Experiences with Succinic Acid ( Amber Acid )

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My understanding of this chemical is that it is a component of the Kreb Cycle or Citric Acid that is either generated in large quantities in a healthy person during completely aerobic respiration or it is present in a certain quantity, and gets essentially recycled over and over, but can be depleted or increased somehow over time. 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immediately, he says this is a precursor step to test whether the person is suitable for his ( work in progress / not peer reviewed etc ) HHV-6 antiviral treatment plan.
To my confused brain even, this made some kind of sense, if the chemicals are not going all the way around the 'circle' and are being diverted at a certain point, then this chemical might not be generated in our cells like normal. Adding it could allow the completion of a segment of the 'circle' that's normally inaccessible due to lack of reagents.

In my opinion this is simply the logical progression of other work done by many labs on metabolic and metabolomic abnormalities with cell respiration processes in Chronic Fatigue Syndrome ( something about Complex V and increased Glycolysis ? ( breaking up sugar to get a bit of energy quickly, a bit like Anaerobic respiration I believe ) and also Increased Lactate ( lactic acid, the thing when you over exercise and get stitch ).

I had faith in Joshua's theories and therefore I quickly bought this drug from Ebay, it came in a box with a Russian name, its alternative name is apparently Amber Acid. Some googling shows that it is used to treat people who have genetic mitochondrial conditions ( a special part of the cell responsible for producing energy which sort of is a primitive cell in itself, that evolved in parallel ). The dosage for that use is 500mg, but the tablets I received were 100 mg, I cut one into 1/3.

When taking the tablet it did taste very acidy as expected, I drank it with tea quickly so the acid didn't get to my teeth. I don't know if that's the right or wrong thing to do.
Almost immediately I felt a strange sensation in the throat / chest area that I don't think was placebo, its hard to explain what it felt like, my speculation is that the chemical was getting directly into the cells and energizing them or something.

After a few minutes, I felt a feeling of relaxation. My heart rate seemed to decrease to normal levels, the aches and general negative feelings in my muscles seemed to slowly abate.
There was no real psychoactive effects, or huge rush of adrenaline or anything. Instead what I noticed is what felt like aerobic respiration beginning to occur, its a feeling that I haven't experienced in a long time, similar to when someone is running or cycling, except I was standing still.

Not long after this I felt a clarity in my brain and a sense of returning to normal,
its difficult to describe, I looked out of the window at some birds flapping their wings at each other and I felt a new capacity to perceive what was happening, this experience carried through to driving my mobility scooter, I was able to perceive the terrain and instantly make decisions of how to navigate it much easier than normal, sort of like going up from 1080p to 4k resolution.
I went upstairs twice, the first time at nearly normal speed, second time I slowed a bit, but still a big improvement, I didn't feel as much 'payback' at the top of the stairs as normal, walking in general was improved and I felt a little lighter but still not normal. I didn't try walking long distance.

Another thing I noticed was that while down at the park, the air seemed... different, it felt like the air I was breathing was overly pure, too pure ? probably a consequence of a normal respiration system with no 'air hunger' or lactic acid blood. I confirmed then that my heart rate was still slowed, calm, completely different to before I took the drug. I started to feel a little tired after around 45 minutes, but not ill tired just normal tired. I can't really tell but I imagine the effects of this drug last 2 to 3 hours. I am certain that none of this is a 'placebo' effect, as I was completely wiped out last night, and had to generate a lot of willpower to get out of bed this morning, generally feeling stiff and incapable of physical activity.
 

nerd

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I'd be interested in the progress and repeatability of this treatment as well.

The only contraindication I see is that this fueling of the CAC increases alpha-Ketoglutarate levels further, and thereby glutamate and GABA levels, which might be responsible for certain kinds of bad phases of CFS/ME symptomatology.

533px-Integrated_Diagram_of_Succinate_Biofunctionality_.png

By Igoronzy - Own work - CC BY-SA 4.0 - Link

The air hunger might be regulated by HIF-1.

