Nicotinamide is available ito every cell, but its side effects make it a less attractive NAD precursor
Nicotinamide, also known as Niacinamide or NAM, relies on the salvage pathway to replenish intracellular NAD. It works in every kind of cell. But it is rate-limited by NAMPT under conditions of aging a metabolic stress, and not only has shown toxicity at high doses, but also can suppress sirtuins. Sirtuins do important work that we would not want suppressed.
PROs: Works in all cell types
CONs: Negative side effects at high doses; potentially rate-limited under some circumstances, may not help gut microbiome
Nicotinamide is a small piece of NAD that can pass through cell walls and help replenish NAD in every type of cell.
So What's Not to Love?
NAM uses the "salvage" pathway to replenish intracellular NAD. That means the nicotinamide first gets turned into NMN, and then the NMN gets turned into NAD.
That first step, turning NAM into NMN requires an enzyme called Nicotinamide phosphoribosyltransferase (NAMPT). NAMPT is considered rate-limiting for this step, because if there isn't enough NAMPT present, then the transaction stops and the NAM can't get past the first step.
NAMPT is pretty common in your body. But it's not infinite. Worse, it can be diminished under particular circumstances. For example, if there are other metabolic processes competing for the NAMPT, -- perhaps if your body is fighting an infection -- you could run out for a while. Or even if you just get older, you might not be able to convert enough NAM into NAD. Here is how the studies describe it:
NAMPT is the primary rate-limiting enzyme in the process of NAM to NMN, which is also declined with age and several disease stress.
In humans, high dependency on NAM for NAD+ synthesis confers vulnerability to its deficiency-mediated decline in NAD+ levels, particularly associated with age-related metabolic changes. It has been estimated that up to 15–20% of the general population and 26% of elderly people may be vitamin B3 deficient, regardless of the B3 dietary intake [emphasis added].
So taking a niacinamide supplement might not help if the salvage pathway in the cells you care about is down-regulated at the NAMPT step due to age or metabolic stress. In other words, sometimes in some people niacinamide will do the trick, and sometimes it won't. The advantage of nicotinamide riboside is that it bypasses the rate-limiting step because NR can be transformed into NMN without requiring NAMPT.
NAM also may inhibit the action of sirtuins, which confer benefits that we would not to inhibit:
NAM represents a physiological inhibitor of sirtuins.
High doses of NAM act as a SIRT1 inhibitor, dramatically reducing lifespan.
-- Antioxidants, February 4, 2023
In this study, the researchers found that NAM provided benefits at low doses, but the harm resulting from the suppression of beneficial enzymes made higher doses toxic:
NAM is more likely to act as an NAD+ precursor at low concentrations but its role leans towards inhibitors of NAD+-dependent enzymes at higher concentrations. Therefore, our findings can be explained by some unknown toxic effects of NAM (e.g., excessive suppression of PARPs and sirtuins) that may outweigh its beneficial effects as NAD+ precursor at high concentrations.
That by itself is a big-deal finding when comparing NAD precursors, because these NAD boosting is done at relatively high concentrations.
Another worry with NAM is that even if it works at lower doses, it has negative side effects at higher doses. Specifically, taking too much NAM can lead to kidney damage, liver damage, and insulin resistance (by using up methyl groups), as well as growth inhibition and reduction of genetic stability (cancer), because excess NAM can reduce PARP and sirtuin activity designed to protect your body.
Here is how the studies describe it:
Long term or high doses of NAM have led to detrimental effects, such as the development of a fatty liver, by reducing the availability of methyl groups…
A study demonstrated the possible adverse effects of high doses of NAM, a precursor of NAD+, and suggested that high doses of NAM can cause genomic instability, reduce cellular methyl pools, and cause insulin resistance through methylated NAM.
NAM preserves the mass and function of pancreatic cells. However, its potential side effects include liver toxicity, oncogenicity, and growth inhibition in animals and humans. In contrast, no side effects of NR have yet to be reported.
High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity...Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions...In rodents, administration of high doses of NAM caused liver steatosis and kidney hypertrophy, effects that were attributed to depletion of methyl donors...NAM treatment caused a significant decrease in insulin sensitivity in human subjects (2 g/day for 2 weeks)
The rate of drug discontinuation was high (42% in the Nam plus lanthanum group and 25% in the Nam only group). Gastrointestinal symptoms and pill burden were the most common reasons cited for discontinuation. Thus, the tolerability of higher doses of Nam (1.5 grams per day in this study) should be carefully considered when designing future studies.
NAM is more likely to act as an NAD+ precursor at low concentrations but its role leans towards inhibitors of NAD+-dependent enzymes at higher concentrations. Therefore, our findings can be explained by some unknown toxic effects of NAM (e.g., excessive suppression of PARPs and sirtuins) that may outweigh its beneficial effects as NAD+ precursor at high concentrations. [Emphasis added]
Oral NAM was also safe and effective in reducing the rates of new non-melanoma skin cancers and actinic keratoses in high-risk patients. However, pharmacological doses of niacin or NAM are poorly tolerated...Additional adverse effects of niacin and NAM include pruritus, skin rash, gastrointestinal disturbances and thrombocytopaenia. Liver cell damage has been observed at intakes of niacin as little as 750 mg/day... 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
At the current moment, both NMN and NR seem to be promising candidates for enhancing NAD+ levels in vascular cells, while administering NAM could be detrimental due to the negative feedback exerted by NAM on SIRT1
-- Antioxidants, February 4, 2023
Effect on the Gut Microbiome
Recent studies have shown that nicotinamide riboside can beneficially condition the gut microbiome, which, in turn, can lead to other beneficial effects.
However, although NR and NA both have been shown to have a beneficial effect on the gut microbiome, a study that compared NA to NAM found that NA, but not NAM, helped:
In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in...favorable microbiome changes...
NAM Can Be Good in Small Doses, But Not the Best
The moral of the story is that niacinamide can work in all cells, but sometimes it won't work well enough -- especially if you are older experiencing metabolic stress. And if you try to make up for that by taking higher doses, not only will that not work due to the rate-limiting nature of NAMPT availability, but it could also lead to severe side-effects, including reduced genomic stability, which you might not even be aware of. NR avoids these risks.