Niacinamide Or Just Plain Niacin?

[Amazoniac]

I shall keep going. Almost nothing intimidates anymore, only these.

- Nicotinamide overload may play a role in the development of type 2 diabetes

"The main findings of this study were that: (1) nicotinamide overload elevates plasma levels of N1-methylnicotinamide associated with oxidative stress and insulin resistance; (2) the skin plays an important role in expelling excess nicotinamide and detoxifying N1-methylnicotinamide; and (3) diabetic subjects have slow plasma N1-methylnicotinamide clearance. These findings may contribute to explain the mechanism of oxidative stress and insulin resistance in a variety of clinical conditions."

"Importantly, diabetic subjects exhibited significantly higher plasma N1-methylnicotinamide levels than non-diabetic subjects after nicotinamide loading, which suggests its involvement in the toxic effects of nicotinamide overload. Indeed, this study demonstrated that N1-methylnicotinamide mimicked the effect of nicotinamide overload, which suggested N1-methylnicotinamide mediation of the toxic effect."

"Consistent with previous research, this study found that N1-methylnicotinamide not only elevated plasma H2O2 levels in vivo, but also directly stimulated H2O2 generation of human erythrocytes in vitro at physiological concentrations, which indicates that N1-methylnicotinamide is a potent trigger of diabetic oxidative stress."

"Oxidative stress may induce NAD depletion, a marker of cell injury[34,35]. Indeed, this study found that N1-methylnicotinamide-induced high plasma H2O2 level was associated with a significant reduction in NAD content in the muscle and liver of rats. Then came the vital question: where did the excess systemic ROS originate? NADH-dependent ROS generation is an important source of intracellular ROS[34]. Accumulating evidence has indicated that diabetes shows a decreased cytosolic NAD+/NADH ratio in a variety of tissues[21]. Importantly, this study demonstrates that N1-methylnicotinamide decreases NAD/NADH ratio in rat erythrocytes in vivo and human erythrocytes in vitro. Thus, it is likely that diabetic oxidative stress is initiated by high plasma N1-methylnicotinamide-induced imbalance in the NAD+/NADH redox couple. Many cellular processes are governed by the enzymes using NAD+/NADH as a cofactor[6,21,34], therefore, it is not difficult to understand why a set of metabolic abnormalities happen in type 2 diabetes."

"Mammalian AOX is a molybdo-flavo enzyme involved in the detoxification of various endogenous and exogenous N-heterocyclic compounds[22,23]. N1-methylnicotinamide is one of the substrates of AOX by which N1-methylnicotinamide is oxidized to pyridones[7], and thus, detoxified. AOX is expressed predominantly in the liver. Therefore, severe liver disease might be expected to reduce plasma N1-methylnicotinamide clearance and subsequent insulin resistance. In fact, it is well known that liver cirrhosis is associated with high incidence of diabetes[36,37]. Pumpo et al[38] have found that cirrhotic patients have high serum N1-methylnicotinamide levels, both in basal values and after nicotinamide loading."

"Tamoxifen, a well-known inducer of non-alcoholic steatohepatitis[24], is found to inhibit strongly AOX activity[23] and its expression (Figure (Figure5C).5C). Collectively, it seems that the decrease in N1-methylnicotinamide detoxification may be involved in hepatogenic insulin resistance."

"AOX is also expressed in the skin[26], which suggests skin involvement in N1-methylnicotinamide detoxification. Moreover, as found in this study, human sweat glands can excrete excess nicotinamide. Therefore, decreased skin function may be implicated in N1-methylnicotinamide-induced insulin resistance. In fact, severe burns may induce long-lasting insulin resistance, a well-documented but poorly understood phenomenon[31,39]. The present study demonstrated that severe burns significantly delayed N1-methylnicotinamide clearance, which suggests that long-lasting post-burn insulin resistance may involve a decrease in nicotinamide detoxification and excretion."

"Sweat gland activity fluctuates according to ambient temperature; the most significant feature of the gland. Therefore, sweat gland inactivity is expected to slow nicotinamide catabolism and thereby increase the danger of developing insulin resistance."
?​

- [9] Nicotinamide: A double edged sword - ScienceDirect

"[..]catabolism is predominately N-methylation to N-methyl nicotinamide catalyzed by the enzyme Nicotinamide N-methyl transferase (NNMT) [11]. This enzyme barely exists in herbivores suggesting that it has been developed by evolution to deal with the higher nicotinamide intake of carnivores and omnivores [12]."

"Around 1980 a mini-epidemic that involved a different pyridine, MPTP, occurred again in extreme circumstances [13,14]. Drug addicts took the compound parentrally and gave themselves acute Parkinsonism. Both in patients and in subsequent animal models there are striking similarities with idiopathic Parkinson’s and only arguable differences many of which may be explained by the acuteness of the situation in the drug addicts and animal model and the chronic nature of the condition in idiopathic Parkinson’s. There is no other known source of MPTP. However, under experimental conditions, it can be produced from 4-phenylpyridine known to be present in diet and to form MPPC directly using the same enzyme that is involved with Nicotinamide catabolism, NNMT [15] (Fig. 1). S-adenosyl methionine (SAM) is the methyl donor. This reaction can produce a range of N-methyl pyridines and also N-methylated beta-carbolines and isoquinolines that are potential or proven dopaminergic toxins [16,17]. So there are some plausible protoxins present in diet and more than one may well be involved."

"Once charged with the N-methyl group, no toxin [on its way out] can cross the blood/brain barrier, so the toxication step has to take place in the brain. The enzyme NNMT has recently been shown to be present in the brain of humans [26] and rats [27]. The enzyme’s activity, protein and RNA levels are increased in the brain of patients with PD [26,28]."

"N-methyl nicotinamide has useful functions, for instance, in inhibiting the export of choline [34] and may confer an early biologic advantage to high methylators [35] and their developing brain, perhaps affecting personality type and cognition and put them on a different trajectory for Alzheimer’s Disease. However, choline may further boost methylation in dopaminergic neurones, as it is a methyl donor, and increased acetylcholine would not help pharmacologically in the parkinsonian brain. N-methyl nicotinamide is toxic under certain experimental conditions using the same mechanisms as MPPC but having between 1/5th and 1/50th of the toxicity [27,36]."

"The dose of the protoxin MPTP required to cause acute Parkinsonism is approximately 500 mg to 2 g in more chronic year long experiments. The average nicotinamide intake in Western populations is around 35 mg a day. The recommended daily allowance is around 15 mg a day. About 20 mg a day, if an overdose equates to 350 g over 50 years. Even at 1/50th of the toxicity and accepting that very chronic exposure would be safer, that is a lot of MPPC equivalents that we now know will reach neurones."

"[..]alcoholics who are likely to be nicotinamide deficient tend not to get PD [46]."

"High N-methylator status, largely on a genetic basis, is present in 25% of the population and may be over represented in the PD population. One would predict that high N-methylator status could have been a risk factor for Pellagra as well as it would drive nicotinamide levels down at the same time as increasing N-methylated derivatives. High methylation may alter the dynamics of cognition and perhaps personality toward that seen with PD patients who stereotypically are industrious and puritanical premorbidly rather than risk takers. 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). Excess methylation in one pathway might reduce available SAM for other methylation reactions such as that of dopamine (and vice versa when there is exogenous levodopa) and DNA giving links to behavior, mood and carcinogenesis. 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. Two substrates caffeine and nicotine that are addictive and link with limbic reward mechanisms and dopamine metabolism would be quite a coincidence especially as several drugs of addiction such as cocaine, heroin, meperidine and amphetamine 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."

"More careful scrutiny of diet in future case control studies need to be aware of a possible ‘U’ shape curve [tut] with toxicity of nicotinamide in the middle to high range but perhaps leveling off or becoming protective at higher dosages. These should be combined with assessments of other vitamins that affect nicotinamide levels, such as pyridoxine, riboflavin, thiamin, and other compounds that influence the amount of methyl donor SAM, such as methionine and choline intake, B12 and folate, studied if possible in combination with assessing nicotinamide/tryptophan and methylator status biochemically, and factoring in the effects of inhibitors such as nicotine, caffeine and other methylxanthines such as theobromine (in chocolate)."​

The adaptations that take the places when the metabolism slows down, must reflect in slow processing and disposing unwanted stuff. Perhaps this is linked to having trouble handling caffeine. Xanthin oxidase requires similar nutrients as aldehyd oxidase, so riboflavin and molybdenum must be involved. It must stem from liver inflammation, which is odd since it's just ornamental. But if you have trouble with detoxification, it's possible that you are more prone to the adverse effects of niacin, especially as nicotinamide.

