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Monday, 6 March 2017

Time to update the Autism Polypill?


It has been a long time since I added anything new to my autism Polypill. This is the combination of therapies that consistently, and materially reduce the symptoms of autism in Monty, now aged 13 with ASD.

As regular readers will be aware, due to the heterogeneous nature of autism, what works wonders for one person with autism may be totally ineffective, or even make matters worse, in another person with a different type of autism.
However, once you have found one therapy that is effective you have an opportunity to identify the underlying biological dysfunction that you have stumbled upon, without the need for any fancy genetic or metabolic testing.  Then you can look for other therapies for that dysfunction and other people who fall into that sub-group of autism and see what else works for them.
I am surprised how many people do respond to some of the therapies I am highlighting in this blog. 

Time to update?

I had been expecting to add the Biogaia Protectis probiotic bacteria to the Polypill.  It does indeed work in Monty and in other readers, but prolonged use does have a problem, at least in some people.  The behavioral effects fade and, in our case, it switches from suppressing allergy to promoting allergy.
The person who originally told us about Biogaia for autism uses the more potent Biogaia Gastrus, which contains the Protectis bacteria and a second one.  She uses a high dosage and uses it three weeks on and one week off.
Like some other readers found, Monty had an immediate negative reaction to the second bacteria in Biogaia Gastrus.  We are users of Biogaia Protectis, but not every day.
A long time ago I proposed the flavonoid Tangeritin/Sytrinol as a safe PPAR gamma agonist that is also a P2Y2 receptor antagonist. Research studies have shown that the flavonoids Tangeritin and kaempferol are antagonists at P2Y2 receptors and may be of interest as potential anti-inflammatory drugs.  Robert Naviaux, from the University of California at San Diego, believes that antipurinergic therapy is a key potential strategy to treat autism and also chronic fatigue syndrome and fibromyalgia.
The broccoli sprout powder already in the Polypill is a rich source of kaempferol.
Tangeritin/Sytrinol has been shown to have sufficient bioavailability to reduce the level of cholesterol in people with high cholesterol.   

KBr

The most likely contender to enter the Polypill for everyday use is potassium bromide (KBr), it does seem to tick all the boxes. 

·        It works

·        It continues to work after longer term use

·        Mode of action is understood

·        Safety record is very well understood

·        Effective at a low dosage

·        Not expensive, about 30 cents a day.  Much less if you use bulk KBr.

KBr should be effective in people who respond to bumetanide, since they both reduce intra-cellular chloride levels, but by different mechanisms.
In people who stop responding to bumetanide, I think KBr might be a good choice.  In responders to bumetanide, increasing inflammation due to an unrelated condition, may further reduce the expression of the KCC2 transporter that lets chloride exit neurons. So the inflammation increases the level of intracellular chloride and wipes out the benefit that was being produced by the bumetanide.  The effect of the KBr will be to reduce chloride again, this time by substitution with the relatively inert bromide.
It is also possible that some people with severe autism do not respond to bumetanide because their chloride level is so high that bumetanide is not sufficiently potent.  In those people the additive effect of KBr might just tip the balance.
In some countries bumetanide tablets include potassium chloride (KCl) to compensate for potassium lost in diuresis.  The cleverer thing in autism would be to add KBr, since you benefit from the K+ and the Br-.
Due to the very long half-life, you need to take a low dosage of KBr for 4 to 6 weeks until you reach the peak level of Br- in your body.  Only then can you judge whether you are a responder or not. 
What I am considering the autism dose (8mg/Kg) is far lower than the dose used for intractable pediatric epilepsy (30-50mg/Kg), specifically to avoid the known side effects.  The main side effect at high doses is bromo-acne. Children with intractable epilepsy opt for some facial spots over seizures.
Quite possibly a higher KBr dosage would be even more effective in autism, but then you will for sure be dealing with bromo-acne.


