Niacinamide Or Just Plain Niacin?

[Amazoniac]

Yes I see that, but can you significantly raise NAD+ with that dose? Either way, for me personally niacinamide has always been a mixed bag, the times I tried it.

No, I am from het land dat deels onder de zeespiegel ligt: Nederland

40 mg + content of the meal should be about 3x the RDA in one sitting.

NAD levels are dramatically altered by dietary levels of niacin.[59]

https://www.l-i-g-h-t.com/transcript-337
"coffee is a major dietary source of niacin"

Gerson in his book:
"Niacin is administered for a long time: 50 mg. six times daily, rarely more; after four to six months the dosage should be reduced."

Have you considered buying it pure?

Cool! I think Kasper is from there.

 

[Suikerbuik]

40 mg + content of the meal should be about 3x the RDA in one sitting.


https://www.l-i-g-h-t.com/transcript-337
"coffee is a major dietary source of niacin"

Gerson in his book:
"Niacin is administered for a long time: 50 mg. six times daily, rarely more; after four to six months the dosage should be reduced."

Have you considered buying it pure?

Cool! I think Kasper is from there.

Thank you as usual. I've seen that quote, but in the light of a forced vitamin B3 deficiency it is logic that dietary niacin increases NAD levels (it's not clear from the abstract, ref 59).

I should have it pure; I will try ~40mg doses when I feel like to. (Right now I'm most stable/balanced/energetic with vitamin K and methylene blue (<1mg) only, and proper diet of course.)

Yeah Kasper is from here too, as is Vinero and other people.

 

[Amazoniac]

- Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice

"[..]in the old mice in this study, NAM depressed NAM salvage and did not produce a net boost in the NAD metabolome. While the increased SIRT1 accumulation might have been anticipated based on Me-Nam-dependent stabilization mechanism (Hong et al., 2015; Trammell and Brenner, 2015), the ability of NAM to depress NAMPT expression was not anticipated. Quantitative metabolomic analysis has made it clear that oral NR boosts hepatic NAD metabolism and sirtuin activity independently of NAMPT (Ratajczak et al., 2016; Fletcher et al., 2017), thereby leading to a wave of hepatic NAM production (Trammell et al., 2016a). Whether this metabolite would undermine or amplify the effect of the boosted NAD metabolome remains in question. Further work is needed to determine whether alteration of the control of NAM catabolism in the liver can promote pro-longevity effects like those elicited by the NAD precursors NR and NMN (de Picciotto et al., 2016; Mills et al., 2016). The data in this study support salutary effects of NAM."​

- https://www.researchgate.net/scientific-contributions/40089704_Adrian_C_Williams:

- Nicotinamide: A double edged sword - ScienceDirect (#41)
- Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis Evolved and Became a Determinant of Ageing Diseases: Hypotheses and Lessons from Pellagra (*)
- Big Brains, Meat, Tuberculosis, and the Nicotinamide Switches: Co-Evolutionary Relationships with Modern Repercussions?
- Big brains, meat, tuberculosis and the nicotinamide switches: Co-evolutionary relationships with modern repercussions on longevity and disease? - ScienceDirect
- Meat and Nicotinamide: A Causal Role in Human Evolution, History, and Demographics
- Meat Intake and the Dose of Vitamin B3 – Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures?​

When you read right away his compilation of food sources, you start hoping that it was just a typo for mg/1000g and not that he based most of his arguments on that.​

 

[Amazoniac]

- Biochemistry of Nicotinic Acid and Nicotinamide (Abram Hoffer)

"Pellagra is due to a deficiency of NAD, and it is conceivable that a patient may have normal quantities of nicotinic acid in the diet and have pellagra because of a failure to synthesize NAD."

"The best known pathway for losing pyridine molecules is by the methylation of nicotinamide to N methyl nicotinamide. This reaction is accelerated by methyl donors such as methionine and is inhibited by tranquilizer phenothiazines, but not by nontranquilizer phenothiazines. Buscaino (1966) found this reaction accelerated in acute schizophrenic blood in vitro. Another way of losing pyridine is by excessive conjugation of nicotinic acid with glycine to form nicotinuric acid. This reaction theoretically can be blocked by para amino benzoic acid (PABA) which is a competitor for glycine."

"The pyridine nucleotide cycle also involves the adrenaline, oxidized adrenaline and adrenochrome cycle and several other substances including riboflavin and the coenzyme FAD, ascorbic acid and dehydroascorbic acid. It also is under the control of the pituitary gland. When animals are hypophysectomized the deamidation of nicotinamide to nicotinic acid is greatly increased."

"Robie [1966] believes nicotinic acid is much more effective for schizophrenia than nicotinamide. My experience is the same, especially for chronic schizophrenics."

"Nicotinamide should be less toxic because it is not acidic."

"In some experiments dogs were injured by nicotinic acid, but not by sodium nicotinate. Dogs seem especially sensitive to acidity."

