UA-45667900-1

Wednesday, 21 December 2016

Synergistic Benefit of Low Dose Dopamine (Greek Coffee) and Diuretics (Bumetanide/Furosemide); better than Bromocriptine?


I did think of highlighting this post to the Bumetanide researchers in France, but I do not think they would take it seriously.


Another one to mention would be this new study, funded by Rodakis, to look at why some antibiotics improve some autism.  Dr Luna at Baylor College is running the study.  Its basic assumption is that the effect must be to do with bacteria, but as our reader Agnieszka has highlighted, common penicillin type antibiotics increase expression of the gene GLT-1 which then reduces glutamate in the brain.  It has nothing to do with bacteria.  Maybe for other antibiotics the effect does relate to bacteria.


But if you tell Dr Luna about GLT-1, quite likely she will not be interested.  




Researchers will compare the gut microbiome (bacteria, yeasts and fungi found in the gut) and metabolome (small biological molecules produced by the microbes) of those who experience a change in symptoms during antibiotic use to those who do not. The study may provide valuable insight into when and why these changes occur and how this information can be harnessed for future interventions.  


There is even a case study very well documented here:-


Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature

Petra, our regular reader from Greece, has pointed out that Bumetanide has a greater effect in her adult son, with Asperger’s, when taken with Greek coffee and suggested why this might be. 

Her reference is this article:- 





It shows that the diuretic effect of low dose furosemide, with dopamine, is greater than the effect of high dose furosemide.



The diuretic effect of Furosemide is via the transporter NKCC2, which is the same affected by Bumetanide. 

NKCC2 is found in your kidneys, while the very similar NKCC1 is found in your brain.  Furosemide and Bumetanide affect both NKCC1 and NKCC2.

The caffeine in coffee is known to indirectly produce dopamine in your body.

Greek coffee is nothing like your instant coffee or watery Starbucks coffee, it contains a serious amount of caffeine. 

The question is how does dopamine interact with furosemide/bumetanide and will the effect in the kidney (NKCC2) also affect the brain (NKCC1). 

By more effectively blocking NKCC1 in neurons you would further lower chloride levels and potentially further improve cognitive functioning.  

This would further validate Petra’s observation. 

Then we would consider if there is an alternative to Greek coffee, or just accept that caffeine is the simplest and safest method to enhance Bumetanide.    

In the then end my conclusion is that coffee, or just the caffeine, is a better option than a selective Dopamine D2 receptor agonist.  But there is an interesting drug called Bromocriptine that may be better in some cases. 

Not only is it a dopamine D2 receptor agonist, but Bromocriptine also “inhibits the release of glutamate, by reversing the GLT-1 (EAAT2) transporter”. 

We came across the GLT-1 (EAAT2) transporter when we found why some people with autism improve when on beta-lactam antibiotics (that include the penicillin ones).   

GLT-1/ EAAT2 is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. EAAT2 is responsible for over 90% of glutamate reuptake within the brain 

We saw that the drug riluzole approved for the treatment of ALS (Amyotrophic Lateral Sclerosis) upregulates EAAT2/GLT-1.
I suggested that people with autism who improve on penicillin types antibiotics should get a similar effect from riluzole.  But riluzole is one of those monstrously expensive drugs.  

Based on my logic, we would then think that bromocriptine should help treat ALS (Amyotrophic Lateral Sclerosis).  What did I find when I looked it up:- 



So then how much does Bromocriptine cost?  It is a cheap generic.  So a cost effective potential drug for ALS. 

Bromocriptine has two potentially useful functions (Dopamine D2 and GLT-1),but it has numerous other effects:- 

Bromocriptine blocks the release of a hormone called prolactin, but this should not be an issue for males. 

Risperidone, one of only two drugs approved for side effects of autism, can boost levels of prolactin.  Elevated prolactin levels are linked to a range of side effects, including gynecomastia, or growth of breasts, in men and boys.  This did not stop the drug being approved.

Bromocriptine agonizes the following monoamine receptors

  • Dopamine D1 family
    • D1 (Ki=682 nM)
    • D5 (Ki=496 nM)
  • Dopamine D2 family
    • D2 (Ki=2.96 nM)
    • D3 (Ki=5.42 nM)
    • D4 (Ki=328 nM)
  • Serotonin 5-HT
  • Adrenergic α family
  • Adrenergic β family
    • β1 (Ki=589 nM)
    • β2 (Ki=741 nM)

  
This is why drugs have side effects. 

