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Wednesday, 4 October 2017

Sodium Benzoate and GABRA5 - Raising Cognitive Function in Autism


I am still looking for additional cognitive enhancing autism therapies. It seems the best way to find them may actually be to reread my own blog.
A long time ago I suggested that Cinnamon could well be therapeutic in autism, most likely (but not entirely) due to the sodium benzoate (NaB) it produces in your body.


Sodium benzoate (NaB) is both a drug used to reduce ammonia in your blood and a common food additive that acts as a preservative.
NaB has many biological effects.  One effect relates to a protein called DJ-1, which is produced by a Parkinson’s gene (PARK7). I had noticed that when the body tries to turn on its anti-oxidant genes after the switch Nrf2 is activated, the process cannot proceed without enough DJ-1.  This is why Peter Barnes, from my Dean’s list, suggested that patients with COPD might benefit from more DJ-1.  COPD is a kind of severe asthma which occurs with severe oxidative stress, the oxidative stress stops the standard asthma drugs from working, which is why so many people die from COPD. Oxidative stress is a key feature of most autism.
To make more DJ-1 you can use sodium benzoate (NaB) which is produced gradually in the body if you eat cinnamon. So in theory cinnamon is like sustained release NaB, it is also extremely cheap.
Independently of all this NaB has been trialled in schizophrenia and a further larger trial is in progress.  Autism is not schizophrenia, but the hundreds of genes miss-expressed in autism do overlap with the hundreds of genes miss-expressed in schizophrenia, so I call schizophrenia autism’s big brother. 

GABAA α5 subunit
The scientist readers of this blog may recall that there are two sub-units of the GABAA receptor that I am seeking to modify, to improve cognition.  One is the α3 subunit and the other is the α5 subunit. Low dose clonazepam works for α3.
The α5 subunit is the target of a new drug to improve cognition in people with Down Syndrome (DS).
Very recent research links the same sub-unit to autism, so it is not just me looking at this.

Reduced expression of α5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior                                                                                                              

As is often the case, it looks like some people might need to “turn up the volume” from α5GABAA receptors and others might need to turn it down.
I had yet to find a practical way to affect α5GABAA. Now I have realized that I have already stumbled upon such a way to do it.
Pahan, a researcher in Chicago, has shown that he can improve cognition in mice using cinnamon. He noted that in poor learners GABRA5 was elevated, but that after one month of cinnamon GABRA5 was normalized. 

Cognitive loss in autism, schizophrenia and Down Syndrome
Most people might associate MR/ID with autism and indeed Down Syndrome; you likely do not really consider people with schizophrenia to have MR/ID. In reality, cognitive loss is a common feature/problem in schizophrenia and indeed bipolar, just not enough to be called MR/ID.
Those researching schizophrenia seem to focus on NMDA receptors, whereas my blog only goes into the great depths of science when it comes to GABAA . To the schizophrenia researchers NaB is interesting because it is a d-amino acid oxidase inhibitor, which means that it will enhance NMDA function.  So if you are one of those people with too little NDMA activity (NMDAR hypofunction) then sodium benzoate should make you feel better.
The schizophrenia researchers think NaB is helpful because of its effect on NMDA, for me it is GABRA5 that is of great interest. The same should be true for parents of kids with Down Syndrome (DS). We have seen that bumetanide should, and indeed does, help DS.  It looks to me that NaB/Cinnamon should further help them and no need to wait for Roche to commercialize their GABRA5 drug. 

NaB and Cinnamon
I am yet to determine how much NaB is produced by say 3g of cinnamon.
The clinical trials of NaB use 1g per day in adults. People using cinnamon, like Dr Pahan, for cognition or just lowing blood pressure and blood sugar use around 3g.
It is quite difficult to give a teaspoonful of cinnamon to a child, whereas NaB dissolves in water and does not taste so bad. 

NaB and Cinnamon Trials
I did trial cinnamon by putting it in in large gelatin capsules and at the time I did think it had an effect, but I doubt I got close to Dr Pahan’s dosage.
A prudent dose of NaB would seem to be 6mg/Kg twice a day. This is similar to what is now being trialed in schizophrenia.
A small number of people do not tolerate NaB and logically also cinnamon.  They are DAAO inhibitors, just like Risperidone. People who are histamine intolerant need to avoid DAAO inhibitors. If you have allergies it does not mean you are histamine intolerant.
I did try NaB on myself and I did not notice any effect.


Conclusion
I had already obtained some NaB to follow up on my earlier trial of cinnamon.  Having read about the effect of NaB on GABRA5 expression, I am even more curious to see if it helps.
Any positive effect might be due to DJ-1 boosting the effect of Nrf-2, it might be boosting NMDA or it might be reducing GABRA5 expression. In some people all three would be useful.


Press release:- 


Pahan a researcher at Rush University and the Jesse Brown VA Medical Center in Chicago, has found that cinnamon turns poor learners into good ones—among mice, that is. He hopes the same will hold true for people.

His group published their latest findings online June 24, 2016, in the Journal of Neuroimmune Pharmacology.

"The increase in learning in poor-learning mice after cinnamon treatment was significant," says Pahan. "For example, poor-learning mice took about 150 seconds to find the right hole in the Barnes maze test. On the other hand, after one month of cinnamon treatment, poor-learning mice were finding the right hole within 60 seconds."

Pahan's research shows that the effect appears to be due mainly to sodium benzoate—a chemical produced as cinnamon is broken down in the body.

In their study, Pahan's group first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food. 


In analyzing baseline disparities between the good and poor learners, Pahan's team found differences in two brain proteins. The gap was all but erased when cinnamon was given. 


"Little is known about the changes that occur in the brains of poor learners," says Pahan. "We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment." 


