Niacin is the first form of Vitamin B3. It works sometimes, but not always, and there are issues...
Niacin, also known as Nicotinic Acid, NA, or Vitamin B3, could be the right choice.
PROs: Inexpensive, easily available, good in some cell types
CONs: Uncomfortable flushing, toxicity at higher doses, not for neurons or viral infection
The Benefits of Niacin
Between around 1906-1940, millions of Americans developed "Pellagra," a devastating illness characterized by the four Ds: Dermatitis, Diarrhea, Dementia, and Death. Approximately 100,000 Americans died of it.
It took more than a decade for researchers to determine that Pellagra was not an infectious disease, but resulted from a dietary deficiency, and another decade-plus before it was discovered that the culprit was a lack of vitamin B3.
Today, you do not have Pellagra because your diet contains adequate amounts of niacin, which is present in meat, milk, and eggs. Just to make sure, the FDA requires that grain products like flour, rice, corn meal, pasta, and cereal be fortified with niacin, too.
The recommended daily value for niacin is about 15 mg. No more is required partly because that's all you need to ward off Pellagra, and partly because if you go much higher than 15 mg -- say, 30 mg -- niacin causes flushing and itching for most people. It's not harmful; just uncomfortable.
Beyond Pellagra
Scientists subsequently discovered that Niacin does more than just prevent Pellagra. At higher doses, Niacin lowers blood lipids, reducing bad cholesterol and increasing good cholesteral. Niacin became a prescription medication for that purpose. By 2009, millions of Americans were being prescribed niacin to reduce the risk of heart disease. And of course, using higher-dose NAD precursors like Niacin to increase NAD levels has demonstrated all kinds of positive effects in animal models.
Harmful Side Effects of Niacin
Niacin's flushing sensation isn't harmful, and it may even diminish over time. However, other effects of high-dose Niacin are more concerning. Studies show that Niacin can cause liver damage, aggravate Type 2 Diabetes, and even harm vision.
Here is what the studies say:
"All formulations of niacin have been implicated in causing hepatotoxicity."
"Niacin should not be used at gram dosages without medical supervision…" Statistically significant adverse effects beginning at 1,000mg, with anecodotal reports of adverse effects at 500mg and 750mg..."
Liver cell damage has been observed at intakes of niacin as little as 750 mg/day. In addition, high niacin doses impair glucose tolerance, presumably by decreasing insulin sensitivity, and long-term niacin therapy was associated with a modest increase in risk of new onset Type 2 diabetes mellitus. NAM is generally better tolerated than niacin, although gastrointestinal disturbances and signs of liver toxicity have been reported at doses ˃10 g/day -- -- NAM is better tolerated than NA, and NR is better tolerated than NAM (emphasis added)
The National Institutes of Health's Office of Dietary Supplements offers a stern warning on Niacin safety:
When taken in pharmacologic doses of 1,000 to 3,000 mg/day, nicotinic acid can also cause more serious adverse effects...These adverse effects can include hypotension severe enough to increase the risk of falls; fatigue; impaired glucose tolerance and insulin resistance; gastrointestinal effects, such as nausea, heartburn, and abdominal pain; and ocular effects, such as blurred or impaired vision and macular edema (a buildup of fluid at the center of the retina). High doses of nicotinic acid taken over months or years can also be hepatotoxic; effects can include increased levels of liver enzymes; hepatic dysfunction resulting in fatigue, nausea, and anorexia; hepatitis; and acute liver failure... [emphasis added]
Limited Efficacy
If you're interested in Niacin as a method of raising NAD, a bigger issue even than the side effects may be the fact that the metabolic pathway that Niacin must travel to replenish intracellular NAD isn't equally available in all cell types.
Specifically, in order for Niacin to become NAD, the first step in the pathway is that the nicotinic acid (NA) must be transformed into nicotinic acid mononucleotide (NaMN). The enzyme that does the transformation is called "nicotinic acid phosphoribosyltransferase" (NaPRT). If NaPRT is not present in the cell, then the NA is stopped dead in its tracks and does not eventually become NAD.
NaPRT is present in many cell types. It is abundantly expressed in the liver, kidney, and GI tract, but less in other tissue types, such as eye, pancreas, muscle, and especially neurons. Here is how the studies describe it:
The enzyme nicotinate phosphoribosyltransferase (NAPRT) [is] rate-limiting in the NAD salvage pathway that starts from nicotinic acid
It should be realized that not every cell is capable of converting each NAD+ precursor to NAD+ at all times...Expression of the Preiss-Handler pathway is required to utilize [niacin]...The fact that DRG neurons cannot be protected from damage-induced neuropathy by Na or Nam without concurrent gene expression of Na or Nam salvage genes suggests that NR is a uniquely useful precursor to the nervous system.
We found that the de novo and Preiss-Handler pathways are not functional in Dorsal Root Ganglion axons, and that these neurons relied on the NAM salvage pathway for NAD+ synthesis.
Skeletal muscles...lack the Preiss-Handler pathway...
The lack of NAPRT expression in muscle compromises the ability of NA to have any direct effect on its NAD+ content.
NA is essentially ineffective at augmenting NAD+ in resting bacteria, mammalian cells, zebrafish, and mice; however, NA may help to replenish the NAD+ pool through the Preiss-Handler pathway when activated during inhibition of the NAMPT-dependent salvage pathway. Interestingly, NA works only at a low dosage in these conditions...
In this study, Nicotinamide Riboside (NR), but not Niacin (NA), was able to robustly rescue intracellular NAD levels during viral infection. It turns out that the virus down-regulates the metabolic pathways associated with tryptophan and niacin:
NAD boosting approaches involving increased de novo or NA-dependent synthesis are unlikely to be strongly effective because they require expression of genes such as QPRT, NADSYN, and NAPRT that are depressed by SARS-CoV-2 infection. Consistent with gene expression changes, in the cellular infection system, we showed that addition of NA only modestly reduced virus replication.
In this study of longevity using a mouse model of aging based on DNA repair, nicotinamide riboside was able to extend lifespan by 25%, whereas Niacin did not extend lifespan. The authors suggested that this was probably because the Niacin pathways are not active in some tissues, including the brain:
NA is unlikely to be used in the brain but rather in spleen, intestine, pancreas and liver. This could explain the difference we noted in our results; whereas NA specifically delayed the onset of imbalance, NR significantly extended lifespan, beyond the maximum age reached by any of the other drugs tested
What this means is that niacin can effectively replenish NAD in some cell types, but it will be limited or even blocked in other cell types if NAPRT is not adequately available. So if you are trying to replenish NAD just in your liver or gut, NA might do the trick. But if you are concerned about nerves, the brain, your eyes, or your lungs, NA may not be as effective as other precursors.
Conclusion
Although Niacin may be the least expensive and most easily available of the NAD precursors, it might do the least for you, given that you may already be getting moderate amounts in your diet anyway, you can't take large amounts without risking multiple types of toxicity, and it may not be available in some of the cells that need it most, like nerves, or at the moment you need it the most, like upon encountering a coronavirus.
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