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.
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-Sitosterol, Stigmasterol, Avenasterol 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.
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-Sitosterol, Stigmasterol, Avenasterol 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?
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.
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.
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.
Great summary, thanks Peter!
ReplyDeleteStarted 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.
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.
DeleteOn 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.
Congratulations DR both to the advancements and the possibility to participate in a study. Do you know when the trial is supposed to start?
DeleteAlso, 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
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.
DeleteWe 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@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@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...
DeleteCommercialization 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...
Hi DR and big thanks for that update!
DeleteYour 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
A little update on the bumetanide: in the end my kids didn't make it into the study (they're on the "backup" list).
DeleteSo I decided to take things into my own hands and do the bumetanide trial at home. We started a bit over a month ago, 1mg administered in the morning, a little bit of potassium supplement (bananas, tomatoes, and some supplement). Checked the potassium levels after 2 weeks, and all normal, will check again soon. So far we've seen some positives in both kids, nothing crazy, but for the little one we have noticed increased anxiety. I wanted to ask if someone have seen this with bumetanide? It might be unrelated. No matter what, we are planning to do at least 3 months.
On the gene mutation front (PDZ4 for both kids), we have been asked permission to do a biopsy on both kids (which we accepted) for a research in the US... I can't seem to find which study it is, I'll post it later when I find the paper. Thanks to all!
David
David, I think the diuresis itself will cause anxiety in some people.
DeletePDZ domains make up proteins like Glutamate receptor-interacting protein (GRIP) and HOMER. Both of which are linked to autism.
https://en.wikipedia.org/wiki/PDZ_domain
Once you know which genes/proteins are affected you will know much more about the sub-type of autism by understanding what the gene does.
I found back the study in question:
Deletehttps://clinicalstudies.info.nih.gov/ProtocolDetails.aspx?A_1976-HG-0238.html
I'm not sure in which way it could help us.
Peter, the only thing I know as of now is the mutation in question, that occurred on the gene PDZD4 (and the protein affected): do you know who could help me understand it to find out what is their sub-type of autism?
Thanks again
David
Thanks for the update David, and good luck the upcoming months!
Delete/Ling
David, PDZ4 (your first comment) and PDZD4 are slightly different.
DeleteIf it is PDZD4 then you have a precise diagnosis.
You can look it up in an autism gene database.
https://gene.sfari.org/database/human-gene/PDZD4
https://www.alliancegenome.org/gene/HGNC:21167
https://www.genecards.org/cgi-bin/carddisp.pl?gene=PDZD4
Your gene is part of the PDZ family of proteins that includes other better studied autism genes/proteins.
If you cannot find a researcher who looks as PDZD4 I would contact one that looks at one of the other PDZ genes. The most well documented PDZ proteins are PSD-95, GRIP, and HOMER.
Whoever gave you the original diagnosis is the first person to go back to for more information. Did they also look for this genetic variation in both parents?
Most autism genetic testing is done using samples from the child and both parents and looks at what is unusual but only present in the child.
In the US the MAPS/DAN doctors seem to refer to Dr Boles when it is a question of genes.
I would suggest finding a researcher who is interested in PDZD4 or just PDZ. You can do this by looking at the research that has been published and then just email the author(s).
Yes sorry, it is PDZD4.
DeleteYes they did look for that variation and found the same in my wife. That is why they wanted to test the grandparents (especially grandpa, because if he had it it would make it a benign mutation), but we couldn't get them to test, so they decided to go ahead and do biopsies on both kids instead.
They were interested because they found 5 families with the same mutation around the world (I think 1 French, 1 Chinese, 2 Americans and us (Spain)).
We are now waiting for them to tell us something about this (study that I linked in my second message).
I will contact the first researcher who gave us the diagnosis.
Thank you for your help Peter, much appreciated.
David
Obviously meant "stimming" not "stinking" :/
ReplyDeleteHere 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:
ReplyDeletePress 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.
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:
DeletePress 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.
Thanks for highlighting that Tyler, Ive always been skeptical about long term effects of keto diets, especially with regards to benefits:side effect ratio.
DeleteI 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.
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:
ReplyDeletePress 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.
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.
DeleteI 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.
The amount of spam and ads that get posted is getting a bit out of hands and its starting to annoy me.
ReplyDeletePeter is there any way you can go back to the old posting system, where a post would be checked before published?
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.
DeleteHi Peter and all,
ReplyDeleteMy 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 ?
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?
DeleteVia 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.
Hi Luis,
DeleteSome 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
Hello Peter and all,
ReplyDeleteThis 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
Un tio, I cannot say about paracetamol, but NSAIDS like ibuprofen do seem to improve some people's autism.
DeleteParacetamol depletes GSH, so in theory should worsen autism.
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:
ReplyDeletePress 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.
This comment has been removed by the author.
ReplyDeletePeter, 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 :)
ReplyDeleteI have no reason to think being male/female affects the response. It appears that many people respond, but the extent of that response varies.
