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Friday, 13 October 2017

Nitric Oxide (NO), Arginase and Endothelial Dysfunction in Autism








Endothelial dysfunction is not something people associate with autism. It is something I have covered previously in this blog and if you search on Google my post is about all you will find.
Endothelial dysfunction is acknowledged to be very important in diabetes, which is characterized by ROS (reactive oxygen species), reduced NO (nitric oxide) , reduced eNOS (endothelial nitric oxide synthase) and too much Arginase. There is also Peroxynitrite (ONOO), an ion we have encountered before.
In autism we do already know from the research that VEGF (Vascular endothelial growth factor) is disturbed and there will be a post on that.
So when you put it all this together, it is odd that nobody has researched endothelial dysfunction and autism.  When I find something like this, my fallback is always schizophrenia. What about Endothelial Dysfunction and Schizophrenia? Sure enough, there is plenty of research on the subject, like this paper.


We tested the hypothesis that subjects with schizophrenia have impaired endothelial function.
Our findings suggest that a diagnosis of schizophrenia is associated with impaired microvascular function as indicated by lower values of VTI, irrespective of many other clinical characteristics. It might be an early indicator of cardiovascular risk in schizophrenia, and might help to identify high-risk individuals.

Endothelial Dysfunction does ultimately cause all kinds of problems in later life.  What is relevant to this blog is the potential neurological benefit of improving endothelial function in younger people, if any.
We need to recall that historically there have been very few older people with more severe autism; they did not live to the age when typical problems caused by endothelial dysfunction become apparent. 

Overlapping causes of Endothelial Dysfunction
The interesting question is just how many of the possible causes of endothelial dysfunction occur in autism. 
So far the following factors seem to apply to autism:-
·        Oxidative stress (ROS)

·        Reduced eNOS and nitic oxide (NO)    

·         VEGF (Vascular endothelial growth factor) is disturbed

·         Even estrogen deficiency can play a role and this is reduced in autism
People with autism who use calcium folinate (Leucoverin) are already quenching  Peroxynitrite (ONOO) another factor in Endothelial Dysfunction.                                                               

Is Arginine/Arginase disturbed in Autism?
One well known anomaly in diabetes is a high level of an enzyme called Arginase, resulting in reduced production of nitric oxide (NO) in endothelial cells.
Here again we have to revert to looking at schizophrenia, as the closest thing to autism. Here there are no surprises. 

Previous research implicates altered metabolism of l-arginine, a versatile amino acid with a number of bioactive metabolites, in the pathogenesis of schizophrenia. The present study, for we believe the first time, systematically compared the metabolic profile of l-arginine in the frontal cortex (Brodmann's area 8) obtained post-mortem from schizophrenic individuals and age- and gender-matched non-psychiatric controls (n=20 per group). The enzyme assays revealed no change in total nitric oxide synthase (NOS) activity, but significantly increased arginase activity in the schizophrenia group. Western blot showed reduced endothelial NOS protein expression and increased arginase II protein level in the disease group. High-performance liquid chromatography and liquid chromatography/mass spectrometric assays confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between l-ornithine level and the duration of illness. Moreover, cluster analyses revealed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. The present study provides further evidence of altered brain arginine metabolism in schizophrenia, which enhances our understanding of the pathogenesis of schizophrenia and may lead to the future development of novel preventions and/or therapeutics for the disease






Arginine metabolic pathways. l-arginine can be metabolized by NOS, arginase and ADC to form a number of bioactive molecules (see the Introduction for detailed description). We found increased levels of arginase activity, arginase II protein expression and agmatine tissue concentration (indicated by the red letters and arrows), and reduced eNOS protein expression and GABA level (indicated by the green letters and arrows) in the schizophrenia cases. ADC, arginine decarboxylase; BA8, Brodmann's area 8; eNOS, endothelial NOS; GABA, γ-aminobutyric acid; iNOS, inducible NOS; NO, nitric oxide; NOS, nitric oxide synthase; nNOS, neuronal NOS.  

It is of interest to note that the plasma agmatine level was increased over threefold in schizophrenic patients relative to healthy controls



The present study, interestingly, found an over 50% increase in arginase activity in BA8 accompanied by a significant upregulation of arginase II in the schizophrenia group. It is currently unclear how arginase changes in blood correlate with those in the brain tissue

Polyamines and agmatine have also been implicated in psychiatric disorders


L-Norvaline for Aspie1983?
One reader has raised issue of whether L-Norvaline would be a good idea.
L-Norvaline is an arginase inhibitor, used by body builders to increase nitric oxide.
L-arginine is used as a substrate by both nitric oxide synthase (NOS) and arginase to produce nitric oxide (NO) and urea, respectively.
If you inhibit arginase you shift the L-arginine over towards nitric oxide production.
People with diabetes and, as we saw above schizophrenia, have elevated levels of arginase. This will cause them to have a reduced level of nitric oxide. Reduced nitric oxide will contribute to Endothelial Dysfunction.
So it looks like L-Norvaline might well be beneficial in diabetes and schizophrenia.
L-Norvaline  might slow the conversion of ammonia to urea, if arginase was low to start with.  If arginase was elevated to start with you might expect no impact on the conversion of ammonia to urea.


Agmatine, Polyamines & L-citrulline 
Agmatine may already be elevated in schizophrenia, but it looks like a little extra can be beneficial in autism.
Polyamines can also be good for you if they increase autophagy. Which specific polyamine you want is an open question.
In the schizophrenia study L-citrulline is reduced. This makes sense because L-arginine has been shifted over towards  urea by elevated arginase. L-citrulline is a byproduct when nitric oxide (NO) is produced.
Perhaps unexpectedly, l-Citrulline is also a potent endogenous precursor of l-arginine. In a recent clinical study, l-citrulline supplementation dose-dependently increases plasma l-arginine levels in healthy human volunteers more effectively than equivalent doses of l-arginine itself.
Aspie1983 might not need to supplement L-citrulline, if he used L-Norvaline .

Altered brain arginine metabolism in autism?
I suspect Aspie1983 is not the only one with an altered brain arginine metabolism.
There appear to be many therapeutic options and they are all body building supplements because they will all increase nitric oxide (NO).
They will all improve Endothelial Dysfunction, which was the original subject of this post.

Conclusion
It certainly seems like Endothelial Dysfunction is present in some autism and that numerous established therapies should help.
We are already targeting oxidative stress with antioxidants and some people use calcium folinate that will target nitrosative stress.
The therapies that increase NO and/or eNOS include:-
·        Agmatine

·        L-arginine

·        L-citrulline

·        L- norvaline

·        Cocoa flavanols

·        Beetroot juice

·        L-taurine does increase eNOS and NO, but it is not clear how

There are products sold to body builders that include several of these and some clever additional ones.

Like this one, 12 grams made up of:-
1.   L-Citrulline
2.   L-Taurine
3.   Agmatine Sulfate 
4.   Glycerol Monostearate
5.   Dan-Shen, a Chinese cardio-protective herb that increases NO and also behaves like low dose aspirin
6.   Beetroot Powder
7.   L-Norvaline
8.   Hesperidin, a citrus flavonoid that increases NO
9.   Black pepper extract; piperine is known to affect NO release


Dan-Shen :- there are numerous clinical trials on Dan-Shen and its active ingredient. It has even been suggested to treat PANS/PANDAS.

These clinical trials include treating altitude sickness.

Hesperiden is found in oranges and indeed peppermint, but in oranges it is most abundant in the white inner part of the peel. Orange peel is a home remedy to lower cholesterol. Research shows that Hesperiden (and naringin) is a potent cholesterol lowering substance.

You would think that you can have too much of a good thing, that is too much endothelial nitric oxide; ask a body builder.
There is more to this subject, beyond the body builder’s science; the related areas to look at are angiogenesis and lymphangiogenesis. These are very much influenced by VEGF (Vascular Endothelial Growth Factor). In the next post we will see that there is evidence suggesting blood vessel growth can be unchecked in some autism resulting in unstable blood flow, not simply reduced flow.
So while the view from today’s post is that in autism there may be restricted blood flow, rather like in vascular dementia, the real situation is likely more complex.
We also have the issue of how the lymphatic system, that collects waste materials from the body (including the brain), may also be affected. With blood vessels there may be “too much growth” but in the case of lymphatic system there may be too little. This is all governed by VEGF.
We have already seen that autophagy and mitophagy are reduced in some autism and are a defining feature of Huntingdon’s Disease. Accumulation of waste products in the brain has consequences. Improved autophagy, possible via the same polyamines referred to in the earlier graphic, and improved lymphangiogenesis could be therapeutic. It appears that the brain flushes out waste products to the lymphatic system while you sleep; Alzheimer's is most prevalent in people who sleep very little.





