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Wednesday, 11 January 2017

Enhancing the effect of Bumetanide in Autism


Many readers of this blog, and some of those who leave comments, are using the Bumetanide therapy proposed by Ben-Ari and Lemonnier.

At some point it should become an approved autism drug and Ben Ari has already patented it for use in Down Syndrome, so I guess that will come later on.

I have been developing my own add-on therapies that might help people for whom a high level of intracellular chloride is part of their autism, or indeed Down Sydrome.  If Bumetanide has a profound impact on your autism, this is almost certainly you.

Monty, aged 13 with ASD

After 4 years of Bumetanide, it continues to be effective and if Monty stops taking it there is a gradual cognitive decline over a few days, presumably as chloride concentration gradually increases.

In spite of an odd temporary Tourette’s type verbal tic that developed after an infection before Christmas, I have been getting plenty of feedback that Monty has got cleverer in 2017.  So it looks like some bumetanide add-on does indeed work.


The Colosseum

Monty’s big brother continues to be a fan of Lego and indeed Nanoblocks from Japan.  Nanoblocks is like extremely small Lego.

Having completed the Colossuem, his latest Nanoblocks model, he asked Monty “where is it?”.

Back came the answer, unprompted, “Italy”.

This was a big surprise.

That was not the answer big brother expected, he expected no answer or a silly answer like “over there”.



Add-ons

The first is potassium bromide (KBr) which was the original epilepsy therapy 150 years ago.  One of its effects is that the bromide (Br-) part competes with chloride (Cl-) to enter neurons and bromide is known to be faster.  As a result some of the chloride inside cells is replaced by bromide.  Bromide is extremely similar to chloride, but is not reactive; this is why it can be used with any anti-epileptic drug (AED) without fear of negative interactions.

KBr has an extremely long half-life, meaning that if you take it every day it will take 4-6 weeks to reach its stable level in your body.

KBr is used for pediatric epilepsy in Germany and Austria and for epilepsy in pet dogs all over the world.  

A dose of 8mg/kg is far below the dose used for epilepsy, but does have a bumetanide enhancing effect in one 50kg boy.

The even more recent add-on is based on the experience of our reader Petra’s son with Asperger’s, who found that taking his bumetanide with Greek coffee seemed to make it more effective.

It turns out that dopamine is known to increase the effect of diuretics on the chloride cotransport NKCC2 in your kidneys.  There is a myth that coffee is a diuretic, but it is clear where this myth has come from.  Coffee will increase diuresis and so does caffeine.

In the brain it is the chloride cotransporter NKCC1 that is also blocked by bumetanide.  So it would be plausible that dopamine/coffee/caffeine it might have the same effect on NKCC1 as it does on the very similar NKCC2.

The cheap and widely available 50mg caffeine tablets do seem to serve as a proxy for a steaming cup of Greek coffee.  Indeed 50mg of caffeine is more like a weak cup of instant coffee.

I did much earlier propose the use of Diamox/ Acetazolamide to reduce chloride.  It seems that in some neurons 2/3 of the chloride enters via NKCC1 and 1/3 via the exchanger AE3.  Diamox/ Acetazolamide works via AE3.

Diamox has some other ion channel effects, making it useful in some epilepsy.

Some readers of this blog use Diamox, but in Monty it seems to cause reflux.

Caffeine is a very simple add-on to try.





62 comments:

  1. Peter, good luck with caffeine.

    I use Greek coffee because it's also a good source of cafestol and kahweol.

    "Cafestol and kahweol: Filtering out cholesterol boosters"

    Coffee drinkers concerned about cholesterol weren't happy about some early study results showing that coffee seems to increase cholesterol levels, and "bad" LDL cholesterol levels in particular. But upon closer inspection, the bad news turned out to be not so bad, because the cholesterol-raising effect seems to be limited to coffee that hasn't been filtered, which includes Turkish coffee, coffee brewed in a French press, and the boiled coffee consumed in Scandinavia.

    The cholesterol-raising ingredients in coffee are oily substances called diterpenes, and the two main types in coffee are cafestol (pronounced CAF-es-tol) and kahweol (pronounced KAH-we-awl). They are present either as oily droplets or in the grounds floating in the coffee. But a paper filter traps most of the cafestol and kahweol, so coffee that's been filtered probably has little, if any, effect on cholesterol levels.

    The best evidence is for paper filters, but an interesting study published in 2011 showed that filtering methods used in Singapore (the so-called sock method, which uses a cotton-nylon cloth) and India (metal mesh) were also effective at trapping cafestol.

    Espresso contains more cafestol and kahweol than paper-filtered coffee, but because it is consumed in smaller amounts, it may not have much of an effect on people's LDL level.

    There is a twist to this aspect of the coffee story, because cafestol and kahweol may also have some health benefits that are lost when they're filtered out. The research is in the preliminary stages, but cafestol and kahweol could have some anticancer effects and be good for the liver.

