NMN and NR: Pipeline, FDA Status, and What Comes Next

Why the FDA Pulled NMN from the Supplement Aisle

The FDA announced in November 2022 that NMN could no longer be marketed as a dietary supplement in the United States. The agency's reasoning hinged on Section 201(ff)(3)(B)(ii) of the Federal Food, Drug, and Cosmetic Act, a provision that excludes any article "authorized for investigation as a new drug" from the supplement definition if no prior supplement marketing history exists [1].

The trigger was an IND filing by Metro International Biotech (MIB), a company co-founded by Harvard geneticist David Sinclair. MIB submitted its application for MIB-626, a crystalline beta-form of NMN, before any NMN supplement company had established a compliant New Dietary Ingredient (NDI) notification with the FDA. The timing created a legal gap that the agency exploited to remove NMN from the supplement pathway entirely.

The Natural Products Association (NPA) and several NMN manufacturers challenged this decision, arguing that NMN had been marketed as a supplement before the IND was filed. An FDA constituent update clarified the agency's position: "NMN has been authorized for investigation as a new drug for which the existence of such substantial clinical investigations has been made public" [1]. A federal lawsuit seeking to reverse the exclusion remains active as of early 2026.

This decision did not affect NR (nicotinamide riboside). The two molecules differ by a single phosphate group but ended up on opposite sides of a regulatory boundary.

NR Retains Its Place as a Dietary Supplement

NR has followed a more conventional regulatory path. ChromaDex, which markets NR under the brand name Niagen, completed self-affirmed Generally Recognized as Safe (GRAS) determination in 2016 and received two favorable FDA New Dietary Ingredient (NDI) notifications [2].

The distinction matters for consumers and clinicians. NR can be legally sold, advertised, and purchased across all 50 states without a prescription. ChromaDex has published over a dozen sponsored clinical trials in peer-reviewed journals, building a regulatory dossier that the NMN supplement industry never assembled before the FDA intervened.

A 2019 safety assessment by Conze, Brenner, and Kruger evaluated NR at doses up to 1,000 mg twice daily in healthy overweight adults and reported no clinically significant adverse events over eight weeks [3]. The National Institutes of Health lists NR as a form of vitamin B3, giving it an established position within the existing nutrient framework. This classification provides a layer of regulatory protection that NMN lacked.

Still, NR's supplement status does not mean the compound has been evaluated by the FDA for efficacy against any disease. All marketed NR products carry the standard structure/function claim disclaimer, and no therapeutic claims are permitted.

MIB-626: The NMN Drug Candidate

Metro International Biotech's MIB-626 represents the most advanced pharmaceutical development program for any NAD+ precursor. The compound is a proprietary crystalline form of beta-nicotinamide mononucleotide designed for pharmaceutical manufacturing consistency, something that bulk supplement-grade NMN powders cannot guarantee.

The company's Phase I data demonstrated that single doses of MIB-626 (up to 3,000 mg) and multiple doses (1,000 mg twice daily for 14 days) were well-tolerated in healthy adults [4]. The Phase II program has expanded into several disease areas: acute kidney injury in hospitalized COVID-19 patients, age-related metabolic dysfunction, and skeletal muscle performance in older adults.

A published Phase II study examined MIB-626 at 1,000 mg once or twice daily in overweight or obese adults aged 55 and older over 28 days. The compound significantly increased whole-blood NAD+ levels and reduced body weight compared to placebo, though the study was not powered for weight loss as a primary endpoint [4]. MIB has not yet disclosed key Phase III trial timelines, and no FDA approval target date has been announced.

The commercial implications are significant. If MIB-626 receives FDA approval for any indication, the IND preclusion that removed NMN from the supplement market would become permanent. An approved NDA would make it nearly impossible for NMN to return to over-the-counter supplement shelves under current law.

Clinical Trials: What NMN Data Actually Shows

The most cited NMN human trial is Yoshino et al. (2021), published in Science. This randomized, placebo-controlled, double-blind study enrolled 25 postmenopausal women with prediabetes and administered 250 mg/day of NMN for 10 weeks. The results showed a 25% improvement in skeletal muscle insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp), along with increases in muscle NAD+ metabolites of approximately 30% [5]. The sample was small. The effect was real but narrow.

Dr. Samuel Klein, the study's senior author at Washington University School of Medicine, stated: "NMN improved the ability of insulin to increase glucose uptake in skeletal muscle, which is often abnormal in people with obesity, prediabetes, or type 2 diabetes" [5].

A 2022 randomized controlled trial by Yi et al. tested NMN at 300, 600, and 900 mg/day for 60 days in 80 healthy middle-aged adults. The 600 mg group showed the greatest increase in blood NAD+ levels (38% above baseline), and all groups demonstrated improved six-minute walk test performance compared to placebo [6]. No dose-response relationship was observed for the walking test, which raises questions about the clinical significance of the higher doses.

A separate 12-week trial in 30 healthy runners found that NMN at 300, 600, or 1,200 mg/day improved aerobic capacity (measured by ventilatory threshold) in a dose-dependent fashion, with the highest dose group gaining 10.1% over placebo [7]. These are encouraging signals but not the kind of large, multi-center data that the FDA requires for drug approval.

All published NMN trials share common limitations: small sample sizes (typically N < 100), short durations (8 to 12 weeks), and surrogate endpoints rather than hard clinical outcomes like cardiovascular events or mortality reduction.