"Nicotinic acid and nicotinamide are remarkably safe compared with the whole field of chemotherapy. I doubt whether anyone could commit suicide with it. Recently, a subject just beginning treatment took about 90 grams nicotinic acid at one time. She later had a stomach ache, but there was no change in level of consciousness at any time. But no matter how safe a chemical may be, every patient taking it and every physician prescribing it must be aware that side effects and toxic effects can and will occur and must know how to deal with them."​

- The Chemistry and Biochemistry of Niacin (B3)

"Nicotinic acid and nicotinamide (Table 7.1) are colourless crystalline substances; each is insoluble or only sparingly soluble in organic solvents. Nicotinic acid is slightly soluble in water and ethanol; nicotinamide is very soluble in water and moderately soluble in ethanol."

"Nicotinic acid is zwitterionic in nature; at high pH it is negatively charged at the carboxylic function, while at low pH it is positively charged at the pyridinyl nitrogen. Thus it is considered an amphoteric molecule because it forms salts with acids as well as bases (Mullangi and Srinivas 2011) (Figure 7.1)."

"Both nicotinic acid and nicotinamide are very stable in dry form (Gonc¸alves et al. 2011); in solution nicotinamide is hydrolysed by acids and bases to yield nicotinic acid."

"Meat and fish have the scarce free form of niacin and niacinamide but contain high levels of NAD/ NADP, which are available as niacinamide after digestion (Prousky et al. 2011)." [It's possible that the guy above was accounting for these]

"In tissues that lack the complete de novo NAD biosynthesis pathway, nicotinamide is thought to be chosen over nicotinic acid as the main precursor for NAD biosynthesis (Houtkooper et al. 2010)."​

This diagram is useful:

Metabolism of sulfur amino acids. (from Stearoyl-CoA Desaturase-1: Is It the Link between Sulfur Amino Acids and Lipid Metabolism?)

Spoiler: Expand

X at the center (below AdoMet), is the methyl group acceptor (in the case here, niacin), which becomes methylated ('N¹-methylnicotinamide' or 'NMN'). As the name does the implyings, methyltransferases are the enzymes required for transfering these groups.

Glycine (through another transferase called 'Glycine N-methyltransferase', 'GNMT' that Terma talked about earlier) can prevent an excess of methionine acting in a similar manner as niacin. Sonlercevy, too much methionine depletes usable glycine, and a diet that minimizes animal proteids can help to conserve it.

N¹-methylnicotinamide can be further metabolized for excretion to two molecules that require aldehyd oxidase (pg. 2). The enzyme needs mainly riboflavin and molybdenum. Molybdenum is also involved in the final degradation of cysteid. Here as well, a diet that minimizes animal proteids has the potential to spare it.

According to what have been posted, it's the recycling on the right (betain but affecting cholin as well) that can be compromised with high doses.
Glycine, creatine and choline should prevent problems.

For low doses of niacin, depletion doesn't seem to be a concern.
What's puzzling is why Gerson didn't choose nicotinamide over nicotinic acid since it appears to be superior.

Favoring nicotinamide:
- Nicotinamide stimulates repair of DNA damage in human lymphocytes - ScienceDirect

Favoring nicotinic acid:
- Comparative Effects of Nicotinic Acid and Nicotinamide on Cholera Toxin-induced Secretion in Rabbit Ileum

 

[SOMO]

@Amazoniac Is Niacin Flush caused by...
1. FFA/NEFA Release
2. Prostaglandin production
3. Adrenaline increase?

Or perhaps its all of these?

This study talks about changing O3:O6 ratio in adipose, which is worrisome, considering I used to supplement heavily with PUFA (Fish Oil AND Hemp Oil and that other sludge.)
Prolonged niacin treatment leads to increased adipose tissue poly-unsaturated fatty acid synthesis and an anti-inflammatory lipid and oxylipin plasma profile

Short term niacin treatment inhibits non-esterified fatty acid (NEFA) release from adipocytes and stimulates prostaglandin release from skin Langerhans cells, but the acute effects diminish upon prolonged treatment, while the beneficial effects remain...Also, adipocytes from niacin treated mice secreted more of the PUFA docosahexaenoic acid (DHA) ex vivo. This resulted in an increased DHA/arachidonic acid (AA) ratio in the adipocyte FA secretion profile and in plasma of niacin treated mice. Interestingly, the DHA metabolite 19,20-dihydroxy docosapentaenoic acid (19,20-diHDPA) was increased in plasma of niacin treated mice. Both an increased DHA/AA ratio and increased 19,20-diHDPA are indicative for an anti-inflammatory profile

Any reason why a higher DHA:AA ratio would be better? Does "anti-inflammatory" profile really mean immune-suppressive profile, since O3 is going up proportionately?

 

[Terma]

Consider this..
https://link.springer.com/article/10.1007/s00125-015-3678-5

This is what I was talking about in the beginning:

In fact, there is evidence that the effects of excess nicotinamide on insulin resistance are mediated by MNA, the product of the reaction catalysed by NNMT

Any study that uses MNA as the means to experimentally inhibit NNMT by product feedback inhibition should be laughed at.

This also has interesting consequences:

NNMT knockdown led to an increase in the SAM/SAH ratio and histone methylation in vitro [14] and in vivo [4]

I guess you could compensate with more glycine and/or RA, but the question becomes tissue-specific, though at least these are all major in liver.

