"Niacin" and "Niagen" may sound the same, but inside the body they work differently
Niacin (also known as "nicotinic acid," or NA), and Niagen (a trademarked product also known as "nicotinamide riboside" or NR), are both forms of vitamin B3 that can replenish intracellular NAD.
But there the similarities end. Once inside the body, they have different effects, and they do their work through different pathways.
Niacin (NA) is the original form of Vitamin B3. The other two forms more recently discovered are nicotinamide (NAM) and nicotinamide riboside (NR).
In the diagram below, you can see Niacin on the left has some similarities with nicotinamide riboside on the right, because they both have in common the purple section near the bottom. However, there are important differences.
On the left, at the bottom of the Niacin molecule, circled in red, is an oxygen atom and a hydrogen atom (called a "hydroxyl"). On the right side, circled in green, the purple nicotinamide molecule instead has a nitrogen atom and two hydrogen atoms (that's called an amide, which is the "amide" in "nicotinamide").
So the purple and red together are called "nicotinic acid,"and the purple and green together are called "nicotinamide."
Nicotinamide riboside also includes includes the nicotinamide in purple and green, PLUS the large ribose group on the top right, indicated in blue.
So you can see that chemically, Niacin one the left and Nicotinamide Riboside on the right are very different molecules.
You can also see that nicotinamide -- the purple and green on the right -- is different from both Niacin on the left, because NAM has an amide instead of a hydroxyl, and different also from nicotinamide riboside, because nicotinamide is missing the entire ribose group. However, it is accurate to say that nicotinamide is a piece of nicotinamide riboside, a smaller component.
The differences between these three molecules are sufficient that you would expect them to behave somewhat differently. But those differences get magnified in the metabolic system, because although all three have similar purposes -- helping cells build NAD molecules -- each one has its own separate dedicated pathway for doing that.
Why Does NAD Matter?
Here is an NAD molecule:
NAD molecules are central to all metabolism in all cells. Cells that run out of NAD will die. You can see below, in blue, that the nicotinamide riboside is actually a part of the NAD molecule:
You might remember from high school chemistry that "mitochondria are the powerhouse of the cells." What you might not remember is what fuels the mitochondria? The answer is NAD.
NAD not only powers the mitochondria, but it also provides the energy necessary for cellular maintenance and repair processes by molecules called PARPs and Sirtuins. PARPs, among other things, help fight against viral infections. Sirtuins, among other things, help repair damage to DNA. So we really want PARPs and Sirtuins to have the energy they need to do their jobs.
Indeed, if you experience significant DNA damage or viral infection, your NAD levels will drop because the NAD present gets used up. But that's okay, because your body can make more NAD, using the smaller pieces of NAD called "NAD precursors." NAD precursors are the three forms of vitamin B3 that we just considered: NA, NAM, and NR. All three can be made into NAD.
Not All NAD Precursors Are Equal
There are two reasons why you might prefer different precursors at different times or for different purposes. The first has to do with the differences in the metabolic pathways. The second has to do with different undesired side effects.
Although NA, NAM, and NR can all make NAD, each one feeds a different metabolic pathway. A metabolic pathway is simply a series of steps where molecules get built piece by piece, eventually into NAD. Here is what the three pathways look like:
Each intermediate step in a metabolic pathway (like "NMN") requires a particular enzyme that does the transformation (like "NAMPT"). Different metabolic pathways rely on different enzymes and different steps to get to the same destination.
But here is the catch: Not every enzyme needed for every metabolic pathway is equally available in every type of tissue. So, for example, niacin works well in the spleen, intestine, pancreas, liver, and some parts of the eye, but the niacin pathway does not work well, or hardly at all, in neurons generally, the brain specifically, muscles, and other parts of the eye.
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
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.
Unlike with niacin, the pathways for nicotinamide and nicotinamide riboside, are present in every type of tissue.
However, it's not quite as simple as that, because not only does the pathway have to be potentially active in the tissue, but the enzymes needed to do the work have to be present in adequate quantities when you need them, and that turns out not always to be so.
For nicotinamide, the rate-limiting enzyme is called NAMPT. If NAMPT is not present in adequate quantities, then the NAM pathway slows or stops, and the presence of nicotinamide will not lead to NAD in that tissue. A problem with NAM specifically is that NAMPT levels get lower with age and with stress.
So although the NAM pathway is theoretically available in all tissue types, it may not be working well at any particular moment, and especially not if you are old or experiencing metabolic stress. Of course, when you are experiencing metabolic stress is exactly when you might most need to replenish NAD.
What Was That About Side Effects?
Niacin has known side effects that are not seen with NAM and NR. Most famous is "flushing," a tingling sensation accompanied by reddening of the skin that most people experience and find uncomfortable. The flushing isn't harmful at all; it's completely safe. But if you take much more than the recommended 15 mg, you might experience it.
Niacin causes more severe side effects at much higher doses. The Mayo Clinic warns of potential for gout, liver damage, diabetes, and more at niacin doses of 2,000mg or more. Niacin used to be prescribed at such high doses to lower cholesterol, because at high doses it does that. But, according to a 2022 study, "niacin is rarely used in clinical practice these days due to some of its side effects."
Nicotinamide (NAM), too, has side effects at high doses, over 2,000mg that according to a 2022 study "may outweigh its beneficial effects as an NAD+ precursor at higher concentrations."
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.
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.
Nicotinamide Riboside (NR), by contrast, seems to have no negative side effects yet reported.
In humans, NR has been administered to doses up to 2 g/day, without any apparent side effects.
It's easy to get confused. There are multiple forms of vitamin B3, and they each replenish NAD by different mechanisms, and have different effectiveness, at different times, in different tissues.
So it is important not to conflate the effectiveness of the three. Some people say, "I'll just take niacin, because that's proven." And indeed, of the three, only niacin has been proven to lower cholesterol. But what's also proven about niacin is not only its effectiveness at low doses, but its ineffectiveness in some tissues (like neurons) and at some times (for example, the niacin pathway gets downregulated during viral infection.)
It is equally important not to conflate the side effects of the three. Only niacin causes flushing. Both niacin and NAM can cause liver harm at very high doses, but only NAM is shown to impair cellular protection mechanisms at high doses.
Nicotinamide riboside does not seem to have any of those side effects.
That could be because NR is newer, and there simply hasn't been time for those side effects to manifest. However, NR is not THAT new. It has been available to consumers as a health supplement for about seven years, and has been the subject of hundreds of preclinical investigations, as well as dozens of human clinical trials, some run at doses as high as 2,000mg.
That isn't to say that scientists may eventually come to a different conclusion as new evidence comes in. But the current state of the science is that benefits are shown, and the risks of NR are apparently no more than the risks of the other forms of vitamin B3, and in fact they seem to be less.