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Monday, 3 April 2017

Different Types of Excitatory/Inhibitory Imbalance in Autism, Fragile-X & Schizophrenia


There is much written in the complex scientific literature about the Excitatory/Inhibitory (E/I) imbalance between neurotransmitters in autism. 

Many clinical trials have already been carried out, particularly in Fragile-X.  These trials were generally ruled as failures, in spite of a significant minority who responded quite well in some of these trials.

As we saw in the recent post on the stage II trial of bumetanide in severe autism, there is so much “background noise” in the results from these trials and it is easy to ignore a small group who are responders.  I think if you have less than 40%, or so, of positive responders they likely will get lost in the data. 

You inevitably get a significant minority who appear to respond to the placebo, because people with autism usually have good and bad days and testing is very subjective.

There are numerous positive anecdotes from people who participated in these “failed” trials.  If you have a child who only ever speaks single words, but while on the trial drug starts speaking full sentences and then reverts to single words after the trial, you do have to take note. I doubt this is a coincidence.

Here are some of the trialed drugs, just in Fragile-X, that were supposed to target the E/I imbalance:-

Metabotropic glutamate receptor 5 (mGluR5) antagonist

·        Mavoglurant

·        Lithium

mGluR5 negative allosteric modulator

·        Fenobam

N-methyl-D-aspartic acid (NMDA) antagonist

·        Memantine

Glutamate re-uptake promoter

·        Riluzole

Suggested to have effects on NMDA & mGluR5 & GABAA

·        Acamprosate

GABAB agonist

·        Arbaclofen

Positive allosteric modulator (PAM) of GABAA receptor

·        Ganaxolone


Best not to be too clever

Some things you might use to modify the E/I imbalance can appear to have the opposite effect, as was highlighted in the comments in the post below:-



So whilst it is always a good idea to try and figure things out, you may end up getting things the wrong way around, mixing up hypo and hyper.

The MIT people who work on Fragile-X are really clever and they have not figured it all out.


Fragile-X and Idiopathic Autism

Fragile-X gets a great deal of attention, because its biological basis is understood.  It results in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development.

We saw in the recent post about eIF4E, that this could lead to an E/I imbalance and then autism.




Our reader AJ started looking at elF4E and moved on to EIF4E- binding protein number 1.

In the green and orange boxes below you can find elF4E and elF4E-BP2.

This has likely sent some readers to sleep, but for those whose child has Fragile-X, I suggest they read on, because it is exactly here that the lack of fragile X mental retardation protein (FMRP) causes a big problem.  The interaction between FMRP on the binding proteins of elF4E, cause the problem with neuroligins (NLGNs), which causes the E/I imbalance.  Look at the red oval shape labeled FMRP and green egg-shaped NLGNs.

In which case, while AJ might naturally think Ribavirin is a bit risky for idiopathic autism, it might indeed be very effective in some Fragile-X.  You would hope some researcher would investigate this.




Can you have more than one type of E/I imbalance?

Readers whose child responds well to bumetanide probably wonder if they have solved their E/I imbalance.

I think they have most likely improved just one dysfunction that fits under the umbrella term E/I imbalance.  There are likely other dysfunctions that if treated could further improve cognition and behavior.

On the side of GABA, it looks like turning up the volume on α3 sub-unit and turning down the volume on α5 may help. We await the (expensive) Down syndrome drug Basmisanil for the latter, given that the cheap 80 year old drug Cardiazol is no longer widely available. Turning up the volume on α3 sub-unit can be achieved extremely cheaply, and safely, using a tiny dose of Clonazepam.

It does appear that targeting glutamate is going to be rewarding for at least some of those who respond to bumetanide.

One agonist of NMDA receptors is aspartic acid. Our reader Tyler is a fan of L-Aspartic Acid, that is sold as a supplement that may boost athletic performance.  

Others include D-Cycloserine, already used in autism trials; also D-Serine and L-Serine.

D-Serine is synthesized in the brain from L-serine, its enantiomer, it serves as a neuromodulator by co-activating NMDA receptors, making them able to open if they then also bind glutamate. D-serine is a potent agonist at the glycine site of NMDA receptors. For the receptor to open, glutamate and either glycine or D-serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg2+ or Pb2+).

D-Serine is being studied as a potential treatment for schizophrenia and L-serine is in FDA-approved human clinical trials as a possible treatment for ALS/Motor neuron disease.  

You may be thinking, my kid has autism, what has this got to do with ALS/Motor neuron disease (from the ice bucket challenge)? Well one of the Fragile-X trial drugs at the beginning of this post is Riluzole, a drug developed for specially for ALS.  Although it does not help that much in ALS, it does something potentially very useful for some autism, ADHD and schizophrenia; it clears away excess glutamate.


Fragile-X is likely quite different to many other types of autism

I suspect that within Fragile-X there are many variations in the downstream biological dysfunctions and so that even within this definable group, there may be no universal therapies.  So for some people an mGluR5 antagonist may be appropriate, but not for others.

Even within this discrete group, we come back to the need for personalized medicine.

I do not think Fragile-X is a good model for broader autism.


Glutamate Therapies

There are not so many glutamate therapies, so while the guys at MIT might disapprove, it would not be hard to apply some thoughtful trial and error.

You have:

mGluR5

     ·        mGluR5 agonists (only research compounds)

·        mGluR5 positive allosteric modulators (only research compounds)

·        mGluR5 antagonists (Mavoglurant, Lithium)

·        mGluR5 negative allosteric modulators (Fenobam, Pu-erh tea decreases mGluR5 expression )

Today you can only really treat too much mGluR5 activity.  It there is too little activity, the required drugs are not yet available.  I wonder how many people with Fragile-X are drinking Pu-erh tea, it is widely available.


