Protocols by Charles Sieg

Supplement

NAD+

What NAD+ does, whether it really declines with age, and what the trials show for nicotinamide riboside, NMN, nicotinamide, and IV NAD+.

Overall evidence Mixed21 sourcesReviewed November 5, 2026

Oral NR and NMN reliably raise NAD+ measures in blood, but trials of strength, blood sugar, and fitness are small, short, often funded by the seller, and inconsistent.

The short version

  • I take NAD. "NAD" can mean three different things: an oral precursor such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), or NAD+ itself, usually given by IV. The research differs for each, so this page covers all three.
  • NAD+ is a coenzyme in energy metabolism and DNA repair, and levels appear lower in older people in the tissues studied1,2,3.
  • Oral NR and NMN raise NAD+ or its metabolites in blood, and short trials found them well tolerated, but benefits for muscle, blood sugar, and fitness are inconsistent4,5,6,7.
  • Nicotinamide, a different molecule, cut new skin cancers by 23 percent in one large trial of high-risk adults, and did nothing in a trial of transplant recipients8,9.
  • For IV NAD+, the data are one retrospective report from a company that sells infusions, and a 2026 review found no eligible outcome trials10,7.

The protocol

This is what trials used, not a prescription. I have not listed my own form, dose, or timing here.

FormDoses tested in humansDuration
Nicotinamide riboside (NR), oral100, 300, or 1,000 mg a day5; 1,000 mg a day, as 500 mg twice daily in one trial4,11,12; 2,000 mg a day131 week to 12 weeks
Nicotinamide mononucleotide (NMN), oral250 mg a day14,15; 300, 600, or 900 mg a day6; 300, 600, or 1,200 mg a day166 weeks to 12 weeks
Nicotinamide (not a direct NAD+ booster product)500 mg twice daily for 12 months812 months
NAD+ or NR by IV500 mg a day for four days in one clinic review104 days

Timing: the show notes for the FoundMyFitness episode with Charles Brenner say he describes NR as typically taken in the morning with breakfast and as not feeling like a stimulant17.

What to expect: blood NAD+ goes up. In one 8-week trial of 140 overweight adults, whole blood NAD+ rose 22, 51, and 142 percent at 100, 300, and 1,000 mg of NR5. Whether that turns into anything you can feel or measure is much less clear, as the trials below show.

Why it works

NAD+ is a coenzyme for redox reactions and for enzymes such as sirtuins, CD38, and PARPs. It is involved in energy metabolism, DNA repair, and immune function1. NR and NMN are building blocks the body can convert to NAD+. NAD+ itself carries phosphate groups that keep it from entering cells, per Charles Brenner on the FoundMyFitness episode, and NMN is converted back to NR before it gets in17.

Does NAD+ decline with age?

Probably, in some tissues, but the evidence is correlational.

  • A 2012 study of human skin from 49 people aged 0 to 77 found NAD+ fell with age in males (r = -0.706) and females (r = -0.537)2.
  • A 2022 study comparing muscle from young adults and older adults found NAD+ was one of the most prominent metabolites lower in older adults. It was lowest in physically impaired older people, and exercise-trained older adults had levels closer to those of young adults3. This is cross-sectional, so it cannot say whether low NAD+ causes poor muscle function or the reverse.
  • A 2021 review in Nature Reviews Molecular Cell Biology describes a gradual decline in tissue and cellular NAD+ with age in rodents and humans, and says whether repletion benefits aging humans is still an open question1.

What the research says

Strong Oral NR and NMN raise NAD+ measures in blood. In a 6-week crossover trial of 24 middle-aged and older adults who completed it, 1,000 mg a day of NR raised blood-cell NAD+ about 60 percent (a one-tailed test, P = 0.048)4. In an 8-week trial, NR raised whole blood NAD+ dose-dependently, and there were no serious adverse events and no flushing5. A 60-day trial of 80 adults found blood NAD rose with 300, 600, and 900 mg of NMN, with no safety issues6. A 2026 systematic review of 33 human trials agrees: NR and NMN reliably raised NAD-related metabolites and were generally well tolerated over weeks to months7.

Mixed Muscle, blood sugar, and fitness.