The researchers also examined brain cells taken from the mice. They found that sodium benzoate enhanced the structural integrity of the cells—namely in the dendrites, the tree-like extensions of neurons that enable them to communicate with other brain cells

As for himself, Pahan isn't waiting for clinical trials. He takes about a teaspoonful—about 3.5 grams—of cinnamon powder mixed with honey as a supplement every night.  
Should the research on cinnamon continue to move forward, he envisions a similar remedy being adopted by struggling students worldwide. 


The paper itself:- 


This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity. 

We have seen that cinnamon and NaB modify T cells and protect mice from experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Cinnamon and NaB also upregulate neuroprotective molecules (Parkin and DJ-1) and protect dopaminergic neurons in MPTP mouse model of Parkinson’s disease.  Recently, we have seen that cinnamon and NaB attenuate the activation of p21ras, reduce the formation of reactive oxygen species and protect memory and learning in 5XFAD model of AD. Here we delineate that NaB is also capable of improving plasticity in cultured hippocampal neurons. Our conclusion is based on the following: First, NaB upregulated the expression of a number of plasticity-associated molecules (NR2A, GluR1, Arc, and PSD95) in hippocampal neurons. Second, Gabra5 is known to support long-term depression. It is interesting to see that NaB did not stimulate the expression of Gabra5 in hippocampal neurons. Third, NaB increased the number, size and maturation of dendritic spines in cultured hippocampal neurons, suggesting a beneficial role of NaB in regulating the synaptic efficacy of neurons. Fourth, we observed that NaB did not alter the calcium dependent excitability of hippocampal neurons, but rather stimulated inbound calcium currents in these neurons through ionotropic glutamate receptor. Together, these results clearly demonstrate that NaB is capable of increasing neuronal plasticity.

These results suggest that NaB and cinnamon should not cause health problems and that these compounds may have prospects in boosting plasticity in poor learners and in dementia patients. In summary, we have demonstrated that cinnamon metabolite NaB upregulates plasticity-associated molecules and calcium influx in cultured hippocampal neurons via activation of CREB. While spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones, oral administration of cinnamon and NaB increased memory consolidation-induced activation of CREB and expression of plasticity-related molecules in vivo in the hippocampus of poor learning mice and improved their memory and learning almost to the level that observed in untreated good learning ones. These results highlight a novel plasticity-boosting property of cinnamon and its metabolite NaB and suggest that this widely-used spice and/or NaB may be explored for stimulating synaptic plasticity and performance in poor learners.


The schizophrenia trials:-







Plenty of people with schizophrenia now self-treat with NaB; just look on google.

P.S.
There is now is a small trial in autism:-

A Pilot Trial of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added on Augmentative and Alternative Communication Intervention for Non-Communicative Children with Autism Spectrum Disorders

https://www.omicsonline.org/open-access/a-pilot-trial-of-sodium-benzoate-a-damino-acid-oxidase-inhibitor-added-on-augmentative-and-alternative-communication-intervention-2161-1025-1000192.php?aid=83472&view=mobile


Results: We noted improvement of communication in half of the children on benzoate. An activation effect was reported by caregivers in three of the six children, and was corroborated by clinician’s observation. Conclusion: Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with more children participated for clarification of its efficacy.


56 comments:

  1. My oldest son won't eat french toast, but my younger three get french toast every morning before school which roughly translates to two pieces of bread, two eggs for plenty of b vitamins and choline, and 2/3 teaspoon of ceylon cinammon. I had independently read the research you cited about hippocampal learning being optimized in slower learners via sodium benzoate.

    Anyways, french toast is how I deliver the cinnamon to my kids. You can also probably mix it easily with a vanilla protein shake too.

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  2. Tyler, do you attribute a specific benefit to the cinnamon?

    For a fussy eater, NaB itself looks the easiest solution. I wonder how much the amount of NaB produced varies by the batch of cinnamon and that person's liver.

    Anyway, both NaB and cinnamon are among the cheapest interventions you could have.

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    1. Not really. I have three kids diagnosed with autism and my twins have some social issues and handwriting issues but are ahead of their peers in other ways. In their case the cinammon is more for general brain health just as eggs are in that they are high in b12 among many other things and it is hard to get b12 in the diet naturally with other foods. Some gut bacteria help produce b12 endogenously, but as we well know in autism the diversity of gut bacteria is reduced. I guess you could look at it as insurance.

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  3. How do you know if you need to upregulate or downregulate α5GABAA? Physical characteristics? Behavioral? This may be mumbo jumbo but We have this cinnamon: New Chapter Cinnamon Force that says is it 94 mg of Cinnamon (cinnamomun aromaticum and cinnamomun venum) by hydroethanalic extract and 46 mg of Cinnamon (cinnamomun aromaticum and cinnamomun venum) of supercritical extract. Is that a lot? Peter, would be happy to go pick you up and send you a couple of bottles gratis to thank you for your blog :) Maria

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    1. Maria, I am seeking to down regulate α5GABAA and upregulate α3GABAA. Both of which could increase IQ in a person with sub optimal cognition. So if a person has a very high IQ, I would not bother with these interventions.

      I would use either Ceylon Cinnamon, which you can buy in bulk very cheaply or Sodium Benzoate which you can also buy in bulk very cheaply. A one year supply will cost 10-20 dollars/euros.

      Sodium benzoate is easier to administer.

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  4. I wonder if cinnamon would have an effect on motor planning and coordination given its effect on parts of the brain including Parkinsons. Has anyone seen an improvement in motor or coordination. I will check and see if there are any studies for this?