Summertime Add-ons

One conclusion from the gene studies is that often in autism and schizophrenia there are variances in the genes linked to the immune system. So the immune–related therapies that help Monty a great deal during spring and summer may indeed be applicable to a substantial sub-group of autism. For others they are likely to be ineffective.
I am hopeful of yet another step forward this summer using the amino acid L-histidine.  Histidine is very closely related to histamine and you might think that would be the last thing that could help in those prone to allergy-driven autism flare-ups.  However in an earlier post we saw that there is a paradoxical effect when raising the level of histidine, inhibits the release of histamine from mast cells.  We also saw that histidine has an inhibitory effect on mTOR, one of the suggested common core autism pathways that was highlighted yet again in the gene studies.
L-histidine, is an essential amino acid that is not synthesized in humans.  You have to eat it.





31 comments:

  1. Peter, I am lowering valproate dose, planning to do a sprinkle 125mg a day and stay there.Do you think that potassium bromide could be a kind of substitute? Also iam doing histidine since almost 2 months.Now he sleeps all night but had to increase 5htp to 50 mg.
    Valentina

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    1. Potassium Bromide (KBr) works differently to valproate, but there is evidence that for some people KBr makes other anti-epileptics work better. Outside of Germany/Austria little use is made of KBr for epilepsy. Combining with valproate would be experimental and you should ask your neurologist; perhaps in Uruguay they respect German medicine. The literature is in English.

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    2. Ok Peter,my neurologist is argentinian and I go to BsAs each time I see him, he was neuropediatrician at Heidelberg University of Germany.So,I imagine he highly respect German medicine.
      Valentina

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    3. He must be familar then with KBr use, so you are in luck. Ask him about it.

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    4. First I will have to tell him all the changes I made lately but since the change was for the better, I hope he will take it well!

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  2. Hi everyone,

    Running from meeting to meeting today but found something extraordinary - could Bumetanidr be working because it reduces CSF vs chloride reduction in cells? I'll shae my thoughts but please check out BIG news today on CSF levels being related to ASD.

    I'm working so will write more later but cold CSF pressure reduction be a solution??? I'll post links after work but big wow. Reason why se ASD kids have larger head circumference?

    Your friend in this battle ,

    AJ

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    1. There are multiple problems here with regards to extra CSF. For one, one phenotype of autism involves macrocephaly which means having a very large head. Something has to do fit in that extra space so if it is not extra brain tissue, it will be CSF. In autism there seems to be both extra brain tissue early in life, and then in adulthood you sometimes end up having smaller than average amounts of brain tissue (just like you have in diseased Alzheimer's brains or aging brains in general) with extra CSF taking up the space where there used to be brain tissue.

      The paper suggested extra-axial CSF which basically means that on the sides of the head the CSF is just collecting and sitting there and possibly causing hydrocephalus with increasing pressure and little drainage through the cerebral aqueduct.

      Chloride levels tend to be higher in CSF than in blood, but I have no idea if Bumetanide would have any effect because its mechanism of action in neurons is different than that in the kidneys, however a contrarian way of looking at things that supports your hypothesis is that:

      (1) Vasopressin (levels seem to be lower in those with autism both in the periphery (where it is known as ADH) as well as the brain. Vasopressin is released by the paraventricular nucleus and the supraoptic nucleus in the hypothalamus upon the arcuate nucleus detecting a loss in blood volume whioh for all intents and purposes means a drop in blood pressure (reducing the amount of water in the body reduces the pressure of the blood).

      (2) Blood pressure in the brain is thought to track with CSF pressure so the brain's detection of reduced blood pressure (releasing vasopressin) is not going to be tripped if there are already high levels of pressure in the brain for other reasons (such as CSF not being drained properly). As I have pointed out before, maybe some of the effect of diuretics like bumetanide which help some people with autism is twofold in that it both reduces intracranial pressure by reducing blood pressure overall, as well as causing the hypothalamus to register a drop in blood pressure causing it to produce more vasopressin which filters to the body via the pituitary gland and the brain via hypothalamic connections.

      (3) Vasopressin in humans is thought to be very important for theory of mind and pair bonding (in males at least) even though high levels are also tied to anxiety and aggression. I have read about 10 papers on the subject and unfortunately still can't get a clear idea on where the consensus lies here because there may not be any (I have seen suggestions for intranasal vasopressin therapy for autism and I have seen suggestions for vasopressin receptor antagonism as well). Most of the papers suggest vasopressin as being a possible candidate for improving social function deficits in autism (especially for males).

