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Wednesday, 4 January 2017

Histidine for Allergy, but as an effective MTOR inhibitor?



Today’s post is likely to be of interest to those dealing with allergy and mast cell activation, but it may have broader implications for those with excess brain mTOR activity.
In the jargon, we are told that:
enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder”.
I have discussed mTOR and mTOR inhibitors previously on this blog.



Amino acids, not just for body builders?


mTOR plays a key role in aging and many human diseases ranging from cancer, diabetes and obesity to autism and Alzheimer’s.

The greatest interest in mTOR seems to be in cancer care.  Many cancer genes and pathways are also involved in autism, so we can benefit from the cancer research.  Another autism gene that is also a cancer gene is PTEN.  PTEN is a tumor suppressor and in the most common male cancer, prostate cancer (PCa), what happens is that PTEN gets turned off and so the cancer continues to grow.  If you upregulate PTEN you slow the cancer growth and if you upregulated this gene in those people at risk of Pca perhaps they would never develop this cancer in the first place?  PTEN is upregulated by statin-type drugs and people already on this type of drug have better PCa prognoses.   The beneficial of effect of statins on PCa is known, but the mechanism being PTEN upregulation does not seem to have been noticed. No surprise there.

Inhibiting mTOR using cancer drugs is very expensive.

Other substances affecting mTOR include amino acids, growth factors, insulin, and oxidative stress.

The amino acid Leucine is an mTOR activator, we don’t need that.  We actually want the opposite effect and, at least in mice, we can get it from some of the other amino acids. 


          Highlights 

·        Amino acids, his, lys and thr, inhibited mTOR pathway in antigen-activated mast cells



·        Amino acids, his, lys and thr inhibited degranulation and cytokine production of mast cells



·        Amino acid diet reversed mTOR activity in the brain and behavioral deficits in allergic and BTBR mice.



Neuroprotective and anti-inflammatory diet reduced behavioral deficits only in allergic mice.

              Abstract

Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMCs. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi-nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T + Itpr3tf/J mice. Cow’s milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD.

  

So in mice a combination of the three amino acids Histidine, Lysine and Threonine reduced brain mTOR activity and improved autism.

I did look at all three of these amino acids and their other effects and I choose Histidine. 
Histidine can be produced in adult humans in very small amounts, but in young children they need to obtain some from other sources, usually dietary.

Histidine is the precursor of histamine.  Histamine has both good and bad effects.

Histidine decarboxylase (HDC) is the enzyme that catalyzes the reaction that produces histamine from histidine with the help of vitamin B6 as follows:



You can treat allergy by inhibiting HDC.

Tritoqualine, is an inhibitor of the enzyme histidine decarboxylase and therefore an atypical antihistamine,

You might think that having extra histidine would result in extra histamine, but this appears not to be the case.  There is a paradoxical reaction where increasing histadine actually seems to reduce the release of histamine from the mast cells that store it.  This may indeed be a case of feedback loops working in our favour.

So it seems that histidine may give two different benefits, it reduces IgE-mediated mast cell activation and it reduces mTOR signalling in the brain.

If the effect on mTOR is sufficient we would then benefit from an increase in autophagy, the cellular garbage disposal service that does not work well in autism.  We might eventually see a benefit from increased synaptic pruning which might be seen in improved cognition.  



Recap on mTOR and Synaptic Pruning

This has been covered in earlier posts.

In autism loss of mTOR-dependent macro-autophagy causes synaptic pruning deficits; this results in too many dendritic spines.









A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.

A feature of autism is usually too many, but can be too few, dendritic spines.  In an earlier post we saw how the shape of individual spines affects their function.  The shape is constantly changing and can be influenced by external therapy. Wnt signaling affects dendritic spine morphology and so using this pathway you could fine-tune dendritic spine shape.  We did look at PAK1 inhibitors in connection with this.

Synaptic pruning is an ongoing process well into adolescence.

So it may be possible to improve synapse density and structure well after the onset of autism.

It should be noted that using Rapalogs, the usual mTOR inhibiting drugs, would have a negative effect in the minority of autism that feature hypo-active growth signalling.  That would be people born with small heads and small bodies.  So a child affected by the zika virus, might very likely exhibit autism and ID, but likely has too few dendritic spines and would then need more mTOR, rather than less.

Rapalog drugs like Everolimus are very expensive, but as in this recent paper do show effect in some autism. 



The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.

mTOR Complex 1 (mTORC1) is composed of MTOR, regulatory-associated protein of MTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2.



How do amino acids affect mTOR?

This is not fully understood by anyone, but here is a relevant paper, for those interested.




Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance.

We then discuss how mTORC1 activation by amino acids controls insulin signaling, a key aspect of body metabolism, and how deregulation of mTOR signaling can promote metabolic disease. 

Concluding remarks


Recent findings of new mediators and their regulatory mechanisms have broadened our understanding of amino acid-induced mTOR signaling. In addition to the role of the TSC1-TSC2-Rheb hub in transducing upstream signals from growth factors, stressors and energy to mTOR, the lysosomal regulation of mTOR functions as a platform to connect nutrient signals to the Rheb axis. Furthermore, two parallel pathways of amino acid signaling explain the diverse regulation of mTOR signaling. It is yet to be determined which regulators sense amino acids directly and whether the two pathways require separate amino acid sensing mechanisms. The identification of a direct amino acid sensor will shed light on these uncertainties.

A more integrated understanding of mTOR regulation in amino acid signaling will open the door for new therapeutic approaches for metabolic diseases, especially type 2 diabetes. Already, metformin, an antidiabetic drug, inhibits mTOR in an AMP-activated kinase (AMPK)-independent and Rag-dependent manner,64 providing further support for the idea that the regulation of amino acid sensing could be a therapeutic target for diabetes.



How typical is the level of amino acids in autism?



As regards essential amino acid levels, autistic children had significant lower plasma levels of leucine, isoleucine, phenylalanine, methionine and cystine than controls (P < 0.05),while there was no statistical difference in the level of tryptophan, valine, threonine, arginine, lysine and histidine (P > 0.05). In non-essential amino acid levels, phosphoserine was significantly raised in autistic children than in controls (P < 0.05). Autistic children had lower level of hydroxyproline, serine and tyrosine than controls (P < 0.05). On the other hand there was no significant difference in levels of taurin, asparagine, alanine, citrulline, GABA, glycine, glutamic acid, and ornithine (P > 0.05).

There was no significant difference between cases and controls as regards the levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma) (P > 0.05).



  

Conclusion 

For the more common hyperactive pro growth signaling pathway types of autism, histidine should be a good amino acid, whereas for the hypoactive type, that might feature microcephaly, leucine should be a good choice.

Histidine is already used by some people to treat allergy.

Histidine does have numerous other functions and one relates to zinc, so it is suggested that people who supplement histidine add a little zinc. For this reason German histidine supplements thoughtfully all seem to include zinc.

Histidine also has some direct antioxidant effects and has an effect on Superoxide dismutase (SOD).

It is not clear how much histidine would be needed in humans to achieve the mTOR inhibiting effect found in mice.

The RDA for younger teenagers is histidine  850 mg and leucine 2450 mg.  What the therapeutic dose to affect mTOR in humans remains to be seen.

Histidine is also claimed to help ulcers, which is plausible.

For allergy some people are taking 1,500mg of histidine a day.






95 comments:

  1. Hi Peter,

    Could you explain what 'mechanical stimuli affecting mTOR complex' means.

    Also, it is worth consideration that activity diet 2, (anti-inflammatory and neuroprotective), did not do a anything for the non allergic 'autistic' mice. Does this have wider implications? I know this is just a mouse model but btbr mice model is the most studied one when it comes to autism research and I was wondering if that could very well imply (and which we are observing as well) that autistic kids with comorbidities like allergies have a higher probability to respond to a wide range o f interventions (anti inflammatory and neuroprotective could include so many treatments), as compared to just autistic. Does being just autistic restrict the scope of improvement? Or have I taken a tangent..the study is making a different conclusion.

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    1. Mechanical stimuli means exercise

      Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774173/

      I concluded that diet 1 was much more effective since it helped in both mouse models and quite possibly needs only one of the three amino acid supplements. Diet 2 had more components and was less effective, so I ignore it.

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  2. Peter, I remember asking you what your thought was about Histidine for autism,when we were talking about histamine behaviour reactons. Luckly now I have a positive answear!, I have it at home but I hadn´t dare to use it for my son. But I wanted to ask you also about l leucine,as is an MTOR activator and that is not good. What about using BCAAs for my son´s dyskinesias?, should I exclude l leucine from your point of view?
    Valentina

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    1. Valentina, there are some genetic disorders that affect leucine. If you had one of those then you would have low levels and benefit from a supplement. Body builders take leucine because by activation mTOR they believe it will cause muscles to grow. Since mTOR is over active in most autism, taking large amounts of leucine, like the 10g taken daily by body builders, would not be a good idea. You do need some leucine in your diet.

