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Sunday, 27 August 2017

Agmatine - a Magic Bullet in Clinical Neuroscience?


Today’s post is about Agmatine, a naturally occurring metabolite of the amino acid arginine, which is referred to in recent studies as both a “magic bullet” and a “magic shotgun”.
Normally when things sound too good to be true, you do need to be rather suspicious, but our reader Tyler has already been trialing Agmatine over the summer months and he continues to be a big believer.
As we will see in this post Agmatine has multiple different effects and while this is often the case with drugs and gives them both good and bad effects, in the case of Agmatine this ability to affect multiple targets is put forward as an advantage.
NAC, the antioxidant now widely used in autism, also has numerous beneficial effects and can even reverse propionic acid induced autism. I think we can call NAC a silver bullet.
You will recall that amino acids are the building blocks of proteins. Nine amino acids are called essential for humans because they cannot be produced by the human body and so must be taken in as food. Arginine is classified as a conditionally essential amino acid, depending on the developmental stage and health status of the individual. Preterm infants are unable to synthesize or create arginine internally, making the amino acid nutritionally essential for them.

Agmatine
Agmatine was discovered in 1910.  It is a chemical substance which is naturally created from the chemical arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably neurotransmitter systems, ion channels, nitric oxide (NO) synthesis and polyamine metabolism.
Many of agmatine’s effects are potentially relevant to neurological conditions like autism. My initial thought was that with so many different effects, how likely would it be that the overall effect would be positive?
  • Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.
  • Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca2+ channels, and acid-sensing ion channels (ASICs).
  • Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system.
  • Nitric oxide (NO) synthesis modulation. Differential inhibition by agmatine of all isoforms of NO synthase (NOS) is reported.
  • Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme.
  • Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation.
  • Matrix metalloproteases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9.
  • Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation.
  • NADPH oxidase. Activation of the enzyme leading to H2O2 production.

Different effects are likely to predominate at different doses, as with many drugs.
Of the above effects many are implicated in autism.
Nicotinic, NMDA, and serotonin receptors are all deeply implicated in autism.
All the above ion channels including ASICs, which have not yet been covered in this blog, are implicated in autism. Acid Sensing Ion Channels (ASICs) are implicated in autism via the genetic research and surprisingly brain pH is disturbed in many neurological conditions. 
“Maintaining the physiological pH of interstitial fluid is crucial for normal cellular functions. In disease states, tissue acidosis is a common pathologic change causing abnormal activation of acid-sensing ion channels (ASICs), which according to cumulative evidence, significantly contributes to inflammation, mitochondrial dysfunction, and other pathologic mechanisms (i.e., pain, stroke, and psychiatric conditions). Thus, it has become increasingly clear that ASICs are critical in the progression of neurologic diseases.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449961/

Nitric oxide is relevant to autism and any vasodilatory effect might be helpful to those with reduced cerebral blood flow. This benefit potentially goes beyond those with vascular dementia and may enhance memory and cognition in some.
It the effect on nitric oxide which body builders think gives them a benefit from taking Agmatine.
Polyamines and spermidine in particular are involved in autophagy, which is the intra-cellular garbage disposal service. When autophagy is impaired, as in many neurological conditions, this accumulating garbage gets in the way of cellular function. We already know that improving autophagy is one method of combating cognitive decline. We know that autophagy is impaired in autism.
NADPH oxidase and nNOS (Neuronal nitric oxide synthase) redox signaling cascades interact in the brain to affect both cognitive function and social behavior. I am not sure whether Agmatine will have a good or bad effect.                                                                  

The Research
I would be the first to point out that the Agmatine research is not like the high powered research we see from the scientists on this blog’s Dean’s List, but that does not mean the Agmatine may not be highly beneficial.  It is more like the copious research on antioxidants.


Agmatine, the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α2-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague. The purification and biochemical characterization of natural mammalian arginine decarboxylase and agmatinase still are open issues. Nevertheless, the agmatinergic system is currently one of the most promising candidates in order to pharmacologically interfere with some major diseases of the central nervous system, which are summarized in the present review. Particularly with respect to major depression, agmatine, its derivatives, and metabolizing enzymes show great promise for the development of an improved treatment of this common disease.                                                                                                                         


Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.


