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Thursday, 11 May 2017

Tardive Dyskinesia (TD)  - Amino Acids, VMAT2, Diamox, B6 etc


Today’s post is about Tardive Dyskinesia which is a side effect eventually experienced by about 30% of people taking antipsychotic drugs, like risperidone, widely prescribed in both autism and schizophrenia.




Enough money for your lifetime supply of a VMAT2 inhibitor?


Tardive Dyskinesia (TD) is a disorder resulting in involuntary, repetitive body movements, which might think of as tics or grimaces.

It appears that the longer the drug is taken the greater the chance of developing Tardive Dyskinesia.


Tics are quite common in autism and not just in those taking psychiatric drugs.

Tourette’s syndrome is a well-known tic disorder that does overlap with autism, it used to be considered rare, but now 1% of children are thought to be affected.  Some common Tourette’s tics are eye blinking, coughing, throat clearing, sniffing, and facial movements.

People diagnosed with Tourette’s might also be diagnosed with ADHD, OCD or indeed autism.  

We saw in some Italian research that young children with Tourette’s type autism have a fair chance of seeing their symptoms of autism substantially fade away. It was called Dysmaturational Syndrome.


The part of the brain that is thought to be affected in  Tardive Dyskinesia is that same part suspected in Tourette’s and indeed PANDAS/PANS; it is the basal ganglia.  


Avoiding Tardive Dyskinesia

The best way to avoid Tardive Dyskinesia is not to use antipsychotic/ neuroleptic drugs.

It appears that high doses of melatonin and other antioxidants may give a protective effect from developing Tardive Dyskinesia. 


Treating Tardive Dyskinesia

Much is written about treating Tardive Dyskinesia (TD), because nobody yet has found a cure for it, nonetheless there is a long list of partially effective therapies.

Given that the underlying basis of TD may very likely to overlap to some extent with Tourette’s and PANDAS/PANS it is over broader interest.  


A Review of off-label Treatments  for Tardive Dyskinesia 

The Spanish study below gives a good overview of most therapies, but exclude the very recent therapies based on VMAT2. 






  
All of the studies in the review were small, but you can see that some therapies did seem to help, including:-

·        Vitamin E

·        Vitamin B6

·        Acetazolamide/Diamox

·        Amino Acids

·        Piracetam


I proposed Acetazolamide/Diamox to potentially treat some autism a while back and some readers of this blog do find it effective.

Piracetam is the world’s first cognitive enhancing (nootropic) drug.  It was discovered by mistake when trying to make a cure for motion sickness.

Amino acids may look an odd choice, but in males, and only males, branched chain  amino acids (BCAAs) valine, isoleucine, and leucine in a 3:3:4 ratio appears to be beneficial.  Another amino acid called Phenylalanine is associated with tardive dyskinesia in men but not in women. It is an established fact that an increase in BCAAs will cause a reduction in phenylalanine in the brain, among a range of other effects.

Phenylalanine is a precursor for dopamine (as well as  tyrosine, norepinephrine, and epinephrine). 

One theory is that tardive dyskinesia results primarily from neuroleptic-induced dopamine supersensitivity. So if the BCAAs reduce the amount of dopamine produced, this might explain their effect.



VMAT2

VMAT2 transports monoamines - particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine - from cellular cytosol into synaptic vesicles. Inhibiting VMAT2 will reduce the release of dopamine. 

In some circumstances VMAT2 is necessary for the release of the neurotransmitter GABA. 

Drugs that inhibit VMAT2 appear to help treat Tardive Dyskinesia and one drug Valbenazine/Ingrezza was FDA approved for this purpose in April 2017. Not surprisingly, it is now being investigated to treat Tourette’s syndrome. 

Valbenazine is known to cause a reversible reduction of dopamine release by selectively inhibiting VMAT2. 



Conclusion

Since our regular reader Valentina is dealing with Tardive Dyskinesia, she will probably be very interested in Valbenazine.