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    2. May be I should try a BCAAs compound that has a ratio 1.1.1 and not 2.1.1, leucine, isoleucine and valine, between 3 and 6 g total. And could add l histidine 500mg?
      Valentina

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    3. The thing about leucine and all BCAA's is that they may have a strong effect peripherally in muscle and adipose tissue, but you can't just dump massive amounts of BCAA's into the brain (unless you inject them) because that prcoess is tightly regulated by the LNAA transporter which is shared with the aromatic amino acids and depending on whose research you read, a few other amino acids including glutamine as well. If leucine supplementation's effects scaled from muscles to the brain, then bodybuilders and professional athletes would have serious neurological issues from the high amount of protein they ingest, including free form amino acids such as BCAAs as they immediately have the kind of hyperactive mTOR regulation you find in some kinds of autism.

      In fact, a recently discovered rare form of autism involves a genetic defect of one of the LNAA transporter proteins:

      https://www.ncbi.nlm.nih.gov/pubmed/27912058

      Which in effect causes BCAA's to not be able to get into the brain and was rescued (in mice) by injecting their brains directly with a BCAA solution.

      With regards to histidine, it appears histidine participates in LNAA transport competition with the BCAA'a and aromatic amino acids as well:

      Paper:

      http://jn.nutrition.org/content/130/4/1016S.full

      Table:

      http://jn.nutrition.org/content/130/4/1016S/T1.expansion.html

      and another paper suggests both system L (LNAA transport) and System N (the one Glutamine primarily uses):

      http://booksandjournals.brillonline.com/content/journals/10.1163/15693910260698294

      This is interesting, because glutamine, glutamate, GABA, and aspartate all belong to the same regulated pool of amino acids and in the brain constantly shift from one to the other which means unless you overwhelm the brain's ability to uptake glutamine, glutamate, aspartate, or GABA via injection (as is the case in many experiments on animals) they will all more or less be converted back and forth among each other so that if you have more of one, then you have less of another. This also means that in theory more peripheral histidine might lower glutamine levels into the brain (via competition in system N) which could help lower systemically high glutamate levels provided BCAA's helped block access via system L which Glutamine can also use. I am sure somebody has done some kind of experiment on this (competitively blocking both transport systems so that less Glutamine makes it into the brain) so I will be sure to look this up.

      Now with regards to mTOR regulation and dieting, it is affected by many things as you well know, but generally feeding of any sort upregulates it, and fasting downregulates it and supplementing BCAA's and in particular leucine is only part of the equation as both insulin and leucine independently increase mTOR expression in muscle and adipose tissue. The brain is a different story.

      First of all the brain is able to sense leucine intake via the hypothalamus which has pseudo access to the peripheral blood supply which has downstream effects on the rest of the brain and body in terms of whether to conserve energy and break down tissue for energy (catabolism) or increase its expenditure (anabolism):

      http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084094

      Also, the strongest activators of mTORC1 in neurons are insulin and BDNF:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005960/

      while Leucine in effect has a ceiling in terms of stimulation via competition with other amino acids for the System L transporters (this is generally true of muscle cells as well which is why some BCAA formulations have a leucine to valine, and isoleucine ration of 9:1:1 or even greater).

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    4. So therapeutically the only type of diet that is going to significantly lower mTORC1 is going to be fasting and/or a ketogenic diet which means very low carb, borderline low to very low protein, with the rest of the calories being fats from diet or else fats yielded by the fermentation of soluble fiber.

      For growing children, a long-term very low protein diet (such as a ketogenic diet) is going to pose a lot of other problems obviously, while in adults ketogenic diets don't have the same type of concerns (and may even be optimal for longevity purposes).

      In the end, there are many open questions with feeding strategies as they relate to mTOR and autism and the only good short-term way to know what is best is to simply try out a particular diet and see how things go after a month.

      I will definitely look into histidine some more myself as that is one amino acid I have really overlooked in terms of understanding and am glad you made this excelllent post in terms of discussing an alternative view to histidine and histamine and autism as conventional wisdom of course suggests otherwise.

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    5. Tyler, speaking of fasting, what are your thoughts on this: http://healinghistamine.com/fasting-mimicking-diet-for-mast-cells-and-histamine/

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    6. Tyler, I always wanted to give histidine to my son, now I have the confirmation, but this is not an easy topic. To simplificate it, BCAAs and Histidine could lower high glutamate levels because both of them participate in LNAA transport? If this is correct, wich would be the ratio of BCAAs and histidine? sorry if I am reiterative. I would also like to know Peter´s opinion.
      Thanks
      Valentina

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    7. Well first of all, unless you have some test saying that someone's brain has high glutamate levels via indirect methods such as metabolites in their urine or blood or more invasively their cerebral spinal fluid (CSF), then speculating any further about this is not going to be useful. Many of the hyperactivity problems you see in autism have to do with receptor dysfunction, not the levels of neurotransmitters themselves. That being said, what I have read is that in some studies you have excess GABA in the brain (generally functioning in an inhibitory manner) while also having a high Glutamate/GABA ratio. Since Glutamate, Glutamine, GABA, and Aspartate are all recycled to a degree, adding more GABA won't necessarily bring about more inhibition. That is why there are GABA analogues (drugs) that do this and don't feed back into being broken back down into something else.

      So in theory, to reduce brain glutamate levels you would need to either manipulate the supply of brain glutamate via some homeostatic mechanism that regulates its levels and the levels of GABA, Aspartate, and Glutamine, or else you need to block all of them from entry.

      Now glutamate and aspartate get very limited access to the blood brain barrier and compete with each other (I think it is called the anionic transport system) and GABA is thought to either be completely blocked or else it has only limited access as well (a recent study suggested oral GABA ingestion caused a rise in inhibitory signaling in the striatum which should not occur if GABA cannot readily enter the brain, but in this study it suggested it does which contradicts older studies). So in a nutshell, the primary method of the brain producing Glutamate and GABA is via peripheral glutamine getting into the brain.

      So to answer your question, if you competitively blocked all blood brain barrier transporters for glutamine while limiting foods high in glutamine/aspartate/glutamate/GABA, then you could lower brain glutamate levels.

      I am sure there has been some research on this matter, but I have not really investigated it so far so I can't really say if this type of therapy would actually work, rather I was only speculating on it in the above post.

      The thing most people realize is that if you lower brain glutamine levels in order to lower brain glutamate levels, you will also lower brain GABA levels. Now if there is excess GABA as well as Glutamate floating around, then this might be a good thing because chronically excess levels of a neurotransmitter will generally cause the dysfunction and downregulation of the corresponding receptors for that receptor (desensitization) which results in little to no signaling for that receptor which can obviously cause pathological problems if left untreated (this pattern happens with many addictive drugs).

      Last but not least, unless you have a sophisticated lab do tests on your son, you won't really know for sure what helps or hurts in this regard so really all you can do is try it out (progressively) and see if it makes things better or worse after a week or two of trialing. Also I must add, if glutamate receptors are hypothetically desensitized already you may want to give any intervention more than a day or two before making a judgement because it will be like a heroin addict going cold turkey, as it will take time for the receptors to upregulate in number and density to compensate for there no longer being a flood of excess glutamate/GABA/aspartate/glutamine in the brain.

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    8. Tanya, I actually posted a comment a while back on this blog about the Fasting Mimicking Diet and the group's research on resetting the immune system and how it might relate to autism.

      And as for this blogger's thinking that fasting has helped him/her with histamine issues I can't really give any firm opinion, because the FMD studies that were done were intended for totally different research purposes. With regards to what a 3-4 day water fast (or this FMD diet which is suggested to achieve the same results), what is thought to happen is that many of the immune cells floating around in your blood get broken down for energy (consumed) because the immune system is a very energy hungry part of the body and when you are literally starving, your body needs to make cellular sacrifices to reduce energy expenditure and supply protein to all other areas of the body for maintaining homeostasis. Then when the body detects that food is plentiful again (breaking the fast), then in theory the stem cells in your bone marrow mass produce a whole new immune system.

      This is all very compelling research, but doing one of these fasts is unlikely to get permanent results and would need to be done periodically, assuming it worked at all for histamine issues.

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    9. Valentina, if you want to lower glutamate levels you might want to talk to your doctor relative about trying Riluzole. This is a drug developed for ALS to lower glutamate levels and is now being trialed for autism, OCD and anxiety. The original drug is very expensive but there are now much cheaper generic versions available. Even if you tried it for just a few days then you would know if "too much glutamate" was the problem.

      There are various different glutamate receptors implied in different types of autism, which might be treated by a drug specific to that receptor.

