Objective: To determine the safety of oral nicotinamide riboside (NR) 3000 mg daily for 4 weeks in Parkinson’s disease (PD). Secondary objectives: To assess NRs tolerability, effect on the nicotinamide adenine dinucleotide (NAD) metabolome and effect on clinical severity of PD.

Background: NAD replenishment therapy with NR has shown promise in preclinical and clinical studies on PD and other neurodegenerative disorders. Previous findings suggest that the neurometabolic and clinical responses to NR may be heterogeneous, indicating that higher doses should be explored. The safety range and optimal dose of NR therapy for PD remain undetermined, and doses higher than 2000 mg daily have not been tested on humans.

Method: A double-blind, placebo-controlled, randomized phase I trial of 3000 mg NR daily for 4 weeks in patients with PD. Patients were examined for adverse events weekly and blood was collected for safety laboratory tests 7 times during the trial. Patients were scored by MDS-UPDRS and flash- frozen whole blood and urine samples were collected for liquid chromatography mass spectrometry (LCMS) and NADMED (NADMED, Helsinki, Finland) analysis at baseline and at the end of study.

Results: 20 patients were randomized to NR or placebo and completed the trial. No moderate/severe adverse events or signs of toxicity likely attributed to NR were observed. NR-recipients exhibited a significant improvement in total MDS-UPDRS. This change was associated with a shorter interval from the last levodopa dose at the time of visit, however both groups were classified as being in on-phase at time of examination. NR-recipients demonstrated augmentation of the NAD metabolome with up to 5-fold increase in blood NAD⁺ levels. A mild increase in homocysteine was observed in the NR group in serum, but not whole blood samples, while other metabolite levels reflecting the integrity of the methyl donor pool remained unchanged.

Conclusion: Our results establish that oral 3000 mg NR daily for a 4-week period is safe, induces a pronounced augmentation of the NAD metabolome, and may be associated with a clinical symptomatic improvement in PD. Our findings do not guarantee long-term safety but allow for a dose range extension of NR in clinical trials up to 3000 mg daily, provided appropriate safety monitoring.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nr-safe-a-randomized-double-blind-safety-trial-of-high-dose-nicotinamide-riboside-in-parkinsons-disease/