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by Nils Osmar

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme found in every cell in your body. It plays essential roles in energy metabolism, DNA repair, and the regulation of cellular aging processes.

Some studies suggest that NAD+ levels decline significantly with age — by roughly half by age 60 — and this decline is associated with reduced cellular resilience and many of the health changes we associate with getting older. (Note: Other studies contradict these findings, and suggest that the decline may not be as great. Nonetheless, many people are supplementing as an anti-aging strategy.)

You can’t effectively supplement NAD+ directly, because the molecule is too large to enter cells. Instead, our bodies build NAD+ from smaller precursor molecules. (Think of supplementation with a precursor as being similar to wanting to build something, the size of a car in your living room. A pre-assembled car would not go through the front door, but you could carry the parts in and assemble it inside.)

Four of the most widely discussed precursors are nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinic acid (NA, commonly called niacin), and niacinamide (also called nicotinamide, or NAM). All four are members of the vitamin B3 family, and all four raise NAD+ levels — but through different pathways and with different side effects.

Re: which is best — it depends on which benefits you’re looking for, and which side effects you’re concerned about. Here’s what the research currently tells us about each one.

Here’s a quick summary. Scroll down for more details!

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Nicotinic Acid (Niacin) (NA)

The oldest player on the field. Nicotinic acid was first identified as a treatment for pellagra in the 1930s, and it’s been used as a lipid-lowering agent since the 1950s. It raises NAD+ through the Preiss-Handler pathway, a three-step conversion process.

Key benefits: NA is the only one of these four precursors with well-established effects on blood lipids. At therapeutic doses (typically 1,000–2,000 mg/day under medical supervision), it can lower LDL cholesterol and triglycerides while raising HDL — the so-called “good” cholesterol. None of the other three precursors have demonstrated comparable lipid benefits in human trials.

Key concerns: The big one is flushing — a harmless but often uncomfortable itching and reddening and warming of the skin caused by vasodilation. This is the side effect that drives many people away from niacin. A few important distinctions about niacin formulations:

• Immediate-release niacin causes the most flushing but carries relatively low liver toxicity risk.
• Extended-release niacin produces less flushing and, at doses of 2g/day or below, has a reasonable safety profile. This is the formulation with the strongest clinical evidence for lipid benefits.
• “No-flush” niacin (inositol hexanicotinate) virtually eliminates flushing — but research consistently shows it releases very little free nicotinic acid and has no meaningful effect on lipid profiles. As one researcher bluntly put it, it’s “flush-free” because it’s essentially “benefit-free” as well.

The other significant concern with nicotinic acid is its effect on blood glucose. High-dose niacin can reduce insulin sensitivity, and large clinical trials have found an increased risk of developing diabetes with long-term use. This makes it a poor fit for anyone already managing blood sugar issues, unless the lipid benefits clearly outweigh the risks under medical guidance. (When I take no-flush niacin, I take it along with some berberine, which lowers blood sugar.) (Interestingly, berberine has similar cholesterol-lowering benefits, another reason I take them together.)

NA can also elevate uric acid levels and, particularly in sustained-release formulations. Flush-free niacin carries a risk of liver toxicity at very doses as low as 500-750 mg.

Niacinamide (Nicotinamide / NAM)

Cheap but problematic. Niacinamide is the form of B3 most commonly found in fortified foods and multivitamins. It raises NAD+ through the salvage pathway — first being converted to NMN by the enzyme NAMPT, then from NMN to NAD+.

Key benefits: Niacinamide is widely used in dermatology, with strong clinical evidence for skin health benefits including reduced inflammation and improved barrier function. It’s also well-tolerated at moderate doses and is by far the cheapest NAD+ precursor available. It does not cause the flushing associated with nicotinic acid.

Key concerns: There are two areas of genuine debate.

First, sirtuin inhibition. Niacinamide inhibits sirtuins (particularly SIRT1) in laboratory settings, which has raised concerns in the longevity community. Sirtuins are NAD+-dependent enzymes involved in DNA repair, stress resistance, and cellular maintenance — exactly the things most people are trying to support by boosting NAD+.

However, the picture is more complicated than it first appears. Recent research suggests that once niacinamide enters cells, it’s rapidly converted to NAD+, which then increases substrate availability for sirtuins. The net effect may be stimulatory rather than inhibitory, but this remains an open question, and high sustained doses could theoretically tip the balance the wrong way. David Sinclair of Harvard has specifically cautioned against high doses of niacinamide for this reason.

Second, like nicotinic acid, niacinamide has been associated with impaired glucose tolerance in animal studies, particularly at higher doses and with chronic use. One mouse study found that even relatively low-dose chronic niacinamide supplementation (100 mg/kg/day) induced glucose intolerance and skeletal muscle lipid accumulation. The clinical relevance of this in humans at typical supplement doses is still being worked out, but it’s a legitimate flag.

Unlike nicotinic acid, niacinamide does not improve lipid profiles. It can’t be used for improving cholesterol.