There are people blaming N-methylnicotinamide for the problems, but I don't know if that's correct. Copper seems to decrease the activity of Nicotinamide N-methyltransferase (the enzyme that methylates it) and manganese in excess increase it. However maybe the focus should be on improving the activity of aldehyd oxidase, which processes it further for excretion and prevents the accumulation of N-methylnicotinamide.

It's also possible that this is a protective mechanism, and not methylating it would be more damaging as suggested by the first quote from the second link. If that's the case, lowering it would be a nicht, nicht for sure. But I'm just making the thoughts out of the loud.

And what happens to tryptophan when niacin is in excess?

Check out what are the best food sources of niacin and their cholin content. Even though niacin supplementation in lower doses should not be a problem, it can be when the rest of the diet is poor.

 

[Amazoniac]

dUMPing the entire text and more with little criteria:

- Dietary methyl-consuming compounds and metabolic syndrome

"Methyl consumers include a variety of compounds that are metabolized by methylation and are known to be involved in both the generation of ROS and aberrant methylation status of the body. Methyl consumers from dietary sources are usually toxic xenobiotics, such as pesticides, heavy metals, food additives and even clinical drugs. In the past few decades, there has been a significant increase in methyl consumers in dietary sources that is primarily due to pollution, food additives and food fortification."

"Methylation status reflects a balance between methyl supply from dietary methyl donors (primarily betaine, choline and methionine) and methyl consumption by a variety of endogenous and exogenous methyl consumers."

"Betaine is derived from either diet or the conversion of choline by choline oxidase.[17] It has an important role in maintaining the methionine-homocysteine cycle, not only for its direct participation in the methylation of homocysteine to form methionine, but also for its metabolites that contribute to the formation of 5,10-methylenetetrahydrofolate, the precursor of 5-methyltetrahydrofolate.[18,19]"

"Because all of the methyl consumers from either endogenous or exogenous sources share the same pool of labile methyl donors, it is conceivable that an increase in any methyl consumer(s) may influence not only the methylation of other methyl consumers due to its increasing demand for labile methyl groups. Therefore, there seems to be no doubt that the level of methyl consumers is an important factor in determining the methylation profiles of the body, which has been largely ignored in the etiological study of metabolic syndrome and its related diseases."

"Plasma homocysteine levels are determined by three main factors: (1) the remethylation rate of homocysteine to methionine; (2) the conversion rate of homocysteine to cystathionine; and most importantly, (3) the amount of methylation of substrates."

"increasing evidence from clinical trials indicates that although folic acid and vitamin B12 supplementation could reduce plasma homocysteine levels, they have no effect on T2D and cardiovascular events.[22,23,24,25] This implies that the increased prevalence of CVD may not be a simple matter of folate deficiency. Moreover, excessive folic acid may lead to a waste of labile methyl-group donors."

"One unexplored cause for the increasing prevalence of metabolic syndrome, T2D and CVD are changes in dietary content of methyl consumers. It is known that almost all of the homocysteine is derived as an intermediate in the methionine-homocysteine cycle, because the amount of homocysteine from dietary sources is very limited.[27] This means that the methylation of both endogenous and exogenous methyl consumers provides the dominant source of plasma homocysteine. Although guanidinoacetate and phosphatidylethanolamine are known to be two major endogenous methyl consumers used to synthesize creatine and phosphatidylcholine, respectively,28 there is no evidence of increase in the level of guanidinoacetate or phosphatidylethanolamine in metabolic syndrome or its related diseases. In contrast, increased exogenous methyl consumers, such as niacin,[26,29,30] levodopa[31] and arsenic,[32] may contribute to elevated plasma homocysteine levels. Given that diet is a major risk factor for hyperhomocysteinemia33 and that there has been a significant increase in dietary methyl consumers in the past few decades due to pollution, food additives, food fortification and high meat intake,[34,35] it seems very likely that increased dietary methyl consumers may be a significant factor in the prevalence of hyperhomocysteinemia and its related diseases."

"Some studies indicated that hyperhomocysteinemia is rarely seen in metabolic syndrome,[36,37] but frequently seen in its primary clinical outcomes, T2D[9,10,11] and CVD.[8,12] This phenomenon may reflect a difference in the compensatory capacity in the conversion of homocysteine to methionine or cystathionine, since plasma homocysteine levels are also found to go up with age.[9,38,39] Moreover, because the production of homocysteine is mainly determined by diet,[33] metabolic syndrome patients, even those with CVD, may have normal plasma homocysteine if they have shifted to a low methyl consumer diet and/or have a higher capability to convert homocysteine to methionine (for example, due to folate supplementation) or to cystathionine. From this point of view, it seems that plasma homocysteine may not be a reliable indicator of the imbalance between methyl supply and consumption, especially in the early stage of metabolic syndrome."

"To date, although few studies have attempted to explain the etiology and prevalence of metabolic syndrome from the standpoint of increased methyl consumers, numerous studies have provided strong evidence that methyl consumers, both endogenous and exogenous, may be involved in the pathogenesis of metabolic syndrome and its related diseases."

"Arsenic is a ubiquitous environmental contaminant and is also one of the most common methyl consumers."

"Niacin (nicotinic acid and nicotinamide) is a water-soluble vitamin and a common methyl consumer.[46] Dietary nicotinic acid is derived from plant foods, while nicotinamide is derived from animal foods and typically used for food fortification. Fortified grains have provided an additional niacin source. Excessive niacin is converted to N1-methylnicotinamide via an SAM-dependent methylation, and then to pyridinones.[46] This metabolic pathway depends on the supply of SAM and methyl donors. However, there is some difference between the degradation of the two active forms of niacin. Nicotinic acid can be either converted to nicotinamide and then degraded via the nicotinamide catabolic pathway (methyl-consuming catabolic pathway), or excreted in the urine unchanged and as nicotinuric acid (non-methyl-consuming catabolic pathway).[47] In contrast, nicotinamide is rarely excreted into the urine in its original form due to a high rate of tubular reabsorption.[48] Thus, equivalent doses of nicotinamide may consume more methyl groups than nicotinic acid."

"The well-known toxicities of niacin are glucose intolerance, insulin resistance, liver enzyme elevations, fatty liver and steatosis.[46,49,50,51,52,53,54,55] Our recent studies have shown that there is a strong lag-correlation between the prevalence of obesity and diabetes in the US population and the increased per capita consumption of niacin, which was attributed primarily to the consumption of fortified grains.[34,35]"

"The toxic effects of niacin may involve a variety of mechanisms, including methyl depletion, changes in NAD-dependent reactions and excessive ROS generation. Methyl depletion as a consequence of niacin toxicity has been confirmed by the observations that hepatic toxicity can be prevented by choline and betaine supplements.[30,55] It is known that methyl deficiency may limit the formation of very low density lipoprotein and low density lipoprotein in the liver due to decreased phosphatidylcholine synthesis, which may result in a decrease in the levels of plasma very low density lipoprotein and low density lipoprotein, as demonstrated in rats by Mookerjea et al.[56] On the other hand, the decreased transport of fat from the liver may lead to an accumulation of fat in the liver, and as a result, fatty liver and steatosis may occur.[57] Moreover, adequate phosphatidylcholine is also required for the formation and clearance of chylomicrons from the intestinal mucosa.[58] Therefore, methyl deficiency-induced decrease in phosphatidylcholine synthesis is also expected to reduce the plasma chylomicron levels. Similarly, choline deficiency has been demonstrated to lower the level of plasma chylomicrons.[56] Interestingly, niacin has been found to induce both lipid-lowering effect[52] and adverse hepatic outcomes.[46,52,54,55] Thus, it seems that the lipid-lowering effect of niacin may be mediated by methyl depletion, which, although improving cardiovascular outcomes, may increase the risk of adverse hepatic outcomes."

