A Phase III trial investigating a cellular-energy-enhancing supplement did not demonstrate a slowdown of Parkinson’s disease, casting doubt on this therapeutic strategy. Reported in JAMA, the study found that nicotinamide riboside (NR), which serves as a precursor to nicotinamide adenine dinucleotide (NAD), provided no observable clinical advantage for individuals with early-stage Parkinson’s disease after an overall twelve-month regimen. Those who took the supplement showed marginally poorer results than the placebo group, though in this study the gap was deemed too minor to be clinically significant.
Cellular energy production, DNA repair, and other cellular health processes rely on the molecule NAD. Researchers have been interested in NAD’s role in mitochondrial function as a potential therapeutic target for neurodegenerative disorders like Parkinson’s disease, which involves mitochondrial dysfunction and impaired cellular metabolism. Previous lab research and smaller clinical studies suggested that boosting NAD levels could improve neuronal function and protect dopamine-producing neurons. To see if this translated to clinical benefits, Charalampos Tzoulis and colleagues at the University of Bergen and Haukeland University Hospital conducted the NOPARK trial.
The NOPARK trial was a randomized, double-blind study that included 410 patients with early Parkinson’s disease across 11 centers in Norway. For 52 weeks, participants received either nicotinamide riboside or a placebo, and researchers evaluated changes in motor symptoms, daily functioning, and other disease manifestations. Despite a promising biological rationale, the treatment did not improve outcomes. In fact, patients who received nicotinamide riboside showed slightly greater symptom worsening than those who received the placebo, and brain imaging showed no evidence that the supplement slowed dopamine system deterioration. The treatment group also experienced greater worsening of nonmotor symptoms, although the overall clinical outcome difference was relatively small.
The findings highlight an important issue in developing therapies for neurodegenerative diseases: successfully modifying a biological pathway does not necessarily translate into improved patient outcomes. “We had a strong biological rationale for testing this treatment,” Tzoulis said in a statement. “NR clearly increased NAD metabolism, but this did not translate into clinical improvement.” The negative findings do not establish that NAD metabolism is irrelevant to Parkinson’s disease. Rather, they suggest that increasing NAD availability through NR supplementation, at the tested dose and treatment duration, is insufficient to produce a meaningful clinical benefit. The trial also illustrates why encouraging results from small mechanistic studies require confirmation in larger randomized investigations before a potential treatment can be considered clinically effective.
The researchers concluded that their findings do not support nicotinamide riboside as a disease-modifying treatment for early Parkinson’s disease. They also advised against using NAD-boosting supplements specifically to treat Parkinson’s outside controlled clinical trials. However, the results do not rule out potential applications of NAD-targeting therapies in other conditions, where underlying disease mechanisms may differ. Further analyses of the NOPARK data will explore whether particular patient subgroups responded differently, potentially informing future research into metabolic interventions.