 

[Terma]

This is not news, but you might also be interested in knowing this, which shows the complementary/antagonism of RA and T3 on a different level:
Triiodothyronine treatment attenuates the induction of hepatic glycine N-methyltransferase by retinoic acid and elevates plasma homocysteine concentrations in rats — University of Illinois at Urbana-Champaign

Recent studies indicated that hormonal imbalances have a role in modulating the metabolism of methyl groups and homocysteine, interrelated pathways that when disrupted, are associated with a number of pathologies. Retinoic acid (RA) was shown to induce hepatic glycine N-methyltransferase (GNMT), a key regulatory protein in methyl group metabolism, and to reduce circulating homocysteine levels. Because thyroid status influences the hepatic folate-dependent one-carbon pool and retinoids can alter thyroid hormone levels, the aim of this study was to examine the interaction between retinoids and thyroid function. For hypothyroid studies, rats were administered 0.5 g/L propylthiouracil in the drinking water for 15 d, and RA [30 μmol/(kg·d)] for the final 5 d. For hyperthyroid studies, rats were treated with RA [30 μmol/(kg·d)] for 8 d and triiodothyronine [T3; 50 μg/(100 g·d)] the last 4 d. T3 treatment prevented the RA-mediated increase in GNMT activity. However, GNMT abundance remained elevated, indicating that GNMT regulation by T3 in RA-treated rats may be, at least in part, at the post-translational level. In addition, T3 treatment elevated plasma levels of homocysteine 177%, an elevation that was prevented by RA. T 3-mediated hyperhomocysteinemia may be due to a 70% decrease in hepatic betaine-homocysteine S-methyltransferase, the enzyme that catalyzes folate-independent remethylation of homocysteine, whereas the RA-mediated stimulation of hepatic homocysteine remethylation by folate-dependent methionine synthase may contribute to lowering plasma homocysteine levels. These findings indicate that thyroid hormones, alone and in conjunction with RA, play an important role in the regulation of methyl group and homocysteine metabolism.

 

[Amazoniac]

This is what I was talking about in the beginning:

Any study that uses MNA as the means to experimentally inhibit NNMT by product feedback inhibition should be laughed at.

This also has interesting consequences:

I guess you could compensate with more glycine and/or RA, but the question becomes tissue-specific, though at least these are all major in liver.

Have you read this?

 

[Terma]

Have you read this?

Yeah, that part is dear to me.

I mean in the sense of, quantitatively how many methyl groups would get spared by successful therapeutic inhibition of NNMT? For figuring out what doses of glycine/RA/other you need afterward. I find this difficult because I don't experience any overt or even noticeable symptoms from "excessive" methyl consumption (I can take 6g TMG and not tell a difference).

[This matters especially if you're trying to do MR, you wouldn't want to sabotage your efforts]

 

[Amazoniac]

I don't think it's a good idea to block ways for excreting its excess.

The problem with methyl transfering diagrams is that you eventually realize that the same nutrient or enzyme participates in various other reactions still within passing the groups, so it ends up being something like this. For example: I read from Chris that glycine is used as buffer for the process to run smoothly. Most diagrams only show that it can be methylated from methionine, but only a few indicate what happens afterwards; if this same nutrient is actually what's used elsewhere.

The first time that you mentioned glycine I thought that you had in mind its sparing effect on choline or something related to the folate cycle with the enzyme that converts serine to glycine.

Perhaps you can use the molecular weight of methyl radical to estimate how much is being excreted. It must be difficult because it varies depending on the dose. But it should only be concerning for higher doses of niacin or if there's not enough methyl groups.

 

[Terma]

It doesn't have to be absolutes, we can talk about reducing NNMT levels. Nobody knows if full NNMT ablation is safe.

Chris is [partly] right, and while I was thinking most specifically about GNMT, I usually think about glycine as a cofactor-slash-substrate for it - whereas other hormone and hormone-like substances like RA control the actual protein levels of GNMT - that's despite the studies focusing on GNMT that suggested that glycine alone is enough (they don't examine context fully and it is usually in methionine high excess). So I consider the glycine as necessary for GNMT to "run smoothly" but the real control is elsewhere, especially in this context there wouldn't be an abundance of methionine.

I didn't have SHMT in mind, and I don't remember its dynamics (and there are 2 of them), but iirc yeah a high load of glycine might impair SHMT from running forward.

A second factor (which I was thinking about) is that the extra methionine can be captured into creatine synthesis limited by glycine and arginine.

Point being, glycine is antagonistic toward methionine and methyl group surplus one way or another.

There's not a lot of research on the fate of the methylated Sarcosine, if that's part what you were referring to with the spaghetti drawing; but presumably it doesn't go toward undesirables like PEMT, for example.


[edit: I should say, in one of those sentences above, I might be misremembering some of the GNMT studies with some other ones that used glycine not focusing on GNMT, but this wasn't the point anyway]

 

[Terma]

This article you posted is, as predicted, though short, one of the most interesting I've read all year...
Nicotinamide: A double edged sword - ScienceDirect

First of all, they note that Niacinamide could potentially be helping some conditions simply by hogging up NNMT which can produce more dangerous toxins than MNA if exposed to them. I like this angle, but who knows if it's true in common diseases.

Alternatively, it could be accelerating the enzyme (though one of these ideas has to be wrong? or circumstantial, or dose-dependent?):

Nicotinamide and stress induce (as do
presumably other substrates) the enzyme NNMT creating a
more indirect way to toxicity by accelerating the conversion
of all protoxins into toxins (Fig. 1).