NMDA agonists

D-Cycloserine an antibiotic with similar structure to D-Alanine (D-Cycloserine was trialed in autism and schizophrenia)

ɑ-amino acids:

·         Aspartic acid (trialed and used  by Tyler, suggested for schizophrenia)

·         D-Serine (trialed in schizophrenia)




NMDA antagonists


·        Memantine (widely used off-label in autism, but failed in clinical trials)


·        Ketamine (trialed intra-nasal in autism)


Glutamate re-uptake promoters via GLT-1


·        Riluzole


·        Bromocriptine


·        Beta-lactam antibiotics









64 comments:

  1. Thankyou Peter for the post and the link,and the image post,another that made me laugh.
    Valentina

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  2. Hi Kritika,

    I remember you were trying to see if Cardiazol was available in India? Is it? Do you know if KBr is available there as well?

    Many thanks.

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    Replies
    1. Hi RG,

      Yes, in fact I had tried to find out about the availability of cardiazol but it seems difficult to procure through local chemists..even the ones around premier hospitals. In fact they deny evem keeping the drug. But I think it was availabe online and very cheap at that..with a doctors prescription though. I did not pursue it further...you have reminded me to try and get a peesctiption if possible. I never enquired about kbr but its easily available online..as a veterinary med!

      Regards

      Delete
  3. Hey Peter we recently had a discussion about trehalose bioavailability and I just came across a very recent study on humans using what you might consider a megadose of trehalose (100g/d) which when finished showed significant effects and improvements in arterial microvasculature in healthy middle aged and older adults (MA/O):

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

    Ironically most Americans consume more calories in the form of sucrose per day so who is to say it is a megadose, but I am guessing they use this large dose to overwhelm the trehalase enzyme which is present in considerable quantities in the upper intestine, liver, and blood.

    What they found is for adults who did not gain more than 2.3kg in weight over 12 weeks, their endothelium-dependent dilation (EDD) improved by 30%. In other words, they found no improvements in the macrovasculature (as they expected) but considerable improvements in the microvasculature, a topic relevant to autism especially with regards to the microvasculature of the blood brain barrier. It is also interesting (and with respect to autism and some interventions suggested on this blog) that the improvements in EDD were abolished from nitric oxide inhibition which suggests obviously that trehalose's positive effects on the microvasculature are nitric oxide dependent. If oxidative stress (in some autisms) is a direct cause of BBB permeability, perhaps megdose trehalose could be a magic bullet in this regard (one can only hope).

    ReplyDelete
  4. One more thing for anyone who might consider megadose trehalose. Here is a link to the brand I have at home:

    https://www.swansonvitamins.com/swanson-ultra-pure-trehalose-1-lb-454-grams-pwdr

    If you were to do 100 grams a day (which you would probably scale down for a child), that would cause you to run through 2 of those containers in 9 days which comes out to be roughly $2.67 (American) per day which is obviously not cheap and considering it eventually is metabolized to 400 calories a day in glucose, you obviously would want to cut back on carbs in other areas because you will be getting plenty from trehalose. One nice thing about trehalose is that unlike pretty much every other sugar I am aware of, it is not absorbed really fast in the stomach, rather it does not get broken down into glucose until it gets to the small intestine and any trehalose not broken down by trehalase is absorbed passively by the intestinal lumen (which is the idea behind the megadosing) or else excreted.

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  5. Just came across a novel bit of research that explores the brain-gut axis, rather than the more conventionally known gut-brain axis:

    Press Release (No Paper):

    https://www.sciencedaily.com/releases/2017/04/170403123508.htm

    What they did in this research is apply a new use of Transcranial Magnetic Stimulation they call "Deep Transcranial Magnetic Stimulation" or dTMS to an area of the brain in obese subjects that is very difficult to target with regular TMS called the insula. This stimulation ended up changing the gut microbiota of the subjects to have a composition more reflective of healthy/skinny subjects and caused a 3% average weight loss over the study period.

    Now what is interesting here is not really the technique but the idea of changing the gut microbiome via the brain itself. The stimulation area they chose was the insula and one interesting thing is that the area they likely targeted which included the prefrontal cortex (which means they focused on the anterior insula) is also parallel to many endocrine subcortical nuclei, including the hypothalamus. There is no paper available, so I am just speculating that in addition to stimulating the insula, they likely stimulated feeding centers in the brain which primarily are master regulated via the hypothalamic nuclei even though reward areas of the brain are very important, not to mention parts of the insula involved in whether you "feel" one way or another toward a food (i.e. is it good, bad, disgusting, etc.).

    With respect to autism where impaired endocrine signaling and a compromised microbiome is just part of the story, the idea of using the brain to change the microbiome, rather than the other way around is intriguing. It also suggests, simply supplementing with probiotics in some people may not be enough as the gut microbiota could be constantly pushed back into a compromised state via the brain itself.

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    Replies
    1. Hi Tyler,

      Thanks for posting this! The gut/brain axis was interesting enough, but the idea that there is two way communication versus one, is big. The fact that the brain can impact the but microbiome is fascinating - and to your point, interventions aimed at changing the gut microbiome of ASD patients may be inadequate if the brain keeps sending messages to turn the good microbiome bad. The key then would be to change the message from the brain.

      AJ

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  6. Hi everyone,

    Thought you'd be interested in this:

    http://www.telegraph.co.uk/news/2017/04/05/marmite-may-boost-brain-even-help-stave-dementia/

    Marmite appears to boost GABA - could it be helpful to us?

    It can never be something tasty like a KitKat bar that our kids would actually crave - it has to be something that will taste odd to them.

    Hope you find this interesting!

    AJ

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    Replies
    1. Hi AJ,

      I was just curious about the effects you could perceive, of the many naturally occurring compounds...astaxanthin, apigenin I remember..you were trialling on your daughter. Any breakthrough with any other intervention. Would be grateful for a brief summary.