    Chlorogenic acid and other antioxidants

    Explanations for the association between coffee consumption and lower rates of heart disease and diabetes often point to chlorogenic acid and other obscure antioxidant substances as the responsible parties. Antioxidants are substances that sop up reactive molecules before they have a chance to harm sensitive tissue like the lining of blood vessels. Chlorogenic acid was probably the main antioxidant in your cup of coffee this morning. Some experiments have shown that it may also inhibit absorption of glucose in the digestive system and even out insulin levels.

    Chlorogenic acid might be another coffee ingredient with a split personality. Along with caffeine, it seems to push up levels of homocysteine, an amino acid that has been associated with artery-clogging atherosclerosis.

    This extract is from Harvard Health publications.

    The clogging effect may be a problem though.



    ReplyDelete
    Replies
    1. Peter,
      Do you have any experience using Dipro-B to lower intra cellular Chloride levels? My son has Down Syndrome and has been on Bumetanide for about 4 months, I just recently increased his dose to 1mg 2 times a day, but am interested in learning about more ways to normalize chloride levels in the neurons. Thank you,
      Christine DeSilva

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    2. Christine, I have been giving 8mg/kg of KBrfor the last few months and it does indeed work. Due to the very long half life it takes 4-6 weeks to show the full effect. It works for at least one other reader of this blog.

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    3. Peter since you have been using kb-r are you doing this as add-on to bumetanide or looking to potentially drop bumetanide use only kb-r with the positive effect of no potassium loss and no duiresis. Wondering if any side effects from kb-r you may have noticed.

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    4. I would ideally use a prodrug of bumetanide, like one called BUM5. It passes through the blood brain barrier much better than bumetanide and is then converted to bumetanide. This type of drug will eventually be commercialized, there are already patents.

      Kbr has well known side effects at high doses and this is why its use in epilepsy has faded away to almost zero.

      At the low dose I use there is very mild "bromo-acne", at high doses I imagine you would get a spotty face. Because it increases some secretions, it could potentially worsen asthma.

      So I intend to get the most from the current version of bumetanide, but use add-on therapies that further lower chloride.

      Interestingly while bumetanide just failed a long running trial (NEMO) to reduce seizures in young children, BUM5 was recently found to reverse one model of seizures on which bumetanide had no effect. It is all about bioavailability inside the brain.

      Delete
  2. Hi Peter and everyone,

    Hope all is well!

    The more I read about Bumetanide on this site, the more exciting it sounds to me, as I haven't yet tried to use this mechanism for my daughter and its sounds like it has good potential.

    I see 2 options for me: Using Bumetanide or a more accessible natural compound (depending on if I can access Bumetanide and if it's Ok for a 4 year old girl).

    Peter / Tyler / and those in the know - would you kindly provide some insights on what alternatives I would have if I can't access Bumetanide? Are there natural options, and what would you say are the most important targets (i.e. NKCC1, anything else I should research)?

    And if I can somehow access Bumetainde, what would the approximate dosage be for a small child (i.e. 4 year old girl)?

    Any insights would be much appreciated. I too will do research into the relevant targets and will share any findings.

    Much appreciated as always - if I can find one thing that makes my daughter better, I will literally be the happiest person in the world :-)

    Thanks everyone, and I have high hopes for 2017!

    AJ

    ReplyDelete
    Replies
    1. AJ, Bumetanide is a very old drug, even given to newborns. Not everyone is going to be a responder, but you have a 50% chance, which beats almost everything else.

      Most readers in North America are either showing the research to their doctor and obtaining it locally, or they are buying it online from Mexico.

      I started with 1 mg a day, but the researchers are using 1 mg twice a day. This is irrespective of weight.

      After 2-8 weeks the cumulative effect of blocking NKCC1 has resulted in more normal levels of chloride. The person then appears to have less severe symptoms of autism and improved cognition.

      I would invest your time in sourcing 40 bumetanide tablets rather than seeking natural alternatives.

      Generic bumetanide is very cheap. It is also called Bumex and Miccil.

      You just need to add back some potassium via diet and a supplement. Drink extra water comes naturally to most people.

      Delete
    2. Hi AJ,

      Children included into 2012 French Bumetanide clinical trial were 3-11 years old:

      https://www.ncbi.nlm.nih.gov/pubmed/23233021

      I know that in France Bumetanide has long been used outside clinical trial as autism treatment for children as young as 2 years old. In France they usually use 2 x 0,5 mg for children weighing less than 25 kg.

      When my 7yo son started Bumetanide he did not tolerate dose higher than 2 x 0,5 mg. Now 2 years later I am increasing the dose and he seems fine. Some younger children use 2 x 1 mg with no problem.

      I don't know any natural compound comparable to Bumetanide. With Bumetanide you have the advantage that you use medicine backed by clinical studies with predictable effects.

      Delete
    3. AJ, you should try low dosage clonazepam as that should show an impact/change if your child has misfiring GABA and none if not.

      Clonazepam is relatively straightforward to get prescribed (in 500mg dose) as an anti-anxiety pill, you'd need a 25-50mg dosage for the switch flip similar to bumetanide (no higher, see archives). No real downside at this "subclinical" dosage.

      If you see a change (any change) with this, then you can move onto bumetanide.

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    4. Hi Agnieszka,

      Could you have a look at this paper about Verapamil metabolism when there is inflammation?

