Succinic Acid For Metformin Induced Lactic Acidosis

Hans

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It's well known by now that metformin inhibits mitochondrial function and can increase lactate. One of its life extension "benefits" is that it inhibits complex I and increases AMPK. Aspirin can do that as well and is much safer as well.

This study has found that succinic rescues mitochondrial function.

https://www.ncbi.nlm.nih.gov/pubmed/30251134
"Inhibition of the respiratory chain complex I plays a key role in the pathogenesis of metformin-induced lactic acidosis. In a work recently published in this journal, a novel cell-permeable succinate prodrug (NV118) increased in vitro mitochondrial oxygen consumption coupled with energy production and decreased lactate production in intact human platelets intoxicated with metformin. This result was interpreted in light of a "bypass" strategy. NV118 entered platelets and released succinate in their cytoplasm; succinate in turn donated electrons to complex II and thus reactivated the flow of electrons to the distal part of the respiratory chain independent of complex I. Herein, I will (1) comment on these findings; (2) highlight the potential therapeutic application of succinate in other critical conditions accompanied by complex I inhibition, including sepsis, traumatic brain injury, and inherited neurological disorders; and (3) examine the most important issues that remain to be solved to transfer these observations to the bedside."

If high doses of aspirin also inhibit complex I, it would be a good idea to use succinic acid with the aspirin to mitigate the lactic acid production.
 

LeeLemonoil

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It’s only bypassing complex I. Better than nothing, but in physiology those things always come at a cost. Better would be to more directly „rescue“ complex 1 or offset its inhibition more directly than bypassing
 
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It’s only bypassing complex I. Better than nothing, but in physiology those things always come at a cost. Better would be to more directly „rescue“ complex 1 or offset its inhibition more directly than bypassing
Yes agreed. I won't take metformin or recommend it. It was just an interesting study and it can be useful if combined with aspirin.
 

cjm

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If high doses of aspirin also inhibit complex I, it would be a good idea to use succinic acid with the aspirin to mitigate the lactic acid production.

Interesting! Been trying a lot of new things and combinations recently and somehow I've settled into this "stack" -- oral succinic acid and topical aspirin in a hot bath -- and I do think there's something special about it.

What's the highest succinic acid dosage you've seen used in studies? The hypertrophy study you posted had a high end dose of 1,400mg for a 70kg human. I just took 2g. I'm surprised how much of an effect it has on its own!

I'd like to see if the combo (not forgetting about the heat from the bath) helps with exercise intolerance.
 
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Interesting! Been trying a lot of new things and combinations recently and somehow I've settled into this "stack" -- oral succinic acid and topical aspirin in a hot bath -- and I do think there's something special about it.

What's the highest succinic acid dosage you've seen used in studies? The hypertrophy study you posted had a high end dose of 1,400mg for a 70kg human. I just took 2g. I'm surprised how much of an effect it has on its own!

I'd like to see if the combo (not forgetting about the heat from the bath) helps with exercise intolerance.
As a side note, very high doses of aspirin are most likely needed to inhibit complex I, if it does that at all. There was a study on this, but the results were too phony. I discussed it in my aspirin and mitochondria article.
I too love topical aspirin especially if I had some kind of topical injury.

How did you feel from the 2g dose? In terms of dosing, I'd probably try 200-400mg or at least increase the dose till I find my sweet spot.

Just be sure to have carbs before and during hot therapy. :)
 

cjm

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As a side note, very high doses of aspirin are most likely needed to inhibit complex I, if it does that at all. There was a study on this, but the results were too phony. I discussed it in my aspirin and mitochondria article.
I too love topical aspirin especially if I had some kind of topical injury.

How did you feel from the 2g dose? In terms of dosing, I'd probably try 200-400mg or at least increase the dose till I find my sweet spot.

Just be sure to have carbs before and during hot therapy. :)

Ya, I usually take an ice cold Coke in with me : )

2g succinic acid is not overwhelming at all. I had been dabbling with the lower doses before. It feels like it turns my muscles on without over activating my mind.

I am using a hefty scoop of aspirin in the bath, 28 grams, the bigger side of the Aniprin scoop. It lets me make the bath hotter and ultimately more deeply relaxing. It has been a good time to work out the block in my diaphragm and practice normal breathing.
 

cjm

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There was a study on this, but the results were too phony. I discussed it in my aspirin and mitochondria article.

Very informative review, thanks for the write up.

"Most of the fearmongering of aspirin destroying the mitochondria is unfound and bad science. Many human studies show that those taking 3-4g for many months on end or even 7-9g for a few weeks suffer little to no side effects.

But if you want to play it on the safe side, you can take compounds that support the electron transport chain to ensure energy production remains optimal. Compounds such as methylene blue, vitamin K2 (MK-4), succinic acid and CoQ10."


