Discussion
toxicity, PD, neurological and non-neurological diseases
ADVERSE EVENTS
Our study met its primary outcome and established that orally administered NR at a dose of 3000 mg daily is well tolerated in PD over a course of 4 weeks. NR-recipients developed no moderate or severe adverse events. Furthermore, there were no mild adverse events likely attributed to NR, and no other clinical or biochemical signs of toxicity. While our data do not guarantee long-term safety, they allow future dose-optimization and efficacy studies to extend the tested dose range of NR to 3000 mg daily, provided that appropriate safety monitoring is implemented. In our opinion, adequate dose experimentation in clinical trials will be paramount, in order to adequately explore and exploit potential dose-dependent beneficial effects in PD, as well as the multitude of other neurological and non-neurological diseases, for which NR is currently being tested. Indicatively, there are 44 NR-related trials registered at NR-treatment improved clinical symptoms of PD, measured by MDS-UPDRS, while this remained unchanged in the placebo group. This improvement was driven mostly by MDS-UPDRS part III, which assesses motor function, and part I, which assesses non-motor aspects of daily living. Interestingly, a qualitatively similar but weaker effect was seen in the NADPARK trial where participants consumed 1000 mg NR dailyAt a dose of 3000 mg daily, NR treatment greatly augmented the NAD-metabolome, including a ~3.7-fold (range 1.8–5.8-fold) increase in whole blood NADIn addition to prominently elevated NADFinally, the observed increase in ADPR, a signaling molecule derived from NADNR treatment was associated with a mild but significant increase in serum HCy levels. A similar HCy increase was recently reported with escalating NR supplementation from 250 to 1000 mg over 5 months