— October 8, 2026 · Nicotinamide Riboside Fails in Parkinson’s Phase 3 Trial

Table of Contents

1. At a Glance
2. What Was Done
3. What Was Found, Number by Number
4. Side Effects and Safety
5. How It Was Expected to Work
6. How It Fits With Earlier Research
7. What It Cannot Show
8. What the Researchers Said
9. What Remains Unknown
10. Sources and Primary Documents
11. Key Research Papers
12. Connections
13. Featured Videos

At a Glance

• The paper — Brakedal B, Skeie GO, Derad C, et al., Tzoulis C. “Nicotinamide Riboside for Patients With Early-Stage Parkinson Disease: The NOPARK Randomized Clinical Trial.” JAMA, published online October 8, 2026.
• Who ran it — neurologists at Haukeland University Hospital and the University of Bergen, with ten other Norwegian hospitals; statisticians in Göttingen, Germany, and researchers in New York were co-authors.
• Design — randomised, double-blind, placebo-controlled phase 3 trial at 11 centres in Norway (ClinicalTrials.gov NCT03568968).
• Who took part — 410 adults randomised out of 537 screened; Parkinson’s diagnosed within the previous two years; early stage; average age 65.6 years; 34% women.
• What they took — nicotinamide riboside 500 mg twice a day (1,000 mg a day) or matching placebo, for 52 weeks, on top of their usual Parkinson’s medicine.
• Main result — total symptom score up 2.45 points with nicotinamide riboside, down 0.27 with placebo; difference 2.72 points in favour of placebo (P = .02), below the 5.2-point threshold for a clinically important worsening.
• Secondary results — four of five key secondary measures showed no difference; non-motor symptoms worsened more with nicotinamide riboside (4.22 points on a 360-point scale, P = .009).
• Safety — serious adverse events in 8.3% of the nicotinamide riboside group and 14.1% of the placebo group.

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What Was Done

The trial enrolled people between May 6, 2020, and June 20, 2024, and the last follow-up visit took place on June 19, 2025. To take part, a person had to be 35 or older and have had Parkinson’s diagnosed within the two years before joining. The disease had to be at an early stage: below stage 3 on the Hoehn and Yahr scale, the stage at which balance problems appear. Each person also needed a brain scan confirming loss of the dopamine-producing nerve fibres that Parkinson’s damages, and a medication routine that had been stable before enrolment.

The trial registry lists the main exclusions. They included dementia, atypical forms of parkinsonism, a genetically confirmed mitochondrial disease, and high-dose vitamin B3 supplements in the 30 days before joining.

Participants were randomly assigned to one of two groups:

• Nicotinamide riboside group (206 people): 500 mg capsules twice a day, a total of 1,000 mg daily, for 52 weeks. The capsules were a nicotinamide riboside preparation provided by its supplier, and the registry classes the product as a dietary supplement.
• Placebo group (204 people): identical-looking capsules with no active ingredient, on the same schedule.

Everyone continued their usual Parkinson’s treatment. The primary outcome was the change over 52 weeks in the total score of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), the standard clinical rating of Parkinson’s severity. The trial used parts I to III, which run from 0 to 236 points, with higher scores meaning more severe disease:

• Part I — non-motor experiences of daily living, such as sleep, mood and thinking.
• Part II — motor experiences of daily living, such as dressing, eating and walking, as the patient reports them.
• Part III — a motor examination by a clinician, covering tremor, stiffness, slowness and balance.

The paper gives the size of change that counts as clinically important: an improvement of 6.7 points or a worsening of 5.2 points. Five key secondary outcomes were named in advance: parts I, II and III scored separately; a dopamine transporter scan (DAT-SPECT), which shows how much of the brain’s dopamine system remains; and the Non-Motor Symptoms Scale, a 30-item questionnaire scored from 0 to 360. The registry lists further measures, including a thinking test, a quality-of-life questionnaire and disease stage. The abstract does not report those results.

The results were analysed with a standard model for repeated measurements, with 393 participants included in the primary analysis.