  • NR did not improve insulin sensitivity in 40 obese men at 2,000 mg a day for 12 weeks13.
  • NR for 21 days in 12 older men changed the muscle NAD+ metabolome and lowered circulating inflammatory cytokines, but did not change mitochondrial bioenergetics11.
  • NR at 1,000 mg a day for a week did not raise muscle NAD+ or change exercise metabolism in 8 young men12.
  • NMN at 250 mg a day for 10 weeks raised insulin-stimulated glucose disposal by 25 percent in 25 postmenopausal women with prediabetes, though body weight, blood sugar, and lipids did not change and muscle NAD+ was unchanged14.
  • NMN at 250 mg a day in men over 65 improved gait speed and left-hand grip by nominal, uncorrected statistics15.
  • NMN raised oxygen uptake and power at the ventilatory thresholds in 48 amateur runners in the medium (600 mg) and high (1,200 mg) dose groups, but VO2max did not differ16.
  • NMN improved the 6-minute walk distance in 80 middle-aged adults, but not HOMA-IR6.
  • The 2026 systematic review summed it up: functional, metabolic, and vascular effects were "inconsistent, often null, or limited to specific endpoints"7.

Funding matters here. ChromaDex, which sells NR, supplied or funded the 6-week and 8-week NR trials4,5. Mitsubishi Corporation Life Sciences funded the older-men NMN trial and employed three authors15. In the NMN trial in women, one author receives patent-licensing fees and another is an inventor on an NMN patent application14. Several authors of the 80-person NMN trial work for NMN companies6.

Mixed Nicotinamide and skin cancer. Nicotinamide is the form of vitamin B3 that skin-cancer trials tested. In 386 adults with at least two prior non-melanoma skin cancers, 500 mg twice daily for 12 months cut new non-melanoma skin cancers by 23 percent (95% CI 4 to 38; P = 0.02), with a 20 percent drop in basal-cell carcinomas that was not significant and a 30 percent drop in squamous-cell carcinomas at the borderline (P = 0.05). The benefit did not persist after stopping8. A trial of 158 organ-transplant recipients, stopped early for poor recruitment, found no difference: 207 new keratinocyte cancers on nicotinamide and 210 on placebo (rate ratio 1.0)9. The notes for the 2026 Brenner episode mention the Australian trials17.

Early IV NAD+. A 2026 retrospective review of records from a commercial clinic compared four days of 500 mg NAD+ by IV with 500 mg NR by IV. The NAD+ infusions caused moderate to severe GI symptoms, faster heart rate, and chest pressure, stretching the infusion to an average of 97 minutes versus 37 for NR. All symptoms resolved when the infusion stopped. The authors work for the company that sells these infusions, and the abstract gives no participant numbers10. The 2026 systematic review found no eligible outcome trials of IV or intramuscular NAD+ for anti-aging or wellness7.

FDA status of NMN

On September 29, 2025, the FDA issued letters reversing its earlier position: NMN is not excluded from the definition of a dietary supplement, because it was marketed as a supplement in the U.S. before it was authorized as a drug investigation. The agency granted the petition in part and denied it in part18,19. The reversal followed a citizen petition and a federal lawsuit filed in August 2024, and replaced the FDA's 2022 position20. NMN is still a new dietary ingredient, so companies generally must file a notification with the FDA before marketing it, unless the ingredient comes from a supplier that already filed19. This summary rests on trade and law-firm reports of the FDA letters, not the letters themselves, and the current notification status for individual NMN products is not confirmed here.

Rhonda Patrick on NAD

Rhonda Patrick has covered NAD in at least two full episodes.

  • "NAD+ in Aging: Role of Nicotinamide Riboside and Nicotinamide Mononucleotide" (FoundMyFitness, posted January 29, 2020, solo). The show notes say oral NR and NMN appear to be converted to nicotinamide before becoming NAD+, that animal benefits come mostly from high doses in mice, that human data are small, and that oral NAD+ has poor bioavailability, so more research is needed on delivery21.
  • #109, "How To Boost NAD Levels To Fight Inflammation, Improve Recovery, and Slow Aging | Dr. Charles Brenner" (posted February 10, 2026). Brenner is a City of Hope researcher and chief scientific advisor to Niagen and NADmed. The notes say he describes NR as the best safety-tested precursor, that clinical doses are generally around 1 gram a day, and that the clinical data for oral NR is much more extensive than for IV NAD. They say Patrick takes 1,000 mg daily of Tru Niagen and raised a mouse study in which NMN injection accelerated pancreatic tumor growth, which Brenner said may not reflect human cancer17. Brenner's advisory roles are a conflict of interest to weigh.
  • Short clips with David Sinclair appear on the FoundMyFitness NAD tag page, but no full Sinclair or Eric Verdin episode turned up, so none is cited here.

Patrick's views here are hers and her guest's. Nothing on this page means she endorses me or this site.