Joshua's apoptosis protocol might also profit from this since this can increase ROS production. But I think his model is still incomplete and without a complete model, you can't be sure if you're triggering apoptosis of the right cells, i.e. transfected cells.
 
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I might take a smaller dose tomorrow to give me the energy to prepare for the anti-viral / chinese medicine treatment. Based on what Joshua says, having the body able to generate energy normally for a while might allow critical metabolites to recharge to normal levels, improving health, but I'm a little bit concerned about the effects of taking it regularly, because forcefully switching things on in the body that perhaps are off for good reason (?) seems as if it could cause some issues.

I developed a light headache about an hour after taking the drug, which I still have roughly 6 hours on, but it doesn't outweigh the positives, its no more unpleasant than the post-exertional headaches I've had in past months, which can last for nearly a week.
 
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I tried doses up to 500mg with no noticeable effect.

Succinic acid doesn't enter cells and then enter mitochondria in appreciable quantities. Some may diffuse in, but succinic acid is actively transported out of the mitochondrial matrix and diffuses out of mitochondrial membranes. I couldn't find much evidence that taking succinic acid supplements would increase succinic acid inside of mitochondria.

Succinate prodrugs that are cell-permeable are being developed to overcome this problem. This paper has a good overview of why succinic acid doesn't enter cells and why a cell-permeable prodrug could be interesting: https://www.nature.com/articles/ncomms12317

Succinic acid does have other functions in the body, though. There is a succinic acid receptor expressed in many different tissues. Some immune cells are stimulated by succinic acid to produce certain types of inflammation in the gut. A good paper on the subject is here: https://pubmed.ncbi.nlm.nih.gov/30583500/ (The Role of Succinate in the Regulation of Intestinal Inflammation)

Succinic acid also has some interactions with the renin-angiotensin system, which is disturbed in CFS. See https://pubmed.ncbi.nlm.nih.gov/22729752/ (https://pubmed.ncbi.nlm.nih.gov/22729752/)

High succinic acid levels are associated with several disease states, so I would be cautious about supplementing it long term.

The alternative medicine protocol going around that uses the NutrEval test and succinic acid has been debunked on the other forums, so I won't go into it more here. The NutrEval test isn't useful because it doesn't measure succinic acid in cells. Succinic acid in your urine and blood serves a different purpose.
 
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I tried doses up to 500mg with no noticeable effect.

Succinic acid doesn't enter cells and then enter mitochondria in appreciable quantities. Some may diffuse in, but succinic acid is actively transported out of the mitochondrial matrix and diffuses out of mitochondrial membranes. I couldn't find much evidence that taking succinic acid supplements would increase succinic acid inside of mitochondria.

Succinate prodrugs that are cell-permeable are being developed to overcome this problem. This paper has a good overview of why succinic acid doesn't enter cells and why a cell-permeable prodrug could be interesting: https://www.nature.com/articles/ncomms12317

Succinic acid does have other functions in the body, though. There is a succinic acid receptor expressed in many different tissues. Some immune cells are stimulated by succinic acid to produce certain types of inflammation in the gut. A good paper on the subject is here: https://pubmed.ncbi.nlm.nih.gov/30583500/ (The Role of Succinate in the Regulation of Intestinal Inflammation)

Succinic acid also has some interactions with the renin-angiotensin system, which is disturbed in CFS. See https://pubmed.ncbi.nlm.nih.gov/22729752/ (https://pubmed.ncbi.nlm.nih.gov/22729752/)

High succinic acid levels are associated with several disease states, so I would be cautious about supplementing it long term.

The alternative medicine protocol going around that uses the NutrEval test and succinic acid has been debunked on the other forums, so I won't go into it more here. The NutrEval test isn't useful because it doesn't measure succinic acid in cells. Succinic acid in your urine and blood serves a different purpose.
Isn't that science based on normal individuals who have normal levels of metabolites though ? might be different for people who have depleted levels of succinate and similar things, diffusion gradient. I'm not a biochemistry expert, I am just following a paper thats been published that postulates a theory as to what may be going on, that I find to be a satisfactory explanation in light of past findings. I have estimated that the chance of a treatment appearing in this time frame to be very high, for various reasons so I am not surprised when someone comes along and presents what they claim could be one.