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What Was Found, Number by Number

The 393 people in the primary analysis had an average age of 65.6 years, and 133 of them (34%) were women. After 52 weeks:

• Total MDS-UPDRS score, nicotinamide riboside group: up 2.45 points (95% CI 0.80 to 4.10), meaning slightly worse.
• Total MDS-UPDRS score, placebo group: down 0.27 points (95% CI −1.95 to 1.40), meaning essentially unchanged.
• Difference between the groups, adjusted: 2.72 points in favour of placebo (95% CI 0.47 to 4.98; P = .02).
• Key secondary outcomes: four of the five showed no significant difference between the groups. Those four were parts I, II and III scored separately and the dopamine transporter scan.
• Non-Motor Symptoms Scale: worse with nicotinamide riboside than with placebo, adjusted difference 4.22 points (95% CI 1.07 to 7.37; P = .009) on a scale that runs to 360.

The paper and its announcement frame the main result in two ways. Statistically, the 2.72-point gap is unlikely to be due to chance alone at the conventional threshold (P = .02). Clinically, it is small. Even the upper end of its confidence interval, 4.98 points, lies below the 5.2-point worsening the paper treats as clinically important. The University of Bergen’s announcement put it this way: the difference was “statistically significant, but modest and below the commonly used threshold for a clinically important difference.” Neither framing points to a benefit: the trial found no improvement on any of its main measures.

The difference in non-motor symptoms was a secondary outcome. Trials are designed and sized around their primary outcome, so a secondary result like this one is generally read as a signal that needs confirmation, not as a finding in its own right.

On the biology, the study director, Professor Charalampos Tzoulis, said in the announcement that nicotinamide riboside “clearly increased NAD metabolism, but this did not translate into clinical improvement.” Published summaries of the full paper report a marked rise in total blood NAD in the treated group. They also report that the scan-based measure of NAD relative to ATP in the brain did not differ significantly between the groups at 52 weeks. Neither figure is in the abstract, and neither has been checked here against the full text.

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Side Effects and Safety

In the safety population, serious adverse events occurred in 17 of 205 people taking nicotinamide riboside (8.3%) and in 29 of 205 taking placebo (14.1%). Serious adverse events include hospital admissions and other serious medical events, whatever their cause. Published summaries of the full paper report that the difference between the groups was not statistically significant. The university’s announcement said adverse events occurred at a similar frequency in the two groups. The abstract gives no breakdown of milder side effects.

The trial’s main safety-related finding is therefore not a side effect in the usual sense. It is the direction of the result: over a year, scores on the main scale and on the non-motor scale moved slightly in the wrong direction with nicotinamide riboside compared with placebo. Published summaries of the full paper say the authors could not explain why. They mention two possibilities: that raising NAD for a long time affects some biological process in Parkinson’s, or that nicotinamide riboside interacts with dopamine-replacement medicines.

Earlier short trials had found nicotinamide riboside well tolerated. In NR-SAFE, 20 people with Parkinson’s took 1,500 mg twice a day or placebo for four weeks. No moderate or severe adverse events occurred, and the treated group had a slight early rise in serum homocysteine. A one-month trial cannot show what happens over a year, which is the gap NOPARK was built to fill.

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How It Was Expected to Work

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme, a helper molecule that enzymes need in order to work. The University of Bergen’s announcement describes it as essential for cellular energy metabolism and for processes including DNA repair and the regulation of inflammation. Much of that energy work takes place in the mitochondria, the cell’s power plants.

The body builds NAD+ from several forms of vitamin B3. These include niacin (nicotinic acid), nicotinamide, nicotinamide riboside and nicotinamide mononucleotide (NMN), and the site compares them on its NAD+ precursors page. A 2016 study showed that single oral doses of 100, 300 and 1,000 mg of nicotinamide riboside raised blood NAD+ and related molecules in a dose-dependent way. A 2018 laboratory study found that human nerve cells use an enzyme called NRK1 to turn such precursors into NAD+.

