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Wednesday, 10 October 2018

Ketone Therapy in Autism (Summary of Parts 1-6)




Open the above file via Google Drive, so it is big enough to read. Click the link below. You can also take links from it to the relevant blog post.

https://drive.google.com/file/d/1Jl_JMUrX7suXz0n_yJPCLPinrvdddBhI/view?usp=sharing

In the mini series of posts on ketones and autism we have come across a long list of effects that will benefit certain groups of people.



1.     Change in gut Bacteria


2.     Ketones as a brain fuel    


3.     Niacin Receptor HCA2/ GPR109A

4.     NAD sparing

5.     CtBP Activation by reducing NADH/NAD+ ratio

6.     NLRP3 Inflammasome inhibition

7.     Class 1 HDAC inhibition

8.     Increase BDNF

9.     Ramification of Microglia

10.PKA activation

11.PPAR gamma activation
It was interesting that the beneficial effect of the Ketogenic Diet in epilepsy is driven by changes the high fat diet makes to the bacteria in your gut and seems to have nothing really to do with ketones. Well it took a hundred years to figure that one out.
In the case of Alzheimer’s, you can see that more than one effect is potentially beneficial. People with Alzheimer’s do have low glucose uptake to the brain, but they also have elevated inflammatory cytokine IL-1B.
In Huntington’s it is the HDAC inhibition effect that seems to be what helps.  This brings us back to HDAC inhibition as a potentially transformative therapy with long lasting effects. It appears that the small number of people who achieve long lasting benefit from short term use of sulforaphane or EGCG may have experienced HDAC inhibition changing the expression of up to 200 genes.  In the case of sulforaphane from broccoli, some people have gut bacteria that produces large amounts of the enzyme myrosinase, which means they convert very much more of the glucoraphanin in broccoli to sulforaphane (an HDAC inhibitor).
It does look like a low dose of a potent HDAC inhibiting cancer drug is what is needed by certain single gene autisms and perhaps some idiopathic autism. This was covered in a dedicated post where we saw the long-lasting benefit of short-term use of Romidepsin. Vorinostat, a very similar drug, but which is taken orally, should be trialled in Shank 3, Pitt Hopkins and Kabuki, to see if the same transformative long-lasting effect can be reproduced.
In Multiple Sclerosis (MS) the effect on Niacin receptor HCA2/GPR109A should help a lot, but so should PKA activation.
In mitochondrial disease it was suggested that increased ketosis will help conserve NAD, which may be deficient. Also, using ketones as an alternative brain fuel may bypass problems that occur when glucose is supposed to be the fuel and thereby boost brain function. The most important effect is likely to be activation of PPAR gamma by C10, which increases the number of mitochondria and boosts the enzyme complex 1.
Many of the people with autism and an overactive immune system stand to benefit from activating CtBP, inhibiting the NLRP3 inflammasome, or activating HCA2/GPR109A.
I think there should be clinical trials using a potent HCA2 activator in autism comorbid with immune over-activation. 
We can see that some people who respond to BHB, experience an immune rebound on cessation, so this helps narrow down the likely beneficial mode of action.  In this immune sub-group, the idea to using other activators of HCA2/GPR109A would seem worthwhile. 

PPAR gamma activation should help those with mitochondrial dysfunction, but this effect is produced only by C10, not BHB or C8. For C10 you eat a ketogenic diet or add it as a supplement (e.g. cheaper MCT oil, or coconut oil).

As recently highlighted by our reader Agnieszka, perhaps the fever effect in autism can be explained by short-term ketosis. Fever is known to sometimes raise the level of ketones, particularly in children (it is called non-diabetic ketosis).  So if your child's autism improves during, or just after fever, test the level of ketones in their urine.


Conclusion

We may have shown the benefits of a high fat ketogenic diet, but there are very many different fats and they do not all produce the same effects.

There are many saturated fatty acids, they are numbered based on how many Carbon atoms they have.

So, C8, known as Caprylic acid has the formula  C8H16O2

Eating C8 looks to be a great way to increase the level of ketones in your blood.

Eating C10 should be good for people with mitochondrial dysfunction and people with diabetes.

Your food contains many other saturated fatty acids and your gut bacteria produce even more.


Common Name Systematic Name Structural Formula Lipid Numbers
Propionic acid Propanoic acid CH3CH2COOH C3:0
Butyric acid Butanoic acid CH3(CH2)2COOH C4:0
Valeric acid Pentanoic acid CH3(CH2)3COOH C5:0
Caproic acid Hexanoic acid CH3(CH2)4COOH C6:0
Enanthic acid Heptanoic acid CH3(CH2)5COOH C7:0
Caprylic acid Octanoic acid CH3(CH2)6COOH C8:0
Pelargonic acid Nonanoic acid CH3(CH2)7COOH C9:0
Capric acid Decanoic acid CH3(CH2)8COOH C10:0
Undecylic acid Undecanoic acid CH3(CH2)9COOH C11:0
Lauric acid Dodecanoic acid CH3(CH2)10COOH C12:0
Tridecylic acid Tridecanoic acid CH3(CH2)11COOH C13:0
Myristic acid Tetradecanoic acid CH3(CH2)12COOH C14:0
Pentadecylic acid Pentadecanoic acid CH3(CH2)13COOH C15:0
Palmitic acid Hexadecanoic acid CH3(CH2)14COOH C16:0
Margaric acid Heptadecanoic acid CH3(CH2)15COOH C17:0
Stearic acid Octadecanoic acid CH3(CH2)16COOH C18:0
Nonadecylic acid Nonadecanoic acid CH3(CH2)17COOH C19:0
Arachidic acid Eicosanoic acid CH3(CH2)18COOH C20:0

C4, familiar as Butyric acid, helps maintain the integrity of the intestinal barrier and the blood brain barrier.  Butyric acid, or butyrate, is also an HDAC inhibitor and it seems that in animal models, and some humans, a small amount can be beneficial but large amounts can have a negative effect. A small amount in humans seems to be about 500 mg a day.  There are earlier posts is this blog on butyrate.

C3, familiar as Propionic acid, is bad for you and too much propionic acid will by itself cause autistic behaviours. NAC counters the effect of propionic acid in mouse models.

All those people eating coconut oil are consuming a 99% mixture of fatty acids with 1% phytosterols.

