Subject: NMN vs NR: A Deep Dive For Researchers Who Didn’t Get What They Hoped From NAD+
From: Derek from Research Radar <[email-masked]>
To: [email-masked]
Date: Mon, 11 May 2026 14:07:04 +0000
List-Id: <derekpruski.substack.com>

View this post on the web at https://derekpruski.substack.com/p/nmn-vs-nr-a-deep-dive-for-researchers

Read this first: Everything below is for research and educational purposes only. Nothing here is medical advice. If you’re considering anything for personal use, that’s a conversation for a qualified clinician — not a Substack post.
The Landscape
The NAD+ conversation has gotten messy. IV NAD+. SubQ NAD+. NMN. NR. NA. NAM. Every podcast names a different “best” precursor.
A lot of researchers have looked at NAD+ protocols — usually subQ, sometimes IV — and walked away unimpressed by the data. Small effects, often nothing you can clearly tie back to the protocol. Then they read about NMN or NR and wonder if the field picked the wrong format from the start.
That confusion isn’t on the researcher. The NAD+ space has three real debates running at the same time:
Does direct NAD+ administration even work, or does the molecule get broken down before it can do anything useful inside cells?
Between NMN and NR, is there a real difference, or are they basically the same?
What dose, how long, and what outcomes are realistic?
This post walks through all three.
NAD+ Biology In One Page
NAD+ (nicotinamide adenine dinucleotide) is a helper molecule used in almost every metabolic process — ATP production, DNA repair, sirtuin activity, PARP activity, mitochondrial function. It exists in every cell, and cells contain far more NAD+ than they do its precursors.
NAD+ levels drop with age. That drop tracks with mitochondrial dysfunction, more DNA damage, lower sirtuin activity, and most of the hallmarks of aging. Whether the drop is the cause or just a symptom is debated, but the link is solid.
You don’t get NAD+ directly from food in any real amount. The body builds NAD+ from precursors through a few different pathways:
Tryptophan (de novo pathway) — slow, inefficient
NA / nicotinic acid (Preiss-Handler pathway) — causes flushing, well-studied
NAM / nicotinamide (salvage pathway) — the main recycling route
NR / nicotinamide riboside — joins the salvage pathway one step further along
NMN / nicotinamide mononucleotide — one step closer to NAD+ than NR
The supplement world mostly lives in the last two. Everything else is either old news (niacin) or impractical (tryptophan loading).
The SubQ NAD+ Debate
This is the elephant in the room, and it’s why a lot of researchers feel the broader NAD+ story isn’t delivering.
The pro-subQ argument is simple: oral NAD+ has terrible bioavailability (often cited at 2-10%), so the logic goes — skip the gut, put it directly into the bloodstream, and it should work better. SubQ NAD+ administration has become popular at longevity clinics because it’s more practical than IV but supposedly delivers more than oral.
The skeptical argument is about mechanism. NAD+ is a big, charged molecule. Cells don’t have a known door (transporter) that lets a circulating NAD+ molecule walk into a muscle cell or neuron and start working as a coenzyme. The body builds its NAD+ pool inside cells from precursors. It doesn’t import NAD+ from outside.
Eric Verdin, President of the Buck Institute for Research on Aging, has been the loudest voice on this. His position: when you administer NAD+ subQ or IV, most of it gets broken down to nicotinamide before it ever reaches cells. The end result inside cells is basically the same as if you’d just taken nicotinamide orally. Charles Brenner (the researcher who first identified NR as an NAD+ precursor) has been even blunter — he’s called NAD+ administration outside the cell mechanistically incoherent.
So what does that mean for the research showing modest or no benefit from subQ NAD+? Two fair reads:
The molecule gets chopped up into nicotinamide and the rest of the NAD+ structure within minutes of administration. What actually raises cellular NAD+ is just nicotinamide — same as a B3 vitamin. Plausible. Fits the biochemistry.
Or: it briefly raises NAD+ in the blood, but tissue NAD+ — which is what actually matters — barely moves because cells make their own and don’t need imported NAD+.
Either way, the end result is the same: subQ NAD+ may be functioning as nicotinamide administration. And as the next section covers, nicotinamide is the weakest of the precursors for keeping NAD+ high over time.
This is the key context for anyone reading the NAD+ literature. Weak results from subQ NAD+ research aren’t evidence that NAD+ doesn’t matter. They’re evidence that the delivery format probably isn’t doing what the marketing claims.
