NAD/NADH Ratio - The One Metabolic Cause To Rule Them All

[Motorneuron]

Niacinamide makes what exactly worse?

If your NAD+ salvage pathway is impaired , niacinamide (NAM) won't do much. Worst case, none of the B3's will do much at all for increasing NAD+.

However, there are other ways to increase NAD+. For example, quinones such as beta-lapachone (from Pau D'Arco) are known to increase the NAD+/NADH ratio even in the presence of a defective NAD+ salvage pathway. Have you tried Lapodin or Pau D'Arco?

Thanks, I've never tried those ... but I tried a small amount of K2 on the wrist and it had a very positive effect ... only 10mcg ... but I have no idea if it somehow drained the way and the accumulation of the ratio in favor of the NADH. From what I understand K2 behaves like a quinone.

I believe niacinamide has to be combined with ribose to make nicotinamide riboside ... I probably use a ridiculous dosage for my critical health so 100mg might be irrelevant in MY case

 

[Jam]

If using a source of Pau D'Arco is an alcohol extraction superior to a glycerite? I see lots of companies claiming the latter but the studies say otherwise.i have a feeling a lot of the glycerite tinctures claims of superiority are mostly about people who have reservations of taking alchohol, no matter how little quantity

Yes. The best source would be high-quality powdered bark, but hard to know for sure that you're getting a quality product. NOW Foods Pau D'Arco has always worked well for me. Otherwise, something like Lapodin is probably your best bet, even though it also contains emodin, but at least you know exactly how much beta-lapachone you're getting. I personally combine the two (Lapodin with the powdered bark), as the latter has other beneficial compounds that synergize with the beta-lapachone.

 

[Motorneuron]

Yes. The best source would be high-quality powdered bark, but hard to know for sure that you're getting a quality product. NOW Foods Pau D'Arco has always worked well for me. Otherwise, something like Lapodin is probably your best bet, even though it also contains emodin, but at least you know exactly how much beta-lapachone you're getting. I personally combine the two (Lapodin with the powdered bark), as the latter has other beneficial compounds that synergize with the beta-lapachone.

Does methylene blue behave similarly at low dose by donating electrons? Do high-dose and low-dose quinones have a different impact on mitochondrial transport?

 

[Motorneuron]