Nicotinamide Riboside (NR)

The first “next-generation” precursor. NR gained attention after a 2007 study showed it substantially raised NAD+ levels in yeast, and subsequent studies demonstrated it could boost NAD+ in mammalian cells by up to 270%. It enters cells directly via NR kinase enzymes, which convert it to NMN and then to NAD+. This bypasses the NAMPT bottleneck that can limit niacinamide’s effectiveness, particularly as NAMPT activity declines with age.

Key benefits: NR is the most extensively studied precursor in human clinical trials, with over 40 ongoing or completed studies. It has been shown to nearly double whole-blood NAD+ levels and is generally well-tolerated. It does not cause flushing. Human trials have not shown the blood glucose disruptions associated with nicotinic acid and niacinamide, though one mouse study using very high doses of NR in an obesogenic diet context did find reduced metabolic flexibility and glucose intolerance — a reminder that dose matters.

Key concerns: NR’s primary limitation is practical: it’s more expensive than niacin or niacinamide. It also has less long-term human outcome data than the older B3 forms. While it effectively raises NAD+ levels, the question of whether that translates into measurable clinical benefits (slower aging, reduced disease risk) in humans is still being answered. NR does not have nicotinic acid’s lipid-modifying effects. There have also been questions about its stability — NR can degrade to niacinamide if not stored properly, which would defeat the purpose of choosing it in the first place.

Nicotinamide Mononucleotide (NMN)

The direct precursor — with a regulatory asterisk. NMN is one step closer to NAD+ than NR in the biosynthetic pathway. Once inside cells, it requires only a single enzymatic step (via NMNAT) to become NAD+. This theoretical efficiency has made it hugely popular, particularly after it was widely promoted as an NAD booster by David Sinclair.

Key benefits: Animal research on NMN has been impressive, with studies showing improved insulin sensitivity, enhanced energy metabolism, and healthier aging markers in mice. A key 2021 human study found NMN improved muscle insulin sensitivity in prediabetic women. NMN does not cause flushing. Human trials have not shown the blood glucose disruptions seen with nicotinic acid and niacinamide. A meta-analysis of human RCTs found NMN supplementation had no negative effect on fasting glucose or insulin resistance markers.

Key concerns: There’s an ongoing scientific debate about whether NMN can enter cells directly. Some researchers maintain it must first be converted to NR (by losing its phosphate group), then re-converted to NMN inside the cell — which would make it functionally equivalent to NR but with an extra step.

There is evidence of a dedicated NMN transporter (Slc12a8) in both mice and humans, which would suggest that it is important in an evolutionary sense (though this finding has been questioned).

The human evidence base for NMN is smaller than for NR, with roughly half as many completed clinical trials. (This is not necessarily because NMN is less interesting or promising to study, it’s because a company selling NR provided large quantities of the supplement for free to researchers early on, getting a Headstart on the research; NMN is still catching up.)

Quality control with NMN has been a well-documented issue — independent testing of NMN products sold on Amazon has found that many don’t contain what their labels claim.

In the United States, NMN’s regulatory status has been complicated. In late 2022, the FDA issued letters stating that NMN was excluded from the definition of a dietary supplement, though products remain widely available. However, the FDA later relented and has allowed NMN to continue to be sold.

What We Don’t Know

It’s worth being direct about the gaps.

While all four precursors reliably raise NAD+ levels in blood, we still don’t have definitive long-term human outcome data proving that NAD+ supplementation extends lifespan. The animal data is encouraging, but the translation to humans is ongoing. We also don’t fully understand the optimal dosing, timing, or cycling of any of these precursors — or whether combining them might be more effective than using any single one.

I personally take three NAD boosters, niacin, NR and NMN. I alternate them on different days. This is a personal preference; there’s not strong evidence for benefits from alternating them. I don’t expect any of these supplements to increase my lifespan, but I do see it as a kind of insurance to support DNA repair. So I’m hoping to have a healthspan-improving benefit. I don’t think we need large amounts; I’ve cut back from taking 1 g of NMN, for example, to taking 500 mg on the days when I take it. I will sometimes take some additional NA when my lipids start going out of balance.

Do we really need NAD+ boosters of any kind? The answer is unknown. I take supplements as a kind of insurance policy.

Quick Comparison

NMN — NAD+ precursor. No flushing. No known blood glucose concerns. Does not improve lipids.

NR — NAD+ precursor. No flushing. No known blood glucose concerns. Does not improve lipids.

Nicotinic Acid (Niacin) — NAD+ precursor.  Improves lipids. Causes flushing (except “no-flush” forms, which don’t appear to work). Raises blood sugar. Can trigger diabetes at high doses. Could cause liver damage in extended release form.

Niacinamide — NAD+ precursor.  Proven skin health benefits. No flushing. Can raise blood sugar and can even trigger diabetes at high doses. Raises blood sugar. Can trigger diabetes at high doses. Does not improve lipids. May inhibit sirtuin genes.

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More from Nils:

• Rekindle School classes in Seattle: Rekindl.e School
• Anti-Aging Youtube channel Pathways to Longevity
• Anti-Aging Facebook group: Anti-Aging and Life Extension
• Exploring possible consciousness in Claude.AI and other LLMs: AI Consciousness
• Donations make this website possible. To donate using Buymeacoffee, please click here

Thanks to: Claude Opus 4.6 and Perplexity.ai for fact checking and research assistance.