The idea of treating Parkinson’s this way rests on three lines of evidence:

• Energy failure in Parkinson’s. In 1989, researchers reported a deficiency of mitochondrial complex I, a key part of the cell’s energy-making chain, in Parkinson’s disease. A 2018 paper described mitochondrial dysfunction as “emerging as key” in the disease.
• Laboratory rescue. In nerve cells grown from patients with a genetic form of Parkinson’s (linked to the GBA gene), raising NAD+ with nicotinamide riboside improved mitochondrial function. In fruit-fly models it prevented the age-related loss of dopamine-producing neurons and the decline in movement.
• Early human signals. In NADPARK, a one-month trial in 30 people, nicotinamide riboside raised NAD levels in the brain, by varying amounts. People whose brain NAD rose showed changes in brain metabolism that went with mild clinical improvement.

The movement symptoms of Parkinson’s come mainly from the loss of dopamine-producing nerve cells in the substantia nigra, deep in the brain, and of the fibres they send to the striatum. This is the nigrostriatal pathway that the trial’s entry scan checked. The idea was that better-fuelled neurons would die more slowly, so that symptoms would progress more slowly. Over one year, NOPARK did not find that effect. On the trial’s own scan of the dopamine system there was no significant difference between the groups.

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How It Fits With Earlier Research

NOPARK is the third randomised trial of nicotinamide riboside in Parkinson’s from the same Bergen group, and the first built to test whether it changes the course of the disease:

• NADPARK (2022, Cell Metabolism) — a phase 1 trial in 30 newly diagnosed people who had not yet started treatment, given 1,000 mg a day or placebo for 30 days. Nicotinamide riboside was well tolerated and raised brain NAD levels by varying amounts, and raised related molecules in the spinal fluid. It lowered inflammatory signalling molecules in blood and spinal fluid. People whose brain NAD rose showed altered brain metabolism that went with mild clinical improvement. The authors wrote that this warranted “further investigation in larger trials.”
• NR-SAFE (2023, Nature Communications) — a four-week safety trial in 20 people at 3,000 mg a day. Blood NAD+ rose up to five-fold, and total MDS-UPDRS scores improved. The authors noted that the improvement was also associated with a shorter interval since the last levodopa dose, which means the timing of the usual medicine could explain part of it.
• NOPARK (2026, JAMA) — 410 people for 52 weeks at 1,000 mg a day. No improvement, and a small worsening compared with placebo.

Small, short, early trials are designed to check safety and look for signals, and their encouraging results do not always hold up in a large, long, double-blind trial. The study director noted in the announcement that “earlier, smaller clinical studies had produced encouraging findings.”

Outside Parkinson’s, nicotinamide riboside has been studied mainly as an NAD+ booster for ageing. A 2018 crossover trial in healthy middle-aged and older adults found six weeks of supplementation well tolerated, and found that it stimulated NAD+ metabolism. Reviews in 2018 and 2021 summarised the animal evidence for NAD-boosting molecules and the roles of NAD+ in ageing. A May 2026 study in Nature Metabolism, covering seven human cohorts, challenged a premise behind much of that interest. It found that whole-blood NAD+ stayed “remarkably stable with age and across lifestyle interventions.” Blood NAD+ did change in response to nicotinamide riboside supplementation. The site’s NAD boosters page covers that debate.

Two other recent items on the site concern relatives of nicotinamide riboside. The October 11, 2026 news roundup covers a single-arm trial of niacin, another form of vitamin B3, added to treatment for glioblastoma, a different disease, in a study with no control group. And in September 2025 the US Food and Drug Administration concluded that NMN, a closely related NAD+ precursor, is not excluded from the dietary-supplement definition. That decision concerned NMN’s legal status, not whether it works (FDA and NMN, 2025).