Really cool factoids I need to look more into:

Nicotine and probably caffeine are
substrates for NNMT [11] and are protective factors for
Parkinson’s [46].

Nicotine may act as a competitive inhibitor
of NNMT boosting intraneuronal nicotinamide thereby
protecting against dopaminergic neurodegeneration

several drugs of
addiction such as cocaine, heroin, meperidine and amphet-
amine derivatives like ecstasy are N-methyl compounds and
therefore may affect this pathway so it will be important to
understand the role of NNMT/nicotinamide in this context.

One could speculate that evolution has developed a drive
mechanism for more nicotinamide to aid brain and physical
development and that long latency toxicity is just an accident
of nature.

Next they write,

Once charged with the N-methyl group, no toxin can
cross the blood/brain barrier, so the toxication step has to
take place in the brain.

While they mean that MNA will not cross into the brain, it also means N-methylated metabolites should also not readily cross out of it unless metabolized further by MNA and N-MethylX-degrading enzymes or whatnot. This has huge implications for overdoing nicotinamide, methyl overconsumption, and brain detoxification mechanisms.


Then out of nowhere:

N-methyl nicotinamide has useful functions, for instance,
in inhibiting the export of choline

So excess nicotinamide in the brain becomes cholinergic? "Oops", I guess? (Then again people are going way above what RP ever recommended for B3)
Elevation of cerebrospinal fluid choline levels by nicotinamide involves the enzymatic formation of N1-methylnicotinamide in brain tissue. - PubMed - NCBI

Nicotinamide administration can elevate plasma and brain choline levels and produce a marginal increase in striatal acetylcholine levels in the rat. We now report that subcutaneous nicotinamide produces a substantial and long-lasting rise in cisternal cerebrospinal fluid (CSF) levels of choline in free-moving rats, possibly through the enzymatic formation of N1-methylnicotinamide (NMN) in brain. CSF choline levels peaked 2 hours after nicotinamide administration and were accompanied by increases in striatal, cortical, hippocampal and plasma choline levels. The enzymatic formation of [3H]NMN in rat brain was evaluated by incubating aliquots of rat brain cytosol with unlabelled nicotinamide and the methyl donor [3H]S-adenosylmethionine. High performance liquid chromatography and radiochemical detection demonstrated that [3H]NMN was specifically formed by a brain cytosolic enzyme. The production of [3H]NMN was dependent on exogenous nicotinamide and could be prevented by denaturing the cytosol. The metabolism of nicotinamide to NMN in rat brain may explain the rise in CSF choline levels since NMN, a quaternary amine, can inhibit choline transport at the choroid villus and reduce choline clearance.

I don't have time to read that one today, but damn that should be interesting.

 

[Amazoniac]

Ever since I read..

Co-administration of equimolar doses of betaine may alleviate the hepatotoxic risk associated with niacin therapy​

..it bothered me because the suggestions seemed a bit arbitrary. Unfortunately there's isn't much information on reasonable doses of niacin. The greater the dose, the clearer the effects and the less limited you are by sensitivity of techmology required, and it must be why experiments with low doses are rarer.

The author of that publication recommended equimolar doses of betaine and niacin to avoid problems of methyl group depletion. His explanations were vague and didn't offer anything much concrete. To avoid supplying anything beyond what's needed to prevent the depletion, you have to know what happens to niacin when low doses are used, but like it was mentioned it's difficult to find such experiments.

The following one was the best that I could find (although it only involved few people), but I'm going to be using it as reference for its details:

Metabolic Response of Humans to Ingestion of Nicotinic Acid and Nicotinamide

The images below show what happened to humanoids that were given graded doses of niacin. The behavior of nicotinic acid is in blue; and nicotinamide is in orange. The horizontal axis marks the doses of 100, 500, 1000, 2000, 3000 mg. The vertical axis represents the amount of metabolite excretion:

Spoiler

Lower doses are more predictable than higher, as you increase, the interpimptual variances appear.

The concerning metabolites carrying a methyl group for excretion are:

- N1-Methylnicotinamide
- N1-Methyl-2-pyridone-5-carboxamide
- N1-Methyl-4-pyridone-3-carboxamide​

And when you make the overlappings of those two images..

Spoiler

It's blurred, but what matters and can be noted is that no one died with a 3000 mg dose, which is nice. Also, that the methylated metabolites (red) tend to be higher with nicotinamide. The heart is just to draw the attention to the low dose.

I don't know why the authors decided to grade the vertical axis in 250 mg increments, it only makes it more difficult to grasp.
I'm mentioning this because the excretion of N1-methylnicotinamide with a 100 mg dose of nicotinamide was quite high, something like 70 mg. Same thing for N1-Methyl-2-pyridone-5-carboxamide, about 80 mg or so. The excretion products exceeded the dose, and were identified many hours after administration. However, since they increased along with the doses, they might indeed be responding to them.

Unfortunately, the lowest dose was 100 mg, so the unknown between 0-100 mg had to be estimated. This is how it went:

Spoiler

For the divisions, squares were used instead of rectangles to give an idea of how much is excreted in relation to the niacid doses, otherwise it becomes distorted and it's difficult to grasp.