71 comments:

  1. Hi Peter,

    Thanks for raising awareness of this, I certainly hope that some others can also benefit from this information.
    I can only speak for myself, but Im almost certain that alot of other people and kids out there with autism/asd also have improper vascular responses (vasoreactivity), ofcourse raising eNOS/NO through precursors can correct these issues.

    Could it be that 'feeding' NO-donors/precursors, has an impact on maintaining BH4 levels?
    By supplying precursors such as citrulline a large part of the BH4 pool now becomes available for neurotransmitter production (BH4 is necesarry for tryptophan hydroxylase and tyrosine hydroxylase).
    Citrulline is also know to increase VEGF.

    Taurine seems to raise nitric oxide through raising H2S (hydrogen sulfide) which is also a gas. On top of that taurine is pretty much a wonder molecule, it is being research for its possible link to longevity and positively effects the glutamate/gaba balance.

    Alot of kids with autism are extremely low in sulfur at baseline conditions compared to regular kids and I will bet my life on it that they also have low H2S levels (taurine, NAC, sulforaphane - they are all sulfur containing compounds I do not believe this is a co-incidence):

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266205/table/T6/

    (part of study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266205/)

    _____

    Sulfur as a Signaling Nutrient Through Hydrogen Sulfide

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684266/

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  2. All so interesting. I have a Pandas son who has significant Sydenham's Chorea that took a long time to get control of (I think a compromised bbb was a sign. factor because we were treating it) and is now doing great. According to the doc, my son has/had vascular issues (but hadn't heard of Danshen). However, I wonder since he is taking sulforaphane, fish oil, and cocoa flavanoids, that he is helping him for lots of reasons. I do always wonder if it isn't just reduced, but unstable as you said. Peter, curious your thoughts? I think cocoa flav. could be a winner for him as he has not been taking it for a long time.

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    1. I would try some of the other therapies that increase NO. In my son Agmatine has much more effect than Cocoa; but the mechanisms are not the same. Tyler suggests the two together might be a good idea. I think you just have to see what helps in your particular case with some short trials.

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  3. Not to beat a dead horse on trehalose which I have mentioned before on this blog but here is a repost of a study showing improved endothelial function from ORAL trehalose ingestion of 100g per day:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931825/

    Here is another that suggests as little as 10g per day improves glucose tolerance which should indirectly improve arterial function as metabolic syndrome rapidly degrades arterial function.

    https://www.ncbi.nlm.nih.gov/pubmed/28202842

    Trehalose has been shown to activate TFEB which is its mTOR independent method of enhancing autophagy. Poor autophagy in endothelial tissue is a hallmark of cardiovascular disease which includes high blood pressure.

    Trehalose should be cheaper than it is right now, but considering it is a sugar, instead of using grape juice for sweetening drinks (high in sucrose) or using an artificial sweetener like Stevia or sucralose, you can see if copious amounts of trehalose are a good switch without much effort (by calories I believe it is 40% as sweet as sugar).

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    1. Hi Tyler,

      Thanks for reposting! I've added it to my shopping list. I used Agave nectar to sweeten my daughter's Pu-Erh tea, and now I'll use Trehalose so that I get the added benefits you've noted and still sweeten her tea.

      Thanks for bringing this back up!

      AJ

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  4. Excellent post and comments... My son clearly benefits from citrulline. Curious if I should add lysine in for balance? He was/is one of those pans/infections kids. I have not seen anything that looks like a viral rash since using regular twice daily doses of citrulline...

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    1. Tanya, I think lysine is worth a try. It does many clever things and has shown a positive effect in a schizophrenia trial. It is needed to produced carnitine which is needed by mitochondria, and people with mitochondrial dysfunction respond to L-carnitine. I bought some lysine a while back and intend to trial it.

      What are the benefits of citrulline in your son?

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    2. Hi Peter,

      I have used L-lysine (500-1000mg) briefly in the past and I believe it did have an effect on stress reduction.

      Also very little is needed to get an effect, doses as low 500mg can be effective (empty stomach is necesarry with lysine as with other aminoacids).
      I do remember I experienced minor nausea after taking l-lysine.

      2 studies caught my eye in the past with regards to lysine:

      l-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC307574/

      "Lys blunted stress-induced anxiety in rats (23), whereas a dietary deficiency of Lys increased stress-induced colonic transit and anxiety, because of an enhanced transmission of 5-HT in the amygdala"


      Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans:
      https://www.jstage.jst.go.jp/article/biomedres/28/2/28_2_85/_pdf

      This study used 2.64gram lysine and 2.64gram arginine and showed that this combination can effectively lower basal cortisol levels (this was done in healthy humans, so it might have an even more pronounced effect in those with high cortisol levels at baseline).
      Another thing that I found striking is by looking at the post stress responses is that the lysine + arginine group has a stronger cortisol response immediately after stress exposure (indicating a better stress reponse/more effective glucocorticoid receptors?) and their cortisol levels dropped way faster compared to the control group.

      Also please note, cortisol is not the devil it is infact a powerfull anti-inflammatory hormone.
      Cortisol is also crucial in healthy stress response, balance is the key, and this combination seems to improve the response and more rapid lowering of cortisol after the stressor has subsided.

      Lysine is also necesarry for carnitine production, along with vitamin c

      Keep in mind however that Lysine levels seems to be elvated in those with autism yet strongly lowered carnitine levels (impaired conversion?), multiple studies have showed this.

      A quote from one of the studies:

      'A deletion of the 6-N-trimethyllysine dioxygenase gene, the first enzyme of the carnitine biosynthesis pathway in mitochondria, was discovered while studying probands with autism'

      Trimethyllysine dioxygenase has vitamin c and iron as a co-factor.
      Not surprisingly vitamin c supplementation has also found effiacy in improving autism symptoms in multiple studies.
      Vitamin c is also very important for oxytocin production.

      I would not be surprised if vitamin c supplementation would lower lysine levels in kids with autism by increasing the conversion to carnitine (however this is just a hypothesis)

      Studies of carnitine supplementation in autism also showed a correlation between improvement in symptoms, higher carnitine levels in the body and handgrip strength.

      My personal experience with L-carnitine (500-2000mg daily) is that it has a quite strong energetic effect, 1000mg at once I have found more than enough, when I would go higher this would induce a hyperactivity effect in me.
      Seems to me the anti-stress effect it gave me was due to delaying mental fatigue from socializing, not so much from raising awareness of what was happening.

      I have also used glycine propionyl-l-carnitine (glycocarn) which is an expensive form of carnitine that is used for intermittent claudication and peripheral arterial disease, it is is effective at raising nitric oxide levels and lowering lactate.
      The effect of GPLC I found to be spot on, it seemed to give me energy to do what I needed to do in daily life without making me hyperactive. In fact I found it to be mentally calming.

      It a shame this supplement is so expensive.

      My experience with Acetyl L-Carnitine however has been bad personally, in doses from 250-750mg daily it seemed to induce anxiety and gaze aversion in me, I would get anxiety by looking at people on street, let alone looking them into the eyes.

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    3. Hi Tanya,

      First of all good to hear your son benefits from it.

      I Was wondering about your dose and form of citrulline.
      Personally Im currently using 3grams twice daily of L-citrulline powder (doctors best).
      Keep in mind I weigh about 95kilo, so the dose Im taking would be much lower for kids.

      In the past I have also used citrulline malate, but this seemed to have more of a forced energetic feeling on me, all in all I like L-citrulline way more but this is ofcourse subjective.

      Have you also noticed the anti-irritability effect of citrulline on your son?

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    4. Hi Peter and Aspie1983,
      Peter: the very first thing I noticed was the intermittent cold hands and feet symptom is gone. Also the intermittent drained blood look from face is gone. Is this helping iron metabolism? I thought it was the other way around - that iron boosted NO. Or is it just better blood flow to head? I think the citrulline is also helping with the mast cell issues and maybe histamine but I need more time to know for sure.
      Aspie1983
      I tried l-citrulline in the past for ammonia. I couldn't really notice benefit then, but there were many things going on then. Right now I am using citrulline malate 750mg twice a day. My son is 18 and weighs about 110 lbs (50kgs). I can't really say for sure if it affects irritability, because I added in the fish oils with higher epa to dha before citrulline and that really uplifted his mood and spirits. Thanks so much for sharing your experiences with lysine. I am going to add a small dose for balance, 500mgs. I notice the same in my son with Acetyl l carnitine - edginess. But he is ok with l-carnitine. I no longer give because I didn't notice long term it was making much of an overall positive difference. It does seem to help his bowels when they get a little sluggish. He will ask for it.