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What It Cannot Show

• One dose, one year. The trial tested 1,000 mg a day for 52 weeks. It cannot say what higher doses would do; NR-SAFE’s authors had proposed testing up to 3,000 mg a day in phase 2 trials. Nor can it say what longer treatment would do.
• Early disease only. Everyone had been diagnosed within two years and was below Hoehn and Yahr stage 3. The result does not describe later-stage Parkinson’s or other forms of parkinsonism.
• One population. Participants were recruited in Norway, and about two-thirds were men.
• Not every participant analysed. Of 410 people randomised, 393 were in the primary analysis.
• Other compounds and other conditions. The trial tested nicotinamide riboside in Parkinson’s. It did not test NMN, niacin or nicotinamide, and it did not test other diseases or healthy people. According to the announcement as summarised by Medical Xpress, the researchers acknowledged that the findings do not rule out effects in other conditions.
• Symptoms versus progression. Published summaries of the full paper list the authors’ own limitations. People were assessed while on their usual medicine, which could hide subtle motor changes. There was no “washout” period off treatment at the end, so effects on day-to-day symptoms cannot be fully separated from effects on the underlying disease. And the dopamine scans may not be sensitive enough to detect small changes within one year.
• The worsening is small and unexplained. The gap between groups was below the clinically important threshold, and the non-motor finding is a secondary outcome. Neither the abstract nor the announcement gives a mechanism.

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What the Researchers Said

The University of Bergen announced the results on October 8, 2026. Professor Charalampos Tzoulis, the study director at Haukeland University Hospital and the University of Bergen, said: “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.” He added: “Our results therefore do not support NR as a treatment to slow Parkinson’s disease.”

The research team’s announcement also stated: “We do not recommend that people with Parkinson’s disease use NR or other NAD-boosting supplements outside controlled clinical studies.” On brain imaging it said the scans “showed no evidence that NR either slowed or accelerated changes in the brain’s dopamine system.” Coverage on October 9 reported that the team plans further analyses of the NOPARK data, including whether particular groups of patients responded differently.

Funding and interests. The trial’s lead sponsor was Haukeland University Hospital. The announcement lists Norwegian public research funders and a research foundation as its funders. The nicotinamide riboside capsules were supplied by a company that makes the compound. The paper’s disclosure statement reports that two investigators, including the study director, hold granted or pending patents on the use of nicotinamide riboside to treat Parkinson’s disease. Those patents are licensed to the supplier’s corporate group, from which the study director also reported personal fees. Several other authors reported fees or grants from drug companies.

JAMA published an accompanying comment on the trial the same day; it has not been reviewed for this report. No statement on the trial from a medicines regulator was found.

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What Remains Unknown

• Why the treated group did slightly worse. Whether this was chance, an effect on some biological process, or an interaction with dopamine-replacement medicines is not settled by the published results.
• Whether the brain was reached. NADPARK found a variable rise in brain NAD over one month. Published summaries of NOPARK describe a clear rise in blood NAD but no significant difference in the brain’s NAD-to-ATP measure at one year. How much of an oral dose acts in the brain over the long term is still an open question.
• Subgroups. The team plans to look at whether particular patients responded differently. Any such findings would be exploratory and would need a new trial to confirm.
• Other doses and other precursors. NOPARK does not address higher doses, or other NAD+ precursors such as NMN, in Parkinson’s.
• The value of blood NAD+ as a marker. The authors of the May 2026 seven-cohort study wrote that their results “challenge the utility of blood NAD+ levels as a biomarker of ageing or lifestyle factors.” In NOPARK, a rise in NAD metabolism did not translate into clinical benefit in Parkinson’s.
• Other conditions. Trials of NAD+ precursors in other diseases are separate questions that NOPARK does not answer.

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Sources and Primary Documents

Every figure attributed to the trial above was taken from the paper’s abstract (PubMed record) or from its registry entry, unless the text marks it as coming from summaries of the full paper. Quotations are from the University of Bergen’s announcement.