I decided to leave those more precise formulas out of curiosity, but for simplification, you can just consider the underlined part, as if it was linear. The other parts start to make a difference as you increase the dose; since we're concerned with the effects of low doses, it should suffice.
The yellow part is the percentage of the niacin dose that will appear as the given metabolite.

There are some problems with the curves, but they should not affect the concerning area. Keep in mind the reference numbers had to be guessed because they weren't provided.

I should comment that the behavior of niacin might be different when doses lower than 100 mg at a time are used. It's possible it changes the behavior to something like this:

Spoiler

..where there isn't much excretion up until the capability to use it isn't exceeded, followed by a sharp increase as soon as it goes beyond that.

So this discussion only serves for a conservative guess. In other words, the need for methyl groups to negate the detrimental effects can be much lower than our prediction.

For a 50 mg dose of nicotinamide (using those numbers in yellow):

- N1-Methylnicotinamide: 50 * 80% = 40 mg
- N1-Methyl-2-pyridone-5-carboxamide: 50 * 90% = 45 mg
- N1-Methyl-4-pyridone-3-carboxamide: 50 * 40% = 20 mg

Total: 105 mg of methylated metabolites excreted​

Now that we have that estimation, we can guess the proportion of methyl groups excreted based on molecular weights, also known as my crutch calculation.

- N1-Methylnicotinamide: 136.154 g/mol
- N1-Methyl-2-pyridone-5-carboxamide: 152.059 g/mol
- N1-Methyl-4-pyridone-3-carboxamide: 152.151 g/mol​

All 3 have 1 methyl group in the molecule.

- Methyl radical: 15.04 g/mol​

Then, the proportion of methyl group is as follows:

- N1-Methylnicotinamide: 11%
- N1-Methyl-2-pyridone-5-carboxamide: 10%
- N1-Methyl-4-pyridone-3-carboxamide: 10%​

So, from that, you have an idea that the methyl group is about 10% of the molecule weight for all three.

10% of 105 mg = 10 mg. This is (in theory) the maximum loss of methyl groups that needs to be compensated when a nicotinamide dose of 50 mg is used.

Betaine has three methyl groups per molecule, but probably only one can be used to correct this issue more directly.

- Betaine (anhydrous/crystalline/pure): 117.148 g/mol​

And again:

- Methyl radical: 15.04 g/mol​

So, the useful radical in betaine constitutes 12% of the molecule.

If 10 mg is what needs to be compensated, it means that it is those 12%. Then, 85 mg is 100% and is the dose needed to negate issues of methyl group depletion for a 50 mg dose of nicotinamide. Of course this is a rough estimation (yet conservative, because the requirement might be lower than this).

I figured it's helpful to have these notions, or at least something more concrete that can be criticized. If you can spot the mistakes, let me know.

This shouldn't be a concern when someone eats natural foods since the best sources of niacin usually have way more cholin; and in the case of nicotinamide, the food sources often have more methionine as well, so a depletion in methyl groups is very unlikely. Regarding betaine, I read somewhere that the content of foods has been overestimated, but out of curiosity, here's an useful table.

 

[Amazoniac]

@Wiscounselor - do you have an opinion on this topic?

Niacin sometimes refers to nicotinic acid or... | Ray Peat Forum

Not sure about this. If the effect is mediated through transient methyl group depletion, then nicotinamide should be worse than the acid for the same dose.

From the experiment:

"In humans, nicotinamide is degraded mainly via methylation to produce methylated metabolites, N1-methyl nicotinamide and 2-Py[6]. Evidently, excess nicotinamide can increase the consumption of labile methyl groups. Betaine serves as a methyl donor in a reaction converting homocysteine to methionine, whereas choline can be converted to betaine in the liver and kidney[9]. Therefore, the levels of plasma choline and betaine are indicators of the size of methyl-group pool of the body. The present findings that nicotinamide load had a more profound influence on plasma betaine than choline suggest that betaine is a more effective methyl donor than choline."

Spoiler: Figures

"Fig. 3. Plasma betaine (A) and choline (B) levels before
and 5 h after nicotinamide load. Means ± SEM, n = 9.
*P < 0.05 vs before nicotinamide load (–1 h)."

"Fig. 4. Plasma serotonin (A) and histamine (B) levels
before and 5 h after nicotinamide load. Means ± SEM, n = 9.
*P < 0.05 vs before nicotinamide load (–1 h)."

"[..]tryptophan is degraded through tryptophan-kynurenineniacin and tryptophan-serotonin pathways. These two pathways function together to regulate tryptophan homeostasis. For example, an increase in nicotinamide intake can lead to an increase in urinary excretion of 5-hydroxyindoleacetic acid, a metabolite of serotonin[10], suggesting an increase in tryptophan degradation through tryptophan-serotonin pathway (i.e., an increase in serotonin synthesis). Moreover, nicotinamide may affect methylation-mediated serotonin degradation by competing for methyl groups. Therefore, high nicotinamide intake may increase serotonin levels by a mechanism of increased synthesis and decreased degradation."

"In summary, excess nicotinamide increases the plasma monoamine-neurotransmitter levels."​

What we're left with is the prostaglandin issue. But perhaps it doesn't happen when low doses are taken, only amounts that do the elicitings on the the flushings.

