Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial, 2025, Wu et al.

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Chandelier

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Chao-Yi Wu a, William Cody Reynolds a, Isabel Abril a, Alison J. McManus a, Charles Brenner b, Gabriel González-Irizarry a, Leidys Gutiérrez-Martínez a c, Olivia Sun b, Jonathan Rosand c d e f, Rudolph E. Tanzi c g h, Steven E. Arnold a i, Edmarie Guzmán-Vélez

Summary​

Background​

Long-COVID often involves cognitive difficulties, immune dysregulation, and mitochondrial dysfunction. Studies suggest nicotinamide adenine dinucleotide (NAD+) precursors like nicotinamide riboside (NR) may reduce inflammation and support mitochondrial and neurological function. This double-blind, placebo (PBO)-controlled clinical trial with a placebo lead-in phase evaluated the effects of NR (2000 mg/day) on NAD+ and changes in cognitive and long-COVID symptoms.

Methods​

This was a 24-week, double-blind, placebo-controlled trial at a single center in Boston, USA, between August 2021 and September 2023. 58 community-dwelling participants with long-COVID were randomized 2:1 to the NR-NR group (NR for 20 weeks) or the PBO-NR group (PBO for 10 weeks, followed by NR for 10 weeks). The primary outcome was cognition, assessed using the Everyday Cognition scale (ECog), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and Trail Making Test-B (TMT-B). Secondary outcomes included the Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Pittsburgh Sleep Quality Index. We conducted a mixed model for repeated measures to compare groups, then post-hoc and unadjusted for multiplicity, combined both groups to explore changes from baseline after 10 weeks of NR. This trial was registered with ClinicalTrials.gov (NCT04809974) in 2021.

Findings​

37 participants (64%) were assigned to NR-NR, and 21 participants (36%) to PBO-NR. There was a 32.4% and 51.4% dropout in the NR-NR group at 10 weeks and 20 weeks, respectively, vs. 14.3% dropout at each timepoint in the PBO-NR group. In the NR-NR group, NAD+ levels increased by 2.6- to 3.1-fold after 5–10 weeks of supplementation, respectively, and remained elevated at 20 weeks. In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR, respectively. No significant between-group differences were observed for cognitive outcomes (ECog, RBANS, TMT-B; p-values = 0.47–0.74). There were no significant differences in fatigue severity (p = 0.59), sleep quality p = 0.69), and symptoms of anxiety (p = 0.84) or depression (p = 0.20) between PBO and NR groups. In post-hoc exploratory analysis, examining within-group changes during 5 and 10 weeks of NR intake by grouping all participants during the first 10 weeks of the NR phase, there were significant differences from baseline after 10 weeks of NR in executive functioning, fatigue severity, sleep quality, and symptoms of depression (compared with no significant changes in TMT-B, FSS, PSQI, BAI, or BDI scores during the PBO phase). One serious adverse event was reported, deemed unrelated to the study drug or trial.

Interpretation​

In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials.

Funding​

This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103).

DOI: 10.1016/j.eclinm.2025.103633

Lancet | ScienceDirect
 
So massive dropout, and it doesn’t look like there were any meaningful changes.

The subjective outcomes during the NR phases have limited reliability due to the increased risk of bias from the lack of blinding.

It seems like a pretty clear null result, and I struggle to see how it would be justified to do another study.
 
I don’t fully understand what actually happened to the patients.

Procedures​

The trial consisted of a screening visit, a 2-week PBO lead-in period followed by a baseline visit, 4 visits every 5 weeks, and an end-of-study phone call 2 weeks after the last visit, for a total of 24 weeks. After the initial screening visit, all participants were provided PBO (4 pills twice daily) for 2 weeks.
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Did the patients know that the lead in was placebo?
After the PBO lead-in period, participants had a baseline assessment visit and were assigned, based on their sequence, to receive 2000 mg of NR (4 capsules of 250 mg twice daily) or PBO (4 capsules twice daily) for 10 weeks. After 10 weeks, people in the PBO group switched to the NR phase (PBO-NR), while people in the NR group continued to stay in the NR phase (NR-NR). A check-in about safety was performed at every visit.
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And did the patients know that regardless of which group they were in, they’d get NR for the last phase?
 
I’ve been looking through the protocol. I can’t find anything about what the patients knew about the different arms.

The screening visit was estimated to take 3 hours. The 2 week assessment would take 4-5 hours. That probably rules out a lot of the more severely affected patients.

There’s also this conflict of interests:
NR and matching PBO were provided by ChromaDex, Inc., a Niagen Bioscience company (Los Angeles, CA).
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This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103).
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Drs. Brenner and Tanzi are on the scientific advisory board and hold equity in Niagen Bioscience. Dr. Arnold has received grants or contracts from AbbVie, AC Immune, Alzheimer's Association, Athira, Challenger Foundation, Novartis, Seer Biosciences, Venture Well, ChromaDex, Ionis Pharmaceuticals, Janssen Pharmaceuticals, John Sperling Foundation, NIH, Gatehouse Bio, Eli Lilly/Fortrea, and Superfluid Dx. He is also a consultant for Allyx Therapeutics, BioVe, Bob's Last Marathon, Merck, Jocasta Neuroscience, Sage Therapeutics, Sanofi, and Vandria, and has received payment for expert testimony for Foster and Eldredge, and ProSelect Insurance Co. All other authors have no declarations of interest directly related to the contents of the work presented herein.
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The funder of the study had no role in study design, data collection, data analysis, or data interpretation. Team members of Niagen Bioscience reviewed the manuscript. None of the authors was paid to write this article.
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www.eurekalert.org

Research spotlight: Trial evaluates a vitamin B3 derivative in people with long COVID

Chao-Yi Wu, PhD, OT, from the Department of Neurology and Edmarie Guzmán-Vélez, PhD, of the Department of Psychiatry at Mass General Brigham, are the lead and senior authors of a paper published in eClinicalMedicine, “Effects of Nicotinamide Riboside on NAD+ Levels, Cognition, and Symptom...
www.eurekalert.org

News Release 14-Nov-2025

Research spotlight: Trial evaluates a vitamin B3 derivative in people with long COVID​

Millions of people worldwide continue to experience lingering symptoms after COVID-19, a condition known as long COVID.