“Agmatine is now considered to be capable of exerting modulatory actions simultaneously at multiple target sites, thus fitting the therapeutic profile of a ‘magic shotgun’ for complex disorders”
  
Mitochondrial protection 

Agmatine has been shown to exert direct protective effects on mitochondria at nanomolar concentrations. It has also been shown

to alleviate oxidative stress-induced mitochondrial swelling, possibly by acting as a free radical scavenger, and prevent Ca2+-dependent induction of mitochondrial permeability transition (MPT) by modulating itochondrial membrane potential and NF-kappaB activation and references therein). Importantly, these effects are implicated in apoptotic cell death. Therefore, mitochondrial protection is considered essential in contributing to the general cytoprotective effects of agmatine in various bodily systems and, thus, to its beneficial effects in a spectrum of disease models. Of special interest is a potential for agmatine utility in neurodegenerativediseases where mitochondrial malfunctions have been implicated (e.g., Parkinson’s disease).  

Drug development: therapeutic potential outweighing risks 

There remain constraints on progress towards practical development of agmatine as a drug. First, the lower level of protection against commercial competition afforded by ‘usage’ patents for new indications of known compounds, such as agmatine with its long known methods of chemical synthesis, is viewed as being much less lucrative by drug developers than that provided by ‘composition of matter’ patents for new chemical entities. Second, although research of new compounds to modulate endogenous agmatine metabolism holds promise, it is rudimentary and remains speculative. Third, even though agmatine, as a naturally occurring substance, has been developed and introduced to the dietary supplement and nutraceutical market, nutraceutical products in the USA fall under the ‘Dietary Supplement Health and Education Act (DSHEA)’, which forbids promotion of nutraceuticals for the treatment, cure, or prevention of any disease. Similar regulatory restrictions exist worldwide and severely limit the advertising of nutraceuticals to the medical market. 

Despite these constraints, compelling evidence indicates the therapeutic potential of agmatine for a spectrum of diseases. A summary of the advances made and the gaps still remaining for future research are indicated in Table 2. Although comparative efficacy studies with presently available drugs are still required, the broad safety profile of agmatine has been established with no serious adverse effects, either as a stand-alone or as an add-on treatment. This should be a paramount advantage when compared with most existing drugs and certainly to combination therapy.

Moreover, its general cytoprotective actions suggest that agmatine should be considered not only as a curative, but also as a preventive therapeutic.



Tyler’s Comments

Tyler’s comments in this blog regarding the use of Agmatine suggest that at different doses, the effect does indeed vary. At lower doses there can be negative effects like anxiety and aggression, but at 1.2 g (in a 50kg boy) the main affect is enhanced cognition.





In treating strictly defined autism, cognitive function is often the most important target, unlike in milder forms of autism.

Tyler’s main purpose for trialing Agmatine was that it is thought to normalize the opioid system in the brain, via its action on adrenoreceptors.  Then came a mouse study in the valproic acid model of autism.



Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD. 


in addition to a study in OCD:-



Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. Obsessive-compulsive disorder is classified as an anxiety disorder under DSM-IV-TR guidelines. In OCD, the levels of serotonin and nitric oxide decreased; whereas levels of dopamine and glutamate increased in brain. Environmental conditions such as isolation from social surroundings lead to anxiety and increased level of aggression. The present study was designed to examine the effect of agmatine in social isolation induced obsessive-compulsive behavior on marble burying behavior and locomotor activity. Agmatine (20, 40 and 80 mg/kg, i.p.) was administered in different groups of mice; activity was observed 30 min after dosing. Acute treatment of agmatine (40 and 80 mg/kg, i.p.) significantly reduced marble burying behavior. Moreover, hyperlocomotion was observed in socially isolated animals and agmatine was found to attenuate the same without affecting basal locomotions. In conclusion, agmatine effectively decreases social isolation induced obsessive-compulsive behavior in mice


I think it is fair to say that we do not know which mode(s) of action are in effect at this dosage. Clearly dosage is very important.

Given the importance of maximizing cognitive function in those with some cognitive dysfunction, Agmatine is clearly well worthy of further investigation.


Conclusion

Agmatine does indeed seem to have to potential to benefit some people with neurological disorders.  Is it a magic bullet for everyone? I doubt it, but that is an unrealistic expectation for any drug.

If it can improve cognition, even in a minority of autism, that would be a significant finding. Hopefully other readers of this blog will have the same positive experience as Tyler.  It will be interesting to find out how the effective dose varies. Depending on which brand you use, 1 teaspoon (5ml) of agmatine powder contains between 2.2 and 3.5 grams, which looks odd.  Probably best to weigh it to be sure.