The problem is the price. The drug will apparently cost $60,000 a year in the US.

So for the time being it is best to work through the list of very cheap interventions that do seem to be partially effective, at least in some people.













44 comments:

  1. Thank you Peter for the post, if dopamine supersensitivity would be a diagnosis, I would choose it instead of his autism diagnosis.What my son has is not Tourette, but something similar, an certainly this became clearer after the use of risperidone. I mean, he was born with this problem, fronto temporal region is the location. Once I said here that I didn´t know what the neurologist was thinking many years ago. If someone had de predisposition to develop TD, that was my son.The last time I went to the neurologist he knew that my son had TD and suggested double the bet, duplicating the dose, sure,it was too late and it was easier than doing what I am doing.
    I will have to wait a cheaper version of Valbenzine , I think is a matter of time. If it was FDA approved, that is amazing.
    Valentina

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    Replies
    1. Valentina, did you try Piracetam? It is both a cheap generic drug and a supplement in some countries.

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    2. Would you believe me that I was cheking it now?? here it is called Inteluz 800 mg 30 tablets from Gautier. Whhich dose would you recomend me?
      Valentina

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    3. Valentina, as you probably well know now, long-term use of antipsychotics (at least in animal research) leads to dopamine receptors being sensitized. Maybe you just need more patience than anything else after discontinuing antipsychotic medication in your son and track these incidents over the next 3-6 months before making a decision about overall progress.

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    4. Valentina, in one clinical trial they used 4,800 mg per day.

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    5. I will start with 800 mg a day and will up to half the dose they used in the trial,2400 mg that are 3 tablets a day and will see what happens.

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  2. Ok Tyler, this is difficult, I will have to wait until I can get a clearer conclusion, but don´t you think that piracetam in low dose could be of any help?
    Valentina

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    1. I don't know much about piracetam other than its use for a very long time as a pro-drug for other smart drug research and that I have seen many anecdotal reports on other autism boards in it being a top intervention. Piracetam dosage is a hard topic because it's exact mechanism of action is still speculated upon in spite of it being around for such a long time. I would take Peter's advice here because I have not read any papers on piracetam to date which means my analysis here is based on second hand information and anecdotals.

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    2. Valentina,

      I too was contemplating about piracetam as it might give a cognitive boost to some, is generally safe and is said to increase seizure threshold. However, I did read some studies about piracetam causing myoclonic seizures in those who were susceptible on abrupt discontinuation of the drug. So it does not seem as benign...this seems to be true for most nootropiks.

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  3. Does giving doses of Phenylalanine help or hurt TD?

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    1. It should hurt it. That would suggest that if you have TD you should avoid the sweetener aspartame, which produces phenylalanine.

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    2. The amount of phenylalanine derived from the breakdown of aspartame is quite small relative to the amount of phenylalanine you find in a normal diet. When researching the topic a while ago, finding foods that had protein with a low amount of aromatic amino acids seemed almost futile. Ancedotally, my son loves peanut butter and peanut butter is super high in phenylalanine though he has never seemed to have the kind of negative reactions he will have when compared to a high sugar meal like birthday cake so I would say artificial sweeteners including aspartame are the lesser of two evils when compared to real sugar. Last but not least, my son due to his lack of inhibitions routinely steals my diet mountan dew and will even poor himself his own when I am busy dealing with my other children if I don't hide it well. He usually gets a cognitive boost from the stuff, but unsurprisingly it also delays bedtime which is hard enough to maintain as things are.

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  4. Peter, you are probably already aware of it (maybe even have mentioned it somewhere) but your blog/case is actually referred to in this review article from MIT (2015):
    https://www.omicsonline.com/open-access/the-possible-link-between-autism-and-glyphosate-acting-as-glycine-mimetic-a-review-of-evidence-from-the-literature-with-analysis-1747-0862-1000187.php?aid=64626
    Congratulations! :)
    /Ling

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  5. Peter, I will get Miyarisan soon,which dose should I use?Could it help my son also with electrical activity?
    Valentina

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  6. Valentina, the Miyari tablets are tiny and melt in the mouth. The standard Japanese dose is from 3 to 18 tablets a day. I would start at a low dose and then increase.