      Wishes

      Delete
    2. Hi Kritika,

      Hope all is well with you. Kritika, I would say that the only compound I can say for sure has had an impact on my daughter is 5-HTP. The impact is really noticeable. I give her 0.5mg/kg twice a day (1 mg/kg total per day) and the difference is noticeable. I had bought it and held onto it, not sure if I sure try it, and then I read something Peter had written and that gave me more confidence - tried and it and wow. My daughter's mood improved a lot. She was already a happy kid, but she immediately became a lot happier, less cranky, etc. I don't know if it'll work for your son, but it worked for us.

      My daughter is constantly improving in terms of her speech, but I don't know if its her natural progression or my treatment protocol. I recently added Huperzine and Citicoline and school just said they see recent improvements in her speech, but again, I can't say if its related. All that to say, I haven't yet had a "WOW" where I give a supplement and she immediately improves a lot.

      I will say that I just read something Peter wrote about improved Oxytocin with Biogastrus Protectis. I will likely try that next.

      Hope that's helpful Kritika, and all the best to you and your family!

      AJ

      Delete
    3. Hi AJ,

      Thanks. I am currently trying, rather finishing off my bottle of Biogaia protectis, on alternate days, as i had opened it and then stopped using it and it is to be consumed within a certain time period following opening.

      But the dramatic mood enhancement and communication improvement which we had seen with bio amicus reuteri was missing with protects. Not sure if its because of difference in strain or my sons changed biochemistry or change in weather. After this, I am done with L. Reuteri as I am unable to decide what kind of positive effects I am looking for to justify its long term use.

      Currently just trying to revisit basic supplementation... Plus some methylation stuff.

      Beet wishes

      Delete
  7. Peter
    I started my 6 year old son autism on Bumetanide 1mg Two times a day 2 weeks ago. I am seeing changes with him on this. Urination is just more volume not that much more often. He is calmer, has much less OCD and better balance already, also better sentence structure when talking. These changes are coupled with some unusual episodes in which he seems to be laughing & totally on another planet about 3 times a day for about 10 minutes. My son is an unusual kid as far as responding to things. Many things that other kids respond to he has had a bad response to. NAC made him stare off & make strange noises for long durations where you could get him to hear us. This seems to happen with other amino acids that we have tried. Broccoli Sprout Powder (Enduracell) seems to make him calm yet happy. So this one has been pretty good.
    I am hopeful about the Bumetanide since I see that it does have an effect on him. School considers him autistic with hyperlexia since he is a good learner with gifts in reading and math. He has a negative part of his personality in which he accomplishes great things if you are not watching him but will NOT share his gifts. An example he will count by 9 s or even 8 s to 100 but if you say " that's great can you do that again, he will scream very loudly "NO, I won't " . The same with reading & the same with playing his instruments. Peter I know you are not a doctor, by when reading his description are their any other compounds that may help him? Also I know to just stick with the Bumetanide to see those changes all the way through. I am supplementing potassium. Also is your son still using Bumetanide.

    Thank you

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    Replies
    1. Pierrette, my son has been taking Bumetanide since December 2012, so we are committed to it.

      Your son sounds like he has Asperger's.

      I would continue with the bumetanide. If he does not have big issues, I would not get carried away with therapies.

      5-HTP is widely used and does correct a common biological dysfunction. It is very cheap and easy to trial. You can get it in gelatin capsules and just pour out the correct amount into a drink. I would try 0.5mg/kg at breakfast and see if you have a more cheerful son later in the day. People who do respond seem to use 0.5mg/kg twice a day, but once may be enough.

      When he is older and if he has more behavioral issues you could try baclofen, which many people with Asperger's respond to; but not all of them.

      If you want to make him more emotional/loving/caring, the Biogaia Protectis probiotic produces oxytocin among other effects. It really does have this effect in many people. Biogaia Gastrus has a second bacteria in it. We use Protectis, but not every day.

      Delete
    2. Pierrette, how you describe your son being resistant to sharing his gifts - a kind of performance anxiety - you might be interested in what Donna Williams has to say on this. She is an Australian woman on the spectrum who has written several books and works with families - she describes this scenario as "exposure anxiety". My son is the same - except he will say "go away" or leave me alone please"... I find her insights so helpful. She shares her very personal experiences and addresses the emotional health, not just the biology, and how that impacts so much. Give her a google.Of all the adults on the spectrum writing books and speaking at seminars, I always found her insights and experiences more like my son - very creative soul, sensitive, and deep in to the sensory stuff. Best wishes!

      Delete
    3. Peter:

      I appreciate the great recommendations, I am not knowledgeable on what supplement could improve mood and less anxiety, so thanks for these, I will wait 30 more days on this bumetanide to see if mood is improved with less sodium chloride in his cells!!! If not I will try these! He is currently on a probiotic Lacto Rueteri which I chose because it is supposed to positively effect mood & oxytocin. I will have to track it and see if the days I don't give it may be his more problematic days. The Biogaia Protectis may be even more effective then Lacto Rueteri. I have not tried the 5-HTP. After 30 more days I will try the dosage you suggested if needed. As far as issues go. He is a great learner but a very poor communicator. He is in Half mainstream Kindergarten/ Half Hyperlexia class, (he prefers the hyperlexia class with just 5 other kids) and since he does not share and show I had to tell school that he could read & do math & after he was there for months they let me know that he was quite gifted at reading & math, they thought they were informing me of something I did not know. So communication is a BIG problem for him. He does make autism noises so they tend to think that he has problems learning and his not wanting to talk to them made it that much harder. Thank you Peter & Thank you for a very informative blog

      Tanya:
      I am glad you wrote that post I really never had someone explain this as "exposure anxiety" & yes his other phrases are "please leave me alone", "please close the door behind you", & "I would like some privacy, please leave". Like I said I am hoping the bumetanide relieves some of this anxiety and I will look up Donna Williams for more insight!