Cautions

  • Most supporting trials are small, short (6 to 12 weeks), and often funded by companies that sell the precursor4,15,5.
  • NR and NMN both degrade into nicotinamide, and a mouse model suggested NMN may promote cancer progression in a specific senescent-cell setting, according to Patrick's 2020 notes. This is mouse data21.
  • Brenner says there is no human pregnancy safety data for NR, that sourcing is the biggest safety issue, and that people with cancer or on chemotherapy should talk to a doctor17.
  • NAD+ by IV caused moderate to severe symptoms in a clinic review, and I found no outcome trials10,7.
  • Nicotinamide skin-cancer results do not carry over to NR or NMN, and the benefit disappeared in transplant recipients and after stopping8,9.

References

  1. Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology. 2021;22(2):119-141.ReviewPubMed 33353981 · DOI

    What it found: Review of NAD+ as a coenzyme for redox reactions and for sirtuins, CD38, and PARPs, with roles in metabolism, DNA repair, and immune function. Describes a gradual decline in tissue NAD+ with age in model organisms including rodents and humans, and says whether repletion helps aging humans remains open.

    Limits: A narrative review, much of it based on animal data, and it does not test any supplement in people.

  2. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS ONE. 2012;7(7):e42357.Cross-sectional studyPubMed 22848760 · DOI

    What it found: Cross-sectional study of human pelvic skin from 49 people aged 0 to 77. NAD+ fell with age in males (r = -0.706, p = 0.001) and females (r = -0.537, p = 0.01), alongside rising DNA damage and PARP activity.

    Limits: Skin from surgical patients, correlational only, so it cannot show that low NAD+ causes aging or that supplements reverse it.

  3. Janssens GE, Grevendonk L, Perez RZ, Schomakers BV, de Vogel-van den Bosch J, Geurts JMW, et al. Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nature Aging. 2022;2(3):254-263.Cross-sectional studyPubMed 37118369 · DOI

    What it found: Cross-sectional comparison of skeletal muscle metabolomes in young adults and older adults who were exercise-trained, normally active, or physically impaired. NAD+ was among the most prominently lower metabolites in older adults, lowest in the impaired group, and closer to young levels in the trained group; NAD+ correlated with daily steps and muscle function.

    Limits: Cross-sectional with no causal direction, and the abstract gives no numerical values.

  4. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications. 2018;9(1):1286.Randomized trialPubMed 29599478 · DOI

    What it found: Randomized, double-blind, placebo-controlled crossover trial (2 x 6 weeks) of 500 mg NR twice daily; 24 of 30 randomized adults completed it. Blood-cell NAD+ rose about 60 percent (one-tailed P = 0.048); blood pressure and arterial stiffness changes were exploratory and not significant after correction; adverse events were mild.

    Limits: Small, 6 weeks, a one-tailed primary test, and ChromaDex, which sells NR, supplied the pills and part of the funding.

  5. Conze D, Brenner C, Kruger CL. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Scientific Reports. 2019;9(1):9772.Randomized trialPubMed 31278280 · DOI

    What it found: Eight-week randomized, double-blind, placebo-controlled trial of 140 overweight adults taking 100, 300, or 1,000 mg/day of NR. Whole blood NAD+ rose 22, 51, and 142 percent; no serious adverse events or flushing, and adverse events did not differ from placebo.

    Limits: Eight weeks, a biomarker outcome rather than health outcomes, and funded by ChromaDex, which employs two authors and licenses NR intellectual property from a third.

  6. Yi L, Maier AB, Tao R, Lin Z, Vaidya A, Pendse S, et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience. 2023;45(1):29-43.Randomized trialPubMed 36482258 · DOI

    What it found: Sixty-day randomized, double-blind trial of 80 healthy middle-aged adults taking placebo or 300, 600, or 900 mg/day NMN. Blood NAD rose in all NMN groups (p <= 0.001), 6-minute walk distance improved (p < 0.01), HOMA-IR did not differ, and no safety problems were found.

    Limits: Sixty days, a small trial with several outcomes tested, and authors are employees of NMN companies (Abinopharm and ABA Chemicals).

  7. Gallagher C, Emmanuel OO. NAD+ supplementation for anti-aging and wellness: A PRISMA-guided systematic review of preclinical and clinical evidence. Ageing Research Reviews. 2026;116:103057.Systematic reviewPubMed 41655607 · DOI

    What it found: PRISMA review (January 2010 to October 2025) of 113 studies, 33 human (28 randomized) and 80 rodent. Oral NR and NMN reliably raised NAD-related metabolites and were generally well tolerated, but functional, metabolic, and vascular effects were inconsistent or null; no eligible outcome trials tested IV or intramuscular NAD+.