@SOMO - I didn't miss your message, it's just that I didn't know what to reply.
The mechanism and mitigation of niacin-induced flushing

 

[Amazoniac]

Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats

"Another interesting finding of the present study is that nicotinamide supplementation significantly reduces uracil content in rat hepatic DNA. A possible explanation for this may involve deoxythymidine monophosphate synthesis. As shown in Fig. 1, dimethylglycine, sarcosine and glycine, which may be derived from betaine catabolism, are involved in the formation of 5,10-methylenetetrahydrofolate, an essential cofactor for the synthesis of deoxythymidine monophosphate from deoxyuridine monophosphate. Thus, the increased catabolism of betaine induced by nicotinamide supplementation could increase the levels of its metabolites, which may facilitate the synthesis of 5,10-methylenetetrahydrofolate-dependent deoxythymidine monophosphate and consequently reduce uracil incorporation into DNA during DNA replication."

Spoiler

Indeed: only one methyl group of betaine supports the regeneration directly.

--
https://raypeatforum.com/community/...t-raising-adrenaline.20665/page-2#post-287774

 

[Amazoniac]

85 mg is 100% and is the dose needed to negate issues of methyl group depletion for a 50 mg dose of nicotinamide

I was making the thoughts as to why the calculation yielded a higher value for betaine in relation to the nicotinamide dose, ending up being different than equal parts of each.

Their graph can be helpful:

Spoiler

On the right, when you make the transposings of the blues, you realize than somewhere between 0 and 100 mg is the moment that gives you the steepest increase in excretory metabolites of all doses. So it might not be wrong to think that the need for something like betaine isn't in equal parts, but being greater for betaine when low doses are concerned.

Adding to that, you have to consider that the colored line above is just one excretory metabolit, and if you were to stack up all those that carry a methyl group for excretion, the amount being eliminated exceeds by far what is ingested at the beginning.

Ps.:
It is interesting that only when doses exceed 2000 mg that methylated nicotinamide is the major metabolit being eliminated, yet the shift (in theory) starts to happen at 1000 mg.

 

[Amazoniac]

Spoiler: Unreliable relative content of nutrients of some foods

..and I still wonder if nicotinic acid (low doses) isn't more sustainable for those that don't any many animal products.

 

[Amazoniac]

The problem in suggesting betaine supplementation along with niacin is that it assumes that the weak link is in regenerating methionine from homocysteine. But Chris made a good point that the problem might be further ahead on the cycle, and that perhaps the body already has too much of those but can't use them.

Betaine might kick in as emergency when the cycle can't run as fast as the metabolism of niacin.

"Methylation is a key mechanism for the degradation of nicotinamide and xenobiotics (13). The present finding that nicotinamide supplementation was associated with a dose-dependent decrease in plasma betaine levels but an increase in choline levels suggests that the methyl groups used for nicotinamide methylation are derived mainly from betaine rather than from choline. The decreased utilisation of choline may be due to the oxidative injury of the liver and kidneys, which are responsible for the conversion of choline to betaine (28). Thus, it appears that under oxidative stress conditions, betaine is an effective methyl donor, but choline is not. This may help explain why the metabolic syndrome, which is characterised by oxidative stress (29, 30), is associated with high plasma choline levels and low betaine levels (31)."

B12 should be relevant.
If you consider that nicotinamide isn't found in foods without it, maybe one cooperates with the other.

- Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Levels of Nicotinic Acid and Nicotinamide (Niacin)

"In animal tissues niacin is present mainly as the coenzymes NAD and NADP (Henderson, 1983; Turner and Hughes, 1962)."

"The flushing activity appears to be related to the presence of a carboxyl group on the pyridine nucleus since compounds lacking this function, including nicotinamide, are not associated with facial flushing (Bean and Spies, 1940)."

Stolen from the unknown.​

tut
"Low doses of nicotinic acid may produce mild but noticeable flushing when taken on an empty stomach (Hathcock, 1997) and this represents the adverse effect detected at the lowest doses. An early study (Smith et al., 1937) reported that a single oral dose of 60 mg nicotinic acid produced marked flushing, which was not associated with changes in heart rate or blood pressure. Spies et al. (1938) reported flushing in 5% and about 50% of subjects given single oral doses of 50 mg and 100 mg nicotinic acid, respectively. The dose-response for flushing was examined further by Sebrell and Butler (1938) who gave 3 groups of 6 subjects daily dose of 10, 30 or 50 mg nicotinic acid for 92 days as single oral doses given in solution added to tomato juice and consumed with the mid-day meal; flushing was reported intermittently by 4, 2 and 0 of the subjects given 50, 30 and 10 mg, respectively. The response is possibly related to periods of rapid increase in plasma concentrations of nicotinic acid, because the response is greater after intravenous dosage and is blunted if taken orally with food (Bean and Spies, 1940)."

"The only reports of flushing associated with the ingestion of nicotinic acid with food have occurred following the addition of free nicotinic acid to food prior to consumption."​

tut
- Investigation of niacin on parameters of metabolism in a physiologic dose: randomized, double-blind clinical trial with three different dosages

"In summary, the results suggest that nicotinic acid in a dosage of 16.7 mg does not cause flushing symptoms. An accumulation could not be identified and a repeated intake up to a dosage of 50.1 mg was very well tolerated. In higher doses up to 50.1 mg as a single dose, transient flushing symptoms are rarely possible. However, the intake of nicotinic acid up to a dose of 50.1 mg investigated within this trial does not cause any nicotinic acid-induced changes regarding the central metabolic parameters blood pressure, pulse and skin temperature."