"Niacin is the precursor of the important coenzymes NAD and NADP. NAD levels are dramatically altered by dietary levels of niacin.[59] Since NAD and NADP are crucial in redox reactions,[59] excessive niacin may lead to significant impacts on the redox status of the body by affecting NAD contents. Our recent study demonstrated that excessive nicotinamide might increase the generation of hydrogen peroxide, a highly ROS, and have a role in the development of insulin resistance.[35,60]"

"Although niacin fortification has been implemented to prevent niacin deficiency (that is, pellagra) for more than half a century, there are virtually no studies that document and track the long-term changes of the levels of plasma niacin and labile methyl donors, or the changes in the redox status." "[..]fortification-induced long-term high-level niacin exposure may lead to persistent niacin overload. It has shown that nicotinamide at physiological concentrations is degraded mainly via the methyl-consuming mechanism,[61] and that the appearance of non-methylated metabolites of nicotinamide in urine indicates nicotinamide overload and toxicity.[47,62] Most importantly, long-term high-level niacin exposure has been observed to induce a methyl-group deficiency state and fatty liver due to an increased need for methylation of niacin in animal studies.[55,63]"

"Catecholamines, primarily norepinephrine and epinephrine that mediate the cardiovascular effect of the sympathetic system,[66] are important endogenous methyl consumers. Catecholamines are known to be a major risk factor for hypertension and CVD, because they can increase heart rate, blood pressure and ROS production.[67,68,69,70]

Elevated catecholamines may be caused by two factors: (1) an increase in catecholamines release from the sympathetic nervous system and (2) a decrease in their degradation (that is, inactivation). Methylation is a crucial step in the degradation of catecholamines, which involves two methyltransferases: phenylethanolamine N-methyltransferase and catechol O-methyltransferase, where the former catalyzes norepinephrine to epinephrine and the latter converts catecholamines to methylated derivatives.[66] A lack of methyl groups may decrease the degradation of catecholamines and thus contribute to elevated circulating catecholamines. Hence, the increased level of unmethylated intermediates of catecholamines, such as dihydroxyphenylglycol and dihydroxymandelic acid[71,72,73] observed in patients with hypertension and CVD may be related to methyl depletion/deficiency.

Since the methylation reactions of both catecholamines and exogenous methyl consumers utilize SAM as a methyl donor, it is expected that the decrease in the levels of SAM and methyl donors as induced by excessive exogenous methyl consumers may limit the methylation-mediated degradation of catecholamines. In this regard, we have recently observed that in healthy subjects, an excess of niacin can significantly increase the levels of plasma norepinephrine and homocysteine and was associated with a significant decrease in the levels of plasma betaine and normetanephrine as the methylated derivative (unpublished data), which suggests that chronic high niacin intake may contribute to elevated circulating catecholamines."

"Folic acid, the synthetic oxidized form of folate used for supplementation and fortification, is an unusual methyl consumer. Unlike 5-methyltetrahydrofolate which is the predominant natural form of folate in plants,[74] folic acid has to be reduced to tetrahydrofolate, and then further converted to the active form 5-methyltetrahydrofolate in the body (Figure 1)." "Most importantly, excessive folic acid is eliminated through the urine primarily in its metabolic forms,[20] especially 5-methyltetrahydrofolate,[75] and thus results in a waste of SAM and the methyl donors. Folic acid supplementation and fortification have been found to significantly increase the urinary excretion of 5-methyltetrahydrofolate.[75] Theoretically, excessive folic acid may worsen rather than alleviate methyl-group deficiency."

"Vegetables generally contain much more betaine than folate. For example, 100 g of spinach, one of the richest vegetable sources of folate, contains only ∼50 μg of folate,[74] but has ∼600 mg of betaine and 22 mg of choline.[77] Therefore, diet-induced folate deficiency may be accompanied by a more severe deficiency of methyl-group donors. Thus, it seems that the importance of folate in the increasing prevalence of metabolic syndrome and its related diseases is overestimated."

"[..]chronic exposure to excessive methyl consumers may result in extensive oxidative injury, including liver, vascular and islet β-cell injury, as well as insulin resistance, which are observed in metabolic syndrome and its related diseases. Most importantly, liver injury may delay the clearance of toxic substances and further promote the development of metabolic syndrome. This may explain the observed association between liver diseases and metabolic syndrome.[78]"

"The property of dietary methyl consumer-induced oxidative stress is that it occurs soon after meal due to excessive ROS generation, which leads to an increase in early postprandial insulin secretion due to β-cell compensation, and then is gradually attenuated with the clearance of the produced ROS. However, the clearance of plasma insulin is slower than that of the produced ROS, so increased plasma insulin may induce late postprandial hypoglycemia with the recovery of insulin sensitivity, and thus increase appetite. Such a change has been observed by using an oral glucose tolerance test plus nicotinamide in young healthy subjects.[35] The increased appetite may lead to an increase in energy intake and subsequent obesity. As a result, the long-term persistent β-cell compensation together with the oxidative β-cell damage may eventually induce β-cell failure and T2D, which may account for the associations between arsenic[42,43,44] or niacin[34,35] exposure and the prevalence of metabolic syndrome and its related diseases."

It must be wise to adjust the supplemental dose in an amount that doesn't lead to more stress.​

"On the other hand, increased methyl consumer-induced methyl depletion may upset the balance between methyl-group supply and consumption, and thus disturb all the methylation reactions of the body, including phosphatidylcholine synthesis, catecholamine degradation and DNA methylation. Decreased phosphatidylcholine synthesis limits the syntheses of lipoproteins, which would lead to accumulation of fat and cholesterol in the liver and subsequent fatty liver and lipid profile changes. The combination of methyl consumer-induced liver injury and fatty liver may have a role in the development of non-alcoholic fatty liver disease, a common disease in the Western world. Decreased methylation-mediated catecholamine inactivation may lead to an increase in circulating catecholamines, which contributes to the development of oxidative stress, hypertension and atherosclerosis. Excessive methyl consumer-induced methyl depletion may affect DNA methylation status, as observed in arsenic exposure.[45]"

"Mental stress such as depression, anxiety and hyperactivity is linked to an increased sympathetic overactivity,[79] which may induce more catecholamines release and thus accelerate cardiovascular outcomes. High fat intake is a major causal factor in lipid disorders, and low vegetable intake decreases the supply of betaine, a major methyl donor; hence, the combination of high fat intake and methyl depletion/deficiency may accelerate the development of fatty liver and atherosclerosis."

"Decreased skin functions might be a potent risk factor for metabolic syndrome and its related diseases, which has not yet received much attention. Skin being the largest organ in the body has two major functions linked to the clearance of xenobiotics. They involve the xenobiotic-metabolizing enzymes[80] and the sweat glands.[81] Most importantly, some toxic compounds (for example, nicotinamide[60]) cannot be effectively excreted through urine in its natural form, but can be eliminated through sweat. Therefore, sweating can prevent oxidative stress and also avoid methyl depletion. Evidently, skin functions are no doubt influenced by skin integrity and the body surface temperature. Decreased skin functions by low ambient temperature (for example, cold season), physical inactivity (especially sedentary in air-conditioned environments) or skin loss (for example, severe burn) may increase the risk for metabolic syndrome and its outcomes."

Mocking over-exercisers is ignorance and lack of empathy. They do it for a reason, the cause has to be fixed and they'll ease on activity.
https://raypeatforum.com/community/threads/escaping-learned-helplessness.4127/page-5#post-85826
​

"Figure 2 shows that the toxicity of methyl consumers is not merely a matter of methyl depletion. Supplementation of methyl donors, although alleviating methyl consumer-induced methyl depletion, cannot prevent methyl consumer-induced ROS generation and the resultant oxidative cell damage. This implies that without reducing the level of methyl consumers, supplementation of methyl donors alone may not achieve the desired therapeutic effect."​

- Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule

"Although Nam is the predominant endogenous precursor of the NAD+ salvage pathway, early reports suggested that it may not be as effective as other biosynthesis precursors in increasing NAD+ levels [41]; however, this likely reflects the relatively small dose of Nam used. Additionally, Nam effects likely depend on cell/tissue type and the pathophysiologic state. For instance, in a nonstressed state, Nam is inferior to NA as an NAD+ precursor in the liver [81], whereas under HFD-induced metabolic challenge, Nam is a more powerful NAD+ precursor and SIRT1 activator than NA [82]. Nam has been used for many years for a variety of therapeutic applications (such as diabetes mellitus) at doses up to 3 g/d, with minimal side effects [83]. Unlike NA, Nam has no GPR109A agonist activity [80], thus escaping the prostaglandin-mediated vasodilatory side effects."

"Although we have described the different pathways to NAD+ biosynthesis, it must be emphasized that not all tissues are capable of converting each precursor to NAD+ with equal efficacy, owing to the differences in the cell- and tissue-specific enzyme expression. For instance, cells must express the kynurenine pathway for de novo NAD+ synthesis, clearly active in the liver and brain [12], and must possess the Preiss–Handler pathway to use NA, which is active in most organs but less prominent in skeletal muscle. In contrast, the salvage pathways are crucial in all tissues to conserve NAD+ sufficiency [220]. Supporting this notion, the recommended daily allowance for NA is in milligrams, whereas an estimated 6 to 9 g of NAD+ are required daily to match turnover [58]. This is facilitated by the high affinity of NAMPT for Nam; thus, even small amounts of Nam are effectively converted to NMN and then NAD+ [221]."