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    5. Tanya, I wonder if something as simple as cold feet/hands is a marker for some of the people that need more NO. Having high blood pressure would mark another group, but they may not have cold feet/hands. My son does sometimes have cold feet and he responded very well to Agmatine. I will try citrulline.

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    6. Hi Tanya,how did your son respond to agmatine? I will add fish oil and glucosamine for neuronal hyperexitability. Did you try luteolin and quercetin low dose? Valentina

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    7. My son didn't tespond well to agmatine. Valentina

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    8. Spot on Peter, I also am far more prone to vasoconstriction in the extremities compared to other people my age. I used to get painfull hands especially hands in the colder months (november-february).
      This is also tons less with citrulline and ginkgo bilobo, allthought I only tend to use ginkgo in the mid of winter, because I have noticed it can sometimes give a bit of anxiety (not alot though) at times if I dose too high.
      Now ginkgo is used in improving microcirculation and improving cognition, could it be that citrulline also targets this issue?

      Having said that I have used galantamine (which is used for vascular dementia) in the past and still have more than half the bottle left, it seemed to give me the sludge type of symptoms that get mentioned on the side effects and also it seemed to bring back memories, but only negative ones, thats what I disliked about it, it was very odd, one would expect if memories can be retrieved more easily also good ones would pop up, but that was unfortunatly not the case.
      I was doing 2mg and 4mg by the way, I think dosing any higher would makes me too tired for daily activies, sleep did improve on it though, I forgot to add that, allthough not dramatically.

      With regards to the type of citrulline used, it could be that my crebs cycle is allready quite normalized since I have became alot healthier and my blood levels have improved throughout the years, and that extra malic acid (used alot by people with fibro) sends my energy levels to uncomfortable levels.

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    9. Hi Valentina, While I was waiting on my agmatine order, I decided to continue citrulline malate and increase the dose. He was doing well and I didn't want to rock the boat. He seems to be in a little bit of a gut flare (bacteria?) - whenever this happens I always try to avoid any kind of sulfury type of supplement. Not sure if agmatine sulfate would be in the same sulfur supplement group as NAC taurine of methionine, but I avoid just in case when he has a flare up. Did you see anything negative with agmatine?

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    10. Valentina, forgot to add about the luteolin and quercetin: I tried both in the Neuroprotek supplement and it eventually made him a little aggressive at the time. I think it is the quercetin. I have never tried luteolin alone.

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    11. Aspie1983, Question for you: if you have addressed this before my apologies, have you tried 5mthf for NO/ammonia and do you know your bh4 status? Do you know if you have mthfr a1298c snp?

      https://www.ncbi.nlm.nih.gov/pubmed/16940192

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    12. Tanya this might be due the dysruption of progesterone by them:

      Endocrine disrupting activities of the flavonoid nutraceuticals luteolin and quercetin.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851288/

      Common autism supplement affects endocrine system
      https://www.sciencedaily.com/releases/2013/07/130715151158.htm

      As you can see they blocking progesterone, I know that Peter has made a post about neurosteroids/pregnenolone in the past on his blog.
      Now progesterone happens to act as a neurosteroid.
      On top of that it is a precursor to allopregnanolone (which ssri's raise aswell even at low doses that do not inhibit SERT and is even considered a major part of the mood raising effects of ssri's like prozac), progesterone and allopregnanolone also have a strong effect on gaba receptors.

      Now it doesnt end there, progesterone very powerfully modulates serotonin, especially in the amygdala.

      Progesterone Level Predicts Serotonin-1A Receptor Binding in the Male Human Brain.
      https://www.karger.com/Article/Abstract/328432 (not sure if im allowed to post the full article? most of you will know how to gain access to it anyway I think by now)

      'We found that P levels explained up to 65% of the variability in 5-HT 1A receptor binding (see online suppl. tables 3–5). Multiple linear regression analyses, including P plasma level, age and radiochemical variables as predictors revealed a strong negative effect of P on the 5-HT 1A receptor binding ( fig. 1 ) in the amygdala ( R2 = 0.46, p = 0.0069),retrosplenial cortex ( R2 = 0.65, p = 0.0063) and orbitofrontal cortex ( R2 = 0.41, p = 0.0147).'

      Im sure your son will respond horrible to 5ht1a agonists cause blocking progesterone will increase 5ht1a binding in the amygdala and other regions critical to emotion.
      I can only speak for myself that when I was 12-18 and lived with my parents that SSRI's also made me aggressive, but back then SSRI's were a considered a cure-all and no distinguishment was made between Major Depressive Disorder(lower serotonin type of depression) and autistic type of depression (elevated endorphins/serotonin, resulting in anhedonia, apathy/flat affect and social isolation).

      My mother has Crohn's desease and was on very strong opioids, cox2-i type painkillers and antidepressants, used them during pregnancy and nearly died while giving birth, and voila I was born resulting in... you guessed it Aspergers.
      Crohn's, antidepressants and opioids its not hard to see the correlation im trying to make.
      Now I would never blame my mother it is not her fault, just to clarify that.

      Once again, lysine acts as serotonin antagonist in the amygdala, allthough it maily acts as a 5ht4 antagonist there it also reduces 5ht1a, 5ht2a and some other receptors (read the lysine study posted earlier you can scroll down to the graphs and it shows the inhibitory effect of lysine).

      Something you could also try is Damiana which is used as an herbal tea and has progesterone binding activity (it is used in mexico as a relaxing/aphrodisiac type of tea).
      I have tried it and it is very nice, but the effect lasts like 2-3hours, it helps with sleep aswell.
      It is not that expensive at all, costs like 6-7euros for a bag of 80grams here in the Netherlands.

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    13. Tania,you are possibly right,my son has problems with sulfate compounds,zinc sulfate, nac,agmatine sulfate and also he tolerates very low dose ala, 200 mg, he becomes very hyperactive and with many movements. He is also having problems with histamine.I will try luteolin 100mg and quercetin very low dose, may be 30 mg, with no phenol enzymes. Valentina

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    14. In light of this discussion on Citrulline/Agmatine, I think I should point out the BCAA product I use called "Scivation Xtend" in addition to having a 2:1:1 ratio of L-Leucine:L-Isoleucine:L-Valine, (3.5g, 1.75g, 1.75g), Xtend also has 2.5g of Glutamine and 1g of Citrulline Malate plus 220mg of sodium and 170mg of potassium and some 640mcg of B6 (Pyroxidine Hydrochloride).

      I am not entirely sure which BCAA product Valentina uses (I assume it is this one I recommmended), but you do get a decent amount of Citrulline per serving of BCAA's which could either help or hurt depending on the situation. The reason I recommend Scivation Xtend above all the others, is the others all tasted too horrible and Scivation Xtend is reasonably priced and has many different flavors that do a great job of masking the very bitter taste of pure BCAA powder.

      On top of that, it is recommended not to supplement Arginine and/or Citruline in conjunction with Agmatine at the same time because they compete for the same enzyme in the digestive tract for absorption (if my memory serves correctly). A nice summary of other contraindications between Agmatine and Citrulline/Arginine can be found here (this is just some other persons opinions on Agmatine that I generally agree with based upon everything else I have read):

      https://examine.com/supplements/agmatine/

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    15. Hi Tanya,

      Yes i have indeed tried 5mhtf, it seemed to make me irritable, any methldonor seems to do this to me, including MSM and TMG (this was an unpleasant experience for me).

      Pretty sure im an overmethylator, however I never got this tested, but my b12 were double the upper limit last blood test and my folic acid levels were high aswell though still within range.

      I gone to the lab last friday to get my liver values, urea, creatinine, b12 and d3 levels tested, I hope they have came down now since I have stopped the heavy dose b-complex a while ago aswell as the d3 supplementation.

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    16. Hi Tyler,iam using Bcaas from nutrabio 5g per dose,yes,the taste is horrible but it has no other fillers.i make a blend with avocado, olive oil and flax seeds with bcaas and valproic acid.So, i wouldn't have this problem with citrulline and agmatine together. Can change for xtend brand as iam doing an order now. I wanted to ask you about luteolin, it is known that it acts as s dopamine reuptake enhancer, that would be good or bad for my son. Valentina

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    17. Tanya I forgot to ask, what is your son officially diagnosed with?

      Also your son seems to have most of the symptoms that I do if I understand correctly?

      You could try a low dose of citicoline (cdp-choline), Ive been on it a few weeks now and been doing incredibly well.

      It can be a little bit euphoric at times and there has been a huge increase in my cognitive function.