      (4) Another thing to consider with respect to oxytocin is that vasopressin and oxytocin are usually released together as they are produced by the same nuclei in the hypothalamus, so if vasopressin is not being released then perhaps you could have oxytocin deficits as well. On top of that, one of the main output neurotransmitters of the superchiasmatic nucleus which is the master clock of circadian rhythms in the brain (and body as well) happens to be vasopressin as well and circadian rhythms seem to be reciprocally tied to thirst and blood pressure which is why people normally will become a little thirsty a few hours before bed as the body wants to store up on water so it does not become dehydrated at night during sleep.

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    2. So if we were to assume this hypothesis has any merit, dealing with vasopressin deficiency via intranasal vasopressin or else synthetic vasopressin which is prescribed as a bedwetting solution would be the wrong intervention as all this would do is cause increasing blood pressure which would increase the pressure in the brain even further. Perhaps simple diuretics and mega-replacement of electrolytes would do the most good here as you would probably have the person with autism running their blood pressure a bit lower than normal (unfortunately serious medical supervision would be required here as messing around with blood pressure at the levels I am suggesting could be extremely dangerous without daily monitoring).

      Of course, this in all likelihood would not be a silver bullet, but I have never dared go over 1mg a day of Bumetanide and have no used any other diuretics unless you count the occasional caffeine when my son steals one of my beverages. I also supplement a lot of Potassium Gluconate to make up for the wasting effects of Bumetanide, but due to there not having any doctors that take autism seriously (especially Bumetanide treatment), being more aggressive with this treatment would be very foolish without the tools to properly monitor his electrolyte levels (which requires prescriptions and insurance payments and lots of other headaches).

      Nevertheless, this won't be a silver bullet. Autism is developmental and many other challenges remain from developmental trajectories being thrown off likely as early as the second trimester of pregnancy. If diuretics do help deal with this CSF issue, it will at least be one more problem knocked down which could be preventing other interventions from working very well or at least to their full potential.

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    3. Hi Tyler,

      As always, thanks for your insightful comments.

      For those who haven't seen the news, it can be found here:

      https://medicalxpress.com/news/2017-03-infant-mris-autism-linked-cerebrospinal.html

      When I looked for drugs that are intended to lower CSF pressure, it turned up Acetazolamide (Diamox) which has been talked about a lot on this board.

      I also found Bumetanide was supposed to be helpful as well in this regard.

      I know they're diuretics, and therefore would reduce pressure, but wonder if the improvements seen via Diamox and / or Bumetanide have as much to do with their reduction of CSF pressure as reduction in cellular chloride.

      I'm just starting to look for natural ways to lower CSF, and am looking at natural Carbonic Anhydrase Inhibitors.

      I will share my findings with everyone, and ask if everyone can share theirs too? Together, we can make a good list.

      So far, very early one, Rosmarinic Acid looks like an option:

      http://dergipark.gov.tr/download/article-file/124762

      As well as full spectrum pomegranate:

      https://www.ncbi.nlm.nih.gov/pubmed/8220326

      I still need to do go through the following, so if anyone finds anything of interest in it, please respond.

      My hope is that we can use this knowledge to add to our armamentarium against this condition.

      Have a great night everyone!

      AJ

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    4. And another paper for us to dig through for natural Carbonic Anhydrase Inhibitors

      http://www98.griffith.edu.au/dspace/bitstream/handle/10072/62969/97566_1.pdf;sequence=1

      AJ

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    5. The problem is not "too much CSF", rather the drainage of CSF seems to be a problem so if you have CSF being produced at a constant rate in the brain and it is not being drained properly, then obviously you will have increased CSF pressure as well. CSF does many things, but flushing out junk is one of them so if CSF is not draining properly, you will have all sorts of metabolites and toxins that just kind of literally float around the brain, rather than being properly drained and eventually excreted in urine. I don't know of any long-term ways of dealing with this problem other than perhaps diuretics. Short-term I think calcium channel blockers are sometimes used and in extreme cases the skullcap is removed to let the brain expand until the brain swelling has subsided (obviously not something you would want for your child).

