A supplement designed to boost cellular energy metabolism has failed to slow Parkinson’s disease in a large Phase III clinical trial, challenging a promising approach to treating neurodegeneration.
The findings, published in JAMA, showed that nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD), offered no clinical benefit to patients with early-stage Parkinson’s disease after one year of treatment. Participants receiving the supplement experienced slightly worse outcomes than those given placebo, although the difference was considered too small to be clinically meaningful.
The results represent a setback for efforts to target cellular metabolism as a disease-modifying strategy in Parkinson’s, where available treatments primarily manage symptoms rather than halt neurodegeneration.
Promising biological rationale falls short
NAD is an essential molecule involved in cellular energy production, DNA repair, and other processes that maintain cell health. Its role in mitochondrial function has made it an attractive therapeutic target for neurodegenerative disorders, including Parkinson’s disease, in which mitochondrial dysfunction and impaired cellular metabolism are implicated.
Earlier laboratory research and smaller clinical studies suggested that increasing NAD availability could improve neuronal function and potentially protect vulnerable dopamine-producing neurons.
To test whether these biological effects translated into meaningful clinical improvements, researchers led by Charalampos Tzoulis, MD, PhD, at the University of Bergen and Haukeland University Hospital conducted the NOPARK trial.
The randomized, double-blind study enrolled 410 patients with early Parkinson’s disease across 11 Norwegian centers. Participants received either nicotinamide riboside or placebo for 52 weeks, with researchers assessing changes in motor symptoms, daily functioning, and other manifestations of the disease.
Despite the promising biological rationale, treatment failed to improve outcomes. Patients receiving NR showed modestly greater symptom worsening than those receiving placebo, while brain imaging revealed no evidence that the supplement slowed deterioration of the dopamine system.
The treatment group also experienced greater worsening of nonmotor symptoms, although the overall difference in clinical outcomes was relatively small.
Biological activity does not guarantee clinical benefit
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.
Implications for future Parkinson’s treatments
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.
