Clinical trial shows NAD+ supplementation improves fatigue and sleep in long COVID patients — Evidence Review
Published in eClinicalMedicine, by researchers from Mass General Brigham
Researched by
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Table of Contents
Long COVID patients who took high-dose nicotinamide riboside (NR) to boost NAD+ levels reported improvements in fatigue, sleep, and mood, though no major differences were seen in cognitive scores compared to placebo. Related research generally supports the potential benefit of NAD+ or similar interventions for fatigue and quality of life in post-viral syndromes, including long COVID, as summarized by the recent Mass General Brigham study.
- Multiple studies have found that NAD+ supplementation, alone or with other agents, may alleviate fatigue and improve quality of life in people experiencing post-viral or chronic fatigue conditions, supporting the exploratory findings of the NR trial 1 2.
- Evidence from related conditions like ME/CFS suggests supplements targeting energy metabolism, such as NADH and CoQ10, can reduce cognitive fatigue and improve sleep, indicating broader potential for NAD+-related interventions 2.
- Research on other NAD+-modulating compounds (e.g., apigenin) also links cellular energy pathways to sleep and neurological symptoms, providing mechanistic support for targeting NAD+ in long COVID and similar syndromes 3.
Study Overview and Key Findings
The persistence of neurological symptoms such as fatigue, brain fog, and sleep disturbances in long COVID has highlighted the urgent need for targeted therapies. Recent insights into cellular energy metabolism suggest that disruption of the NAD+ pathway may play a role in these lingering symptoms. The Mass General Brigham study was designed to rigorously test whether supplementing with high-dose nicotinamide riboside, a precursor to NAD+, could safely improve cognitive and other neurological outcomes in affected individuals. Unlike prior pilot studies, this trial incorporated a double-blind, placebo-controlled design and tracked a broad spectrum of symptoms over 20 weeks.
| Property | Value |
|---|---|
| Organization | Mass General Brigham |
| Journal Name | eClinicalMedicine |
| Authors | Chao-Yi Wu, Edmarie Guzmán-Vélez, William Cody Reynolds, Isabel Abril, Alison J. McManus, Charles Brenner, Gabriel González-Irizarry, Leidys Gutiérrez-Martínez, Jonathan Rosand, Rudolph E. Tanzi, Steven Arnold |
| Population | People with long COVID |
| Sample Size | n=58 |
| Methods | Randomized Controlled Trial (RCT) |
| Outcome | Cognitive function, fatigue, sleep, mood |
| Results | Some participants reported improved fatigue and sleep after NR supplementation. |
Literature Review: Related Studies
To better understand how this new study fits within the broader research landscape, we searched the Consensus database (over 200 million research papers) for related studies. The following search queries were used:
- NAD+ supplement long COVID fatigue
- NAD+ supplementation brain fog improvement
- NAD+ effects on sleep quality
| Topic | Key Findings |
|---|---|
| Does NAD+ supplementation improve fatigue in long COVID and related conditions? | - NAD+ supplementation (including NR and NADH) is associated with reduced fatigue and improved quality of life in some patients with long COVID or post-viral fatigue 1 2. - Not all individuals respond equally; subset analyses suggest that certain patients may benefit more than others 1. |
| What is the impact of NAD+ or related supplements on cognitive symptoms ("brain fog")? | - CoQ10 plus NADH supplementation reduced cognitive fatigue and improved cognitive function in ME/CFS, a condition with overlapping features to long COVID 2. - NR supplementation did not significantly improve cognitive scores overall in long COVID, though some executive function benefits were reported [New Study, 2]. |
| Can NAD+ modulation affect sleep quality and mood? | - NAD+ or NADH supplementation is linked to improved sleep duration and efficiency in ME/CFS, and NR showed self-reported sleep improvements in long COVID [2, New Study]. - Apigenin, which can increase NAD+ levels, is associated with better sleep quality and mood in both animal models and some human cohorts 3. |
| Are NAD+-targeted strategies safe and well-tolerated in these populations? | - Both NR and NAD+ interventions, as well as related compounds, generally show favorable safety profiles, with mild and manageable side effects [1,2, New Study]. |
Does NAD+ supplementation improve fatigue in long COVID and related conditions?
Both the new Mass General Brigham study and prior research suggest that NAD+ supplementation may help reduce fatigue in individuals with long COVID or similar post-viral conditions. While the randomized trial found only modest symptom improvements overall, exploratory analyses and prior non-RCT studies indicate that a subset of patients may experience meaningful benefits, particularly in fatigue and quality of life.
