NR-SAFE: high-dose nicotinamide riboside

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Henning Berven, Charalampos Tzoulis and colleagues, Haukeland University Hospital and University of Bergen, Norway. Nature Communications 14:7793, November 2023. Single site. Registry NCT05344404.

What happened

Nicotinamide riboside (NR) is a vitamin B3 form that cells turn into NAD, a molecule needed to make energy. NADPARK (landmark 209) used 1,000 mg a day and raised brain NAD unevenly. NR-SAFE asked whether a higher dose was safe enough to try.

• Design. Randomised, double-blind, placebo-controlled. 26 people screened, 20 enrolled (10 NR, 10 placebo), April to July 2022. NR 1,500 mg twice daily (3,000 mg a day) for 4 weeks. All 20 finished.
• Safety. 42 side effects in total (25 on NR, 17 on placebo; 9 of 10 on NR and 8 of 10 on placebo had at least one). All were mild; none moderate or severe. Two NR participants had a symptom-free slow heart rate (58 and 46 beats a minute). Homocysteine in blood (a marker linked to vascular risk) rose modestly on NR, though the authors say the methyl-donor pool stayed intact.
• Chemistry. Whole-blood NAD+ rose about 3.7-fold on NR (range 1.8–5.8; the abstract says "up to 5-fold").
• Symptoms. Total MDS-UPDRS (parts I–IV, a standard symptom score) fell from 51.0 to 40.3 on NR (within-group p = 0.007) and was unchanged on placebo (41.8 at both visits); the between-group difference had p = 0.02. The NR group started higher. The authors call this preliminary: the NR group's last levodopa dose was closer to testing time, which could explain part of it, and the trial was designed to detect worsening, not improvement.

Why it moved us toward a cure

It set a safe upper dose for the energy-failure idea that began with landmark 209. The 3,000 mg dose is the top step of the escalation arm in the later dose-finding trial (landmark 210). The big test, NOPARK (landmark 172), used 1,000 mg a day and found no benefit, with slightly worse scores than placebo, so the safety result now matters only if a higher dose is still worth trying.

Outcome

Advanced as a safety study. It showed no short-term safety problem at 3,000 mg. Four weeks and 20 people cannot show long-term safety, and the authors advise against use outside trials. The paper discloses pending patents on NR for Parkinson's held by two of the authors.

Sources

• Berven et al., Nat Commun 2023, DOI 10.1038/s41467-023-43514-6, PMC10684646
• ClinicalTrials.gov NCT05344404 (registry lists phase "not applicable"; the paper calls it Phase I)
• Paper read in full via Europe PMC (PMC10684646).
• Not yet verified: whether N-DOSE's 3,000 mg step was chosen because of NR-SAFE (inferred from matching doses; the paper cites N-DOSE as already ongoing).