Phytosterols like β-SitosterolStigmasterolAvenasterol and Campesterol likely explain why coconut oil actually reduces "bad" cholesterol, rather than increasing it, as predicted by the American Heart Association and others. This counters the negative effect of the Palmitic acid (C16).

Lauric acid (C12) is thought to increase HDL ("good") cholesterol and may have a beneficial effect on acne.

Myristic acid (C14) is also thought to increase HDL ("good") cholesterol.

Palmitic acid (C16) raises LDL ("bad") cholesterol and large amounts have other negative effects.

Oleic acid is also found in olive oil and is seen as a fat with beneficial effects.



Fatty acid content of coconut oil
Type of fatty acid pct
Caprylic saturated C8
7%
Decanoic saturated C10
8%
Lauric saturated C12
48%
Myristic saturated C14
16%
Palmitic saturated C16
9.5%
Oleic monounsaturated C18:1
6.5%
Other
5%
black: Saturated; grey: Monounsaturated; blue: Polyunsaturated


So the only "bad" part of coconut oil is the Palmitic acid (C16).

As for MCT oil, what is in that?


In pharmaceutical MCT oil, like the one sold by Nestle, the contents are:-


Shorter than C8      1%
C8 (Octanoic)      54%
C10 (Decanoic)   41%
Longer than C10    4%

What is the effect of those fatty acids with more than 10 carbon atoms?  Nobody likely knows.



Cooking with MCT Oil? 

This is what Nestle has in mind for dinner.


Mct Spaghetti With Meat Sauce






4 Tbsp. MCT Oil® (Medium Chain Triglycerides)
1 lb. very lean ground veal or beef
1 tsp. salt
1/2 tsp. pepper
1/4 cup chopped onion
3 Tbsp. chopped green pepper
1 cup MCT Tomato Sauce (see recipe on site)
2 cups cooked spaghetti

Heat MCT Oil; add veal, salt and pepper.
Cook until meat is brown.
Add onion, green pepper, and tomato sauce. Cook for 30 minutes over low heat.
Add cooked spaghetti, stir and serve.





62 comments:

  1. Great summary, thanks Peter!
    Started yesterday with the C8 oil (didn't receive the BHB yet). Will keep the board posted on the results.
    Interesting comment about the fever effect. Reason we are trying the C8/BHB is that we did the ketogenic diet some years ago (actually it was SCD), and the improvements were huge (especially the hyperactivity was way down). But after a year and a half we couldn't do it anymore, and as soon as we went back to a normal diet the hyperactivity/stinking/etc... went back up. So we are looking forward to seeing if the C8/BHB will bring us similar results. Thanks a lot again.

    ReplyDelete
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    1. After 10 days on the C8 (just started BHB in addition 3 days ago), I can report that we're seeing positive results in both kids, even the school noticed something and wrote it down in their daily report. I will keep sharing if we're seeing more improvement with the BHB.

      On a side note, we've just been contacted to participate in the "international" bumetanide study... I live in the Spanish Basque country, and they say there will be 400 kids in the study, half from 2-7 years old and half from 7-18. They will choose 12 kids from where I live. They say the study will last a year. I will keep you posted in case we've been included in the study.

      Delete
    2. Congratulations DR both to the advancements and the possibility to participate in a study. Do you know when the trial is supposed to start?
      Also, thank you for sharing your endeavours with the community. It would be very interesting to see yet another comparison of C8/BHB to Bumetanide.

      /Ling

      Delete
    3. DR, thanks for posting your results. What dose of C8 are you using? Feedback from school is one of the most objectives measures you can use. When they notice a change it cannot be the parental placebo effect.

      Delete
    4. We started slow, right now we are at 5ml a day of C8 and about 1800mg of BHB. The positive effects are seen with the youngest (5 y.o.), the big brother (8 y.o.) we haven't seen positive results yet. I plan increase the C8 to 10ml this week.

      Delete
    5. @Ling: thanks. No idea at the moment when the trial is supposed to start. I will try to get more information and keep you updated.

      Delete
    6. @Ling: Hi, I have more info about the bumetanide trial. It's supposed to start next month, selection process will last 4 weeks, then 52 weeks trial (they have already started in some places like Madrid and Barcelona). The fist 6 months will be randomized, double-blind, placebo controlled, while the last 6 months everyone will get the bumetanide. The dose will be 0.5mg twice a day (1mg per day). They came up with this dosage from phase 2, almost no one developed adverse secondary effects at 0.5 twice a day. There will be lots of checkups, blood tests, ECG, renal ultrasounds etc...
      Commercialization is planned for 2023... The bumetanide comes in a liquid form.
      They won't permit two siblings to participate at the same time, only one (they explain they were afraid of meds swapping).
      That's all I know for the moment...

      Delete
    7. Hi DR and big thanks for that update!
      Your experience will be very interesting for many of the readers of this blog, if you want to share it. :-)
      Did you get to know which one of your children that will get into the trial? And did you find any dose of BHB/C8 that have worked for big brother too?

      All my best wishes on this journey,

      /Ling

      Delete
  2. Obviously meant "stimming" not "stinking" :/

    ReplyDelete
  3. Here is another idea for an intervention that is cheap, almost certainly safe, and based upon some new research which shows that the amino acid L-Alanine changes glucose metabolism in a manner similar to metformin by activating AMPK:

    Press Release:

    https://www.sciencedaily.com/releases/2018/10/181010144438.htm

    Paper:

    https://www.sciencedirect.com/science/article/pii/S2212877818307889?via%3Dihub

    A quick search on Google of this site for AMPK turns up many, many search results so I won't go into all of them, but it is thought in many autisms AMPK activation can improve autism symptoms. Here are a few I dug up pretty fast:

    AMPK from exercise improves symptoms in autistic children

    https://www.omicsonline.org/open-access/the-increase-of-ampactivated-protein-kinase-during-physical-activitiescan-reduce-symptoms-of-autistic-children-PNN-1000102.pdf


    AMPK inhibits mTOR

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813866/


    The Naviaux study which shows suramin therapy increased blood levels of AICAR which activates AMPK.

    https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.424


    The original study with L-Alanine was done on rats, however, it did show that oral L-Alanine supplementation raised blood levels of L-Alanine which is obviously necessary for it to be therapeutically useful today as injecting L-Alanine is both impractical and would take time to study in humans as to its safety just as megadoses of B-12 are safe to take orally because B-12 is poorly metabolized, but if injected you can do serious nerve damage with the wrong dose.