      J Clin Pharmacol. 2009 Mar;49(3):301-11. doi: 10.1177/0091270008328099. Epub 2009 Jan 23.

      Influence of controlled rheumatoid arthritis on the action and disposition of verapamil: focus on infliximab.
      Ling S1, Lewanczuk RZ, Russell AS, Ihejirika B, Jamali F.

      I am quite sure that my son has trouble in drug metabolism and among other factors I suspect arthritis like inflammation.
      Maybe inflammation interferes with Bumetanide metabolism.
      Arthritis is connected to ER stress response and there are, unfortunately only a few studies, connecting PTSD with arthritis inflammation.
      I was wondering how low dose aspirin may help with this.



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    5. Hi Em, thank you! I know Clonazepam will be much easier to acces. I will try Bum with my daughters doc, Clon if I can't get Bum (worst case scenario I can get Clonazepam for me and split the pills)

      Thanks for your input - it's amazing what can be accomplished with a community line this, and so glad Peter started this blog to disseminate life changing info.

      AJ

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    6. Hi Petra,

      It seems that they studied verapamil concentration in arthritis patients, but those with inflammation under control (in remission) and found no difference compared to healthy persons. And at the same time they wrote: ”A large degree of variability was observed for all measured cardiovascular responses to verapamil” – so they saw variable effects despite no differences in drug levels. So maybe it is not only verapamil metabolism and blood concentrations which impacts the effects in real life.

      I also found other studies indeed saying that compromised drug metabolism can be related to active inflammation:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139248/

      They say: „Theoretically, infectious or inflammatory disease states can modulate drug pharmacokinetics via several mechanisms.” „Theoretically”, so in fact I am not sure if effects are predictable in practice. Do you think your son metabolizes verapamil too slow? Or the effect is too small?

      With regard to Bumetanide, I don’t know if inflammation can affect its metabolism, but it may influence its effect in a different way. For example the paper highlighted by Peter about bromide use for chloride regulation says: „Concomitantly with the inflammation, changes in expression of NKCC1 and KCC2 co-transporters have been observed that resemble the immature brain”.

      Delete
    7. Hi Agnieszka,
      Thank you so much for your feedback. Your replies are always very helpful.
      I am just investigating the possibility of compromised drug metabolism during inflammation and potential interventions to help with.

      Delete
  3. At the moment there are many, many, many things that could in theory be done to regulate NKCC1 and KCC2, but they are indirect (like upregulating IGF-1) and not effective enough to make a big difference, though intranasal IGF-1 probably deserves more attention because you can always increase or decrease the dosage depending on what the ceiling of effect happens to be. The best and only way to deal with either blocking NKCC1 or enhancing KCC2 is bumetanide unfortunately. There are other related diuretics like furosemide, however, it blocks both NKCC1 and KCC2 which is not what we want here. There are other interventions Peter has suggested in this post, but I personally don't know how strong they are and their levels of side effects, but they are probably better suggestions than any I could really give at this time.

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    Replies
    1. Hi Peter, Agnieszja, and Tyler,

      Thank you each of you for your insights!

      Ok, I will definitely have to trial Bumetanide - I will put together all the relevant info I think my daughters doctor may need to try it and will keep my fingers crossed she will try it.

      If she doesn't agrree, do you know of a trustworthy online Mexican pharmacy that I can use?

      Again, a genuine and heartfelt thank you to the three of you - if this works, you will have changed an amazing little girl's life.

      AJ

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    2. Peter has my email address. He can send it to you.

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    3. Hey Tyler, please feel free to reach out to me at aj.brookes@yahoo.com - any info would be MUCH appreciate

      Thanks as always!

      AJ

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    4. @AJ, I don't know of any Mexican Pharmacy but there is a Canadian Pharmacy that sources drugs from all over the world, www.universaldrugstore.com I have ordered some of my meds from them when insurance cost was too high.

      My review of this pharmacy, http://www.healingwell.com/community/default.aspx?f=38&m=2751917

      Delete
    5. Hi Noel,

      Thanks for providing this info - I'll look into them. Since I'm in Canada, it may actually make it easier for them to ship it to me.

      Appreciate the info!

      AJ

      Delete
  4. Peter, Tyler, Petra, Seth, anyone else who can help ... i tried the tiniest bit of bumetinide --1/8 of a pill -- on my son with pitt Hopkins syndrome ... he was clearly a responder ... but almost too much ... became more agitated, lots of yelling, hyper, tons of urine, dark circles under eyes... any ideas on what's going on here? I see that it's having an effect ... but just not exactly the one I want?

    ReplyDelete
    Replies
    1. Audrey, did this happen as soon as you started with bumetanide, or after a couple of weeks? It takes at least a week or two to lower chloride levels, so if the effect was much earlier then it may have been something else.

      Bumetanide lowers the level of potassium and that will start to happen straight away. Some people are more effected by this than others.

      If the lost fluid is not replaced that will also have effects.

