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NMN and NR Side Effects: Delayed-Onset Adverse Events Explained

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At a glance

  • Longest randomized follow-up / about 12 weeks [5]
  • Shortest trial / 21 days, NR 1 g/day in 12 men aged 70-80 [1]
  • Highest NMN dose tested / 1,250 mg once daily for up to 4 weeks [6]
  • Highest NR dose tested / 3,000 mg/day for 4 weeks [7]
  • Most detailed adverse-event list / 14 mild events in 7 of 30 people on NR 1,000 mg/day [4]
  • Groups not studied / pregnant or breastfeeding women, children, people with cancer or kidney or liver disease [5]

What the short trials recorded

NMN and NR are precursors the body converts to NAD+, a coenzyme in cellular energy metabolism [8].

In an 80-person trial, healthy middle-aged adults took placebo or NMN 300, 600 or 900 mg once daily for 60 days; the investigators reported no safety issues [9]. In a four-week trial of 31 healthy adults aged 20-65 given NMN 1,250 mg once daily or placebo, there were no severe adverse events and no changes beyond normal physiological variation [6]. In a 12-week trial of 30 healthy adults, 15 received NMN 250 mg/day and 15 received placebo; no obvious adverse effects were observed [2].

The most detailed list comes from a six-week crossover study of 30 adults aged 55-79 taking NR 1,000 mg/day: 14 mild events in 7 participants — nausea, flushing, leg cramps and bruising — with no serious events [4]. In a 12-week trial, 40 sedentary men with obesity were assigned to NR 1,000 mg twice daily or placebo, with no serious adverse events reported [3]. In a four-week trial of 20 people with Parkinson's disease, 10 received NR 3,000 mg/day and 10 received placebo; no moderate or severe adverse events occurred in the NR group [7].

One self-reported effect

In a 21-day crossover study of 12 men aged 70-80, four men (33%) reported increased libido on NR and none on placebo, with no clinical adverse events recorded [1].

Methylation and homocysteine during dosing

In that same 21-day study, NR 1 g/day raised nicotinamide-methylation products about 5-fold in muscle, indicating clearance of excess nicotinamide through methylation [1]. In the four-week NR-SAFE trial, NR recipients had a slight initial rise in serum homocysteine, and the authors judged the methyl donor pool intact [7].

What is unknown after 12 weeks

Cancer risk with chronic NAD+ boosting has been raised as a theoretical concern, but no human data were identified [5]. The trials were also small, with 12 to 140 participants, and pregnant or breastfeeding women, children, and people with cancer or kidney or liver disease were not among those studied [5]. A PubMed search for human drug-interaction studies of NMN or NR (CYP, transporter or pharmacodynamic) found none [5].

Frequently asked questions

What delayed side effects have been reported with NMN or NR?
The trials recorded mild events during dosing, including nausea, flushing, leg cramps and bruising with NR. Safety data beyond about 12 weeks are lacking, so whether new side effects emerge with longer use is unknown [4][5].
How long were people followed in these trials?
From 21 days to 12 weeks. NMN has been tested at 250 mg/day for 12 weeks and at 1,250 mg/day for up to 4 weeks; NR at 1,000 mg/day for 6 weeks, 2,000 mg/day for 12 weeks and 3,000 mg/day for 4 weeks [2][6][4][3][7].
Can NMN or NR increase cancer risk?
No human data address that. Cancer risk with chronic NAD+ boosting has been raised as a theoretical concern, and no human data were identified [5].
Does NR cause flushing?
Flushing was one of the mild events recorded during a six-week crossover study of NR 1,000 mg/day, alongside nausea, leg cramps and bruising; 14 mild events occurred in 7 of 30 participants and there were no serious events [4].
Does NMN interact with prescription drugs?
A PubMed search found no human drug-interaction studies of NMN or NR, including CYP, transporter or pharmacodynamic studies [5].

References

  1. 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 Rep. 2019;28(7):1717-1728.e6. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures
  2. Okabe K, Yaku K, Uchida Y, Fukamizu Y, Sato T, Sakurai T, et al. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Front Nutr. 2022;9:868640. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects
  3. 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. Am J Clin Nutr. 2018;108(2):343-353. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects
  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. Nat Commun. 2018;9(1):1286. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults
  5. Freeberg KA, Udovich CC, Martens CR, Seals DR, Craighead DH. Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current Knowledge and Future Directions. J Gerontol A Biol Sci Med Sci. 2023;78(12):2435-2448. Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current Knowledge and Future Directions
  6. Fukamizu Y, Uchida Y, Shigekawa A, Sato T, Kosaka H, Sakurai T. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Sci Rep. 2022;12(1):14442. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women
  7. Berven H, Kverneng S, Sheard E, Søgnen M, Af Geijerstam SA, Haugarvoll K, et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease. Nat Commun. 2023;14(1):7793. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease
  8. 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. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women
  9. 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. 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
Evidence overview for NMN and NR Side Effects: Delayed-Onset Adverse Events Explained