"In the absence of head-to-head studies comparing the different compounds under defined conditions, it is currently not possible to identify the optimal NAD+ augmenting agent. The ubiquitous expression of NRKs, makes NR a precursor that can affect whole-body metabolism [162]. The inability of NR to activate the GPR109A receptor mitigates the undesirable NA side effects, and, unlike Nam, NR does not inhibit sirtuins. Furthermore, NAD+ generated from NR can target both nuclear and mitochondrial NAD+ pools, activating the respective compartmental sirtuins (i.e., nuclear SIRT1 and mitochondrial SIRT3) [54]. This may be an advantage over other molecules, such as PARP inhibitors, with effects confined to the nucleus [67]. Similar to NR, NMN metabolism into NAD+ is governed by the salvage pathway. However, NMN availability has not been characterized in the diet [93, 222], unlike the naturally available NR."

"We still have a limited understanding of the molecular interconversions of the administered NAD+ precursors. Illustrating this, administered NR is converted to Nam in the circulation before entering the cell [208, 227], whereas NMN is transformed extracellularly into NR, which then enters the cell and converts into NAD+ [227]."​

- The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways

"In mammals, NAM is thought to be the main niacin-derived NAD+ precursor (24, 25), but the pathway for NA is also conserved (7)."​

- NAD+ and its precursors in human longevity

"NR is a natural product, the so-called hidden vitamin found in cow’s milk [12]."​

 

[Amazoniac]

I'm just collecting. Hopefully these will make more sense over time.

The problem with more recent publications is that most are authored by people that are willing to promote nicotinamide riboside for commercial reasons, so the other forms have been neglected and the information in general can be shady.

Sometimes they refer to nicotinamide as Nam or NM.

- Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD + Precursor Vitamins in Human Nutrition

"In meats, Na and Nam are scarce and NAD+ and NADP are the abundant sources of niacin (34, 86). Nam is produced by mucosal enzymes that cleave NAD+ (86), and Na is produced from Nam by deamination by bacterial nicotinamidase in the gut (13). Both Na and Nam are absorbed from the alimentary canal and enter the bloodstream for distribution to tissues (40, 82, 86). Studies indicate that Nam is the dominant absorbed form of niacin when the dietary sources are NAD+ and NADP (16, 35, 36, 81). However, it has also been reported that NAD+ is digested by pyrophosphatases to NMN and hydrolyzed to NR, which was found in the lumen of the upper small intestine (32). We surmise that NR is incorporated into the cellular NAD+ pool via the action of Nrk pathway (14) or via Nam salvage after conversion to Nam by phosphorolysis (8)."

"We have hypothesized that the beneficial effects of high-dose Na derive simply from NAD+ biosynthesis (7, 14). The fact that Nam is not beneficial in promoting reverse cholesterol transport can be explained in two ways. First, Na is a better NAD+ precursor than Nam in liver (16). Second, if the requirement for elevated NAD+ biosynthesis for improved reverse cholesterol transport depends on sirtuin function, one would expect Nam to be inhibitory."​

- Modulating NAD+ metabolism, from bench to bedside

Spoiler: Fig 1

"NAD+ synthesis from NAM requires only two steps: NAM gets first converted by nicotinamide phosphoribosyltransferase (NAMPRT) into NAM mononucleotide (NMN), which in its turn leads to the production of NAD+ in a reaction catalyzed by nicotinamide mononucleotide adenylyltransferase (NMNAT) (Fig 1). Three different isoforms of NMNAT have been reported, each of them possessing a specific subcellular localization: NMNAT1 is a nuclear enzyme (Emanuelli et al, 2001; Yalowitz et al, 2004), NMNAT2 is located in the cytosol and Golgi apparatus (Yalowitz et al, 2004; Berger et al, 2005), while NMNAT3 was detected in the cytosol and mitochondria (Zhang et al, 2003; Berger et al, 2005; Yang et al, 2007). NR also gets converted into NMN by nicotinamide riboside kinase (NRK) (Bieganowski & Brenner, 2004). Mammals possess two isoforms of NRK: an ubiquitously expressed NRK1 and NRK2, whose expression was mainly detected in heart, skeletal muscle, brown adipose tissue (BAT), and liver (Bogan & Brenner, 2008). Interestingly, it has been recently reported that NRK1 is required for NAD+ synthesis not only from the exogenously administered NR, but also NMN (Ratajczak et al, 2016). Both NAM and NR operate via the “amidated” route to produce NAD+ (Fig 1)."

"Nicotinic acid, in its turn, initiates the “deamidated” route (Fig 1). Conversion of NA into NA mononucleotide (NAMN) constitutes the first step of this route, which most often is referred as the Preiss–Handler pathway (Preiss & Handler, 1958). The NMNATs recognize both NAMN and NMN as substrates; however, in the case of NAMN the conversion results in NA adenine dinucleotide (NAAD), and therefore, one additional step, catalyzed by NAD synthetase (NADS), is required to produce NAD+ (Fig 1). Interestingly, it has been recently reported that NR leads to the production of NAAD via a yet-unknown mechanism (Trammell et al, 2016a)."

"The existence of different pathways leading to NAD+ production raises questions on the relative importance of each pathway and which of them possess the highest potential to boost NAD+ levels. The preferable precursor for NAD+ production within the organism is hence still a matter of debate. There is evidence that NAM possesses a higher NAD+ boosting capability when compared to NA in different organs in mice (Collins & Chaykin, 1971, 1972; Mori et al, 2014; Yang et al, 2014). Additionally, in human plasma, levels of NAM were reported to be fivefold higher than NA levels (Jacobson et al, 1995). However, several other studies claim the opposite: NA is a more effective NAD+ precursor than NAM (Ijichi et al, 1966; Hagino et al, 1968; Lin & Henderson, 1972; Williams et al, 1985; Jackson et al, 1995; Hara et al, 2007). It is important to mention that in Mori et al (2014) the authors quantified the activity of NMNAT and NADS; therefore, the comparison was rather made between the “deamidated” (e.g., from NA) and “amidated” route, which includes both NAM and NR. And even if the authors of this study claim that NAM is the main precursor for NAD+ synthesis, the possibility of a significant contribution of other precursors using the amidated NAD+ biosynthesis route (e.g., NR) cannot be discounted. In support of this, a very recent study showed that NR has a greater capacity over NA and NAM to boost hepatic NAD+ levels (Trammell et al, 2016a). It is also important to mention that both NA and NAM have reported side effects, whereas no adverse effects are currently reported for NR. NA activates the G protein-coupled receptor, GPR109A and causes flushing, characterized by vasodilation and a burning sensation (Benyo et al, 2006). While NAM raises health concerns for treatment of diabetic patients, as high doses of NAM can be hepatotoxic (Knip et al, 2000)."​

- Niacin: chemical forms, bioavailability, and health effects

"Intestinal uptakes of NA are rapid and nearly stoichiometric, 2 i.e., bolus doses of up to 3–4 g NA are almost completely absorbed by adults.10 Once absorbed in the intestine, 15–30% of the plasma NA is bound to protein. 1 The overall dose-response relationships of NA are well known.11 Nutritional functions related to NM-containing coenzymes1 occur at lower levels of intake (15–18 mg/day), while the undesirable vasodilative flushing effect may occur when intakes exceed 50 mg/day.12,13 The beneficial effects on serum lipid profiles occur at much higher levels of intake (500– 3,000 mg/day). These widely studied impacts on serum lipids are accompanied by low but significant risks of liver and intestinal pathologies.8"

"Intakes of 1 g or more per day not only provide pharmacological benefits but also carry a significant risk of adverse effects, thus requiring medical monitoring and supervision. High intakes of NA produce a vasodilative effect that can result in an intense itching or burning sensation of the skin known as the“niacin flush.” Flushing may be classified as a nuisance effect. It is initiated via prostaglandin D2-mediated vasodilatation of small subcutaneous blood vessels. The vasodilatation is associated with an unpleasant sensation of intense warmth and itching that commonly starts in the face and neck and can proceed down through the body. Some individuals may experience a rash, hypotension, and/or dizziness.56 Flushing appears about 30 minutes after intake of NA, and 2–4 hours after intake of ER-NA. Skin-flushing reactions usually persist over only a few doses until the body develops a natural tolerance. The daily dose is generally administered over several hours in three parts to reduce flushing. Each portion may be increased gradually until the desired total dose is achieved. Liver function tests and tests for uric acid, fasting blood glucose, and lipid levels should be conducted as the dose is administered. When used as an antihyperlipidemic agent, adverse reactions may require decreased dosage or discontinuation in favor of other agents."