DeleteIt looks like one effect of BHB is on mood and not just on people with ASD.
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?
Delete5,000 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.
DeleteHi Peter,
ReplyDeleteHope 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
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.
DeleteThere 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.
Hi Peter,
ReplyDeleteThanks 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
Hi Peter,
DeleteWe 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
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?
ReplyDeleteI wonder if the buttermilk/MFGM subject somehow is related too.
/Ling
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?
ReplyDeleteI 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
For those who use ketogenic diets:
ReplyDeleteAdenosine, 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.
Forgot to add this:
ReplyDeleteAdenosine 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.
Aspie1983, very interesting and reminded me also about this:
Delete"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.
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).
DeleteIm 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.
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.
DeleteAgnieszka 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.
Maybe limonene is something that I could respond to aswell:
DeleteLimonene, 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.
Thanks Aspie1983.
DeleteInterestingly, 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.
Aspie1983,
DeleteI 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.
Also, I do want to add that citrus fruits can trigger the mast cells to release more histamine.
DeleteHi Never Give Up,
DeleteI 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.
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.
DeleteI 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.
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.
DeleteThat 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.
Hi Never Give Up,
DeleteI 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
Happy if you report your experiences, whatever they are, Scott!
DeleteAspie1983, 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
"I truly wonder why adenosine agonists are not use in ASD and autism yet"
DeleteI think it's because adenosine agonists can cause cardiovascular issues.
https://en.wikipedia.org/wiki/Adenosine#Supraventricular_tachycardia
https://en.wikipedia.org/wiki/Adenosine#Mechanism_of_action
https://www.reddit.com/r/askscience/comments/3x84b2/what_are_the_psychoactive_effects_of_an_adenosine/cy2dwn2?utm_source=share&utm_medium=web2x&context=3
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.
ReplyDeleteValentina
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.
ReplyDeleteKeep 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.
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.
ReplyDeleteMy 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?
ReplyDelete/Ling
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:
ReplyDelete"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
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.
ReplyDelete/Ling
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.
DeletePeople 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.
Orange juice or anything similar is unfortunately not taste approved here either. Highly impractical!
ReplyDeleteDepending 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
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.
DeleteLing, you can actually cook with C8. For example you can add it to scrambled eggs or any tomato based ragu/Bolognese.
Delete:-) Now you got _me_ hungry!
Delete/Ling
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.
ReplyDeleteDosage 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
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?
DeleteIt 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
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.
DeleteValentina
Hi Ling!
DeleteMy 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
It's kinda funny, the Wikipedia description of mania does indeed look like a description of common ketone effects, with a few negative words sprinkled on top:
Delete"The symptoms of mania include heightened mood (either euphoric or irritable); flight of ideas and pressure of speech; and increased energy, decreased need for sleep, and hyperactivity."
/Ling
Just a quick question Ling, and it may have no relevance to your child but...is she having diarrhea or tummy troubles? Only asking because for us, MCT oil brought about a lot of negative digestion issues that were usually preceded by some hyperactivity and irritability (naturally).
ReplyDeletemkate
Hi mkate!
DeleteIt's been a while since my trial of C8, so I don't remember all details, but I am sure I would have mentioned any odd gut behaviour if there was any. So no, I don't think so.
It was not "hyperactivity and irritability" but rather "hyperactivity and manic sillyness".
/Ling
mkate, different brands of MCT and different combinations of C8 and C10 seem to cause bad effects in some people. Even "pure C8" products vary and in the same person one gives a great result and the other GI problems. This is unfortunately due to poor quality control by supplement companies.
DeleteOuch! I hate reporting on failures.
DeleteMy retrial of C8, same bottle as above, this time without some of the other interventions that raise serotonin, had to be stopped a few days in because of gut pain.
We didn't see anything like this last time when my daughter was having the time of her life, now she even refused to eat on two days in a row until I got her to communicate what the problem was. When C8 was stopped, so was gut pain.
We didn't reach any state resembling mania or hyperactivity this time, maybe because we stopped so early, but possibly saw less need for sleep.
/Ling
Hi Peter, quick question as I'm confused by this epigentic silencing of genes. I have aspergers and have noticed that a ketogenic diet does induce short term changes, which could possibly be due to an epigenetic effect on silenced genes. Many anecdotal reports are coming out about carnivore/keto diets as being effective dietary interventions. How does HDAC inhibition in the Shank 3 deficient mice model relate to epigenetics? Surely it's just epigenetic "silencing" or reduced expression of the Shank 3 gene (along with up to 200 other genes) which is the problem, not a mutation of the gene? if this is the case, many more than the 1% of autistics would see improvement based upon the HDAC inhibition upregulating the genes in question.. or am I missing something? Thanks
ReplyDeleteAdam, in the Skank3 deficient model of autism, a single 3 day treatment of Romidepsin, an HDAC inhibitor reversed their “autism”/ social behavior deficits for 3 weeks.