      Delete
  8. The NMDA antagonist Amantadine has proved very helpful for my son... however after two years we have reached max dose and tolerance is waning... any suggestions on how to achieve the same effect?

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    1. Audrey, Amantadine also increases dopamine release, and blocks dopamine reuptake. It may be this effect that gave the benefit. I think you said L-DOPA did not help, there is also Carbidopa. I did a post on dopamine.

      https://epiphanyasd.blogspot.com/2017/02/secondary-monoamine-neurotransmitter.html

      Amantadine is used off-label in MS.

      I think you once mentioned you use Minocycline. This should reduce microglial activation.

      One reader of this blog uses the Japanese drug Ibudilast. In Japan it is used to treat asthma, so it is a drug for long term use.

      Ibudilast has been found to stabilize microglia and in the US is now being trialed as a therapy for MS.

      So while Ibudilast is not the same as Amantadine, it might be interesting.

      Delete
    2. thanks Peter. Yes we use minocycline too... though it also seems to have tapered off in effectiveness. And I'm never quite sure about the dose. Yes... Zandopa, a natural form of L-dopa based on Mucuna was quite impressvie for my son... increased movement, language, etc. But only once... the next day it did not work. I waited a few weeks and tried again... and never got that same amazing response as the first time. :( I will look into ibudilast... thank you Peter

      Delete
    3. Hi Peter, and all. My Ibudilast arrived today from Japan. Can anyone give me advice on dosing for a 40lb, 6 y.o.?
      Thanks so much

      Delete
    4. Audrey, in Japan the dose for asthma is 10mg twice a day. Your son is 1/3 the weight of a Japanese adult.
      It is experimental use, but the current trial in the US to treat MS is going well and has been extended. At least one reader of this blog finds Ibudilast helpful for autism, but I do not know her dose.

      Delete
  9. Peter, have you seen this article?

    https://www.ncbi.nlm.nih.gov/pubmed/27645286
    It first sounds as if it is just about stuttering, but it seems that adrenocorticotropic hormone (ACTH) has good effects on autism as well. The common denominator is epileptic activity (electrical status epilepticus in sleep - ESES).
    I stumbled on this while looking for information on transcranial direct current stimulation and epilepsy.
    /Ling

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    Replies
    1. Ling, thanks for the link.

      That link would be very interesting for Tanya and Agnieszka.

      There is also interest regarding corticotropin releasing hormone (CRH) and autism.

      Stuttering is a troubling feature for many with autism.

      Central hormonal dysfunction is one of my suggested core issues in autism. ACTH is part of the hypothalamic-pituitary-adrenal axis. A problem with one hormone then disturbs many others.

      The problem with hormones is that they are controlled by feedback loops and it is hard to find solutions that are long lasting and without negative consequences.

      ACTH is interesting. Low ACTH and cortisol levels are symptoms of ACTH deficiency, which is treatable.

      Delete
    2. ESES might be underdiagnosed in autism, but I think it’s important to consider even if it’s only a kind of epiphenomenon. I am not sure, but I think they used high dose ACTH as in infantile spasms, a severe early childhood epilepsy and it was suggested that ACTH might be anitiinflammatory/immunomodulatory in such case.

      Recently Diamox was also found effective for ESES and improved communication, school performance and behavior in children included here:
      https://www.ncbi.nlm.nih.gov/pubmed/26230617

      Ling, I saw you considered EEG for your daughter. I think these papers (and many others) show that it is really a good idea and the best would be prolonged sleep EEG, otherwise things like ESES might not appear in the result. Good luck with finding help for your daughter.

      Paradoxically, speech disfluency in my son developed along with improvement in EEG and huge cognitive step forward. His sleep epileptiform discharges disappeared on acetazolamide. His awake EEG abnormal slowing reduced gradually on Bumetanide and is now considered borderline.

      Delete
    3. Thanks Agnieszka!
      Actually it was this publication that made me insist on having an EEG for my daughter: http://treatingautism.org.uk/wp-content/uploads/2017/04/Seizures-in-Autism-information-sheet.pdf
      I am sure you know it well... :-)
      /Ling

      Delete
    4. Hi Ling, I learned from a neurologit today that he has never seen a normal EEG in a child with autism. Did you complete the EEG and was there any findings? I think the deep sleep EEG would be important for us and I thank you for posting that link as I will be taking it to our peds at the next visit.

      Delete
  10. Peter - I noticed earlier that you said that Biogaia Protectis increases Oxytocin - I didn't realize that and would love that effect. I looked online and found that they have both drops and tablets. Is one more effective than the other between the drops and the tablet in your opinion? And what dosage would you recommend for a 35 pound 4 year old? If my daughter's sociability at school improves due to this product, it would be great news for us.

    Thanks in advance Peter!

    AJ

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    Replies
    1. AJ, Bioamicus are in Toronto and you might want to try their L.reuteri and compare with Protectis.

      In our 50kg (110 pounds)case, just one tablet is enough to make the effect I assume comes from oxytocin. I think 5 drops = 1 tablet.

      The Bioamicus bacteria is very slightly different and it is entirely plausible that different people might respond better to different versions. Diet may also have an influence.

      Delete
    2. Hi Peter, Thank you! I will definitely try it and didn't realize there was an option (Bioamicus) in my own backyard. I will certainly try it. Much appreciated Peter!

      AJ

      Delete
  11. It looks like I am dealing with a specific hypo-NMDA variant, which is what this post is about.

    The long genetic link (published only so that others with downstream genetic syndromes are able to find this post) for this would be:
    Too little SATB2 - downregulates TBR1 (partly via upregulation of BCL11B/CTIP2) - resulting in downregulation of GRIN2B.