NMN vs NR — What They Actually Are
NR (nicotinamide riboside) is nicotinamide attached to a ribose sugar. Discovered as an NAD+ precursor by Charles Brenner’s lab in 2004. Patented and sold by ChromaDex under the Niagen brand. The most studied NAD+ precursor in humans by trial count.
NMN (nicotinamide mononucleotide) is NR with a phosphate group added. One enzymatic step closer to NAD+ in the pathway. Closely tied to David Sinclair’s lab at Harvard, which published the landmark 2013 paper showing NMN reversed multiple aging markers in mice.
The two are more similar than different. For years there was a debate about whether NMN gets absorbed whole (through a gut transporter called Slc12a8) or first gets stripped down to NR in the gut and then taken up. The 2025 Christen et al. study in Nature Metabolism mostly settled it: NMN’s path through nicotinamide and then nicotinic acid looked a lot like NR’s, and both changed gut bacteria in similar ways.
Practically: NMN and NR aren’t fundamentally different molecules. They feed into the same pathway, raise NAD+ to similar levels at similar doses, and have overlapping (but not identical) downstream effects.
The differences that do matter:
Stability and delivery. NMN holds up better in water. NR holds up better as a chloride salt in capsules. Both come in solid oral capsule forms now.
Regulatory status. NR has been an established dietary supplement in the US for years. NMN had a rougher path — the FDA pulled it from the supplement category in November 2022 over the drug preclusion clause (MetroBiotech’s MIB-626 was in drug development). After a multi-year fight led by the Natural Products Association, the FDA reversed itself on September 29, 2025, confirming NMN is lawful as a dietary supplement. As of late 2025, NMN is back on Amazon and standard retail.
Evidence depth. NR has a longer track record of human trials. NMN’s evidence base is catching up fast — as of mid-2025, at least five NMN RCTs and ten NR RCTs have reported metabolic outcomes, with more on the way.
What The Human Data Shows
This is where the picture sharpens. We’re not just looking at rodents anymore.
The head-to-head trial (Christen et al., 2025, Nature Metabolism). The first direct human comparison of NR, NMN, and nicotinamide. NR and NMN both roughly doubled blood NAD+ over 14 days. Nicotinamide didn’t. Short-term, nicotinamide raised NAD+ faster, but the effect didn’t last. The conclusion: NR and NMN are comparable for keeping NAD+ elevated long-term. Nicotinamide isn’t a good pick for sustained elevation.
NR human trials (overall). Across multiple placebo-controlled trials at doses from 100 mg to 2000 mg/day, NR reliably raises whole-blood NAD+, is well-tolerated, and has shown some improvements in muscle acetylcarnitine levels, arterial stiffness, blood pressure, and inflammatory markers. Honest summary: NAD+ goes up, safety is clean, functional outcomes are hit-or-miss. The twin study (Lapatto et al., 2023) used escalating NR doses of 250 to 1000 mg/day for 5 months in BMI-discordant identical twins. It showed improved muscle mitochondrial numbers, better myoblast differentiation, and changes in gut microbiota — but no real improvement in body fat or metabolic health.
NMN human trials. The 250 mg/day Japanese trial in older men (Igarashi et al., 2022) showed measurable NAD+ elevation and “nominally significant” improvements in muscle function over 6-12 weeks. The MIB-626 trial in hospitalized COVID-19 patients with acute kidney injury (2 g/day for 14 days) showed safe NAD+ elevation in a clinical setting. More recent NMN trials have reported improvements in sleep quality, walking speed in older adults, insulin sensitivity, and exercise performance.
Where both come up short. Neither NMN nor NR has been shown to extend human lifespan, prevent specific age-related diseases, or reverse aging in any meaningful way. The trials are short (usually 8-12 weeks, longest around 5-6 months), small (median around 40 people), and mostly in healthy populations where there isn’t much room to improve. What the trials do show consistently: NAD+ goes up with both, safety is good at doses up to 2 g/day, and downstream effects are real but modest.
The honest takeaway from the literature: a big chunk of the disappointment in NAD+ outcomes probably comes down to the wrong precursor (oral nicotinamide alone isn’t great), the wrong delivery format (subQ NAD+ may not actually do what the marketing claims), or expecting too much of a “feel” from raising NAD+ in the first place.
Why NAD+ Interventions Don’t Feel Like Much
Worth its own section because it trips up almost every read of the literature.
The marketing around NAD+ — especially IV and subQ — strongly implies an experience: energy, mental clarity, almost a stimulant-like effect. Some user reports describe that. A lot don’t. Controlled trials don’t even measure “feel” as a primary outcome.