DeleteIn Shank3-deficient mice, β-catenin migrates out of synapses, accumulates in the nucleus, and up-regulates the expression of HDAC2.
Inhibiting excessive HDAC2 selectively increases the expression of Grin2a and various actin regulatory genes, which in turn restored excitatory synapse function.
As with many things in autism, too much or too little HDAC will cause problems.
HDAC regulates the expression of genes via an epigenetic process.
The ketogenic diet and the ketone BHB have so many effects, it is very hard to know which one is providing the benefit in any one individual.
Ahh, I didn't realise SHANK3 up-regulated the expression HDAC. Is it possible that a HDAC inhibitor could play a role in more types of autism, where epigenetic effects have been observed, despite not having a SHANK3 mutation? Are there other gene mutations which could result in a lowered expression of HDAC? I know the William Walsh was doing work to investigate methylation defects, which I'd imagine could result in impacts in gene expression. I'm afraid my knowledge on biochem and genetics is somewhat limited, although I'd certainly like to learn more.
DeletePeter, is there a known reason why C10 has a bad effect in some?
ReplyDeleteC10 has multiple effects which would normally either not be noticed or would be beneficial. Quite often people experience GI problems from some brands of MCT oil and this may relate to impurities.
DeleteYou could have a negative reaction to C10 being a PPAR gamma agonist, but more likely perhaps is some impurity in the product.
Hi Peter,
ReplyDeleteI tried the BHB(ketoforce x 5ml) + C8, I noticed definite effects like increased speech, but it only lasts for like 3-4 hours then there is a crash. I am going to try tweaking it with smaller doses I seem to be sensitive to everything and need half your doses. Unsure if I will continue it. I think a method for giving this during the day would be to add it to some water and drink it slowly over the day. It is very mild tasting.
Hi Peter,
ReplyDeleteI would really like to try BHB + C8 with my adult son (around 170 lbs). He is a great responder to BCAAs/NAC as recommended by Tyler in regards to the mood disorder which has taken precedence over speech and cognition unfortunately in the past 10 years.
Any idea about dosing ?
Nancy
Nancy I would suggest you use D-BHB. One place that sell it is in the link below where it is called D-max.
Deletehttps://julianbakery.com/product-category/supplements/ketones/
This company suggests a dose containing 7g of D-BHB, which seems reasonable.
You can add 20ml of C8 oil and this will also produce BHB over a longer time frame.
The molecule BHB comes in “left handed” and “right handed” versions, so we have D-BHB, L-BHB and just a mixture of both. The only one you need is the D-BHB, so it is much better/cheaper to buy D-BHB rather than the original product that was BHB (mixture of L and D).
I had same question, glad that Nancy asked and thanks for your reply.
DeleteI have started C8 (two tablespoons a day) for my 6 years old (positive so far), but not BHB yet. thanks for sharing the link to BHB, it seems like one of those products has high calcium in, just wandered why. hence question i had is if increased sodium would necessitate additional supplementation of Potassium or Calcium? or is it not that big of a deal given sodium amount is not that high. Thanks.
Timur BHB supplements are commonly salts or esters. BHB has to be attached to something. In the case of BHB salts it is sodium, potassium, calcium or magnesium.
DeleteIf you are supplementing potassium, you get the potassium from the BHB salt instead. This would be bumetanide users for example.
Personally I would choose potassium and I would avoid calcium. Some products have a mixture.
Thanks Peter. I seem to recall reading here at one point that certain brands of C8 are preferred over others, leading to different responses. Do you have a recommendation?
ReplyDeleteNancy
At one point, I thought you were recommending this
ReplyDeletehttps://www.iherb.com/pr/julian-bakery-instaketones-potassium-0-91-lbs-414-g/77539 but I can't tell if that is D-BHB.
On the julian bakery website, it appears that D-Max with sodium is the option rather than potassium. Should I be looking for one with potassium?
Thanks for your guidance.
Nancy
Nancy, there are many products called MCT (medium chained triglycerides) they contain C8, C10, C12 etc hopefully as indicated on the label. The effects are not exactly the same.
DeleteMy conclusion was that it is C8 that you want and there are 100% C8 products like this one.
https://www.iherb.com/pr/sports-research-organic-mct-c8-oil-unflavored-16-fl-oz-473-ml/84966
When it comes to BHB, iHerb still sell the old version you refer to:
https://www.iherb.com/pr/julian-bakery-instaketones-potassium-0-91-lbs-414-g/77539
It looks like they are nearly out of stock. They never stocked the new version, which is potassium D-BHB. This product exists on the producer’s website, but they are now out of stock.
If you want potassium D-BHB you could email the producer (Julian Bakery) and ask if they are going to get it back in stock. I think this is the ideal product.
You could use sodium D BHB, or the old potassium BHB (which is 50% D and 50%L).