1. Brakedal B, Skeie GO, Derad C, Alstadhaug KB, Anundskås I, Berven H, et al. (2026). Nicotinamide Riboside for Patients With Early-Stage Parkinson Disease: The NOPARK Randomized Clinical Trial. JAMA, published online October 8, 2026:e2618828. — doi:10.1001/jama.2026.18828 · PubMed PMID: 42848371
2. ClinicalTrials.gov. A Randomized Controlled Trial of Nicotinamide Riboside Supplementation in Early Parkinson’s Disease: the NOPARK Study. Lead sponsor Haukeland University Hospital; status completed. — NCT03568968
3. University of Bergen (October 8, 2026). Major trial of NAD-boosting treatment finds no benefit in Parkinson’s disease. Press release via EurekAlert. — EurekAlert news release 1146813

Coverage: News-Medical, October 8, 2026 (Nicotinamide riboside fails to slow progression of early Parkinson’s disease); Inside Precision Medicine, October 9, 2026 (trial coverage); Medical Xpress (NAD-boosting treatment shows no Parkinson’s benefit in yearlong trial). A later News-Medical article (October 12, 2026: Year-long trial finds NAD-boosting supplement fails to improve early Parkinson’s symptoms) summarised the full paper; it is the source of the details marked above as coming from summaries.

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Key Research Papers

Background papers on nicotinamide riboside, NAD+ and Parkinson’s disease. Each entry was checked against PubMed and Crossref before it was written down.

1. Brakedal B, Dölle C, Riemer F, Ma Y, Nido GS, Skeie GO, et al. (2022). The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metabolism 34(3):396-407.e6. — PubMed PMID: 35235774
2. Berven H, Kverneng S, Sheard E, Søgnen M, Af Geijerstam SA, Haugarvoll K, Skeie GO, Dölle C, Tzoulis C (2023). NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease. Nature Communications 14(1):7793. — PubMed PMID: 38016950
3. Schöndorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, et al. (2018). The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease. Cell Reports 23(10):2976-2988. — PubMed PMID: 29874584
4. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989). Mitochondrial complex I deficiency in Parkinson’s disease. The Lancet 333(8649):1269. — PubMed PMID: 2566813
5. Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, et al. (2016). Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature Communications 7:12948. — PubMed PMID: 27721479
6. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications 9(1):1286. — PubMed PMID: 29599478
7. Rajman L, Chwalek K, Sinclair DA (2018). Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metabolism 27(3):529-547. — PubMed PMID: 29514064
8. Covarrubias AJ, Perrone R, Grozio A, Verdin E (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology 22(2):119-141. — PubMed PMID: 33353981
9. Trętowicz MM, Scantlebery AML, Schomakers BV, Eroğlu KD, van Weeghel M, Spek V, et al. (2026). Human whole-blood NAD+ levels do not vary with age or lifestyle interventions. Nature Metabolism 8(6):1282-1290. — PubMed PMID: 42135539

PubMed Topic Searches

1. PubMed: Nicotinamide riboside and Parkinson’s disease
2. PubMed: Randomised trials of NAD+ precursors
3. PubMed: Mitochondrial complex I and Parkinson’s disease
4. PubMed: Phase 3 trials of disease-modifying therapy in Parkinson’s
5. PubMed: Whole-blood NAD+ and ageing

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Connections

• News Archive
• Parkinson’s Disease — symptoms, causes and research
• Parkinson’s Disease: History — from James Parkinson to dopamine
• NAD+ and NMN — cellular energy and the science of ageing
• NAD+ Precursors Compared — niacin, niacinamide, NR and NMN side by side
• NAD+ and Mitochondrial Function — the energy research behind the trial
• Vitamin B3 — the vitamin family nicotinamide riboside belongs to
• Vitamin B3 as an NAD+ Precursor — how B3 forms become NAD+
• Vitamin B3 Food Sources — whole foods that supply niacin
• NAD Boosters for Longevity — the NMN and NR debate
• FDA and NMN, 2025 — the regulator’s decision on NMN’s supplement status
• Mitochondria — animation of how cells make energy
• Glutathione and Parkinson’s — another line of Parkinson’s metabolism research
• News, October 11, 2026 — roundup including niacin in glioblastoma
• Longevity — the site’s section on healthy ageing

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