Yes, there is a congestion and it is called excessive glycolysis and not enough Krebs cycle activity or electron transport chain (ETC) activity. I mentioned this a few times in the Danny Roddy podcasts. Carbs go through glycolysis and generate pyruvate. In the process existing NAD in the body is reduced to NADH. So, at the end of glycolysis there is a buildup of both pyruvate and NADH. If the enzyme pyruvate dehydrogenase (PDH, Pyruvate dehydrogenase - Wikipedia), which is downregulated in virtually all diseases/hypothyroidism/cancer, is not working well then the body is stuck and since it needs its NAD to continue operating at all it will have to oxidize that excess NADH back to NAD somehow. In normal metabolism the oxidants are quinones and ultimately oxygen. But in anaerobic glycolysis there is no oxygen so the body will use pyruvate as the emergency oxidizing agent. So, the enzyme LDH will oxidize NADH back to NAD using pyruvate as the oxidant and this will generate NAD and lactate. In cancer, this process occurs even when oxygen is present and it called excessive aerobic glycolysis. Giving niacinamide will raise NAD and the total NAD+NADH pool because new NAD will be generated from niacinamide. This helps as the activity of PDH depends on the NAD/NADH ratio (as well as thiamine and magnesium). So far it has not been shown that raising the total pool of NAD+NAH by supplying extra niacinamide is a bad thing. To the contrary, the body always needs nucleotides and niacinamide also inhibits SIRT1 and fatty acid oxidation, which are all good things. But if you don't want to consume extra niacinamide and raise the total pool then you need other oxidizing agents to avoid LDH getting activated and generating lactate. Quinones like vitamin K2 and emodin, and especially methylene blue (MB) are all oxidizing agents that can oxidize NADH back to NAD even if there is an issue like cancer. So, with quinones/MB you can avoid the excessive lactate buildup and can raise the NAD/NADH ratio even in cases of excessive aerobic glycolysis. If the NAD/NADH ratio is raised, and assuming there is no thiamine/magnesium deficiency the enzyme PDH will resume working. Quite a bit of work has been done on cancer, diatebes and other metabolic diseases to see if there is an actual damage to PDH in those conditions and the answer so far is a resounding NO. So, PDH is simply downregulated and can be upregulated by raising the NAD/NADH ratio and/or supplying extra thiamine. As a side note, the case with thiamine is especially interesting as it also inhibits the enzyme PDK just like the anti-cancer drug DCA does. In addition, MB can help the electrons from food bypass complex I, II, and III of the mitochondrial electron transport chain in case they are not working properly and if this was not good enough MB can also activate the last complex (IV) also known as cytochrome C oxidase (which Peat has written about extensively) in cases where it is being blocked by things like NO or PUFA. Very few other chemicals can match MB in its systemically pro-metabolic effects. Thyroid (T3) is one of them and progesterone is another. DHEA, niacinamide, pregnenolone, magnesium, etc are next in the metabolic ladder. Thus, it becomes immediately clear why Peat writes about all of these chemicals in pretty much every newsletter.
Furthermore, the importance of high NAD/NADH ratio does not stop with glycolysis ad pyruvate. NAD is also needed in the Krebs cycle, so a high NAD/NADH ratio contributed to high activity of the Krebs cycle. NAD is consumes (reduced) and NADH relesed in the following Krebs cycle steps: oxidation of malate to oxaloacetate, oxidation of isocitrate to alpha-ketoglutarate, and oxidation of alpha-ketoglutarate to Succinyl-CoA. Why is high activity of the Krebs cycle important? Because high activity of Krebs cycle or ETC inhibits glycolysis. So, in a cancer cell where glycolysis is excessive and Krebs/ETC activity is low this is how you get these cells to revert to normal - by inhibiting this excessive glycolysis. As long as glycolysis is excessive and lactate is overproduced the cell will continue growing and dividing. Also, it is the Krebs cycle where CO2 is being generated and since CO2 also inhibits lactate formation it is another important reason to keep Krebs cycle activity high.
In summary, a combination of MB, niacinamide, thiamine, and biotin can be a very powerful pro-metabolic stack which should benefit virtually all conditions. Thyroid (T3) may also be needed in the most extremely deranged cases but the stack should provide noticeable benefit to the vast majority of people. I mention biotin because biotin is another chemical that can help the buildup of pyruvate bypass the PDH and enter the Krebs cycle, which also avoids overactivation of LDH. Biotin activates (Effects of biotin on pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and markers for glucose and lipid homeostasis in type... - PubMed - NCBI) the enzyme pyruvate decarboxylase (PDC, Pyruvate decarboxylase - Wikipedia) which can convert pyruvate to oxaloacetate and this allows metabolism to continue on to the Krebs cycle. PDC is the alternaive to PDH if it is not working or downregulated for some reason but given that they both have same cofactors, it is uncommon to have one of them working well and the other one not. The cofactors for PDC are also thiamine and magnesium, so you immediately see why it is important to have thiamine and magnesium in sufficient quantities - both PDH and PDC depend on them as cofactors.
I may be oversimplifying it a bit but I think this is a good illustration of quite a few of Ray's points and one of this depends on studies - i.e. as Gbolduev likes to say this is standard biochemistry written in every book and makes it immediately clear what Pest is all about and why it works.

Hey @Travis, @Such_Saturation and @aguilaroja - please review and keep me honest here if I made any mistakes. Thanks in advance.

why is progesterone considered pro metabolic?

 

[Jam]

Does methylene blue behave similarly at low dose by donating electrons? Do high-dose and low-dose quinones have a different impact on mitochondrial transport?

Both donate and accept electrons as needed.

 

[Motorneuron]

Both donate and accept electrons as needed.

K2 MK7 or rather MK4?

 

[Inaut]

K2 MK7 or rather MK4?

I think his response was to the methylene blue comment

 

[ddjd]

Here in Minsk Cytoflavin is also sold in tablets. 1 tablet contains: Succinic Acid 300mg, Inosine 50mg, Nicotinamide 25mg, Riboflavin 5mg. Doses: 2 tablets twice a day 30 min before eating.
10ml ampule contains: Succinic Acid 1000mg, Inosine 200mg, Nicotinamide 100mg, Riboflavin 20mg. Once a day.

Bloody hell that's like the most peat supplement ever. Got to love the Russians

 

[Inaut]

Bloody hell that's like the most peat supplement ever. Got to love the Russians

If anybody has a good source let me know. I bet ordering will be tough for us "Westerners" now

 

[Regina]

If anybody has a good source let me know. I bet ordering will be tough for us "Westerners" now

There's always cardenosine.

 

[FitnessMike]

Niacinamide must be a missing link for my energy production cycle to finally function properly, as it seems that my NDT started working better.

The only problem is that it causes insomnia, anyone has any idea to combat that effect?

 

[A-Tim]

Niacinamide must be a missing link for my energy production cycle to finally function properly, as it seems that my NDT started working better.

The only problem is that it causes insomnia, anyone has any idea to combat that effect?

Have you tried a low dose first thing in the morning. If no insomnia, taper up until you find the point at which insomnia occurs. Taper back a little and hold the line there.

 

[Jessie]

Niacinamide must be a missing link for my energy production cycle to finally function properly, as it seems that my NDT started working better.

The only problem is that it causes insomnia, anyone has any idea to combat that effect?

Do you know what your vitamin D status is? Niacinamide can lower PTH, which is the primary antagonist to thyroid hormone. However the primary antagonist to PTH is vitamin D.