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    2. Dark circles and puffiness are caused by many reasons, but excess electrolytes (which cause fluid retention) can be one reason. Are you resupplementing potassium back into his diet? Also, because of the frequent urination, your son may end up becoming very thirsty and then drink too much water which could cause puffiness in the eyes. When my son first started bumetanide, I never noticed puffiness under his eyes, but he did pee quite a lot. I give him 2 tablespoons of potassium gluconate with his drink. BTW, in the USA the only way to get a sufficient amount of supplemented potassium is in powder form as there is some archaic federal law that limits potassium capsules and pills to being less than 100mg each because of early fears of potassium being used for suicide since potassium chloride is used in lethal injection. Also No-Salt or similar products containing potassium chloride is another way to add potassium back into his diet, but I think potassium gluconate is by far and away the best way (Now Foods has a good affordable powder form you can get on Amazon).

      Also, as I am sure you probably know that cyanosis and dark circles under the eyes are a symptom of Pitt Hopkins (just to be clear I only did a quick read as a result of your post so I am not commenting with any sense of authority as this is a very rare genetic syndrome).

      The agitation and yelling could be a lot of things. Bumetanide improves GABAergic tone, but since this is new to his brain it might take a while to getting used to, just like any other drug, especially since his brain circuits may be abnormally wired so as to compensate for depolarized GABAergic signalling (to prevent seizures) and that you may have a situation where an inhibitory circuit that inhibits another inhibitory circuit (disinhibition) was previous not too inhibitory and bumetanide helped increase inhibition on the first circuit and not the other. The basal ganglia (which is very much involved in behavior) has lots of complicated GABAergic circuits that work this way, so any pharmacological intervention specifically geared towards that brain structure is a crapshoot until you actually test something out over a significant period of time and see what (if anything) stabilizes.

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    3. Peter... it happened right away... the very first day... you think he maybe just lost too much potassium? I have never seen him urinate so much and it was such a smalldose! Something about the way he metabolizes drugs is off--and I can't figure out how to fix it:(

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    4. Thanks so
      Much for this thoughtful response ! So Tyler, would you try again with a very tiny bit... this time supplementing potassium?

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    5. Tyler, speaking of potassium - what are your thoughts on potassium bicarbonate? I ordered bulk potassium bicarbonate via Amazon to use for histamine reaction (mixed with a bit of sodium bicarbonate) - and it is very effective helping those symptoms - and if I remember to give him a small dose before bedtime, it seems his sleep is better... I wonder though about this source as the only source for potassium for the day.. Would it be ok?. I have switched to a balance magnesium and potassium aspartate product and it seems to have helped tremendously with fighting what I thought might be the "teen blues" or just lazy teen energy.

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    6. I don't know anything about potassium bicarbonate. I just know the potassium gluconate powder was the best option I settled on, especially since it is in powder form since the 99mg capsule formulations you buy at the drug store are like 2% of RDA (i.e. you need like 6 or 7 of them to get the potassium found in a banana). I don't think it matters much what type of potassium you get as long as it has decent bioavailability.

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    7. Tanya
      With regards to this quote . I wonder though about this source as the only source for potassium for the day.. Would it be ok?. I have switched to a balance magnesium and potassium aspartate product
      Would you please give the name of the product I have an interest in a magnesium and potassium product.
      Thank you.

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    8. sorry I just saw this ! I am using GNC magnesium and potassium aspartate - a balanced blend - as per the Dr. Derrick Lonsdale information

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  5. Tyler,today my son told me he would start to make a daily press, to my surprise he showed me a lot of headlines he wrote in his ipad about current topics, music, cinema, such as,the singer of Pet S.Boys talked about his story¨,¨PMCartney played a concert in London with R.Star¨, or ¨attack on Istanbul¨.He is 10. I also wanted to ask you about something you wrote me about dopamine:reduce the dopamine receptor blockade while reducing the supply of excess dopamine,why i want to reduce the blockade of the dopamine receptor?, would not be better if it keeps blocked? Choline can interfere with receptor function and Melatonin suppresses dopamine activity. Should I use them?Sorry for the confusion.
    Valentina

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    Replies
    1. OK, a better analogy here would be drug addiction, of which most forms deal with dopamine signalling at one point or another. Cocaine for instance causes a massive release of dopamine into one of the primary reward areas of the brain (nucleus accumbens) which if done chronically will cause the dopaminergic neurons to decrease the number of receptors so as to normalize the signaling. Why does this happen? Well unless the brain compensates for increased or decreased neurotransmitter levels, then you will always have situations where circuits will keep eering towards epilepsy (uninhibited excitation) or coma (excess inhibition). The brain is amazing at regulating this all on its own, but to do this it has to adjust its levels of processing on the fly and one way it does that is through building new receptors when a particular neurotransmitter is low (to increase the chance of a neurotransmitter binding to one of the receptors) or else destroying receptors when there is an excess of a type of neurotransmitter floating around. Generally cells do this through a special type of receptor called an autoreceptor which samples the environment to get an idea of if there is too much of a type of neurotransmitter or too little and act accordingly.

      There is also a situation when you have chronically high neurotransmitter levels and the autoreceptors get worn out more or less (desensitized) and don't work very well anymore. For example with the insulin receptor, this is called insulin resistance (which I am sure you have heard of).