But for people with ALS who cannot afford riluzole, the cheap generic bromocriptine might be a good choice.

How about bromocriptine for autism? 

Well there was a trial in Italy a long time ago on girls with Rett syndrome 



Twelve typical cases of the Rett syndrome and one forme fruste were treated with bromocriptine for six months and then had a washout for two months followed by resumption of the bromocriptine treatment. During the first bromocriptine treatment there were improvements in communication and relaxation in some of the girls: a more regular sleep pattern was observed in 4 and a more varied facial expression in 8, and 4 girls began to utter a few words. The bouts of hyperpnea disappeared in 5 and grinding of the teeth in 3. There was also a reduction in stereotypic hand activities in 5 girls and signs of improved motor abilities in 3. The washout caused a general decrease in the positive effects of the previously administered bromocriptine and resumption of the treatment with this drug led to less marked improvement. Metoclopramide was tested in all the girls before the treatment, and it was noted that, while endorphins were hyporesponsive, prolactin was hyperresponsive. This test was repeated two months after the bromocriptine treatment had been performed and, while beta-lipotropin remained unchanged, beta-endorphin showed increased responsiveness.



Current use of Dopamine with Lower Dose Diuretics 

There is extensive knowledge of the effect of taking dopamine with a bumetanide type diuretic. 

Bumetanide by itself has a plateau above which a higher dose causes no further diuresis, but when combined with dopamine there is more diuresis.  Alternatively you can use a lower dose of bumetanide and get the same amount of diuresis by adding dopamine. 

Of interest to people with autism, it is found that you can reduce the amount of potassium lost for the same amount of diuresis.

    










The effects of a combination of dopamine and bumetanide were studied in eight patients with oliguria not responsive to conventional treatment. Dopamine was infused at a rate of 3 чg/kg/min and bumetanide was given as a 0.05-0.1 mg/kg bolus every 2 hours intravenously. Administration continued for 3 to 15 days. Urine output, blood urea nitrogen, serum creatinine, the ratio of urine to plasma osmolarity, free water clearance, and serum electrolytes were measured before, during, and after the administration period. Six of the eight patients responded with an increase in urine output and improvement of the other variables ; the other two did not. We conclude that the combination of dopamine and high-dose bumetanide is effective in increasing diuresis in critically ill patients in the early stages of oliguria



How does dopamine interact with NKCC1/2?

This is a very logical question, but there is something in the literature on this subject.  It does come from frogs, but it was all I could find.




The different murine D2-type dopamine receptors (D2L, D2S, D3L, D3S, and D4) were expressed in Xenopus laevis oocytes. The D2-type receptors were all similarly and efficiently expressed in Xenopus oocytes and were shown to bind the D2 antagonist [125I]sulpride. They were all shown to activate Cl influx upon agonist stimulation. Using the diagnostic inhibitor bumetanide, we were able to separate the Na+/K+/2Cl cotransporter component of the Cl influx from the total unidirectional Cl influx. The D3L subtype was found to operate exclusively through the bumetanide-insensitive Cl influx whereas the other D2-type receptors acted on the Na+/K+/2Cl cotransporter as well. The pertussis toxin sensitivity of the receptor-activated chloride influx via the Na+/K+/2Cl cotransporter varied between the various D2-type receptors showing that they may couple to different G proteins, and activate different second messenger systems.


In contrast to the D2 and D3 receptor subtypes, D4 receptor activity was not significantly altered by the presence of PTX, suggesting that in Xenopus oocytes it may couple with one or more PTX-insensitive G proteins to cause changes in Cl3 influx. By contrast, in the case of the D2 receptor, PTX reduced the total Cl3 influx mediated by the D2S isoform by approximately 67%, and that mediated by the D2L isoform by approximately 40% (Fig. 2A). However, the activities of the two components of this ion influx, namely the bumetanide sensitive Na/K/2Cl- cotransporter and the bumetanide-insensitive Cl- influx, differed between these two isoforms. While the bumetanide-insensitive Cl3 influx was reduced by approximately 60% by PTX for the D2L isoform, it was only slightly reduced for the D2S isoform (Fig. 2C). Thus, the majority of the inhibitory effect of PTX on the D2S-induced influx was caused by uncoupling from the signalling cascade that activates the Na/K/2Cl- cotransporter. On the other hand, the signal transduction pathway that activates the cotransporter after stimulation of the D2L receptor remained relatively unaffected by PTX (Fig. 2B), indicating that D2S and D2L couple to different G proteins when expressed in Xenopus oocytes. For the D3 receptor, both long and short isoforms showed a reduction (50^60%) in the presence of PTX, at the bumetanide-insensitive Cl- influx (Fig. 2C), whereas for both D3 receptor isoforms, PTX had little or no effect on the Na/K/2Cl- cotransporter, indicated by the bumetanide-sensitive component of the Cl3 influx (Fig. 2B).  