    Also, in autism and with respect to the recent topics, glucose issues in autism would obviously benefit from exogenous ketones or the ketogenic diet, but perhaps L-Alanine could be of significant benefit to those not on a ketogenic diet, especially with respect to its apparent mTOR inhibition.

    ReplyDelete
    Replies
    1. To follow up on this research as well as the recent blog posts on the ketogenic diet, here is some new research showing benefits of the ketogenic diet in helping to prevent cognitive decline in aging mice:

      Press Release:

      https://www.sciencedaily.com/releases/2018/10/181012092949.htm

      Paper:

      https://www.frontiersin.org/articles/10.3389/fnagi.2018.00225/full

      The takeaway here is that it is shown that the primary cognitive benefits of a ketogenic diet, at least with respect to two mouse models of brain aging and Alzheimer's disease, are due to mTOR inhibition brought about by the ketogenic diet and the effects mTOR inhibition have on increased cerebral blood flow.

      Even though this study has nothing to do with autism directly, mTOR hyperactivation in autism is kind of becoming a theme now in a lot of research so anything to reduce it may improve symptoms which may be useful as a ketogenic diet is hard to maintain compliance on, and there is some concern that from recent evidence that if the ketogenic diet is high in palmitic acid (saturated fat), that the risk of cardiovascular disease increases greatly. This means that the best ketogenic diet is going to need to be very high in unsaturated fats, such as foods high polyunsaturated fats which are generally not as palatable as eating bacon and eggs.

      Delete
    2. Thanks for highlighting that Tyler, Ive always been skeptical about long term effects of keto diets, especially with regards to benefits:side effect ratio.
      I like the idea of certain recipies such as the spagetti posted above.

      As an adult with ASD/aspergers myself its easy to get over the fact that healthy food doesnt always taste the best, for example I take daily on average 1-2 full tablespoons of oliveoil and wash it down with a bit of water, as cooking the oil some of the healthy ingredients is lost.

      I can see this being problematic for kids with autism who are often very picky eaters.

      Delete
  4. Here is a kind of far out there theory on how valproate might help induce autism based on some new research which accidentally discovered a method of converting GABAergic striatal neurons into dopaminergic neurons:

    Press Release:

    https://www.sciencedaily.com/releases/2018/10/181011112421.htm

    Paper:

    https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(18)30389-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2213671118303898%3Fshowall%3Dtrue

    The original goal of the research was to induce glial cells into being epigenetically reprogrammed into striatal dopamine neurons. However, what the researchers discovered was that nothing happened to the glial cells, rather some of the GABAergic striatal neurons changed into dopaminergic via the use of three transcriptional regulators plus valproic acid.

    Now, one very interesting thing is that in the striatum there seems to be a deficit of GABAergic transmission and an excess of extracellular dopamine floating around. Why is this the case? Well there are many theories, but this research suggests that the ratio of GABAergic expressing cells (95% of the striatum in a healthy human), could be shifted in a human exposed to valproate during pregnancy via excessive dopamine expressing neurons.

    The other interesting thing about this research with respect to autism is that it suggests that it may be true that no neuron is in a permanent finalized state, rather they could be induced to change into a completely different neuron if the right transcription factors, plus a series of HDAC inhibitors such as valproate.

    All of this I stress is just an idea I thought about and has no real research to directly back it up via showing how valproate exposure could cause various brain cells to be reprogrammed into different types of brain cells in numbers undesirable for healthy neural development. Nevertheless, it also suggests therapeutic hope for literally changing to brain cell composition of the brain when certain developmental windows have already closed naturally.

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    Replies
    1. Tyler, I contacted a researcher in regards to Valproate and epigenetic reprogramming of striatal dopamine neurons. I believe that somehow the use of Depakote along with other neurologic insults amplified my son's autism condition. I cannot say who the researcher is to protect privacy but I believe that these shifts can occur with Depakote use during development when there are other areas of the histological and neurodevelopmental regions of the enteric system with damage and brain damage from glial activation. Valproate and Depakote also have an effect in the microbiome. These microbial effects, hepatic load- endotoxic effects, and epigenetic effects are of extreme importance in the decision making process of prescribing therapies; however, I realize this is not a priority in current practice.

      I do not understand why ADHD amphetamines are discussed with me at appointments. I do not understand how they would be effective when there is a complex multi factorial process going on that needs to be understood. I realize that the use of these amphetamines will only create more problems and I don't understand where these doctors heads are sometimes.

      Delete
  5. The amount of spam and ads that get posted is getting a bit out of hands and its starting to annoy me.
    Peter is there any way you can go back to the old posting system, where a post would be checked before published?

    ReplyDelete
    Replies
    1. Most spam is on the older posts, so I have made comments on posts older than 14 days subject to moderation. If you have too much moderation on posts, you get less comments, because people expect to see their comment published immediately.

      Delete
  6. Hi Peter and all,
    My boy (18) is autistic and struggles against hypoglycemia. At first, I thought that MCT would be good for him, but I think that it has worsened the hypoglycemia. Do you have any thoughts, please ?

    ReplyDelete
    Replies
    1. Luis, non diabetic hypoglycaemia has various possible causes, some of which are relevant to autism. Have you established with your doctor/endocrinologist the cause of the hypoglycaemia?

      Via its effect on PPAR gamma there will be an effect from MCT oil. It may be that MCT oil is not a good choice for your son.

      You could try BHB and see if that gives a benefit, without any negative effects.

      Delete
    2. Hi Luis,
      Some people get little or no symptoms from low glucose levels, it seems to be related to how well adapted the body is to using fatty acids and/or ketones. See e.g. http://high-fat-nutrition.blogspot.com/search/label/HbA1c%3A%20Low%20glucose%20and%20acid%20%28palmitic%29
      (The comments are interesting.)
      I guess if alternative fuels can be used, then the low glucose levels may be less of a problem.
      Aspie2

      Delete
  7. Hello Peter and all,

    This is un tio. I have a question which has nothing to do with this post but I will use this section to do it:

    does anybody give paracetamol to his autist son or daughter, and check if autism goes worse or better?