Agmatine sulphate/sulfate is widely available in North America as a body builder’s supplement, but is banned in Europe. It was not banned for safety reasons, rather some odd EU rule that since it was not sold before 1997, it now needs to go through an approval process, that someone would have to pay for, before it can continue to be sold. Agmatine is not such an effective body building supplement to warrant anyone investing much in it. Hopefully the FDA will not ban it in the US.





25 comments:

  1. Peter,

    It would be really helpful if AJ too could share his experience with agmatine...I believe he was treating his daughter with this.

    I would love to run a trial on my son but am worried about its blood pressure lowering effect which ironically seem to be associated with lots of supplements/drugs being used for autism. Low blood pressure spells serious trouble for both me as well as my son...learnt it the hard way. Can low bp caused by agmatine be managed with a little salty snack? Is bulk supplements a good brand for agmatine?

    Any input would be appreciated.

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    1. Hi Kritika,

      Yes, I do use Agmatine, amount 500mg per day, split between about 300mg in the morning and 200mg in the evening.

      My daughter is always improving so I can't say what is her natural growth and what is due to any one supplement but I've had her on agmatine for at least a month and I haven't seen a WOW but it may be helping so I'll keep using it.

      My big news is that the new doctor I saw prescribed compounded Oxytocin so we've been on that for a few days. No noticeable difference yet I'm afraid - I was hoping for a noticeable change soon after starting but nothing yet.

      If anyone has used Oxytocin and did get an improvement, would you kindly share the dosage and how long it took for the improvement?

      Thanks,

      AJ

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    2. Thanks AJ,

      I totally understand how difficult it is to state with any certainty if the positives one observes can be attributed to an intervention or just spontaneous growth and development, especially in a young child. I face that predicament all the time and therefore have decided that only if something gives me big, profound, cant be missed kind of improvements which I have not seen before, only then I will be able to justify stuffing my son with experimental chemicals. For instance, if something makes my son speak without being prompted and not just for a day or two, then I will continue giving it. Many drugs and supplements affect ones sugar levels, cortisol levels and blood pressure...these are a strict no no for my son.

      As for oxytocin, I thought the effects show pretty fast...maybe I was wrong. Did you ever try Bioamius reuteri? It showed clear upliftment in mood, interaction and improvement in speech in two days time in my son at five drops per day...these effects were not replicated with other l.reuteri products. Bumetanide after one month of use also produced what in hindsight seem big changes in combination with Bioamicus reuteri but without medical assistance, managing side effects became difficult...likely imbalance in electrolyte levels. NAC also showed some promise but ultimately gastric discomfort could not be ignored.

      Apart from these three, oral mb12 also immediately showed increased awareness but its known to interfere with melatonin production and lack of sleep ultimately led to a deadly combo of adverse impacts on behaviour. Folinic acid at micro doses had a rapid and huge jump in spontaneous speech but only for a few days..it was too potent an inter vention with side effects reflected in spiralling down behaviour and health.

      I will revisit all these sups/drugs again but with extreme caution and care so as to avoid side effects and just stop at the hint of any deterioration. Last year my son was your daughters age...side effects were limited to whining. This year we experienced aggression and one episode of SIB and extreme weakness and fainting. So do be mindful of simple variables like sleep, pattern of urination, any sign of fatigue.

      Unwarranted advice but thought I will share.

      My best wishes for your daughter


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    3. AJ, if your oxytocin is intranasal, it appears to be very important how you sniff it. This is the same case with kids and asthma inhalers, they often do not use them optimally. This is why a new type of nasal inhaler is being developed for oxytocin, which should always work.

      I agree with Kritika that perhaps the best way to boost oxytocin is via L.reuteri. The effect is from the first day and it is continuously produced in the gut, rather than a sudden surge from a nasal spray.

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    4. Hi Peter and Kritika,

      Thank you both for your comments and advice - I always appreciate any input.

      Peter, thank you for noting that how the oxytocin is sprayed is important - I in fact went on YouTube and watched videos on this front and there was one from an ENT that I tried to follow, but my daughter was squirming like crazy each time, but she is getting better as she realizes its painless so I'm hoping to see if there is any impact once she is actually using the spray properly.