      Also, Rosmarinic Acid does many things, among them in that it is a GABA transaminase inhibitor (valproate shares this property as well, though it is much more potent). GABA transaminase breaks down GABA so inhibiting this enzyme is thought to raise GABA levels. If the only problem with GABA signaling in the brain is low levels of GABA, then this can help but obviously more neurotransmitters does not always equal more signaling.

      On another note, one intervention I used to do for dealing with histamine issues was perilla oil which is high in rosemarinic acid that I would mix into a chocolate shake. I have not done that in a while because there are only so many interventions you can do at a time (because between school and everything else there is only so much time).

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    6. Hi Tyler, good point about drainage, agree that this could be the cause of increased pressure.

      I'm going to start on Rosmarinic acid and will report my findings. Aldo using full spectrum pomegranate as pomegranate constituents are carbonic anhydrase inhibitors.

      You're right about Perilla oil, which was one option I looked at for Rosmarinic Acid.

      Fingers crossed that we can find something new to help many of us.

      AJ

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  3. Is Broccoli Sprout Extract still part of your PolyPill?

    I just read an interesting study linking Broccoli Sprout Extract to improvements in obesity, specifically via activation of the NRF2 pathway:

    Press Release: https://www.sciencedaily.com/releases/2017/03/170307100402.htm

    Paper:

    Autism and obesity are linked (beyond medication induced obesity) and this caught my attention. Also, for some strange reason the Enduracell powder seems to cause some transient hyperactivity which also means he has a harder time concentrating. Enduracell has more than just Broccoli Sprout Extract obviously, but I was wondering what it could be. I recall you saying too much of the "Super Sprouts" did more harm than good but I could be mistaken here. Perhaps this is just a reaction that has short-term side effects while long-term usage might be very positive, but I am a little perplexed here because there are no stimulants in this product that I am aware of.

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    1. Tyler, the Broccoli Sprout Extract is still part of my PolyPill.

      There are numerous good things in broccoli, even without any sulforaphane.

      There was a post a long time ago about central hypothyroidism and low levels of the enzyme D2.

      https://epiphanyasd.blogspot.com/2013/09/central-hypothyroidism-or-low-brain-d2.html

      In that post the research suggested that in some autism oxidative stress reduced the level of D2 and this reduced the conversion of the prohormone T4 into the active hormone T3. One method of increasing D2 was kaempferol.

      So perhaps in your son, he already has enough D2 and the broccoli powder gives him extra T3 which makes him hyper.

      My dose of broccoli is much lower than that suggested in the packaging.

      It does not taste very nice, but most people with or without autism stand to benefit from it. The only group that should avoid it are people who already have cancer, since they often want less NRF2. It should be great for COPD and diabetes.

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    2. I used the Super Sprouts first but I think much of its efficacy was gone by the time it made its trip in hot shipping containers from Australia to here in the states. The product I am using at the moment is the Enduracell Pomgenex which has Pomegranate juice concentrate, Broccoli Sprouts with Myrosinase, and Coconut Water. Could not find any research or anecdotal comments about any of them causing hyperactivity in children, rather the opposite (Pomegranate compounds supposedly activate nrf2 as well or so I read). I am using a lower amount than the recommended amount for an adult (especially since it is so expensive), so your guess on thyroid hormone is what I am going with for now because I have no better ideas myself. Maybe a one day on and one day off routine might work better. If I recall correctly, the original broccoli sprout extract study had participants dosing three times a week in high doses (I could be wrong so don't hold me to this because this is just from memory).

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    3. Tyler, my son got hyperactive and finally ended up with full insomnia on the Super Sprouts. Otherwise the effects were genuinely good, but one needs to sleep at least sometimes. The same happened to him on prednisone and Mito-Q.

      With regard to your previous comment about Bumetanide dosing, how much does your son weigh? In France they use Bumetanide 2 x 1 mg off label in children of 25kg weight or more. I have switched to 2 x 1 mg recently with clearly visible cognitive effect, which apparently also showed up on iq testing that each child is required to have done in my country applying for special ed services at school.