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  5. How would you look at this study== do you think this was set of rats who needed to down regulate https://www.ncbi.nlm.nih.gov/pubmed/24419445 The performance of the NaB-treated rats was impaired in the elevated plus maze, an indicator of anxiety. Their riding time in fixed and accelerating speed rotarods was decreased, indicating motor impairment.

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    1. In your study the rats were fed 200mg/kg of NaB. In Pahan's study he fed mice 50mg/kg. In my "study" I am feeding a human 6mg/kg; the same as the human schizophrenia trial.

      Pahan has proposed cinnamon for Parkinson's. It has also been trialed in models of Alzheimer's.

      The effect should be dose dependent and should be affected by whatever dysfunction is present at the start.

      I think we should expect 1 teaspoon of cinnamon to have its effects on blood pressure, blood sugar, cholesterol in most people, but behavioral/cognitive effects in only some people.

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    2. Peter,

      How long have you been giving Monty NaB? I'm interested to hear the results.

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    3. Jolene, I have just started. I did use cinnamon on and off for a few months. Both do seem to have a cognitive effect, not huge but it is noticeable. NaB is very easy to add to any drink.

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    4. Thanks Peter. I just ordered some NaB. I'll be trialling it as soon as I get it.

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    5. Jolene,

      Not related to this post but would like to know if your son is stil going strong on kudzu. I was retrialling bumetanide starting off very slow (1 mg every alternate day) this time so as to be able to monitor side effects and might increase it a daily dose in a few days time. Would be grateful if you could share your continued experience with kudzu as it is next on my list.

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    6. Hi,

      He is still doing well on Kudzu. I tweaked the administration a little bit recently, and have seen improvements. I give him 3 capsules (1800 mg)/day, one at each meal. The half life is about 3-4 hours. I was seeing aggression in the evening, which was eliminated by giving the last dose at dinner (I had previously been giving him 1.5 capsules at breakfast and lunch). I hope this helps!

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  6. Here might be another simple intervention to reduce neuronal hyperexcitation via a method of cooling specific parts of the brain (this paper is specific to epilepsy) called "focal cooling":

    Press Release:

    https://www.sciencedaily.com/releases/2017/10/171005141831.htm

    Paper:

    http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1005736

    Now as far as implementing this intervention, I do know that with respect to skin, the response in the body to cool temperature is to increase body temperature (not what we want here) and pump more heated blood to the internal organs and brain. To get around this problem for cooling the body for sports purposes, a group at Stanford came up with a device that I think I mentioned on this blog a long time ago they called "The Glove" which is a pressurized cold glove which cools the outgoing blood going back to the heart, but does not induce thermogenesis and reduced blood flow to the periphery.

    Now with respect to cooling the head, I know that Russians have done cold water dousing for centuries under the idea that it invigorates the immune system and prevents sickness. Acute application of cold water on the face will also activate the mammalian dive reflex which will cause increased circulation of blood to the brain. This can be a good or a bad thing with respect to autism, but if you can cool the head long enough, you will at least get a temporary, yet small reduction in cranial temperature until the blood from the body heats the brain back up again via homeostatic mechanisms. You will also unfortunately get activation of the sympathetic nervous system and the catecholamines that go along with it.

    Nevertheless, it would be an interesting idea for a study just to see what happens as you have several dynamics going on which could be on balance good for autistic behavior, if not only temporarily.

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  7. "glymphatics" - fascinating. Maybe a missing link in understanding all the complications and potentials for treatment.

    https://www.washingtonpost.com/national/health-science/when-scientists-saw-the-mouse-heads-glowing-they-knew-the-discovery-was-big/2017/05/19/f33cc574-246a-11e7-a1b3-faff0034e2de_story.html?utm_term=.fbec8012b8f8

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    1. Tanya, this may relate to the reduced VEGF (vascular endothial growth factor) found in severe autism. One effect via VEGFR-4 is on the lymphatic system, which may result in a reduced capacity in autism to clear waste products from the brain. So lyphatics and glymphatics might very well be impaired in autism due to lack of VEGF. There will be a post on VEGF soon because VEGF-1 is dysfunctional in autism and this may also help explain the high prevalence of allergy and immune disease.

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  8. I really looked forward to that post Peter - will be like Christmas morn' for me ;)
    And as the article above stated, Omega 3s help with glymphatics. Another bonus of omega3 supplementation. Glad I tried it again - my son is still doing well with it.
    https://www.sciencedaily.com/releases/2016/10/161026105336.htm

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  9. Can only speak for myself, but omega3 fishoils is one of those things I cannot go without.

    Apparantly the ratio of epa:dha is crucial though, from what Ive remember reading is that they kind of compete with eachother (not sure if thats true though).

    For example Ive used Swansons superior essential fatty acids EFA's called Super DHA 500, which 500mg dha and 125mg epa per capsule.
    I found that while on this supplement my fine motor skills to improve and that I was less distracted by things during daily activities.

    On the other hands theres Marinol Omega3 which im currently using now which has 420mg EPA and 300mg DHA per dose, I have found that on this supplement Im somewhat more friendly so to speak.

    Same with Now Foods Omega-3 which has 180mg EPA and 120mg DHA which seemed to make me more friendly and calm aswell.

    This has been my subjective experience, but I know for a fact that omega3's (especially EPA I believe) can act as prolyl endopeptidase inhibitor (thereby decreasing peptide breakdown, such as oxytocin and vasopressin).

    While DHA seems to be more involved in NMDA receptor regulation.

    Another thing I would like to mention is that the high DHA product from swanson seemed to increase my insomnia if taken at dinner, this is no surprise too much as about everything that affects/modulates NMDA receptors to some degree seems to induce insomnia in me if taken during dinner/darkness: glycine, d-aspartic acid, zma(zinc magnesium aspartate), cinnamon seems to disrupt my sleep aswell if taken at dinner, basically everything that increases NMDA activity.

