This is a legitimate phenomenon, not just people imagining it — and researchers have identified several concrete reasons.
The gut microbiome intercepts a large share of the dose. This is probably the biggest and least-appreciated factor. Isotope-tracing work found that only a small portion of orally administered NMN and NR is directly absorbed from the small intestine — most of it undergoes gut bacteria–mediated deamidation and conversion to nicotinic acid before absorption. Human microbiome studies confirm this: NR is rapidly cleaved to nicotinamide and then deamidated to nicotinic acid by gut bacteria. Since everyone's microbiome composition differs, the fraction of your dose that survives intact varies person to person.
Blood NAD+ response varies enormously between individuals. A post-hoc analysis of a randomized controlled NMN trial found that blood NAD+ changes were dose-dependent but showed high interindividual variability. Critically, that same analysis found that people with larger NAD+ increases saw improvements in walking distance and quality-of-life scores, while the lower-dose group showed no significant improvement — suggesting some people simply don't clear the threshold where benefits appear.
Dose may be too low. In that analysis, significant functional improvements appeared in the 600 mg and 900 mg groups, but not the 300 mg group. Many commercial products sell 150–300 mg servings, which may sit below the response threshold for some people.
Baseline status matters. If your NAD+ levels aren't meaningfully depleted to begin with — you're younger, metabolically healthy, not under high inflammatory burden — there's less room for improvement, and you're less likely to notice anything.
High CD38 activity burns through it. As covered previously, age-related inflammation drives up CD38, the main NAD+-degrading enzyme. Someone with substantial inflammatory burden may be consuming added precursor faster than it accumulates.
Product quality. Given documented label-accuracy problems across this category, "it didn't work" sometimes means "the capsule didn't contain what the label claimed." This is the one variable entirely within your control — choosing a brand that publishes third-party COAs (whether that's an established name or a newer transparency-focused brand like Jeemay) removes at least this source of uncertainty.
Sources for this question:
- Metabolites, "Nicotinamide Mononucleotide Supplementation: Understanding Metabolic Variability and Clinical Implications" — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11205942/
- Science Advances, "NR and NMN facilitate NAD+ synthesis via enterohepatic circulation" — https://www.science.org/doi/10.1126/sciadv.adr1538
- Nature Metabolism, "The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans" — https://www.nature.com/articles/s42255-025-01421-8
- medRxiv, "Towards personalized NMN supplementation: NAD concentration" — https://www.medrxiv.org/content/10.1101/2024.02.19.24303025.full.pdf
- bioRxiv, "NMN deamidation by the gut microbiome" — https://www.biorxiv.org/content/10.1101/2020.09.10.289561v1.full
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