    I'm not saying anybody should try, I'm just asking if anybody did try for any reason (for example fever) and could see any change.

    Thanks,

    Regards,

    Un tio

    ReplyDelete
    Replies
    1. Un tio, I cannot say about paracetamol, but NSAIDS like ibuprofen do seem to improve some people's autism.

      Paracetamol depletes GSH, so in theory should worsen autism.

      Delete
  8. Here is some very interesting research on brain development consequences from Caesarian section, and in particular a reduction of vasopressin expressing cells in the hypothalamus:

    Press Release:

    https://www.sciencedaily.com/releases/2018/10/181015152908.htm

    Paper:

    http://www.pnas.org/content/early/2018/10/09/1811962115

    Many factors associated with autism such as age of the mother, obesity, and gestational diabetes are also associated with Caesarian delivery, but vasopressin issues seem to be associated as well. The brain has two separate nuclei in each hemisphere which secrete vasopressin. One is the paraventricular nucleus in which in this study there was a reduction in vasopressin expressing cells in mice delivered by caesarean section, and the other is the supraoptic nucleus which was not look at in this study.

    Also, even though the PVN had the greatest increase in cell death among brain regions investigated, many other primary subcortical regions involved in stress regulation had increased rates of cell death as well, many of which express CRH which drives the HPA axis.

    It is also worth noting that if there is a reduction in vasopressin levels in the brain shortly after birth, vasopressin receptors may not be regulated to the appropriate number. In addition, caesarean section born mice also have reduced distress ultrasonic call amplitude as well which in effect means they are less interested in their mother's attention and this feature was more biased in males than females.

    Last but not least, the oxytocin mediated exitatory to inhibitory GABAergic switch (the reason for Bumetanide therapy) is speculated upon with respect to the decline in vasopressin as the oxytocin and vasopressin peptides are very similar and more or less are co-released in the same areas of the hypothalamus.

    ReplyDelete
  9. This comment has been removed by the author.

    ReplyDelete
  10. Peter, in your research, did you find that males vs. females would be better responders to keto and these treatments. One of my four children has some mood issues and lack of interest in things, and I am wondering if one of these treatments would naturally give her a little more energy and positivity :)

    ReplyDelete
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    1. I have no reason to think being male/female affects the response. It appears that many people respond, but the extent of that response varies.

      It looks like one effect of BHB is on mood and not just on people with ASD.

      Delete
    2. Thanks Peter. Yes, that is what I thought. I have a keto which says a proprietary blend (whatever that means!) of 800 mg (2 capsules) of magnesium beta hydroxybutyrate, calcium beta hydroxybutyrate, sodium beta hydroxybutyrate. How much should someone take? Does this sound like an efficacious dosage? Do you know and is there a brand that is better(I don't think you would know this but checking anyway). Is your son taking BHB and if so how have been the results?

      Delete
    3. 5,000 mg of BHB has a positive effect in my son's case. It promotes speech and also seems to improve cognition. Ketoforce seems to work well. It is not cheap at this dosage.

      Delete
  11. Hi Peter,

    Hope all is well!

    Peter, we continue to see the improvement in our daughter with the C8 and BHB (I also added some MCT due to C10 and the mito results we had received from Dr. G) in the areas of speech mainly and I believe cognition as well. It’s a sustained improvement at this point, which is great news, so a big thank you to you for your Keto series. I can honestly say that all of the interventions we’ve tried thus far, this is by the far the most effective one yet.

    I do have a question for you about BHB – I’ve been using about 250 - 300mgs of BHB (excluding the Sodium/Calcium/Magnesium) X 2 / day so getting about 500 - 600mgs per day of BHB, and have been wanting to titrate up given that we are seeing real benefits and wondering if they are dose dependent. I’ve been looking for anything that tells me about upper limits for BHB use but haven’t seen anything. Other than the sodium content (about 9% of the Keto blend I’m using, so I’m using about 54mgs per day now at the current dosage split into 2), have you seen anything in your research about upper limits of BHB (ideally in mgs / kg, but anything is fine, even in animal models) or is the BHB considered GRAS and no real upper limits are relevant other than the sodium?

    I’m hoping to maximize the clear benefits we’re already seeing, assuming the effect is dose dependent, while steering clear of any side effects. I want to continue to titrate up slowly, but if there is a known reasonable upper threshold, it would be good to know. As you know, my daughter is tall and thin, weighing in at 42 pounds.

    Thanks in advance for any insights Peter!

    AJ

    ReplyDelete
    Replies
    1. AJ, at vastly higher levels of BHB you can arrive at ketoacidosis, but your level of BHB is still far below the level of people on a ketogenic diet or that in babies fed only on their mother's milk.

      There is a chart that is widely used:

      https://aviewtoyourhealth.wordpress.com/2016/06/23/weight-loss-and-more/optimal-ketosis-range-2/

      You are way over to the left. If you are concerned you can buy ketone testing strips for urine.

      The limiting factor with BHB supplements is changes to electrolyte level. So a blood test of K, Na, Mg Ca etc would show any problem.

      Delete
  12. Hi Peter,

    Thanks so much for the information! I'll titrate up a little more and let everyone know if I continue to see a dose dependent improvement. If we continue to improvement at higher levels, wow, will this have been a great intervention.

    As always, much appreciated Peter!

    AJ

    ReplyDelete
    Replies
    1. Hi Peter,

      We finally got the ketone test strips today, did our first test, and you were exactly right. We are way off on the left side of the chart you had shown, which makes the positive effect we've seen that much more interesting since it's a noticeable positive impact at what is effectively a low dose.

      I'm titrating up a bit more and will keep everyone posted, but the effect is hard to discount as a coincidence, and if the effect is dose dependent with more room for improvement, this could be a very exciting finding for us indeed.

      Thanks again Peter, and I'll keep you posted on what we see with the increased dosage (I'm titrating slowly and will do the test strips regularly to find the right dosage).

      Have a great evening Peter!

      AJ

      Delete
  13. In a way, isn’t it very intuitive that immature neurons (where GABA switch never happened) benefit from a diet or supplements that mimic energy supply for babies?
    I wonder if the buttermilk/MFGM subject somehow is related too.