      The video is at
      https://www.youtube.com/watch?v=tnEre7FHUAQ

      With respect to L Reuteri, I had tried BioAmicus (which I believe from nearby here in Ontario) but I didn't see any impact so I'm now using BioGaia Protectis to see if that works. They sell it at our major pharmacy in Canada and also at Walmart, so its easy to get.

      Peter - any preference, BioAmicus or BioGaia Protectis?

      Finally, as an update, the new doctor I'm seeing will run OAT / metal test via urine, and I believe someone (Maybe Tanya) had noted that Great Plains Lab was soon going to have one for mycotoxins, so I may run that as well.

      Finally, I am also wanting to run a full DNA test, but unfortunately all the ones funded by our government or research (like Holland Bloorview) need blood or a ridiculous amount of saliva, so I'm looking into private labs. The costs are high (about $2K - $3.5K US) but I think it would be helpful to know if there any mutations, duplications, deletions etc.

      I'll keep everyone posted on any new relevant research I find, and of course, how my daughter is doing on Oxytocin, and also how the tests go.

      Have a great night everyone!

      AJ

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    5. @AJ,

      A word of caution with regards to running a full DNA test. Most of the sequencing done at this moment is exome sequencing only, that Baylor charges $7K. This completely disregards any regulatory elements in intronic as well as inter-genic regions. The exomes may be fine but if the mutation lies in a regulatory region, having 'fine' exome doesn't help.

      I am hoping someone will come up with expression profiling of our kids, that will give you more idea about how the genes are being expressed. If something is out of order (compared to the control NT kids), then you can go back and sequence only that much of region to see if its due to any mutation, else it could make a gigantic database of expression profiles and hopefully using data mining there is some hope that symptoms could be correlated with expression profiles.

      I get it, its a long shot, still if I am to go genetic way, this is the way I would go. Otherwise even knowing mutations won't help unless CRISPR is available for general population. I am not particularly fond of genetic studies because even after knowing something there is no way to address those mutations.

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    6. Hi anon, Yes, I agree with you. Your comment "I get it, its a long shot..." perfectly explains it. If we don't find anything, I'll re-do a more detailed analysis of the whole genome (versus an exome panel) down the road. As the tech gets better, and cheaper, we can keep going at it until we realize what the issue is. It may be the "dark genome" (formerly and mistakenly known as "junk DNA") which as you know, accounts for like 98% of our DNA.

      In terms of why I'm doing it, I think there are likely some mutations that may be amenable to current treatment, the recent paper on MeCP2 being an example. If the issue is a CNV, and my daughter has extra copies of gene X, then I would look at how I can knock down the relevant protein to normal levels (assuming extra copies means extra expression).

      My long term hope is CRISPR, if its due to a mutation. Given how long it takes the FDA to approve a new treatment, I suspect that patients will initially go to some tropical destination housing a clinic, they prep the relevant CRISPR with the targeting moeity (who knows, lipid nano-carriers that cross the BBB, AAV-like vector, by then it may something we've never thought of).

      Thanks for your input, especially if you're the same anon that provided the link to the full papers - that was a game changer for me.

      Have a wonderful night!

      AJ

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    7. AJ, I have only tried Biogaia and it works for us. BioAmicus comes from Canada, so may be easier for you to obtain and seems to have the same effect in other people.

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    8. Hi AJ we are in Canada as well and through BC kids applied to our provincial health to test for a free whole exome sequence (the application was written by our genetics Dr) - it is a blood test, they will also look at mitochondrial DNA. you may also want to contact the MSSNG study at Sick Kids, we are a part of this and the results can take up to a year but is it a much detailed study and free. I would get a referral from your doctor to genetics at Sick Kids and go from there. All these are blood work, both parents and the child. Alternatively there was a cheek swab study through Queens University we were going to enrol with it is a DNA study I believe but since it shares data with MSSNG we just did that one. AM

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    9. Hi AM,

      Thank you kindly for the info! I had actually contacted Dr. Scherer at Sick Kids, and he couldn't have been more kind. The big issue we had was that he could only do the test via blood draw, and we couldn't do that. Again, I was really impressed about how nice he was.

      Interestingly, I'm applying for provincial funding for a cheek swab test, and my fingers are tightly crossed. I'm hoping to hear back within a month.

      I didn't know about the test at Queens, and will definitely contact them if my funding doesn't come through. I'm actually not that far from Queens, so we can easily drive there unless they send us the cheek swab test (hopefully its still ongoing).