It may be revealing to you that your PTH has been suppressing your ability to utilize NDT properly. In which case you could use something like zinc, calcium, magnesium, or D3 instead.

 

[FitnessMike]

Have you tried a low dose first thing in the morning. If no insomnia, taper up until you find the point at which insomnia occurs. Taper back a little and hold the line there.

that's the plan, 250mg doesn't cause insomnia but won't increase pulse much, if i would manage to take 1g of niacinamide that would be splendid

 

[FitnessMike]

Do you know what your vitamin D status is? Niacinamide can lower PTH, which is the primary antagonist to thyroid hormone. However the primary antagonist to PTH is vitamin D.

It may be revealing to you that your PTH has been suppressing your ability to utilize NDT properly. In which case you could use something like zinc, calcium, magnesium, or D3 instead.

My Vit D is decent level around 120, I also consume dairy so calcium is in daily. I was thinking about how niacinamide maybe upregulates NAD which was probably low in hypothyroid people and this is how energy production is supported better with niacinamide and thus better pulse, that is pure speculation, but we know b3 is crucial in energy production.

Reacting so well to niacinamide makes me believe that I might be missing a cofactor in the energy production cycle.

 

[Jessie]

My Vit D is decent level around 120, I also consume dairy so calcium is in daily. I was thinking about how niacinamide maybe upregulates NAD which was probably low in hypothyroid people and this is how energy production is supported better with niacinamide and thus better pulse, that is pure speculation, but we know b3 is crucial in energy production.

Reacting so well to niacinamide makes me believe that I might be missing a cofactor in the energy production cycle.

Yeah, I would say that's a plausible explanation. NAD is unquestionably low in hypo people. It may also be related to niacin's ability to lower fatty acids in the serum. Or both, which is likely.

 

[FitnessMike]

Yeah, I would say that's a plausible explanation. NAD is unquestionably low in hypo people. It may also be related to niacin's ability to lower fatty acids in the serum. Or both, which is likely.

Have you got any idea how to negate insomnia coming from higher doses of b1/b3?

 

[Jessie]

Have you got any idea how to negate insomnia coming from higher doses of b1/b3?

Well B1 can be energizing. In fact many people compare it to thyroid supplementation. So It's probably best to take that up in the day. At least 6-8 hours before bed.

The B3 is a bit of a mystery. Can't really say for sure why that would be causing insomnia. Most of the evidence I've seen suggest it's actually a sedative. https://www.researchgate.net/public..._benzodiazepine-like_properties_A_case_report


B3 is a metabolic enhancer, so making sure you top off your liver glycogen before bed would be wise. Glass of warm milk with sugar and gelatin might help.

 

[FitnessMike]

Well B1 can be energizing. In fact many people compare it to thyroid supplementation. So It's probably best to take that up in the day. At least 6-8 hours before bed.

The B3 is a bit of a mystery. Can't really say for sure why that would be causing insomnia. Most of the evidence I've seen suggest it's actually a sedative. https://www.researchgate.net/publication/268221528_Niacinamide's_potent_role_in_alleviating_anxiety_with_its_benzodiazepine-like_properties_A_case_report


B3 is a metabolic enhancer, so making sure you top off your liver glycogen before bed would be wise. Glass of warm milk with sugar and gelatin might help.

either of them in doses 500mg gives me onset insomnia, taken first thing in the morning, it makes brain wired somehow due to some neurotransmitters probably...

 

[Badger]

Yeah, unfortunately they are still pursuing the same old and discredited theory that activating sirtuins is the key to reverse aging and disease. Pterostilbene is just a more bioavailable form of resveratrol and Peat wrote a whole article on the resveratrol scam. I posted about it a few times too. If you search the forum for resveratrol you will find the threads. The infamous drug Vioxx, which killed quite a few people is also a stilbene and most/all stilbenes (including resveratrol) are estrogenic.
Aside from the nicotinamide riboside being crazy expensive for no good reason, a much better supplement to raise NAD/NADH ratio and achieve a host of other benefits would be a combination of plan niacinamide with methylene blue.

"Many of the extensive studies on the potential health benefits of pterostilbene were conducted by Dr. Agnes Rimando, a scientist with the United States Department of Agriculture, in collaboration with many U.S. and other international research groups. This review highlights the pterostilbene research of Dr. Rimando."

Chemistry of Pterostilbene and Its Metabolic Effects

Chemistry of Pterostilbene and Its Metabolic Effects - PubMed

Pterostilbene, 3',5'-dimethoxy-4-hydroxystilbene, is a resveratrol analogue and has been reported to have similar and often potent health-promoting properties. Pterostilbene has been shown to reduce weight gain, liver fat, plasma cholesterol, adiposity, inflammatory biomarkers, blood glucose...

pubmed.ncbi.nlm.nih.gov