    It is Piracetam rather than Miyari that may effect electrical activity. I found this list of papers one doctor has prepared:

    Kunneke PS. A controlled clinical trial on the effect of piracetam in epileptic children. Br J Clin Practice 33(9): 266-271, 1979. 16 children with epilepsy and learning disorders given piracetam or placebo for 6 weeks. No effect on severity or frequency of seizures noted. Researchers report a positive effect on visual perception and on memory as tested by digit spans.

    Brown, P et al. Effectiveness of piracetam in cortical myoclonus. Movement Disorders 8(1): 63-68, 1993. 21 patients with cortical myoclonus were evaluated in a double-blind, controlled study with placebo. Piracetam markedly helped myoclonus. No interaction seen between piracetam and anticonvulsants. Note: sudden withdrawal of piracetam caused worsening of myoclonus and seizures.

    Ikeda A et al Clinical trial of piracetam in patients with myoclonus: Nationwide multiinstitution study in Japan. Movement Disorders 11(6): 691-700, 1996. 60 adults studied, with good results.

    Van Vleymen V and Van Zandijke M Piracetam in the treatment of myoclonus: an overview. Acta Neurol Belg 96: 270-280, 1996. This paper summarizes all trials and case reports known to the authors to date. It showed efficacy in several types of myoclonus, there was no obvious interaction with anticonvulsants, and adverse effects were rare.

    Guerrini R et al. Cortical myoclonus in Angelman syndrome. Ann Neurol Jul;40(1):39-48, 1996. 11 patients with Angelman syndrome, ages 3 to 28 years. All had myoclonus with abnormal EEG activity. 5 were given piracetam, with good results for all five patients.

    Dulac O et al. Myoclonus and epilepsy in childhood: 1996 Royaumont meeting. Epilepsy Research 30:91-106, 1998. This paper is a terrific resource for the description and etiology of all types of myoclonus. However, the portion dealing with treatment takes up only 2 full pages. Piracetam gets a brief mention: "In various types of cortical myoclonus including progressive myoclonic epilepsy and post anoxic myoclonus, it has marked effect on over one third of the cases...but is poorly effective against thalamocortical and subcortical myoclonus."

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    1. Peter, I don,t know what to do about piracetam because in spite it could work for diskinesyas, I don´t think that it could help with my son´s electrical activity because the dysfunction is subcortical and piracetam is poorly effective in this level,as it is said in the papers.
      Valentina

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    2. Tyler,I wanted to know why my son needs to receive more dopamine at d2 receptors? Should he receive the same amount of dopamine at d1 and d2 receptors while limiting its excess? In other words I must stabilize dopamine levels unlocking d2 receptors? Should I avoid supplements that limit dopamine in d2 receptors like lithium? I ask because diamox depletes lithium and he should take it.
      Valentina

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    3. Valentina, it is widely used. I think the only way to see if it helps is to make a short trial.

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    4. Dopamine activates both d1 and d2 receptors which is why they are called dopamine receptors. Dopamine drives the d1 pathway stronger so if d1 signaling is too high relative to d2 signaling you want to limit dopamine and perhaps find alternative ways of activating d2 expressing neurons that do not also have high affinity for d1 receptors. This usually means something unnatural like a drug. Also d2 expressing neurons as well as just about every other type of neuron have synapses that respond to other compounds. For example a typical interneuron can both be driven by glutamate receptors and inhibited by GABA receptors via other GABA expressing interneurons..

