NAD-boosting supplement fails to improve symptoms in Parkinson’s trial

Nicotinamide riboside (NR) — an oral supplement designed to increase nicotinamide adenine dinucleotide (NAD), a molecule needed for cells to produce energy and function properly — did not improve symptoms in people with Parkinson’s disease compared with a placebo in a Phase 3 clinical trial.

“We had a strong biological rationale for testing this treatment, and earlier, smaller clinical studies had produced encouraging findings. NR clearly increased NAD metabolism, but this did not translate into clinical improvement,” Charalampos Tzoulis, PhD, a professor at the University of Bergen and Haukeland University Hospital in Bergen, Norway, who led the study, said in a university press release.

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The results, “Nicotinamide Riboside for Patients With Early-Stage Parkinson Disease The NOPARK Randomized Clinical Trial,” were published in JAMA. NR, a form of vitamin B3, is available under the brand name Niagen, marketed by Niagen Bioscience, formerly ChromaDex Corporation. ChromaDex Inc., a Niagen Bioscience subsidiary, supplied both NR and the placebo for the study.

Parkinson’s develops as nerve cells in the brain become damaged and die, leading to motor and nonmotor symptoms. Problems with mitochondria, the structures that produce energy for cells, are thought to play a role in the disease’s development and progression. NAD is essential for healthy mitochondrial function, and increasing its levels may help protect nerve cells from damage. Researchers wanted to see whether NR could help protect these cells by boosting NAD levels and supporting energy production.

An earlier, small clinical study called NADPARK (NCT03816020) found that NR increased NAD levels in the brain after about one month. Building on those findings, researchers launched a larger Phase 3 trial, NOPARK (NCT03568968), to test whether NR could slow Parkinson’s progression.

The trial enrolled 410 people with early Parkinson’s who were 35 or older and had been diagnosed within the previous two years and were taking stable doses of Parkinson’s medications. Participants were randomly assigned to take either 500 mg of NR twice daily or a placebo for 52 weeks (one year).

The trial’s main goal was to determine whether NR improved symptoms and daily functioning, as measured by the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS). Researchers used the first three parts of this scale to assess movement, daily activities, and nonmotor symptoms. The combined score for these three parts ranges from 0 to 236, with higher scores indicating more severe problems.

Parkinson’s symptoms worsen slightly more with NR

Of the 410 participants, 393 were included in the main analysis. Their average age was 65.6 years. After one year, scores on the MDS-UPDRS increased by 2.45 points in the NR group, indicating worsening symptoms. Scores in the placebo group decreased by 0.27 points. The 2.72-point difference was statistically significant and favored placebo, but it was too small to be considered clinically meaningful.

The researchers also measured nonmotor symptoms, including problems with mood and sleep. Overall, nonmotor symptoms worsened more in the NR group than in the placebo group. While NR increased blood NAD levels, this did not translate into less severe symptoms or slower disease progression. Participants in both groups reported health problems, including high blood pressure, low folate levels, falls, nausea, and fainting. Most adverse events reported during the study were considered unrelated or unlikely to be related to treatment.

Overall, despite increasing blood NAD levels, NR did not improve clinical outcomes in people with early Parkinson’s disease. “These findings do not support nicotinamide riboside as a disease-modifying treatment for Parkinson disease,” the researchers wrote.

“We are deeply grateful to the participants and their families for their trust, time, and commitment. Although the results were not what we had hoped for, their contribution has answered an important medical question and provided valuable guidance for future research. We also thank our colleagues at all 11 centers, whose dedication made this national study possible,” Tzoulis said.