      I absolutely plan on providing my results with Dr. Scherer if my funding comes through, given how nice he was with us, and because I just want to help our cause. In fact, I'll share it with any researchers who are interested (I believe that Holland Bloorview is also doing research on ASD genetics so I will also share it with them). If our test results can help solve this mystery, why not share it.

      I'll keep everyone posted.

      I'm proud of how much great research we do in Canada, for a country 10% of the population of our good neighbours down south. If you haven't checked out what is happening at Holland Bloorview, check out their ASD site and all the research they are doing. I know U of T and McMaster are also doing some good research, and now I know Queens is also doing good work.

      Have a wonderful day AM

      AJ

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  2. Don't give our politicians any ideas here: PLEASE!

    It was pathetic enough when Claire McCaskill, a bought and paid for senator for big pharma, unilaterally got an obscure supplement with potential for Alzheimers among other medical applications banned under the dishonest notion of "protecting the public", even though nobody has ever died or seriously injured themselves from Picamilon.

    Thankfully, Agmatine is more widely used so there would be more people ticked off from it being banned in the USA, nevertheless I would not be surprised if one of those companies that endlessly advertise patent protected blood pressure products gives Claire McCaskill or some other corrupt senator in our country a call on the phone and demand that they "protect the public" as well.

    It is sickening how many people are dying in the USA from opioid abuse which is a crisis with 110% blame on big pharma and corrupt doctors taking cash payouts for pushing opioids on people who don't even need them. Then they have "congressional hearings" to talk about the problems in an abstract way and in the end nobody goes to jail or even gets seriously sued for killing more Americans than all of the terrorism and wars we have been involved in for the last 50 years.

    So yah hopefully our government and those entities which own it will not see Agmatine as a threat to big pharma's profits because it has been a big winner so far with my child in helping deal with a condition the government is content to give lip service to while doing next to nothing in a manner that can be actually taken seriously, and I am obviously not just talking about the opioid crisis which also applies in this context.

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  3. Tyler, today I will get agmatine, I read that it enhances the effect of valproate, so it should be a good match. I think that it will be positive, taking in consideration that our kids seem to have similar problems.I have a doubt with the dosage,do I have to calculate it based on 20 mg per kg? You give to your child 1.2g, not 1g.The positive change in my son is amazing,I remember you told me,in my summer, that I would have to wait a considerable time,8 months to be precise,and here we are!So many mad moments in the middle, but it was worth it. Now, as Peter says, I have to be very careful. Valentina

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  4. Well the studies done were on rats and mice and the human dose i came up with was scaled from that used in the valproate induced autism study in rats and then I scaled that number based upon average human intestinal absorbability of agmatine since the rat study used injections directly into the blood. Peter has a link in this blog post using the exact methadology I used. Whether this is an optimum dose for humans with autism is an open question. Hope this helps.

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  5. Hello Peter and Tanya,

    Today met neurologist whom I liked as she seemed patient and receptive...she wrote down a battery of tests, the biochemical ones being ammonia, lactate, VBG, baby shield for inborn errors of metabolism and mito dysfunction (urine GCMS+TMS 47+5). So hopefully in ten days time I might have something to guide me further. She also said that we might explore chromosomal microarray test later. She had the opinion that only about 15% kids show aberrations in lab findings regarding biochemmistry but good to follow standard protocol.

    She plans to treat him through pharmacotherapy and said it helps some kids a lot..add drugs? I am bit nervous there but lets see what she has to offer. All the best to me.

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    1. Kritika, it is good to have a neurologist who is so helpful. Hopefully something beneficial will be the result.

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  6. Peter, I just came across an interesting article on acidity and neuropsychiatric disorders in Scientific American that likely discusses a bit about your next topic on ASICS:

    https://www.scientificamerican.com/article/are-some-psychiatric-disorders-a-ph-problem/

    I normally don't link to magazine articles that discuss research and studies without linking to those as well, but I thought you might find it interesting even though much of the material is likely redundant to you by now.

    On another note, the improvements I have seen with my son using L-Aspartic Acid I have sometimes thought may also be due, if not exclussively, to helping regulate ammonia homeostasis in the body and brain as L-Aspartic Acid helps break down ammonia via the urea cycle. My original use for L-Aspartic Acid was for helping regulate the opioid system, but as ASICS seem to be very prevalent in the amygdala (as are opioid receptors), the answer could be far simpler in that my son has high ammonia levels (we have never tested this as doing these tests properly is very expensive from my understanding).