I would take a bath in K2 if I could afford it. Stuff is magic for muscles.
 
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Hans

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2g succinic acid is not overwhelming at all. I had been dabbling with the lower doses before. It feels like it turns my muscles on without over activating my mind.
Really interesting. Do you feel stronger in a way and more explosive at that dose?
 

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Really interesting. Do you feel stronger in a way and more explosive at that dose?

100%. Deeper awareness of muscle, less "noise", less weakness, more "calm ready" energy, maybe better reflex/tendon action.
 
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100%. Deeper awareness of muscle, less "noise", less weakness, more "calm ready" energy, maybe better reflex/tendon action.
Great! Where do you buy yours?
 

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No I haven't, but it's definitely on my list.

I'd definitely be curious to see how it works for you. It works better in a stack. On its own, in a body in good health, I bet it doesn't do much. I was reading an article about how succinate leaves the mitochondria goes to other parts of the body but only under stress:

"...under normal energy balance, mitochondrial succinate serves its principal role in energy production in the Krebs cycle. Neither accumulation of succinate in the mitochondria nor leakage of succinate out of the mitochondria occurs..."

Maintenance of Homeostasis in the Aging Hypothalamus: The Central and Peripheral Roles of Succinate

~~~

I started taking Alka Seltzer in addition to the aspirin baths and got some extra energy in combination with the succinic acid. I took about 2g aspirin yesterday in divided doses in combination with 2g of succinic in a single dose upon waking.

I'm also wondering if calcium would make good scientific sense in this stack and have started experimenting with some powdered bone (not ideal, just what I have on hand). I got a surge of energy after ~700mg elemental calcium (1/2 tsp) last night, being mindful to take some magnesium along with it (bicarb water).

"This is certainly only one reason, but given how important for metabolism it is I thought it is worth mentioning. Calcium activates the enzyme pyruvate dehydrogenase (PDH), which takes the pyruvate produced by glycolysis, converts it to Acetyl-Co-A and thus starts the Krebs cycle. Calcium also seems to activate the other enzymes participating in the Krebs cycle."

Why Ray Recommends Eating Lots Of Calcium
 
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I'd definitely be curious to see how it works for you. It works better in a stack. On its own, in a body in good health, I bet it doesn't do much. I was reading an article about how succinate leaves the mitochondria goes to other parts of the body but only under stress:

"...under normal energy balance, mitochondrial succinate serves its principal role in energy production in the Krebs cycle. Neither accumulation of succinate in the mitochondria nor leakage of succinate out of the mitochondria occurs..."

Maintenance of Homeostasis in the Aging Hypothalamus: The Central and Peripheral Roles of Succinate

~~~

I started taking Alka Seltzer in addition to the aspirin baths and got some extra energy in combination with the succinic acid. I took about 2g aspirin yesterday in divided doses in combination with 2g of succinic in a single dose upon waking.

I'm also wondering if calcium would make good scientific sense in this stack and have started experimenting with some powdered bone (not ideal, just what I have on hand). I got a surge of energy after ~700mg elemental calcium (1/2 tsp) last night, being mindful to take some magnesium along with it (bicarb water).

"This is certainly only one reason, but given how important for metabolism it is I thought it is worth mentioning. Calcium activates the enzyme pyruvate dehydrogenase (PDH), which takes the pyruvate produced by glycolysis, converts it to Acetyl-Co-A and thus starts the Krebs cycle. Calcium also seems to activate the other enzymes participating in the Krebs cycle."

Why Ray Recommends Eating Lots Of Calcium
Even though in a healthy individual it might not do much, but it will probably still have a beneficial effect on exercise performance when there is a lot of demand on the system. I'm particularly interested in the effect of feeling more connected as you mentioned. That's when the magic happens.

In terms of calcium, I always have at least 2.4g per day and sometimes up to 6g (all from dairy) so I don't think I'll benefit more there lol. But yeah, calcium is definitely essential for proper glucose oxidation.
 

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when there is a lot of demand on the system

I used to always see generality in demands. Personal observation: in a lactic-acid-dominated body, mental demands are prominent, since the muscles are burdened (or burden the whole system) to a point where the mind loses awareness of them. Now that I'm making new body connections, I'm sensing the hunger and force of my muscles. My mental demands ("marching orders") are going away almost as a side effect of greater body feeling. I swear to God I can feel my liver for the first time. Breathing is becoming normal.

n terms of calcium, I always have at least 2.4g per day and sometimes up to 6g (all from dairy) so I don't think I'll benefit more there lol. But yeah, calcium is definitely essential for proper glucose oxidation.

Nice! Kind of inspiring, haha! When my appetite is up, ice cream is a good friend : )

Glucose oxidation is finally starting to make sense to me.
 