      My son is prone to hypokalemia and with 2 x 0,5 mg Bumetanide he required 48 mEq K daily, however with increased Bumetanide dose he did not need any more potassium. The only issue in him is keeping him hydrated enough. This is manageable, compared to gains on higher dose.

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    4. Hummm, I will take all of that into consideration. I suppose I will just do the Pomgenex right after school except on speech therapy days so it has enough time to work through his system before bedtime. My son is now around 100 pounds (45 kilos) at age 8 so maybe it is time to change things up a little bit.

      Also, why did give your son prednisone? Coincidentally I have some for some ankle inflammation that subsided which I was too busy/distracted to use for myself (turns out barefoot running on a treadmill fixed that problem better than any drugs would have). Just wondering.

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    5. I don't mean to discourage you from the Pomgenex, but just remember that I also looked for anecdotal commments about hyperactivity on broccoli sprouts and did not find any at that time.

      Also I don't think it's common to stop sleeping from Mito-Q and I don't know any other child with sleep issues on broccoli sprouts.

      Re prednisone: my son is diagnosed with mast cell activation syndrome and prednisone is used for MCAS flare-ups. That's what he got it for and this was consulted with immunologist. Well, I cannot say I did not have this study at the back of my mind:
      https://www.ncbi.nlm.nih.gov/pubmed/24885033

      Prednisone controlled MCAS symptoms well, but also after a week or two his speech got better and what was most surprising he started speaking English during language lessons at his preschool, which he always attended, but never spoke before. After three weeks he was almost manic and stopped sleeping, so I quit prednisone. Unfortunately all good effects were temporary.

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  4. Peter, which would be a reliable source of KBr? I think it is only sold for Pets in the form of crystals, or not for human consumption.
    Valentina

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    1. Ideally you would use Dibro-Be mono, which is the German drug form for humans.

      It is a very simple compound and was used all over the world in large quantities in humans 150 years ago. Now it sits in the pet pharmacy.

      Your German-trained neurologist might be able to help you.

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    2. Peter, I had passed on your posts on KBr to a friend of mine who has a young child with severe refractory epilepsy and autism. Dr. Chez is their doctor and when she brought it up with him, he was quite interested, but unhappy with the politics of big pharma which has led to it not being available here.

      I am sure my doctor would also be willing to try it for my daughter, any ideas regarding sourcing?

      Many thanks.

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    3. In the US the FDA have a scheme where doctors can officially apply to use a drug not licensed in the US. So Dr Chez could use this scheme and then prescribe Dibro-Be mono, the German drug. Then the patient could buy it from a German pharmacy all entirely legally. I am sure the German/Austrian authors of the KBr papers would talk directly with Dr Chez if he contacted them.

      If you cannot access Dibro-Be mono, the other choices are just the Kbr powder sold for non-medical purposes, or the veterinary form. The best thing would be for Chez to read up on the literature (which is in English) and contact the German/Austrian doctors.