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    18. Thanks for the links Aspie1983. Yes it makes sense especially for my son - he has COMT mutation. Quercetin and luteolin inhibit COMT. And I do not use SSRIs for him. Damiana tea - have never heard of that - I will look in to it, sounds interesting! My son loves to drink teas after his meals. This would be easy to try. I think it is so soothing for his gut. I tried citicholine many years ago when we were trying a 5mthf protocol. I should probably try it again separately, and see what happens now.
      And he is diagnosed with Autism.

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    19. Be warned, damiana doesnt taste really good lol (I have gotten used to the taste).
      You could try the capsules, Ive used natures way in the past and it gives the exact same effect as the bulk powder I currently use.
      Most websites recommend 4grams of powdered herb, thats what I have been using.

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    20. I have no experience with Lutrolin other than to say my grandfather and now mother take it because they believe it is good for failing eyesight. Usually dopamine is good for eyesight so it sounds strange that it is a dopamine reuptake enhancer and it is used for this reason. I think it has other antioxidant properties as well.

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    21. I am sorry Valentina, I was thinking of lutein instead of luteolin.

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    22. Aspie1983, If i were to trail Citicoline on my Son, age 4 with ASD, 35lbs, What dosage would you recommend?

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    23. Hi Daniel,

      I have been using both 250mg daily aswell as 2x 250mg daily since starting, I've come to the conclusion that 2x 250mg daily is definatly more effective (especially in raising social awareness and seems to increase my interest in daily activites - no surprise it also upregulates dopamine receptors aswell as acetylcholine receptors).

      However it can also give some excitement and euphoria I noticed (especially after my 2nd dose of the day which I take at around 2pm - around 2hours after lunch).
      I would definatly not start with a full 250mg capsule Daniel Which seems to be the normal dose that is in the CDP-choline capsule, you could start trying with half a capsule since your son his weight is so much less than mine (95kilo which would be about what? 210 pounds I think?).

      One more thing, empty stomach seems to work best for me, taking it with food the effect seems less pronounced.

      One thing more I would like to raise awareness of though is that CDP-Choline apparantly also raises Uridine levels (which are often raised in autism). Im not sure what to make of it, but Uridine is also used as a 'nootropic'.

      Delete
    24. Peter and Tanya,

      With regards to the lysine being beneficial, it seems that Naviaux also mentions it in one of his papers that was mentioned in the recently posted video:

      Metabolic features of the cell danger response
      http://www.sciencedirect.com/science/article/pii/S1567724913002390?via%3Dihub

      quote taken from his paper:

      "4.14. Lysine
      The antiviral CDR is strongly regulated by the post-translational state of lysines on histones and immune effector proteins like the double strand RNA binding protein known as RIG1 (retinoic acid inducible gene 1), and the mitochondrial antiviral sensor (MAVS) (Jiang et al., 2012). Lysine ubiquitination facilitates oligomerization of RIG1, which is required for efficient binding to MAVS and interferon induction. SAM-mediated lysine methylation stabilizes proteins, inhibits ubiquitination, and works to oppose increased proteasome-mediated protein turnover that is part of the CDR. Dietary lysine is an antagonist of the gut serotonin receptor 4 (5HTR4), is anxiolytic (Smriga and Torii, 2003), and opposes the CDR."

      Now the whole CDR thing is new to me and im sure to a lot of others, but Im assuming that this indicates that lysine is beneficial in his CDR model of autism?

      He also mentions what I did a few days ago about the 5ht4 antagonism, I even linked a paper from what I remember that lysine supplementation can lower 5ht4a binding (and a few other 5ht receptors) in the amygdala.

      Delete
    25. Hi Tanya,

      Any update on the lysine, is it still going well?

      Delete
    26. Hi aspie1983-
      Well it seems there are certain foods that are causing flares- the most recent flare I thought went away but it’s back after the other night’s dinner. in other words, his gut is still after all the years not in100% shape . So I am going to stop supplements for 2 weeks and trial the low lectin diet to see if I can pinpoint that as the immediate trigger. I don’t think he was having any problems with lysine though. As soon as I get my answer after this trial I will add the lysine back in. Are you using it now?

      Delete
    27. Hi Tanya,

      Sorry to hear that, have you tried Miyarisan (clostridicum butyricum), I believe this was the probiotic that permanently helped me even after I discontinued it.

      Im considering going back on it in 2018 to see if I can get more benefits out of it.

      As for the lysine mine has arrived but Im going very strong on cordyceps militaris once again :D.
      I have to say the first 2 days when I was back on it I tried 2x 1.5gram daily (so totalling 3gram) and the effect was far less pronounced then when I am using 2x 3grams a day (totalling 6grams daily).

      Though the effects are definatly felt at 2x 1.5gram daily, 2x 3gram feels so so much better.

      Once again I would like to point out that this effect is NOT PLACEBO, this effect I only feel with cordyceps and I feel it really is due to supressing my overactive immunesystem.

      Good luck Tanya.

      Delete
    28. HimAspie, after your comments about your positive response to miyarisan, i decided to give it a try. Waiting for the order to come from Japan. Fingers crossed it goes well... I don't even think I will need a full two weeks to test removing the higher lectin foods - I've already got the answer that they have really been messing things up for him - yesterday he had crazy behavior, like a drug addict searching for oatmeal, after the second day on the trial broke out in a few rashes, and then some flu like symptoms today. I guess this is that opiod effect some the lectins are having on him - withdrawal. So going to lighten the load and just remove the rice and beans and oats out of his diet until things calm. I am grateful he is such a good eater and isn't feeling deprived without them on the menu (after a few crazy moments the first day) I'm tinking of testing out N acetyl glucosamine also.. Really hoping miyarisan helps.

      Delete
  5. Hi everyone,

    This seems interesting - A dietary supplement dampens the brain hyperexcitability seen in seizures or epilepsy

    https://medicalxpress.com/news/2017-10-dietary-supplement-dampens-brain-hyperexcitability.html

    Looks like Glucosamine may have some potential in brain hyperexcitability.

    http://www.jneurosci.org/content/37/34/8207

    AJ

    ReplyDelete
    Replies
    1. AJ, that is interesting, particularly for anyone with epilepsy of just odd electrical activity on their EEG.
      We can add to our list "protein O-GlcNAcylation as a regulator of neuronal excitability".

      Glucosamine is sold as a drug in Europe to treat arthritis.

      Delete
    2. Hi Peter, it seems that NAG (n-acetyl glucosamine) is far more brain specific than glucosamine sulfate (the most common form of glucosamine).

      Could be possible that the effects were due to the acetyl groups?

      Delete
    3. Aspie, it looks like to do work differently:-

      Differential metabolic effects of glucosamine and N-acetylglucosamine in human articular chondrocytes
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785807/

      Delete
    4. Good point, all in all, im very wary of glucosamine sulfate and ubiquinol.

      Either one of these gave me a huge cyst on my upper back, this happened all within one week, by the time it got removed it was about 3x5cm and I was really scared.

      Though I do have a tendency to think its the ubiquinol which has an effect on lipid metabolism.

      If you can remember sone of my older posts my bloodtests showed that my triglycerids are also abnormal.
      They are always very very low, a lot of my blood tests also showed they were below the bottom limit and I do eat enough fat. This happened during the ubiquinol and glucosamine (glucosamine sulfate to be specific) supplementation.

      Also ubiquinol made me tired every single time, Ive always found this very odd, in my case I would take 200mg at dinner and I would start yawning all the time less than half an hour later.

      With regards to the n-acetyl glucosamine, there have been reports on depression forums that this particular form of glucosamine somewhat alleviated their anhedonia type symptoms and that was one of the only supplements that did this that they tried.

      Delete
  6. Sometimes I feel as if autism/asd both have 2 dysfunctional systems:
    mitochondrial like dysfuctions and social dysfunctions and improving the mitochondrial side of the dysfunction seems to annihilate the irritability of autism/asd (atleast for me), but the impaired social function remains (feelings of empathy).

    The nitric oxide donors and omega3 fatty acids feel as the 'oil' for the car to me.

    Where as cordyceps for me, opened me up emotionally, which i highly suspect can be done through immune modulation/gut microbes (very specific ones, not any random probiotic will give this effect), cordyceps is also very high in beta-d-glucans.

    To give you an idea how powerfull microbes can be on an emotional level:

    https://en.wikipedia.org/wiki/Behavior-altering_parasites
    Read up on Toxoplasma gondii and Mermithid nematodes it will blow your mind how powerfull this can affect behavior and emotion!


