NAD+ supplement shows early promise for long COVID fatigue and brain fog

Long COVID still affects people worldwide with stubborn symptoms like fatigue and cognitive issues. A clinical trial tested whether boosting NAD+ using nicotinamide riboside could help. Although overall group differences were limited, many participants showed encouraging improvements after taking NR for at least 10 weeks. The findings suggest NAD+ enhancement may offer symptom relief for some individuals.

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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.

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.

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:

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.

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.

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

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.

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.

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).

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.

Materials provided by Mass General Brigham. Note: Content may be edited for style and length.