      So a blunt force approach to excess levels of a neurotransmitter has been to simply block the receptor or when there is not enough of the neurotransmitter (or it is being cleared from the synapse too fast) you have drugs which block the proteins that clear the neurotransmitters from the synapse (such as SSRI's). Going this route is going to cause a lot of long-term problems, the biggest of which are drug dependence (since the autoreceptors are still taking a beating), or in the case of SSRI's the increased receptor signalling may cause the body to produce far less neurotransmitter so if you go off of them you have wild swings in signaling so that with SSRI's you end up with side effects like suicidal ideation and other problems.

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    2. So in my opinion you don't want to go the "dirty drug" route unless you absolutely have to even though obviously with many diseases, it is the best option available (at least short-term).

      This of course is all very unintuitive and takes a while to wrap your head around. So your problem originally with your son was high extracellular dopamine levels in the brain (I am guessing that is why your pediatrician gave you risperidone if he even tested for dopamine in the first place), and the brute force way of dealing with that problem is to block the receptor hard and risperidone does a good job of that THROUGHOUT THE ENTIRE BRAIN. Dopamine does a lot of different things and one pathway affects the pituitary gland's secretion of prolactin via D2 receptors (which are inhibitory while D1 receptors are generally excitatory). Since prolactin is continuously released from the pituitary in the absence of inhibition, the D2 receptor block by risperidone causes aberrant prolactin release.

      So the root problem with respect to dopamine is too much extracellular dopamine floating in the brain. Dopamine like Serotonin does not cross the blood brain well so dopamine in the body generally will not affect brain dopamine levels (unless the BBB is leaky of course). So if there are excess dopamine levels in the body and brain, reducing them all around would be great but is not always an option for both situations and only may be an option in the body but not the brain and vice versa. So I don't know the history of why so many dirty drugs get prescribed by doctors after a 15 minute visit besides all the major accusations such as big pharma being too cozy with doctors and too profit centered or the fact that many people would have little reason to keep coming back to specialist doctors if they said "well go to your local GNC and buy some supplements for bodybuilders to help fix your child's brain".

      So if you can normalize extracellular levels in the brain, there is a better chance that dopamine receptor levels at the synapses will normalize given enough time and you will have better cognitive function without the nasty side effects of broad spectrum dopamine receptor antagonists like risperidone which ironically cause even higher levels of dopamine to be produced in the brain because of the receptor blockage (receptors try to balance themselves relative to neurotransmitter levels and neurotransmitter release is balanced according to receptor signaling).

      The hyperkinesia your son experiences is normally a symptom of excess dopamine (like when someone does cocaine), but remember in many parts of the brain you have inhibitive circuits inhibiting other inhibitive circuits and if one circuit can no longer regulate its own activity because the autoreceptors are burned out, then the other inhibitive circuit that is supposed to be inhibited is no longer inhibiting its target which can lead to hyperkinesia. This same problem happens with long-term L-DOPA (precursor to dopamine) usage in Parkinson's disease because the excess dopamine added to the brain is used as a brute force method of dopamine signaling. The problem is that you can have some circuits in the basal ganglia that have more D1 receptors relative to D2 receptors and so things get way out of balance after the receptor numbers have compensated for the excess dopamine.

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    3. Tyler this is very interesting! Thank you! What then do you recommend to increase the action of the receptors. I believe my son has this issue -- too much extra cellular dopamine... not enough receptor activity ? Thank you all for all your help and advice

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    4. Tyler, that is very interesting, and imo the likely reason behind the effect of so many things taken at micro-doses. Clonazepam being an obvious example, but also practice of micro-dosing opioids like LSD, psylocibin, MDMA (if all the personal reports and articles that have been pouring in lately are to be trusted :). Then there is the more familiar Low Dose Naltrexone ... all the things that are not supposed to work at such minute doses. But as you explained so well, taking them on a regular basis for periods of say several months could possibly be tweaking/normalising expression levels of neuronal receptors.

      When you say "Dopamine like Serotonin does not cross the blood brain well so dopamine in the body generally will not affect brain dopamine levels..." I am not sure about that, there was a great article a couple of years ago (I wish I saved it) explaining the feedback loop between the two. Complicated and only vaguely remembered, but the take home message was that the brain will be maintain its levels of x relative to blood levels ... the most interesting twist in the story was that often raising blood levels of x will lead to brain dumping/reducing its own levels of that substance.

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    5. Yah you are actually right as I have read the same stuff about the body and brain maintaining dopamine homeostasis relative to each other. What I meant is that acutely, dopamine (the molecule) and serotonin do not cross the blood brain barrier, and neither does melatonin for that matter. Bananas have lots of melatonin but they don't make you sleepy. There are other foods that are very high in serotonin as well, but they won't do much as far as affecting your mood.

      Dopamine's primary precursor molecule is L-DOPA and Serotonin's is 5-HTP, both of which cross the blood brain barrier very well.

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    6. I forgot to mention that if there are high levels of aromatic amino acids in the blood from supplementation or else natural sources, the levels will rise in the peripheral as well as the brain because there are relatively more aromatic amino acids than other amino acids which use the LNAA transporter. This is why levels in the body naturally follow those in the brain. Supplementing free form BCAA's or other amino acids for that matter is not a natural way to get protein.