- Fatigue reduction and improved quality of life were observed in over half of participants in a pilot study using NAD+ and low-dose naltrexone for post-COVID fatigue 1.
- The current RCT found self-reported improvements in fatigue for those who took NR for at least 10 weeks [New Study].
- Not all patients responded equally, highlighting the need to identify which subgroups benefit most [1, New Study].
- Larger trials are needed to confirm these findings and optimize patient selection [1, New Study].
What is the impact of NAD+ or related supplements on cognitive symptoms ("brain fog")?
Cognitive symptoms, including brain fog and executive dysfunction, are prominent in long COVID. While the new study did not find significant group-level improvements in cognitive test scores with NR, related research in ME/CFS found that NADH, especially in combination with CoQ10, can reduce cognitive fatigue and improve cognitive function. These findings suggest that NAD+-targeted supplements may have potential for cognitive symptoms, though results are not uniformly positive.
- The new study reported no major cognitive score improvements overall, but some executive function gains were noted in exploratory analyses [New Study].
- CoQ10 and NADH supplementation led to significant reductions in cognitive fatigue in ME/CFS patients 2.
- The overlap between ME/CFS and long COVID supports the relevance of these findings to post-COVID cognitive symptoms 2.
- More research is needed to clarify cognitive effects and identify optimal interventions [2, New Study].
Can NAD+ modulation affect sleep quality and mood?
Sleep disturbances and mood changes are common in both long COVID and other post-viral syndromes. Evidence from the new study and related research indicates that NAD+-boosting strategies, including NR, NADH, and apigenin, may positively impact sleep quality and mood, particularly in those with baseline disturbances.
- NR supplementation was associated with improved self-reported sleep and mood after at least 10 weeks in the long COVID trial [New Study].
- Similar improvements in sleep duration and efficiency were seen with NADH/CoQ10 in ME/CFS 2.
- Apigenin, a natural NAD+-modulator, is linked to better sleep and mood in animal models and human cohorts 3.
- These findings highlight a potential therapeutic role for NAD+ modulation in sleep and mood symptoms across multiple conditions [2,3, New Study].
Are NAD+-targeted strategies safe and well-tolerated in these populations?
Safety is a critical consideration for any intervention, especially in populations with ongoing health concerns. Across the studies reviewed, NAD+-related supplements—including NR, NADH, and apigenin—were generally safe and well-tolerated, with most adverse effects being mild and transient.
- NR supplementation in the new trial led to only mild side effects (e.g., rash, bruising), and few discontinuations [New Study].
- NAD+ and low-dose naltrexone were well-tolerated in a pilot study, with side effects managed by dose adjustment 1.
- Mild skin irritation was noted with iontophoresis-based NAD+ delivery in one study 1.
- Overall, NAD+-modulating strategies appear suitable for further study in these populations [1,2,3, New Study].
Future Research Questions
Although the latest findings provide valuable insights, larger and more diverse studies are needed to clarify who benefits most and how NAD+-targeted therapies can be optimized. Future research should address mechanistic questions, patient subgroup responses, and long-term outcomes.
| Research Question | Relevance |
|---|---|
| Which subgroups of long COVID patients benefit most from NAD+ supplementation? | Identifying biomarkers or clinical characteristics that predict response could help tailor therapies, as not all patients appear to benefit equally [1, New Study]. |
| Does NAD+ supplementation reduce inflammation in long COVID? | Since inflammation is implicated in long COVID and NAD+ may regulate immune responses, understanding this mechanism could clarify how supplementation affects symptoms [New Study, 3]. |
| What are the long-term effects and safety of high-dose NR in diverse populations? | Most studies to date are short-term or have small sample sizes; assessing long-term outcomes and safety in varied populations is essential for clinical adoption [1,2, New Study]. |
| Can combining NAD+ supplementation with other therapies (e.g. CoQ10, LDN) enhance symptom reduction in long COVID? | Evidence from ME/CFS and pilot long COVID studies suggests potential additive or synergistic effects when combining NAD+ with other agents 1 2. |
| How does baseline NAD+ level or metabolic status affect the response to NAD+ supplementation in long COVID? | Baseline differences in NAD+ metabolism or energy status may explain variability in treatment response and could be used to personalize interventions [1,2, New Study]. |