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    1. Tyler, thanks for the link. That is one of the few articles you can find on the subject of ASICs and pH. The more you look into the subject the more low brain pH (brain acidosis) looks like a classic feature of neurological diseases, just like oxidative stress.

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    2. Peter,

      I am perplexed. Usually my son like any other child, would become irritable during an illness. Now with a bad viral bacterial combo infection (which seems to go on forever and has not spared my husband and me), he is really really happy but with a major OCD which seems to be becoming more and more elaborate. Running back and forth between wall or pieces of furniture, switch boards has now graduated to touching those entities with both palms and those entities now include people as well as, would you believe, a plate full of food. What the hell is going on?He has already completed seven days course of antibiotics but still has lot of nasal congestion...so do I. But what to do about sons bizarre behaviour which he demonstrated at the neurologist s clinic as she watched calmly. I asked her if it could be strep related an d she said PANDAS presents as jerky movement though I have read ocds are also linked to bacterial as well as viral infection..probably triggered by oxidative stress or immune system activity. Any thoughts or should I just wait it out.

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    3. Hi Tyler and Peter,

      Tyler, thanks for sharing the article - just read it and its fascinating.

      Tyler and Peter, this idea of acidity / ph levels is interesting in light of a paper I had recently linked, which can be found at:

      https://www.ncbi.nlm.nih.gov/pubmed/28831647

      The full version, which anon kindly showed us how to access, provides a lot of interesting info, and lactate dehydrogenase and pyruvate were noticeably different than NTs.

      It may not be related to brain PH, but Caspase 7 was so far off NT, that I'm going to look into it to see where it may be relevant.

      If anyone has any insights, please share.

      AJ

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    4. Kritika, hopefully as the infection fades so will the OCD. If the OCD remains that would be the time to take some action.

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    5. I would just like to highlight this comment by the author in the article Tyler posted:

      "
      Even as it becomes clearer that brain acidity may be a key characteristic of schizophrenia and bipolar disorder, whether it is a cause or an effect remains an open question. According to Miyakawa, one possibility is that the increased acidity results from higher-than-normal neuronal activity in the brains of people with these disorders. “The neurons are more activated, more energy is needed, and that energy is provided by lactate,” he explains.

      Another popular theory is that the greater brain acidity among people with these psychiatric disorders could be due to impairments in mitochondria, the powerhouses of cells, Regenold says. Richard Maddock, a psychiatry professor at the University of California, Davis, who did not take part in the new study, also believes that this could be the case. However, he adds, these two hypotheses are “not mutually exclusive.”

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  7. Hi everyone,

    I'm always on the lookout for additional anti-purinregic options further to Dr. Naviaux's research, and found the following:

    https://www.ncbi.nlm.nih.gov/pubmed/28741143

    So Salidroside is a component of Rhodiola Rosea, but some extracts have the Salidroside level standardized to 1%, while others have it at 3% or even 5%. I'm going to try the Webber Naturals one as it seems to be at 3%.

    I'll keep everyone posted - I'm not expecting a cure, I don't even know if at 3%, a normal dose even affects the P2X7 receptors enough to see a difference... but I will always give anything with a chance a try.

    If anyone has any comments on Rhodiola Rosea, especially if you're tried it, please share.

    AJ

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  8. Hi everyone,

    A new paper that may give us yet another clue to this mystery we call ASD:

    Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder

    http://journal.frontiersin.org/article/10.3389/fnmol.2017.00250/full

    I'm always a big fan of papers that show a difference in some aspect of the ASD biology relative to normal controls, as these provide us with big clues. In this case, it's miR-140-3p

    I'll dig through it and post any items of interest, and ask everyone to kindly share any insights from this paper.

    AJ

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  9. You have to be careful with Rhodiola since it substantially raises dopamine. People who took it reported calmness, less anxiety, but racing thoughts, borderline schizophrenic. For that reason, it is contraindicated for people with bipolar disorder and schizophrenia.

    V

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  10. Hi Readers, I am interested in those who are new to agmatine, what their findings have been? How has it helped you or your child (or not). What impacts have you seen (and how would you describe you or your child's situation -- regressive, etc) Thanks MH

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