PTX = pertussis toxin
  

Caffeine among its many effects is effectively a dopamine D2/3 receptor agonist.





Conclusion

As I understand from the large scale trial use of bumetanide use in autism, there is indeed an issue with hypokalemia (loss of potassium).  

I would think that this should be solvable using a supplement and dietary potassium.  Agnieszka pointed out that kiwis have the advantage of potassium with little carbohydrate, as do avocados. Bananas and orange juice are the traditional potassium-rich foods for people on diuretics. 

This is a case where the care giver has to play an active role, it is not just about the doctor prescribing a pill.  The care giver has to manage the process to minimize the side effects.  So potassium needs to be managed, as does fluid intake. 

For people who struggle with hypokalemia, the idea of a lower dose of bumetanide, but with dopamine, could be interesting.  The other method is to add a potassium sparing diuretic like spironolactone. 

For my son, the dietary option, plus 250mg of potassium twice a day, is very effective.  Now I just have to persuade him to take a Greek coffee with his breakfast. 

For people whose autism responds to penicillin type antibiotics and who take bumetanide then Bromocriptine might be interesting as a caffeine alternative.








25 comments:

  1. Hi Peter,

    I was wondering if the synergistic effect of coffee on Petra's son when on bumetanide might not be related just to dopamine but the blood pressure enhancing effect of a strong coffee, as well. If I remember right, Petra's son had issues with low BP when on bumetanide.

    But I too have observed that even the effect of NSAIDS is best when taken with tea or coffee. I had used this combination but had forgotten or rather got lazy in recent years and had ended up with a never ending headache and endless popping of brufen without any respite, like RG. Petra, thanks for reminding us.

    Finally, there is something to ruminate about here regarding trying a lower dose of bumetanide, or any drug for that matter or combining them with other stuff to circumvent the negative impacts.

    Peter, what is the relationship between serotonin and speech, if any.

    Respectful regards

    ReplyDelete
  2. Hi Peter,
    Thanks for developing the hypothesis of adding dopamine with diuretics here.
    Since I believe Bumetanide seems to be the "flag ship" of many people's autism treatment plan, I just wanted to make the best of it.
    Things like allergies, inflammation, potassium sparing, dehydration, are all to be addressed to while on Bumetanide. Still, despite rescuing those, I noticed some kind of oxidative stress after the drug and somehow felt as if it was coming from kidneys.
    At the same time I wanted to rescue his dopamine levels and that's about when I reintroduced coffee, Greek coffee this time.
    I think other kinds of coffee might also work. We used a big iced instant coffee while he was giving private lessons at home and really helped with brain fog, sociability, stimming...My son, not being a coffee lover, this wasn't a daily habit.
    Anyway, for us seems a beter choice as it is also good for GERD (something good is there)and could be served twice or three times a day giving a long lasting mildest boost.
    After all, in Greece, all "decent" grandpas, take their diuretics with a nice cup of Greek coffee.
    And Peter, if you want to initiate Monty to it, you have to do it right, no sugar added, to enjoy the full taste and aroma.

    ReplyDelete
  3. Trying to answer the question you put here:
    " How does dopamine interact with diuretics and the effect in the kidney also affect the brain?"
    ... and this might sound "science fiction"... it could be through astrocytes.
    First, there is direct evidence for expression of dopamine receptors
    on astrocytes.
    Second, astrocytes are in many organs, such as liver, kidneys, lungs, pancreas and communicate with brain.
    People with acute kidney injury have neurological problems as there are functional changes in the brain.

    ReplyDelete
  4. Reducing brain glutamate is not the only non-antimicrobia way antibiotics could be reducing autism symptoms.

    Great review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746177/

    "Antibiotics can be effective in treatment of a broad spectrum of diseases and pathological conditions other than those of infectious etiology and, in this capacity, may find widespread applications beyond the intended antimicrobial use."