"Flushing effect. The recommended dietary intakes of 15–18 mg/day carry no known risk of adverse effects, but the vasodilative flushing effect can be quite pronounced at intakes as low as 50 mg/day and may occur infrequently at intakes as low as 30 mg/day, depending on the circumstances of the intake. Important modifiers of flushing risk include empty or full stomach; dissolved versus crystalline form of NA; and bolus administration versus intake spread over several hours. The flushing effect can be managed effectively in most patients, provided they are given proper instructions and the dose is slowly titrated upward to reach therapeutic levels.56"

"Hepatotoxicity and gastrointestinal toxicity. These adverse effects, which can be severe, definitely provide cause for concern about the safety of daily intakes of 1 g NA or higher, the level at which toxicity usually occurs. Hepatotoxicity is detected most often as increases in serum levels of selected liver enzymes,39 but the severity of hepatotoxicity can range from elevated liver enzymes to acute liver failure.57 Although the likelihood of liver toxicity is significant, it is nevertheless low enough that NA at intakes of up to 2–4 g/day may be used safely and effectively as an antihyperlipidemia drug under medical monitoring and supervision. Although available on the market as a dietary supplement in tablets of 500 mg and 750 mg, NA should not be used at gram dosages without medical supervision. There is a strong correlation between the minimal adverse effects identified through clinical trials and those suggested by the published anecdotal case reports. Many severe reactions to NA, especially liver toxicity, have involved ill-advised or uninformed switching from NA preparations to ER-NA formulations without adjusting the dose.12"

"Most reported adverse reactions to NA have occurred with intakes of 2–6 g/day. There are only two anecdotal cases reported in which intake levels below 1,000 mg/day produced an adverse effect: in one, ER-NA was administered at 500 mg/day, and in the other,NA was given at 750 mg/day.12 The clinical trial of McKenney et al.31 investigated two groups of adult subjects, one given NA and the other ER-NA, each containing subgroups that covered a range of doses. These two treatment groups were observed for 6 weeks at dosage levels of 500, 1,000, 1,500, 2,000, and 3,000 mg/day. The data showed no adverse reactions at 500 mg/day for either form of NA but did show statistically significant effects beginning at 1,000 mg/day (gastrointestinal effects for NA, and mild liver toxicity for ER-NA). The gastrointestinal side effects ranged in severity from nausea to, in the extreme, recurrence of peptic ulcer that had been asymptomatic for 7 years.31 Quantities of NA above 1 g should not be self-administered as a dietary supplement but may be safely used under the care and monitoring of a healthcare provider. Such an application, it should be noted, constitutes a pharmaceutical use, not a dietary supplement use."

"[Nicotinamide] has been tested at multigram intakes, with inconsistent evidence of adverse effects.7,58 One study reported a range of adverse effects, including headache, heartburn, nausea, gastrointestinal disturbances, and fatigue at a dose of 3,000 mg/day supplemental NM for 3–36 months59; however, few details were provided and no controls were included for comparison. Although these effects might have been caused by NM, they are not unique to any specific substance or condition. Other supplementation trials60–64 have reported no adverse effects at NM intake levels of up to 3,000 mg/day. However, the studies in which the highest doses were administered primarily looked for possible beneficial effect in patients with type 1 diabetes mellitus, and it is unclear how the possible adverse effects were evaluated. Because of the small database, the EVM applied an uncertainty factor of 3 and adjusted to a standard body weight of 60 kg to set a total dietary intake guidance level of 600 mg/day NM, or 560 mg/day of supplemental NM.7"

"It is suggested that the safe upper limit for supplemental NA formulations be set at 500 mg/day, a level associated with neither adverse effects in clinical trials nor anecdotal reports of adverse reactions, other than vasodilative dermal flushing.8"

"Because NM does not produce a vasodilative dermal flush, the SCF and EVM established separate UL values for this compound on bases that are different from those for NA. These values are 900 mg/day and 500 mg/day, respectively. Inexplicably, the IOM did not establish a UL for NM separately from that for NA, even though NM does not produce the vasodilative flushing that was the basis of the UL for NA.2 Instead, the IOM applied the 35 mg UL to all forms of “niacin.” The IOM provided no discussion to address this anomaly. Previous risk analysis suggested a safe upper limit of supplemental NM of 1,500 mg/day,8 as well as the 900 mg/day and 500 mg/day values in the SCF and EVM reports."​

- Excessive nicotinic acid increases methyl consumption and hydrogen peroxide generation in rats

Equivalent humand doses used here in mg for..
Nicotinic acid: 16, 65, 130.
Nicotinamide: 65.
But they were injected. Tut.

I guess it was not the reason for them to choose that route, because there are other ways of administering, but keep in the minds that animals reject or eat less food when it tastes bad from suspicious supplements. However people try to out of the smarts their body consuming colossal doses of certain nutrients thinking that an off taste is not a warning sign and has no importance just like our livers.​

Spoiler: Daily average consumption throughout the ears

"Type 2 diabetes involves oxidative stress, insulin resistance and epigenetic changes: the latter are linked to methyl metabolism (Zhou et al., 2011). Our recent ecological analysis has suggested that increased prevalence of obesity and type 2 diabetes might involve niacin consumption, primarily due to fortification of grain with niacin (Zhou et al., 2010). If niacin plays a causal role in obesity and type 2 diabetes, it should induce oxidative stress and insulin resistance, and affect methyl metabolism. In fact, nicotinamide and nicotinic acid have been known to induce glucose intolerance (Institute of Medicine, 1998) and insulin resistance (Kahn et al., 1989; Greenbaum et al., 1996; Chang et al., 2006), although the role of long-term high exposure to niacin in the development of type 2 diabetes remains unsolved. Our previous studies demonstrated that nicotinamide can cause oxidative stress (Zhou et al., 2009; Li et al., 2010) and deletion of methyl groups (Sun et al., 2012), which it is proposed accounts for insulin resistance and epigenetic changes in type 2 diabetes (Zhou et al., 2011). The present results showed that nicotinic acid also increased the generation of H2O2 and N1-methylnicotinimade, the latter being a methyl group consuming process (Sun et al., 2012). These findings further supported the hypothesis that chronic high niacin exposure may be a potent risk factor for type 2 diabetes.

Nicotinic acid and nicotinamide come from different dietary sources: dietary nicotinic acid is derived from plant foods, while nicotinamide is derived from animal foods. Fortified grains have provided an additional nicotinamide source, as nicotinamide is typically used for food supplements and food fortification. Moreover, there are some differences between the degradation of nicotinic acid and nicotinamide (Zhou et al., 2011). Excessive nicotinamide is rarely excreted into the urine, and has to be converted to N1-methylnicotinamide before elimination (Knip et al., 2000), whereas nicotinic acid can be either converted to nicotinamide and then degraded via the nicotinamide catabolic pathway, or excreted in the urine unchanged and as nicotinuric acid (Menon et al., 2007). This may explain why nicotinamide-treated rats have much higher plasma N1-methylnicotinamide levels than nicotinic acid-treated rats. Since the methylation of niacin increases the consumption of the body’s methyl groups which are also necessary for other methylation reactions, including DNA methylation (Zhou et al., 2011). Thus, it is conceivable that chronic high niacin exposure might induce methyl pool depletion, and thus play a role in DNA methylation-mediated epigenetic changes, but further studies are needed to confirm this.

It should be noted that nicotinamide exposure increases the content of rat liver glycogen, while nicotinic acid exposure decreases it. This suggests that nicotinamide may increase the synthesis of glycogen in rat liver. Since nicotinamide is the primary precursor of nicotinamide adenine dinucleotide, an essential coenzyme in many enzymes in glucose metabolism, the increase in liver glycogen synthesis by nicotinamide may involve changes in the activity of glycogen synthetic enzymes. Interestingly, evidence has indicated that obesity is associated with increased hepatic glycogen content (Allick et al., 2004) on the one hand, and on the other hand, that the sharp increase in the prevalence of obesity has occurred following the worldwide spread of mandatory fortification with nicotinamide (Zhou et al., 2010). Thus, it may be possible that an excess nicotinamide-induced increase in hepatic glycogen synthesis may play a role in the development of obesity. Studying the relationship between excessive nicotinamide intake and hepatic glycogen synthesis might be a promising way to gain more insight into the pathophysiology of obesity."

Spoiler: Bloody tables

 

[Suikerbuik]

@Amazoniac After everything you have read (and likely experimented) do you use any supplemental nicotinamide or niacin? If so, what dose do you feel most comfortable with, and do you use betaine?

Thank you for this comprehensive info by the way, I enjoy it.

 

[Amazoniac]

@Amazoniac After everything you have read (and likely experimented) do you use any supplemental nicotinamide or niacin? If so, what dose do you feel most comfortable with, and do you use betaine?

Thank you for this comprehensive info by the way, I enjoy it.

