Image source: Alegre, et al., 2025
For years, NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside) have been leading choices for raising NAD+ levels. Their popularity stems from the limitations of traditional forms of vitamin B3:
- Nicotinic acid (NA): Causes uncomfortable skin flushing and has limited ability to raise NAD+ in tissues.
- Nicotinamide (NAM): Can block sirtuins (longevity-related enzymes) and relies on an enzyme (NAMPT) that becomes less active with age.
In contrast, NMN and NR feed directly into the NAD⁺ salvage pathway, offering a more efficient route to replenish NAD+ without these issues.
Why Don’t We Just Take NAD+ Directly?
Given that NAD+ is the end goal, why don’t supplements just contain NAD+ itself? Early research suggested that oral NAD+ is poorly absorbed.
In the 1980s, studies using radiolabeled NAD+ in rats found that:
- NAD+ is broken down into NMN and 5’-AMP in the digestive system.
- 5’-AMP is further degraded into adenosine and inosine.
- NMN is converted to NR, which then turns into NAM before absorption.
These findings led to the widespread assumption that oral NAD+ is ineffective, prompting researchers and the supplement industry to shift focus toward more direct solutions, including:
- NAD+ precursors (NMN/NR): Thought to be absorbed directly and converted into NAD+ inside cells.
- IV NAD+ therapy: Bypasses the gut entirely, delivering NAD+ straight into the bloodstream.
New Insights Suggest a More Nuanced NAD+ Story
However, emerging evidence suggests a more nuanced picture:
- Even IV NAD+ gets broken down: When NAD+ is given intravenously, extracellular enzymes (CD38, CD73, CD157) break it into NAM, NMN, and ADPR before cells take it up. This suggests that IV NAD+ may work partly by supplying these intermediate molecules rather than intact NAD+.
- Oral NMN and NR also get converted to NAM: Contrary to earlier assumptions that NMN and NR are absorbed directly, research now shows they are largely metabolized into NAM in the gut. Yet, they still produce benefits that plain NAM supplementation doesn’t. This implies that:
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- The breakdown process itself may matter.
- Intermediate metabolites might have unique biological effects.
Why This Matters
If oral NAD+ is first broken down into NMN and NR before eventually becoming NAM, then it may be functionally similar to supplementing with precursors.
Rather than being "useless," oral NAD+ is another pathway to support NAD+ levels.
What Does This Mean for NAD+ Supplementation?
Does this mean oral NAD+ is superior? Not necessarily. But it does suggest that the long-standing assumption that oral NAD+ is ineffective is oversimplified and not really accurate.
Current research is showing that:
- Different precursors may have unique biological effects.
- How a supplement is taken - oral, liposomal, IV, sublingual - matters.
- Enzyme activity varies between tissues and individuals, which affects outcomes.
- The “journey” of a molecule - how it breaks down, travels, and gets rebuilt - may impact health just as much as the final NAD+ level.
The Bottom Line
Instead of asking whether oral NAD+ “works” in the traditional sense, the better question may be: What are the different ways NAD+ and its precursors influence the body, and how can we use that to improve health?
Science is continuing to uncover the answers, but it is increasingly clear that NAD+ metabolism is more dynamic than we once thought. This deeper insight allows us to develop more personalized, effective strategies for supporting healthy aging.