    /Ling

    ReplyDelete
  14. In a way, isn't it very intuitive that immature neurons (where GABA switch never happened) benefit from a diet or supplements that mimic the energy supply/metabolism in babies?
    I know the research shows it is much more complicated, but I can't help thinking that maybe also the whole MFGM/buttermilk subject could be related.

    /Ling

    ReplyDelete
  15. For those who use ketogenic diets:

    Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic
    Relationship Between Metabolism and Brain Activity
    http://pages.ucsd.edu/~mboyle/COGS163/pdf-files/Adenosine,%20Ketogenic%20Diet%20and%20Epilepsy%20The%20Emerging%20Therapeutic%20Relationship%20Between%20Metabolism%20and%20Brain%20Activity.pdf

    Adenosine A1 and A3 also seem to influence SERT activity and can thus control the amount of serotonin in the brain.
    Theres quite some papers on this, including polymorphism of A2A and A3 in autism.

    ReplyDelete
  16. Forgot to add this:

    Adenosine A2A receptor modulates neuroimmune function through Th17/retinoid-related orphan receptor gamma t (RORγt) signaling in a BTBR T+ Itpr3tf/J mouse model of autism.
    https://www.ncbi.nlm.nih.gov/pubmed/28438638

    Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome.
    https://www.ncbi.nlm.nih.gov/pubmed/23953133

    Lipopolysaccharide-induced serotonin transporter up-regulation involves PKG-I and p38MAPK activation partially through A3 adenosine receptor.
    https://www.ncbi.nlm.nih.gov/pubmed/26781794

    Rapid stimulation of presynaptic serotonin transport by A(3) adenosine receptors.
    https://www.ncbi.nlm.nih.gov/pubmed/17460150
    "Whether A3ARs regulate SERT in the central nervous system (CNS) is unknown. Here we report that the A3AR agonist N6-(3-iodobenzyl)-N-methyl-5′carbamoyladenosine (IB-MECA) -->>RAPIDLY (10 min) and selectively stimulates 5-HT transport in mouse midbrain, hippocampal, and cortical synaptosomes." <<-- remember when I said I can feel cordyceps literally soon as it hits my gut (cordycepin has extremely fast absorption in the gut and being an agonist at A3 it makes sense, it rapidly lowers my brain serotonin... but the problem with cordycepin is that it has a very poor halflife).

    Also sildenafil (viagra), was shown to increase brain oxytocin before, aswell as increase SERT, this effect is dependant upon PKG stimulation and is the same pathway that adenosine A3 follows to increase SERT transcription:

    Stimulation of serotonin transport by the cyclic GMP phosphodiesterase-5 inhibitor sildenafil.
    https://www.ncbi.nlm.nih.gov/pubmed/15507214

    I truely wonder why adenosine agonists are not use in ASD and autism yet, quite shocking actually. I respond well to cordyceps (obviously contains cordycepin and adenosine and cordycepin has been shown to stimulate A1, A2A, A2B and A3 receptors).

    Also besides having 2 short serotonin alleles (23andme confirmed on SLC6A4), 1 ADORA2A snp mutation (23andme confirmed and autism study related), 1 ADHD ADORA2A snp mutation (23andme confirmed and adhd study related), 5HT2AR snp mutation linked to crohn's/arthritis and have elevated urea.

    A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release.
    https://www.ncbi.nlm.nih.gov/pubmed/22146575

    The A3 adenosine receptor (A3AR): therapeutic target and predictive biological marker in rheumatoid arthritis.
    https://www.ncbi.nlm.nih.gov/pubmed/26886128

    Seems that the circle is complete and it might also explain my urea problems, from what I have read on a bunch of studies about urea is that it seems to compete with adenosine receptor binding. High urea = high serotonin in my case without a doubt, probably by some of snp mutations, crappy adenosine a3 ligand binding = low serotonin transporter expression = high serotonin.

    If anyone knows of some med/supplement other than cordyceps that acts as a PAM/agonist at adenosine a3 receptors please let me know as you would help me A LOT.

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    1. Aspie1983, very interesting and reminded me also about this:

      "Adenosine 2A receptors (A2ARs) are typically activated by adenosine but can also be activated by various A2AR-selective agonists. A2ARs are found on both glial cells and neurons and activation following inflammation has been shown to increase IL-10 and decrease proinflammatory molecules released from a variety of different inflammatory cell types in culture"

      http://www.ncbi.nlm.nih.gov/pubmed/25446571
      "The therapeutic potential of interleukin-10 in neuroimmune diseases."

      Decreased IL-10 expression was found to be associated with a sub-type of ASD.

      Could you share what cordyceps brand do you use? Perhaps you wrote it before, but I can't find now.

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    2. Real mushrooms cordyceps militaris I normally use, and has more of a calming/mellow effect on me, similar to how damiana somewhat feels (though damiana is somewhat more for at end of the day, interesting btw that damiana is classed a phytoprogesten, one of the only that does so without being a phytoestrogen it seems and progesterone itself is a powerfull ADA inhibitor - this breaks down adenosine normally).
      Im very sure that topical progesterone will make me feel very good but I dont want to go the hormonal route.

      Currently Im using a local brand corydceps (vitaminesperpost which is a dutch vendor), this has a lot higher cordycepin and cordycepicacid ratio, this seems to do less for an uplifting mood so to speak but has more of CNS relaxation effect on me and also seems to improve my sleep this extract.
      Oh yeah nearly forgot to add, the effect that the local brand cordyceps militaris extract on me with regards to anxiety is very unique, it feels like everything within a 6-7 ft radius of me is important, where as everything outside the radius feels like "oh well when I bump into that I will see what happens/take care of it". Very unique feeling, wouldnt necesarry call it an antidepressant effect it more feels like it has a very powerfull effect on information filtering, something that SSRI's were never able to take care of for me, they just dull everything.

      With regards to TNF-alpha/IL-1B/IL6/IL10/IL17a/IL23a yep. Everything that raises IL10 helps me and everything that lowers tnf-a,il-1b, il-6, il-17a, il-23.

      I talked to my psych btw hes agreed to let me try donepezil soon (2-3 weeks when he gets back from holiday), hope I respond to it. Cholinergics have been weird for me, I respond bad to galantamine, yet positive to cdp-choline and VERY POSITIVE to alpha-gpc, but alpha-gpc gives me bad side effects such as crazy acne.