Here’s the mechanism reason: NAD+ is a coenzyme. Coenzymes don’t usually produce a felt effect. They’re tools that enzymes use to run reactions in the background. Raising NAD+ by 50% doesn’t produce a sensation any more than raising cellular ATP would. Both are necessary for cells to function. Neither is something you actually feel.
What trials do show with NMN or NR at adequate doses over months: better exercise tolerance, small gains in muscle endurance or strength, better sleep in some subgroups, lower inflammation markers, lower acylcarnitines (mitochondria using fuel more efficiently), and sometimes better insulin sensitivity. None of these are dramatic. Most are measurable, not noticeable.
If NAD+ protocols are being judged against a stimulant-like response, they’ll look disappointing no matter the format. That’s not the protocol failing. That’s the marketing setting bad expectations.
Dosing Patterns From The Literature
What the trials have actually used — not what supplement companies recommend.
NR. Single-dose pharmacokinetics tested at 100, 300, and 1000 mg, with dose-dependent increases in blood NAD+. Long-term dosing trials have used 250 mg up to 2000 mg/day. 1000 mg/day (usually 500 mg twice a day) is the most-studied dose with functional results. Time to measurable NAD+ rise: days. Time to functional effects: 8-12 weeks at minimum.
NMN. Single-dose safety established at 100, 250, and 500 mg in healthy Japanese men. Long-term trials have used 250 mg/day to 1250 mg/day for 4-12 weeks. 500-1000 mg/day is where most positive results come from. The 250 mg/day older-men trial showed effects but smaller ones. Time course is similar to NR — NAD+ rises in days, functional changes show up at 6-12 weeks and beyond.
Timing. Both NMN and NR have been used with and without food in trials. Food doesn’t really get in the way of absorption. Morning dosing is the convention but not based on evidence.
Combination protocols. Some longevity clinics use subQ NAD+ as a “loading” phase and then oral NMN or NR for maintenance. The reasoning is shaky for the reasons covered earlier. No published RCT shows combination protocols beat oral precursor alone.
Stacking with sirtuin activators (resveratrol, pterostilbene). Common in commercial products, often with weak human data. The story — that you need NAD+ as fuel for sirtuins, so giving both raises sirtuin activity more than either alone — sounds reasonable but isn’t well-supported in trials.
Where The Research Points
For studies where subQ NAD+ didn’t produce clear functional outcomes: the literature backs oral NMN or NR at clinically tested doses (500-1000 mg/day) for at least 12 weeks as the more evidence-supported path. The mechanism is more solid. The trial data is stronger.
For research models where NR didn’t show obvious benefit: switching to NMN probably won’t change much, but the 2025 Christen et al. data does point to some difference in short-term kinetics. Honest answer: for most populations they’re interchangeable.
For research models where both NR and NMN at adequate doses for adequate duration didn’t produce functional benefit: the question probably isn’t “which precursor” but “does raising NAD+ even matter in this model.” Younger subjects with already-high NAD+ aren’t likely to see big effects. Older subjects, sedentary populations, or those with metabolic dysfunction are more likely to show measurable changes — which is exactly what trial subgroups tend to confirm.
For evidence depth: NR has the longest track record. For being one step closer to NAD+ in the pathway, with the caveat of a noisier regulatory history: NMN. They mostly converge.
Product Suggestions
Here are some good suggestions from products off Amazon.
NR:
Option 1 [ https://substack.com/redirect/cc11084b-8946-4ee1-92cb-88a534bd1170?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Option 2 [ https://substack.com/redirect/0d8335b6-57e8-4ebe-b292-16d87ad30def?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Option 3 [ https://substack.com/redirect/d710ce76-fa4b-48ea-b1f5-5e3fe96095a3?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NMN:
Option 1 [ https://substack.com/redirect/6d413a2b-66dc-4455-92f0-fcd4dc9c7046?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Option 2 [ https://substack.com/redirect/ad37a6ad-ddaa-4590-a329-fb803e76c2b8?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Option 3 [ https://substack.com/redirect/8bcd6fc0-d8d8-4cac-bde6-ce7a009549fb?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Things Worth Researching Further
The Christen et al. 2025 paper [ https://substack.com/redirect/633714cd-402f-41e0-81a0-1b8a748e0c8f?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ] in Nature Metabolism for the head-to-head NR/NMN/Nam comparison and the gut microbiome angle. The original NMN paper from Sinclair’s lab (2013) and the follow-up mouse aging work. Charles Brenner’s writing on NAD+ biology and his criticism of NAD+ administration outside the cell. Eric Verdin’s public talks on NAD+ delivery formats. The 2023 twin study on NR — useful for understanding what NR doesn’t do as much as what it does. The MIB-626 trials for NMN in clinical populations. The September 2025 FDA reversal on NMN supplement status for the regulatory backstory.