I don't really know what the alternative medicine thing is about that you mention, I don't go to other forums only Youtube. As I understand it, Whitney Defoe and family already looked into supernatural solutions to the disease by way of the Native Americans, this was mentioned in the book The Puzzle Solver. I am looking for conventional interventions of the pharmaceutical variety, which includes chemicals that are naturally occurring in various plants. I am sorry you didn't see any change with the amber acid, I am not sure why that might be.
 
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Isn't that science based on normal individuals who have normal levels of metabolites though ? might be different for people who have depleted levels of succinate and similar things, diffusion gradient.
The paper used Rotenone to interrupt Complex I in the mitochondria, so they specifically tested the scenario in which the mitochondria are inhibited.

I'm not a biochemistry expert, I am just following a paper thats been published that postulates a theory as to what may be going on, that I find to be a satisfactory explanation in light of past findings. I have estimated that the chance of a treatment appearing in this time frame to be very high, for various reasons so I am not surprised when someone comes along and presents what they claim could be one.
Be careful. The document you're referring to isn't a published paper. It was uploaded to ResearchGate, which is like a social network where anyone can upload documents. The paper hasn't been peer-reviewed or accepted into any journals. You should treat it like a blog post or a forum post.



I don't really know what the alternative medicine thing is about that you mention, I don't go to other forums only Youtube.
The document with the succinic acid protocol is alternative medicine. The author is a fitness trainer who claims to treat everything from CFS to Multiple Sclerosis to Parkinson's to HIV with his mixtures of supplements and herbal remedies.
 
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Hip

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I couldn't find much evidence that taking succinic acid supplements would increase succinic acid inside of mitochondria.
Yes, neither could I.

Succinate / succinic acid does not appear to be able to enter the mitochondrial Krebs cycle, at least at normal doses.

This diagram indicates the inputs and outputs of the Krebs cycle:
Krebs_cycle.png


As you can, some of the steps in the Krebs cycle have inputs (black arrows), where substances can enter the mitochondria to replenish the cycle.

And some of the steps have outputs (red arrows), where substances manufactured in the Krebs cycle can leave the mitochondria and be used elsewhere in the cell.

However, the succinate step does not seem to have any inputs or outputs, so if we assume that diagram is correct, it suggests that succinate supplementation will not be able to get succinate into the mitochondria.



This 2017 in vitro paper indicates that a very high dose of succinate supplementation does have beneficial effects on mitochondrial energy production in astrocyte and microglial cells which were impaired using the toxin rotenone (which inhibits mitochondria complex I), and does appear to get into mitochondria.

However, the concentration of succinate they used in vitro was extremely high, 6 to 24 mM (6 mM equates to 0.7 mg/ml). This concentration resulted in an increase in the oxygen consumption rate of mitochondria by 20%.

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.

So yes you can get succinate into mitochondria if you take extremely high doses. But these doses may actually be fatal, since the oral LD50 of succinic acid for rats is 6740 mg/kg, which suggests the lethal dose for humans will be around 90 grams.

Thus at normal dose levels, which are typically up to 500 mg daily, I don't think we have any evidence of succinate getting into mitochondria.



The 2017 paper also mentions other research in humans where carbon-13 labelled succinate was proven to be metabolized by the Krebs cycle in vivo in humans with traumatic brain injury. But here they again used very high concentrations of 12 mM infused into a brain injury using microdialysis.




Succinate / succinic acid also has immune stimulating effects, so it is possible it may have other benefits for ME/CFS not directly linked to mitochondria.

This paper for example indicates that extracellular succinate has an effect on the macrophages of the immune system, via its action on the succinate receptor 1. When succinate activates this receptor, it results in an anti-inflammatory macrophage phenotype. Although the paper also says accumulation of succinate inside macrophages activates a pro-inflammatory program.

