Experiences with Succinic Acid ( Amber Acid )

[joshua.leisk]

If you wanted to achieve the same concentration in the body, the oral succinate dose needed to attain this concentration of 0.7 mg/ml (in the 40,000 ml of body fluids) we can calculate as 57 grams! That's assuming 100% bioavailability and zero plasma protein binding.

Hi Hip

I'd recommend trying this link:
http://vmh.uni.lu/minerva/index.xhtml?id=ReconMap-3&x=33887&y=30543&zoom=10&search=succinate&

It's a rather neat interactive pathway explorer.

I remember someone on the PR discord got strangely attached to a simplified diagram of the TCA cycle. I thought that conversation was long-since settled, but perhaps the conversation was abandoned and information missed.

Here's one known transporter:
https://en.wikipedia.org/wiki/Mitochondrial_dicarboxylate_carrier

One of my little projects has been trying to equate succinate to glucose on a calorific basis. I need some lab time to properly test this, however my best guess (which will get revised at some point, so please don't take this as anything more than an indication) is that 50mg of succinate is similar to 50g of glucose.

 

[nerd]

I guess high-dose Thiamine remains the better way to correct the CAC then.

Although I'd appreciate a way for not feeling air hunger anymore.

 

[joshua.leisk]

I guess high-dose Thiamine remains the better way to correct the CAC then.

Although I'd appreciate a way for not feeling air hunger anymore.

High dose B12 and P5P would do that.. or some ACV capsules... but my experience is that it's much easier to turn off the alterations directly from CtBP->SIRT4-NF-kB, etc.. that way you can also start getting on with killing / replacing the infected cells... not an enjoyable process, but worth it.

 

[Reading_Steiner]

Lots of researchers tend to think that their line of research is the 'answer to everything', thats natural, just watch a few videos from open medicine foundation, theres a fellow that thinks the CDR / Dauer state is the answer to everything, even though we are not hampsters and cannot hibernate, he says he can cure autism but I don't see it happening in the real world yet, does that make him alternative medicine ? Joshua might be some sort of personal trainer but his science seems to be bang on, you can dispute the specifics of the papers if you find issues in that regard.

 

[nerd]

High dose B12 and P5P would do that.. or some ACV capsules

These are just refueling the succinate though, aren't they? High-dose Thiamine can upregulate the alpha-KGDH. At least this is my theory why there have been anecdotal success stories with very high doses of Thiamine. By the way, high levels of succinate can also suppress the alpha-KGDH, but I assume this is an unlikely case. However, it is a reason to go smoothly with succinate and its precursors.

CtBP->SIRT4-NF-kB

NFkB is influenced by a whole range of viral signals. I'll write a comment about this in your primary post so that this doesn't get off-topic.

 

[Dubitat]

Here's one known transporter:
https://en.wikipedia.org/wiki/Mitochondrial_dicarboxylate_carrier

The first line of this article explains that the Mitochondrial Dicarboxylate Carrier operates on the inner mitochondrial membrane.

Succinate cannot reach this transporter if it is not cell-permeable.

The paper I cited previously shows that succinate is not cell-permeable with experimental evidence: https://www.nature.com/articles/ncomms12317

As Hip explained, it's possible that succinate has other actions throughout the body due to the widespread presence of succinic acid receptors. I don't think it's fruitful to continue discussions about succinic acid entering cells in significant quantities when all literature indicates otherwise.

One of my little projects has been trying to equate succinate to glucose on a calorific basis. I need some lab time to properly test this, however my best guess (which will get revised at some point, so please don't take this as anything more than an indication) is that 50mg of succinate is similar to 50g of glucose.

50g of glucose contains 200 calories.

50mg of succinic acid is certainly not equivalent to 200 calories, and my 500mg dose was not equivalent to 2000 calories.

This is a physically impossible claim. No substance can be that calorie-dense.

 

[Reading_Steiner]

Going back to what was said about it not being able to get into the cells, it obviously can do otherwise it would not be used as a treatment for mitochondrial disease https://www.medicinesforchildren.or...content-type/leaflet/pdf/20111209192733_0.pdf

I have decided not to take any more of this substance, it is very powerful ! it seems a bit like our equivalent of cocaine or meth amphetamine, gets you going but probably not good for the body in the long run. ( never took those illegal drugs just guessing what its like ).

 

[godlovesatrier]

One thing I have also noticed with taking something that works/helps. Is that while one area might go into remission, physical fatigue for example, neurological symptoms will get a lot worse. Or the neurological symptoms improve massively (like when I took the airnergy device) but the physical exertional tolerance declined dramatically.

While the high dose thiamine has been amazing, I went out thismorning and I haven't crashed all day, nor do I have any muscle fatigue. I was out for about an hour. Normally my muscles would be very stiff and fatigued from that, especially as I had to drive in some light traffic. But they aren't. Even so mentally I have a whopping headache currently and I know it will only get worse as the evening goes on. Plus the high dose thiamine began to make me suffer neurologically (I think because of the way it changes/increases carb metabolism). Hence I got very hungry, felt spaced out and then had difficulty concentrating.

