Introduction
Parkinson’s disease, PD, neurological disorders
ADVERSE EVENTS, ADVERSE EFFECTS, MOVEMENT DISORDER, DISEASES, NEUROLOGICAL DISORDERS
Parkinson’s disease (PD) affects 1–2% of the population over 65 years, and is one of the fastest growing neurological disorders worldwideIncreasing cellular levels of nicotinamide adenine dinucleotide (NAD) has been proposed as a potential neuroprotective therapeutic strategy for neurodegenerationNAD levels decline with age, possibly due to multiple and only partially understood processes, and this has been proposed to contribute to age-related diseases, including parkinsonismsIn the NADPARK study, a recent randomized double-blind clinical trial of NAD replenishment therapy with nicotinamide riboside (NR) in PD, we showed that oral intake of 1000 mg NR daily for 30 days significantly augments cerebral NAD levelsThese findings suggested that NR may hold promise as a neuroprotective therapy for PD, which warrants further clinical investigation. An important knowledge gap in that regard is that the safety range and optimal dose of NR therapy for PD remain undetermined. In the setting of a potential neuroprotective intervention, it is critical that the given dose is sufficient to achieve the desired effects. While the NADPARK trial showed a robust neurometabolic response to NR, the effect size was variable, and not all NR-recipients respondedIn preclinical studies on rats, adverse effects appeared with doses beyond 1000 mg/kg/day, which corresponds to approximately 9700 mg/day for a 60 kg adult humanMost clinical studies with NR in adult humans to date have used up to 1000 mg dailyTo determine the safety of high-dose NR therapy, we performed a double-blind, randomized phase I trial of 3000 mg NR daily in individuals with PD. The primary outcome of the study was the incidence of treatment-associated moderate and severe adverse events (AEs). Secondary outcomes were the between-group difference in treatment-associated mild AEs, change in the clinical severity of PD, measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)We show that oral NR treatment at a dose of 3000 mg daily for a 4-week period is well tolerated without moderate or severe adverse events, induces a pronounced augmentation of the NAD metabolome, and may be associated with clinical symptomatic improvement in PD. These findings support the possibility of extending the dose range of NR up to 3000 mg in clinical trials, provided adequate safety monitoring. However, the long-term safety of this dose has not yet been established.