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    5. Sorry Tyler, the last question, if d1 signaling is stronger than d2, why do risperidone and other antipsychotics instead of activating d2 neurons,act by blocking d2 receptors and not d1?
      Valentina

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    6. Because risperidone is a drug and it has different affinities for many different receptors (not just dopamine receptors). Dopamine does as well, but receptors that are primarily and naturally activated by dopamine itself are typically called dopamine receptors. That is just the historical labeling of that type of receptor. Kind of like NMDA receptors have many different chemical compounds that activate them, including glutamate, even though they are called NMDA for N-Methyl-D-Aspartate receptors because the first substance found to bind to them was N-Methyl-D-Aspartate. Opioid receptors are called opioid receptors because it was found they were strongly activated by opium, even though the human body does not actually produce opium internally. Naturally, endorphins and enkephalins among many other hormones, peptides, and neurotransmitters have different levels of affinity for the various types of opioid receptors.

      Also, drugs that block receptors will sort of attach to the receptor site but not chemically "unlock" the receptor to cause the cell to then proceed with some other function like opening an ion channel or some sort of chain reaction causing a gene to be transcribed into RNA.

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    7. Valentina here is some very, very, very new research concerning this very topic:

      https://spectrumnews.org/news/altered-circuit-may-underlie-repetitive-behaviors-autism/

      This study deals with GABAA receptor transmission in the basal ganglia rather than dopamine. What the researchers found was that in this particular circuit that connects the prefrontal cortex to the cerebellum (which is important for behavior), there were increased levels of GABAA receptors in most areas of the basal ganglia, but in one particular part of the basal ganglia called the subthalamic nucleus, there were decreased levels of of GABAA receptors. What this usually means is that there is a lack of GABA or GABA mimetics in the basal ganglia as an increase in receptor count usually (but not always) occurs in response to a decrease in neurotransmitter levels. If there was an excess of GABA in that part of the brain, you would expect to find less receptors than normal, eventually leading to desensitization of the synapse.

      So focusing on improving GABA function in that particular area of the brain (if you are not doing so already) might be another area of intervention to improve your son's symptoms.

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    8. Valentina, on Tyler's point about GABAA receptors - when I was searching information for how micro dose clonazepam might interact with COMT mutations, I found a bit in a paper about how using clonazepam combined with vit e is helpful in treating tardive dyskinesia. You probably already know this, but wanted to share just in case.

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    9. Thank you Tanya, clonazepam is something I have been leaving for many reasons, I can´t get it easly and impossible without prescription. I know that besides dyskinesia it could help with electrical activity. But now I am trying diamox with good results.
      Valentina

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  7. You (Peter) recently just discussed the use of beetroot juice somewhere as an intervention (couldn't find comment). Well, some research today suggests that beetroot juice might help some people with autism who have excess sympathetic nervous system activity which is common with excess catecholamine signaling:

    Press Release:

    https://www.sciencedaily.com/releases/2017/05/170510115522.htm

    Paper:

    http://ajpheart.physiology.org/content/early/2017/05/01/ajpheart.00163.2017

    Besides the attenuation of sympathetic nervous system activity, it was also found that beetroot juice did not affect blood pressure which is an important consideration with beetroot juice as a therapy with respect to all of the other blood pressure related interventions/drugs mentioned on this blog.

    Now I just need to get my son to drink some that I had saved for use in a half-marathon that I forgot to drink the morning of the race.

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    1. I drink beetroot juice every day, since reading all about its properties. You actually feel different having drunk it.

      The brand I now use tastes much better since it is 25% apple juice, otherwise it tastes pretty bad.

      I will try and get my son to start drinking it, but more as a drink than a medicine. You only need a small glass (150-200ml).

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    2. Well the juice I have was just from pickling eggs for easter. I assume the brand is probably some local European brand, but if not it might save some time with trial and error if you could per chance make a recommendation.

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    3. Tyler, I do not think the brand matters. If it is 100% beetroot juice, if you add apple juice it becomes more drinkable.

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  8. Hi everyone and Happy Sunday!