    ReplyDelete
  5. Petra,

    That direction of thought seems quite intelligent as I had an intuitive feeling that bumetanides odd effects on my son had to do with
    something more than just hypokaelima or falling BP.

    ReplyDelete
  6. Peter, Tyler, reduced behavioral flexibility,OCD, movement disorders, uncontrollable laughter, hyperexitability,could be the result of subclinical epileptiform discharges?.I don't know if an altered dopaminergic function and excess glutamate are the result of the epileptiform discharges or viceversa in my son's case. The first logic drug from the first time , since he was 3, was valproate to sabilize the electrical activity. But I don't know for how long valproate would have to do its work. In addition, dopaminergic and glutamate neurotransmission works synergistically. More dopamine like Greek coffee is something that my son should avoid? Thinking of the best therapeutic approach, could be glutamate antagonists like tizanidine in conjunction with dopamine antagonists or could be dopamine agonists? I have not this clear. What I notice is that there are a few children with autism and subclinical epileptiform activity.In this blog only mine and Agnieszka's son.
    Valentina

    ReplyDelete
    Replies
    1. My son EEG was not great because the sampling was not ideal, but the result was "presence of atypical activity" with a reccomendation to repeat when he is older. But it was not altered enough that they find necessary a new try right away.

      Delete
    2. Jane, my son's first EEG when he was 3 was quite altered: asymmetric acute biohemispheric waves on the right frontal and left temporal regions, with marked frontotemporal asymmetry.Now he is 10 and his EEG has improved a lot. Valproate and EEG every 6 months during the first years,were vital, otherwise, I don't know what would have happened . But clearly, is not your son's case, don't worry.
      Valentina

      Delete
    3. My oldest son's EEG at around age 3 was negative for seizures. Basically what they did is had an ambulatory EEG hooked up to him for a day and then they took the data out and sent it to a specialist. Unfortunately, the data is in a proprietary format for software that if my memory serves me correctly was in the 5 figure range. This was 4 years ago though. My son has also had all the same symptoms you describe but they have gotten better with time.

      Now I have no idea if your son is having petite mal seizures or not, but I would guess probably not unless it was at least detected by EEG. For non-verbal children it is really hard to tell so this is just the only way to really do it right now.

      As far as dopamine goes, well it does many different things in the body just as glutamate does. What matters more is how specific circuits are activated and in what part of the brain. This is why even drugs for specific receptor types for dopamine have lots of undesirable side effects. So having the "right" amount of dopamine signaling is very important and very specific to whatever pathology you are trying to treat which modern medicine in my opinion does not treat very well because of the aforementioned reasons.

      So in ADHD, stimulants to increase dopamine in the prefrontal cortex are thought to act through a mechanism where there is a tonic level of dopamine signaling that is too low in ADHD which if too low can cause hyperactivity, while if dopamine is too high the burst form of dopamine signaling is affected which causes the kind of side effects that strong stimulants seem to have in normal people. These are just theories though, but generally speaking dopamine its most classical sense in normal people acts as an emplifier of glutamatergic signaling which causes an increase in the signal to noise ratio of excitatory signaling (the same thing that happens with attention). The problem is that if there is too much dopamine then basically everything gets amplified (not just what your selective attention is towards) and so you have lots of aberrant firing of neurons in the brain which makes concentration and focus difficult if not impossible.

      I also must stress caffeine does a lot more than just influence dopamine, especially with respect to autism.

      Last but not least, I have not read any recent studies on the subject but I have read in some old reviews that epilepsy ends up occurring in about 20% of those diagnosed with ASD which is a high enough rate that like Peter has suggested before, it might be wise to do whatever you can in trying to prevent that first seizure even if nothing abnormal shows up in an EEG of your child because epileptic problems usually start in the teenage years and once you start getting them, they keep coming more frequently and the problems on go downhill from there.

      Delete
    4. Valentina, my son doesn't have symptoms of any kind of seizure activity, but I've convinced the Dr. to do EEG and MRI on the basis of his regression.

      I believe that if this kind of testing was part of the standard of care, small anomalies and oddities would be commonly detected and maybe patterns would be observed.

      As his results weren't "perfect" I'll keep following as he ages, and hope its only me worrying for nothing as usual :)

      Its good to know that for your son the situation is under control and he is improving.

      Jane.