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    3. Btw I think the whole reason that these agenosine analogues and progesterone raising herbs work for me because the net end result seems to be A3 activation and this will induce SERT expression and rapidly lower my brain serotonin thus temporarily annihilate my apathy. Till ofcourse I eat... (this is something I have always noticed, if im a very good mood due to a supplement, soon as I eat I know its game over)... because eating carbs/eating in general activates tryptophan hydroxylase and dumps serotonin in the brain and the circle is complete again :S.

      Agnieszka have you done a 23andme test yet? this reveals SO MUCH info, it has confirmed all my suspicions and has helped me narrow down incredibly what meds/supps are for me and which are not.

      OXTR mutation A:G, comt warrior gene (low dopamine) 2 short SERT alleles (basically my brain is 24/7 on an SSRI without even taking an SSRI which is still often infuriating to me considering my parents/psychs had given me SSRI's for about 10 years of my life), 2 adenosine mutations, 5ht2ar polymorphism associated with gout/arthritis/crohn's. Its almost scary so accurate is 23andme.

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    4. Maybe limonene is something that I could respond to aswell:

      Limonene, a natural cyclic terpene, is an agonistic ligand for adenosine A(2A) receptors.
      https://www.ncbi.nlm.nih.gov/pubmed/21134357

      This is highly present in citrus fruits (remember my orange juice cravings?).
      Orange juice seems to have about everything my brain/body needs:
      vitamin c for oxytocin synthesis, myo-inositol for anti-ocd/relaxing properties, nobiletin also (recently I talked about this how nobiletin is very powerfull according to studies in synchronizing circadian rhythm through per2 and bmal1), calcium-d-gluconate (I seem to have estrogen dominance and cal-d-gluc increases estrogen metabolism to dispose of it) and also limonene it contains.

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    5. Thanks Aspie1983.

      Interestingly, if I was to point out the most important BHB effect on me it would be about information filtering in a way you described it.

      I haven't done 23andme, but all my family was tested as a part of my son's WES. It is not the same, but I can have access to raw data as well. For me it is somewhat overwhelming, but I am happy to hear you found it helpful.

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    6. Aspie1983,

      I have been very interested in plant terpenes. I am trying to find terpenes that might stimulate the CB1 receptor in the endocannabinoid system. Perrottetinenic acid in Liverwort seems to stimulate the CB1 receptor. I was thinking of looking into theobroma cocoa r/t anandamide. I live in a place where it is very expensive to obtain Medical Marijuanna. All I really need are some leaves but instead I am trying to stimulate CB1 with terpenes aside from Marijuanna. Charlottes Web and Keto diet are helpful but I am thinking that CB1 stimulation from microdosing THCa is going to help with behavior and improved seizure control. We recently moved and the everything in this biome is new. The pollens, the insects, the seasons. So if you can imagine the mast cell activation, etc. Then I ran into a phenol problem. I was using quercetin and I over did it with phenol rich foods on top of the polyphenol quercetin and he had a seizure from too many phenols. Usually his ears turn cherry red when he has too many phenols- while it was a mild seizure where he was able to walk and respond partially it was still frustrating because I did not realize that the quercetin I was using for the mast cells was a polyphenol so I could have avoided a lot of the phenol rich foods I used for the day. He is also on a keto diet which has been helpful.

      There has to be other terpenes though that might help. I find on the keto diet that occasional chocolates that I make really seem to improve things. I make them with cocoa butter (stearic acid), cocoa, and a very small amount of agave. I suppose I could use a different sweetener.

      So lets say you want to find ways to increase Vagal tone to really help the Brain-Gut axis and you have a child that has difficulty with the exercises to increase Vagal tone is there another methodology? I am thinking that the keto diet combined with a Vagal therapy of some kind without artificial stimulation would be beneficial. My concern with artificial Vagus Nerve Stimulation is that it might somehow impair the Brain-Gut and Gut-Brain feedback loop mechanisms because they are inter-reliant on one another. I believe that the necessary enzymes needed to decrease the hepatic load are partially impacted by autonomic dysfunction and vagal tone. I am wondering if anyone who uses Cranial Sacral therapy or MNRI knows about alternative exercises to stimulate vagal communication.



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    7. Also, I do want to add that citrus fruits can trigger the mast cells to release more histamine.

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    8. Hi Never Give Up,
      I daily consume 50grams of 85% cocoa rich chocolate in the morning (yes I know the morning lol), it helps my mood a lot.
      Lots of people are worried about chocolate making them fat, in fact cocoa has been shown to increase insulin sensitivity/pgc1a upregulation and helps turn WAT into BAT (white into brown fat).
      On top of that like you said chocolate is not called for nothing food of the gods, it contains tons of amides, including PEA (low in ADHD and also autism often it seems), anandamides, beta carbolines and obviously catechin and epicatechin.

      Also like you said the CB1 receptor is very important (especially in social functioning in autism/asd), I believe there was quite a few studies that showed decreased cb1 expression and increased cb2 expression in asd/autism.

      Maca contains a FAAH-inhibitor and should raise endogenous endocannabis.
      Lots of marijuana and adhd users also seem addicted/use a lot of peanut butter and cocoa and swear by it to potentiate weed.
      Personally I love peanuts and peanutbutter also (see my post history). Peanutbutter for example contains diacylglycerol, this fuels endogenous cannabinoid signalling.

      My experience is that a breakfast incorporating peanutbutter, high cocoa chocolate and a glass of fresh orange juice is a potent mood booster, I seem to have elucidated atleast some of the reasons behind this and in the past I seemed to have been subconsciously giving my body through this what it needed.

      I recently started taking yakult again (this is L. casei shirota) and it has strong effects on my mood, though it does lower my libido a bit (this strain has been shown to increase serotonin in stools after 14 days). That being said this probiotic does feel very good to me and I found that it affects vagus signalling:

      Probiotic Lactobacillus casei strain Shirota (this is Yakult, available in the supermarket atleast in europe) relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models.
      https://www.ncbi.nlm.nih.gov/pubmed/26896291

      Academic stress-induced increases in salivary cortisol levels and the incidence rate of physical symptoms were significantly suppressed in the LcS group compared with the placebo group. In rats pretreated with LcS, WAS-induced increases in plasma corticosterone were significantly suppressed, and the number of CRF-expressing cells in the PVN was reduced. Intragastric administration of LcS stimulated gastric vagal afferent activity in a dose-dependent manner

      Also interesting about what you say about histamine/mast cell activation, as odd as it may sound after I sneeze like crazy (taking 2-3grams vitamin c almost always make me sneeze like mad for 5-10secs) I seem to get a strong mood elevation.

