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A new randomized clinical trial tested whether boosting a key cellular energy molecule could ease lingering cognitive and physical symptoms of long COVID. Researchers gave high-dose nicotinamide riboside, a form of vitamin B3, to people with persistent complaints such as brain fog, fatigue, and sleep problems to see if raising cellular NAD plus levels would change outcomes.
Why scientists are looking at NAD plus and nicotinamide riboside
Long COVID affects millions worldwide and commonly includes neurological symptoms like memory lapses, difficulty concentrating, and slowed thinking often described as brain fog. Other frequent complaints are chronic fatigue, sleep disturbance, and mood changes. The biological roots of these symptoms are likely complex, involving immune activation, inflammation, vascular and clotting changes, and autonomic dysfunction.
Among the cellular mechanisms under scrutiny is disruption of energy metabolism. Nicotinamide adenine dinucleotide, abbreviated NAD plus, is a molecule present in every human cell that plays a central role in energy production, DNA repair, immune signaling, and regulation of inflammation. Prior research has suggested that viral infections and the inflammatory state that follows can perturb NAD plus biology, potentially contributing to persistent symptoms.
Nicotinamide riboside, or NR, is a bioavailable form of vitamin B3 that cells can use to make NAD plus. NR is available as a dietary supplement and has drawn attention because it can increase blood and tissue NAD plus in controlled settings. That biochemical effect prompted investigators at Mass General Brigham to ask a practical clinical question: if we safely boost NAD plus in people with long COVID, will their cognition or other symptoms improve?
Trial design and who took part
The study, led by researchers including Chao Yi Wu and Edmarie Guzm an Velez at Mass General Brigham, was conducted at Massachusetts General Hospital and published in eClinicalMedicine. It was a randomized, placebo controlled study run between August 2021 and September 2023. The trial enrolled 58 participants who met criteria for long COVID and reported cognitive or physical symptoms persisting after initial SARS CoV 2 infection.
Participants were randomized into two arms. One group started high dose NR immediately, receiving 2,000 mg per day for 20 weeks. The other group received a placebo for the first 10 weeks and then crossed over to receive NR for the next 10 weeks. The study was blinded so that neither participants nor researchers knew who received active NR during the placebo phase.
Investigators measured NAD plus levels by blood tests and tracked clinical outcomes using structured surveys and cognitive tests at baseline, 10 weeks, and 20 weeks. Symptoms assessed included subjective fatigue, sleep quality, mood and standardized measures of memory, attention and executive function.
What the results showed
Of 58 enrolled participants, 37 were randomized to start NR immediately and 21 began with placebo. Only 18 participants completed the full protocol, with others withdrawing for a variety of reasons including reinfection with COVID 19, relocation, medication changes, or suspected side effects. This attrition limited the study's statistical power.
When the randomized groups were compared, the primary cognitive outcomes did not show significant differences between immediate NR and placebo. Likewise, group level measures of fatigue, sleep disturbance and mood were not markedly different in the main analysis.
However, exploratory post hoc analyses that pooled participants who had taken NR for at least 10 weeks suggested signal s worth noting. In that larger sample, individuals reported reductions in fatigue, improved sleep scores, and lower depressive symptoms compared to their baseline assessments after 10 weeks of NR. Some participants also improved on a task of executive functioning, indicating potential gains in planning, cognitive flexibility and task switching for a subset of people.
Safety data were reassuring. Most adverse events were mild, such as easy bruising or rash, and only a few participants discontinued because of side effects. Importantly, NR supplementation produced the expected biochemical effect, reliably increasing blood NAD plus levels in study participants.
What this means for people with long COVID
The study does not prove that NR is a universal cure for long COVID cognitive complaints. The randomized comparison failed to show clear, statistically robust benefits on the main cognitive endpoints, and the trial was limited by a small sample size and participant dropout. Still, the exploratory findings offer a plausible biological and clinical signal: raising NAD plus may relieve fatigue, improve sleep, and help mood for some individuals living with long COVID.
Why might NR help some people but not others? One hypothesis is heterogeneity in underlying biology. Long COVID likely represents multiple overlapping processes. People whose symptoms are driven in part by disrupted cellular metabolism or NAD plus depletion might be more likely to benefit than those whose symptoms stem primarily from persistent inflammation, vascular injury, or autonomic dysfunction. Baseline NAD plus levels, degree of inflammation, sex, age, and comorbidities could all influence response.
Next steps for research
The investigators recommend larger, more diverse trials designed to identify subgroups most likely to respond. Future studies should stratify participants by baseline NAD plus or inflammatory markers, include longer follow up, and combine objective measures such as wearable activity monitoring and biomarkers with patient reported outcomes. Additional research could also test whether combining NR with anti inflammatory strategies or rehabilitation yields additive benefit.
Mass General Brigham researchers plan further analyses of physical activity data collected during the trial and will examine whether other supplements or medications taken by participants altered NR's effects. These secondary analyses may help shape targeted trials that can answer who benefits most and why.
Expert Insight
Dr Maria Alvarez, a neurologist and clinical researcher not involved in the trial, offered context on the findings. 'This study is an important step because it translates a clear biochemical intervention into a human trial for long COVID,' she said. 'The safety signal is encouraging and the exploratory improvements in fatigue and sleep suggest a mechanism worth pursuing. But we need larger trials and better patient selection to understand true clinical benefit.'
'For patients,' Dr Alvarez added, 'this is not a green light to self prescribe high dose supplements without medical guidance. We still need clearer evidence on who should try NR, optimal dosing, and long term safety.'
For clinicians and researchers, the trial underscores a broader research strategy: target cellular energy pathways alongside inflammation and autonomic dysfunction to address the multifactorial nature of long COVID.
Overall, boosting NAD plus via nicotinamide riboside is a biologically plausible and relatively safe approach that merits further study. Large scale trials with biomarker guided enrollment and robust retention will be essential to determine whether this accessible supplement can become part of an evidence based toolkit for easing persistent long COVID symptoms.
Source: scitechdaily
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