# Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies
## 5 Potential Safety Considerations/Concerns  
Clinical trials on NR and NMN administration demonstrated their safety regarding toxicity and their ability to efficiently increase NAD+ levels in healthy volunteers so far [111]. NR was granted \"Generally Recognised as Safe status\" by the US Food and Drug Administration (FDA). NR has also been reviewed and approved by Health Canada, the European Food Safety Authority (EFSA), and the Therapeutic Goods Administration of Australia, although there may be some safety concerns, at least in mice. A high dose of dietary NR caused glucose intolerance and dysfunction of the white adipose tissue in mice fed a slightly obesogenic diet [112]. [PERSON] and coworkers (2000), as well as [PERSON] and coworkers (2008), reported impaired glucose metabolism in mice supplemented with NMN and NAM [113; 114]. Currently there are no long-term human safety trials evaluating the safety of NAD+ boosters NR and NMN. Current data are based on small participant numbers of a few small-scale human clinical trials that implied that increased NAD+ levels from NAD+ boosters were safe in humans [115; 116; 117; 118; 110; 69; 107; 108]. For example, in the blood of 12 subjects with a single oral dose of 1000 mg, NR increased NAD+ by 2.7-fold [107]. Oral ingestion of NR, 250-1000 mg/d for 9 days, resulted in a 2-fold increase in NAD+ in 140 healthy volunteers [108]. There are seven clinical trials on NR [110; 117; 119; 120; 121; 107] and far fewer data on the safety and oral availability of NMN in humans. Only one clinical trial involving 10 volunteers receiving a single oral dose of 100-500 mg NMN indicated safety and efficacy of NMN, as no significant adverse effects were observed [116]. In a recent study, NMN supplementation increased muscle insulin sensitivity, insulin signaling, and remodeling in overweight or obese women with prediabetes [122]. Most side effects reported during NAM, NR, and NMN administration are minor (e.g., diarrhea, nausea, rashes, flushing, calf cramps, thrombocytopenia, erythema pruritis, skin burning, fatigue, abdominal discomfort, and headache) and are relatively infrequent [123; 124]. Increased acetylarnitine concentrations in skeletal muscle and minor changes in body composition and sleep pattern were reported in a recent study of NR supplementation in healthy obese individuals [125]. On the other hand, there have been more clinical trials evaluating the safety of NA and NAM, and the pharmacokinetics of NA and NAM have been studied in detail [96]. Supplemented NA can result in hot flashes and increased blood sugar as well as homocysteine levels in high doses. Overdose of nicotinamide (NAM) can cause hepatotoxicity in rare cases [103]. In NAM-treated rats, impaired glucose tolerance and increased hepatic and renal markers of oxidative DNA damage have been observed [126].  
Evidence for health risk assessment is still limited, and long-term oral ingestion of NAD+ precursors NR and NMN has not yet been studied in long-term human clinical trials, or human clinical trials have not been completed. In addition, there are insufficient data on the elevation of NAD+ levels in various clinical conditions. Therefore, the long-term consequences of increasing NAD+ levels have yet to be investigated in-depth in human clinical trials.