      Biogaia gastrus (another probiotic) is pro-histaminergic in the gut through regulate H1/H2 receptors and supressing TNF-a.

      Regarding keto: I have been considering trying it, but whenever I eat lower carbs than average for example I have noticed I get extremely high energy levels/get impulsive, Im not sure if it is for me.

      Im from the Netherlands, I should really try a low dose of weed but I absolutely HATE any form of smoke (I have a 23andme cyp1a2 mutation - this is the arylhydrocarbon stuff) and this liver enzyme regulates how the body transforms toxins. Especiall diesel exhaust, the slightest fume that reaches my nose makes me gag/puke.
      Eating 'spacecake' is hard to dose from what I have heard.

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    9. Aspie1983, I would never use Marijuanna where the THCa went through decarboxylation. This is because I am not looking for the psychoactive effect in a young kiddo. The leaves of the plant from Marijuanna can be juiced or made into a smoothie. Unless your running your power smoothie for a long time creating a great deal of heat you are not going to decarb that leaf. I have eaten the leaves myself and they do not get you high. They are very strong tasting though so if you are using them in a smoothie just a few will do, especially if you know a grower that is obsessed with the quality of the plant. I know a grower in a legal state. Where I live the cards are pricey and you have to pay that annually.....Another reminder of the need to relocate..yet again. Not all the states are like that for the cards.

      I was researching orthosilicic acid in a non liquid form for removal of Al. The problem with using OSA from water sources is the plastic bottles and the endocrine disrupting compounds in those bottles. I came across OSA 28 to help plants, apparently it is much better at providing a good root development medium than Pot.Ash for plants. I wonder how this OSA 28 was developed and its potential use in eliminating body burden of Al in the various areas of the body.

      It would be interesting if there was another way of eliminating this Al from the glia, some other mechanism.

      The reason the TSO study is interesting that Peter mentions in this article is that even though it didn't show promising results it shows that people are looking into other mechanisms and areas of focus to potentially achieve positive outcomes for the issues in treating this condition.

      Thanks for the information on Maca and Peanut butter. This is funny because my son has to have occassional Peanut butter. While I know it is problematic in some ways due to the PUFAs and phenols, I know it contains other beneficial compounds. Thanks for the info on Yakult and Maca-- I will look into that more.

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    10. Yeah I would never advice it for a kid. Im 35 myself and I have smoked weed before in the past and I do remember it makes me social (somewhat excessively as in hugging everyone), also my 23andme shows that I have an increase suspectability to cannabis induced psychosis and thats the reason why Im also somewhat afraid to try it again.
      That being said, usually when a chemical/medicine/drug intake is through smoke it has a fast onset and a fast peak.

      Do you know if eating space cake would be more of a 'time released' version of weed?

      Cannabinoids seem to have a good bad rep in general btw, despite them also possibly being able to cause problem they can also be therapeutic I reckon. For example multiple studies have shown that THC and other mixed cb1/cb2 ligands increase 5ht2a receptor expression in the brain.
      I reckon most forms of autism that have social problems such as indifference/lack of wanting to play with friends are hypo 5ht2a expressors (I know I am myself).

      When you say Al, I take it you mean aluminum by that, if so I have to admit I have not done a lot of reading on heavy metal detox, my knowledge ends at alpha lipoic acid/nac for moving around/disposing heavy metals.

      Regarding peanutbutter once more, Ive also tried to find out why I both love eating and it seems to help me give more joy in life, the fact that it contains DAG is one (yet normal peanuts also give me nearly the same effect as peanutbutter). I know peanuts are a decent source of resveratrol, I wonder if that has an influence (I have not tried resveratrol myself yet btw as a supplement).

      @Peter, Im not sure if you knew this allready but after my exptensive research on probiotics it seems widely accepted that most lactobacillus strains seems to act against propionic acid, which makes me wonder if this an additional feature that pherhaps gastrus has to offer.

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    11. Hi Never Give Up,
      I also am working with both the kids on the "Fiji Water" OSA AL detox. My kids do drink a lot of water but the recommended amount is like 1.5L per day I think. Anyways, I came across this choline stabilized OSA in concentrated drop form and will be adding that to the supplement cocktail soon. Just thought you may be interested.

      https://us.supersmart.com/article.pl?id=0464

      Also here is a link talking about how the CH stabilized OSA is the most bioavailable source of silicon.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546016/

      Also to Ling,
      I have also just purchased the C8 and BHB Salt. I also have some bumetanide that I hadn't started my younger one (4yr old) on yet. I think you posted below what the effect of both of those together will be. I'll do the C8 and BHB first to see if there is an effect there and then probably start the bumetanide after that.

      Scott

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    12. Happy if you report your experiences, whatever they are, Scott!

      Aspie1983, what you say about the 5HT2a receptor sounds a lot like what I've found out too. Looks like some children with my daughters genetic disorder get the somewhat same effect from cannabidiol that I get from Bacopa. I wonder which intervention on the receptor is the safest one.

      /Ling

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  17. Hi Aspie 1983, I always wanted to give my son yakult, l casei shirota, to help with his chronic constipation and SIBO, but Iam concerned with the amount of sugar of this product.
    Valentina

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  18. Yeah the despite the bottles being relatively small they contain around 40 or 50calories worth of sugars, I didnt experience any problem from taking them thats all I can say about it really.
    Keep in mind pretty much all food you buy in the supermarket has some sugar (often hidden), but even fruit has sugars, its hard to completely avoid.
    Im not sure if l. casei shirota is also available as pills or anything as I have not looked into that but from what I understand it is a patented strain and the developers so to speak most likely have put them in these small bottles so they appeal to a broader audience.

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  19. I think the next treatments might look at exosomes and mRNA as treatment. How would this work in Neurodegenerative and Neurodevelopmental injury and complexities? Translating all of this should be individualized but it takes a complex understanding of the interplays going on within the individual. Within the Mast cells there are these exosomes. Using these small nm exosomes as biomarkers of disease. Somehow integrating AI to analyse this mass amount of data and decoding of interfunctioning of micro environment.


