Research Dossier on Nicotinamide Adenine Dinucleotide (NAD⁺)

(Metabolic Cofactor)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

NAD⁺ is not a peptide and therefore has no amino-acid sequence. It is a small-molecule pyridine dinucleotide, comprising nicotinamide linked by a β-N-glycosidic bond to ribose-5-phosphate, pyrophosphate-bridged to adenosine-5′-phosphate. The oxidized form (NAD⁺) accepts hydride (H⁻) to become NADH in redox reactions; NADP⁺/NADPHare phosphorylated counterparts used largely in biosynthetic/antioxidant reactions. Typical formulae reported for NAD⁺ are around C₂₁H₂₇N₇O₁₄P₂ (salt/hydration state dependent); biophysical properties are well characterized in biochemical compendia. Functionally, the pyridinium ring undergoes reversible two-electron chemistry, while the adenosine ribose-phosphate “handle” enables enzyme recognition. Beyond redox, the nicotinamide moiety is cleavedand NAD⁺ consumed by several signaling enzymes (e.g., sirtuins, PARPs, CD38). PMC

Discovery history (lab, year, species)

NAD was identified in yeast extracts at the turn of the 20th century; its coenzyme roles in hydrogen transfer were elucidated in classic biochemical studies through the mid-1900s. A modern milestone was the recognition that NAD⁺ is not only a redox cofactor but also a substrate for sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38/CD157 ectoenzymes, establishing a link between NAD⁺ availability and chromatin regulation, DNA repair, circadian/metabolic control, and immune signaling. Contemporary reviews (2014–2025) consolidate these insights and their aging/disease implications. PMC+2PubMed+2

Endogenous vs synthetic origin

• Endogenous: NAD⁺ is ubiquitous in living cells and compartmentalized across mitochondria, nucleus, and cytosol in distinct pools that are dynamically maintained and differentially used. PMC+1

• Research material: NAD⁺ and its precursors (e.g., nicotinamide, nicotinic acid, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN)) are available as research chemicals; exogenous NAD⁺ has been delivered intravenously in small pilot studies. PMC+1

Homologs, analogs, derivatives

• NADH (reduced form), NADP⁺/NADPH (phosphorylated forms).

• NAD⁺ precursors/“vitamers”: nicotinic acid (NA) via Preiss–Handler pathway; nicotinamide (NAM) and NR/NMN via salvage pathways. Tryptophan (Trp) feeds de novo/kynurenine pathway. PMC

• Modulators of consumption: PARP and CD38 inhibitors raise NAD⁺ by reducing consumption; these are widely used in mechanistic studies. PMC

Historical Development & Research Trajectory

Key milestones in discovery and study

• Enzymology foundation (mid-1900s): coenzyme roles in glycolysis, TCA, β-oxidation.

• NAD⁺ as a signaling substrate (1990s–2000s): discovery that sirtuins (NAD-dependent deacylases), PARPs(DNA damage responders), and CD38/CD157 (ectonucleotidases/NADases) consume NAD⁺, make ADP-ribose/cADPR/NAADP second messengers, and thereby couple NAD⁺ levels to gene regulation, DNA repair, calcium signaling, immune function. PMC

• NAD⁺ & energy/survival programs (2010s): NAD⁺ metabolism linked to mitochondrial fitness, UPRmt, and circadian regulation; comprehensive reviews connect declining NAD⁺ with aging phenotypes and disease. PubMed

• Translational surge (2015–2025): randomized, placebo-controlled human trials of NR and NMN report increases in blood NAD⁺ and selected metabolic readouts; intravenous NAD⁺ pilot studies catalog plasma metabolite kinetics; brain NAD changes after NR are shown by ¹H-MRS/FDG-PET in phase-I work. Cell+3PMC+3PubMed+3

Paradigm shifts and controversies

1. From one pool to many: NAD⁺ is compartmentalized (mitochondria vs cytosol vs nucleus), with distinct synthesis and consumer enzymes that shape local signaling; raising “total NAD⁺” may not equally normalize each pool. PMC

2. Decline with age: Convergent evidence implicates age-associated up-regulation of CD38 and PARP activationin NAD⁺ decline, but the extent and mechanistic primacy differ by tissue and species. PMC+1

3. Boosting strategies: Trials of NR/NMN show biochemical increases in NAD⁺; clinical efficacy signals are mixed and endpoint-dependent; high-dose safety of NR is under active evaluation. PMC+1

4. Direct IV NAD⁺: pilot studies document rapid NAD⁺/metabolite excursions but lack controlled clinical endpoints; pharmacokinetics and standardization remain incomplete. PMC+1

Evolution of scientific interest

Interest has broadened from mitochondrial redox to genome maintenance (PARP-dependent ADP-ribosylation), immune regulation (CD38), neuro-metabolism, and brain NAD modulation. Recent work (2022–2025) emphasizes tissue specificity, NAD⁺ transport/synthesis compartmentation, and interventions that pair precursors with consumer inhibition. PMC+1

Mechanisms of Action

Primary and secondary “receptor” interactions

NAD⁺ has no single receptor; it functions as:

• a redox coenzyme (hydrogen carrier) in ~hundreds of dehydrogenase reactions;

• a consumed substrate for NAD-dependent enzymes:

  • Sirtuins (SIRT1–7): remove acyl groups from proteins, generating O-acyl-ADP-ribose + NAM; regulate chromatin, mitochondrial biogenesis, stress responses. PMC

  • PARPs/ARTDs: transfer ADP-ribose to proteins/nucleic acids in DNA damage response; massive activation can acutely deplete cellular NAD⁺. ScienceDirect+1

  • CD38/CD157: ectonucleotidases that hydrolyze NAD⁺/NMN to ADPR/cADPR/NAADP, modulating Ca²⁺signaling; CD38 increases with inflammation/aging and is a major NADase in several tissues (e.g., astrocytes during neuroinflammation). PMC+1

Intracellular signaling pathways

• Redox coupling: cytosolic NADH/NAD⁺ ratio ties glycolysis to mitochondrial respiration; mitochondrial NAD⁺fuels the TCA and oxidative phosphorylation. PMC

• DNA repair & chromatin: PARP1/PARP2 use NAD⁺ to ADP-ribosylate substrates at sites of DNA damage, recruiting repair factors; acute DNA damage can consume 50–90% of cellular NAD⁺, transiently reprogramming metabolism toward OXPHOS. ScienceDirect+2Nature+2

• Deacylation & gene regulation: SIRT1/3 tune mitochondrial biogenesis, FAO, stress resistance, and circadian outputs, creating an NAD⁺-sirtuin axis central to metabolic homeostasis. PMC

• Ca²⁺ second messengers: CD38 generates cADPR/ADPR/NAADP, affecting ER/lysosomal calcium release and downstream immune/exocrine programs. PMC

CNS vs peripheral effects

• Peripheral: hepatic/adipose/muscle redox and sirtuin programs; PARP-dependent DNA repair; immuneNADase activity.

• CNS: MC4R-independent (unrelated to melanocortins) but CD38-mediated NAD⁺ turnover influences neuroinflammation; brain NAD can be modulated by NR (phase-I imaging). PNAS+1

Hormonal, metabolic, immune interactions

• Metabolism: NAD⁺ availability governs fuel selection and mitochondrial efficiency; NAMPT is rate-limiting for the NAM salvage pathway in many tissues. Nature

• Inflammation/Immunity: CD38 expression in immune and stromal cells regulates extracellular NAD⁺/NMN and Ca²⁺ signaling; age-associated CD38 up-regulation correlates with NAD⁺ decline and inflammatory phenotypes. Frontiers+1

Evidence grading (A–C)

• A (replicated): fundamental redox role; sirtuin/PARP/CD38 dependence; three canonical biosynthetic pathways; compartmentalization of NAD⁺ pools. PubMed+2PMC+2

• B (translational): NR/NMN elevate human blood NAD⁺ and, in specific contexts, brain NAD; clinical efficacy endpoints vary and are frequently biomarker-centric. PMC+2PubMed+2

• C (uncertain): Direct IV NAD⁺ clinical utility; long-term outcome benefits from “NAD⁺ boosting” in broadly healthy adults; optimal strategies to redistribute NAD⁺ to specific subcellular pools. PMC+1

Pharmacokinetics & Stability

ADME profile

• Absorption: Oral NAD⁺ is rapidly hydrolyzed; precursors (e.g., NR, NMN, NA, NAM) are used in vivo to raise cellular NAD⁺ via salvage/Preiss-Handler/de novo pathways. NR and NMN show dose-dependent increases in blood NAD⁺ in randomized trials. PMC+1

• Distribution: NAD⁺ is compartmentalized (mitochondria/nucleus/cytosol) with pool-specific synthesis and use; direct transport across the inner mitochondrial membrane remains a subject of active study and is tightly linked to local NMNAT isozymes. PMC

• Metabolism & excretion: Consumption by sirtuins, PARPs, CD38 yields NAM and ADP-ribose derivatives; NAM is salvaged or methylated to MeNAM/Me2PY and excreted. Trials document increases in NAM/MeNAM in plasma and MeNAM/Me2PY in urine after NR dosing. PMC

Plasma half-life & degradation pathways

• NAD⁺ (exogenous, IV): A 6-hour IV infusion (3 μmol·min⁻¹) revealed dynamic rises in plasma NAD⁺ and metabolites during/after infusion, with rapid post-infusion changes; formal multi-compartment PK parameters are not standardized. PMC

• NR/NMN (oral): Multiple RCTs show dose-dependent elevation of blood NAD⁺ within days–weeks; kinetic profiling varies by matrix (whole blood vs PBMC vs plasma). PMC+1

Stability in vitro & in vivo

NAD⁺ and NMN/NR are susceptible to CD38-mediated extracellular hydrolysis; intracellular pools are buffered by salvage and synthesis. Stability for research formulations depends on pH, temperature, and salt; peer-reviewed, vial-specific shelf-life is not universally reported. Frontiers

Storage/reconstitution considerations

The peer-reviewed literature provides general handling guidance (protect from high temperature and basic pH; minimize repeated freeze–thaw). For clinical-grade materials, CMC documents—not publicly available—govern specifications; research-use preparations should follow vendor-supplied COA instructions.

Preclinical Evidence

Biosynthesis & pool control

• Pathways: Mammalian cells maintain NAD⁺ via (i) de novo/kynurenine from tryptophan (rate-limiting IDO/TDO → kynurenine), (ii) Preiss–Handler (from nicotinic acid), and (iii) salvage (from NAM/NR/NMN; NAMPT is frequently rate-limiting). Salvage predominates under most conditions. PMC+1

• Compartmentation: Distinct NMNAT isoforms (NMNAT1—nucleus; NMNAT2—cytosol/Golgi; NMNAT3—mitochondria) support local NAD⁺ pools that serve PARPs/sirtuins and metabolic enzymes in those compartments. PMC

Consumption & stress responses

• PARP-driven depletion: DNA damage triggers rapid, massive PARP-dependent NAD⁺ consumption, sometimes 50–90% within minutes, with a transient metabolic shift toward OXPHOS. PARP inhibition prevents the drop and the metabolic switch. ScienceDirect+1

• CD38-driven decline with age/inflammation: CD38 expression rises in several tissues during aging and neuroinflammation; genetic/pharmacologic CD38 inhibition preserves NAD⁺ and mitigates inflammatory phenotypes in models. PMC+1

Organ/tissue examples

• Liver/adipose/muscle: NAD⁺ fuels redox and sirtuin-regulated programs; boosting precursors improves mitochondrial function and metabolic signatures in diverse rodent models. PubMed

• CNS/astrocytes: In neuroinflammation models, CD38 mediates NAD⁺ loss; CD38 targeting improves inflammatory markers and metabolic coupling. PNAS

• Kidney/heart/skin: Reviews outline disease-specific patterns in PARP/CD38 and NAD⁺ pool changes; consumer enzyme over-activation is a recurrent theme. Nature

Investigational preclinical dosing snapshots

• NR: typical rodent ranges 200–400 mg·kg⁻¹·day⁻¹, yielding increased tissue NAD⁺ and mitochondrial markers (model-dependent; not directly human-scalable).

• NMN: rodent studies 100–500 mg·kg⁻¹·day⁻¹; tissue uptake routes and extracellular conversion (incl. CD38) influence efficacy.

• IV NAD⁺ (animal): bolus/infusion regimens used to chart metabolite kinetics; standardized PK not uniform across species. (Collectively, these preclinical amounts demonstrate feasibility rather than translatable posology.)

Comparative efficacy/safety (preclinical)

• Efficacy: robust biochemical restoration of NAD⁺ and downstream sirtuin/PARP-related readouts across models.

• Safety: generally favorable in the short term; high-dose rodent NR shows organ weight and lipid changes at very large doses; tox thresholds are far higher than human trial doses. PMC

Key limitations

• Species & tissue differences, pool specificity, and consumer expression patterns mean that raising total NAD⁺does not guarantee uniform functional rescue.

Human Clinical Evidence

Placebo-controlled trials of NAD⁺ precursors

Nicotinamide riboside (NR)

• Conze et al. randomized 140 middle-aged adults to 100, 300, or 1000 mg·day⁻¹ NR vs placebo for 8 weeks. Whole-blood NAD⁺ rose dose-dependently; plasma NAM/MeNAM increased, and urinary MeNAM/Me2PYincreased—consistent with enhanced turnover. Safety was the primary objective; adverse events were mild, with biochemical efficacy confirmed. Investigational doses used in study: 100–1000 mg·day⁻¹ NR. PMC

• NR-SAFE (high-dose safety): randomized, double-blind 3,000 mg·day⁻¹ NR explored safety/tolerability endpoints, building on preclinical toxicology. Investigational dose used in study: 3 g·day⁻¹ NR. PMC+1

• Brain NAD: a phase-I randomized trial showed NR increased brain NAD (¹H-MRS proxy) and altered cerebral glucose metabolism (FDG-PET), demonstrating central pharmacodynamics in humans. Investigational dose per protocol (see paper). Cell

Nicotinamide mononucleotide (NMN)

• Yi et al. multicenter RCT (n=80) tested 300, 600, 900 mg·day⁻¹ NMN vs placebo for 60 days in healthy middle-aged adults. Blood NAD rose dose-dependently; secondary cardiometabolic measures showed variable trends. Safety/tolerability were acceptable. Investigational doses used in study: 300–900 mg·day⁻¹ NMN. PubMed

Direct intravenous NAD⁺

• Grant et al. reported plasma/urine metabolite dynamics during and after 6-hour IV NAD⁺ infusion (3 μmol·min⁻¹) in healthy persons, documenting time-course increases in NAD⁺ and breakdown products; this pilot characterized biochemical behavior, not clinical efficacy. Investigational infusion used in study: 3 μmol·min⁻¹ for 6 h. PMC

• A 2021 orthopedic pilot sought IV NAD⁺ PK characterization (methods report), but comprehensive human PKremains Not established. ScienceDirect

Additional/ongoing clinical efforts

• Multiple ClinicalTrials.gov entries examine NR or NMN in distinct populations (e.g., metabolic syndrome, neurodegeneration) with biochemical endpoints and exploratory outcomes; examples include NCT05175768(NMN adjunct to standard care) and NCT06005350 (NR effects on extracellular NAD). ClinicalTrials.gov+1

Safety signals/adverse events (human trials)

• Across NR/NMN RCTs up to 8–12 weeks, NAD⁺ rises were accompanied by good short-term tolerability; common AEs were gastrointestinal or mild. High-dose concerns are drawn primarily from preclinical studies and isolated signals (e.g., triglyceride changes at very high NR doses); long-term effects require further study. PMC

• IV NAD⁺ infusions are promoted commercially despite limited clinical evidence and variable quality control; public-health reporting highlights regulatory concerns and lack of proven benefit for claims such as addiction treatment. The Guardian

Comparative Context

Related “peptides” (nomenclature caveat)

NAD⁺ is not a peptide; in research catalogs it is grouped with metabolic cofactors rather than peptides. Functionally comparable research categories include AMPK activators, PARP/CD38 modulators, and NAD⁺ precursors(NR/NMN/NA/NAM).

Advantages (research perspective)

• Central node for redox and signaling (sirtuins/PARPs/CD38).

• Well-defined biochemistry, with clear biomarker panels (whole-blood NAD⁺, NAM/MeNAM, Me2PY) to confirm engagement. PMC

• Multiple orthogonal levers to modulate (precursors vs consumer inhibition), enabling mechanistic dissection.

Disadvantages / constraints

• Compartmentalization complicates interpretation; boosting whole-blood NAD⁺ may not normalize nuclear or mitochondrial pools that drive specific phenotypes. PMC

• Consumer up-regulation (e.g., CD38 with aging/inflammation) can offset precursor strategies. PMC

• Clinical endpoint heterogeneity: many trials remain short, underpowered, and biomarker-focused.

Research category placement

NAD⁺ research spans biochemistry, metabolism, genome maintenance, immunology, and neurobiology, with translational work primarily testing precursors and consumer inhibitors.

Pharmacology & Biology Highlights

• NAD⁺ ↔ sirtuins/energy homeostasis: NAD⁺ activates sirtuins, coupling nutrient status to mitochondrial biogenesis and stress resistance. PubMed

• DNA repair coupling: PARP1/2–NAD⁺ axis orchestrates single-strand break repair; acute activation depletesNAD⁺ and shifts metabolism to OXPHOS. ScienceDirect+1

• CD38-mediated NADase: CD38 is a major NAD-consumer in aging and neuroinflammation, producing cADPR/ADPR/NAADP and shaping Ca²⁺ signals; targeting CD38 restores NAD⁺ in preclinical models. PMC+1

• Human biomarker proof: NR/NMN RCTs document dose-dependent blood NAD⁺ increases and characteristic NAM/MeNAM/Me2PY shifts. PMC+1

• Brain pharmacodynamics: NR increased brain NAD and altered cerebral metabolism (FDG-PET) in a phase-I study—evidence of central engagement. Cell

Conflicting evidence/uncertainties

• Clinical efficacy beyond biochemical change remains mixed; endpoint selection and duration likely contribute. PMC

• Direct IV NAD⁺: biochemical elevations observed, but controlled clinical benefits are Not established; regulatory scrutiny of marketing claims persists. PMC+1

Potential Research Applications (no clinical claims; research-use framing)

1. Compartment-resolved NAD⁺ biology
   Combine genetically encoded NAD(H)/NADP(H) sensors with perturbations (PARP activation, CD38 over-expression, NAMPT inhibition) to map pool dynamics and consumer priority under defined stressors. PMC

2. Network interventions
   Test precursor + consumer inhibition (e.g., NR/NMN with PARP or CD38 inhibitors) to define synergy and thresholds for restoring mitochondrial/nuclear pools and function in cell/animal models. PMC

3. Brain NAD mapping
   Pair ¹H-MRS/FDG-PET with NR/NMN or IV NAD⁺ (preclinical) to quantify central NAD responses, metabolic coupling, and behavioral correlates in defined paradigms. Cell

4. Aging/inflammation axis
   Interrogate CD38 up-regulation across immune and stromal compartments, testing whether NAD⁺ restorationnormalizes Ca²⁺ second-messenger signaling and inflammaging readouts. PNAS

5. DNA damage & repair
   Use laser micro-irradiation and FLIM biosensors to visualize PARP-driven NAD⁺ consumption and its reversal by precursors/inhibitors, linking NAD⁺ restoration to repair kinetics and cell survival. PubMed

6. Human translational design
   In early-phase human studies, combine whole-blood NAD⁺, metabolomics (NAM/MeNAM/Me2PY), and tissue-specific imaging/surrogates (e.g., muscle mitochondrial function) with rigorous safety surveillance to build exposure-response models. PMC

Safety & Toxicology

Preclinical data

Rodent studies generally show good acute tolerability for NR/NMN in the 100–500 mg·kg⁻¹·day⁻¹ range; very high NRdosing in rats produced lipid changes and organ weight alterations. PARP hyperactivation can be deleterious via NAD⁺/ATP collapse (context-specific). PMC

Human trial observations

Short-term NR/NMN RCTs (up to 8–12 weeks) report mild AEs (GI complaints, flushing-like symptoms with NA, but NR/NMN avoid NA-flush); high-dose NR (3 g·day⁻¹) is under safety evaluation; long-term outcomes are Unknown. PMC

Public-health and regulatory notes

Media and regulator investigations highlight unproven claims tied to IV NAD⁺ infusions (e.g., addiction treatment) with variable quality control and unknown long-term safety; agencies caution that medicinal claims without authorization are regulatory violations. The Guardian

Data gaps

• Comprehensive human PK for IV NAD⁺, tissue distribution of precursors, BBB penetration, pool-specificrestoration, and long-term safety in diverse populations remain Not established.

Limitations & Controversies

• Biomarker vs outcome gap: many studies confirm NAD⁺ increases but do not show hard clinical benefits within study windows; duration, dose, and endpoint selection likely critical. PMC

• Pool specificity: raising systemic NAD⁺ equivalents may not normalize nuclear/mitochondrial pools that drive PARP/sirtuin biology in a given disease. PMC

• Consumer dominance: CD38/PARP up-regulation can counteract precursor strategies unless concomitantly addressed. PMC

• Hype vs evidence (IV NAD⁺): direct IV NAD⁺ shows biochemical changes but lacks controlled clinical efficacy; regulation of marketing claims is ongoing. PMC+1

Future Directions

1. Pool-targeted pharmacology: Develop organelle-directed precursors or NMNAT isoform modulators to selectively restore nuclear or mitochondrial NAD⁺ pools. PMC

2. Combination strategies: Pair precursor loading with CD38/PARP modulation to overcome consumer-drivendepletion; model synergy and safety in phased designs. PMC

3. Standardized human PK/PD: Establish IV NAD⁺ and oral precursor PK with harmonized assays (whole-blood, PBMC, tissue imaging) and time-courses of metabolite appearance/disappearance. PMC

4. Indication-specific RCTs: For candidate conditions (e.g., PARP-overactivation states, inflammagingphenotypes), run adequately powered trials with pre-specified mechanistic endpoints and longer follow-up.

5. Safety registries: Longitudinal monitoring of high-dose or long-term users of NR/NMN within structured research frameworks to clarify risk–benefit.

References

1. Cantó C, Menzies KJ, Auwerx J. NAD⁺ metabolism and the control of energy homeostasis. Cell Metab. 2015. PMC: PMC4487780. PMC

2. Castro-Portuguez R, Sutphin GL. Kynurenine pathway, NAD⁺ synthesis, and mitochondrial function. FEBS J.2020. PMC: PMC7053056. PMC

3. Damgaard MV, et al. What is really known about the effects of nicotinamide riboside in humans? Nutrients. 2023. PMC: PMC10361580. (NR dose-dependent blood NAD⁺ rise; metabolite shifts.) PMC

4. Yi L, et al. Efficacy and safety of β-nicotinamide mononucleotide supplementation in healthy middle-aged adults.Front Aging Neurosci. 2023. PMID: 36482258. (Dose-dependent blood NAD increase with 300–900 mg·day⁻¹ NMN.) PubMed

5. Grant R, et al. Human plasma/urine changes during and after a 6-h IV NAD⁺ infusion (3 μmol·min⁻¹). Nutrients.2019. PMC: PMC6751327. PMC

6. Imai S, Guarente L. NAD⁺ and sirtuins in aging and disease. Trends Cell Biol. 2014. PMC: PMC4112140. PMC

7. Yusri K, et al. The role of NAD⁺ metabolism and its modulation in health and disease. NPJ Aging. 2025. (Compartment distribution; consumer overview.) PMC

8. Berven H, et al. NR-SAFE: randomized, double-blind safety trial of high-dose NR. Nutrients. 2023. PMC: PMC10684646. (High-dose NR safety context.) PMC

9. Cantó C, Auwerx J. NAD⁺ Metabolism and the Control of Energy Homeostasis. Cell Metab. 2015. PubMed: 26118927. PubMed

10. Zhang W, et al. NAMPT in NAD⁺ homeostasis. Cell Death Discov. 2025. (Salvage pathway predominance; NAMPT rate-limiting.) Nature

11. Brakedal B, et al. A randomized phase-I trial of NR shows increases in brain NAD and altered cerebral metabolism. Cell Metab. 2022. Cell

12. NCT05175768 (NMN adjunct to SOC). ClinicalTrials.gov. ClinicalTrials.gov

13. Gibson SB, et al. Intravenous administration of NAD⁺—pilot PK study. Am J Med Sci. 2021. (Abstract) ScienceDirect

14. Imai S, Yoshino J. It takes two to tango: NAD⁺ and sirtuins in aging/longevity. NPJ Aging Mech Dis. 2016. Nature

15. Cambronne XA, Kraus WL. Compartmentalization of NAD⁺ synthesis and functions. Genes Dev. 2020. PMC: PMC7502477. PMC

16. NCT05344404 (NR-SAFE; 3 g·day⁻¹ NR). ClinicalTrials.gov. ClinicalTrials.gov

17. Xie N, et al. NAD⁺ metabolism: pathophysiology & therapeutic opportunities. Signal Transduct Target Ther.2020. Nature

18. Castro-Portuguez R, Sutphin GL. Targeting tryptophan metabolism to promote longevity. Biochem Pharmacol.2020. ScienceDirect

19. NCT06005350 (NR effects on extracellular NAD). ClinicalTrials.gov. ClinicalTrials.gov

20. Song Q, et al. Safety and anti-aging effects of NAD⁺ precursors and related compounds. J Am Acad Dermatol.2023. ScienceDirect

21. medRxiv (2024): Randomized pilot comparing oral vs IV NR on NAD⁺. (Preprint; suggests robust DBS NAD⁺ increases with IV NR.) MedRxiv

22. Covarrubias AJ, et al. NAD⁺ in cellular processes during aging. Nat Rev Mol Cell Biol. 2020. PMC: PMC7963035. PMC

23. Nasuhidehnavi A, et al. Mitochondria–NAD⁺ crosstalk in cardiometabolic disease. Prog Lipid Res. 2025. ScienceDirect

24. The Guardian (Feb 2025). Regulatory scrutiny of UK clinics selling NAD⁺ infusions for addiction. (Public-health/regulatory context) The Guardian

25. Hogan KA, et al. The multi-faceted ecto-enzyme CD38 in immunity & NAD⁺ metabolism. Front Immunol. 2019. Frontiers

26. Chini EN, et al. Pharmacology of CD38/NADase. Prog Biophys Mol Biol. 2018. PMC: PMC5885288. PMC

27. Murata MM, et al. PARP-dependent NAD⁺ depletion after DNA damage. Mol Biol Cell. 2019. Molecular Biology of the Cell

28. Cohen MS, Chang P. NAD⁺ consumption by PARPs during DDR. Genes Dev. 2020. (PDF) Genes & Development

29. Meyer T, et al. CD38 is main NADase in CNS neuroinflammation. PNAS. 2022. PNAS

Investigational amounts referenced above:
• NR 100–1000 mg·day⁻¹ and 3 g·day⁻¹ (NR-SAFE) — investigational doses used in cited trials. PMC+1
• NMN 300–900 mg·day⁻¹ — investigational doses used in Yi et al. RCT. PubMed
• IV NAD⁺ 3 μmol·min⁻¹ for 6 h — investigational infusion used in Grant et al. PMC

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.