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    7. Valentina, Tyler, this case report has just been published on succesfull use of nicotinic partial agonist vernicline in a boy with autism and severe anxiety/aggressive behaviours. https://www.ncbi.nlm.nih.gov/pubmed/27123827

      From the paper: "To the best of our knowledge, this is only the second report of an individual with autism treated with varenicline. The first report was of a high-functioning 9-year old and this one was of a severely impaired 19-year old. In both cases, there was an ABA experiment of nature
      in which after initial improvement, varenicline was stopped because of concerns about potential long-term effects, then after deterioration, varenicline was resumed with resumption of im-
      provement. In both cases, the parents elected to continue varenicline as they were impressed with the results and noticed a drastic worsening of symptoms to prevarenicline levels after stopping the
      medication. This patient has remained on varenicline for over a year with no noticeable side effects.

      This case advances the knowledge base by demonstrating the biochemical effects and expected interaction with genome, particularly the dopamine effects...
      As a partial agonist of... nAChRs, varenicline may aid in reestablishing balance in the dopamine pathway through chronic channel activation at low levels. In an animal model, use of varenicline was also found to significantly increase striatal DRD2, with the effects being long lasting (Crunelle et al. 2011). In the patient presented in this study, dopamine imbalance was predictable from genetic studies..."

      Lots more details in the paper, well worth a read.

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    8. Chantix (what varenicline is advertised as here in the United States) is equivalent to using methadone to get people off of opioid dependencies in that they bind to their targeted receptors not as strongly as the substance they are trying to abstain from.

      Before even reading the paper I suspected that this is a low-dose therapy akin to the idea behind low-dose naltrexone (LDN). In areas of the brain where dopamine receptors are highly expressed, you can think of D1 receptors as the gas and D2 receptors as the brakes. If the autoreceptors for D2 expressing neurons are burned out, sometimes a small amount of an artificial substance that can target them can get the homeostasis train rolling again (or at least that is the idea) and allow those cells to regulate their receptor levels appropriately and relative to whatever else is going on in the brain.

      From the case history of the young man, it seems like his parents had gone through every doctor prescribed autism drug intervention I have ever even heard of under the idea that if you throw enough stuff at the wall, then hopefully something sticks. When kids get older then managing symptoms can become much harder and the choices can become much more desperate so I sympathize with this man's parents.

      Simply, fixing D2 receptors is probably not going to cure anyone's dopamine problems, but this is promising research even though the conflict of interest list of past research funding for some of the researchers is noteworthy. Last but not least, Ohio State University for better or for worse is not shy about corporate sponsored research funding so maybe in a year or so we might see an expanded study if the drug company that sells Chantix feels there is enough of a market to pursue the research for label use.

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  6. Here is maybe another explanation for SIB and biting behavior in some people with autism:

    Press Release:

    https://www.sciencedaily.com/releases/2017/01/170112130133.htm

    Paper:

    http://www.cell.com/cell/abstract/S0092-8674(16)31743-3?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867416317433%3Fshowall%3Dtrue

    This of course was done in mice, but may be conserved up to humans as well. What they found is that there are two circuits in the central amygdala (one of the most morphologically dysfunctional regions of the brain in autism) that control pursuit of prey as well as the killing of prey.

    I won't go into anymore detail than that, but what is interesting is that SIB (of which there are many theories) could be explained as an adaptation response to wanting to bite something, and since biting other people will cause additional problems for the person with autism engaging in biting other people (corporal punishment, shame, etc.) they bite themselves instead since they have to bite something and because of downregulated pain responses possibly due to TRPV1 receptor dysfunction (the one affected by capsaicin which is what gives the hot spice sensation in chili powder), they just happen to bit themselves because it is more convenient and does not really hurt them in the sensory sense.

    Some people with autism not only do they engage in SIB, but will also routinely bite other people with and without provocation. They will avoid hitting or kicking and just attack with teeth and won't stop the behavior until they finally execute the action.

    The only thing that really helped at the time when things were super bad with my son was aspartate but why I am not entirely sure other than to go by the original researcher's 30 year old hypothesis and nowadays I suspect Kappa Opioid Receptor is part of the story (back then this receptor had not even been discovered), but it is just a suspicion with no evidence to back it up.

    This particular circuit for biting happens to end with both glutamate and GABA expressing neurons as its target, but the central dysfunction sounds like it is most likely in the amygdala. Oxytocin has an ameliorating response in the amygdala, so I would be interested to hear of anyone who has had major problems with SIB respond well to Biogaia Gastrus as one of the L Reuteri strains is supposed to significantly improve oxytocin tone in the brain.

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  7. On Potassium bromide, the reason it was tapered off for humans was the long-term build up in the system. Would it not be better to pulse the dosage for this reason to try and achieve the lowest level possible or is the dosage low enough not to cause concerns?

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    1. Em, in the German speaking world they never stopped using potassium bromide. At high doses there can be side effects. In the old days, doses as high as 6g a day were common.