"[There] are many studies to assess the effects and safety of nicotinic acid in pharmacological doses between 500 and 2,000 mg (American Society of Health-System Pharmacists 1997; Mills et al. 2003; McKenney 2004; Cefali et al. 2006). However, to define upper limits for the use of nicotinic acid in dietary supplements, studies with low doses are essential. Actual recommendations often refer to studies that date back in the 1930s (Rachmilewitz and Glueck 1938; Sebrell and Butler 1938; Spies et al. 1938a, 1938b)."

"[..]volunteers [72, total] received the following amounts of nicotinic acid:
Study arm 1, 3x 16.7 mg;
Study arm 2, 1x 33.4 mg;
Study arm 3, 1x 50.1 mg."

Effects and discussion:

Spoiler: Figure 1: Non-Daniel values of the pulse rate after intake of study preparations

(a) multi-vitamin preparation with nicotinic acid
(b) multi-vitamin preparation with nicotinamide
(c) separate evaluation of volunteers experiencing flush symptoms (n=8)

Spoiler: Figure 2: Non-Jennifer values of diastolic and systolic blood pressures after intake of study preparations

(a) multivitamin preparation with nicotinic acid
(b) multi-vitamin preparation with nicotinamide
(c) separate evaluation of volunteers experiencing flush symptoms (n=8)

"The mechanism of nicotinic acid-induced flushing has extensively been investigated over the past years. In 2000 Lorenzen et al. characterized a G-protein coupled receptor for nicotinic acid (Lorenzen et al. 2001). In 2003 this receptor was identified as GPR109A (Tunaru et al. 2003). Importantly, nicotinamide is not an agonist of this receptor (Lorenzen et al. 2001). GPR109A is highly expressed in adipocytes and immune cells but was not detected in other major tissues; for example, liver or heart (Soudijn and Ijzerman 2007; Kamanna et al. 2008). In adipocytes, the activation of this receptor leads to a decreased level of cAMP, resulting in a decreased hormone-sensitive triglyceride lipase activity. In this way, nicotinic acid performs its well-known antilipolytic effects. The activation of the GPR109A receptor in dendritic cells of the skin or in dermal macrophages leads to the mobilization of arachidonic acid and its conversion to prostaglandin D2 and prostaglandin E2 that have a vasodilative effect (Benyo et al. 2005; Pike 2005; Maciejewski-Lenoir et al. 2006). In confirmation of these findings, it was shown that antagonism of the prostaglandin D2 receptor suppresses nicotinic acid-induced flushing (Cheng et al. 2006)."

"There is evidence that the flushing symptoms occur while the concentration of nicotinic acid and nicotinuric acid in plasma is increasing, independently of the absolute concentration (Cayen 1985; Neuvonen et al. 1991).

According to the literature, the symptoms mostly occur within minutes after intake of nicotinic acid and they can last for just a few minutes up to 2 h with high doses. The volunteers experiencing flush symptoms in our trial reported the flush symptoms within the time interval described in the literature. With regular intake over a longer period, an adaption effect develops and the symptoms diminish (Mills et al. 2003; Cefali et al. 2006; Guyton and Bays 2007)."

"The absorption of nicotinic acid and nicotinamide mainly takes place in the upper small intestine. In low doses, both forms of niacin are absorbed via a sodium-mediated, facilitated diffusion process. In higher doses, niacin is absorbed by 'not them for sure' of passive diffusion (Bechgaard and Jespersen 1977). Peak plasma levels are reached within 30-60 min after oral intake. Absorption of nicotinic acid is nearly complete as about 88% of an oral dose is recovered in the urine as nicotinic acid or its metabolites. Nicotinic acid undergoes extensive, saturable first-pass metabolism in the liver. It is metabolized by two hepatic pathways. The so-called amidation pathway comprises several redox reactions with intermediates such as nicotinamide and NAD, ending in several pyrimidine metabolites. This non-conjugative pathway has a high affinity and a low capacity. The rate of metabolism of this pathway is about 40 mg nicotinic acid per hour. After reaching saturation of the amidation pathway, nicotinic acid is metabolized by the second pathway. At this, nicotinic acid is conjugated with glycine to form nicotinuric acid. This pathway is characterized by a low affinity and a high capacity and is linked with the vasodilative effect of nicotinic acid. The vasodilatation causes sensations of warmth, itching, tingling and intensified redness of the skin (Pieper 2002; Menon et al. 2007). According to Norquist et al. (2007), there is a high consistency of the four individual flushing symptoms."

"Two volunteers classified their symptoms as flushing effects after intake of nicotinamide but not after intake of nicotinic acid. To account for these psychological effects, the trial was conducted in a double-blind cross-over manner with a second multi-vitamin preparation containing niacin exclusively in form of nicotinamide."