So succinate seems to induce both pro-inflammatory and anti-inflammation effects in macrophages. Whether that might have any benefits for ME/CFS is hard to say.
 

joshua.leisk

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Mito-Trans-Simple.png
Hi All, succinate/ succinic acid “powers up” the “fragmented” half of the cycle, alters HIF transcription factors, undoing hypoxia, etc.

Too much causes more ROS and continues the main CFS issue.

It’s useful, in small doses, especially paired with high-dose R-ALA. In our model / experiences, someone can expect be in remission within a day or so, when used correctly.

High dose ACV capsules are a good source of succinic acid.
 
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joshua.leisk

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Oh and ACV has acetate, so in our model, the combination is designed to fix orthostatic intolerance, by assisting acetyl-coa maintenance.
 
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View attachment 42744
This appears to be a diagram that you created.

Do you have any citations or sources to support your claim? Everything we have found in the literature so far contradicts your claim that small doses of oral succinic acid can enter mitochondria in appreciable quantities.


You can usually be in remission within a day or so.
Are you really suggesting that low doses of succinic acid will put people's CFS into remission within days? Forgive me, but your claims are becoming difficult to take seriously. Not only because your protocol didn't work for me, but we haven't seen any claims of CFS remission even though your protocol has been circulating since March.

CFS is an extraordinarily difficult disorder that has eluded many researchers for decades. I think we need to take a step back and acknowledge that it's not going to be put into remission by a simple supplement that several of us have tried without success.

High dose ACV capsules are a good source of succinic acid.
Oh and ACV has acetate, so the combination also fixes orthostatic intolerance.
Likewise, you're also claiming to have cured orthostatic intolerance with simple apple cider vinegar? This forum has many threads about ACV and no one has mentioned that it has fixed their orthostatic intolerance as far as I can find.

I would appreciate if you could at least review the thoughtful response from Hip as well as the papers I cited above. Can you also provide citations for your claims from established sources, not your own diagrams?
 

joshua.leisk

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767E8899-D0D6-47EB-9D86-F3C98CF5E142.jpeg

^This is from the v3.x protocol, which corrects the viral alterations, some of which prevent a normal immune response. According to our research, this will likely be curative.
 
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joshua.leisk

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I might take a smaller dose tomorrow to give me the energy to prepare for the anti-viral / chinese medicine treatment. Based on what Joshua says, having the body able to generate energy normally for a while might allow critical metabolites to recharge to normal levels, improving health, but I'm a little bit concerned about the effects of taking it regularly, because forcefully switching things on in the body that perhaps are off for good reason (?) seems as if it could cause some issues.

I developed a light headache about an hour after taking the drug, which I still have roughly 6 hours on, but it doesn't outweigh the positives, its no more unpleasant than the post-exertional headaches I've had in past months, which can last for nearly a week.
In our disease model, the headache is predictable and is from PEM / urea. It’s created by the extra mitochondrial “pressure” (energy level in the reaction cycle) creating more ROS and nitrogen waste to be disposed of.

This is why in the v2.x clinical trial draft protocol we administer R-ALA following the succinate challenge. In the papers and protocol, we suggest increased water intake to purge the urea. We’ve listed 3.5L / day as a suitable minimum target.
 
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pattismith

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Apple cider vinegar - in 2.x protocol, we used a number of high dose Apple Cider Vinegar capsules, 3-4 times per day, along with R-ALA and some other supplements to reduce reactive oxygen species... plus various other ancillaries.
any vinegar has the same effect (bringing acetic acid), or is there a specific effect of ACV beside acetic acid?
 

joshua.leisk

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any vinegar has the same effect (bringing acetic acid), or is there a specific effect of ACV beside acetic acid?
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.

https://www.researchgate.net/publication/350399073_The_involvement_of_acetate_aspartate_butyrate_and_enzymatic_cofactors_in_the_HASD_CFSME_model

The issue is that according to our research, this is symptomatic relief / remission only. Additionally, this is likely to accelerate the infection. In the third paper, we showed how to turn off the viral alterations instead.

https://www.researchgate.net/publication/350956432_CFSME_A_New_Hope
 
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