    Limits: Pools small, varied trials, and the authors call clinical effectiveness for anti-aging or wellness inconclusive.

  8. Chen AC, Martin AJ, Choy B, Fernández-Peñas P, Dalziell RA, McKenzie CA, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. The New England Journal of Medicine. 2015;373(17):1618-1626.Randomized trialPubMed 26488693 · DOI

    What it found: Phase 3, double-blind trial of 386 adults with at least two prior non-melanoma skin cancers given 500 mg nicotinamide twice daily or placebo for 12 months. New non-melanoma skin cancers were 23 percent lower (95% CI 4 to 38, P = 0.02); basal-cell carcinoma 20 percent lower (P = 0.12), squamous-cell carcinoma 30 percent lower (P = 0.05); no benefit persisted after stopping.

    Limits: High-risk adults only, 12 months of treatment, and nicotinamide is a different molecule from NR or NMN, so the result does not transfer to them. Publicly funded (NHMRC).

  9. Allen NC, Martin AJ, Snaidr VA, Eggins R, Chong AH, Fernández-Peñas P, et al. Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients. The New England Journal of Medicine. 2023;388(9):804-812.Randomized trialPubMed 36856616 · DOI

    What it found: Randomized trial of nicotinamide versus placebo in 158 organ-transplant recipients (79 per group), stopped early for poor recruitment. At 12 months there were 207 new keratinocyte cancers on nicotinamide and 210 on placebo (rate ratio 1.0, 95% CI 0.8 to 1.3, P = 0.96), with similar adverse events.

    Limits: Stopped early and underpowered for smaller effects, and transplant recipients on immunosuppression differ from the high-risk adults in the 2015 trial.

  10. Reyna K, Heinzen G, Patel N, Ritter M, Siojo A, Legere H, et al. Intravenous infusion of nicotinamide adenine dinucleotide (NAD(+)) versus nicotinamide riboside (NR): a retrospective tolerability pilot study in a real-world setting. Frontiers in Aging. 2026;7:1652582.Cohort studyPubMed 41704678 · DOI

    What it found: Retrospective review of clinic records comparing four consecutive days of 500 mg IV NAD+ or 500 mg IV NR with 30-day follow-up. IV NAD+ caused moderate to severe GI symptoms, faster heart rate, and chest pressure, lengthening infusions to an average of 97 minutes versus 37 for NR; symptoms resolved when infusions stopped and routine safety labs did not change significantly.

    Limits: Retrospective, no control group, 30 days, participant numbers not in the abstract, and all authors were employed by the company that sells the infusions.

  11. Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD(+) Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Reports. 2019;28(7):1717-1728.e6.Randomized trialPubMed 31412242 · DOI

    What it found: Placebo-controlled, randomized, double-blind crossover trial in 12 aged men taking 1 g/day of NR for 21 days. NR raised the muscle NAD+ metabolome, lowered circulating inflammatory cytokines, and downregulated mitochondrial gene pathways, but mitochondrial bioenergetics did not change.

    Limits: Twelve men over 3 weeks with no strength or function outcomes, and the abstract gives no effect sizes.

  12. Stocks B, Ashcroft SP, Joanisse S, Dansereau LC, Koay YC, Elhassan YS, et al. Nicotinamide riboside supplementation does not alter whole-body or skeletal muscle metabolic responses to a single bout of endurance exercise. The Journal of Physiology. 2021;599(5):1513-1531.Randomized trialPubMed 33492681 · DOI

    What it found: Randomized placebo-controlled trial in 8 healthy young men taking 1,000 mg/day of NR for one week before an hour of cycling. NR did not raise muscle NAD+ or change substrate use, mitochondrial respiration, or the signaling markers measured, although it raised NAD+ precursors and breakdown products in muscle.

    Limits: Eight young men and one week of supplementation, so it says little about long-term or older populations.

  13. Dollerup OL, Christensen B, Svart M, Schmidt MS, Sulek K, Ringgaard S, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. American Journal of Clinical Nutrition. 2018;108(2):343-353.Randomized trialPubMed 29992272 · DOI

    What it found: Randomized, double-blind, placebo-controlled parallel trial in 40 sedentary men aged 40 to 70 with BMI above 30, taking 1,000 mg NR twice daily (2,000 mg/day) for 12 weeks. NR did not improve insulin sensitivity, glucose metabolism, energy expenditure, lipolysis, or body composition, and no serious adverse events occurred.

    Limits: A null result in 40 obese men at one dose for 12 weeks, so it cannot rule out effects in other groups.