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I used to always see generality in demands. Personal observation: in a lactic-acid-dominated body, mental demands are prominent, since the muscles are burdened (or burden the whole system) to a point where the mind loses awareness of them. Now that I'm making new body connections, I'm sensing the hunger and force of my muscles. My mental demands ("marching orders") are going away almost as a side effect of greater body feeling. I swear to God I can feel my liver for the first time. Breathing is becoming normal.
I'm not sure I completely understand your first sentence. What I think you're saying is that in a lower energy state your brain has to work harder to tell the muscles what to do, but in a higher energy state, muscles are more connected and can work almost independent of the conscious mind. Is that correct?
Just for clarification (if needed), in terms of demand, I was referring to cellular energy production in the muscle. Exercise creates a huge energy demand, so if cellular function isn't optimal, power output might be suboptimal. So succinic acid, by enhancing energy production, can help with connectivity and power output during high energy-demanding tasks.
 

cjm

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I'm not sure I completely understand your first sentence. What I think you're saying is that in a lower energy state your brain has to work harder to tell the muscles what to do, but in a higher energy state, muscles are more connected and can work almost independent of the conscious mind. Is that correct?
Just for clarification (if needed), in terms of demand, I was referring to cellular energy production in the muscle. Exercise creates a huge energy demand, so if cellular function isn't optimal, power output might be suboptimal. So succinic acid, by enhancing energy production, can help with connectivity and power output during high energy-demanding tasks.

Yeah, that's it! The implication was that the brain that's always having to boss muscles around is depleted from the task. Bossing muscles around actually becomes a vicious cycle when the muscles don't relax, the implication being that the energy that might be available for resetting the contracted state is being used by the brain to command a new contraction. Also, there are *always* mental demands and they are wildly subjective compared to physical demands where you can't hallucinate how heavy something is. I was giving them equal footing before but I guess I'm saying it was a trick of the mind.
 

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cjm

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I'm not sure I completely understand your first sentence. What I think you're saying is that in a lower energy state your brain has to work harder to tell the muscles what to do, but in a higher energy state, muscles are more connected and can work almost independent of the conscious mind. Is that correct?
Just for clarification (if needed), in terms of demand, I was referring to cellular energy production in the muscle. Exercise creates a huge energy demand, so if cellular function isn't optimal, power output might be suboptimal. So succinic acid, by enhancing energy production, can help with connectivity and power output during high energy-demanding tasks.

But yes, I think we are on the same page, that there is false generality in comparing physical and mental demands, though I can't resist using cellular energy production in neurons and muscles as a common denominator to draw comparisons. I'd like to offer my personal situation in the 2010's as a mental hell that has been more demanding that any physical workout but it's hard to distill into an easy analogy.

Edit: last thought from the philosopher's chair, but my whole mental/physical distinction feels like masturbation when I remember this Ray quote:

“Nerves and muscle cells should be considered together, because they respond to many things in similar ways. The membrane people don’t like to think that nerves have an contractile properties, but in fact they do twitch slightly when stimulated, showing that in the entire cytoplasm that responds to information, not the hypothetical plasma membrane. When they are overstimulated, they swell, as muscles do when they are fatigued. When a muscle is stretched while it’s trying to contract (as in running downhill; this is called “eccentric contraction”) it becomes inflamed, and the structural damage is cumulative. By exercising muscle with “concentric contractions,” allowing them to shorten against resistance, the cellular damage can be repaired.”

Ray Peat, PhD and Concentric Exercise – Functional Performance Systems (FPS) (not sure the original source)
 
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LadyRae

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Even though in a healthy individual it might not do much, but it will probably still have a beneficial effect on exercise performance when there is a lot of demand on the system. I'm particularly interested in the effect of feeling more connected as you mentioned. That's when the magic happens.

In terms of calcium, I always have at least 2.4g per day and sometimes up to 6g (all from dairy) so I don't think I'll benefit more there lol. But yeah, calcium is definitely essential for proper glucose oxidation.
I've been taking succinic acid in the mornings before I go walking with my dog. A few times a week we throw in some sprints... and handstands at a grassy park. It gives me markedly increased energy and alertness, kind of like caffeine/nictotine/Yohimbe without the anxiety and jitters.

I stack it with 5g methylene blue, 1 g aspirin, and caffeine. (By this point in my morning I've had a lit of coffee ?)

I bought the Amazon product linked earlier in the thread, the 100gm bottle of crystals. I just dip the tip of a knife in and stir that small amount of crystals into warm water. No dosing recommendations on the bottle.

I suspect it is causing loose stools in the evening...has anyone noticed this? No bloating or obvious digestive stress prior to the bathroom experience...

Already enjoying Solban on my face, but I'm curious about applying succinic acid water before bed.
 

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