A randomized controlled trial at Massachusetts General Hospital tested high-dose nicotinamide riboside, a vitamin B3 derivative, to boost NAD+ levels in people with long COVID. Although between-group differences were limited, participants who took the supplement for at least 10 weeks reported improvements in fatigue, sleep, mood, and some executive function measures compared with their own baseline, suggesting potential benefits for some individuals despite mixed overall results.
Long COVID affects large numbers of people worldwide, with persistent symptoms such as fatigue, sleep disturbances, and "brain fog" that can significantly disrupt daily life. Researchers at Massachusetts General Hospital ran a randomized, double-blind, placebo-controlled trial to investigate whether boosting levels of nicotinamide adenine dinucleotide (NAD+) — a molecule essential for cellular energy production, immune function, and inflammation control — could ease these symptoms.
According to Mass General Brigham and a summary published by ScienceDaily, the 24-week trial was conducted at Massachusetts General Hospital between August 2021 and September 2023 and is reported in the journal eClinicalMedicine.
The study enrolled 58 non-hospitalized adults with long COVID, who were randomly assigned to two groups. One group took 2,000 milligrams per day of nicotinamide riboside (NR), a form of vitamin B3 and a precursor to NAD+, for 20 weeks. The other group received a placebo for 10 weeks before switching to NR for the remaining 10 weeks. To minimize bias, neither participants nor study staff initially knew who was receiving the active supplement. Assessments included blood tests to measure NAD+ levels, cognitive testing focused on memory and executive function, and questionnaires about fatigue, sleep, and mood at the start of the study, at 10 weeks, and at 20 weeks.
Of the 58 people enrolled, 37 started NR immediately and 21 began with placebo, according to Mass General Brigham. Only 18 participants completed the full 22-week protocol, with others discontinuing for reasons including COVID-19 reinfection, moving away, changes in medications, or possible side effects. The trial did not find major differences between treatment and placebo groups in the primary cognitive outcomes, such as overall thinking and memory scores, or in group-level measures of fatigue, sleep, and mood.
However, exploratory post hoc analyses that included all participants who took NR for at least 10 weeks showed within-group improvements compared with baseline. In this subset, participants reported better fatigue, sleep quality, and depressive symptoms after 10 weeks of NR supplementation, and some performed better on a test of executive functioning — mental skills involved in planning, organizing, and switching between tasks.
"Millions of people worldwide continue to experience lingering symptoms after COVID-19, a condition known as long COVID," said lead author Chao-Yi Wu, PhD, OT, from the Department of Neurology at Mass General Brigham, in an interview published by the health system. The trial showed that high-dose NR safely increased NAD+ levels in the blood. The most common side effects reported were mild, such as easy bruising or rash; no serious adverse events related to the supplement were reported, and only a few participants stopped treatment because of side effects.
Senior author Edmarie Guzmán-Vélez, PhD, from the Department of Psychiatry at Mass General Brigham, noted that long COVID is a complex condition and stressed the need for larger, more diverse studies to confirm the findings and determine which patients might benefit most. Future research questions include whether men and women respond differently, and whether people with lower baseline NAD+ levels or higher levels of inflammation are more likely to improve with NR.
The results, published in eClinicalMedicine and summarized by Mass General Brigham and ScienceDaily, suggest that enhancing NAD+ may be a promising direction for easing symptoms such as fatigue and poor sleep in at least some people with long COVID, even as the underlying causes of the condition remain unclear. Researchers emphasize that the current trial was small, with high dropout rates and mixed primary outcomes, and that NR is not yet an established treatment for long COVID. Larger, confirmatory trials will be needed before the supplement’s role in managing long COVID symptoms can be determined.