NR Clinical Evidence: Cardiovascular and Metabolic Signals

NR's clinical evidence base is broader, thanks in part to ChromaDex's investment in sponsored trials. The landmark Martens et al. (2018) crossover study enrolled 24 lean, healthy adults aged 55 to 79 and administered NR at 500 mg twice daily (1,000 mg/day total) for six weeks. NR supplementation increased NAD+ metabolites by 60% and reduced aortic systolic blood pressure by 2 mmHg (mean reduction from 125 to 123 mmHg). Pulse wave velocity, a marker of arterial stiffness, trended toward improvement but did not reach statistical significance [8].

Dr. Christopher Martens, the lead author, noted: "This is the first clinical trial to show that NR supplementation is well-tolerated and effectively raises NAD+ levels in healthy older adults" [8].

A 2018 randomized trial by Dollerup et al. administered NR at 1,000 mg twice daily for 12 weeks to 40 insulin-resistant obese men. The study found no improvement in insulin sensitivity, hepatic lipid content, or body composition compared to placebo [9]. This negative result is notable because it tested NR in a metabolically impaired population (unlike the Martens study's healthy cohort) and used a higher dose for a longer duration.

Additional NR trials have examined outcomes in heart failure with preserved ejection fraction (HFpEF), peripheral artery disease, and chronic kidney disease. Results have been mixed. NAD+ levels consistently rise with supplementation, but downstream clinical improvements have been inconsistent across populations and endpoints [10].

Safety Data for NMN and NR

Neither compound has raised serious safety concerns in published human trials. This is one area where the data is consistent.

For NMN, doses up to 1,200 mg/day for 12 weeks have produced no grade 3 or higher adverse events [7]. The most common side effects are mild gastrointestinal symptoms: nausea, bloating, and loose stools, all reported at rates similar to placebo in controlled trials. The MIB-626 Phase I data showed tolerability at single doses up to 3,000 mg [4].

For NR, the Conze et al. (2019) safety evaluation tested doses up to 2,000 mg/day in overweight adults for eight weeks [3]. Blood chemistry panels, complete blood counts, and hepatic function markers remained within normal limits throughout. Mild side effects (flushing, pruritus, headache) occurred infrequently and at comparable rates in both active and placebo arms.

No long-term safety data (beyond 12 weeks of continuous dosing) exists for either compound in humans. Animal studies using NMN and NR at supra-physiologic doses for 12 months have not revealed carcinogenicity or organ toxicity [3], but these models have known translational limitations.

One theoretical concern is that raising NAD+ levels could promote growth of existing occult tumors, since cancer cells also rely on NAD+-dependent metabolic pathways [11]. No clinical evidence supports this risk, but no trial has been powered to detect it. This gap is likely to shape the design of any Phase III program for MIB-626 or competing NAD+ drug candidates.

Next-Generation NAD+ Precursors and Delivery Systems

The pipeline extends beyond standard NMN and NR formulations. Several companies are developing modified NAD+ precursors designed to improve oral bioavailability, target specific tissues, or bypass metabolic bottlenecks.

Reduced forms of both molecules (NRH, the reduced form of NR, and NMNH, the reduced form of NMN) have shown 5 to 10-fold greater potency in raising intracellular NAD+ in preclinical cell models compared to their oxidized counterparts [12]. These reduced precursors enter the cell through different transporters and bypass the rate-limiting NMN adenylyltransferase (NMNAT) step. No human trials have been published for either compound as of May 2026.

Dihydronicotinamide riboside (NRH) has attracted particular attention after mouse studies showed it raised hepatic NAD+ levels by 2.5-fold within one hour of oral dosing, a speed and magnitude not observed with NR or NMN [12]. Toxicology work is ongoing, and NRH's rapid NAD+ elevation may carry risks that slower-acting precursors do not.

Liposomal and enteric-coated NMN formulations are already on the supplement market in jurisdictions outside the US, but none have been tested in controlled human trials. The pharmacokinetic advantage of these delivery systems remains theoretical.

The broader field also includes CD38 inhibitors (compounds that block the enzyme most responsible for NAD+ degradation with age), PARP-1 modulators, and nicotinic acid adenine dinucleotide (NAAD) analogs. Each approach targets a different node in the NAD+ metabolic network. None has advanced beyond Phase I in humans.

What Clinicians Should Watch

The next 24 months will determine whether NAD+ precursors transition from the supplement aisle to the pharmacy shelf. Three developments will shape that outcome.

First, MIB-626 Phase II readouts in acute kidney injury and metabolic dysfunction will signal whether Metro International Biotech pursues Phase III investment or pivots to a different indication. Second, the outcome of the federal lawsuit challenging FDA's NMN exclusion could reopen the supplement pathway or permanently foreclose it. Third, reduced-form precursors like NRH may enter first-in-human studies, potentially offering a more potent alternative to both NMN and NR.

For patients asking about NMN or NR today, the clinical guidance is straightforward. NR is legally available, has a clean short-term safety profile at doses up to 1,000 mg/day, and raises circulating NAD+ levels by 40 to 60% in published trials [3, 8]. It has not been shown to reduce disease risk or extend lifespan in any human study. NMN cannot legally be sold as a supplement in the US, and any product currently marketed as NMN is either mislabeled, sold from an offshore source, or subject to FDA enforcement action.

Prescribers tracking the NAD+ space should monitor ClinicalTrials.gov for MIB-626 updates and the FDA's dietary supplement ingredient directory for any reversal of the NMN exclusion. The 2026 regulatory calendar includes a scheduled FDA public meeting on the IND preclusion provision that may affect other compounds beyond NMN.

The minimum effective dose of NR supported by published human data is 500 mg twice daily (1,000 mg total) for at least six weeks to achieve measurable NAD+ elevation and preliminary cardiovascular biomarker changes [8].