanted to write.The episode with his cousin was incredible,I had never heard him speak like that,like any other person. Valentina

    1. Wow that is awesome though I am not surprised because even though my son is likely much lower functioning than your son, agmatines effects on speech in partucular were acute yet temporary in the sense the positive effectd didn't stick around the next day unless agmatine was taken again.

      As to your question, 1 x 2/3 teaspoon per day or 2 x 1/3 teaspoon per day would be the amount I use scaled from my son to yours as my son is just over 50kg right now.

    2. Perfect, I will double the dose. Thankyou very much!

    3. Tyler, I mean will use in my son the equivalent to 1020 mg, based on your scale.That would be a bit less than half a teaspoon which in bulk is equivalent to 1125 mg.Is it ok? Valentina

    4. Valentina, Tyler,

      Its wonderful that your sons are doing so well in the speech department. Tyler, having a conversation with my son is a dream I dare not even dream. It must be so gratifying for your family.

      My son is 25 kg. Would you be kind enough to share at what dose to start, how to ramp up and what is the target dose. Valentina, are you using bulk supplements? I am going to order agmatine and give it a shot. Speech is a big issue for us right now.


    5. Yes Valentina. My exact methodology for scaling the rat study dosage to human dosage is just following guidelines from other researchers which may not even be correct. In those studies agmatine was given intravenously, so considering oral supplementation, you have to factor in absorbability issues as well, hence why I give my son the 1125mg and not a dose exact to what would be scaled from a rat if the human was given the dose intravenously. So again 2/3 of a teaspoon per day any way you want to give it is what I would do. I just do a full teaspoon in my son in a single sitting per day for several reasons, one being that school now gets in the way of a lot of this stuff we can't really be open about to the staff because American educator types tend to have very strong, yet ignorant opinions in this realm and we have to tread carefully considering they have the power to really screw up our family's life which is always somewhere between a rock and a hard place.

    6. Ok Tyler,I have understood correctly the first time, when I told you that I would double the dose, that night I added 1/3 to the third he had taken in the morning, and he fell asleep right away. So, I will continue like this.Here the educators think the same way, but you can´t tell them.In my school happens something curious and very convenient, the director is more open minded than any teacher,may be because there have been for many years very interesting cases of autism which she has helped in person to move along. She keeps the teachers at bay.But we always will be in a hard place. Valentina

  18. Hi everyone,

    The following paper, titled "Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants" is more relevant to ASD than the title may indicate.

    I keep seeing PSD95 (a protein from the gene DLG4) has been coming up a lot in my research and this paper may indicate its relevance to ASD.

    Hope this is helpful!


  19. Hi Kritika,according to my calculations, if your son´s wight is 25kg, you should give him 750 mg which is exactly 1/3 teaspoon from bulk. The standard dose.I wish you lack with your trial!. Valentina

    1. For the reasons mentioned above, she will want to do half a teaspoon not a third. Of course there are no absolutes here as I, nor anyone else knows what the best human dosage would be, just that the dosage I suggested has worked for my son. Every parent who wants to try this out will inevitably have to figure out the optimum dosage on their own through trial and error as there are too many variables involved to competently make any sort of hard recommendations here.

  20. Thank you Valentina. Wish you good luck too.

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