Final Thoughts
NAD+ biology is real. The decline with age is real. The case for restoring it through precursors is reasonable. What’s muddied the picture is a delivery format — subQ NAD+ — that probably doesn’t do what it claims, casting doubt on the whole thesis.
If your read on NAD+ from the subQ literature has been “this whole space is hype” — the better read is that the wrong tool was being tested. The oral precursors have stronger mechanism, better trial data, and more predictable outcomes. They also don’t produce a big subjective effect, which is exactly what you’d expect given how they actually work.
NMN and NR aren’t dramatic compounds. They’re slow, structural tools that move things you can measure but rarely feel. That’s the point. The compounds that produce the strongest felt effects are usually the ones with the shortest lasting benefit. Mitophagy inducers, NAD+ precursors, mitochondrial biogenesis tools — they all share this profile.
Whether raising NAD+ for years translates into real longevity outcomes in humans is a question the next decade of trials will answer. The mechanisms, the safety data, and the short-term biomarker improvements are already enough to make NMN and NR worth understanding deeply — even if the subQ NAD+ literature has been a letdown.
This is for research and educational purposes only. Nothing in this post is medical advice, and this isn’t a recommendation to use NMN, NR, or any NAD+ format personally. If the topic is of interest for any non-research reason, that’s a conversation for a qualified medical professional.
Drop questions below — happy to go deeper on mechanism, the subQ debate, dosing literature, or any other angle.
References
Head-to-head comparison of NAD+ precursors (2025): Christen S, Cuenoud B, et al. Comparative effects of NR, NMN, and nicotinamide on NAD+ metabolism in humans. Nature Metabolism. 2025. Link [ https://substack.com/redirect/633714cd-402f-41e0-81a0-1b8a748e0c8f?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NR pharmacokinetics in humans: Trammell SAJ, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature Communications. 2016;7:12948. Link [ https://substack.com/redirect/06eaff85-45e0-47dd-bd5a-3fe540e724f1?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NMN safety in healthy older men (250 mg/day): Igarashi M, Nakagawa-Nagahama Y, Miura M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging. 2022;8(1):5. Link [ https://substack.com/redirect/3d9cbbc4-9f70-4fc8-9458-c7a1d29192d0?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NMN single-dose safety in healthy men: Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine Journal. 2020;67(2):153-160.
NMN oral administration efficacy review: Yoshino M, Yoshino J, et al. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Link [ https://substack.com/redirect/c98fc7de-febc-40f9-8a37-9d08ed19bcf6?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NR twin study (5 months, escalating dose): Lapatto HAK, Kuusela M, Heikkinen A, et al. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study. Science Advances. 2023;9(2):eadd5163. Link [ https://substack.com/redirect/d56638f0-43c9-4875-bf16-e204cbc9aed7?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NMN clinical trials updated review: The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update. Link [ https://substack.com/redirect/1ca34b90-20b4-4114-80fe-f329798630d2?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NMN metabolic variability and uptake pathways: Nicotinamide Mononucleotide Supplementation: Understanding Metabolic Variability and Clinical Implications. Link [ https://substack.com/redirect/db89ba87-ec2f-42f8-abcf-8e5830fc69a6?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
MIB-626 NMN in hospitalized patients: Oral MIB-626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID-19 and Acute Kidney Injury. 2025.
NR muscle and bone function trial (Mayo Clinic, NCT03818802): Link [ https://substack.com/redirect/9737018a-4061-459d-b557-f2b4b2758ccc?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
NR functional capacity in older veterans (NCT04691986): Link [ https://substack.com/redirect/a1083f0f-ad4f-476d-b711-078d0b8eda66?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
FDA NMN dietary supplement reversal (September 2025): FDA letters to NMN ingredient suppliers, September 29 and December 2, 2025. NPA [ https://substack.com/redirect/dc4cb2d0-d7e4-453f-84a6-168130522dde?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ] | NutraIngredients [ https://substack.com/redirect/452ce012-978e-4e44-9290-53568f668351?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
— Derek

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