    Just pointing out as many of you allready no on here by now about the difference between the subset of people/kids that benefit from NMDA agonists and NMDA antagonists.

    It would seem a great plan to me that when a kid gets diagnosed with ASD/autism these days that there should be a short trial with both something that enhances NMDA and something that acts as a NMDA antagonist to see how they respond to it, this will greatly help them in the future so they know to which subset they belong.

    One thing everyone with autism/ASD seems to benefit from it NAC, which seems besides obviously increasing glutathione to act as a regulator of NMDA/glutamate, thereby creating a temporary more ideal homeostatis.

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  10. Glycine 3-6gram without food seems to be relaxing/calming for me though when taking during daytime.

    I've always wondered if the reason that autism/asd has disregulated/lowered oxytocin/vasopressin level is due to the fact that we have lowered glutathione.

    If you look at the chemical structure of oxytocin and vasopressin they are nearly identical, also they both contain glutamine, glycine and cysteine.

    Could the deficiency in oxytocin (and possibly vasopressin) be due to the fact that our bodies are stealing all the glutamine (which we are allready very low in as confirmed by science) in an attempt to raise glutathione levels and to maintain/heal the gut-barrier, thereby leaving no glutamine available for oxytocin production.
    On top of that the conversion from glutamate->gaba seems to be far from optimal in autism (hence the vitamin b6/p5p improvement lots get).

    Oxytocin: (Cys – Tyr – ILE – Gln – Asn – Cys – Pro – LEU – Gly – NH2)
    Vasopressin: (Cys – Tyr – PHE – Gln – Asn – Cys – Pro – ARG – Gly – NH2)

    Then there's the BCAA's that temporarily lower serotonin and dopamine in the brain, which are also reduced in autism and not surprisingly that myself and others on the spectrum have noticed benefits from BCAA supplementation (personally BCAA's greatly increases mental clarity for me). Once again, BCAA's are also building blocks of oxytocin (leucine and isoleucine).

    However amino acid's are a double edged sword for me personally as I am 100% certain I have some form of an urea cycle disorder (my urea levels are elevated in every single blood test (approx 2 times the upper limit).

    Question to you personally Peter:
    How was your kid his thirst/urinating frequency without any medications?
    Personally I have noticed I am ALWAYS thirsty and have a fair amount of toilet visits in comparison to others.
    This has been all my life, even as a kid I was known for my excessive thirst. Could this be a sign of vasopressin deficiency? As the main job of vasopressin is to hold (precious) water from a survival perspective.

    Also your kid is on bumetanide from what I understand? From reading the information you have posted the mechanism is mainly gaba modulation.
    Have you considered that vasopressin receptors might upregulate as a defense mechanism in any form of diuresis the body notices (including the fluid control in the brain)?

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  11. Peter,

    How are you measuring this? A food scale? Measuring spoons? My son's dosage comes out to 105 mg and I'm finding it hard to measure such a small dose.

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    1. Jolene, I use a measuring scoop that came with another product, but I also have digital pocket scales that measure to 0.01g. These are very cheap and you can buy them on Amazon. My scoop holds 0.9g and I found what 0.3g looks like.

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    2. Jolene, in the trial in Taiwan I mentioned below the NaB dose was:-

      . For children with body weight equal or more than 15 kg, benzoate was given with 500 mg/day. For children with body weight less than 15 kg, benzoate was given with 250 mg/day


      https://www.omicsonline.org/open-access/a-pilot-trial-of-sodium-benzoate-a-damino-acid-oxidase-inhibitor-added-on-augmentative-and-alternative-communication-intervention-2161-1025-1000192.php?aid=83472&view=mobile

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    3. Thanks Peter! I think that's going to be a lot easier to measure.

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  12. Aspie1983 I am very interested in your insights - after reading several of your posts, much of what you share matches my son. I had tried fish oils, cod liver oil, krill oil other forms of omega 3 like flax oil , just DHA off and on many times over the years and stopped due to not able to notice anything. Then started the higher EPA to DHA ratio, and like you say, now I see my son cannot be without. Definite positive social affect, and uplifts his mood. I will have to try a higher dose of just DHA away from is high epa dose and see what happens.
    My son also has the excessive thirst and many trips to toilet off and on since he was a kid too. I asked the endocrinologist if we should test vasopressin and he just replied with a stony-faced "no". Have you ever tried intranasal oxytocin? Just curious if you ever felt the slightest bit of anxiety over not being able to get a drink of water fast enough? Or even slight anxiety of not getting to a toilet fast enough?

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    1. There is a new study on omega-3:-

      Randomized trial of omega-3 for autism spectrum disorders: Effect on cell membrane composition and behavior

      http://www.sciencedirect.com/science/article/pii/S0924977X17308933

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  13. There actually now is a sodium benzoate trial in autism, published in January 2017. It was only six children.

    A Pilot Trial of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added on Augmentative and Alternative Communication Intervention for Non-Communicative Children with Autism Spectrum Disorders

    https://www.omicsonline.org/open-access/a-pilot-trial-of-sodium-benzoate-a-damino-acid-oxidase-inhibitor-added-on-augmentative-and-alternative-communication-intervention-2161-1025-1000192.php?aid=83472&view=mobile


    Results: We noted improvement of communication in half of the children on benzoate. An activation effect was reported by caregivers in three of the six children, and was corroborated by clinician’s observation. Conclusion: Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with more children participated for clarification of its efficacy.

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  14. Hi Tanya,

    Lots of people have told me in the past to check my blood sugar values especially during days at the beach, cause I would literally drink 4-5 liters of water in the a couple of hours.
    It seems to be very common in alot of people autism to have excessive thirst, I get a full blood panel atleast twice per year and that includes fasting glucose and hba1c, they were always well within range and actually quite good, the only thing that was always striking was very very low triglycerids (now, many of you might see this is a good thing, but it is not in my case i am certain).