I prefer not to comment on that right now because I have many more questions than answers. But it seems to me that the worse effects appear in the middle range when the dose is already very high in relation to normal intake but not enough to be metabolized in an exceptional way yet at the same time not being able to restore NAD+ levels:

the recommended daily allowance for NA is in milligrams, whereas an estimated 6 to 9 g of NAD+ are required daily to match turnover [58]

--
Putting yourself into Raj's oxidized state is great but only until where you have control over the situation. Oxidation and energy production involve stress, some states might call for the extra temporary stress to shatter (Koch's word) whatever has been blocking them, but that causes damage and isn't sustainable.

NAD levels are dramatically altered by dietary levels of niacin.[59] Since NAD and NADP are crucial in redox reactions,[59] excessive niacin may lead to significant impacts on the redox status of the body by affecting NAD contents. Our recent study demonstrated that excessive nicotinamide might increase the generation of hydrogen peroxide, a highly ROS, and have a role in the development of insulin resistance.[35,60]

Therefore it should be better to supplement lower doses regardless of the form.

--
Regarding methyl donors, if the diet is poor in them, that needs to be taken care of. But for extra, it's safer to get them through liver or even yeast extracts to obtain the other interacting nutrients along because you don't know if there's a true deficiency, of if it's in fact inflammation that's impairing their use, with them ending up sitting somewhere causing problems.

"Figure 2 shows that the toxicity of methyl consumers is not merely a matter of methyl depletion. Supplementation of methyl donors, although alleviating methyl consumer-induced methyl depletion, cannot prevent methyl consumer-induced ROS generation and the resultant oxidative cell damage. This implies that without reducing the level of methyl consumers, supplementation of methyl donors alone may not achieve the desired therapeutic effect."

 

[Suikerbuik]

I prefer not to comment on that

Your remaining answer tells enough, thank you. If someone is about to prove there's no limit to human lifespan, I'm sure it's going to be you. Keep up the good info Amazoniac, balance it is.

 

[Amazoniac]

Equivalent humand doses used here in mg/kg for..

Forgot to include that due to language barrier.


- The plasma free fatty acid rebound induced by nicotinic acid

Dogs and rats were injected with nicotinic acid while fasted. The only practical aspect is that the doses were low in comparison with other experiments.

On the previous page here some guys reported that blood niacin levels peaked after 20 minutes of ingestion, so I don't know why they decided to measure blood levels every 30 minutes in an experiment involving injection. But I digest.

Here's what happened when nicotinic acid was given to them while fasted:

<this space won't disappear anymore if a leave this text here>
Divide dose by 1.8 for dogs and 6.2 for rats to get the elivaquent muhan sode.

It's interesting that in this experiment Freeing the Fatty Acids didn't vary with bloody glucose:

"No short-term effects on blood glucose were observed. In this regard, it is interesting to note that no significant changes in blood glucose were observed in the nicotinic acid-treated rats and dogs during the peak increases in plasma FFA"​

<this space won't disappear anymore if a leave this text here>
There was no rebound when adrenal and pituitary of the glands were removed:

<this space won't disappear anymore if a leave this text here>
"In a further examination of the necessity for the pituitary and adrenal glands in FFA rebound, nicotinic acid (10 mg/kg) was administered intravenously to normal rats and plasma corticosterone values were monitored over the 4 hr observation period. Under these conditions, nicotinic acid caused a rapid and significant elevation of corticosterone levels at precisely the times when the rate of increase of plasma FFA was maximal (Fig. 8). The well-known permissive role of adrenocortical hormones in FFA mobilization (17) suggests that adipose tissue is sensitized to the action of pituitary lipolytic factors (probably ACTH) and therefore gives rise to a full expression of FFA rebound."​

<this space won't disappear anymore if a leave this text here>
Concluding that..

"A prominent role for the pituitary-adrenal system is clear from the lack of an FFA rebound in adrenalectomized-hypophysectomized rats. Further evidence for such a role is found in the fact that an increase in plasma corticosterone values parallels the rebound elevation of plasma FFA."​

<this space won't disappear anymore if a leave this text here>
- https://www.lipidjournal.com/article/S1933-2874(08)00139-6/pdf

 

[Amazoniac]

Your remaining answer tells enough, thank you. If someone is about to prove there's no limit to human lifespan, I'm sure it's going to be you. Keep up the good info Amazoniac, balance it is.

Guru, it's nice that you're around. There was a point that I just accepted the dungeons believing there would be no rescue.

 

[Terma]

@Ammozoniac
Some of these studies are excellent and had not seen, thank you for posting them. Especially "Nicotinamide: A double edged sword - ScienceDirect" will be fascinating to read more on, and it's the one that makes you wonder most about organ-specific issues when it comes to supplementation (even brings back the whole betaine vs choline questions, since former is metabolized in liver/kidney while latter permeates everything).

Some however I'd seen and the niacin-obesity connection is plagued by correlation-causation syndrome, it's kind of disgusting.

This study which gets referenced a bit was my favorite feeling of something-must-be-wrong-here:
https://www.nature.com/articles/nature13198?WT.ec_id=NATURE-20140410

In the text you find:

To determine whether the increased energy expenditure with NNMT
inhibition (Fig. 3) is polyamine-dependent, we used N 1 -methylnicotinamide
to inhibit NNMT activity in adipocytes. This induced oxygen consumption
(Fig. 4k–m). Knocking down Ssat (Supplementary Fig. 17), inhibiting ODC
activity 8 or blocking PAO activity abolished N 1 -methylnicotinamide-
induced oxygen consumption (Fig. 4k–m). Thus, NNMT inhibition in
adipocytes autonomously enhances oxygen consumption, and this depends
on polyamine flux

So... they used the end-product MNA (MNAM) as the means to inhibit and judge the effects of the inhibition of NNMT. In 2014.

So happens, couple years after (2017):
https://www.researchgate.net/public...keletal_muscle_coordinating_energy_metabolism

Obesity is a major health problem, and although caloric restriction and exercise are successful strategies to lose adipose tissue in obese individuals, a simultaneous decrease in skeletal muscle mass, negatively effects metabolism and muscle function. To deeper understand molecular events occurring in muscle during weight-loss, we measured the expressional change in human skeletal muscle following a combination of severe caloric restriction and exercise over 4 days in 15 Swedish men. Key metabolic genes were regulated after the intervention, indicating a shift from carbohydrate to fat metabolism. Nicotinamide N-methyltransferase (NNMT) was the most consistently upregulated gene following the energy-deficit exercise. Circulating levels of N1-methylnicotinamide (MNA), the product of NNMT activity, were doubled after the intervention. The fasting-fed state was an important determinant of plasma MNA levels, peaking at ~18 h of fasting and being lowest ~3 h after a meal. In culture, MNA was secreted by isolated human myotubes and stimulated lipolysis directly, with no effect on glucagon or insulin secretion. We propose that MNA is a novel myokine that enhances the utilization of energy stores in response to low muscle energy availability. Future research should focus on applying MNA as a biomarker to identify individuals with metabolic disturbances at an early stage.

(PDF) N1-methylnicotinamide is a signalling.... Available from: https://www.researchgate.net/public...keletal_muscle_coordinating_energy_metabolism [accessed Jul 15 2018].

And lo and behold, their main conclusion/theoresizing was that MNA per se must have proactive effects on metabolism. Increasing lipolysis. So using MNA to inhibit and judge inhibition of NNMT is like asking the nail what it thinks of the hammer.

Now, they stopped short of blasting the last study because they focuzed on muscle rather than WAT, which is a more than valid concern mind you, but I think this puts in question some studies before it, even though not all their ideas in the discussion hold as much water.

This also revived an idea I couldn't shake: Maybe we need to find out how to control the levels/activity of the NNMT enzyme itself, independently of niacin/niacinamide [and methyl/methionine] intake. e.g. how controls the transcription, and if any substances out there block its protein activity outright. That would give us way more control over our bodies, and how it spends methyl groups especially in methionine restriction, and maybe something organ/cell-type specific.

I've become a little bit partial to nicotinic acid myself (indeed in low doses) because as I posted in the other threads it may be associated with phospholipid synthesis as well as promotion of the M2 macrophage state (even though niacinamide also promotes the latter, the nicotinic acid receptor effects suggest nicotinic acid should be stronger in this respect - and I hypothesize nicotinic acid is a more immune-modulating molecule owing to being the direct end-product of the kynurenine pathway which is largely an immune control mechanism - that would indirectly endorse Doctor Peat's suggestion to stick with niacinamide for regular people) - my two favorite B3-related subjects at the moment - don't know if any of those articles explicitly mentioned them or not, but you'll land on them.

(Side note: The first study I posted on obesity hypothesized that increased polyamine synthesis as result of NNMT knockdown would lower obesity! Even without invoking Mr. T, I couldn't follow their logic)

Disclaimer: I obviously didn't read every part of those studies yet, and weekend's already over!