"The volunteers ingested the study preparation for the first time. After intake of the preparation with a single dose of 16.7 mg nicotinic acid and repeated intake in a time interval of 4 h, no flush symptoms were documented. With regard to these results, no accumulation occurred, an observation that can be underlined by the short half-life of nicotinic acid, which is determined to be 2045 min (Cayen 1985)."

"In doses of 33.4 and 50.1 mg as a single dose, flushing symptoms could rarely be seen. These doses of nicotinic acid were in the dimension of the saturation limit of the non-conjugative metabolic pathway in the liver as described above. With this knowledge it is possible to integrate the result of this trial on the basis of cause and effect. The occurrence of flushing symptoms surely displays inter-individual differences and depends on further parameters such as the absorption rate."

"Coming back to the receptor-mediated effects, in spite of the wide distribution of the GPR109A receptor in a large variety of immune cells and adipocytes, the release of prostaglandins as an answer to nicotinic acid-induced activation could only be observed in dermal Langerhans cells (Benyo et al. 2006; Maciejewski-Lenoir et al. 2006; Gille et al. 2008). This information helps to explain why the flushing is a local cutaneous phenomenon and the symptoms are only peripheral effects. The superficial vasodilatation induces a short-term increase of the microcirculation, which is objectively obvious as intensified redness of the skin."​

 

[Terma]

(Sorry I don't have time to keep up with all of it, but I can tell you I did the TMG + B3 combination for a number of years, but ultimately decided choline must be better than TMG, although the quantification aspect is appreciated [tried to do that once but calculations didn't fit my subjective needs at all])

This is finally going somewhere:

Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice - ScienceDirect

There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis. To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors. Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was tested against structurally-related methyltransferases and nicotinamide adenine dinucleotide (NAD+) salvage pathway enzymes. Effects of NNMT inhibitors on lipogenesis and intracellular levels of metabolites, including NNMT reaction product 1-methylnicotianamide (1-MNA) were evaluated in cultured adipocytes. Effects of a potent NNMT inhibitor on obesity measures and plasma lipid were assessed in diet-induced obese mice fed a high-fat diet. Methylquinolinium scaffolds with primary amine substitutions displayed high permeability from passive and active transport across membranes. Importantly, methylquinolinium analogues displayed high selectivity, not inhibiting related SAM-dependent methyltransferases or enzymes in the NAD+ salvage pathway. NNMT inhibitors reduced intracellular 1-MNA, increased intracellular NAD+ and S-(5′-adenosyl)-l-methionine (SAM), and suppressed lipogenesis in adipocytes. Treatment of diet-induced obese mice systemically with a potent NNMT inhibitor significantly reduced body weight and white adipose mass, decreased adipocyte size, and lowered plasma total cholesterol levels. Notably, administration of NNMT inhibitors did not impact total food intake nor produce any observable adverse effects. These results support development of small molecule NNMT inhibitors as therapeutics to reverse diet-induced obesity and validate NNMT as a viable target to treat obesity and related metabolic conditions. Increased flux of key cellular energy regulators, including NAD+ and SAM, may potentially define the therapeutic mechanism-of-action of NNMT inhibitors.

These results suggest that quinolinium-based NNMT inhibitors achieve selectivity by specifically interacting with the NA-binding pocket of NNMT, [17] unlike several known non-selective methyltransferase inhibitors that interact with the SAM - binding pocket, which is highly conserved among SAM - dependent methyltransferases. [34, 35]

These are the authors [or not, whatever, their names all look the same] with the fixation on increased polyamine flux, which they think increases a futile cycle. It's questionable whether that's truly the biggest contributor, but makes little difference at current time. They didn't even bother to describe it again.

So Quinoline (derivatives: Quinine, Pyrroloquinoline quinone) is an NNMT substrate, but 1-methylquinolinium derivatives give the best selectivity as NNMT inhibitors, I couldn't follow all the references yet, to see exact mechanisms.

Now it's posited that Caffeine and Nicotine are competitive NNMT substrates and help Parkinson's that way (I wonder if @Travis would have any interest in this part - as brought up above), but there doesn't appear much interest in pursuing them, for obvious reasons.

They suggest a combined (Nicotinic acid or Niacinamide or NR or NMN, what else?) + NNMT inhibitor therapy, which was a result of our mind-reading session:

It could be predicted that combined administration of sub - maximal doses of dietary supplements and NNMT inhibitors that function as activators of NAD + might produce synergistic improvements in diet - induc ed obesity , and reduce adverse effects associated with chronic high - dose administration of dietary supplemental NAD + precursors . Studies testing the efficacy of NNMT inhibition on diet - induced obesity , both alone and combination with dietary agents, are currently in progress.

I already wondered if Nicotine patch + topical Niacinamide would be viable, or if concentrated Niacinamide is still a bad idea for this. At this rate I might never know since they obviously want a new drug. They might not be entirely wrong either.

Kind of exciting nonetheless.

 

[Amazoniac]

I did the TMG + B3 combination for a number of years, but ultimately decided choline must be better than TMG

VVhv? I can imagine that choline indeed might give you more options on what to do with the excedent since the conversion to betaine is irreversible.

calculations didn't fit my subjective needs at all

The estimation ended up being more or less than you needed?

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- Management of nicotinamide N-methyltransferase overexpression: inhibit the enzyme or reduce nicotinamide intake?
- Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression