Abstract

Nicotinamide riboside (NR), an endogenous precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD+), is characterized as safe and effective at longitudinally elevating NAD+ in blood and tissues, when administered orally. Preclinical research on NR as an augmenter of NAD+ has demonstrated great promise in support of healthy aging, metabolic health, and several diseases, though clinical translation of thesefindings has been limited. Interest in alternative routes of administration of NR has increased in recent years and led to the development of pharmaceutical-grade NR for intravenous and injectable administration. Two separate Phase 1 pilot clinical trials were conducted evaluating NR via bolus injections. While the designs of the two studies are different, the similarities warrant combined presentation to note the similarities, particularly with regards to safety-related outcomes. Trial 1 involved 45 participants that were randomized to a 3x3 design, accounting for three interventions, placebo, NR, and NAD+ and three routes of administration, intramuscular (IM), intravenous (IV), and subcutaneous (SC), resulting in a 9-arm study (placebo IM, n=5; placebo IV, n=5; placebo SC, n=5; NR IM, n=6; NR IV, n=5; NR SC, n=4; NAD+ IM, n=4; NAD+ IV, n=5; and NAD+ SC, n=6). Participants were administered NR once daily for three days, followed by a 7-day washout period. In Trial 2 (n=39), the 2x2 study design incorporated 4-arms for phase 1, where the participants were randomized to 50 or 100 mg of NR, administered either IM or SC in-clinic for 3 consecutive days, followed by a 7-day washout (50 mg IM, n=7; IM, 100 mg IM, n=11; 50 mg SC, n=11; and 100 mg SC, n=10). Phase 2 of Trial 2 involved participants self-administering either 50 or 100 mg of NR subcutaneously. Safety assessments for both trials included vitals, blood biomarkers, participant reported outcomes regarding the experience, and adverse event monitoring. Participant retention for both studies was 100%, and the injections did not result in any attributable unexpected adverse events or experiences. The experiences described by the participants regarding the actual injection varied. In Trial 2, pain more than two minutes after the injection and muscle soreness and tightness were reported by 45.9 and 43.2% of the participants, respectively, regardless of the route of administration or dose. Vitals remained generally consistent throughout both trials, and reductions in systolic blood pressure observed in both trials should be evaluated in larger, properly powered studies. Blood chemistry biomarkers for both trials did not elicit treatment-related patterns. Both trials presented within-group reductions in hsCRP in the NR SC arms, however, given baseline imbalance and small samples size, this finding should be considered hypothesis-generating, only. Overall, in both trials, the interventions, regardless of route of administration were associated with some discomfort but were well tolerated and did not produce any concerning safety signals. It is recommended that comprehensive metabolic and inflammatory panels should continue to be employed in future studies and clinical settings to assess whether consistent patterns emerge in larger populations.

Competing Interest Statement

YNE, JK, RI, JM, and AS are employees of ChromaDex, Inc., a Niagen Bioscience company. Niagen Bioscience is publicly traded (NASDAQ: NAGE) Niagen® and Niagen®Plus are proprietary ingredients of ChromaDex, Inc. Niagen is the active ingredient in several commercial products marketed by ChromaDex, Inc. and Niagen Bioscience. ChromaDex, Inc. holds patents for nicotinamide riboside use through various routes of administration, including injections and intravenously. JC and Nutraceuticals Research Institute (NRI) were contracted by ChromaDex, Inc. to conduct Trial 1. AR and Impact Health Medical FL PA (IHM) were contracted by ChromaDex, Inc. to conduct Trial 2 under the leadership of Halland Chen, MD.

Clinical Trial

ClinicalTrials.gov ID#: NCT06919328 and NCT07251608

Funding Statement

Trial 1 was sponsored by Nutraceuticals Research Institute and funded by ChromaDex, Inc. Trial 2 was sponsored and funded by ChromaDex, Inc.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Nutraceuticals Research Institute (NRI) Institutional Review Board, #1 (NIH OHRP registration number IRB00014538) gave ethical approval to conduct Trial 1 under protocol number 24-09-1300 and was appropriately registered on ClinicalTrials.gov (NCT06919328). The Institutional Review Board of the Institute of Regenerative and Cellular Medicine (HHS/OHRP IRB00009500) gave ethical approval to conduct Trial 2 under protocol number NB-2025-01 (IRB approval number: IRCM-2023-368). The trial was registered on ClinicalTrials.gov (NCT07251608).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the corresponding author.

Abbreviations and AcronymsADPadenosine diphosphateALTalanine aminotransferaseASTaspartate aminotransferaseBili totalbilirubin totalBMIbody mass indexBUNblood urea nitrogenCIconfidence intervalCMPcomprehensive metabolic panelDBPdiastolic blood pressureDPNdiphosphopyridine nucleotideESRerythrocyte sedimentation rateFASfatigue assessment scaleFDAFood & Drug AdministrationGCPgood clinical practiceHHSHealth and Human ServicesHRheart ratehsCRPhigh sensitivity C-reactive proteinIDidentificationIMintramuscularIRBinstitutional review boardITTintent to treatIVintravenousLD50lethal dose 50% populationMCHmean corpuscular hemoglobinMCHCmean corpuscular hemoglobin concentrationMCVmean corpuscular volumeNAniacinNAD+nicotinamide adenine dinucleotide (NAD+)NADHreduced nicotinamide adenine dinucleotide NAM nicotinamideNIHNational Institutes of HealthNMNnicotinamide mononucleotideNOAELno adverse events levelNRnicotinamide riboside chlorideNRINutraceuticals Research InstituteOHRPOffice for Human Research ProtectionsPARPpoly(ADP-ribose) polymerasePIprimary investigatorRBCred blood cellRRrespiratory rateSBPsystolic blood pressureSCsubcutaneousSpO2peripheral capillary oxygen saturationTempTemperatureWBCwhite blood cell