Peer-Reviewed Publication
Mass General Brigham


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COVID-19 | Research

Chao-Yi Wu, PhD, OT, from the Department of Neurology and Edmarie Guzmán-Vélez, PhD, of the Department of Psychiatry at Mass General Brigham, are the lead and senior authors of a paper published in eClinicalMedicine, “Effects of Nicotinamide Riboside on NAD+ Levels, Cognition, and Symptom Recovery in Long-COVID: A Randomized Controlled Trial.”


Q: How would you summarize your study for a lay audience?

Millions of people worldwide continue to experience lingering symptoms after COVID-19, a condition known as long COVID. These symptoms can affect people of all ages and often include neurological issues such as “brain fog,” which makes thinking and memory difficult. Because these problems can significantly disrupt daily life, researchers are working to find effective treatments.

Our clinical trial tested whether raising levels of NAD⁺ — a molecule that helps cells produce energy —through nicotinamide riboside (NR), a form of vitamin B3, could improve health outcomes. Participants took NR supplements for up to 20 weeks, and we tracked changes over time.

Q: What question were you investigating?

The NAD⁺ molecule is present in all human cells and is essential for energy production, immune function and inflammation control. Previous research suggests COVID-19 may interfere with NAD⁺-related biological processes, possibly contributing to neurological symptoms.

In our study, we wanted to know if boosting NAD⁺ through NR supplementation could improve cognitive function and ease common long COVID symptoms.

Q: What methods or approach did you use?

We ran a 24-week clinical trial at Massachusetts General Hospital between August 2021 and September 2023. We enrolled 58 people with long COVID and randomly split them into two groups:

  • One group took 2,000 mg of NR every day for 20 weeks.
  • The other group took a placebo (a fake pill) for 10 weeks, then switched to NR for the next 10 weeks.
To ensure unbiased results, neither the participants nor the researchers knew who was getting the real supplement at first.

We measured NAD⁺ levels through blood tests and asked participants to complete surveys and cognitive tests about memory, sleep, fatigue and mood at the beginning, at 10 weeks and at 20 weeks.

Q: What did you find?

Of the 58 people who joined the study, 37 started NR right away, and 21 began with the placebo. Only 18 people completed the full 22-week protocol. The others left the study for reasons such as getting COVID again, moving, changing medications or experiencing possible side effects.

When we compared the two groups, we didn’t see major differences in thinking or memory scores, which were the main focuses of the study. Other symptoms like fatigue, sleep and mood also didn’t show big differences between groups.

However, in exploratory post hoc analyses with a slightly larger sample size of everyone who took NR for at least 10 weeks, we observed improvements in self-reported fatigue, sleep, and depressive symptoms after 10 weeks of NR supplementation compared to baseline. Some also performed better on a task of executive functioning, a set of mental skills that help us, for example, plan, organize, and switch between tasks. This suggests that some people may benefit from the use of NR, even if the overall results didn’t show clear differences between groups.

Q: What are the implications?

Long COVID affects an estimated 400 million people worldwide, yet its causes remain unclear. In this study, high-dose NR safely boosted NAD⁺ levels. While results were mixed, findings suggest that boosting NAD⁺ may play a role in easing symptoms like fatigue and poor sleep for some people. This points to a promising direction for future treatments.

The most common side effects were mild, such as easy bruising or rash. None were serious, and only a few participants discontinued due to side effects

Q: What are the next steps?

Future studies should include larger and more diverse groups to confirm these findings and identify who benefits most. For example, do men and women respond differently? Are people with lower baseline NAD⁺ levels or higher inflammation more likely to improve? Because long COVID often involves inflammation, an important question is whether boosting NAD⁺ can help reduce it.

We also plan to analyze physical activity data collected during the trial, as well as examine whether other supplements taken by participants influenced NR’s effects.

Authorship: In addition to Guzmán-Vélez, Mass General Brigham authors include William Cody Reynolds, Isabel Abril, Alison J. McManus, Charles Brenner, Gabriel González-Irizarry, Leidys Gutiérrez-Martínez, Jonathan Rosand, Rudolph E. Tanzi, and Steven Arnold.

Paper cited: Wu, CY., et al. “Effects of Nicotinamide Riboside on NAD+ Levels, Cognition, and Symptom Recovery in Long-COVID: A Randomized Controlled Trial.” eClinicalMedicine. DOI: 10.1016/j.eclinm.2025.103633

Funding: This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer’s Association (AARGD-23-114103).

Disclosures: Rudolph Tanzi is on the scientific advisory board and holds equity in Niagen Bioscience. He was not involved in the execution of the trial but contributed to conception, design and interpretation.















Journal​

EClinicalMedicine

DOI​

10.1016/j.eclinm.2025.103633

Method of Research​

Observational study

Subject of Research​

People

Article Title​

Effects of Nicotinamide Riboside on NAD+ Levels, Cognition, and Symptom Recovery in Long-COVID: A Randomized Controlled Trial

Article Publication Date​

12-Nov-2025

COI Statement​

Rudolph Tanzi is on the scientific advisory board and holds equity in Niagen Bioscience. He was not involved in the execution of the trial but contributed to conception, design and interpretation.
 
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