      I think Riluzole will work for some people.

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    10. Valentina, here might be a useful bit of information in explaining what is going on with excess dopamine in the striatum and the hyperkinesia displayed by your son via chronic D2 receptor upregulation as a side effect of risperidone (a strong broad spectrum receptor antagonist).

      http://www.cell.com/neuron/fulltext/S0896-6273(16)30530-X

      You can read the paper, but the video abstract I thought would be helpful to you. The paper is about cocaine, but you can probably generalize it to many other drugs that increase dopamine levels in the brain (even though risperidone is taken to decrease dopamine signaling but over time its side effects take a toll in upregulating the receptors).

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    11. Sorry Valentina, I think I might have posted the wrong paper (with video abstract). Here is the more relevant one to what I was talking about:

      http://www.cell.com/neuron/fulltext/S0896-6273(16)30118-0

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    12. Tyler, Is mast cell involvement an issue with your kids? If so, what do you think about some of Diana Driscoll's ideas re: vagus nerve treatment, specifically the product she developed called Parasym Plus with higher dose thiamin, huperzia, AL carn and choline? Also do you give magnesium along with potassium in aspartate form or are you just using the ZMA product for aspartate source?

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    13. I have used diamine oxidase (DAO) in my son and at the time I thought it had a good effect. It was fairly expensive and we stopped using it but strangely the symptoms we attributed to high histamine (hyperactivity with flush skin) didn't come back.

      As for ZMA, the main reason for ZMA is that it is easier to just dump the capsules in a drink and get my son to take them that way, rather than the previous method I used which was to mix baking soda with L-Aspartic Acid in hot water (yielding monosodium aspartate) so that the L-Aspartic Acid was dissolved. This method produces a salty taste my son eventually got tired of. He won't do pills so I am always forced to be as creative as I can be in coming up with ways to make interventions work. For example, I got some KetOS but have yet to figure out a way for him to take it because it just does not agree with his taste buds. But to answer your question directly, yes the ZMA is strictly for the aspartate. I also give my son Potassium Gluconate to compensate for the lost potassium from bumetanide.

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  3. Interestingly talking about amino acid metabolism and ASD - this study popped up in my email box today - I am still to go through to determine with amino acids they found to be low in CSF but here is is in case anyone wants to reference it: https://spectrumnews.org/news/rare-form-autism-linked-lack-key-nutrient/

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  4. Hi Peter and Petra,

    On his first day of gastrus (afternoon dose), my son displayed little discomfort in the initial few hours following dosing..basically what seemed like acid reflux. But in another few hours, he was bright and full vigour. And by night, he was trying to imitate dance steps in sync with the performer on tv, primarily on songs which in India are nomenclatured as 'item numbers', where item refers to a bombshell who gyrates to double meaning songs, full of innuendoes, which surprisingly are accepted very warmheartedly by our traditional conservative society.

    My son, it seems, had already memorized the moves but this was the firs time he really attempted to actually try and dance with the video on. If he develops this skill even to an average level, this could mean huge for his mainstream school. Parents have such fantasies so I better hold it there. But if gastrus has suddenly given him better body awareness and coordination, then its truly fantastic. Petra, did you observe any change in motor control?

    Peter, I wish you could expedite the process of your book writing. At least, compile an e-book for it becomes very difficult to go back and forth through the blog. There is lot of valuable information but the topics are not in any particular order. A few years earlier, pre marriage and pre baby I would have read through, understood and absorbed your entire blog in six days flat..I was such a psycho. But now the senses are failing..no denying the gerontological fate! Please come out with a book before science becomes Latin to me.

    Regards

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    1. Hi Kritika,

      Best seasonal greetings and happy new year to you and all of us here.

      Kritika, it's really nice that your son responds to Gastrus and this is obvious in his motor coordination.

      I have been using Gastrus non-stop for about half a year and my current dose is 1 or 2 tablets a day. I have used up to 3, but more is not good for my son.

      As I mentioned before it helps with mood improvement and probably with his uric acid which has dropped very close to higher normal means, unless this is a coincidence.

      It never occured to me that it could help with movement, but now that you ask I can recall that during our long summer travelling to different places his movement was great. I just thought this was due to his motivation to see interesting things, anyway it could have been both.

      It's true that some of the first intense results can fade over time, still when I don't give it I think he is left helpless with GI issues.

      Therefore for us Gastrus is quite good and best probiotic tolereted long term.

      I would also like to thank you for a key word you have used while trialling coffee for my son and that is the word "pain". Whatever acts well on my son's apparently dysfunctional pain perception can be really promising in alleviating his kind of anxiety which comes with rigid thinking. I do think that coffee is one of these interventions and I suspect it helps with liver and purine metabolism, maybe through blocking adenosine.

      I was away for some time during Christmas holidays and wasn't able to follow the discussion about Suramin and correction of purinergic function. Being out and about I kept in mind how to fix pain perception and when I entered the blog I saw that you were talking about Suramin. I googled Suramin and pain perception and saw papers that they connect them. It's a pity that it has so many side effects.

      Baclofen helps with pain perception but it stops working after some time maybe because it is also good for addiction through an unknown mechanism. As you have all noticed here my son never self administrates substances to such an extent that I sometimes feel jealous of these model mice which keep self administrating and researchers try to fix them and finally think that this makes things work in reverse.

      Biogaia Gastrus is supposed to raise oxytocin levels and oxytocin can be used in the management of pain.

      Here is just a random paper I found confirming it:Schmerz. 2016 Oct;30(5):457-469.
      [Effect of oxytocin on human pain perception].
      [Article in German]
      Pfeifer AC1, Ditzen B2, Neubauer E3, Schiltenwolf M3.




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    2. Hi Kritika, I remember reading a post from you somewhere questioning how to use nigella - I was intending to reply, but the comment box kept freezing up on my ipad - and then I got a bit busy and was off line for a bit- now I can't find the thread where you were mentioning this - anyway, about nigella, to make it a bit more palatable - have you tried mixing it with a little honey? At first I wasn't sure if my son would take it straight - even though he eats anything, and loves bitters, even bitter teas bitter greens, etc. but nigella is very different. I first mixed it with lemon juice and drizzled over his veggies. he loved it this way. When he was first diagnosed and transitioning from being a picky eater to a kid who would eat anything, I squeezed lemon juice on everything and that seem to be the magic elixir to get him to eat a bigger variety.

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    3. Hi Kritika,
      Gastrus wasn't helping my son, and seemed to exaccerbate his allergies so I stopped it. I had about 5 or 6 chewables left so I decided to take them thinking -- who couldn't use a probiotic :-)
      Very soon after taking the first one my stomach blew up. It was painful and full of pressure. I didn't immediately equate the two, but as I continued taking them over the course of the week it got worse and worse. Just something to consider as I know you have said your son struggles with gas and bloating if I remember.
      Best,
      Christine

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    4. Tanya,
      I was about to ask you about nigella..but since my lazy brain queries seem to fill up peters comment section, I refrained from doing so but here I am..self image go get yourself a decent burial.

      Tanya, unfortunately, my son does not like honey and I have to or rather he has to struggle to get it down..adding nigella will make it impossible. It has such a strong taste. Probably I will try the oil filled capsules. Are you giving the powder? Any more suggestions?

      Today I tried giving my son kutki (picorhiza) powder mixed with honey and he just vomited everything out. Let me warn anybody who is planning to give it to their child that anything more than 20 mg is going to be difficult as it is so bitter that when I opened the container, the fine dust from the powder left the most bitter taste in my mouth. Now I am in a fix..what to do with it.

      And yes, I am in full agreement with what you feel about interventions..behavioural or otherwise. People are persons first. Respect for differences of all types is the first but most important step when it comes to bringing up a child, especially an atypical child. Its a pity that some cannot even accommodate or tolerate difference of opinion. I truly respect your respect for your son.

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    5. Hi Christine,

      Good to hear from you again and thanks for remembering my sons issues. Yes Christine, my son is very sensitive to digestive issues and therefore I am giving him a very conservative dose..only half a tablet and keeping a close watch as well. High dose probiotics will not work for him. Its been only two days and I did take half a tab myself (and yes there was a mild discomfort for few minutes) but its got a bad sour taste so did not try again. Now that you have reminded me, I agree I should take a few more tabs to get a better idea. Thank you so much Christine..I think this was really important.

      Delete
    6. Petra,

      It might be a little premature, but the effect of l.reuteri strains in biogaia gastrus seems to be a little different from that in bioamicus reuteri. Gastrus is giving a kind of masculine, mean edge to his behaviour. With bioamicus, it had an affectionate, sweet stance. I hope we do not see a behavioural deterioration in the coming days as gastrus has been good for speech like bioamicus. Keeping the dose low.

      About suramin trials, theoretically it makes so much sense. Hope things dont get lost in translation.

      Will keep you informed.

      Delete
    7. Hi Petra and Peter,

      I am not able to understand whether gastrus strains have a net beneficial effect or not..he is showing the same response as he did to NAC. Enhanced awareness, assertiveness, receptivity but a mean glint in his eyes and a little edgy behaviour. He was pinching our dog, stomping his feet, tantruming for videos but cognitively good. And I must say he has a super memory..he remembered steps from videos which he had not watched in the last six months. In hindsight I feel that probably if I had experimented by lowering nac dosing..say 600 or even 300 mg per day I would still have seen some good effects without the discomfort that 1800 mg produced. Same with bumetanide and probably gastrus also requires a further reduction..maybe just a quarter of the tablet. I will try that and revisit nac and bumetanide later.


      Another thing, I had some fisetin from doctor's best which was dying a slow death so I decided to redeem it by self consumption. Although it did not do anything perceptible in the three days that I have tajen it, I am having really vivid dreams which I remember from start to end. I was always a good dreamer with sci fi like plots where I was the hero or sometimes even verses which I composed in my dreams the details o f which I would not forget on waking up. But in the past year or two I hardly ever had those funny creative dreams. So fisetin is doing something somewhere in the brain about which I have no knowledge. Hence refraining from giving it to my son for the time being.

      Regards

      Delete
    8. Awww Kritika you are funny! No no funeral! You are a mom with a young son with autism just looking for answers and wanting to help your boy - I admire that.. I definitely understand the urge to want to comment frequently on this blog - with Peter's ideas and the smart parent comments.. About the nigella - other than mixing it with honey or with lemon and drizzling on food, I don't have any other ideas sorry. I'd say with your little guy, just give him some time for his taste buds to come around. I doubt at age 5 my son would have taken it so easily. He had many years of eating lots of bitter greens and drinking different types of teas before we ever tried nigella. ... Kutki - hmmm I have never heard of that - what are you using it for?

      Delete
  5. Here is a good overview of the pros and cons of mTOR I read a while back and dug it up for this discussion:

    https://selfhacked.com/2014/11/03/mtor-natural-mtor-inhibitors/

    Note: I don't agree with a lot of what the author of this blog (in the link) says on some things as his evidence and understanding is usually correct and very insightful, but his conclusions are not always the same as mine on these matters.

    Nevertheless, I think his list of mTOR activators and inhibitors is pretty on the mark with what I have read (aside from some experimental drugs used on animals nobody has access to anyways).

    ReplyDelete
  6. Speaking of to grow or not to grow, here is a study that should give us all hope:

    Press Release:

    https://www.sciencedaily.com/releases/2017/01/170105143504.htm

    In many cases of autism, pruning seems to go awry and you end up with excessive synapses and dendrites which are thought to increase the noisy transmission in the brain that can cause sensory issues in particular and generally lower cognition as the brain has problems getting coherent signals over very large distances.

    What this study suggests (in my opinion) is that anything not pruned in development has the potential to literally grow into new brain tissue via proliferation of excess brain cells. In particular, they looked at one of the more studied areas of the brain called the fusiform gyrus, which has many functions but most popularly one part called the fusiform face area which is involved in processing faces and seems to be dysfunctional in many cases of autism and hyperconnected to limbic areas such as the amygdala while being hypconnected to regulatory regions like the orbitofrontal cortex.

    So in effect this could mean that even rather older children with autism (teens) or perhaps even adults may still have the potential (relative to normal people) to remodel their brain in positive ways that decrease autism symptoms, provided you figure out a way to stimulate brain cells to proliferate and migrate to the correct locations.

    So maybe in light of this research we parents should remind ourselves of the old nursery rhyme of the tortoise and the hare whenever someone falsely alludes to you that nothing much can be done to help your child than other than primitive Pavlovian behavioral therapies.

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    Replies
    1. I like your thinking, Tyler. I am too much of a mama bear to settle for the "nothing can be done" doom and gloom and for anyone to pigeon hole my kid.

      Delete
  7. Hi everyone,

    Just a quick update on my fenugreek leaf tea efforts (for anti-purinergic effect). The first time, I tried giving it to my daughter sweetened with agave nectar and she spat it out, but then I mixed it with a few drops of lemon flavored Carlson Cod liver oil and a bit of pomegranate juice and she's having it. That Carlson lemon flavored cod liver oil changes the flavor of anything you mix it with from unpalatable to something my kid will have (if you're having issues). Always remember to give no more than the recommended dose of cod liver oil as it is fat soluble and builds up over time.

    It's been a few days, no noticeable effect seen, but these things can take months.

    The fenugreek leaf tea itself is relatively easy to make, and doesn't taste bad actually. It's a bit of a grassy taste. I buy the fenugreek fresh, wash and remove the leaves. I dry them in a food dehydrator (about $70) and the put them in hot water for 30 minutes (I bought a tool in which you put tea leaves so that only water goes in and out ~$15).

    I noted the above if anyone wants to try this too.

    Also, I ordered Sytrinol further to RG's recommendation and paper, still waiting for that.

    I did receive the Naringin, which is bitter when mixed with water, and tasted initially ok when mixed with agave nectar, but then after you swallow it, the bitterness comes back on your taste buds, so I have to figure out a solution before giving that to my daughter (maybe a chocolate right after???)

    With Naringin, please remember to treat it like grapefruit (i.e. no meds around the same time you give this). It should be given in isolation as grapefruit affects metabolism of meds.

    Best if luck to all, I'm optimistic a lot of progress will be made in 2017!

    AJ

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    Replies
    1. Hi AJ, I find that I can mix awful tasting items in hazelnut chocolate milk, 1/4 cup (i use this to give her Nystatin which is bitter) she does not refuse it this way. You might want to try, I get it at Save on Foods.

      Delete
    2. Thanks! She loves chocolate, hazelnut butter and / or Nutella, and milk, so will try that.

      AJ

      Delete
  8. Hi Peter, everyone,

    I am at the Mayo Clinic right now, have been here for a week. My daughter's chronic diarrhea worsened on vacation, and we brought her here to have it attended to and also to get a full workup. She is scheduled for a colonoscopy and endoscopic ultrasound on Tuesday. This is to be done under general anesthesia. Do you have any experience of it, any agents that are preferable, such as propofol?

    Many thanks,

    RG

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    Replies
    1. Hi RG,
      Sorry to hear your daughter is ill. Sending your family well wishes
      This might help: https://www.autism.com/pro_anesthesia
      Here's an excerpt:
      Many of the drugs used in anesthesia should be considered relatively safe. For example, Versed® (a benzodiazepine used for sedation, amnesia, and for anxiety) and fentanyl (a potent narcotic) are relatively short-acting and are not heavily metabolized.
      Other drugs might present choices. Propofol, a short-acting agent, is administered intravenously; it is used for induction and also for maintenance of a general anesthetic (i.e., keeping the patient asleep). It contains soybean oil and egg phospholipid, so that fact should be considered for patients with allergies to soy or eggs. Concerns have also been raised regarding a potential for propofol to exacerbate mitochondrial disease. Unfortunately, all general anesthetics have a tendency to inhibit mitochondrial function, but the documented difficulties noted with propofol stem from long-term use in the ICU setting, exceeding the exposure most patients would encounter.4
      Under most circumstances, propofol can be safely used. But if there is a concern, your provider might determine that inhalation induction is appropriate, using sevoflurane. Only two to five percent of sevoflurane is metabolized in the body, making it an excellent choice for many patients. (An older inhalant, halothane, is rarely used now because of its tendency to be challenging to metabolize.)
      Sometimes the provider might want to use ketamine. It is a dissociative anesthetic; in essence, a hallucinogenic. It is usually used for sedation, especially for short procedures like changing dressings on burns. In children – especially so-called difficult pediatric patients – it might be used to make starting an IV easier. Ketamine’s advantage is that it doesn’t depress respiration as other anesthetics might. It’s also easy to use; it can be given orally, intramuscularly, or intravenously. Typical side effects, however, include open eyes, nystagmus, increased salivation, and emergence delirium. Ketamine alters the patient’s sensory perception, which raises questions about its use for these children.
      Special attention must be paid to the topic of nitrous oxide (“laughing gas”). It is one of the oldest anesthetics, and is still used for sedation in dental procedures. In addition, it is used on occasion as a carrier gas with sevoflurane in mask inductions. That is, nitrous oxide is utilized for a second-gas effect to increase the concentration of another inhaled anesthetic agent, thereby allowing the patient to get to sleep faster.
      - See more at: https://www.autism.com/pro_anesthesia#sthash.aNb0c04i.dpuf

      Delete
    2. RG, forgot to mention personal experience: my son has had propofol and sevofluorane in the past for surgery as well as testings like MRI, PET scan, bone marrow biopsy - and he did well. For a teeth cleaning and to treat a cavity when he was about 10 the anesthesiologist at Vanderbilt did not listen to my specific request and used ketamine - it was bad - took 5 hours for my son to wake, and he regressed a bit temporarily . maybe a month or so before he was back to where he was

      Delete
    3. Hi RG,

      Feeling really bad for the discomfort your daughter must be going through. One week o f hospitalization seems a lot to me. Hope you get something helpful through the diagnosis.

      Take care

      Delete
    4. Thank you very much Tanya, much appreciate your input. Good to know about propofol and sevoflourane.

      Kritika, thank you, but I miscommunicated. She is not hospitalized, just being tested and treated as an out patient. Though we are having to spend entire days there. The good thing is that there are a variety of specialists looking at her, including neurologists, endocrinologists etc.

      Delete
    5. Hi RG,

      I am sorry to hear about your daughter's diarrhea and hospital admission.

      I am aware that your daughter has not been diagnosed with mitochondrial dysfunction nor mastocytosis, but I still think that these two sources might be worth considering:

      http://www.mitoaction.org/guide/anesthesia-procedures-and-surgery (the article linked does not open, but is easy to google)

      http://www.mastocytosis.ca/sa.html (Anesthesia in the section Physicians&Emergency)

      Most of the recommendations for anesthesia for patients with mitochondrial disease/dysfunction are easy to follow (eg. maintaining hydration).

      My son had general anesthesia for MRI in 2013, according to what I read and to my discussions with anesthesiologists then, general sedation for diagnostic procedures is of low risk compared to anesthesia for longer surgery (in children with autism it is mostly related to mitochondrial dysfunction).

      I recall that issues with propofol and mitochondrial dysfunction is significant, but mostly for long term use.

      From personal experience: there was not any problem during and after anaesthesia in my son even though it went not as planned (long hours waiting for the procedure unnecesarily fasting). I think they used sevofluran, but I am not sure now. As he is somewhat similar in responses to your daughter I hope it will be as easy for her. Hopefully you will get the answer and a solution for your daughter.

      Delete
  9. Hi everyone,

    On another note, has anyone tried chelation therapy for heavy metals? Two recent papers caught my eye:

    https://www.ncbi.nlm.nih.gov/pubmed/27250967

    https://www.ncbi.nlm.nih.gov/pubmed/27301968

    I did some research to and found that micronized chlorella and cilantro seem to be the best heavy metal chelators, and the following popped up as a formula that had both:

    http://www.bioray.com/ndf/

    Any thoughts from anyone on the impact of lead and arsenic on ASD? Anyone tried a formula like this with micronized chlorella / cilantro? Any insights would me much appreciated.

    I'm considering trying chelation with the formula I found to see if it improves my daughter, and again, any insights would be much appreciated.

    Thanks everyone!

    AJ

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    Replies
    1. Hi AJ,

      So RGs comment, reporting spectacular results with suramin should give us some reason to keep the hopes sky high.

      First, I would be grateful if you could tell me approximately how much fenugreek powder you are adding to your daughters tea. My son is not spitting out stuff but literally had bouts of vomiting following taking in a spoonful of nigella oil as well as picorhiza powder mixed with honey, and justifiably so. So I am planning to cut down quantities to max tolerable dose. Since natural products like fenugreek, picorrhiza or black seed have multiple health benefits, a daily cocktail of these would seem like a sensible long term strategy.

      Second, if you go through other forums you can find lot of positive reports and information about bioray products. In fact I had ordered cytoflora and liver life from them and was planning to order ndf plus too but unbelievable though it may sound, disposed off the package with the garbage by mistake. If you search the net you will find some kids benefiting from mega doses of chlorella..its all intriguing and if true, mechanisms behind the effect seem unclear, not the least because each child is so different. There have been negative reports about misinformation and doubts about efficacy of bioray range, chelation protocols..in fact the so called 'biomed' field. But vulnerable though parents may be, they are no fools. The most dramatic imapact we saw in my son, that of correcting the imitation deficit which was huge for us, was a result of homeopathic treatment, something I did not believe in.
      Placebo effects are seen with synthetic drugs as much as with natural compunds so that is one huge challenge but not unique to alternative therapies. Then you can always experiment with synthetic drugs as and when you feel comfortable.

      So without being too much 'sectarian', I think it would be wise to be flexible but sensible in approach and try to keep up with new information as it floods us. I am writing this not for you but so as to get my own thoughts in order. So I wander through this landscape but with a clear perspective. And not all those who wander are lost.

      And I will update you about our bioray experience if I happen to trial it first.

      Wishes for your daughter

      Delete
    2. Hi AJ
      I had a posted a similar question recently
      We started seeing a DAN in Chicago recently who does do chelation
      We have not done it yet on my son
      But we have used ALA as antI oxidant in past, so we are using the Andrew cutler protocol with ALA
      We have seen some good results , he has started picking up toys for the first time not prompted in the living room and briefly playing with them
      Also has started saying more functionally like I want a snack small things like that
      Small things but you need some thing to keep moving on
      One thing is we also started leucovorin recently around a month before so don't know which is exactly helping
      Thanks
      BK

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    3. Hi Kritika and BHaskar,

      I've done a bit more research on chelation and I did read that Lipoic Acid is apparently a good chelator, so I'm thinking that since I use R-Lipoic Acid (better than ALA as it's only the R version which is effective while ALA has both the R and S form, so you only get half the effective dose) I may be fine for now.

      Also, in further reading, I read up a bit on something called DMSA which sounded like it may also be a good chelator. Until I can figure out if I want to add more chelation than R-Lipoic Acid, I'm going to hold off, and will wait to hear Kritika's experience and yours Bhaskar.

      Thanks Bhaskar for confirming that Lipoic Acids is also a chelator. Please keep us posted if you do further chelation, and what you used. Again, I'm not sure if, above and beyond Lipoic Acid, DMSA is best or micronized chlorella and Cilantro.

      In terms of the Leucovorin, there was really good info on it working for those kids who have antibodies to their Folic Acid receptor, so I'm using L-Methyfolate twice a day at 1 mg/kg like the trial. I haven't seen anything yet but it's only been about 1.5 months.

      My approach is, given that I don't know the cause for my daughter's ASD (haven't done the DNA sequencing yet - waiting for an easier method than the usual blood draw), that I will try several different approaches in the hopes that 1 will work.

      To Kritika - when I make the fenugreek tea, I use about 3 tablespoons of crushed dry fenugreek leaves per cup. I leave them in the hot water for 30 minutes (using a tea infuser). The amount isn't scientifically based, it's just what seemed reasonable if I was making a strong tea.

      Kritika, you mentioned something about RG and Suramin. Did you mean RG has info about good results from the trial or RG's daughter used Suramin?

      Hope the best for your son as well.

      Best to all (especially RG and daughter)

      AJ

      P.S. When the Naviaux paper comes out, if it isn't open access for the full paper, I'm going to buy the full paper and share any insights with the community. I suspect that it will be a key paper for us.

      Delete
    4. AJ, antioxidants will all act as chelators. So if someone responds to an antioxidant it indicates oxidative stress.

      If someone has oxidative stress they may have odd levels of metals in hair tests, this does not mean they have been exposed to toxic levels of heavy metals. People with heart conditions were shown to respond to chelation, but this is because they too have oxidative stress.

      The best way to treat oxidative/nitrosative stress is to use antioxidants and active nrf2.

      The antioxidants safely used long term for other mainstream medical conditions are NAC and ALA.

      If leucoverin does not help, that might suggest no nitrosative stress and no cerebral folic deficiency.

      Delete
    5. Hi Peter,

      Thanks for providing the additional insights! I've been using R-Lipoic Acid for about a month, and wanted to get on NAC as well, but it smells and tastes awful (need to figure out a way to hide it from my daughter as she can't take capsules). I believe it has helped some folks, so definitely need to get on this.

      I've been using the L-Methylfolate at the clinical trial dosage of 1mg/kg X 2 daily for about 2 months without any obvious effect. I'll go another 2 months before deciding if I should continue.

      Thanks as always Peter!

      AJ

      Delete
  10. Hi Peter, everyone, one more concern that I would appreciate your input on. The endocrinologist has ordered an ACTH stimulation test for tomorrow, and I am a bit concerned. Any experience or knowledge about this?

    Many thanks,

    RG

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    1. Cortisol has been suggested to play a role in GI issues associated with autism.

      Increased reaction to stress linked to gastrointestinal issues in children with autism
      https://www.sciencedaily.com/releases/2017/01/170104114330.htm

      Perhaps ask to measure cortisol.

      Delete
    2. Thank you Peter. He specifically wants to check cortisol, because he finds it odd that it used to be high before and currently is low.

      He thinks her diarrhea is because of backed up stools. Currently, all tests and procedures are postponed until she gets over her fever.

      Delete
  11. I just came across another way non-obvious way to upregulate IGF-1 that I happened to find when trying to find some anecdotals to capsaicin capsule usage. The original paper that got me interested on capsaicin is here:

    http://www.cell.com/neuron/fulltext/S0896-6273(08)00032-9

    This paper discusses how while the TRPV1 is responsible for the sensation of heat in the peripheral nervous system, there is strong evidence (from this paper) that it is very important for LTD in the central nervous system and is likely modulated endogenously via endocannabinoids.

    So I know already people take cayenne pepper capsules for reasons ranging from pain management to weight loss, and came across an interesting paper along the way that suggested that capsaicin plus soy isoflavones upregulates IGF-1 first in mice and then in humans to promote hair regrowth in people with hair loss such as male pattern baldness. This intrigued me because my son's favorite meal is for me to go to "Eat at Moes" (a Chipotle competitor) and he loves the spicy ground beef and beans in a bowl. The best natural source of soy isoflavones are from soy beans and you can tell the ground beef has some kick to it just by smelling it (I assume it has plenty of cayenne).

    So here is the paper about upregulating IGF-1 in mice and humans for hair regrowth via IGF-1.

    http://cat.inist.fr/?aModele=afficheN&cpsidt=19062253

    Judging by my recent looks in the mirror, perhaps I should do employ this intervention personally (-:

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  12. "Different diuretics are likely to have different effects on the renal handling of urate, but this has not been critically ascertained; patients receiving more powerful loop diuretics have a higher risk of developing gout than those receiving the weaker thiazides.27 Interestingly, bumetanide has been found to have uricosuric properties."

    Peter, as my son seems to have some issues with excessive serum uric acid and feel a little guilty about using diuretics in the fear of gout attacks, I found this paper on Pubmed which I think is reassuring of using Bumetanide in that case.

    I would also like to ask you -I know you are not an urologist- since you have long experience with Bumetanide, if you think it is normal to urinate after more than an hour and a half of Bumetanide. Does it matter if you give additional fluids and potassium before use or after?

    ReplyDelete
  13. Petra, I think you may get urination more than 90 minutes afterwards, partly because the person is likely drinking lots of fluids. It makes sense to add back the potassium as you lose it. I think my son now drinks a lot and so urinates a lot as a habit. Within limits drinking plenty of water is a good thing, many people do not drink enough.

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  14. Thanks for your reply. I just want to clarify that I meant first urination after around 90 minutes with Bumetanide and usually more than half liter of fluids.

    ReplyDelete
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    1. Petra, that is slow, but people do metabolize drugs very differently. Some people have massive urination and some next to none. You would have to ask your doctor if this indicates a problem.

      Delete
    2. Hi Petra,

      Usually, it is 60mts for my daughter, but recently I noticed that she sometimes can go up to 90 mts. This seems to happen more when she drinks less than her usual amount of water.

      Delete
  15. Tyler, thanks for the link, in my opinion, my son at the age of 2, started to show symptoms of excess dopamine, he squeezed the pillow as if something was hurting him, a kind of clonus, all started with this odd movement. But he was not a child that couldn´t stay still, running from one place to the other. So, his case is quite strange. Now, after 6 years of risperidone, things got worse. But I think that from the first time, before risperidone, he had a kind of hyperactive dopamine transmission, that fortunately didn´t result in somethhing worse, only autism. With respect to Peter and his question of Riluzole and Glutamate, as I said before there is a history of MS on the side of my son´s father, his great gran father, so high glutamate could be also the problem, tizanidine could be a prove of that, it has worked very well. Now, my son is the combo anxiety, OCD and we have been saving form Tourette.
    Valentina

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    1. It is all a gray area, but I would do everything you can to wean him off the risperidone if I were you and if you are going to really go full tilt on trying to manage neurotransmitter levels, you can get an OATS test:

      https://www.greatplainslaboratory.com/organic-acids-test/

      before doing a restrictive intervention, and then after a month doing another OATS test. This depends on your finances and it may tell you nothing, or it may even tempt you to jump to conclusions as to what the problems are because like I mentioned before, high levels of a particular metabolite can be a coping mechanism for something else going wrong, so reducing the levels of say uric acid might actually make things worse (depends on how high). That is why I generally shy away from this kind of analysis, especially because anything in the urine usually tells you nothing about what is actually going on in the brain (there are exceptions of course).

      There are no easy answers here, but if I were trying to do what you sound like you want to do I would to this:

      (1) Get an OATS test to see what the levels of major neurotransmitter metabolites happen to be:

      (2) Employ a protocol to reduce dopamine in the brain (only thing I know of is the BCAA blocking aromatic amino acid therapy), and maybe a diet that is low in aromatic amino acids (tryptophan, tyrosine, phenylalanine) or at least just low in tyrosine/phenylalanine since you seem to think dopamine is the problem.

      (3) Get another OATS test

      (4) Evaluate behavior after a month and if nothing has changed, see if you successfully lowered levels of dopamine, and if both dopamine has been reduced and behavior has not improved (or even gotten worse), then you might have a clue that your problem is a receptor issue that was not corrected via homeostatic mechanisms of reducing dopamine to appropriate levels.

      BTW, my son still can be hyperactive and engages in some SIB, but it is way less than before. That could be just the result of maturity, but I know from experience that if I drop the ball on the most important interventions I employ right now, after about a week things get bad (or so that is how it has seemed).

      Delete
    2. Valentina, one other thing to consider is that in cancer the two main fuel sources cancer cells generally like are glucose first, and glutamine second so there are a wide variety of interventions and drugs to address this problem. Glutamine is found in just about all protein in copious amounts so a ketogenic diet which is defined as minimal protein, very low carb, is sometimes recommended so as to "starve" cancer cells of both glucose and glutamine.

      A study I came across a while back that I had bookmarked specifically discussed this:

      https://www.ncbi.nlm.nih.gov/pubmed/9534081

      and the takeaway was that a low-carb diet when combined with exercise will lower plasma glutamine levels which should also (at least temporarily) lower plasma glutamate levels in the brain, though I say temporarily because the body is constantly burning protein to keep glutamine levels sufficient.

      Delete
    3. Tyler thanks for all, started to see good results with BCAAs, I am giving 2 g a day, a very low amount, because I couldn´t get 5 or 7 g for now. Also, I am in 2 drops of risperidone, do you think that I take it off right now ? It has been a very long process of weaning off, drop by drop for almost a year, think it is enough. Should I increase BCCAS amount anyway?
      Valentina

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    4. Valentina, you are his parent so considering there is no objective way for us at this time to evaluate these kinds of therapies at the moment (i.e. no specific BCAA research on lowering dopamine in those with autism), you have to make that judgement.

      I don't know your child, but you don't want to do anything that causes him to go into a state where he is in a danger to himself or others (the main reason antipsychotics are prescribed in autism), so I would just take it slow and taper it off little by little.

      Delete
    5. I agree with the fact that antipsycotics should be prescribed only in certein cases, where the child is in danger to himself or others, but this was never the case, nor even close. So, I don´t understand why he was prescribed with risperidone for the first time. I think that in autism, it is, or it was at that time, like prescribing aspirin or ibuprofen to someone with a headache. Many neurologists prescribe risperidone only for stereotypies. Big mistake.
      Valentina

      Delete
  16. Peter, what would be the other cheaper options of riluzole?
    Valentina

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    1. Valentina, in many countries there is now a generic version of riluzole, because the patent has expired. It is one quarter of the price, or less. Ask about the generic version, not the original.

      Delete
    2. Valentina, I did mention Bromocriptine in an earlier post which is being trialled for ALS, it is much cheaper, but it has many other effects.

      Delete
    3. Peter,Bromocriptine is a dopamine agonist, if I want to block the D2 receptor or downregulate it, I shoudn¨t use it or not necessarily?. Rilutek is the generic brand for riluzole,will find out the price. What do you think about Trehalose? It is being use in ALS.
      Valentina

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    4. I think that if effective you would only need to try Bromocriptine or Riluzole for a day. It will either make things better, worse or do nothing.

      Trehalose's benefit in ALS relates to increased autophagy and not reducing glutamate. As Petra has pointed out, it is not well absorbed when taken orally.