    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359272/

    "ASD possible gut–brain connection might be driven by MICROBIAL METABOLITES"

    "Evidence of a role for bacterial metabolites in eliciting neurobehavioral symptoms of ASD also comes from a recent study of a maternal immune activation (MIA) model of ASD in mice, in which the MIA mice had significant increases in 8% of 322 serum metabolites, with one particular metabolite, 4-ethylphenylsulfate (4EPS), displaying a striking 46-fold increase. 4EPS is produced by gut bacteria, and treatment with a particular gut bacterial strain (BACTEROIDES FRAGILIS) in early life changed the microbiome structure of MIA offspring mice, restored levels of 4EPS to normal, and greatly improved ASD symptoms. Furthermore, injection of 4EPS into naïve mice resulted in anxiety-like behavior, providing clear evidence that at least one metabolite produced by gut bacteria can substantially affect behavior in mice (56)."

    So, bacteroides fragilis greatly improved ASD symptoms, yet in naïve mice resulted in anxiety-like behavior!

    In normal kids/adults their microbic system is allready filled with bacteroides fragilis and such and they have normal amygdala reactivity. Yet in people such myself (Aspergers), there is a huge malfunction in the amygdala (genetically).

    It seems to me that the exposure to certain bacteria/parasites (yes cordyceps is a parasitic fungus!) induces a defense mechanism through immune/gut modulation and thereby upregulates/restores normal connectivity in emotional regions (mainly the amygdala).
    This seems like a somewhat similar mechanism as the well known fever effect in autism, where social behaviors temporary normalize.

    One mans toxin can be another mans cure it seems.

    ReplyDelete
  7. Ok Tyler, I really would like to know if luteolin could help my son with his dopamine issues, acting as a dopamine reuptake enhancer.Today,after many months,he had a kind of episode of happy madness.He undressed completly in his granparents´s house and went to play at the backyard with total deshinibition and sense of freedom.His grandparents didn´t know what to do.Luckly he was also with his sister who managed the situation as better as she could,she is fourteen.It was a long weekend and the weather was very nice. I am doing gaba but it doesn´t seem to cause any effect. Valentina

    ReplyDelete
    Replies
    1. I don't know much about Luteolin other than it being related to Quercetin. I think it was one of the main ingredients in a commercial autism treatment from a Greek autism researcher called Neuroprotek. I have read other stuff about it in the past when I tried to familiarize myself with every medical.compound natural or.otherwise that I could, but my memory is fuzzy on Luteolin foe whatever reason and therefore I need to reread some stuff before commenting more.

      Delete
  8. A new study which shows intermittent fasting decreases macrophage induced inflammation and upregulates VEGF came out today:

    Press Release:

    https://www.sciencedaily.com/releases/2017/10/171017110041.htm

    In severe autism low levels of VEGF and high levels of VEGFR-1 (VEGF Receptor 1) have been shown in at least one study I read. Even though this study was dealing with obesity and weight loss, I wonder if low VEGF levels in the mother may contribute to the hypothesized obesity induced autism as low levels of VEGF from the mother would cause an upregulation in VEGF receptor count as a response that could be permanently epigenetically programmed in utero. If VEGF levels can be normalized via intermittent fasting as this paper suggests with respect to obesity, then this would be a very good thing.

    ReplyDelete
    Replies
    1. Tyler, it looks like humans evolved based on there being periods of food scarcity. In today's society we now have the opposite, day long grazing on snack foods.

      Periodic fasting is clearly a good idea for many adults.

      VEGF in autism (and cancer) gets very complicated and at the end of the day it looks like increasing eNOS and NO may be the best way to affect VEGF.

      Delete
  9. Another possible beneficial effect of fasting would be depriving bad bacteria in the gut of their fuel (carbohydrates).

    My labs are in by the way, proving how efficient NAC and taurine are in bringing liver values back to normal.

    My creatine kinase still came back in elevated, however I am feeling double as healthy as I did roughly 3 years ago.

    March 2016:
    https://ibb.co/kXvsam

    Started adding vitamin d3 supplementation and eating a whole egg every other day + 2 full eatingspoons of oliveoil.
    Introduction of half a tablet of a b50-complex.

    August 2016:
    https://ibb.co/kx7Nam

    Elevated LD (lactate dehydrogenase) - cordyceps and glycine propionyl-l-carnitine are known to lower this I was not using these at the time of this bloodtest.
    Continued d3 supplementation throughout the winter 5.000iu-10.000iu a day aswell as the b50-complex

    March 2017:
    https://ibb.co/mUx5vm
    and
    https://ibb.co/gq0avm

    B12 and d3 Came in strongly elevated, stopped d3 supplementation instantly and b12 supplementation I stopped at around may I think.

    October 2017 (blood drawn last friday):
    https://ibb.co/fyczMR

    d3 levels have come down to appropiate levels, b12 levels have come down a bit to more optimal levels.
    EGFR and creatinine greatly improved in comparison to a year ago.
    Liver values greatly improved, minor reduction in urea compared to previous bloodtests. CK still elevated.

    Plan for the next 2 months:
    * Continue taking my vitamin 1000mg, NAC 600-1200mg, taurine 3gr, citrulline 6gr, glutamine 5gr, cdp-choline 500mg and omega3's.
    * Adding cordyceps and inositol
    * Start using bright light therapy again in the morning
    * Getting blood drawn early december for the following values:
    - b12
    - d3
    - asat/alat
    - ck
    - ld (lactate dehydrogenase)
    - urea

    If d3 levels have come down more than 15 points then I will add a small dose of 500-2000iu depending on how much the d3 levels have dropped.Getting lactate dehydrogenase and CK drawn, im pretty sure cordyceps will improve my values.


    januari 2018:
    Adding vardenafil to try and improve oxytocin levels, which has allready arrived:
    https://ibb.co/d7J3Fm

    mid februari 2018:
    Introducing low dose phosphatidylserine (100mg), I have used this in the past and felt as if this had some benefits

    ReplyDelete
  10. Aspie1983, may I ask why you are taking the glutamine? Is this for gut healing? I have not read much in comments from others on this blog about gut issues in their kids. Diet still makes or breaks my son - certain foods can still impact him negatively (especially hig oxalate), certain probiotics can still to this day set him back. His gut is helped immensely by mast cell stabilizer but it is still not 100%. So frustrating. Not sure how much infections are still playing a role in this or if this is now becoming an autoimmune issue. I can't imagine what he would be like if I did not pay attention to diet and just fed him anything. At the same time, diet alone is not a cure all. But the gut is probably is biggest problem area. I worry about this the most - more than what is happening in his brain, or I should say not worrying that the problems start there. Sorry this has become part venting post but also plea to others in same boat for ideas.

    ReplyDelete
    Replies
    1. Hi Tanya no worries at all, if I got the time to reply to you I will.

      L-glutamine is very low in almost all people with autism, however dosing is tricky!
      Now we all know about glutamate as a neurotransmitter, however it seems that l-glutamine itself is also present in brain acting as a fuel and is very necesarry, its very tricky and complex and I do not fully understand this myself aswell I have to admit.
      L-glutamine is also necesarry as a building block for glutathione, along with glycine, cysteine (NAC we use) and a bunch of vitamins/minerals.

      My personal experience with L-glutamine:

      I have taken anywhere from 1gram once a day to 2 times 10gram a day, I found that dosing more than 5gram at once would energize my brain too much causing a 'crash' an hour or 2 later.
      It 'feels' to me that the first priority of L-glutamine is the help healing the gut, however going over the optimal amount for someone gut, the rest of the L-glutamine can go in any direction that the body at that certain moment decides is most critical to its survival this can either be the brain as fuel, glutathione production or stored in muscles.
      I have noticed a mental effect from anything over 2grams, this sometimes makes me calm, but at other times it can be energizing.
      Now in the brain glutamine can affect ofcourse the glutamine levels itself in the brain but also convert to glutamate and gaba.
      All are necesarry and glutamate is not the devil, we need glutamate aswell, the key here is as with everything else: balance.
      I would definatly not go over 2x 2grams a day l-glutamine if I was to give a kid with autism l-glutamine and would probably start very low, as low as 500mg on an empty stomach, if that goes well for 2-3 days then go up 2x 500mg daily, slowly working your way up.
      When your son starts going too 'hyper' thats the point what you should lower the dose next day.
      You want him to have enough brainfuel and energy to both be active at school and yet calm enough to not go hyperactive.
      In essence optimal feeding of glutamine, glutamate, gaba and glutathione pathways without overspilling with too much glutamine, my experience is the excess glutamine shows a trend to go towards glutamate production.

      Adding p5p (active form of vitamin b6) in addition to the glutamate keeps the pathways working properly, however also go slow on the p5p.