    With regards to the oxytocin nasal spray, yes I have tried it, I got it from super-smart, I cannot confirm 100% sure it was the real deal as it most online companies do not seem to provide third party testing evidence, but it did seem to have an anxiolytic and open effect on me.

    Another thing I would like to mention about the nasal spray is that you have to read the tutorial about how to properly use nasal sprays, I made the mistake of snorting/inhaling it through one nostril at a time, while closing the other nostril with my hand... however... it is important to not snort/inhale, cause the oxytocin has to be absorbed by the mucous (spelling?) membranes.

    Here is an example with the proper technique how to use it:

    https://www.youtube.com/watch?v=tnEre7FHUAQ

    With regards to oxytocin/vasopressin, Im sure you are aware that there is a also vasopressin nasalspray available, under the name of desmopressin?

    Also with regards to your doctor, im not sure if you feel comfortable with him/her or not, but personally ive gone through atleast 2-3 doctors/psychiatrists to find the right one that is open to discussion and allows me to basically test whatever I want.

    ______

    I can remember as a kid, getting irritated easily whenever I wanted to drink and wasnt allowed to or when there was nothing to drink available, far more so than the average child I believe.

    This has obviously changed since adulthood for me as I can stand and go where ever I want, if I want to go drink I will just drink regardless of the situation.
    But yes I do seem to drink more than 'normal people', another thing that is striking and what others seem to have noticed aswell is that I do not use any salt at all on my food and never have really done so, this is odd as sodium can increase vasopressin, so im unsure wether im vasopressin deficient or not its very complex.

    Could it be that all these years I have been subconsiously avoiding salt/sodium in order to mimic some kind of similar effect that bumetanide induces?

    On a side note, my sodium and potassium seems to be pretty decent in check, the only thing that always stands out is the urea and the mildy elevated liver enzymes (had a liver check in the hospital few years ago and was fine):

    A few of my recent labs:

    https://ibb.co/jZRyMG

    https://ibb.co/nKZJMG

    ___

    Something that has also given me consistent results to keep anxiety in check is taurine, and to no surprise it is an osmolyte, I wonder how I would respond to something like glycerol which is used in pre-workout sports supplements to allow athletes to hold more water.

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  15. The paraventricular nucleus and the supraoptic area of the hypothalamus are the primary areas of the brain for both vasopressin and oxytocin release. The superchiasmatic nucleus which regulates circadian rhythms also expresses vasopressin. In the PVN and the SOA, oxytocin and vasopressin expressing neurons are essentially mixed together so that they usually fire together releasing both vasopressin and oxytocin at the same time. How one or the other neuropeptides get released in greater proportion is an avid area of research but much of this at the moment seems to be due to genetic programming of the neurons themselves so that they are biased to release more or less of oxytocin and vasopressin, such that you can't just stick an electrode in the PVN and selectively activate only oxytocin neurons relative to vasopressin neurons since they are right next to each other.

    Nevertheless, in the autistic brain some areas of the hypothalamus are hyperactive and in others you have reduced neuron counts. A hyperactive release of vasopressin and/or a hypoactive release of oxytocin can also be due to excitatory/inhibitory imbalances dealing with just glutamate and GABA signaling too, so improving inhibitory tone in the hypothalamus could cause more oxytocin release relation to vasopressin though various regions of the hypothalamus which connect to the PVN both have receptors for as well as ex press many different neurotransmitters, hormones, peptides, and other molecules such as sugars, fats, and amino acids.

    Last but not least, low vasopreson will encourage urination. Desmopressin is explicitly used to prevent bedwetting in adolescents. If you are urinating a lot and feel thirsty, it sounds like a yo yo effect with vasopressin which encourages thirst but also discourages urination until physical pressure sensations in the bladder encourage urination by other means.

    Getting thirst in the early evening is natural as the SCN starts releasing more vasopressin as melatonin levels rise. If this is exaggerated, and you get really thirsty, it could be a side effect of melatonin supplementation or else some other circadian disturbance.

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    1. Part 2:
      _______

      So far so good for me on CDP-Choline so far, I seem to be wittier, be able to find my words easier with far less effort and things seem to go more natural with less analyzing and anticipating of possibly stressfull situations.

      The ACTH boost I do not seem to notice, however the potential to raise TSH has cought my eye, I have been on levothyroxine (75mcg) for about 3 years and it has helped tremendously, the lowering of TSH from 5.5 -> 1.5 has made lots of difference in my daily functioning and I can definatly recommend parents to get their kids TSH checked, it is often elevated in ASD.


      Next on my list to try is Vardenafil:

      Vardenafil Enhances Oxytocin Expression in the Paraventricular Nucleus without Sexual Stimulation
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021811/

      What I liked about this study is that it seems to be dose and time dependant, in other words, the longer it is administrated, the stronger of an effect it seems to give.

      Now this study was not done on humans, but technically it should work and I will definatly try it myself in the future, the HED (human equivalent dose) corresponds to ~30mg daily for someone my weight (94kg).


      Probably a stack of multiple things will work best, such as adding inositol to the cdp-choline, however I am focussing on trying suppelements/compounds in isolation before moving to creating an efficient long term stack.

      Delete
  16. Hi Peter,

    Got a question for you regarding my urea levels and how to improve them, I have noticed huge benefits from citrulline and nadh (enada and other sublingual brands that are in blister packs), these all participate in the urea cycle and apparantly get rid of the excess ammonia/glutamate (im not very well informed about the particular process so correct me if im wrong on anything).

