A new clinical trial explored whether raising cellular NAD⁺ levels with high-dose nicotinamide riboside could influence lingering neurological and physical symptoms in long-COVID.
Millions of people around the world continue to live with persistent symptoms after a COVID-19 infection, a condition known as long COVID. These ongoing problems can affect people of all ages and frequently involve neurological complaints such as “brain fog,” which can make thinking and memory tasks feel unusually difficult.
In addition to cognitive changes, long COVID has been linked to fatigue, sleep disturbance, and mood changes, and scientists are actively studying how immune dysregulation, inflammation, and disruptions in cellular energy may contribute to these long-lasting effects.
Scientists are actively studying why these symptoms linger. Current evidence points to a combination of factors, including ongoing immune activation, chronic inflammation, blood vessel and clotting abnormalities, and disruption of the autonomic nervous system, which controls heart rate and blood pressure.
A recent study carried out by Chao-Yi Wu, PhD, OT, from the Department of Neurology, and Edmarie Guzmán-Vélez, PhD, from the Department of Psychiatry at Mass General Brigham, examined whether targeting cellular energy pathways might ease these persistent symptoms.
They recently reported their findings in the journal eClinicalMedicine.
In this randomized clinical trial, the team tested whether increasing levels of nicotinamide adenine dinucleotide (NAD⁺), a molecule that helps cells produce energy, through nicotinamide riboside (NR), a form of vitamin B3, could improve health outcomes for people with long COVID, with participants taking NR supplements for up to 20 weeks while researchers tracked changes in symptoms and cognition over time.
In the following Q&A, the researchers explain their approach, results, and what comes next.
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.
Reference: “Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial” by Chao-Yi Wu, William Cody Reynolds, Isabel Abril, Alison J. McManus, Charles Brenner, Gabriel González-Irizarry, Leidys Gutiérrez-Martínez, Olivia Sun, Jonathan Rosand, Rudolph E. Tanzi, Steven E. Arnold and Edmarie Guzmán-Vélez, 12 November 2025, eClinicalMedicine.
DOI: 10.1016/j.eclinm.2025.103633
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.
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