      How are his stools? I used to have constipation by nature it seems (rabbit like poop so to speak, sometimes even clumped together and painfull toilet visits) untill I somewhat decreased my fiber intake and started using clostridicum butyrate (butyric acid raising probiotic strain - Peter has discussed this one before).
      Im currently not using clostriduicum butyricum (to save money and try other supplements) also I feel I do not need it at the moment.
      Its been a few months since Ive last used the clostridicum butyricum and constipation is completely gone and this part of my body seems to have permanently healed *knock wood*.
      Bloating is also 95% gone, I rarely get it, but sometimes I still do, so theres still minor room for improvement there.
      I do believe I have a genetic predisposal for gut related problems (also as mentioned before my mother has severe crohn disease).
      I've had a horrible gut flora in the past for as long as I could remember, Its definatly not something that the body can automatically adjust to and fix. Pretty sure I was carrying around the bad gut flora from my mom all these years till I started probiotics.

      Its very good that you focus on the gut, this where alot of the problems come from, I will reply later with more detailed information that you will be very interested in to read, especially with regard to propionic acid and intact mitochondria being necesarry to oxidize it so it cannot enter the cerebospinal fluid.

      Also the behavior autistic and asperger patients often show have alot similarity with heroin/opioid addicts (social isolation, morphine/opioid like constipation).

      How are your son his stools? constipation or?

      Delete
    2. Tanya,

      The following shows that is possible that there it is possible to have both hypo and hyper glutamate functioning in autism/asd (different brain areas though).

      Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [¹H]MRS study.
      https://www.ncbi.nlm.nih.gov/pubmed/23838890

      "Of those with ASD, 15 fulfilled the 'narrowly' defined criteria for typical autism, whereas 13 met the 'broader phenotype'. We measured the concentration of the combined glutamate and glutamine signal (Glx), and other important metabolites, using proton magnetic resonance spectroscopy in two brain regions implicated in ASD--the basal ganglia (including the head of caudate and the anterior putamen) and the dorsolateral prefrontal cortex--as well as in a parietal cortex 'control' region. Individuals with ASD had a significant decrease (P<0.001) in concentration of Glx in the basal ganglia, and this was true in both the 'narrow' and 'broader' phenotype. Also, within the ASD sample, reduced basal ganglia Glx was significantly correlated with increased impairment in social communication (P=0.013). In addition, there was a significant reduction in the concentration of other metabolites such as choline, creatine (Cr) and N-acetylaspartate (NAA) in the basal ganglia. In the dorsolateral prefrontal cortex, Cr and NAA were reduced (P<0.05), although Glx was not."

      "In conclusion, individuals across the spectrum of ASD have REGIONALLY SPECIFIC abnormalities in subcortical glutamatergic neurotransmission that are associated with variation in social development."

      This once again highlights the complexity and it seems is glutamate is both a blessing and a curse.

      Delete
    3. Aspie1983 so many thanks for your insights! and everything else you posted after this thread - will read them in depth later tonight. It really is uncanny the similarities in symptoms my son has with you. Yes, B6 (p5p) he needs. Just ran out recently and forgot to order more so maybe that's my sign never to be without it for him. He rarely has bloating now but still does with certain foods that I try out every now and then to see if he his now able to tolerate. When he was younger, we were surprised to learn after an abdomen xray my doctor ordered, that he was very constipated. He never missed a day without going. The doctor told us you can still have daily bowel movements and yet be constipated. This was my son. He still he has sluggish days. He is 18 now and I'm not always following him in to the toilet to check ha! but when he is off behavior wise I do look because it is a good indicator of what is going on. And like you my son has same response at times to high fiber - that can be an indicator of SIBO. But also IBS people have issues with too much fiber. It's all about the gut bacteria and if appropriates amounts are in the right places. I am interested in trying cordyceps now based on all you have shared. It was one of those on my list of things that help with mast cells. Anyway, thanks again. The gut is key for my kid... If I can just crack the code.. Really appreciate your insights

      Delete
  11. Strongly suggest everyone to read the entire article, however I will put some highlight below.

    Enter....:

    Autism: Metabolism, Mitochondria, and the Microbiome
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865378/

    "Could a substance, through co-evolution of the bacteria and host via biochemical processes, be capable of creating repetitive movements, restrictive interests, social impairment, and in some cases, paradoxical isolated brilliance—all behaviors associated with ASD? These biochemical processes include neuroplasticity, learning and memory, neurotransmitters, mitochondria energy production, immune function, intra- and inter-cellular interactions, and gene expression."

    "In addition, they had very restrictive interests, strange movements, and bizarre cravings for food. I was told they suffered from a condition known as autism. Many had digestive issues, and I remember waiting (and waiting!) for some of them to have a bowel movement."

    "Another patient in one of the camps where I worked came to me late one night saying he did not feel so good and confessed that he had completely eaten his pillow!"

    Eating uneatable objects that are impossible to digest, thereby filling his stomach so he wont have enough room in his stomach for other food later on and thereby depriving the bad bacteria of their fuel?
    Opioid induced (self)destructive behaviour?

    I can recognize myself in these strange behaviours from the past like no other. Subconcious attempts to modulate their guts is whats going on it seems.

    I will give myself as an example:

    I used to eat lemons as a kid when I went to restaurants with my parents, what I found amazing was that even as a kid I was eating them I didnt like the taste obviously, but I felt 'the need/urge' to particulary eat lemons.
    I realise now, over 2 decades later that I was subconsiously trying to increase my HCL levels and krebs cycle through the acidity of the lemon and its citric acid contents.

    Unrelated to food/gut but we see this also happening with self injury behaviours which has to with beta endorphin/opioid like overactivity.

    Years ago I felt this need to very look good physically, so I decided to go tanning, after about 5 tanning sessions I noticed how I had been destroying things in my house and was hitting my forehead very hard multiple times against the wall and biting my own hand very hard. I realised this always happened within an hour or two after I came back from the tanning salon.

    If theres one thing my body seems to hate then its beta-endorphin/opioids this might also explain my aversion to alcohol (and its the same reason why alcoholics crave it)
    Temporary re-activation of 'social wanting' through downregulation of opioid receptors during hangover definatly also seems at play for my brief window of feeling 100% human.

    ReplyDelete
  12. With regards to the self harm induced by beta endorphin/opoid overactivity, I think the self harm we are seeing is once again a subconsious mechanism to try and bring the body back to a normal state.
    We all know that pain causes the RELEASE of opioids, it feels as inflicting pain 'flushes' these opioids out of the body and calming down the mind.

    Just as I catch myself having a music preference for sad songs (to subconsiously induce tears and release tension - amazingly human tears actually contain prolactin and opioid like peptides!).

    If you cannot relieve this 'blockade' thats been bothering in the form of crying, you literally become an emotionless robot. As a man of 1.90m it was very hard to accept and see that Im also vulnerable.
    About 5 years ago I was emotionally so dulled that I could not even cry on top of that I was in total social isolation, pulling out the telephone cord, I didnt want help from anyone in any form.

    Surprisingly I found relieve in inducing crying through sad songs and my mood and emotional capacity slowly started to come back I noticed I start leaving the house and talk to people a bit.
    Im sure during crying negative emotions get processed and some brain rewiring takes place including fear extinction and neuro plasticity.

    After all to be human is to be vulnerable.

    Anyways... back to the article:

    "The concept that ASD could be a closed gap junction state seems to fit. Gap junctions are gated by a number of factors including dopamine, calcium, and cytokines; all influenced by PROPIONIC ACID. Gap junctions play a major role in cellular differentiation, and in particular, peripheral nerve, cardiac, uterine, and GI function."
    "Gap junction communication is involved in neurotransmission in the basal ganglia, prefrontal cortex, nucleus accumbens, and hippocampus: all areas that are implicated in seizure and movement disorders."

    ReplyDelete
    Replies
    1. There is already quite a lot of research on mu-opioid receptor antagonists reducing self-harm and improving general behaviors that I am surprised hard dopaminergic drugs like risperidone are still prescribed for aggression, whereas nalaxone/naltrexone is much safer.

      As for gap junctions, they exist throughout the brain, in some areas more than others and all they allow is for fast electrical transmission from neurons to other neurons via direct flow of ions from one neuron to another which can cause a cascade of very fast electrical activity, whereas typical synapse communication requires chemical cues to open ion channels. For instance, in the global pallidus internus (aka medial pallidum) which is responsible for inhibiting related cognitive, motor, and limbic functions to the actual function being selected by the striatum (direct, indirect, hyperdirect pathways), in one paper I read it showed that the increased firing frequency of any neuron in the GPI would cause a cascade of inhibitory output signals to the thalamus to spread via gap junctions. The faster the frequency of stimulation, the stronger the inhibitory tone so to speak.