  14. Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229.Randomized trialPubMed 33888596 · DOI

    What it found: Ten-week randomized, double-blind, placebo-controlled trial of 250 mg/day NMN in 25 postmenopausal women with prediabetes who were overweight or obese (13 NMN, 12 placebo). Insulin-stimulated glucose disposal rose 25 +/- 7 percent per kg fat-free mass (p < 0.01); body weight, fat, blood sugar, and lipids did not change and muscle NAD+ was unchanged.

    Limits: Twenty-five women, 10 weeks, one dose, and women with prediabetes only; some authors disclose NMN patent interests and the capsules came from a supplier.

  15. Igarashi M, Nakagawa-Nagahama Y, Miura M, Kashiwabara K, Yaku K, Sawada 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.Randomized trialPubMed 35927255 · DOI

    What it found: Placebo-controlled, randomized, double-blind trial of 250 mg/day NMN for 6 or 12 weeks in men over 65 (42 randomized). Blood NAD+ rose; gait speed (12-week 1.60 vs 1.30 m/s, P = 0.002) and left-hand grip improved by nominal statistics, with no effect on muscle mass.

    Limits: Tiny groups after a supplier error, no correction for multiple comparisons, and Mitsubishi Corporation Life Sciences funded it and employs three authors.

  16. Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. Journal of the International Society of Sports Nutrition. 2021;18(1):54.Randomized trialPubMed 34238308 · DOI

    What it found: Six-week, four-arm, randomized, double-blind trial of 48 amateur runners given 300, 600, or 1,200 mg/day NMN or placebo. Oxygen uptake, percent of VO2max, and power at the ventilatory thresholds rose more in the 600 and 1,200 mg groups than control; VO2max and peak power did not differ.

    Limits: Twelve per group, six weeks, mostly young men, and the supplier of NMN and placebo was acknowledged for contributing to the research.

  17. Rhonda Patrick (host); Charles Brenner (guest). How To Boost NAD Levels To Fight Inflammation, Improve Recovery, and Slow Aging | Dr. Charles Brenner. FoundMyFitness (episode #109), February 10, 2026.PodcastListen

    What it found: Interview with Charles Brenner, who discloses advisory roles with Niagen and NADmed. Notes say clinical NR doses are generally around 1 g/day, NMN is converted back to NR before entering cells, oral NR has far more clinical data than IV NAD, and Patrick says she takes 1,000 mg daily of Tru Niagen.

    Limits: The guest sells and advises on NR, so his views carry a conflict of interest; the notes were a partial read of a long page, and a directory listed the date as February 9, 2026.

  18. Nutritional Outlook staff. FDA responds to citizen petitions on NMN, amending its position on the ingredient's status as a dietary ingredient. Nutritional Outlook, September 30, 2025.ArticleRead

    What it found: Trade report that the FDA granted the Natural Products Association citizen petition in part and denied it in part, concluding NMN is not excluded from the dietary supplement definition because it was marketed as a supplement in the U.S. before any IND authorization.

    Limits: A secondary trade report, not the FDA letter, which could not be opened.

  19. Harrison TA, Lewis CA. FDA Declares Nicotinamide Mononucleotide Is a Dietary Supplement. Venable LLP, October 2, 2025.ArticleRead

    What it found: Law-firm summary of two FDA letters dated September 29, 2025 finding NMN not excluded from the dietary supplement definition under the race-to-market provision, while noting NMN remains a new dietary ingredient needing a notification (unless sourced from a supplier that already filed) and that self-affirmed GRAS cannot avoid it.

    Limits: A secondary legal summary, not the FDA letters, which could not be opened, and it gives no docket numbers.

  20. CIRS Group. US FDA Confirms NMN Lawful in Dietary Supplements. CIRS Group Regulatory News, October 11, 2025.ArticleRead

    What it found: Regulatory news item reporting that the FDA reversed its 2022 position after a citizen petition and an August 2024 lawsuit by the Natural Products Association, accepting evidence that NMN was sold as a dietary supplement as early as 2017.

    Limits: A secondary consultancy report that does not link the FDA letter and does not address NMN status in 2026.

  21. Rhonda Patrick (host). NAD+ in Aging: Role of Nicotinamide Riboside and Nicotinamide Mononucleotide. FoundMyFitness, January 29, 2020.PodcastListen

    What it found: Solo episode. Show notes explain NAD+ roles, say NAD+ falls with age, note that animal benefits of NR and NMN come mostly from high doses in mice, that human data are small, that oral NAD+ has poor bioavailability, and that one animal model suggested NMN may promote cancer in a senescent-cell setting.

    Limits: A 2020 overview with no new data; the date shown on the page was used, though podcast directories list this as an earlier numbered episode.