    As some of you may remember, I had started using Astaxanthin some time ago as I was trying to find a natural NKCC1 inhibitor / antagonist as I could not get Bumetanide at that time.

    The same researchers just published a paper linked below, that further elucidates Astaxanthin's role as an NKCC1 inhibitor:

    https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-017-0358-z

    I still want to get Bumetanide (ideally over the summer holidays when we can ensure that our daughter is getting enough hydration) but Astaxanthin looks like it may be doing the same thing - my only question is dosage needed and how many times each day I need to dose it. I'm dosing once a day with 6mg, and mixing it with oils for better bioavailability, but I don't know if I should be dosing twice a day. Normal use requires once a day, and I thought I saw its half live at 15 hours somewhere, but if anyone has any thoughts, it would be much appreciated.

    My daughter is constantly improving, but I don't know if that is natural improvement, P5P, or the Astaxanthin, etc.

    Also, didn't know about Beetroot juice - thanks Peter and Tyler. It can never be something kids like, can it? If it turned out gummies were a great treatment for ASD, I'd be so ahead of the curve.

    Have a great day everyone!

    AJ

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    1. AJ, that is interesting. I did buy some Astaxin, but never tried it.

      It is put forward as a potent antioxidant in humans and there is a mouse study in autism.

      Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism.
      https://www.ncbi.nlm.nih.gov/pubmed/25732953

      "Astaxanthin improves the impaired behavior in animal model of autism presumably by its antioxidant activity."

      I wonder at what dose it reduces NKCC1 expression. In your study it says in traumatic brain injury there was "inhibition of NKCC1 expression via the NF-κB signaling pathway".

      In autism there is NKCC1 over-expression, but I do not think it is via NF-κB. Some studies show NF-κB is normal in autism. But you never know.

      Whether it helps as an antioxidant or reducing NKCC1 does not really matter. I wonder if anyone else has tried it. Perhaps they can advise on dosage.

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  9. Here is an interesting paper showing how viruses when entering anywhere in the blood stream can cause an immune response which upregulates TNF-a in the brain that leads to learning and memory problems via a loss of dendritic spines:

    Press Release:

    https://www.sciencedaily.com/releases/2017/05/170515134122.htm

    Paper:

    https://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4340.html

    Poor motor skill acquisition seems to be a hallmark of autism so perhaps in some autisms, immune response to a generic viral infection may cause big problems in the brain via TNF-a.

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    1. Tyler,incredible, yes, I think that my son has a permanent activated microglia,as said recently. Virus and bacterial infection have a clear immune response in my son. When tics appared after a long time, the doctor said he had a respiratory infection of viral origin. Now he is better and tics disappeared. With respect to GABAA, when I was giving Bacilor with an incredible good response, Peter told me that it could be an excelent discovery for targeting GABAA. But it was not easy to take it. Now I am waiting to get Miyarisan and given my son´s autism profile, I think it could be of great help. We will see.
      Valentina

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  10. Gut bacteria seem to be able to affect the blood brain barrier (in mice, probably humans too, with susceptible genes).
    This article is not about autism, but interesting for us since it is shows that gut microbiota can affect the blood brain barrier through immune receptors and cause a severe brain disease.
    http://www.sciencealert.com/researchers-find-gut-bacteria-can-trigger-brain-lesions-that-lead-to-strokes
    (also published in Nature, but this is the easy-read article)
    /Ling

    "suggesting that the bacteria had spread from the site of their infection to affect the growth of cells lining the brain's blood vessels"

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  11. Peter if my son has low succinato/fumarato I have to give him LEUCINA...i`m doing so.But if VMA is low,should I give him also phenileprine'''???

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    1. I am not an expert on this subject.

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    2. I'm not expert either, but looking at this:
      https://www.gdx.net/core/interpretive-guides/Organix-IG.pdf
      Low VMA would mean problem around dopamine beta hydroxylase (conversion of dopamine to noradrenaline). Things that are involved are: oxygen, copper and vitamin C.
      Can you explain thinking behind phenileprine?