    GRIN2B is coding for the NMDA-receptor subunit GluN2B.
    Wikipedia tells us that (in rats) "an increased NR2B/NR2A ratio correlates directly with the stronger excitatory LTP in young animals" and "Both mice and rats that were engineered to over-express GRIN2B in their brains have increased mental ability"

    A very recent case study on a child with GRIN2B mutation:
    "a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B (..) Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation."
    https://www.ncbi.nlm.nih.gov/pubmed/28734458

    And, relevant for more people, findings on OCD genetics:
    "It was found that GRIN2A, GRIN2B and GRIA2 are the most central nodes in the network. Functional and pathway enrichment analysis showed that glutamate-related pathways are the main deficient systems in patients with OCD."
    https://www.ncbi.nlm.nih.gov/pubmed/28608743

    From previous blogposts, we have learned that D-serine, cinnamon, sodium benzoate, D-cycloserine glycine and clioquinol act as agonist on NMDArs. Tyler added L-aspartic acid to this list. Baclofen has beneficial effects through a different mechanism. mGluR5 regulators eventually doesn't help in the GRIN2B case as https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050796/ suggests "the regulation of NMDA receptor by mGluR5 may not involve the NMDA receptor subunit NR2B"

    Some of these interventions are unfortunately off-limits if you have histamine issues. Lower dosing seems very important, since too much of an agonist here can turn into an antagonist. Chronic dosing is of course also different from the once-administered positive results seen in so many studies.

    Some interesting questions are these:
    In hypo-NMDA, is glutamate cleared from the extracellular space by other receptors (AMPAr) or does it build up?
    If you treat hypo-NMDA, how likely do you have to deal with inhibitory issues too? We know KCC2 easily gets downregulated when things go wrong in the brain.
    Can excitotoxity be a cause of only hypo-NMDA?

    /Ling

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    Replies
    1. Another question would be why I see a positive effect with Mg-supplements if dealing with a hypo-NMDAr case. It is a modest effect, but visible. Magnesium is a non-specific inhibitor of NMDA-channels, so it sounds contradictory.

      One obvious reason could be that Mg has many other functions, like reducing cortisol, stabilizing mast cells, antiinflammatory and enhancing BDNF. But, it also stimulates GABAb, which might do the same trick as Baclofen for hypo-NMDA(?)

      And, according to this paper: https://www.ncbi.nlm.nih.gov/pubmed/7576654
      "Extracellular Mg2+, which blocks NMDA channels in a voltage-dependent manner and increases the receptor's affinity for glycine, is shown here to potentiate NMDA responses (..)
      This potentiation (..) is voltage independent (and) is "permitted" by the NR2B subunit and prevented by the NR1 splice variant (..)
      The similarity and nonadditivity of the effects of Mg2+ and spermine suggest that Mg2+ may be the physiological agonist acting at the subunit-specific spermine site."

      So, spermine and Mg seems to have one effect in common which doesn't stack. Was it Tyler who proposed spermine once?

      /Ling

      Delete
    2. So, deepdiving into NMDAr subunit NR2B (which could deserve its own blogpost combined with perhaps LTP enhancement) shows it is very essential to learning and memory, and is implicated in age-related memory decline.
      It also looks like you could combine an NMDAr subunit NR2B agonist like Mg-Threonate with a NMDAr antagonist like memantine to regulate the subunit profile of NMDARrs:
      "We report that a physiological concentration (1 mM) of Mg(2+)(o) decreased memantine inhibition of NR1/2A and NR1/2B receptors nearly 20-fold at a membrane voltage near rest. In contrast, memantine inhibition of the other principal NMDAR subtypes, NR1/2C and NR1/2D receptors, was decreased only approximately 3-fold."
      https://www.ncbi.nlm.nih.gov/pubmed/28877967

      /Ling

      Delete
    3. A very interesting thing happened. The study 2 posts above on a GRIN2B patient receiving D-serine was retracted (but will be republished) because for some reason the patient was given L-serine instead of D-serine. Obviously this still gave very good results! For anyone who can't find D-serine it should work as well with L-serine.
      /Ling

      Delete
    4. Ling it is odd that use L-serine for ALS, but D-serine for schizophrenia. In neurons L-serine is converted into D-serine. You would think one must be best.

      Delete
    5. Hi Ling and Peter,

      I was curious about what you are posting in this thread and found the following:

      https://nootropix.com/sarcosine-d-serine/

      https://www.ncbi.nlm.nih.gov/pubmed/?term=27048272

      Any thoughts about Sarcosine as a glyt-1 inhibitor having some utility? Maybe in combination with other mechanisms, there may be some additive or synergistic benefit.

      I hope this is helpful!

      AJ

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    6. AJ, Sarcosine has been shown to help some people with schizophrenia. Very likely some types of autism may also benefit since the disorders do overlap.

      There are very many partially effective therapies for schizophrenia that may help some people with ASD. The schizophrenia research is more advanced. The same is true with Bipolar, many partially effective treatments exist.

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    7. We have supplemented D-serine in a first 3 week long round now and though it is a very short time I feel confident enough to report on it. Implication of use in our case was suspicion of hypofunction of NMDAr.
      Dosage: around 80 mg/kg and day, divided in 2-3 doses when possible. (1200 mg)
      Age/weight: Almost 3 years old, 15 kg
      It works very well for hairpulling (OCD/neuropathy) manifested a couple of times each day. Effect in less than an hour and fades in perhaps 5 hours or so. No adverse events at all so far. Very easy to administer as a crystalline powder with very slight sweet taste that can go unnoticed in a drink. We haven’t seen any cognitive benefits yet, but it is too early to tell. Safety profile looks very good, I think that the upper limit is around 9 grams per day.
      Could this perhaps be an alternative for NAC, and if so, is this a histamine-safe intervention or not?
      ---
      L-serine (precursor for D-serine in the brain) seems to have the same major effect and is easier to obtain. This is the compound that is trialled in young children with loss-of-function mutations in NMDAr subunits at the moment:
      According to a first-hand source, at the Children's hospital of Barcelona, current L-serine dietary supplement starts with low dose (200mg/kg/day) and, after two weeks, the dose raises the standard range of 500mg/kg/day. Initial observations are that L-serine improvements start with motor skills, reduction of stereotypies (hand washing) and, after few weeks, with a reduction of irritability and improvement of motor gating, together with much more communication.

      /Ling

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    8. Hi Ling,

      Hope you're doing well!

      The info you've provided on dosage in mgs/kg for D/L Serine is really interesting. Thanks for sharing.

      I just recently added l-Serine to my treatment protocol and the dosage I use is miniscule (30Mgs/Kg/Day) in relation to what the Children's Hospital of Barcelona uses. I will slowly titrate up to see if I see any impact. I think I'll at least move up to about 60Mgs/Kg/Day next.

      Hopefully I'll get our genetic test results soon so that I can better target treatments for my daughter's specific issue (assuming the genetic test turns up anything).

      Have a great day Ling!

      AJ



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  12. New review paper on D-serine treatment:
    https://www.frontiersin.org/articles/10.3389/fpsyt.2018.00014/full

    A little bird told me it looks like there will be trials with D-serine for children affected by hypofunction of the NR2B subunit (gene: GRIN2B). Much thanks to the case report mentioned in a comment above and some patient lobbying.

    /Ling

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    Replies
    1. Ling, if you read that paper and follow what is says about sodium benzoate (NaB) and in the references , it would seem that at least for schizophrenia it is NaB that should be trialed. It is safe and ultra cheap, since the doses used or just 1g or 2g a day and NaB is available in bulk.

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    2. I deliberately try to neglect that fact since NaB-containing food unfortunately seems to be untolerable by my daughter...
      /Ling

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    3. Ling, that suggests histamine intolerance, which seems quite common among readers of this blog.

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    4. Peter,

      We generally add a stick or two of cinnamon into our curries to add flavor and my son displays no adverse reaction to this food. Could he still be histamine intolerant....I mean does the amount matter?
      We have issues with most supplements, probiotics and even huge quantities of veggies like avocado, which i later learnt triggers histamine production. And unfortunately, stuff like mb12, folinic acid and bioamicus reuteri which worked with some good effects the first time round before things went bad probably due to histamine production, when I retrialled them, we had no grace period; their was an almost immediate adverse reaction. Would this be histamine intolerance?



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    5. Kritika, apparently 1% of the population have DAO (Diamine oxidase) deficiency and so struggle to degrade histamine. Symptoms include diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus and flushing.

      https://www.ncbi.nlm.nih.gov/pubmed/17490952

      It certainly looks like there will be degrees of DAO deficiency.

      If you eat foods high in histamine you would consistently have the same symptoms, just a matter of their severity, once you have used up all your available DAO.

      I expect not everyone who has self diagnosed DAO deficiency really has it.

      I think you can have an odd reaction to L.reuteri without being DAO deficient.

      People with DAO deficiency have to avoid carbonated drinks, which usually contain sodium benzoate.

      You could look online to see if people with DAO deficiency omit cinnamon from their curries. There are a lot of curry lovers in the world and this would have come up as a problem.

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    6. Still confused...if my son or I dont react adversely to cinnamon in our food or down a carbonated drink or two without breaking out with hives, does that mean we are histamine tolerant.

      Headache? That is such an unhelpful symptom though I have started feeling a little Michael Jacksonish with my developing addiction to painkillers.

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    7. Kritika, I think you have to talk to someone who is histamine intolerant. For some people it really is a big issue.

      It does not look like you have a histamine problem.

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    8. Hi Kritika,

      Was this your son who recently benefited from Augmentin or I am mistaken? If Indian Augmentin is the same as Polish one, then it contains clavulanic acid which is a strong DAO inhibitor:

      "Chloroquine and clavulanic acid showed greatest inhibition potential on diamine oxidase (> 90%)."
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127955/

      I would not expect good effect of Augmentin in a person with histamine intolerance and reduced DAO activity.

      On the other hand, unusual drug reactions seem to happen in mast cell activation disorders, which can occur without histamine intolerance:
      "It is very important to note that such patients often demonstrate even a greater propensity to react to medication excipients (i.e., fillers, binders, dyes, preservatives) than to the active ingredients."

      https://www.ncbi.nlm.nih.gov/pubmed/27132234

      There are more interesting remarks about such hypersensitivity in that paper. I have no idea if this is relevant to your son though.

      Here where I live you can measure DAO blood activity, which sometimes may be helpful. However it is said that normal DAO result does not exclude histamine intolerance, so it is not that simple as I wish it to be ;-)

      All best,
      Agnieszka

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    9. Hi Agneiszka,

      Yes, it was my son who benefited from four days course of augmentin. I stopped at four days because after the first two-three days, we start getting some hints of discomfort, everytime we use augmentin. This could simply be a result of disturbed microflora or it could be the clauvinic acid. .The good effect of beta lactam slowly sullied by negative ones of clauvinic acid (yes, our augmentin contains that).

      Most supplements, all of which I trialled in tablet/capsule form created problems many of which I suspect could be related to excepients...magnesium stearate, silica dioxide. As my son is an expert tablet swalloer, I thought that would be very convenient. Probably trying out the pure powder forms would make more sense. I did trial a pure multivitamin-multimineral at a low dose but that created problems too. Histamine-oxalate issues are also on my mind.
      I will go through the paper you mentioned. How does one diagnose mast cell disorders?

      Regards

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    10. Agneiszka,

      My son is still doing well after that augmentin trial. You know, the entire disposition changes. Its like he is relaxed neurologically. He is happy and holds long eye contact....just put his socks on on his own...very receptive, could almost wash our dog's leash with me instructing him from a distance. Started writing few hindi letters without a template (yes, he is learning to write two languages). I had seen the same effects with cefixime, twice and it is after four days that effects on expressive speech are seen though other positives are seen within 24 hours.

      That such beneficial changes are seen with antibiotics, with mb 12 for a short period, with L. reuteri again for a short while and even with liverlife indicates that we have a intricately linked, complex set of problems. We even have spontaneous periods of cognitive spurt so it is very hard to understand.

      I think I read on this blog itself about a parent who was giving antibiotic for a few days every month as a preventive measure as she suspected the child to be suffering from chronic stomach infection. What about the 2015 study sponsored by parents whose kids responded favourably to antibiotics.

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    11. Kritika,

      I really don't know if 3 days on Augmentin is when to expect DAO inhibition effects. Possibly yes.

      A paper on cefixime and autism/epilepsy was discussed here a while ago:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322506/

      It's about a child whose seizures decreased 'dramatically' after 3 days of cefixime given for diarrhea. The effect lasted 5 months and then parents successfully repeated the trial - to control seizures, not for GI infection. The authors associated it with glutamate regulation by cefixime.
      Kritika, perhaps you can write to them, report your findings and ask for opinion? There is email of the first author published.

      How come this boy improved for so long after treatment with cefixime? This is something I can't understand.

      Anyway, in reply to your question, there are three aspects of MCAD diagnosis: symptoms, response to mast cell stabilizers and laboratory confirmation of mast cell mediators release.

      There is a lot written in a useful way here:
      https://www.novapublishers.com/catalog/product_info.php?products_id=42603

      In short, Fig. 1 in another paper is a good summary of MCAD symptoms:
      http://www.nejm.org/doi/full/10.1056/NEJMra1409760?query=recirc_curatedRelated_article
      It lacks a disclaimer that all physical symptoms can manifest atypically in autism and also as behaviours.




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    12. Agnieszka & Kritika, the long lasting benefit in the above case study likely involves epigenetic changes. This is discussed in the paper below.

      Off-Target drug effects resulting in altered gene expression events with epigenetic and "Quasi-Epigenetic" origins.

      https://www.ncbi.nlm.nih.gov/pubmed/27025785

      "The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors"

      I am putting together a post on the non-antibiotic effects of beta lactam antibiotics, so all these findings do not just get lost in the comments sections of different posts.

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    13. Dear Agneiszka,

      Yes, I had read that case study where cefixime helped this boy with unconcontrallable seizures. Cephalosporins have been linked to reduced glutamate accumulation...it was a review article I think on beneficial, non antimicrobial effects of antibiotics. Five months is indeed a good long period. For us, the positive effects fade by around day 25_30. If it is likely because of epigenetic changes, then it gives me something to ruminate over.

      Thanks for your suggestions and the links. MCAD is something I have to keep in my mind as I explore further.

      Good wishes for your son and daughter

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    14. Dear Peter,

      It would be wondeful if you write a new post on antibiotics though you have mentioned them in your blog earlier also. Epigenetic changes? That is intriguing. What about John Rodakis (guess that was the name of a parent funding his iwn research on antibiotic and autism)? What were their findings?

      Regards and lots of love to Monty...his achievements, cool quotient and all, are an inspiration. Music and sports! What else could one ask for.

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    15. Kritika, the next post will be on beta-lactams. There already is one on macrolides. That leaves Fluoroquinolones and Tetracyclines for future posts.

      I do not know what happened to John Rodakis and finding out ways to treat his son.

      He has a very different strategy to mine. He wants to raise money to fund autism research, to find answers. I think there already is more than enough research to find many of the answers.

      Researchers will always want more money and money is not always the issue. Compare the US Space Program with that of the Soviets. The Soviets achieved a great deal, on a relative pittance compared to NASA.

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    16. I thought their achievements came mostly due to sharaska (sp ?) system - a lot of talent was imprisoned, no? So no need to spend money on salaries.
      Maybe Rosalie thinks if it’s old it’s not useful - new is better.

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    17. Tanya, they had/have very talented people and at the end of the cold war the US Government, recognizing this, took over funding the Russian scientists to work on the International Space Station and similar projects so that unemployed rocket scientists did not go to Iran or North Korea.

      The only way NASA astronauts can get to International Space Station is to go to Kazakhstan and take a Russian spacecraft. NASA does not have any means to get there, since the Shuttle was retired.

      Elon Musk's new Space X launcher offers to launch super heavy satellites for a cost 90% less than NASA's proposed offering. So things are changing for the better.

      The Chinese will also soon be doing more for less, in space.

      My point was we need to get something today from the hundreds of millions of dollars already spent on autism research. Perhaps we need Mr Musk.

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    18. Peter,

      Looking forward to your next post.

      I hate the Soviets. They do cruel bizarre research on animals in cold, snow covered, depressing facilities. Head transplant and all. They have Siberia and Gulag Archipelago!!! I don't like them. Sorry but I allow myself that much naivety.

      Delete
  13. If someone told me I had to get to the moon to find a treatment for my child... Impossible?
    Today, I am sure I somehow would get it.

    I would just need my determination, Internet access to this Peter Lloyd-MacGyver-dude-blog and perhaps adding in a 40 year old russian psychotrophic that make your body create its own oxygen from stardust.

    /Ling, partly dead serious, partly silly

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  14. Maybe someone already posted this, or a similar paper:

    Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine
    https://www.sciencedirect.com/science/article/pii/S0197018613002623?via%3Dihub

    "Prebiotics increased hippocampal BDNF and NR1 subunit expression relative to controls. The intake of GOS also increased hippocampal NR2A subunits, and frontal cortex NR1 and d-serine."

