Healthy Aging Supplement Fails in Large PD Trial

Nicotinamide riboside (NR), a supplement promoted for healthy aging, did not slow the progression of early Parkinson’s disease (PD) in a new phase 3 trial.A derivative of vitamin B3, NR boosts levels of nicotinamide adenine dinucleotide (NAD+), a molecule that helps cells produce energy and supports other functions essential to healthy neurons. These effects and promising results from smaller early trials pointed to NR as a potential treatment in PD.Charalampos Tzoulis, MD, PhDHowever, in the 52-week phase 3 NOPARK trial, 500 mg twice daily of the supplement did not improve clinical outcomes or slow clinical progression compared with placebo in participants with early PD. In fact, motor scores worsened in the NR group while improving slightly with placebo, said lead investigator Charalampos Tzoulis, MD, PhD, professor of neurology and neurogenetics at Haukeland University Hospital and the University of Bergen in Bergen, Norway.“NOPARK was the first study large and long enough to test efficacy reliably,” Tzoulis told Medscape Medical News. “NR produced a clear systemic metabolic response, but this did not translate into clinical benefit.”The study was published online on October 8 in JAMA.The TrialNR is marketed as a longevity supplement because boosting NAD+, which declines with age, could potentially help cells function better and slow age-related decline. However, evidence of anti-aging benefits in humans remains limited.Earlier smaller clinical trials, including NADPARK and NR-SAFE, showed that the supplement increased NAD levels in the brain or blood in patients with PD and was generally well tolerated over several weeks. However, whether these effects would translate into clinical benefits over the longer term remained unclear.NOPARK was a phase 3, randomized, double-blind, placebo-controlled trial conducted at 11 centers in Norway. The study included 410 adults aged 35 years or older who had received an early PD diagnosis within the previous 2 years, had evidence of dopaminergic dysfunction on dopamine transporter imaging, and were receiving stable dopaminergic therapy. Participants also had a Hoehn and Yahr disease stage below 3, indicating early-stage disease without postural instability.Participants were taking levodopa combined with either carbidopa or benserazide three times daily, along with selegiline 10 mg daily, before the trial began. Medication regimens remained unchanged throughout the trial, except when clinically necessary.Investigators randomly assigned participants in a 1:1 ratio to receive oral NR 500 mg twice daily (n = 206) or matching placebo (n = 204) for 52 weeks. The primary analysis included 393 participants (mean age, 65.6 years; 34% women).The primary outcome was the change in total Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score from baseline, assessed while participants were taking their usual PD medications. Higher scores indicated greater disease burden.The investigators also assessed nonmotor symptoms, cognition, quality of life, disease stage, dopamine transporter imaging, and NAD levels in the brain and blood to determine whether NR produced lasting biological changes.Unfavorable Clinical EffectAt 52 weeks, MDS-UPDRS scores increased by 2.45 points with NR and decreased by 0.27 points with placebo, with an adjusted between-group difference of 2.72 points, favoring placebo (P = .02). Although statistically significant, the difference was below the threshold generally considered clinically meaningful for an individual patient.Four of five key secondary outcomes did not differ significantly between groups. However, nonmotor symptoms worsened more with NR, with a 4.22-point adjusted difference on the Non-Motor Symptoms Scale (P = .009).The groups did not differ significantly in individual MDS-UPDRS scores, cognition, or Hoehn and Yahr disease stage. Quality-of-life scores were also lower with NR, with an adjusted between-group difference of -0.019 (P = .02).NR increased blood NAD compared with placebo, with a between-group difference of 30.00 μM (P < .001). However, brain imaging in a subset of 159 participants found that the NAD/ATP-alpha ratio, a marker related to cellular energy metabolism, was similar between groups.Dopamine transporter SPECT imaging also showed no measurable change in putaminal binding, a measure of dopamine transporter availability in the putamen, a brain region involved in movement.Adverse events (AEs) occurred in 54.6% of participants receiving NR vs 53.7% receiving placebo. The most common included hypertension, folate deficiency, falls, nausea, and fainting. Serious AEs occurred in 8.3% of the NR group vs 14.1% of the placebo group and included urinary tract infections and femur fractures.Future of NAD-Boosting TherapiesThe study had several limitations, including assessing participants while they were taking their usual PD medications, the lack of a washout period to distinguish symptom relief from effects on disease progression, and the limited ability of dopamine transporter imaging to detect small changes over 1 year.The NOPARK findings do not prove that every possible approach to targeting NAD metabolism will fail, Tzoulis cautioned.However, “I believe it is unlikely that simply substituting another NAD precursor will produce a fundamentally different outcome, since these compounds share the principal effect of increasing NAD metabolism,” he said.Future trials of NAD-boosting therapies in PD should be based on strong scientific evidence, with close safety monitoring and regular checks to identify treatments that aren’t working or may cause harm, Tzoulis explained.Tzoulis and his colleagues plan to investigate why NR did not improve outcomes, including subgroup responses, links between metabolic changes and clinical outcomes, and interactions with standard PD medications. They also hope to understand why brain NAD levels did not show a sustained increase over the year.Long-Term Effects Under ScrutinyEija Pirinen, PhDNOPARK raises concerns about the effects of prolonged NR treatment, Eija Pirinen, PhD, an associate professor of biomedicine at the University of Oulu in Oulu and a researcher at the University of Helsinki in Helsinki, both in Finland, and Jaan-Olle Andressoo, PhD, a professor of translational neuroscience at the University of Helsinki, told Medscape Medical News in an email.In a 2024 mouse study published in Heliyon, Pirinen, Andressoo, and colleagues examined NR treatment in a mouse model of PD. Although treatment initially improved motor behavior, these benefits did not persist with prolonged exposure. Longer-term treatment was also associated with lower dopamine levels and changes in genes involved in dopamine function. The findings cannot be directly extrapolated to humans, but they highlight the need to study NR’s longer-term effects.Jaan-Olle Andressoo, PhD“For a chronic disease, a short-term positive result is not enough. We need to know what happens when treatment continues,” the researchers told Medscape Medical News.The NOPARK findings do not rule out the possibility that certain patients may respond differently. Patients with lower baseline NAD+ levels or impaired NAD+ metabolism could potentially benefit more from supplementation, Pirinen and Andressoo suggested.“Further analyses of biomarker data from studies such as NOPARK may help clarify whether such responder populations exist,” they added.Pirinen and Andressoo emphasized that further studies should examine how long-term changes in NAD metabolism affect dopamine-producing neurons.Disclosure information for study authors is available in the original study publication. Pirinen and Andressoo reported no relevant financial disclosures.