      Delete
    5. Valentina, Morgan used to have all those behaviours you describe, especially the movement disorders, hyperexcitability, & uncontrollable laughter (the latter accompanied by pupil dilation for over one minute whilst staring DIRECTLY at a bright light in a dim room. The silly behaviour disappeared at the same time the pupils responded properly & shrank). An MRI showed no structural abnormalities, though a sleep-deprived EEG showed “normal abnormal” activity associated with having ASD (no big surprise on reflection). Only one epileptic attack which was diagnosed as being due to high fever.

      All this by way of saying, we too thought Morgan was continually experiencing subclinical epileptiform discharges, though the professionals say no.

      But, all those behaviours have more or less disappeared over the past two years (Morgan is now 7 years 3 months). I attribute this to: A. the Modified Atkins Diet; B. chronic administration of anti-histamines (current favourite is fexofenadine hydrochloride as it also helps reduce irritation due to insect bites); & C. a more mature nervous system.

      All this by way of saying, please read Peter’s post of 18 January 2017 “The Clever Ketogenic Diet for some Autism”, & consider if you might try such a diet. For Morgan, when we first began the MAD over two years ago, his silly behaviours were almost directly correlated with low urinary ketone levels as measured using Ketostix – & calm, alert, responsive behaviours were related to that satisfying deep purple colour on the sticks. Although we have been able to relax the MAD over time, we still get really silly and vague behaviour in the hours & days following refined carb binges. We have been able to avoid constipation by having breakfast of flaxmeal porridge (which in addition to all the soluble fibre, absorbs lots of heavy cream or coconut oil, & has some omega 3s). And the weird contortions & posturings are no more. Alexandria

      Delete
    6. Alexandria, thanks for your input, the high fat diet is of great value for our sons, everything is related to these behaviors, high dopamine, excess glutamate and fotosensitivity and electrical activity or epileptiform discharges. Will follow your advice and will consider MAD, now my son takes an avocado once a day with coconut and oliva oil, that is all. Fexofenadine sounds interesting also to give a try, now he is with histidine and BCAA.
      Regards
      Valentina

      Delete
    7. Alexandria, thanks for sharing.

      My son also used to have epileptiform sleep EEG pattern and similar behaviors. Can you share what other medications (if any) do you use together with MAD apart from antihistamines?

      More and more I think that it's worth to check urinary ketones with Ketostix in every child who experiences "fever effect". Elevated ketones in blood and urine is not a rare thing during fever in children.

      Delete
  7. Coffee,tea,wine,and miso have been known for years to be good probiotics.Every bit as good as yogurt.

    ReplyDelete
    Replies
    1. Hi Roger, Peter and all,

      Roger, thanks for speaking out and share your experience and research.

      Maternal inflammation model could help us draw some useful conclusions about one's autism phenotype, so I am going to give some of my medical records which I think may be relevant to my son's autism.

      When I was a teenager, I had problems with high eye blood pressure and treated with Diamox. Around this period of time and due to an anatomic throat structure, all doctors advised me to check my thyroid. Endocrinologist diagnosed a problem and treated with pills T3/T4(?). A year after, or so, I visited an endocrinologist professor who told me that I might have been marginally affected and I needn't have bothered with it anymore. I also had a staphylococcus infection and severe metal allergy (gold, silver, steel, titanium excluded).

      During my pregnancy I developed inherited superficial thrombophlevitis, which is an inflammatory disease that causes blood clot to form and block some veins usually in one leg. This was the only obvious inflammation I had, but doctors didn't use to call this inflammation, then.

      I stopped milk at a relatively early age and gradually added lots of coffee and some wine to my diet.

      When my son starts having an autistic "build up", I sometimes can see his veins at the side of his forehead swollen. This makes me really concerned about the blood clotting issue.

      It is well known that coffee and moderate alcohol consumption can help as blood thinners. They can also serve in the gut.
      Dairy products, on the other hand, are coagulators. I am making this connection because I find it relevant to an adverse effect my son had after drinking coffee and just right after milk.

      I think that this has something to do with calcium absorption, especially in the GI track where there is decreased absorption rate. We all know that calcium absorption is a huge issue in autism and we often think if we should give or not. Other dairy products seem more well tolerated, maybe because they have a probiotic benefit.
      Anyway, my son's problem was amazingly resolved after a glass of an alcoholic beverage.

      I know a few cases of autism regression while having milk craving. Probably kids' developmental needs make them "shelter" to milk and they get trapped by it.
      I know that we risk osteoporosis and hemorrhage with blood thinners, but blood clotting could even bring more severe consequences.