      The current epilepsy dose for school age kids is 30-50mg per kg.

      https://epiphanyasd.blogspot.com/2016/12/potassium-bromide-for-intractable.html

      The level of bromide accumulates because of the long half-life. This is why it takes 6 weeks to take full effect and why some people probably took too high a dose to speed things up and experienced problems.

      8 mg/kg is far below the epilepsy dose.

      The most common side effect quoted by German doctors is bromo-acne, spots to you and me.

      150 years ago people with epilepsy were treated with potassium bromide for seizures and then arsenic-based lotions for the spots. German doctors today recommend OTC acne lotions.

      At very low doses I think you can get the good effects without any troubling effects.

      You cannot pulse dose potassium bromide because the therapeutic effect is based on the total amount ingested in the last 6 weeks.

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  8. Ok Tyler, now I understand perfectly, I must say that the improvement of his executive functions is remarkable in the last days , besides an important decrease in his continuos movements. I am giving a 2 g low dose of BCAAs, do you think that a high dosage, 7 g, would be even better?
    Valentina

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    1. I have no idea how much would be the optimal amount. Frequency is likely more important than quantity if you ask me because the intestines only have enough enzymes to absorb so many amino acids in a given time frame anyways. If you give him an excess amount of protein or free form amino acids then most of it will just be excreted (waste of money). It is possible with some amino acids to get yourself into a situation called amino-acid imbalance which can cause some problems (theoretically), but I don't think that is really the case with BCAA's since they can be so easily absorbed by muscle while some other amino acids in excess need to be processed by the liver if they are in excess relative to other amino acids.

      7grams of BCAA's are not that much, but I would not exactly try and run an experiment to see how high you can go before you have health problems with your child. Some bodybuilders do extreme amounts of BCAA's (especially high in leucine) and don't really have any big problems long-term, so this is an open question if you ask me.

      So since I can't really answer your question, you can give yourself some context with respect to the study I referred you to on BCAA's and tardive dyskinesia which might be where you want to start from in terms of an idea of where to start. Nevertheless, I have no idea if the researchers in that study kind of just came up with some arbitrary amount of BCAA's for their study or if they had some scientific rationalization for the levels of amino acids (you would have to talk to them directly or email them) as in many human studies medical researchers will sometimes go on the extreme safe side because due to the Oath Of Hippocrates.

      Last but not least, considering how many people use BCAA's for sports and bodybuilding purposes, there are also probably at least a few studies that have explored the safety ceiling for human BCAA consumption. I researched this for aspartate and the level in adults was like 11 grams per day of supplemental aspartate (not including diet) before there were noticeable imbalances of aspartate in the blood. Whether excess aspartate at that level caused undesirable health symptoms was never explored as I am not aware of any studies looking at excess aspartate use over a long period of time as you have with say sugar.

      I am happy to hear this is working out for you in getting him off the risperidone.

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    2. Tyler, you can´t imagine how grateful I am. Getting off risperidone is one of the most difficult things in autism and we wouldn´t have done it without your help. My son asks me when he sees me writing to you: Who is Tyler, is a friend of us? I want to meet him¨, incredible, so we wanted to thankyou very much for your great and desinterested help and we will keep you informed.
      Valentina

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    3. Well thank you but I am nothing special. Just a parent like you, just I have three kids on the spectrum so maybe I am just three times as motivated (-:

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    4. You have a big challenge, don´t doubt that your children will achieve the best they can. I explained to my son the same as you are saying me, ¨Tyler is a parent that has 3 kids like you¨.Your patience and disposition, multiplied by three, is something very valuable in Peter´s blog of now.
      Valentina

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    5. I agree with Valentina - very valuable input! Tyler, your discussion of the aspartate forms made me let go of that old advice I received about avoiding it due to "excitotoxicity". I have seen a difference already since switching to a balanced magnesium potassium aspartate. Look forward to reading more of your contributions especially in terms of nutrient based interventions.

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  9. Tyler, Valentina, Congratulations on your successful attempt to get the boy off risperidone.
    I am following your discussion, just in case my sister decides to stop risperidone for my nephew. He takes 1mg a day and when she tried to reduce the dose to 0,5mg he got worse.
    Tyler, I sent you a reply about Biogaia Gastrus and SIB but something must have happened on the delivery.
    Anyway, my son developed SIB, mostly head banging, after olanzapine and that's why I don't wish to block dopamine anymore, raising it would be more promising.
    I think Biogaia Gastrus could actually rescue SIB for some people.

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    1. Petra, your sister will have to take it easy, if she is decided to remove it, she will have to do it by countdrops, it is not an easy decision and is not an easy process, it all depends on the reason why he was prescribed it. Also, the amount of time he has been taking it, the less time, the easier it gets.
      Valentina

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    2. Well Biogaia Gastrus (one of the strains) is supposed to raise oxytocin levels which in studies on animals shows a calming effect on the amygdala (at least in males while with females it has more of a socializing effect).

      But really, it could be many different things. It could be improved gastrointestinal issues, or reduced inflammation which is important because the amygdala and hippocampus have been shown to be more exposed to blood-brain barrier permeability than other areas of the brain with respect to where they are situated (i.e. they are more vulnerable in pathological blood-brain barrier issues than the cortex).

