Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 41357333 · doi:10.1016/j.eclinm.2025.103633
What was done
A single-center, double-blind, placebo-controlled trial in Boston evaluated oral nicotinamide riboside (NR, 2000 mg/day) in 58 community-dwelling participants with long-COVID. Participants were randomized 2:1 to either continuous NR for 20 weeks (NR-NR, n = 37) or placebo for 10 weeks followed by NR for 10 weeks (PBO-NR, n = 21). The primary outcome was cognitive function assessed via the Everyday Cognition scale (ECog), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and Trail Making Test-B (TMT-B). Secondary outcomes were fatigue (Fatigue Severity Scale), depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), and sleep quality (Pittsburgh Sleep Quality Index). Mixed models for repeated measures were used for group comparisons, followed by unadjusted post-hoc exploratory analyses pooling participants during their first 10 weeks of NR.
What was found
NR raised NAD+ levels 2.6- to 3.1-fold after 5 to 10 weeks in the NR-NR group (remaining elevated at 20 weeks), whereas placebo showed no change (0.93- to 1.0-fold change, 95% CI: 0.5–1.4). Despite this biochemical elevation, there were no significant between-group differences for primary cognitive outcomes (ECog, RBANS, TMT-B; p = 0.47 to 0.74) or secondary measures: fatigue severity (p = 0.59), sleep quality (p = 0.69), anxiety (p = 0.84), or depression (p = 0.20). In unadjusted post-hoc within-group analyses after 10 weeks of NR, participants showed significant baseline improvements in executive functioning, fatigue, sleep quality, and depressive symptoms. Dropout in the NR-NR group was 32.4% at 10 weeks and 51.4% at 20 weeks, compared to 14.3% at each interval in the PBO-NR arm.
Why it matters
Although high-dose NR effectively increases circulating NAD+ levels in long-COVID, this target engagement fails to translate into statistically significant improvements in cognition or symptom burden compared to placebo in a controlled setting.
Limits
The sample size was small (n = 58) and conducted at a single site. High attrition occurred in the continuous NR arm (over 50% by week 20), and positive clinical changes were observed only in post-hoc, unadjusted within-group analyses rather than in controlled between-group comparisons.
Cited by
- supports A clinical study in long COVID patients demonstrated within-group improvements in executive function following nicotinamide riboside supplementation.