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Key Points
- NR and NMN doubled circulating NAD+ levels, NAM did not
- NMN and NR performed comparably, with no significant difference between them
- NAM increased homocysteine levels, reflecting increased methylation demand
- Degradation of NMN and NR depends on different enzymatic pathways
- All three compounds were well tolerated
Study Overview
Sixty-five healthy adults (ages 18-50) were randomly assigned to one of four groups for 14 days:
- Placebo: 17 people took a placebo capsule daily
- Nicotinamide (NAM): 17 people took 500 mg oral NAM capsule daily
- Nicotinamide riboside (NR): 16 people took 1,000 mg oral NR capsule daily
- Nicotinamide mononucleotide (NMN): 15 people took 1,000 mg oral NMN capsule daily
Blood and urine samples were collected before supplementation and for four hours after dosing on day 1 and day 14.
The main goal was to measure changes in baseline whole-blood NAD+, which reflects longer-lasting changes rather than short-lived post-dose spikes.
Understanding how baseline NAD+ is measured and interpreted provides important context for why sustained increases, rather than temporary elevations, are emphasized in human studies.
NMN and NR Doubled NAD+ Levels
Both NR and NMN significantly raised whole-blood NAD+ levels by about two-fold compared with placebo. These increases were consistent and stable, indicating a lasting effect rather than a temporary spike.
- NR increased NAD+ an average of 49.4 µM
- NMN increased NAD+ an average of 43.1 µM
- NAM saw no significant change
In contrast, NAM did not increase baseline NAD+ levels, even after two weeks of daily use.
"After 14 days, chronic administration of NR and NMN significantly increased baseline whole-blood NAD+ concentrations by ~2-fold… while NAM did not."
NAM was absorbed quickly, leading to a brief increase in NAD+ and related byproducts. However, this effect faded as NAM was rapidly metabolized, leaving no lasting increase.
"The intake of Nam also triggered the build-up of its degradation metabolites MeNam and MeXPY in whole blood, and these dynamics were further reflected in plasma and in urine. This suggests that Nam is quickly absorbed, metabolized and excreted after consumption."
There was no statistically significant difference between NMN and NR, indicating comparable effectiveness in raising NAD+.
"Here, we bring additional evidence that these precursors affect NAD+ levels to a similar extent."
NAM Raised Homocysteine Levels, NR and NMN Did Not
In addition to its short-lived effects on NAD+, NAM caused a strong and rapid rise in homocysteine levels, a compound linked to increased risk of heart disease.
This reflects the body's need to use methyl groups to process NAM, limiting the methyl stores available to maintain healthy levels of homocysteine.
"A strong acute increase in homocysteine was specifically detected in response to Nam compared with placebo on day 1 and day 14 with a more than eightfold median increase...This was expected and relates to the transient effect on the methyl pool donor driven by Nam methylation."
This effect was not observed with NMN or NR supplementation.
Different Metabolic Pathways for NMN and NR
Although NMN and NR produced comparable increases in NAD+, researchers found differences in how the body processes them:
- NR degradation primarily involved the purine nucleoside phosphorylase (PNP) pathway
- NMN degradation relied more heavily on CD38-linked activity
"This suggests that degradation of the two compounds depends on distinct enzymatic activities—that is, purine nucleoside phosphorylase (PNP) pathway for NR and CD38 for NMN."
Importantly, both NMN and NR contribute to NAD+ through conversion to NAM and nicotinic acid (NA). However, the study suggests that their distinct routes may help explain why NAD+ precursors can sometimes produce different biological effects, even when overall NAD⁺ outcomes appear similar.
Conclusion
This study is the first to compare NR, NMN, and NAM in humans, clarifying long-standing questions about how these NAD+ boosters work. The findings suggest:
- NMN and NR reliably raise NAD+ levels in humans
- NAM does not support sustained NAD+ elevation
- NAM uniquely increases homocysteine
- NMN and NR perform similarly overall but use different biological pathways
Together, these findings strengthen the case for NMN and NR as preferred NAD+ precursors when the goal is sustained NAD+ support in humans.
"This head-to-head comparison of three NAD+ precursors in healthy adults shows that NR and NMN are comparable in their ability to chronically increase baseline whole-blood NAD+ levels, while Nam provides only an acute transient effect."
