Which randomized trials have measured intramuscular NAD+ directly after NMN or NR supplementation?
Executive summary
Randomized trials of NMN and NR in humans have repeatedly measured blood and peripheral-blood-cell NAD+ metabolites, urine excretion products, and downstream muscle function or protein markers, but the assembled reporting provides no clear randomized trial that directly measured intramuscular (skeletal muscle tissue) NAD+ concentrations after oral NMN or NR supplementation; the literature emphasizes blood/NAD-related metabolites and highlights technical barriers to muscle NAD+ assays [1] [2] [3]. Several randomized, placebo‑controlled trials document blood NAD+ increases or metabolite shifts following NMN/NR, but direct intramuscular NAD+ measurement in RCTs is either not reported in the provided sources or is described as technically challenging and uncommon [1] [4] [2].
1. What the randomized trials actually measured — blood, PBMCs and urine, not muscle NAD+
Most randomized trials cited measure NAD+ system changes in whole blood, PBMCs, or urine metabolites rather than skeletal muscle tissue. A double‑blind randomized trial of 250 mg/day NMN in older men reported significant increases in whole‑blood NAD+ and NAD+-related metabolites after 12 weeks, but the outcomes discussed were blood measures and physiological endpoints rather than direct intramuscular NAD+ concentration measurements [1]. A foundational NR human trial followed serial changes in PBMCs, NAD+ and NAAD and documented time‑dependent rises in those blood-derived metabolites after oral NR dosing, while NAM and NMN did not change in PBMCs—again blood, not muscle tissue, was sampled [2]. Systematic reviews and meta‑analyses likewise summarize consistent blood NAD or metabolite increases across multiple RCTs of NMN/NR while reporting minimal or inconsistent effects on skeletal muscle performance outcomes, underscoring that most RCTs prioritize blood biomarkers and functional tests over direct muscle NAD assays [5] [6].
2. Trials that sampled muscle indirectly or reported muscle endpoints but did not show direct intramuscular NAD+ measures
Some randomized studies evaluated muscle function, proteomic signals, or clinical measures tied to muscle without presenting direct intramuscular NAD+ concentrations. Meta‑analyses that pooled RCTs of NMN/NR report minimal impact on skeletal muscle index, handgrip strength, gait speed and chair‑stand tests in older adults, which are functional endpoints rather than tissue NAD quantification [7] [6]. One clinical report referenced in reviews described elevated insulin‑sensitivity–linked muscle proteins after oral NMN in prediabetic women, but the sources do not document randomized intramuscular NAD+ concentration measurements alongside those proteomic changes [3]. The JCI Insight randomized trial of NR±pterostilbene in experimentally injured elderly muscle tracked muscle injury outcomes and systemic metabolites, yet the published descriptions emphasized systemic and PBMC metabolite changes rather than reporting intramuscular NAD+ levels [2].
3. Why intramuscular NAD+ measurement is rare in RCTs — technical, ethical and interpretive hurdles
Authors explicitly note that direct tissue NAD+ quantification in humans is technically challenging and often invasive, limiting its use in randomized trials; npj Aging warns that dissociating tissue‑level effects (e.g., SIRT3 activation) from systemic NAD+ metabolite changes is difficult and that muscle/tissue studies are technically demanding [1]. Reviews and mechanistic summaries emphasize first‑pass metabolism, extracellular hydrolysis of precursors, and large interindividual variability in blood NAD responses, all of which complicate interpretation of a single muscle biopsy or timepoint as representative [3] [4]. These practical and interpretive constraints help explain why the RCT literature summarized in the provided sources focuses on blood/urine metabolomics and functional endpoints rather than routine intramuscular NAD+ assays [4] [2].
4. Bottom line and what to look for next in primary reports
Based on the provided reporting, no randomized controlled trial cited explicitly reports direct measurements of intramuscular NAD+ concentrations following NMN or NR supplementation; instead, randomized evidence documents blood NAD+/metabolite increases and functional or proteomic muscle signals without paired tissue NAD+ quantification [1] [2] [6]. Future definitive evidence would require RCTs that include pre‑ and post‑supplementation muscle biopsies with validated NAD+ assays and clear temporal sampling, but the existing literature notes the logistical, ethical and analytical barriers to such studies [1] [3]. Readers should treat blood NAD+ increases as indicative of systemic pharmacology but not necessarily proof of intramuscular NAD+ elevation unless a trial explicitly reports muscle tissue NAD+ measurements.