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  5. I started using leucovorin and I saw improvements in some area of speech but it was only requests and filling in words to songs he knows. My son used to speak so well, had early speech, knew many words, he would sing, and met all milestones. He spoke in phrases, sentences, and conversed with this pragmatic speech before his regression. He does not have a mitochondrial disorder. The geneticist looked into past labs and did not see evidence of it. So I decided to finally try the Methyl B12 shots from the MAPS dr. and I just realized something after looking at one of Peters old diagrams. My son also has trans-sulfuration variants- I ran these through Yasko$$ before I knew about 23andMe. He has variants in regulating homocysteine. It seems that this B12 might be the key. It is only the first few days of the injection and the first day is the worst because he is more aware or awake to the world so he is more hyper, more alert, happy, and less stressed but the first day of the shot he has difficulty focusing because he is trying to regulate all of this new sensory input. He is paying attention but taking the world in. Then after 48 hours I notice something amazing. The need for sensory input diminishes and he is begining to try and converse. The conversing is not like it used to be but he is attempting and making more eye contact and making a statement. I am trying to get more information from these statements and he is actually responding (which he wouldn't do before). I am really amazed that I would see a response like this in only one dose so soon. He is definately responding to it. I am glad his receptive skills remained in tact this whole time. I just hope my son doesn't start swearing again. At the begining of his regression he started swearing. Swearing up a storm, calling his preschool teachers names that he made up Bad Ass B**** and more..but then eventually between age 3-4.5 speech diminished and he could not even communicate well with requests. I had to do something fast but little did I know how complicated this gets. Epigenetics, Pharmacogenomics, Insurance companies that don't run certain tests, Supplements, Trialing this and that, and then you throw in the epilepsy he's had since he was 9 month old, the changes in his body from using Anti Epileptics (which I stopped), the changes in his body from diet- glutamate,casein (which I decreased, and stopped casein). The doctors have been the support but I am definately their researcher. Thank goodness for the ketogenic diet for betahydroxybuturate properties and keeping seizure threshold higher so they occur less, and aren't as severe. The Depakote sprinkles contributed to him having high ammonia levels in his blood which directly corresponded to the degree of delay I was seeing. I was given supplements to counteract this reaction but he would not take them. He was a zombie, couldn't focus, and lost his ability to go to the bathroom but finally fixed that. It was a nightmare and I cannot help but wonder what else happened in his brain if there were changes that triggered autism but no one gives me answers....I ran a metals test on my son and it showed that he had levels of antimony and tin off the charts and some mercury and aluminum so obviously he has a hard time eliminating metals. Sorry to bug you with all this everyone but this is my experience. Now he is on a low toxin diet to the best of my ability and I can say he is in a better state than he was but I still have a long way to go. I have stopped the vaccinating because I don't know how the adjuvants are going to play a role in this whole mess I am trying to work with and I don't want to create more problems for a developing brain.

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  6. Hi everyone,

    Just an update you may find of interest. I added 5-htp to my treatment protocol and noticed a minor improvement right away. Speech and mood appear to have gotten s little better, and it's only been a couple weeks. It could just be normal improvement, but it coincided with 5-http so I thought I would share. I'm using 1 mg per kg.

    AJ

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    1. Is that per day or per dose. 5-HTP is recommended to be given 3 times a day, but that amount times 3 was not good for my son.

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    2. What if you have a homozygous variant MAO-A? It would not be beneficial to take 5-HTP right. MAO-A should be functioning so you can process the 5-HTP right?

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    3. I would like to know about functioning of MAO B and COMT to see if he is breaking down excess neurotransmitters. I am trying to get MTR working with 5-Methyl THF in the hopes of signalling MTHFR......Off on a tangent...What about Tyrosine for Dopamine sites on MAO B for sensory behavioral regulation?

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  7. Thank you for sharing that. I have had 5htp ready to give for a couple of weeks but feel reluctant. I used one tablet 100mg myself to see if it's effective for serotonin increase and it was indeed, still felt some nausea and dizziness during the first couple of hours.
    I have started on inositol 2g/day before giving 5htp.
    Really hope it has positive long lasting effect.

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    1. Hi Petra, I'm happy to share. I can't say for sure if 5-htp is the cause of not, but it certainly hasn't had any negative impact. My daughter is about 14kg, so I'm using about 14mg (eyeballing the amount based on capsule size) in the morning.

      All the best!

      AJ

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  8. Hi Peter and other experts
    I would like to do a trial of Diamox?Do you know the recommended dosage for a 37 lb, 5 year old.Bumex did not work for my son.Do you think Diamox would work at all?

    Also,I would like to try Clonazepam later on.I am unable to find any pharmacy that
    would supply it.Any recommendation how to order online?

    What is the difference between Abilify and the other treatments(Bumex/Diamox) etc?Both of them affect the brain.

    Peter,at what age did you child start speaking?I mean knowing the context and talking in full sentences.

    Thank you for all your help
    SB

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    1. SB, Abilify is an antipsychotic drug. It does entirely different things to Bumex/Diamox.

      Whether Diamox will help depends on what dysfunctions and symptoms your son has. I do not use it. Some people use 1/4 of a 250mg tablet.

      My son began to use single words before he was 4. He uses the complexity of speech needed to get him what he wants or to answer someone's question. He is not going to enter into rambling conversations like his brother and likely never will. He would be happy to read aloud or sing a song.

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