      According to the things I noticed so far, RG seems right about not supplementing vitamin D even though there is some marginal deficiency, as it seems that it may be a self protection mechanism. Maybe my son and myself's low levels of LDL, triglycerides lowering total cholesterol is a protective mechanism against calcification/blood clotting?

      This is my approach in the light of the evidence I have had so far. I just want to make sure that my intention is far from advising anyone here to give coffee/alcohol to affected kids, I am sure there are other ways to deal with relevant issues and of course, Peter knows best.

      RG, would you mind saying a few things about your daughter's lipid profile?

      Delete
  8. Hi Peter, Tyler, and community,

    Hope everyone is doing well as we approach the holiday season.

    First, I'd like to share a new research paper that I'm still poring over, and would really appreciate any insights the learned members of the community have. The paper has to do with the urinary metabolites of ASD kids, and some of the latest reading I've been doing has been going back the to Kynurenine pathway:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121959/

    Other relevant papers on Kynurenine pathway:

    https://www.ncbi.nlm.nih.gov/pubmed/26497015

    http://www.futuremedicine.com/doi/pdfplus/10.2217/bmm.14.11


    Relevant paper as it notes the Tryptophan / Serotonin (again, Kynurenine pathway) connection to ASD:

    http://www.fasebj.org/content/28/6/2398.long

    I'll post any insights I arrive at in going through the material, and again, would really appreciate the community's thoughts. Issues with the Kynurenine pathway would certainly explain a lot of the constellation of issues in ASD.

    Depending on where things go amiss in this pathway, one of the questions I'm trying to tackle is, would L-Tryptophan or 5-HTP be a better option? Trial and error?

    Thanks in advance,

    AJ

    ReplyDelete
    Replies
    1. I have a combo therapy to reduce quinolinic acid in the brain that I created for this very reason and still use it today. I think I have quite a few posts on this blog if you can find them that details all of my thoughts on the matter. It seems to help a lot, but it could be helping for other reasons and this is of course all an N=1 sample size since nobody else has reported using it before.

      In summary it is comprised of (the specific brands I use):

      Scivation XTend Watermelon BCAA Powder
      Great Lakes Hyrolyzed Collagen
      Niagen (Nicotanimide Riboside)
      Apigenin

      I also used to include a small amount of 5-HTP with Green Tea extract since this therapy is designed to block L-Kynurenine into the brain, but also blocks Tryptophan as well since they both compete for the same LNAA transporter to get across the blood brain barrier. BCAA's of course also use the LNAA transporter as well as Phenylalanine and Tyrosine which are precursors to dopamine. L-DOPA also competes with 5-HTP for the same enzyme needed for L-DOPA to be converted into dopamine and 5-HTP to be converted into serotonin so replacing the blocked phenylanine and tyrosine was not an issue.

      The therapy works by mimicking an experimental process for studying serotonin deficiency in humans called Acute Tryptophan Depletion which basically means you give the body a bunch of free form amino acids, minus tryptophan, early in the morning to both drain the flood for free tryptophan via protein formation in the liver, as well as by having other LNAA competing amino acids such as BCAA's block tryptophan and L-Kynurenine into the brain.

      Of course doing this causes several side effects. One being low serotonin production in the brain and another being that the brain has problems producing NAD+ as quinolinic acid plus vitamin B6 and another enzyme does this naturally. Low levels of NAD+ cause lots and lots of bad problems. Fortunately, there is a new albeit somewhat expensive supplement that raises NAD+ levels through a different metabolic pathway called Nicotanimide Riboside. This gets around the pellagra like side effects. While tryptophan is blocked with this therapy, 5-HTP (precursor to serotonin) is not. The problems with 5-HTP is it is debatable how much of it when orally ingested gets metabolized directly to serotonin in the gut and how much actually makes it to the brain unscathed for serotonin production in the brain. It is thought green tea extract helps with this as it has been shown to inhibit the enzyme that produces serotonin in the gut (btw, there is a drug called carbidopa that does this much better than Green Tea Extract).

      Apigenin is according to the months and months of research I did for this therapy, the most potent natural IDO inhibitor available. IDO is the enzyme that converts Tryptophan to Kynurenine in response to inflammation (there is another one called TDO which mainly works in the liver).