      You also have a lot of gap junction communication in the thalamic reticular nucleus which is very important in gating sensory information in the thalamus, via the cortex. The TRN receives inputs from the cortex and other parts of the thalamus but has no reciprocal connections with any other parts of the brain. In this sense it is a one way regulatory function, and much of the communication is governed by densely connected inhibitory neurons in the RTN via gap junctions as well.

      If gap junctions were "closed" in autism, people would probably not survive as they are fundamentally critical to neurotransmission. Kind of like if your brain could not respond to glutamate at all (which would mean instant coma and death).

      Delete
    2. Tyler the possible danger with naltrexone (and possibly LDN) would be upregulation of opioid receptors when naltrexone leaves the system aswell as immune potentiation (I can only speak personally but I am 100% sure I have an OVERACTIVE immune system).
      Naltrexone also has a short halflife.

      Even people on forums who are opioid addicts try LDN in attempts to create more sensitive opioid receptors.

      I think I need 'tollerance' to opioids, not to the point where I would be in physical pain, but to the point where my 'social wanting' system comes back online.

      People who have POOR IMMUNE function use LDN before bed in an attempt to upregulate the receptors while they sleep and there have been reports of excellent results for these people, however I would personally never ever touch LDN or naltrexone.

      Once again back to cordyceps:

      I think some of the metabolites from cordyceps either positively modulates my gut or acts as decoy for the immune system.
      Humans have probably became immune through evolution to the noxious effects of cordyceps (zero side effects of cordyceps have been report), but pherhaps our receptors in our guts still detects cordyceps though even though it doesnt exert a negative on effect on the body anymore thanks to evolution.

      In this way cordyceps (and possibly other bacteria/parasites that are not dangerous for humans anymore) possibly act as a 'decoy' for the overactive immunefunction, this means temporary but complete annihilation of all autistic symptoms.
      It seems the immunesystem gives priority to disposing cordyceps, thereby giving the body a 'break'.
      Once the immunesystem is done attacking cordyceps and has successfully disposed it, the autistic symptoms return as the immunesystem starts attack the body again.

      The reverse can also be seen with the study I posted last night about the administration of propionic acid in the cerebrospinal fluid of normal animals, they started displaying the full spectrum of autistic symptoms within 2minutes!!! yet within 30minutes (when their body got rid of the propionic acid in cerebrospinal fluid) they returned back to normal!!!

      We need to find a way to permanently alter the gut homeostasis, this is very hard and could require very specific protocols among austic patients.

      Delete
  13. SELF-CENTERED GASTROINTESTINAL BACTERIA

    "How do people ACT WHEN THEY'RE SICK? Sometimes their behavior changes, but NOT NECESSARILY IN A BAD WAY. There is a gestalt of the things I had seen—special-needs children, my patients, findings from the laboratory, and patients with digestive system complaints who were told they were crazy. And now infectious disease experts are FINDING UNIQUE POPULATIONS OF GI BACTERIA, which on closer evaluation actually produce bioactive fermentation products, PARTICULARY FOLLOWING INGESTION OF THE FOODS MANY OF THESE PATIENTS CRAVE."

    "As a weak acid, PROPIONIC ACID BECOMES MORE LIPID-SOLUBLE in acidotic conditions (ie, DURING “SICKNESS”) and concentrated within cells."

    "Other similar compounds like ETHANOL(ALCOHOL) and VALPROIC ACID, both prenatal risk factors for ASD, also impair propionic acid metabolism."


    "Could GI tract bacteria control behavior? There are examples of this in biology. Rabies and Bornavirus infect the CNS in animals and induce aggression that spreads the virus in the saliva from one animal to another through biting behavior. CORDYCEPS (Ophiocordyceps unilateralis) is a fungal infection that affects the behavior of ants, causing them to climb to the top of plants before they die."

    There we go... the authors even mention cordyceps, I was not even aware of this study before I started supplementing it!

    "Mundane acts such as sneezing with a common cold or increased gastric motility leading to nausea and vomiting in viral gastroenteritis are in the best “interest” of the infectious agent. Could similar things be happening with carbohydrate craving, diarrhea, and fecal smearing in ASD to feed and spread bacteria? The concept seemed heretical but plausible."

    "I was perplexed and intrigued by the seemingly disparate observations of BIZARRE FOOD CRAVINGS, GI symptoms, epilepsy, infectious processes, and metabolic disturbances in this growing number of affected children. However, there were reports that some children appeared to improve, either spontaneously, after certain broad spectrum antibiotics, or possibly by altering their diet."

    Bizarre food cravings... here we go again, attempts to subconsiously modulate the gut population seems whats going on.

    ReplyDelete
  14. "Again, THE IDEA AT A VERY SIMPLISTIC level: feed a GI tract bacteria, and that BACTERIA PRODUCES A NEUROACTIVE COMPOUND that affects brain function and behavior."

    "We began with very simplistic first-level physiology—injecting TINY “PUFFS” OF PROPIONIC ACID INTO THE CEREBROSPINAL FLUID of live adult rats through cannulae inserted into the cerebral ventricles. We could film their behavior and record electrographic activity."

    "IT WAS NOT A SUBTLE RESPONSE. The rats also had brief complex partial seizures that sensitized with repeated exposures, had electrographic changes in their basal ganglia associated with tics, and were socially impaired. They also exhibited increased anxiety and remarkably, would fixate on objects vs other animals, even had “favorite” objects, and would exhibit further “rigid” perseverative behaviors, such as learn a maze without difficulty but not be able to “unlearn” it with maze reversal. All were consistent with the rigid, stereotypic, and impaired social behavior in ASD patients and their peculiar habit of “preferring” objects to people.
    BUT WHAT WAS THE MOST REMARKABLE was that we would give these compounds to an apparently NEUROLOGICALLY INTACT ANIMAL; WITHIN 2 MINUTES, IT WOULD EXHIBIT THESE BEHAVIORS, AND WITHIN 30 MINUTES, IT WOULD REVERT BACK TO APPARENTLY NORMAL BEHAVIOR. WE WERE SHOCKED. Control compounds such as propanol, the nonacidic alcohol analogue of propionic acid, were tested without effect."

    "RECOVERY COULD BE EXPLAINED BY THE FACT THAT PROPIONIC ACID AS A FATTY ACID WOULD GET OXIDIZED IN THE MITOCHONDRIA (defective mitochondria in autism, so no recovery!!!??????), so the animals would first become hyperactive and ignore each other, then half an hour later their behavior would be apparently normal (return to their gut homeostasis with proper working mitochondria???). On one level, we were showing that AN INTACT NERVOUS SYSTEM COULD BE HIJACKED BY A METABOLITE."

    What im thinking that is happening:
    Improper functioning mitochondria (autism) = propionic acid doesnt get oxidized = instead leaks into the cerebrospinal fluid = autism behaviours.

    This once again shows the importance of correcting mitochondrial dysfunction in autism.

    This study also explains my extremely positive and FAST reaction to cordyceps militaris (Ive felt it within 5minutes on an empty stomach as Ive posted before).

    ReplyDelete
  15. "Furthermore, this would in a NORMAL ADULT ANIMAL offer a potential explanation of the fluctuations of behaviors in ASD patients, where behavioral exacerbations occurred during carbohydrate diets (which theoretically would increase propionic acid production from ASD-associated GI bacteria), and remissions occurred following dietary carbohydrate restrictions (which would reduce propionic acid production by GI bacteria)."

    KETO anyone???

    NEUROINFLAMMATION AND CYCLIC ADENOSINE MONOPHOSPHATE RESPONSE ELEMENT-BINDING PROTEIN

    "These had been present throughout their lives,66,67 and the ongoing inflammatory process has some similarity to previous findings in epilepsy patients.68 This is a markedly different finding from what was assumed in the literature: prenatal irreversible brain synaptic alterations."
    "INTRIGUINGLY, NEUROINFLAMMATION ISN'T COMPLETELY A BAD THING; activated microglia and astrocytes have been found to be instrumental in “synaptic shearing,” reorganizing neuronal pathways. It is also implicated in both seizure and in learning and memory."

    "A GI bacterium appeared to be releasing a metabolite that is able to get the brain to “remember” where the bacteria was fed. This might be adaptive, but could overactivation of this pathway lead to “impaired forgetting,” obsessional behaviors, food interests, tics, and the enhanced restrictive memories found in ASD?"