Not trying to make a point here, just stating my experience with the thiamine and a few other treatments, which I know others have also experienced.

 

[Dubitat]

According to @joshua.leisk this chemical is substantially reduced in at least some cases of what we call 'ME/CFS' for want of a better understanding, to the point where if we take it in small quantity ( around 25 mg I think ), we notice a big physiological difference almost immediately, he says this is a precursor step to test whether the person is suitable for his ( work in progress / not peer reviewed etc ) HHV-6 antiviral treatment plan.

@Reading_Steiner what dose of succinic acid did you trial?

Succinic acid is found in significant quantities in apple cider drinks and wine, among other things. Wine typically contains 0.5g/L to 1.5g/L, though some red wines have been observed with up to 3.0g/L. (Source https://scholar.sun.ac.za/handle/10019.1/4228 )

A typical glass of wine is 5oz, which translates to between 74mg and 222mg of succinic acid in an average glass of wine, or up to 444mg in certain red wines.

As much as some people would enjoy learning that CFS can be put into remission by drinking red wine, it doesn't appear that red wine has any such effects on CFS despite the relatively high succinic acid content. Similarly, commonly used doses of Apple Cider Vinegar contain small amounts of succinic acid in the range that supposedly produces these effects, yet none of the previous Apple Cider Vinegar reports on this forum or elsewhere on the internet suggest such dramatic results.



I trialed everything from small doses (1/4 of a 100mg tablet) up to the standard 500mg dose with no noticeable effects, and no reduction of delayed PEM after an exercise challenge. Previous reports on this forum also did not notice any effects from succinic acid. I would be interested to hear experiences from others so we can collect some more data points, but given the prevalence of low level succinic acid consumption in regular diet I'm skeptical that these 25mg doses provide such profound results.

 

[Hip]

Going back to what was said about it not being able to get into the cells, it obviously can do otherwise it would not be used as a treatment for mitochondrial disease https://www.medicinesforchildren.or...content-type/leaflet/pdf/20111209192733_0.pdf

That website is the only one I could find which suggests succinate may help mitochondrial diseases. I cannot find anything else online which promotes succinate supplementation for mito diseases. It may be just wishful thinking that this supplement can into mitochondria.

Obviously it would good for those with mitochondrial diseases if we could get succinate into mitochondria, and that's why researchers are attempting to create pro-drug forms of succinate, such as:

NV118 = diacetoxymethyl succinate
NV189 = bis-(1-acetoxy-ethyl) succinate
NV241 = 1-acetoxyethyl acetoxymethyl succinate

@mitoMAN may be interested in these prodrug forms of succinate. Whether they might help ME/CFS though is another question.

 

[Hip]

Here's one known transporter:
https://en.wikipedia.org/wiki/Mitochondrial_dicarboxylate_carrier

That transporter brings succinate across the inner mitochondrial membrane. But there is also the outer mitochondria membrane to consider.

And you also have to get any succinate you take into cells, and this paper says:

Succinate is a mitochondrial substrate metabolized through complex II (CII). It is not cell membrane-permeable and exogenously given succinate has limited uptake into cells.

No doubt you get some succinate entering into mitochondria, because the studies I mentioned above showed that succinate can enter mitochondria if you use extremely high doses. But at normal doses, I suspect little gets though. If a lot got through, then researchers would not be trying to develop succinate prodrugs in order to deliver succinate into the mitochondrial Krebs cycle, for patients with mito diseases.

 

[5vforest]

Lots of researchers tend to think that their line of research is the 'answer to everything', thats natural, just watch a few videos from open medicine foundation, theres a fellow that thinks the CDR / Dauer state is the answer to everything, even though we are not hampsters and cannot hibernate, he says he can cure autism but I don't see it happening in the real world yet, does that make him alternative medicine ? Joshua might be some sort of personal trainer but his science seems to be bang on, you can dispute the specifics of the papers if you find issues in that regard.

They don't join a patients forum and provide step by step details on what substances to take, because they know that would be irresponsible.

 

[Wishful]

As Hip explained, it's possible that succinate has other actions throughout the body

The wiki: "Succinate can exit the mitochondrial matrix and function in the cytoplasm as well as the extracellular space, changing gene expression patterns, modulating epigenetic landscape or demonstrating hormone-like signaling."

Given those wide-ranging effects, it's really hard to say that because someone has a beneficial effect from it, that it must be due to effects on the Krebs cycle.


Also from the wiki: "As such, succinate links cellular metabolism, especially ATP formation, to the regulation of cellular function."

If ME alters succinate release from mitochondria, it might also be altering succinate's effects elsewhere in the body, and those effects could be countered by supplemental succinate.

 

[nerd]

I also wonder, why is the only available amber acid from this Russian brand? Is it common in Russia to take it?