 

[Amazoniac]

@Ammozoniac
Some of these studies are excellent and had not seen, thank you for posting them. Especially "Nicotinamide: A double edged sword - ScienceDirect" will be fascinating to read more on, and it's the one that makes you wonder most about organ-specific issues when it comes to supplementation (even brings back the whole betaine vs choline questions, since former is metabolized in liver/kidney while latter permeates everything).

Some however I'd seen and the niacin-obesity connection is plagued by correlation-causation syndrome, it's kind of disgusting.

This study which gets referenced a bit was my favorite feeling of something-must-be-wrong-here:
https://www.nature.com/articles/nature13198?WT.ec_id=NATURE-20140410

In the text you find:


So... they used the end-product MNA (MNAM) as the means to inhibit and judge the effects of the inhibition of NNMT. In 2014.

So happens, couple years after (2017):
https://www.researchgate.net/public...keletal_muscle_coordinating_energy_metabolism


And lo and behold, their main conclusion/theoresizing was that MNA per se must have proactive effects on metabolism. Increasing lipolysis. So using MNA to inhibit and judge inhibition of NNMT is like asking the nail what it thinks of the hammer.

Now, they stopped short of blasting the last study because they focuzed on muscle rather than WAT, which is a more than valid concern mind you, but I think this puts in question some studies before it, even though not all their ideas in the discussion hold as much water.

This also revived an idea I couldn't shake: Maybe we need to find out how to control the levels/activity of the NNMT enzyme itself, independently of niacin/niacinamide [and methyl/methionine] intake. e.g. how controls the transcription, and if any substances out there block its protein activity outright. That would give us way more control over our bodies, and how it spends methyl groups especially in methionine restriction, and maybe something organ/cell-type specific.

I've become a little bit partial to nicotinic acid myself (indeed in low doses) because as I posted in the other threads it may be associated with phospholipid synthesis as well as promotion of the M2 macrophage state (even though niacinamide also promotes the latter, the nicotinic acid receptor effects suggest nicotinic acid should be stronger in this respect - and I hypothesize nicotinic acid is a more immune-modulating molecule owing to being the direct end-product of the kynurenine pathway which is largely an immune control mechanism - that would indirectly endorse Doctor Peat's suggestion to stick with niacinamide for regular people) - my two favorite B3-related subjects at the moment - don't know if any of those articles explicitly mentioned them or not, but you'll land on them.

(Side note: The first study I posted on obesity hypothesized that increased polyamine synthesis as result of NNMT knockdown would lower obesity! Even without invoking Mr. T, I couldn't follow their logic)

Disclaimer: I obviously didn't read every part of those studies yet, and weekend's already over!

Consider this..
https://link.springer.com/article/10.1007/s00125-015-3678-5
"[..]we think that increased nicotinamide intake is not the predominant cause of our previously reported NNMT expression and serum MNA changes or phenotype associations. First, NNMT has been reported to be upregulated in preclinical models of diabetes and obesity, independently of nicotinamide intake [3, 4]. Additionally, adipose tissue NNMT expression was found to be higher in obesity-prone than in obesity-resistant mouse strains [4], and higher urinary MNA concentrations were observed in patients with type 2 diabetes compared with healthy controls, and in db/db mice and obese Zucker rats [5], independently of nicotinamide intake. Furthermore, treatment with an antisense oligonucleotide against NNMT was shown to improve insulin sensitivity and to reduce body weight gain in mice fed a high-fat diet compared with mice on the same diet that were treated with vehicle or a non-silencing antisense molecule [4]. Finally, an induction of tissue NNMT expression by nicotinamide has so far only been demonstrated in rats treated with very high doses of nicotinamide [6] exceeding normal dietary intake by several orders of magnitude."

Have you read this part?

There are people blaming N-methylnicotinamide for the problems, but I don't know if that's correct. Copper seems to decrease the activity of Nicotinamide N-methyltransferase (the enzyme that methylates it) and manganese in excess increase it. However maybe the focus should be on improving the activity of aldehyd oxidase, which processes it further for excretion and prevents the accumulation of N-methylnicotinamide.

It's also possible that this is a protective mechanism, and not methylating it would be more damaging as suggested by the first quote from the second link. If that's the case, lowering it would be a nicht, nicht for sure. But I'm just making the thoughts out of the loud.

Their different effects on immunity seem interesting, I'll have to make the readings on that. Thank to you!

 

[Terma]

Re: the "Finally, an induction of tissue NNMT expression by nicotinamide has so far only been demonstrated in rats treated with very high doses of nicotinamide [6] exceeding normal dietary intake by several orders of magnitude." part, I mis-emphasized and meant more controlling NNMT activity regardless of methyl intake. (Derives again from that muscle study, because when fasting you shouldn't have too many methyl groups around - unless you're breaking down tons of phospholipids with phospholipase for the choline - yet NNMT increased in that circumstance)

Regardless, I haven't read that full article (beyond I think seen the abstract and forgotten about it) but I will a.s.a.p. thanks

 

[Terma]

That's since, I mean, what's the point of this thread, and half this forum? Everyone wants to supplement niacin or niacinamide (ideally, both, at the right times; and I already know low-dose is the way to go for chronic use) - that's not a variable for us unless you're doing the 3g/day niacinamide thing (which I years ago gave up on). All we have is our methyl consumption to tweak right now, even if your quotes are saying it doesn't fully offset the issues from increased methyl demand. Also in part because of having read some of these studies before, I felt like the oft-advice to counter methyl consumption with niacinamide is probably not the best idea (glycine and retinoic acid might be more appropriate imo, if measured). So something else has got to give. Maybe that study has a hint.

[My own motivation, though doesn't perfectly follow: some of us want to support NAD synthesis even in methionine restriction - and fasting all the time to increase NAD/NADH ratio is out of the picture]

 

[Amazoniac]

Re: the "Finally, an induction of tissue NNMT expression by nicotinamide has so far only been demonstrated in rats treated with very high doses of nicotinamide [6] exceeding normal dietary intake by several orders of magnitude." part, I mis-emphasized and meant more controlling NNMT activity regardless of methyl intake. (Derives again from that muscle study, because when fasting you shouldn't have too many methyl groups around - unless you're breaking down tons of phospholipids with phospholipase for the choline - yet NNMT increased in that circumstance)

Regardless, I haven't read that full article (beyond I think seen the abstract and forgotten about it) but I will a.s.a.p. thanks

Do you think people that are chronically stressed can have an excess of methyl groups available from muscle wasting? It might explain some confusions.

That's since, I mean, what's the point of this thread, and half this forum? Everyone wants to supplement niacin or niacinamide (ideally, both, at the right times; and I already know low-dose is the way to go for chronic use) - that's not a variable for us unless you're doing the 3g/day niacinamide thing (which I years ago gave up on). All we have is our methyl consumption to tweak right now, even if your quotes are saying it doesn't fully offset the issues from increased methyl demand. Also in part because of having read some of these studies before, I felt like the oft-advice to counter methyl consumption with niacinamide is probably not the best idea (glycine and retinoic acid might be more appropriate imo, if measured). So something else has got to give. Maybe that study has a hint.

[My own motivation, though doesn't perfectly follow: some of us want to support NAD synthesis even in methionine restriction - and fasting all the time to increase NAD/NADH ratio is out of the picture]

There must be a good reason for Gerson to choose nicotinic acid over nicotinamide. Also, what needs to be addressed for niacin supplementation to work properly? What about specific concerns for each form?

What do you mean by glycine and retinoic acid?

 

[Terma]

Do you think people that are chronically stressed can have an excess of methyl groups available from muscle wasting? It might explain some confusions.

For muscle, I didn't read enough to say for sure, but yes I think so [but needs some major quantification work before you can say that matters, sort of like that B3 increasing NNMT expression*[fixed] claim]; but, in ME/CFS at least, in the brains, inflammation and problems increases phospholipase leading to increased choline. Body has a large reserve of choline in phospholipids.

There must be a good reason for Gerson to choose nicotinic acid over nicotinamide. Also, what needs to be addressed for niacin supplementation to work properly? What about specific concerns for each form?

My own ideas, completely non-vetted: https://raypeatforum.com/community/...-insulin-sensitivity.21800/page-2#post-351191
Choline + (oral low-dose only with food) uridine to incorporate the DAG productively. Similar to fructose. The choline is needed not just for methylation but phospholipid synthesis via Kennedy, which should be the preferable pathway.

Niacinamide, eh, I'd defer to haidut.

What do you mean by glycine and retinoic acid?

Glycine/RA are the two things known to support/increase the GNMT enzyme that "wastes" methyl to sarcosine (no relation to my external supplementation of sarcosine for nootropic purposes, yet anyway).