      First part of your question is also very simplified, and it's part of different process (but also in attached pdf).

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    3. Minor update to the above.
      Low VMA just suggests low norepinephrine (and epinephrine). Problem with conversion would be if there are raised levels of HVA (Homovanillate, how Dopamine is excreted).

      There is also direct approach. Quoting this blog ( https://epiphanyasd.blogspot.com/2013/11/ )
      Atomoxetine (Strattera), a selective norepinephrine reuptake inhibitor (SNRI), increase both norepinephrine and dopamine in the prefrontal cortex equally but only norepinephrine, elsewhere in other parts of the brain.

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    4. Paper on Environmental Enrichment
      http://faculty.sites.uci.edu/jjgargus/files/2013/05/Woo-and-Leon-20132.pdf
      says:
      While neither olfactory stimulation nor tactile stimulation evoked much of a noradrenergic response in young rats, the combination of those stimuli evoked a ~300% increase in norepinephrine that did not return to baseline levels for 2 hours (Rangel & Leon, 1995)

      I believe this is the initial set of exercises:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682896/table/T2/

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    5. Another perespective:
      Inhibition of dopamine conversion to norepinephrine by
      Clostridia metabolites
      http://integrativemedicineformentalhealth.com/articles/dopamine_conversion_norepinephrine_IMMH.pdf

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    6. Peter ,anonymous and Tyler, I wanted to know what do you think about clostridium butyricum to treat excess dopamine, in the light of this paper, as c. butyricum kills c. difficile, and may be other bad species of clostridium. But,as it is of the same familiy, would be a possibility that clostridum butyricum could make the problem of excess dopamine worse? I don´t know if continue with Miyarisan.
      Valentina

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  12. Peter and Tyler, I left a comment above,don´t know if you read the link that someone left about excess dopamine and clostridia metabolites, the information I found in the web is not clear about clostridium butyrate, some put it in the bag along with clostridium harmful bacteria, some don´t.The paper is very revealing about my son´s problem with high dopamine and harmful bacteria related to the degree of abnormal behavior,and high HVA.Do you think that to be on the safe side should i change this probiotic for another like rhamnosus or acidophilus or would you keep it?
    Valentina

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    1. Valentina, I would use clostridium butyrate if it provides a benefit. If it does not help or makes things worse, best not to use it.

      Clostridium butyrate and sodium butyrate do help some people, but there is currently no way of knowing who they will be.

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    2. I agree with Peter. Probiotics are too complex in individuals to definitively say whether they are causing specific increases in metabolites unless you test for them directly, and even then it is a tough call since it is pretty much impractical to minimize other potential environmental variables in the gut ecosystem. Just try it and see if things are better or worse or the same after a couple weeks.

      In my opinion, I think when it comes to most probiotic/prebiotic/gut health issues, you should worry less about specific strains of bacteria and fungus, and focus on the basics of gut health which is fiber, fiber, and more fiber (which of course produces butyrate which is needed by the intestines as a fuel source to maintain homeostasis).

      There are some extreme cases where recent scientific discoveries suggest a complete microbiome transplant may make sense, such as the case with chronic clostridium difficile infections where a mega-dose of antibiotics are administered to totally kill off the existing gut microbiota and then the microbiome from a healthy host (i.e. their filtered poop with the bacteria left alive and intact) is either rectally reinserted or else administered by time-released oral capsules that break down in the large intestine, releasing the transplanted bacteria.

      There has been some discussion about doing this specifically for autism, but I am not aware of any studies so far that have done this in humans (I think I remember one with promising results done in mice).

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    3. Thankyou Tyler,next week I will up to 6 tablets a day and stay there, now he is taking 4. Definetly the reaction is not worse, he is calmer than before and no psycho episodes since then.Today is a week with Miyarisan. I am also giving green bananas with xylitol and raw flax seeds.
      Valentina

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