      Delete
    5. Peter, I don´t dare to use Bromocriptine for its dopaminergic stimulant activity, as a D2 agonist, in the case of my son, I am trying to reduce dopamine activity with BCAAs.
      Valentina

      Delete
  17. For people who have children that may engage in SIB or have symptoms synonymous with intermittent explosive disorder, here might be an explanation for where things go wrong:

    Press Release:

    https://www.sciencedaily.com/releases/2017/01/170109124959.htm

    Paper:

    http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4470.html

    This research essentially found that an area of the brainstem that kind of acts as a reflexive behavior area is strongly inhibited by the prefrontal cortex and that if this circuit is weakened, then reflexive behavior such as the behavior resulting from social defeat (being bullied) intensifies. They proved this via another experiment where they interrupted this prefrontal to PAG circuit in the brainstem which caused the mice to behave as if they had been bullied even though they hadn't.

    This may (my opinion only) explain some of the mind-boggling behaviors in classic autism that have no basis in the environment of the child which is doubly frustrating as a parent when other people judge you and assume you did something wrong to elicit bad behavior out of your child (such as assumptions of abuse), just because they have a neurodevelopmental disorder that may result from faulty prefrontal inhibition of this circuit, or possibly from there being little to no axonal projections to the PAG from the PFC to regulate this reflexive behavior circuit in the first place.

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    1. Tyler, very interesting! I am glad you brought this up - the "social defeat" aspect - which I don't think just means being bullied. For my son, his experience with his type of autism alone brings feelings of social defeat. He knows he is missing out on certain things, knows he is treated differently from society, and he doesn't like it - it shows in behaviors. Society tends to think that if a person with autism is minimally verbal, they don't really care about social issues, fitting in, being welcomed - maybe the better characterization is that most feel they aren't aware of this - couldn't disagree more.. It really became more apparent to me in middle school, and now in the teenage years. And even more so since his older brother left for college. I now find myself shifting away from the tendency to biologize everything, looking for answers via those types of remedies. I'm trying to focus on emotional health and providing more opportunity for him. I guess medicines can help put out a fire but in the long run, providing opportunity, meaningful and stimulating opportunity, friendships, and giving them environments where they feel valued helps that emotional state more than anything - and that helps the health of the body.

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    2. Tanya, when it comes to providing warm environment and interaction you might also want to have a closer look into something called Intensive Interaction, if you haven't already.

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    3. Nat, have never heard of that - seems nice as an early intervention approach for those really affected. I was just speaking about social defeat idea in terms of when the kids get older and transitioning to young adulthood. when my son learned to type and proved he cpuld do all the academics the typical kids could, how the perception changed of him in elem school. before that the art teacher didn't even want him in her class - it's a shame he has to constantly prove himself for others to give him a chance. This is what I mean about the social defeat and those who are minimally verbal - no a lot of spoken language does not translate to intellectually impaired necessarily. But academics are by no means everything in life. this is the issue with getting older I am touching on. Probably not making too much sense - I never do when I type on this ipad. Must be a sensory/kinesthetic learning thing for me - i need a keyboard and to use all fingers to type and it come out sounding semi-coherent haha

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    4. Interesting:

      https://www.psychologytoday.com/blog/brain-sense/201105/social-defeat-changes-young-brains

      When the researchers gave the animals certain anti-anxiety drugs that work in humans--drugs that block vasopressin receptors--the anxious behaviors of the socially defeated mice diminished in number. Vasopressin is a hormone. Its levels are known to run high in severely anxious rodents. In humans, it's associated with aggression, stress, and anxiety disorders.

      When the researchers looked at the brains of the socially defeated animals, they found more receptors for vasopressin than normal mice have--particularly in the middle of the forebrain, a region known to be associated with emotion and social behavior. Receptors act like docking sites for hormone molecules. The more receptors the brain has, the more places the hormone has to latch on to nerve cells and affect their functioning. With a larger number of receptors, the defeated mice are, thus, more sensitive to vasopressin, so they respond more strongly to the hormone than other mice do. In this research project, the effect was found to be especially strong in the amygdala, a brain structure that some neuroscientists consider the seat of emotion.

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    5. Peter, Do you know whats the drug used? https://spectrumnews.org/news/vasopressin-blocker-improves-social-deficits-in-rat-autism-model/

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    6. Well the research only looked at "social defeat" since it is easily testable in mice with various experimental paradigms. The researchers hypothesized that this circuit affects pretty much all behavioral responses, while not affecting limbic processing which regulates mood. The analogy is that if someone makes you angry, you don't automatically hit that person in the face (well most people don't) because you have this inhibition from the prefrontal cortex. However, if the PFC is compromised or at least this circuit is, then if you are angered or scared even just a little bit you might lash out. It is kind of like if this circuit was hyperactive and someone attacked you with a knife, you would just stand there and not react and let them stab you to death, but with a healthy modulation of this circuit, you would engage in defensive behavior as best as possible (reflexively) and fight back, while hypoactive regulation of this circuit would cause someone who was simply tapped on the shoulder to immediately become violent via an overreaction.

      At least that was my read on the paper.

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    7. Tanya, the clinical trial data is here:-

      https://clinicaltrials.gov/ct2/show/study/NCT01793441?show_locs=Y#locn

      The drug is called RG7314.

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    8. yes got that tyler. was just bringing up the topic of social defeat and how just that *experience* can change brain structure. Something to think about as kids get older, transition to adulthood, age out of services - in the age window of vulnerability to depression and schizophrenia. I think it is well known that depression is an issue with autistic adults. Not just for the very verbal ones.. Thanks for the info you share - it always gets me thinking and expanding the thoughts

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    9. Tyler, one more question and some background info. : my son is 17 and had really bad experience with a teacher/aide in middle school - homeschooled him for a couple of years and then tried again in high school because he does not like being at home, wanted to go to school where is brother was, and is motivated by the "typical" experience.. Well, it did not go well. long story short - any bit of aba style approaches from teachers and he goes into shock and awe mode - doing anything to get away from it. Now I can see this is almost like a PTSD reaction - couldn't at the time and focused on sensory issues, and training teachers. where i live with a heavy influence of aba, it is hard for these teachers to break that mindset and be willing to try new approaches . My kid does not have negative anti social reactions - he isn't "hard to reach" however, he can be with teachers or anyone with aba approaches - he does not trust them and goes into self preservation mode- so that means, unless there is a paradigm shift in the school system here (and I have tried!), he has to be homeschooled unless i really want trauma and intensified reaction on my hands. am I correct in reaching the conclusion , from this link, that using things to lower BDNF might help this situational/experience- dependent "school aversion"? If so, any ideas on nutrients to try to lower BDNF? His BDNF has not been tested. https://www.ncbi.nlm.nih.gov/pubmed/16469931

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    10. Tanya, my son started having severe social processing issues at 17, although he seems to know social norms.
      He says that it's impossible for him to forget bad experience and he wishes he was neurotypical as most people find it easy to overcome miscommunication.
      I am afraid we are dealing with PTSD which builds up over the years from puberty into adulthood.
      These days he keeps saying "I am in great pain", his lack of expressing emotions at the time of happening, fear conditioning and pain perception have all been mixed up.

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    11. Hummmm, that is a tough one Tanya. On another site I sometimes read just to get an idea of what higher level autistics think and experience called wrongplanet.org, there were several threads that I came across in which the posters (presumably with a diagnosis) extolled the evils of ABA and how much they hated it. In non-verbal children (as is my son though he is progressively using more and more natural speech to communicate his feelings in words) ABA with a harsh therapist can be traumatizing. The original ABA stuff with Lovaas seemed like torture to me and considering that there are many different styles of ABA (Pivotal Response Therapy, Floortime, etc.) to say what type of ABA causes the most harm is hard to say. The classroom my son is in is totally ABA (not my choice but I have four young kids and I have limited options in this regard) and the teacher is getting her master's in ABA, the conversation about treating another human being as a person rather than as a pet dog probably would not make things better for my son. His teacher does work very hard, but I think the best environment for ASD kids is socialization among peers (assuming the peers have been vetted to be supportive), not having a classroom of severe ASD kids stuck in cubicles which is the best way to describe my son's class. I have considered homeschooling as well (my son is 8) but right now I can't make it work with my other responsibilities to my other children, plus a research project I have been working on for this last several years that I hope to get into development (autism related).

      Guess I am off on a tangent here, but I don't think lowering BDNF is going to fix his school aversion as this all sound more like actual PTSD symptoms, not simply a "PTSD reaction". A stepparent I ran into once at a park with my kids had an autistic teenage girl with him (his stepdaughter) who I found out had an identical twin sister (who I later met at an autism function) and both girls were on the more moderate to severe side of the spectrum. Anyways, one of them (the one that stayed home) now has severe PTSD from a school bus driver trying to sexually molest her on the bus. I did not ask for the full story, but he said she would likely have to take medication her whole life to treat the trauma.

      Now, I don't know if the autistic population is more susceptible to PTSD or not, but the symptoms you describe of your son with regards to ABA stuff sounds exactly like PTSD to me. There are a lot of cutting edge therapies for PTSD now that don't involve heavy drugs, so you might want to get him tested for that if you have not done so already and go from there.