    However I benefit both from niagen and nadh supplementation with niagen definatly calming and helping tons with recovering from sore muscles/little pains and nadh giving me an energy booster.

    Would the addition of L-norvaline (arginase inhibitor) be a good or a bad thing in my case? It will no doubt lower my urea levels, but would this cause a buildup of ammonia in my liver/body?

    If it is potentially bad for me to add L-Norvaline to my routine could you give me any other recommendations to normalize my urea levels, as every NO-booster and lactate lowering supplement seems to help me tons (ie. glycine propionyl-l-carnitine and l-citrulline).

    ReplyDelete
    Replies
    1. Aspie 1983, your liver converts ammonia into urea and then urea leaves the body in urine. High levels of ammonia can be caused by the liver not producing urea as it should.

      L-Norvaline is an amino acid that is yet another way to affect nitric oxide (NO). Other than bodybuilders it has been suggested as a therapy for diabetics.

      Arginase is an enzyme needed to convert ammonia into urea. Too much arginase reduces NO production. Diabetics have too much arginase and hence reduced NO production. This causes some of the common comorbidities of diabetes.

      L-Norvaline will help produce more NO but has the potential to slow the conversion of ammonia to urea.

      L-citruline catalyzes the urea cycle enzymes and promotes optimal removal of ammonia.

      Sodium benzoate is an ammonia scavenger and appears to be a standard medical therapy, but can be also be achieved by eating cinnamon.

      I think you need to know whether your ammonia and urea levels are outside the standard references ranges. If they are outside then you need to establish why. There may be an underlying medical dysfunction, or it could be the supplements you are taking.

      Delete
    2. All my blood tests show high urea as posted in an earlier reply:

      https://ibb.co/jZRyMG

      https://ibb.co/nKZJMG

      Im having trouble interpreting if inhibiting arginase would be beneficial, without a doubt it will lower my high urea levels, but according to some studies nitrous waste/ammonia can build up like that, basically it seems like my urea levels are high cause my systems are working overtime to get rid of the excess ammonia reflecting in high urea levels.

      https://academic.oup.com/jb/article-abstract/86/3/745/2186218/Regulation-of-Urea-Synthesis-in-Rat

      "The same conclusion, that L-norvaline inhibits urea synthesis mainly through the inhibition of arginase, was also obtained in the in vivo experiment showing an increased ratio of the concentration of arginine to ornithine. The concentration of acetylglutamate was increased by the addition of L-norvaline both in the perfused liver and in the liver in vivo, probably as a result of secondary effects of the increase in arginine."

      No doubt it will lower my urea levels, but Im wondering if this would be bad or good in my case.

      Delete
    3. Aspie1983, your liver enzymes have become slightly elevated and you have low homocysteine and yet high vitamin B12.

      I would not assume you have high ammonia until you test it. If you have high ammonia I would see a doctor.

      I think you will likely respond well to L-Norvaline, because you respond well to L-citrulline, both increase NO. Using L-Norvaline is going to increase your natural production of L-citrulline. You could also increase NO by drinking 150ml a day of beetroot juice. Keep an eye on your blood pressure.

      If you have high ammonia then the OTC therapy clearly is cinnamon or sodium benzoate, which may also help for other reasons.

      Delete
    4. Hi Peter,

      My liver has always been slightly elevated or around the upper boundaries, this happens in alot of people with ASD/autism it seems: elevated CK, LDH, AST, ALT and urea (in some cases like mine).

      My high b12 levels were due to b-complex supplementation (they are always way too high dosed :S), yet they gave me some the energy to get things done they are very effective at it, but I have dropped them after getting my bloodtests, including dropping the vitamin d3 supplementation.

      https://ibb.co/nJ7kmG

      As you can see my B12 was double the upper limit and d3 nearly triple, im getting my B12 and d3 drawn this friday and results should be in shortly after the weekend, im pretty sure they have come down alot which is a good thing.

      As for beets, I eat them a couple times a week and I sometimes get the 'zonnatura brand' beetroot juice too.

      Citrulline has an happy, energizing, blood pressure lowering effect for me personally.
      I was pre-hypertension about 2-3 years ago and I got a healthy blood pressure now thanks to taurine and l-citrulline, but only as long as I take them.
      There had been times where I ran out of them for about 2 weeks and I could feel my blood pressure and anxiety creeping back up on me.

      With regards to the low homocysteine would this indicated that I have low methionine and low SAM-E?

      Ive tried SAM-E in the past from doses ranging from 400-1200mg but It didnt seem to have a strong effect on me, somewhat stabilizing so to speak but nothing profound, infact a common herb such as panax ginseng has had a better anti-depressant effect on me compared to SAM-E, im puzzled.

      Anyway when my wallet allows it, I will buy Norvaline and use it together with L-Citrulline, not sure about the ideal ratio to stack them but I will start off slow.

      It seems NO-boosters have a mood boosting effect on its own, by acting as an actual messenger system in the brain aswell.

      Delete
    5. Sorry I think I forgot to add the link to the 2nd lab page:

      https://ibb.co/nJ7kmG

      Delete
    6. Aspie1983, I rather assumed you were taking B12, that is why you have low homocysteine. If you are using NAC or ALA that would also reduce homocysteine.

      There are some NO boosting products that include several different amino acids and even beetroot powder, this might be simpler than buying them individually. I do not know about the cost.

      If you do not already use NAC or ALA, that should further improve your endothelial dysfunction.

      Delete
    7. Thanks Peter for your input, I indeed have NAC sustain and ALA sustain here at home, normally I take 600mg NAC sustain twice a day in between meals (so 1200mg daily), this should also keep my liver values somewhat in check.

      Is your son his blood pressure also somewhat elevated in comparison to other kids his age?