    "we are finding that SHORT CHAIN FATTY ACIDS, INCLUDING PROPIONIC ACID, are histone deacetylase inhibitors and thus ARE SWITCHES FOR GENES, particularly those involved in the metabolism of catecholamines, important in anxiety, arousal, movement disorder, aggression, and craving.35 There is the potential that bacteria can control and tinker with our metabolism and even our genes."

    "Now it seems these GI tract short-chain fatty acids are linked to other theories for ASD. ARE THESE BACTERIA ACTING BY “CONTROLLING” THE HOST? Can GI tract bacterial metabolites affect brain function and behavior?"

    ReplyDelete
  16. Other SCFA's such as butyric acid for example increase oxytocin expression in autism models and have other pro-social effects:

    Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model.
    https://www.ncbi.nlm.nih.gov/pubmed/26577018

    Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism.
    https://www.ncbi.nlm.nih.gov/pubmed/25240644

    Now this says valproic acid is beneficial in this model! and if you scroll up you can also read that valproic acid also effects propionic acid metabolism. This is just to show the paradox, yet how effective got modulation can be (valproid acid itself is a drug with harsh side effects)

    Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles (they used sodium butyrate and trichostatin A).
    https://www.ncbi.nlm.nih.gov/pubmed/23727821

    "This was associated with a specific upregulation of oxytocin receptor (OTR, oxtr) and vasopressin V1a receptor (V1aR, avpr1a) in the nucleus accumbens (NAcc), through an increase in histone acetylation at their respective promoters."

    This shows capacity of gut modulation to effect the hedonic tone in the brains reward system.

    Now short chain fatty acids are HDAC-inhibitors, and so is sulforaphane:

    Dietary Sulforaphane, a Histone Deacetylase Inhibitor for Cancer Prevention
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777483/

    ReplyDelete
  17. There has been a lot of discussion on this blog about Zinc and brain pH levels, but a new paper links them both which though not specific to autism, it may be indirectly related:

    Press Release:

    https://www.sciencedaily.com/releases/2017/10/171017092242.htm

    Paper (Open Access):

    https://www.nature.com/articles/s41598-017-12409-0

    ReplyDelete
  18. Here is a new finding which may help describe why more boys than girls are diagnosed with autism via the ERK1 pathway which Peter has discussed extensively in past blog posts:

    Press Release:

    https://www.sciencedaily.com/releases/2017/10/171017091906.htm

    Paper (Open Access):

    https://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017184a.html

    In particular it was found the ERK1 pathway in males seems to directly affect neurotransmission in the striatum as well as increase D2 receptor count (i.e. hypersensitized).

    ReplyDelete
  19. Peter, have you ever looked at P-glycoprotein?

    It just looks interesting...

    P-gp is found in brain capillary endothelial cells
    Decreased P-gp expression has been found in Alzheimer’s Disease brains
    Altered P-gp function has also been linked to inflammatory bowel diseases (IBD)
    Verapamil and Quercetin are inhibitors of P-gp
    This protein also functions as a transporter in the blood–brain barrier

    Wikipedia: https://en.wikipedia.org/wiki/P-glycoprotein

    /Ling

    ReplyDelete
    Replies
    1. Ling, it seems to be a limiting factor in the absorption of drugs, particularly in the brain. So inhibiting P-gp will increase how much of a drug reaches the brain, even though it may not increase how much is in the blood

      Delete
    2. I also found this:

      "Pgp serum levels in patients with drug-resistant epilepsy were significantly elevated compared to patients with medically controlled epilepsy."
      https://www.ncbi.nlm.nih.gov/pubmed/28560774
      /Ling

      Delete
  20. Hi Aspie yes I remember reading in the full Naviaux paper from 2013 I think it was about Lysine as part of treatment factor -also b6. I added in lysine to balance the citrulline. So far, so good.. What Naviaux says resonates with me too - for my son’s version of autism..

    ReplyDelete
    Replies
    1. Are you giving him it without food? I think this is crucial with amino acids, I think it also can be problematic as it requires daily timing.

      Good to hear that your atleast not getting any side effects so far, Ive found some cheap bulk powder on iHerb, 200grams or so should last ages.

      Tanya, was it your son who also had low triglycerids like me?
      I found a supplement that can possibly correct this I think, it is called ALPHA-GPC and its a form of choline.
      It seems very effective at it with P values: 0.0096 (Free choline), 0.0075 (Free fatty acid), 0.0036 (Acetoacetate), 0.0012 (3-Hydroxybutyrate), 0.0360 (Growth hormone)

      Glycerophosphocholine enhances growth hormone secretion and fat oxidation in young adults (assume this in healthy people? so effect might even more pronounced in those with impaired fat oxidation).
      https://www.ncbi.nlm.nih.gov/pubmed/22673596

      A graph from the study:

      alpha gpc group: time 0 60min 120min

      Free choline (mmol/L) 8.1 12.1 11.4
      Free fatty acid (mmol/L) 336 428 694
      Glycerol (mg/dL) 5.3 5.1 6.5
      Acetoacetate (mmol/L) 21.7 19.6 66.8
      3-Hydroxybutyrate (mmol/L) 38.7 33.0 138.0
      Growth hormone (ng/mL) 1.4 4.5 0.5

      placebo group showed no changes at all basically

      ___

      From examine.com (which is reliable source):

      "Alpha-glycerophosphocholine (Alpha-GPC or α-GPC) is a cholinergic compound that is used for its cognitive-promoting properties, and to enhance power output in athletes. It appears to also support cellular membranes, and may aid in preventing cognitive decline."

      "One study has noted that repeated, but not single, injections of Alpha-GPC has resulted in a greater neuronal accumulation of inositol phosphate. This was not blocked by atropine (antagonist of muscarinic cholinergic receptors), and was hypothesized to be due to an increase in phospholipid synthesis.[33] Along these lines, Alpha-GPC has been found to potentiate potassium-invoked calcium release in the hippocampus and receptor-mediated production of inositol phosphate"

      Now as I have said before my 'social opening' improves on inositol supplementation (tastes like sugar by the way), Im not sure if this is the mechanism by which alpha-gpc could work.
      Maybe Peter knows if theres a difference between the two.

      "Possible improvement in phospholipid biosynthesis associated with Alpha-GPC, and events which are seen with Alpha-GPC but are not readily replicated with choline are thought to be due to interactions with phospholipid metabolism"

      Delete
    2. Turns out that inositol is a xanthine oxidase inhibitor which are used for treatment of hyperuricemia and related medical conditions including gout?

      https://en.wikipedia.org/wiki/Xanthine_oxidase_inhibitor

      Delete
  21. yes empty stomach first thing in morning. I'm wondering about a bed time dose - I read some reports of people saying it really helped their quality of sleep when given at bed time.
    Nope not my son with the low triglycerides - last we checked his cholesterol was elevated.

    ReplyDelete
  22. Hi Peter, here is an interesting study about luteolin as a vascular protective agent. It acts on vascular endothelial cells leading to nitric oxide production.May be this is the main reason why is so helpful for many people.

    https://www.ncbi.nlm.nih.gov/pubmed/23604495

    Valentina

    ReplyDelete
  23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729335/#!po=18.4211

    NAD+ depletion from gene mutations is the main cause of Autism. NAD+ precursor Niagen should be able to treat the disease if treatment start early before brain is fully developed

    ReplyDelete
    Replies
    1. I have given my son (Nicotanimide Riboside) Niagen for about 5 or so years now and it has not cured his autism, though I do believe its mitochondrial benefits make it a great supplement in spite of its relatively high cost. Dosages for autism are an open-ended question though. The standard dose is 250mg per day but an obesity trial right now is using 2000mg per day.

      Search my comments on this blog if you want to get a more detailed explanation for why I use it for my son.

      Delete
  24. Could urea be considered a biomarker of improper vasopressin activity?

    Renal urea transporters. Direct and indirect regulation by vasopressin.
    https://www.ncbi.nlm.nih.gov/pubmed/10795928

    Regulation of Renal Urea Transport by Vasopressin
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116377/pdf/tacca122000082.pdf

    The vasopressin-regulated urea transporter in renal inner medullary collecting duct.
    https://www.ncbi.nlm.nih.gov/pubmed/2204274

    Could a single bloodtest confirm wether someone benefits from bumetanide for example? Who knows... time may tell

    ReplyDelete
  25. Came accross this earlier:

    CO-EXPRESSION OF SEROTONIN AND NITRIC OXIDE IN THE RAPHE COMPLEX: CORTICAL VS SUBCORTICAL CIRCUIT
    http://pubmedcentralcanada.ca/pmcc/articles/PMC3412368/

    Note this is just one of many papers showing nitric oxide affecting serotonin in the brain.

    ReplyDelete

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