      As for BDNF, it is upregulated from learning activity (Long Term Potentiation or LTP as it is called) and the autistic brain is thought to be hyperplastic in the sense it learns too much at a time which decreases the signal to noise ratio in the brain (not a great explanation). Calcium inflow to neurons is very important in learning, as well as upregulating BDNF so maybe some of Peter's suggestions like Verapamil might be something to look into if you think BDNF is the problem. Personally from what you describe, it sounds like PTSD which obviously is something you will want treated differently.

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    12. Tyler, thanks for your input. I agree with you completely about the ideal classroom environment. My son would have probably done the best in a Waldorf type school with typical peers (properly vetted though like you say). and I understand your need for school services now - make the most of it while you can - my son had the best experience with elementary school - he had a young and athletic special ed teacher and aides with NO aba influence - just kind hearts and open minds. And lots of time for recess and respect for his need to move and be active. He felt the love from that staff and that made the difference - there was no rigid agenda.

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    13. Petra, thanks so much for sharing! It breaks my heart for your son. Does he say if being able to talk to you about it makes things better, or does it just re ignite things? Have you tried anything specifically for PTSD? I am looking in to EMDR therapy - wondering how or if my son would cooperate with that. have you heard of it?

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    14. Petra, is your son on Verapamil? Even though my daughter is not hfa, she used to have a lot of anxiety from being unable to forget unpleasant experiences. The thoughts used to go round and round in her head, and she too used to confuse it with pain, pointing to her head and saying it was bothering her. Verapamil at 1.25mg per kg put an end to that. The Magnesium taurate at 400mg adds more calming and relaxing. The potassium has opened her up to various sensory experiences, including being able to take in various sounds and sit amidst groups of people, being in noisy environments. Also expanded palate, eats pretty much all foods now, in fact very interested in trying new foods and preparations.

      I think the above three have contributed so very much to her quality of life, her participation and enjoyment of it.

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    15. Thank you RG. As soon as I finish first week insulin trial I could add back some Verapamil, maybe start with 20mg in the afternoon, to see if it can help with anxiety and pain.

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  18. Tyler, I found this scientific research claiming that trehalose oral ingestion is very poorly absorbed.

    "Unfortunately, not only is trehalose initially poorly absorbed from the intestines but within the intestinal wall there is an enzyme (trehalase) which can rapidly degrade trehalose into glucose. For the trehalose that bypasses this enzyme and gets absorbed, the threhalase present in the liver and the blood appears to finalize the digestion leaving little to no trehalose able to reach a cell and exert its therapeutic effects.

    The only way to preserve the effects of trehalose is to avoid oral ingestion by applying the compound topically leading to the promise of trehalose in protecting cellular function being exclusive to the skin, eyes, and hair. It has already shown therapeutic promise for the treatment of dry eye symptoms when used as eye drops, with a potency greater than commercially available products."

    As I mentioned, I already use trehalose eye drops for dry eyes disease, prescribed by the ophthalmologist.
    Do you think this small amount could reach and give benefit to liver? I give it three times a day.
    Or even rubbing trehalose solution upon liver perhaps? Lot's of people do that with castor oil packs.

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    1. Yes this is true to an extent. The thing is that you only have so many digestion enzymes available to metabolize proteins and sugars, and the rest either leaks through the gut passively if it is not too large a molecule, it is metabolized by gut microbes, or else it is excreted.

      The enzyme that humans have for breaking the disaccharide bond of trehalose into two glucose molecules can be overwhelmed. The question then is how much trehalose is passively absorbed by the digestive tract (that which is not broken down by trehalase). In other words, if you use a small amount at a time, most of it will just be converted to glucose, but if you use a large amount, then it is an open question how much of it is actually absorbed.

      Just like anything else you put in your body, eventually it is metabolized and trehalose eventually gets metabolized by the liver into trehalase. Nevertheless, this is where trehalose exerts its beneficial effects with respect to NAFLD in that it competitively blocks the glucose transporter in a particular type of liver cell (can't remember which one off the top of my head) and induces it into a state of autophagy which seems to be compromised in NAFLD. Another thing to consider when using oral trehalose is that your digestive enzymes upregulate or downregulate based upon their exposure to a particular type of food which is one reason why vegetarians will literally get sick if they eat a lot of meat (besides of course any psychosomatic issues). So one option for trehalose usage would be to use it orally once a week and in significant quantities to prevent increasing levels of trehalase production.

      As far as the eye drops go, I don't think trehalose eye drops or topical use will do anything in the body because it is far too little for the reasons I mentioned above. You either need to ingest a lot of it at once (this method I think works, but the science on this is ambiguous if you ask me) or else inject it.

      Last but not least, there was recently some research from a Japanese group on a synthetic analogue of trehalose that gives most if not all the benefits of trehalose, but which is not affected by trehalase. When if ever that becomes commercially available, I really don't know.

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    2. Tyler, thank you very much for your research on trehalose, I'll keep a close eye on it.

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  19. So apparently it is thought that microglia renew themselves at a slow rate so that you can never really clear out the brain immune system while other types of immune cells renew themselves much faster.

    Well new research suggests this is not the case with microglia and that the entire population of the brain renews itself up to 6 times on average over the course of a lifetime:

    Press Release:

    https://www.sciencedaily.com/releases/2017/01/170110121049.htm

    Paper:

    http://www.cell.com/cell-reports/abstract/S2211-1247(16)31746-6?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124716317466%3Fshowall%3Dtrue

    This is exciting because in autism dysfunctional microglia in many hypotheses seem to be public enemy number one in terms of causing problems in the autistic brain. If microglia renew themselves at the rate they seem to in this new paper, then it is conceivable that therapies targeting diseased microglia to kill them may be practical, similar to a novel MS therapy I recently read about (and may have posted here) where stem cells from the bone marrow of the patient are harvested and then "reprogrammed" to not be dysfunctional anymore and then the entire immune system is wiped out with strong chemotherapy drugs. Then once the immune system has been wiped out, these "repreprogrammed" or non-diseased stem cells are put back into the body to create an entirely new and healthy immune system.

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  20. I tried histidine with a bit of zinc for my son and within a few hours, mosquito bite looking rashes appeared. So apprently we are not so lucky with the paradoxical effect? The cogs in my brain are slow this morning - need a little jump start in figuring out what this effect could mean, and if can lend to clues for other areas to support? I learn much more when things go wrong. Anybody have any ideas? thanks in advance

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    1. Tanya, it looks like in your son the histidine was converted to histamine and then you got the classic signs of allergy.

      My son recently had the same rash all over his body after eating someone's home-made salami. He was allergic to something they put in it.

      Is your son histamine intolerant? Many people with austim seem to be. My son is not.

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    2. yes he likely is. He has unstable mast cells and allergies. So the paradoxical effect only works with mast cells? I know he has DAO snps, not certain on hnmt snps, but just assumed. I think this means SAM-e instead. Or more support for methylation (which I thought I was doing enough ) or supporting another histamine processing gene NAT2 which requires pantethine? The salami - any kind of cured meats my son reacts to badly as well. A histamine-y food.

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    3. You will need to stabilise his mast cells for histidine to have a positive impact or its just feeding the histamine fire.

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    4. yes Em, he has been on mast cel stabilizers for a few years now. Prescription as well as natural supports.

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    5. actually more than a few years - he had been on ketotifen when the first signs of asthma, exercise induced asthma, cropped up. This was before we knew about mast cell issues (many many years ago). I was going with Peter's comments and citations in this blog about the paradoxical effect histidine has on preventing mast cells frm releasing hstamine. My son's mast cell skin symptoms are usually hives. Stress is the biggest mast cell degranulator trigger for him at this point. It does get confusing sorting out differences between mast cell and/or histamine intolerance.

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    6. Hi Tanya, out of curiosity do you now give B6 or P5P to your son?

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    7. yes, every day now - and one of the reasons I felt ok about trying this histidine experiment. : /

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    8. I am still not sure what is the mechanism of histidine use for allergy, but as P5P is a cofactor of histidine to histamine conversion maybe it worked as a booster of this reaction and with sufficient amount of histidine available it resulted in histamine overproduction and hives? Is that possible?

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    9. Thanks Agnieszka for you thoughts - and I bet you are right! B6 (p-5-p) for my son is needed to support DAO, but maybe because of this the added bit of histidine pushed him over a threshhold. And maybe this negative reaction means he could benefit from a histidine decarboxylase inhibitor like green tea?? Do you use green tea or an ECGC supplement with your son. I thought I remember reading somewhere it should be avoided when there is mast cell activation. Before I gave the histidine a try, I was reading on a histamine intolerance forum many people having luck with it. Go figure....

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