      Delete
    8. Aspie1983, his blood pressure is at the low end of normal, but many of his therapies do also have a blood pressure lowering effect. I think what matters is blood flow rate and endothelial dysfunction in autism is reducing this. Improved cerebral blood flow appears to improve autism of different origins, so it should be widely beneficial.

      Delete
    9. Oh I see, good to know that his blood pressure is nice.

      How do you feel your son handles the diuretic effect of bumetanide, Im not sure if I could handle it and could imagine it would cause some form of stress/anxiety in me.
      Is there an adaptability phase?

      Delete
    10. Aspie1983, in my son Bumetanide has never been a problem. He takes it in the morning one hour before leaving home, so he has plenty of time to visit the toilet. If you take it 10 minutes before you get on a crowded train with no WC, it would indeed be stressful.

      Other people with Asperger's are taking bumetanide and hundreds of thousands of Grandads/Grandmas take it daily.

      You just need to drink more fluid; my son drinks almost 1 litre before school. Plus you need extra potassium, so an extra banana a day and about 250mg of potassium per 1 mg of bumetanide.

      I think you will have no problems at all.

      Delete
  17. Peter, have you had a look at the relation of glaucoma (a biomarker that older relatives might have) and relevant pathways in autism? For example:

    Epigenetics and Signaling Pathways in Glaucoma (2017)
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292191/

    "Glaucoma is the most common cause of irreversible blindness worldwide. This neurodegenerative disease becomes more prevalent with aging, but predisposing genetic and environmental factors also contribute to increased risk. Emerging evidence now suggests that epigenetics may also be involved, which provides potential new therapeutic targets. These three factors work through several pathways, including TGF-β, MAP kinase, Rho kinase, BDNF, JNK, PI-3/Akt, PTEN, Bcl-2, Caspase, and Calcium-Calpain signaling. Together, these pathways result in the upregulation of proapoptotic gene expression, the downregulation of neuroprotective and prosurvival factors (..)
    Novel therapeutic agents targeting these pathway members have shown preliminary success in animal models and even human trials (..)
    Systemic diseases, such as hypertension or hypotension, hyperlipidemia, diabetes, obstructive sleep apnea, and thyroid disease, are sometimes considered risk factors for glaucoma, but this is controversial. Exercise, antioxidants, and a diet rich in omega-6 and omega-3 fat seem to lower IOP and thus decrease risk (..)
    Mice that fasted every other day were found to have increased retinal histone acetylation, which was accompanied by decreased retinal degeneration, increased visual function, and upregulation of Brain Derived Neurotrophic Factor (BDNF) and catalase"

    and

    Control of Intracellular Calcium Signaling as a Neuroprotective Strategy (2011)
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847496/
    "Glaucoma is characterized by increased intraocular
    pressure and leads to retinal cell death and blindness. Decreased blood flow of the glaucomatous eye indicates the neuronal damage may be similar to glutamatergic ischemic damage observed elsewhere in the CNS. The α2 adrenergic receptor has been found to decrease glutamate toxicity in the retina. NMDA receptors have been detected in the healthy retina and toxic concentrations of glutamate were found in the vitreous humor of the glaucomatous eye."

    /Ling

    ReplyDelete
    Replies
    1. Ling, I think you will find many things comorbid with autism, including glaucoma and indeed cancer. You just look at the affected pathways. If PTEN and BCL2 are involved just Google "Atorvastatin + the condition".

      The Relationship Between Statin Use and Open-Angle Glaucoma
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459293/

      Conclusion

      Statin use was associated with a significant reduction in the risk of OAG (Open-Angle Glaucoma) in persons with hyperlipidemia. Given the mounting evidence of statin protection against OAG including both basic science and observational clinical studies, an interventional prospective study might provide additional insights into the role of statins in the prevention of early OAG.

      Delete
  18. I have been using light therapy for an injury but then became curious about reducing inflammation in autism through NIR light therapy as well.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066074/
    Does anyone have thoughts about this as an effective tool in brain inflammation?
    Thanks
    Nancy

    ReplyDelete
    Replies
    1. Hi Nancy,

      I have been using my light therapy box (10.000lux) the past 3 years and I have found it does help with the SAD (seasonal affective disorder) type of symptoms such as low mood during the colder months, it is has an energizing and mood raising effect (it can raise hormones and neurotransmitters - http://www.latimes.com/science/sciencenow/la-sci-sn-bright-light-libido-20160919-snap-story.html) for me personally so I would strongly recommend it to only use it right after you (or your son?) wakes up. It can even benefit 'normal' people during the darker days.

      When I was painting my house 2 years ago in the early evening once for example I grapped the bright light device cause I did not have a portable light source close and you guessed what happened at night... I strongly regret it, I lay awake till like 5 or 6am because of it.

      On top of that some forms autism (atleast Aspergers, which is what I have) have a decreased cortisol awakening response. The light therapy seems to somewhat correct this, but only if I keep using the device, If I stop using it a few mornings during the winter I can tell the difference.

      30minutes at a distance of ~45cm every morning for me personally, but this highly depends on how advanced your box is, some more modern boxes you can sit way further away and still receive the necesarry 10.000 lux.

      This is mine:

      https://ibb.co/h6OTd6

      DaVita VitaBright 100, im sure theres newer and better models available now, the light sources inside the machine are still working after 3 winters of use.

      Delete
    2. I have a 10,000 lux light box as well and use it on my kids in the morning if they are groggy before school. On cloudy rainy days, they can be especially irritable without it sometimes.