 

[Amazoniac]

For muscle, I didn't read enough to say for sure, but yes I think so [but needs some major quantification work before you can say that matters, sort of like that B3 increasing NNMT expression*[fixed] claim]; but, in ME/CFS at least, in the brains, inflammation and problems increases phospholipase leading to increased choline. Body has a large reserve of choline in phospholipids.


My own ideas, completely non-vetted: https://raypeatforum.com/community/...-insulin-sensitivity.21800/page-2#post-351191
Choline + (oral low-dose only with food) uridine to incorporate the DAG productively. Similar to fructose. The choline is needed not just for methylation but phospholipid synthesis via Kennedy, which should be the preferable pathway.

Niacinamide, eh, I'd defer to haidut.


Glycine/RA are the two things known to support/increase the GNMT enzyme that "wastes" methyl to sarcosine (no relation to my external supplementation of sarcosine for nootropic purposes, yet anyway).

I was trying to find where I posted about muscle breakdown providing choline, but couldn't find it. It's somewhere on the forum.
Your thoughts match what I've been reading. These might interest you and are all relevant to the thread:

Methyl groups are generated in the mammalian tissues during degradation of choline to glycine. Generally in adult rats around 40-45% of the choline uptake is converted to glycine and this value can sometimes increases up to 70% when the choline uptake is very low.

Choline generation via PEMT consumes a significant amount of SAM (3 mole SAM to produce 1 mole choline) and produces homocysteine.

folate supplementation causes a dose-dependent increase in plasma betaine

The metabolic burden of creatine synthesis

Spoiler: Glycine: functions and metabolic faith

https://www.slideshare.net/ranajni_09/met-of-glycine

Also:
Functions and metabolic fate of glycine (fig. 1) from Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review

I didn't know about retinoic acid. Thank to you again!

 

[Suikerbuik]

Forgot to include that due to language barrier.


- The plasma free fatty acid rebound induced by nicotinic acid

Dogs and rats were injected with nicotinic acid while fasted. The only practical aspect is that the doses were low in comparison with other experiments.

On the previous page here some guys reported that blood niacin levels peaked after 20 minutes of ingestion, so I don't know why they decided to measure blood levels every 30 minutes in an experiment involving injection. But I digest.

Here's what happened when nicotinic acid was given to them while fasted:

View attachment 9886 View attachment 9890​

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Divide dose by 1.8 for dogs and 6.2 for rats to get the elivaquent muhan sode.

It's interesting that in this experiment Freeing the Fatty Acids didn't vary with bloody glucose:

"No short-term effects on blood glucose were observed. In this regard, it is interesting to note that no significant changes in blood glucose were observed in the nicotinic acid-treated rats and dogs during the peak increases in plasma FFA"​

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There was no rebound when adrenal and pituitary of the glands were removed:

View attachment 9891
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"In a further examination of the necessity for the pituitary and adrenal glands in FFA rebound, nicotinic acid (10 mg/kg) was administered intravenously to normal rats and plasma corticosterone values were monitored over the 4 hr observation period. Under these conditions, nicotinic acid caused a rapid and significant elevation of corticosterone levels at precisely the times when the rate of increase of plasma FFA was maximal (Fig. 8). The well-known permissive role of adrenocortical hormones in FFA mobilization (17) suggests that adipose tissue is sensitized to the action of pituitary lipolytic factors (probably ACTH) and therefore gives rise to a full expression of FFA rebound."​

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Concluding that..

"A prominent role for the pituitary-adrenal system is clear from the lack of an FFA rebound in adrenalectomized-hypophysectomized rats. Further evidence for such a role is found in the fact that an increase in plasma corticosterone values parallels the rebound elevation of plasma FFA."​

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- https://www.lipidjournal.com/article/S1933-2874(08)00139-6/pdf

Those graphs are amazing and worrisome at the same time. Do you possibly know what happens in a well-fed animal?

 

[Amazoniac]

Those graphs are amazing and worrisome at the same time. Do you possibly know what happens in a well-fed animal?

Suiker, have you noticed that the rebound didn't happen with lower doses even in injected fasted animals? The lowest dog dose (1.0 mg/kg) was equivalent to 40 mg for a 70 kg humanoid. But it still didn't occur for the equivalent of 125 mg.

Are you from South Africa? I remember there was a member from there.

 

[Amazoniac]

Not sure which one I'm going to read in details, so I'm sharing in case others are interested (no specific order):

- THE COMPARATIVE VALUE OF NIACIN AND NICOTINAMIDE
- On the Relative Efficacy of Nicotinamide and Nicotinic Acid as Precursors of Nicotinamide Adenine Dinucleotide
- The pharmacological effects of massive doses of nicotinamide
- Methylation of Nicotinamide in Vitamin B12- and Vitamin B6-Deficient Rats
- Tranquilizing and Antiserotonin Activity of Nicotinamide
- Mechanism of histamine-release inhibition by nicotinamide in in vitro antigen-antibody reaction
- Relationship of nicotinamide and nicotinic acid to hypolipidemia - ScienceDirect
- Biochemistry of Nicotinic Acid and Nicotinamide
- A comparative study of the metabolism of nicotinamide and nicotinic acid in normal and germ-free rats
- Comparative metabolism of nicotinamide and nicotinic acid in mice.
- The Management of Nicotinamide and Nicotinic Acid in the Mouse
- Primitive Earth Synthesis of Nicotinic Acid Derivatives
- Aldehyde oxidase: Catalysis of the oxidation of N1-methylnicotinamide and pyridoxal
- The quinine-oxidizing enzyme and liver aldehyde oxidase

- The Chemistry and Biochemistry of Niacin (B3)

In 1771, Francesco Frapolli made the first reference to the disease as pellagra, meaning ‘rough skin’ in Italian. He linked it with poverty and subsistence on nutritionally marginal corn-based diets.

In 1937, Conrad A. Elvehjem isolated the P-P (pellagra preventive) factor, identified it as nicotinic acid (niacin). [There are publications referring to niacin as 'vitamin PP'.]

The term ‘niacin’ was coined to avoid the associations of nicotinic acid with acids and nicotine, which shocked the public.

- Necessity of combining methionine with nicotinic acid & nicotinamide when one wishes to administer massive & overdoses of these pyridine compounds
- Necessary supplementation of vitamin B12 with folic acid, ascorbic acid and nicotinamide for purposes of liver protection; posological and therapeutic study
- Effects of nicotinamide and nitrogen supplements in low-protein diets containing sulfonamides
- Studies on nicotinamide antagonists
- Nicotinamide and hepatic methionine
- Interaction between thiamine and nicotinamide

 

[Suikerbuik]

Suiker, have you noticed that the rebound didn't happen with lower doses even in injected fasted animals? The lowest dog dose (1.0 mg/kg) was equivalent to 40 mg for a 70 kg humanoid. But it still didn't occur for the equivalent of 125 mg.

Are you from South Africa? I remember there was a member from there.

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

 

[Suikerbuik]

Not sure which one I'm going to read in details, so I'm sharing in case others are interested (no specific order):

- THE COMPARATIVE VALUE OF NIACIN AND NICOTINAMIDE
- On the Relative Efficacy of Nicotinamide and Nicotinic Acid as Precursors of Nicotinamide Adenine Dinucleotide
- The pharmacological effects of massive doses of nicotinamide
- Methylation of Nicotinamide in Vitamin B12- and Vitamin B6-Deficient Rats
- Tranquilizing and Antiserotonin Activity of Nicotinamide
- Mechanism of histamine-release inhibition by nicotinamide in in vitro antigen-antibody reaction
- Relationship of nicotinamide and nicotinic acid to hypolipidemia - ScienceDirect
- Biochemistry of Nicotinic Acid and Nicotinamide
- A comparative study of the metabolism of nicotinamide and nicotinic acid in normal and germ-free rats
- Comparative metabolism of nicotinamide and nicotinic acid in mice.
- The Management of Nicotinamide and Nicotinic Acid in the Mouse
- Primitive Earth Synthesis of Nicotinic Acid Derivatives
- Aldehyde oxidase: Catalysis of the oxidation of N1-methylnicotinamide and pyridoxal
- The quinine-oxidizing enzyme and liver aldehyde oxidase

- The Chemistry and Biochemistry of Niacin (B3)

​

- Necessity of combining methionine with nicotinic acid & nicotinamide when one wishes to administer massive & overdoses of these pyridine compounds
- Necessary supplementation of vitamin B12 with folic acid, ascorbic acid and nicotinamide for purposes of liver protection; posological and therapeutic study
- Effects of nicotinamide and nitrogen supplements in low-protein diets containing sulfonamides
- Studies on nicotinamide antagonists
- Nicotinamide and hepatic methionine
- Interaction between thiamine and nicotinamide

That's a lot of reading! But I'll skim through some of them, as some titles sound interesting, thanks.