      I also used to use 5-HTP but stopped because really the goal here with autism is to upregulate the serotonin receptors in the brain and the way you do that is by preventing excess serotonergic signaling or else hacking the receptors directly with SSRI's which are dirty drugs I would never give to my child (5-HTP I feel is far safer, though as I said I don't feel the need to replace the lost serotonin as upregulating those receptors over time and normalizing them requires serotonin abstinence).

      Delete
    2. Hi Tyler, Thanks so much for your response! I was going to start looking for an IDO inhibitor based on the papers, and appreciate your suggestion that apigenin is the most potent. Apigenin keep popping up as a substanbce in my research that can do many good things in ASD (e.g. modulating microglia activation).

      I was starting to give my daughter BCAAs (I was using one called tri-pep because it's peptide bound, helping with absorption) when I learned that BCAAs can compete with Tryptophan.

      I'm going to look through the blog for your old posts, and again, as always, really appreciate your insights, and your sharing your findings.

      AJ

      Delete
    3. Yes BCAA's compete with Tryptophan as well as L-Kynurenine via IDO upregulation. Another way to reduce L-Kynurenine is via exercise as it causes the muscles to create more Kynurenic Acid via a pathway started by PGC1-alpha (Kynureninc Acid is also created in the brain, but when synthesized in the periphery does not cross the blood brain barrier easily). A paper that came out in the last year suggested that much of exercise's antidepressant effect could be via reduced kynurenine into the brain via exercised muscles burning off the excess kynurenine floating around in the blood stream.

      And if you want more serotonin, then that is why you add 5-HTP and Green Tea Extract or Carbidopa (requires a prescription) to replace the tryptophan that is blocked via BCAA's. You also need Niagen (Nicotanimide Riboside) (normal Niacin or other forms of B3 won't do) to replace the lost NAD synthesis by decreasing L-Kynurenine levels in the brain (almost all L-Kynurenine is created outside of the brain). And last but not least, if you are worried about low dopamine (usually the opposite is the case with autism), you replace the Tyrosine and Phenylalanine that are competitively blocked by BCAA's using Mucuna Pruriens which is an herb that is high in L-DOPA, or if you can get a prescription for L-DOPA then just use that directly.

      But at the moment I no longer do any 5-HTP replacement or L-DOPA replacement which seems to work best long-term for my child.

      If your kid does pills, give her the Niagen and Apigenin in the morning separately and then make a beverage using the BCAA powder and hydrolyzed collagen, and then give the BCAA powder and hydrolyzed collagen again a second time during the day.

      Also, another thing to remember is that any rise in insulin is going to cause your muscle cells to intake BCAA's from the bloodstream which will in effect open the floodgates for tryptophan, tyrosine, phenylalanine and all of their related metabolites (like L-Kynurenine) which use the Large Neutral Amino Acid (LNAA) transporter to cross the blood brain barrier. So ideally, you would give your child this beverage when they first wake up, then wait at least half an hour for the BCAA's to temporarily rise in the blood stream, then eat breakfast (with carbs perhaps) or whatever so that you don't have a lot of tryptophan and L-Kynurenine flooding into the brain at once. Obviously, if you are doing a keto diet, none of this is an issue because your insulin levels will never spike because of low carbs (BCAA's can spike insulin as well but you need a lot more protein to generally spike insulin anywhere as high as just with carbs or carbs/protein).

      Also, L-Kynurenine levels follow circadian rhythms and are highest in the morning and lowest in the evening, but if you do this in the evening and you don't also use 5-HTP it might be wise to also supplement melatonin as well because it is dependent upon serotonin levels several hours before bedtime.

      Last but not least, Scivation XTend seemed to be the most reasonably priced and best tasting. Plus, it didn't have too many other additives other than some extra B6, Citrulline Malate (not a big deal), and some L-Glutamine which is an amino acid some people with autism supplement directly because it is the best way to raise GABA levels in the brain via dietary supplementation as L-Glutamine crosses the blood brain barrier well, but GABA itself does not.

      Delete
    4. Hi Tyler, Thanks very much for providing the additional details above - I really appreciate it! I will definitely go back to the BCAAs using the above protocol and see if it makes an impact. I will actually try the Scivation XTend BCAAs as the one I have (Tri-Pep) has a sickly sweet flavor (watermelon) that my daughter can only handle with a lot of dilution (and I don't blame her).

      I will also order the Niagen - my daughter does pills via my opening them up or crushing them (tablets) and diluting them in grape juice, so I can do this.

      I did notice you've mentioned hydrolyzed collagen in your recommendation. If you wouldn't mind, what is the mechanism you're looking at by including this?

      As always, thanks very much, I'm about 1.5 months into this journey, and although I've had quite a steep learning curve, the more I learn, the more I realize how much more there is to learn than I realized.

      By the way, I've seen that baicalein also is an IDO inhibitor and seems to be relevant to glutamate excitotoxicity:

      https://www.ncbi.nlm.nih.gov/pubmed/27430911

      I'm thinking of incorporating both Apigenin and Baicalein, both IDO inhibitors, as they both appear to help with several aspects of this condition. Any thoughts on baicalein and /or the combination of apigenin and baicalein?

      I wish you and your family a very Merry Christmas (if you celebrate it) and a great 2017!

      AJ

      Delete
    5. I mistyped my first sentence (guess I lost my train of thought from some distraction at home) and said BCAA's compete with L-Tryptophan and L-Kynurenine via IDO upregulation. The first part is true, the second part I added on for some nonsensical reason. IDO is one of the enzymes that help convert tryptophan to L-Kynurenine (as I explained before). I think I meant to say that L-Kynurenine is upregulated by IDO and just forgot to add the stuff about apigenin at the end.

      As for Hydrolyzed Collagen, it is a protein that has many different amino acids but is almost uniquely deficient in tyrosine, phenylalanine, and tryptophan. So by adding the collagen with the BCAA's you get extra protein synthesis in the early morning when protein synthesis is at its highest. You have trytpophan in your blood stream at all times, but by adding in another amino acids, the tryptophan is drained from the blood supply (not completely of course as the body is always breaking down proteins from muscles and other tissues all of the time) and used by the liver for protein synthesis. So you both lower systemic tryptophan levels (which both decreases the activity of the serotonin pathway and kynurenine pathway) and block tryptophan and L-Kynurenine's access to the brain.

      I guess you could say the collagen is optional or at least more important in the morning than in the afternoon when other foods containing tryptophan will have been digested and insulin has been increased presumably from eating food as well (at this stage it is most practical to just block with BCAA's).

      Last but not least, this should not be confused with a rare type of syndromic autism I can't remember off the top of the head which is due to faulty synthesis of BCAA's in the body which is rescued from BCAA supplementation. All of this stuff I have pointed out has nothing to do with that, and is more of a method of blocking excess peripheral inflammation (perhaps ironically from high peripheral serotonin as high peripheral serotonin is associated with peripheral inflammation) from affecting the brain with excess kynurenines which are of course supposed to get in the brain for use in synthesizing NAD+, however, the amount of B6 and enzymes to clear its precursor quinolinic acid may not be sufficient leading to increasing levels of quinolinic acid which can damage DNA as a strong oxidant and is excitotoxic in large quantities as it binds to the NMDA receptor much stronger than glutamate does.

      Ideally, you want to normalize the tryptophan pathways and reduce systemic inflammation which I believe is the cause of a lot of brain inflammation in autism (and most neurodegenerative disorders), but that isn't always possible so this therapy is more of a band-aid for people with autism who have systemic inflammation issues leading to additional cerebral inflammation issues.

      Delete
    6. Hi Tyler,

      Thanks very much, the additional information was just what I was looking for.

      Have a great day!

      AJ

      Delete
  9. Hi Peter and friends.
    I haven't commented in awhile because my son has been going through a rough patch (hormones, trialing different drugs that didn't agree with him).
    I just want to wish those of you who celebrate Christmas or Hanukkah a wonderful holiday and to all of the readers, that all of our kids make some progress in the new year be it big or small. Thank you to everyone for their advice, insight and for passing along the latest in research. It takes a community of people working together sharing information to help our kids reach their potential (whatever that may be).
    Warmly,
    Christine

    ReplyDelete
  10. Hi Peter
    I am new to your blog and would like to read your blog entries in order - is there a way I can see the order by date or a list of the order ... or something?
    Many thanks
    Melinda

    ReplyDelete
    Replies
    1. Melinda, there is a blog archive on the right side of the screen. Just start at the top of the page and go down till you find it. Go to 2013, click on it and then go to March are click on that. Then you can go post by post. The science was much more basic at the start of the blog, but there are some good things nonetheless. There 349 posts so it would take a long time to read them all. Good luck !

      Delete

Post a comment