      Delete
    3. Nancy, I have used NIR, rather IR, extensively. Search some of my older comments and you can get very specific instructions on what I use and where to purchase it. It helped my son quite a bit, but compliance became a problem as he got older since I had to do it while he was asleep. Young kids are basically unresponsive to being disturbed during Stage III and IV or the first sleep cycle of the night. My son eventually started sleeping on his side or belly which made doing this impossible.

      While I did it, it seemed to help quite a bit. I use it myself for other purposes which would take a long time to explain.

      Delete
  19. Hi Aspie1983, this is all very interesting. I am quite sure my asperger's adult son benefits from fish oil, too. How much fish oil do you use daily? I just use a regular 1gr fish oil supplement with 300mg omega 3, 180mg EPA, 120mg DHA and 4.5mg vitamin E once a day.
    He has low triglycerides, low LDL cholesterol, high serum uric acid, low vitamin d and extremely cold feet. I think I should add some cordyceps as you recommended and I am also trying to find the Russian drug Pantogam. Have you any experience with it?
    For your information I use sideritis herb tea and I believe something very good has happened to his cognitive flexibility. There is lots of promising research on sideritis mountain tea and Alzheimer's disease.
    Petra

    ReplyDelete
    Replies
    1. Hi Anon,

      Your son seems to have the same blood 'profile' as me, I used to have below the bottom range LDL aswell aswell as very low total cholesterol till I started increasing my fat intake and eating an egg every other day.
      I used to have low vitamin d levels aswell, I corrected this with supplementation but my levels were almost triple the uppper limit, so I have stopped using them for over 4months now and hopefully my levels have come down.
      On a side note, vitamin d3 supplementation did boost my mood substantially, not suprisingly as vitamin d regulates so much genes, including serotonin, dopamine and oxytocin expression.

      Out of curiosity, have you ever tested your sons Creatine Kinase (CK), ASAT, ALAT, gamma gt, Lactate dehydrogenase (LDH).
      Im 99% sure these are elvated aswell in your son as they are in me.

      I have just read briefly about Pantogam (Hopantenic acid) it seems it increases brain resistance to hypoxia and the effects of toxic substances, stimulates anabolic processes in neurons, has an anticonvulsant effect, reduces the excitability of the motor.
      It also seems to be a CNS-depressant.
      It is one of those exotic russian drugs that you dont hear much from.
      Seems its worth a try.

      Have you tried piracetam (used as a smartdrug/nootropic)? I have used this in the past 400mg but it seemed to send my brains cognitive function into overdrive (though I wasnt getting irritable on it at all) it is known to have an effect on AMPA/NMDA receptors, I think that the ratio of AMPA:NMDA is very crucial for what effect a drug exerts.
      Piracetam also improves the corpus callosum which is the 'highway' between the left and right brain side.

      Now cordyceps is a herb (but its actually considered a pathogenic funghi) used to increase stamina/longue function/kidney healing.

      The omega3 supplement I am currently taking is called Marinol Omega 3 and has 420mg epa and 300mg dha per dose (2 capsules), I take one capsule twice a day with a meal.

      I will read up on sideritis later I have never heard of it.

      Delete
  20. Hi Peter,

    Have you seen any results from trialing sodium benzoate?

    Thanks,

    Jolene

    ReplyDelete
  21. Jolene, everything is going very well at the moment, but I cannot really say the reason is sodium benzoate. I do intend to continue with it.

    ReplyDelete
  22. Hi Peter,
    A quick quest about your sodium benzoate supplement that you were going to trial. Have you been able to find it in capsules or tablets? I have only seen it in powder form and marketed as a preservative which makes me a little nervous using off label, it also potentially tricky to take in powder form. For now I have tracked down some 1200mg cinnamon tablets which wifl do to start with.
    Also, congratulations on your son’s brilliant academic results mentioned in a recent post - must make you so proud, to say the least.
    Cheers
    Teresa

    ReplyDelete
    Replies
    1. Teresa, it is very easy to use the powder form. You just need a tiny measuring scoop, which comes with some other products. It dissolves in any drink. Capsules would just contain the same powder with lots of bulking agents added.

      It is not a complicated chemical and because it is a food additive, it is made in large quantities.

      Cinnamon has more effects and ideally you would eat a teaspoon a day of Ceylon cinnamon, which is inexpensive.

      Delete
  23. Hi Peter, In that case I might stick with the cinnamon capsules and sneaking it in to his diet for now,
    Thanks
    Teresa

    ReplyDelete
  24. Hi Peter,
    Just wanted to report back that we have been very happy with the cinnamon. Always hard to know for sure if it is the cinnamon that is helping but I am certainly seeing improvements in focus, much quicker to get ready of a morning with less reminders, and also more socialising. So we will definitely be continuing with it, thanks for posting about it.
    Teresa

    ReplyDelete
    Replies
    1. Thanks for the update, it is a simple intervention and there are sound reasons why it might help.

      Delete
    2. For me a lot of this autism nonsense finally came to light in my early sixties when I discovered extensive food intolerances. Regarding the NaB: I would test for histamine intolerance first as it is associated with a lack of gut produced diamine oxidase, the chemical that helps handle the large amounts of histamine produced during the digestion of cinnamon (and sounds chemically similar to what is mentioned above as being depleted by NaB. I myself have experienced some decrease in dehydration and excessive urination as the histamine intolerance issue decreases, but I have found a far greater connection with oxalate intolerance. I should also state that while both food intolerances and methylation defects worsen with age, I have no doubt that I have had such things for life...for half of which I've been on disability. Also I heard that there is an autism gene related to the inability to properly digest histamine. Please keep this in mind as you proceed as it sounds like NaB might do the same thing, but slowly over time. Look for increasing allergies, skin problems and frankly dysfunction of pretty much anything in most any organ system. It may still be good for initial brain building but pay special attention to reactions to high histamine foods. Good luck.

      Delete

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