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  10. https://www.theatlantic.com/health/archive/2017/01/autism-cancer/512894/ Peter, did you see this? Would be interested to hear your thoughts, although I am so glad that you write your blog and help me to better understand all these issues and connections, and importantly treatments.

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    1. Yes, I saw this. It is saying the same thing as in this blog, that the same signalling pathways that drive cancer can also lie behind some autism. This does not mean people with autism will get cancer, but does mean than certain future cancer drugs could be repurposed for some autism. You would ideally know a lot about your sub-type of autism before doing this.

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    2. I wasn't very clear, but yes I thought they were saying the same thing, you just have been saying it for a much longer time. Thank you !

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  11. Tyler, as I can´t get nicotinamide riboside for the moment I decided to try l tryptophan, don´t know if there is inlflammation or not, 250 mg a day would be fine while he takes BCAA?
    Valentina

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    1. For the NR, even if you did one capsule a day (the recommended dosage for adults is 2) then that would help. For most young healthy people, NR is a waste of money because your body produces plenty of NAD+. For aging people, people with inflammation issues, and people with mitochondrial diseases (of which many autisms are a part of), I think it is one of the best options around and for BCAA therapy with the intent of restricting kynurenine, I feel it is necessary for helping keep the NAD+/NADH ratio optimal. To prevent Pellagra, regular old Vitamin B3 (Niacin) works just fine so if you are not doing NR, I would just supplement some niacin to be on the safe side. I could go into a long spiel about why you really want NR and not just Niacin with regards to this therapy, but I would just do what you said you were going to do and just see how it goes. If your son does not have inflammation issues with regards to the kynurenine pathway for tryptophan, then the more exotic suggesions I have made are not necessary (and NR is not cheap of course).

      There are many tests to see if there are peripheral inflammation issues in the body. A test of C-Reactive protein (CRP) is the most common one doctors use.

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  12. Valentina, was just thinking since you are mentioning dopamine issues and in one of your comments you mentioned issues with tardive dyskensia - was wondering if you have tested to see if there is an autoimmune driver for your son's symptoms brought on by infection? have you tested to rule out dopamine receptor antibodies? Tyler please share your thoughts on treatments for autoimmune issues and if you have ever done a Cunningham Panel test for your kids.

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    1. Hi Tanya, do you mean that this problem with dopamine could have to do with something like Pandas or Pans in my son?
      Valentina

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    2. Yes Valentina. I was just curious if this has been ruled out ? do you think this might be an issue for your son? There are so many variables.

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    3. Tyler,Tanya thanks, of course I think this might be an issue, my son has an altered immune system, prone to infection, last year his eosinophils were high, he had parasites,allergy of course, and last year he had lymphopenia, low count wihte immmune cells, that now is corrected. I am also concerned about L tryptopan and its relation to immune response, this theme is highly complex and exceeds me. Quinolinic acid may be involved in Huntington Chorea, and perhaps could have to do with dyskinesias, I don´t say tardive because my son showed odd movements before risperidone. So, asking Tyler, with this background, should I stay away from tryptophan or should I give him a very small amount, let say 50 mg. Sorry, but this is very complex, but perhaps didn´t tell him the full story.
      Valentina

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    4. Well I only suggested Tryptophan because you can't or don't want to use NR. Competitively blocking tryptophan (via BCAA's will yield two potential problems. One is decreased serotonin in the brain. I think short-term this will cause problems as one study on acute tryptophan depletion showed in autistic individuals in terms of behavior and general irritability. In the long-run reducing the levels of serotonin in the brain could be a good thing because it will upregulate the serotonergic receptors and hopefully lead to proper serotonergic signaling. So when I first started I used 5-HTP. It worked great for a while and then if I missed one does of 5-HTP things would be really bad. I stopped using 5-HTP and things eventually normalized even though I kept up the BCAA's. The other problem I mentioned is that kynurenine is converted into NAD+ via quinolinic acid. The BCAA therapy is specifically to lower quinolinic acid (that was my primary goal even though it should also lower dopamine unless you supplement it back in via tyrosine or L-DOPA/Mucuna Pruriens).

      So really, if things are going fine without NR using BCAA's you can stick with it, but just to be super-safe make sure he is getting regular old Niacin supplemented as well so you don't have to worry about pellagra. Ideally, you would want to have NR instead, even if you can only afford a small amount.

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  13. Tyler, when I can get NR I will stick to it, in the meantime will add small doses of tryptophan and niacinamide or nicotinic acid that is niacin b3, which amount of both would be safe?
    Valentina

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  14. One more way to enhance the effect of Bumetanide?

    https://www.ncbi.nlm.nih.gov/pubmed/25449033

    "our study demonstrates that the clinically available drug probenecid can be used to increase brain levels of bumetanide and decrease its elimination"

    Wikipedia: Probenecid, also sold under the brandname Probalan, is a medication that increases uric acid excretion in the urine.

    /Ling

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    1. Ling, well spotted; that is very relevant.

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