    NR1 and NR2a are important subunits of the NMDA receptor and D-serine is a NMDAr agonist that also is in use for those with too little NR2b subunits. So, good for all types of NMDAr hypofunction.

    /Ling

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    Replies
    1. Ling from what I have read the ratios between the subunits, especially increased NR2B/NR2A ratio. NR2B has a bad rep, but it is extremely important.

      From wiki:

      Function
      NR2B has been associated with age- and visual-experience-dependent plasticity in the neocortex of rats, where an increased NR2B/NR2A ratio correlates directly with the stronger excitatory LTP in young animals. This is thought to contribute to experience-dependent refinement of developing cortical circuits.[7]

      ----->> Both mice and rats that were engineered to over-express GRIN2B in their brains have increased mental ability.[8][9] <<-----

      I know you have been looking into LTP enhancement, how come you have not tried piracetam yet? It has a profound effect on me to be honest.

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    2. What I've learnt recently is that different compounds target different subunits of the NMDA receptor, or at different sites:

      NR1 too low -> use Baclofen
      NR2B too low -> use Magnesium (mostly seen as a NMDA antagonist, but it also ups the expression of the gene for NR2B)
      NR2B too high -> use sodium butyrate
      NR2A too low -> use Bacopa, retinoic acid, high frequency stimulation, fluoxetine
      Both NR2A and B too low -> PDE inhibitors & forskolin

      Glycine acts as an NMDA agonist mostly at extrasynaptic sites while D-serine acts as an agonist mostly at synaptic sites.
      Memantine acts as an antagonist at extrasynaptic sites.

      Wikipedia has a really good page on the NMDA receptor and I can really recommend reading it as a whole.

      @Aspie: I am working on a protocol targeting a very specific genetic cascade. So, what I try is drugs and supplements that have a direct connection to the genes I know are up/downregulated in my daughter. Since so many things are awry (not only L-LTP), I need to focus on root causes to cover as much as possible with as few interventions as possible.
      Also, since we are talking about a non-verbal toddler who also happens to be the apple of my eye, safety issues and available papers on use in children are limiting factors.

      /Ling

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    3. Ling,

      I see lots of people taking antifungals other stuff that messes with the gut daily on this blog, I find it absolutely frightening and imo its like russian roulette, and they seem to do it under the motto just to 'try it' with barely any knowledge behind it. Very irresponsible imo.

      If you look up to piracetam, it is actually very save, if you payed attention I have posted papers before showing that its been using in doses up 20grams daily for years in certain patients without much if any at all side effects.

      Let me just tell you as someone with ASD/aspergers myself and having been on meds SSRI's antipsychotics, even tried baclofen. These all had HORRIBLE side effects on me and these are not candy, pretty much every strong drug out there can cause set the path towards full blown diabetes, well then you insulin resistance in someone with autism, when that happens people can forget about trying to fix their beloved ones with autism on this subreddit, cause they will be on a mission impossible.

      I wish the best of luck to you Ling, but keep in mind that it might just be wiser to give someone with autism that works then settle with it, there seem to be an endless trialing n error of things (yes im guilty of this myself but im nearly done what works for me).

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    4. Thanks Aspie for caring and wishing me luck, because I will need that too.
      Your recommendations of piracetam have not gone undetected and I'll certainly look into it more, when I get an empty trial slot.

      /Ling

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  15. Time for a Bacopa trial report.
    It will only cover a start, and not a stopping of the supplement, and is clouded by concomitant use of other things (mainly aimed at memory), but since there are no reports except for Tylers (“not approved because of taste issues” right?) I thought it might still have some value. The aim was to raise NMDA receptor functionality, hoping for memory and GABA effects too.

    My daughter was 3y3m on day 1 of this trial, and 16 kg.

    Doctor’s Best Bacopa with Synapsa brand, 55% bacosides. Capsules for adults are 320 mg. I divided these into 6 and gave one part in the morning and one part on evening, so approximately 2*50 mg/day. This is a modest dose, but given the lack of trials with children of her age I wanted to test tolerance first. Also, I divided the dose on morning/evening because Bacopa has a bit bitter taste and can be hard on the stomach. We experienced no taste aversion by stirring it with blueberry soup + straw.

    Trial length so far: 9 weeks. Most effects are expected to be seen at 8-12 weeks.

    Week 1-5, nothing to say. Eventually a bit worse than baseline, but she had a tooth coming up at the same time and I blame it on that. Slept well.

    After 6 weeks I realized that she suddenly can stick out her tongue, just by asking her to do that. It’s a skill I’ve previously tried to practice with the help of snacks and mouth toys, with very little result and I think I abandoned my efforts 6 months ago or so. This was unexpected since she has oral apraxia. Some new sounds in her “vocabulary”. No more plasters on her knees, very good balance.

    7 weeks. She points to birds in the sky and to letters she has learned on signs. More accurate at noticing details, even far away. Has started to shake her head for “no” instead of pushing things away with her hand.

    8-9 weeks. Painted a picture at daycare and used signs to tell what it depicted. At the supermarket, pointed at some flowers and signed “mum”, “buy” to the person following her. (Yeah, she actually bought me flowers!!) Had the courage to greet a few adult persons at a party by touching their hands – she is usually anxious to the point that she doesn’t want to look at her own grandmother. Told me that she didn’t want a specific sauce to her rice, before tasting it (she just saw the colour and recognized it).

    Overall during the summer, her long-term memory is much better. It is not just about learning colours and letters, but also about developing/showing a personality. It is nice to get to learn her likes and dislikes.

    Side effects so far: For some reason, she has started to push her hands to her eyes a lot. Any ideas on that would be appreciated!

    /Ling

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