 

[Dubitat]

Some very important context for this discussion: Joshua Leisk has filed for 4 patents on his protocols which he intends to commercialize. He mentions this in his first document and also on this forum. The patent filings can be found through the Australian Patent Search portal by searching for his name, although the contents of the patent filings are currently hidden.

Without seeing the patents we cannot know what is claimed. However, this does introduce a potential notable conflict of interest in this discussion: If he publicly acknowledges that any of his specific claims in the patents are flawed or incorrect, that could put the value of his patents in jeopardy.

All of my research agrees with everything Hip has explained in great detail already: It does not appear feasible that the low dose succinic acid in these protocols would enter mitochondria in sufficient quantities to make a difference. We have found multiple documents with experimental evidence that contradict the claim that succinic acid is cell permeable. Unfortunately, acknowledging this contradictory evidence would put the author's patent filings and eventual profits at risk.

I suggest we all keep this potential conflict of interest in mind when considering the author's claims.

 

[pattismith]

All vinegars will have acetic acid, however in the second paper, I researched a large number of different fruit vinegars and found that ACV had a really nice profile of organic acids and vitamins.

Sorry to be iff topic, but would you tell me how much Acetic acid is in a 1200 mg tablet of ACV?

 

[Reading_Steiner]

How quickly does gene expression and epigenetics change ? the effect of this stuff for me seems to be fully active within 30 minutes but I started to feel a difference within 5 to 10 minutes. I don't drink red wine as alcohol can be unhealthy for you at the best of times, its interesting to know though. Again my intuition tells me that the green tea and beta glucan treatment will work, so I may not get much more opportunity to observe the effects of this succinic acid.

 

[Wishful]

How quickly does gene expression and epigenetics change ? the effect of this stuff for me seems to be fully active within 30 minutes but I started to feel a difference within 5 to 10 minutes.

I don't know how fast the epigenetic changes occur, but T2, which affects RNA transcription, made me feel significantly better within an hour. My guess is that succinic acid was working for you via a similar gene-expression mechanism.

 

[Reading_Steiner]

Don't know why but I ended up bored and looking into this.

Abnormally accumulated succinate in mitochondria which causes by inherited or somatic mutations in random subunits of SDH will be freely transported to the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane [20]. Elevated concentrations of succinate in the cytosol have been confirmed to inhibit HIF-1α prolyl hydroxylases (PHD) [20], which hereafter hydroxylate the highly conserved prolyl residues on HIF-1α. After being hydroxylated, the von Hippen-Lindau (pVHL) E3 ubiquitin ligase recognizes the HIF-1α domain, then inciting proteasomes degradation which is termed ubiquitination [52]. This so-called catabolism of HIF-1α can be inhibited upon PHD inactivation due to the presence of succinate in the cytosol, and PHD inactivation finally results in activation and stabilization of HIF-1α. HIF-1α can then bind to HIF response elements (HREs) in target genes, resulting in upregulation of many glycolytic enzymes that regulate energy metabolism, thereby improving vasomotor response, promoting cell proliferation and enhancing angiogenesis which are indispensable in tumor maturation and invasion

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581152/
Probably nothing to do with GPR91. So Joshua was right, this hypoxia inducible factor is important. I think it is fixing the blood flow problems that occur in some people with CFS. It could also be tuning the metabolism to generate a bit more energy. https://www.healthrising.org/blog/2021/05/06/small-nerve-fiber-snf-energy-chronic-fatigue-syndrome/

Thought I would look to see what peoples experiences were in general with drinking while ME/CFSed, to get an idea of the risks, found LOADS of people talking about alcohol improving their symptoms.
https://forums.phoenixrising.me/threads/oh-alcohol.55862/
https://forums.phoenixrising.me/threads/alcohol-helps-me.79256/
It must be the succinic acid, its also present in beer in significant amounts

 

[joshua.leisk]

These are just refueling the succinate though, aren't they? High-dose Thiamine can upregulate the alpha-KGDH. At least this is my theory why there have been anecdotal success stories with very high doses of Thiamine. By the way, high levels of succinate can also suppress the alpha-KGDH, but I assume this is an unlikely case. However, it is a reason to go smoothly with succinate and its precursors.

You nailed it. The interesting thing is that at really high levels, they go from acting as a backup route to succinate when a-KGDH is low, to creating excess energy in the cycle. Chronic excess dosing can reliably induce the “CFS/ME” metabolic state, in healthy people.

The reason for this is that unlike energy derived from pyruvate/Acetyl-CoA, succinate and fumarate are the main “bypass” inputs into the cycle, with respect to the a-KGDH (ROS limiter).. if you feed the cycle after the limiter, the cycle continues generating ROS and further impairs a-KGDH.

So you can “patch” the hypoxia and HIF issues using high dose B12+P5P, or succinate, which includes fixing the collagen synthesis issues, etc., however this also feeds / accelerates the viral protein synthesis tasks, leading to increased viral takeover of the host.