Popular Longevity Supplement Fails to Meet Endpoint in Parkinson’s Trial

Nicotinamide riboside, a form of vitamin B3 that increases cellular levels of nicotinamide adenine dinucleotide (NAD+), had no significant clinical benefit in early Parkinson’s disease, the NOPARK randomized trial showed.

Commonly marketed as an over-the-counter longevity supplement, oral nicotinamide riboside was associated with modestly worse outcomes compared with placebo over 1 year, reported Charalampos Tzoulis, PhD, of Haukeland University Hospital and the University of Bergen in Norway, and co-authors in JAMA.

The primary outcome was the change from baseline in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) total scores, which include both a motor examination and patient experiences of daily living.

After 52 weeks, MDS-UPDRS total scores in the nicotinamide riboside group worsened by an average of 2.45 points, while scores in the placebo group trended toward improvement (adjusted mean difference 2.72 points, 95% CI 0.47-4.98, P=0.02).

Nonmotor symptom burden also worsened more with nicotinamide riboside (P=0.009). There was no imaging evidence that nicotinamide riboside either slowed or accelerated changes in the dopamine system.

Serious adverse events occurred in 8.3% of the nicotinamide riboside group and 14.1% of the placebo group. Hypertension was the most common adverse event in both groups; most adverse events were considered unrelated or unlikely to be related to treatment. One participant in the nicotinamide riboside group had cardiac arrest and died.

The findings do not support nicotinamide riboside to slow Parkinson’s disease, Tzoulis noted.

“We had a strong biological rationale for testing this treatment, and earlier smaller clinical studies had produced encouraging findings,” he said in a statement. “Nicotinamide riboside clearly increased NAD metabolism, but this did not translate into clinical improvement.”

NAD is essential for cellular energy metabolism, DNA repair, and inflammation regulation; NAD+ is the active form the body uses for energy production and repair. Both animal studies and small trials in humans have suggested that nicotinamide riboside, a precursor to NAD+, might provide benefit in Parkinson’s disease.

The phase III NOPARK trial tested whether nicotinamide riboside might delay Parkinson’s progression. It is the largest trial to date of an NAD-boosting treatment in a neurologic disorder, Tzoulis noted.

The study randomized 410 patients at 11 centers in Norway. Participants were diagnosed with Parkinson’s within 2 years before enrollment and had a Hoehn and Yahr disease stage less than 3, confirmatory findings on dopamine transporter single-photon emission computed tomography, and stable dopaminergic treatment. The trial excluded people with dementia, atypical parkinsonism, other neurodegenerative disorders, or recent high-dose vitamin B3 use.

The cohort had a mean age of 66 years, and 66% were men. Participants were randomized to twice-daily oral nicotinamide riboside 500 mg (206 people) or placebo (204 people) for 1 year.

Median adherence to nicotinamide riboside was 99.6%. The treatment was associated with marked increases in NAD+ ratios and in total blood NAD levels: at week 52, the mean between-group difference in total blood NAD was 30.00 μM (P<0.001).

There was no significant between-group difference in Montreal Cognitive Assessment score changes. EuroQol 5-Dimension 5-Level assessment (EQ-5D-5L) index values were lower in the nicotinamide riboside group than in the placebo group.

“Although the between-group difference in total MDS-UPDRS score was modest and below commonly cited thresholds for minimum clinically important difference, the consistency of the findings across clinical end points, sensitivity analyses, and prespecified subgroup analyses supports the robustness of the overall result,” Tzoulis and colleagues wrote.

“Given the widespread use of nicotinamide riboside as an over-the-counter supplement and the growing number of NAD augmentation trials, these findings have immediate clinical relevance,” they added.

The placebo group’s lack of disease progression in this trial may partly reflect the effects of dopaminergic therapy, they noted.

“It is possible that sustained NAD augmentation may exert unfavorable biological effects in the context of Parkinson’s disease biology through yet undiscovered mechanisms,” Tzoulis and colleagues suggested. “Alternatively, nicotinamide riboside may interact with dopaminergic therapy, producing symptomatic worsening.”

The trial did not have a washout phase, the researchers acknowledged. Dopamine transporter imaging has limited sensitivity to detect subtle changes over 1 year, they pointed out.

Nicotinamide riboside continues to be investigated in clinical studies. Supplement maker Niagen Bioscience recently announced plans to start a large randomized placebo-controlled trial in conjunction with Mass General Brigham to test healthy aging outcomes and related biomarkers.