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  20. My mind can't help trying to compare ketone therapy to bumetanide use. As I think I understand most of the mechanisms, I still feel very unsure of what the pro and cons of each are in comparison. I understand BHB+C8 haven't been tested at all on children, and someone mentioned it to be expensive too. But effectwise? Can the therapies be combined, or would that be unnecessary? Is ketone therapy really not changing the I/E ratio then, like the KD and bumetanide does?

    /Ling

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  21. I recently learned that butyrate has an effect on fetal hemoglobin too (Hb F). Not sure if this has any meaning to anyone (except maybe for people with sickle cell disease), but anyone using it would of course want to know about about all of its effects:

    "Butyrate was previously shown to increase embryonic globin gene expression in chickens pretreated with 5-azacytidine, cause higher levels of Hb F at birth in infants born to diabetic mothers, delay the switch from fetal to adult hemoglobin in sheep exposed to butyrate in utero, and increase Hb F levels in adult baboons
    []
    In most patients who receive butyrate, Hb F levels increase gradually over several months of therapy. However, in some patients, Hb F levels increase within a few days of initiating butyrate therapy.
    []
    The mechanism responsible for the increased efficiency of γ-globin mRNA translation is not yet known. Although our studies have shown that butyrate increases the efficiency of translation of γ-globin mRNA, but not that of α- or β-globin mRNA, it is not clear whether other cellular mRNAs may be translated more efficiently in the presence of butyrate. We speculate that the effect of butyrate on the efficiency of mRNA translation may be a result of changes in the acetylation of proteins involved in mRNA translation."

    http://www.bloodjournal.org/content/105/4/1807?sso-checked=true

    /Ling

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  22. Anyone who knows a BHB brand with better taste than KetoForce? I'm not sure I can get it taste approved and the lime taste is very hard to hide.

    /Ling

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    1. Ling, Ketoforce is alkaline and even the producer says it tastes drinking sea water. You need to mix it with something acidic like orange juice.

      People complain about the taste of most BHB salt products.

      There are some very new even more potent products that contain BHB esters. They can raise blood BHB levels substantially, to the level of full ketogenic diet. But they are even more expensive.

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  23. Orange juice or anything similar is unfortunately not taste approved here either. Highly impractical!
    Depending on the amount, maybe a fruit/youghurt smoothie could work. I'm aiming at a trial of 1 week C8 followed by one week of C8+BHB hoping to at least see if there is any effect.
    For short trials, price is a lesser matter than taste. But my last trial nearly destroyed the general administration routine due to taste issues, and that scares me more than anything.

    /LING

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    Replies
    1. Ling, maybe start by introducing new foods. If she eats mandarins, kiwis etc then you have more flavours at your disposal. Apple juice has a similar pH to orange juice. I have used both with KetoForce.

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    2. Ling, you can actually cook with C8. For example you can add it to scrambled eggs or any tomato based ragu/Bolognese.

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    3. :-) Now you got _me_ hungry!

      /Ling

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  24. Here is my first, short-term report on C8 oil. It is our second 7-10 days round, and there have been other factors at play, so the reliability is so-so.
    Dosage 2*2,5 ml of KetoForce C8 daily first days, after that titrating up to almost 2*5 ml daily for an 18 kg 3 1/2 year old.

    First of all, this oil is extremely easy to administer since it is tasteless. The label says not to use it in cooking due to low smoking point, but I doubt putting it in warm food will make it less efficient.

    The major effect we are seeing is "activity". It's not hyperactivity (yet). The floors of our home are suddenly flooded with toys and instead of doing 1-2 activities per evening my daughter initiates perhaps 5 activities (jigsaws, books, trains, doll house...). We've also noticed that she wants to stand by the table for dinner instead of sitting, as if she is on her way to something else...
    She is also happier, maybe too happy at times(!) Giggling that interrupts her interaction with others. Actually, we have seen episodes on the border of mania, one evening she was standing up in her bed laughing, screaming and being silly and couldn't go to sleep until 1 1/2 hour later than normal.
    We have also seen some physical aggressiveness, which could be due to teething issues but since I don't know I'm mentioning it anyway.

    Cognitively - maybe better, but not sure.

    Language gains - Not speech, but I think we have more signing. That manic evening (the last before we stopped the trial) she had a long dialogue with me "Dad work, mum work, me work" "Work supermarket, haha!" "Buy supermarket" "Buy fish, icecream, milk" at the time she usually sleeps deeply.

    One person told me he/she had to stop SSRIs while on keto because both together caused mania. Since my other interventions Fisetin and Bacopa have an effect on serotonin as well, I'm thinking that maybe this is the main reason to the positive and negative effects we are seeing.

    /Ling

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    1. AJ, you did describe something similar to the "almost hyperactivity" we have been seeing. I think you also tried 5-HTP in the past - any similarities?
      It is interesting that I see such a strong reaction to C8 alone, without any BHB. Could I expect that BHB would add anything? I don't have any ketostrips, so can't tell if ketosis is happening or not.

      /Ling

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    2. Hi Ling, my son is also on C8 since 10 days and also see some episodes of mania and too much laughter at bedtime. He takes a 1000 mg capsule per day.
      Valentina

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    3. Hi Ling!

      My daughter is like the Tasmanian Devil from the old cartoons, you just see a dust cloud, arms, legs, and a lot of commotion (and lots of singing and yelling) … But she has always had lot of energy, so it's hard to distinguish between what is caused by C8 / Keto and what is natural.

      The one thing I will say about C8 and BHB salts is, I feel like we saw benefits with them at a low relative dose that we haven't yet seen with esters, yet C8 and BHB salts affect ketone levels so little (at least at the doses we use) that the ketone strips don't pick them up.

      Your description of your daughter sounds so much like mine (lots of activity, can't sit for more than 2 minutes at dinner, etc.) In fact, we HAVE to use Melatonin (about 1.5mgs) to be able to put her to bed, otherwise, she would be up til midnight. If you haven't tried Melatonin yet, it is the answer to many prayers :)

      I did use to use 5-HTP for a while, I actually stopped as I wasn't sure I was getting benefits, and wanted to reduce the many supplements we were using.

      Hope all is well!

      AJ

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