Advanced NAD⁺ Therapies & Precursors: Beyond NR & NMN

July 24, 2025

Nicotinamide adenine dinucleotide (NAD⁺) is a pivotal coenzyme in cellular metabolism, acting as an electron carrier in redox reactions, a substrate for sirtuins, and a regulator of DNA repair enzymes (PARPs). As NAD⁺ levels decline with age or chronic metabolic stress, mitochondrial efficiency, genomic stability, and overall cellular resilience suffer. While nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have garnered attention as NAD⁺ precursors, emerging strategies aim to optimize NAD⁺ more effectively and sustainably. In this article, we’ll explore alternative precursors (e.g., nicotinic acid riboside, dihydronicotinamide riboside), NADase inhibitors, methylation considerations, and combination protocols that enhance NAD⁺ bioavailability without directly administering NAD⁺, all while prioritizing your safety and providing a comprehensive roadmap for cellular rejuvenation.

Why NAD⁺ Matters: A Cellular Linchpin

NAD⁺ plays three key roles in cellular homeostasis:

  1. Redox Reactions & Energy Production
    NAD⁺ acts as a key electron carrier in cellular metabolism. During glycolysis and the tricarboxylic acid (TCA) cycle (aka Kreb Cycle), NAD⁺ accepts electrons and is reduced to NADH. NADH then donates these electrons to Complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial electron transport chain (ETC). This electron transfer initiates a series of reactions that ultimately drive ATP synthesis through oxidative phosphorylation. *During your next zoom with Dr. Seeds mention “ubiquinone oxidoreductase to really impress him!*
  2. Sirtuin Activation
    Sirtuins (SIRT1-7) are NAD⁺-dependent deacetylases that regulate gene expression, mitochondrial biogenesis, stress responses and aging. Elevating NAD⁺ levels enhances SIRT1 activity in the nucleus. SIRT1 deacetylates transcriptional regulators (p53, NF-κB, and FOXO family proteins) which positively impacts DNA repair and immune/inflammatory responses. SIRT1 also deacetylates and activates PGC-1α, which is master regulator of mitochondrial biogenesis and energy metabolism. SIRT3 deacetylates and activates multiple enzymes involved in the electron transport chain (ETC) and oxidative phosphorylation leading to enhanced mitochondrial efficiency and reduced Reactive Oxygen Species (ROS) production.
  3. PARP-Mediated DNA Repair
    Poly (ADP-ribose) polymerases (PARPs) use NAD⁺ to add ADP-ribose units to damaged DNA segments, enabling repair. PARylation recruits DNA repair proteins and remodels chromatin structure to facilitate DNA repair mechanisms such as base excision repair. Chronic DNA damage (e.g., from ROS or genotoxic stress) hyperactivates PARP, depleting intracellular NAD⁺ levels, leading to energy failure and, if severe enough, cell death. Sustained NAD⁺ availability is thus essential to maintain genomic integrity and efficient PARP-mediated DNA repair.

With advancing age, NAD⁺ pools shrink due to decreased biosynthesis and increased consumption by PARPs and NADases (e.g., CD38). Restoring NAD⁺ is critical for mitochondrial function, metabolic regulation, and cellular longevity. However, the solution isn’t as simple as just supplying NAD⁺ directly; effective restoration requires addressing the balance between NAD⁺ production, degradation, and recycling to ensure sustained and safe cellular benefits.

Beyond NR & NMN: Alternative NAD⁺ Precursors

Nicotinic Acid Riboside (NAR)

Biochemistry & Mechanism
Nicotinic acid riboside (NAR) is an NAD⁺ precursor that, like nicotinamide riboside (NR), feeds into NAD⁺ salvage pathways via nicotinamide riboside kinase (NRK). However, unlike NR, which yields nicotinamide (NAM) after NAD⁺ hydrolysis, NAR releases nicotinic acid (NA), thereby engaging the Preiss–Handler pathway for NAD⁺ biosynthesis. The key conversion steps are:

  • NAR → nicotinic acid mononucleotide (NaMN) via NRK
  • NaMN → nicotinic acid adenine dinucleotide (NaAD) via NMN adenylyltransferase (NMNAT)
  • NaAD → NAD⁺ via NAD synthase, incorporating an amide donor (glutamine)

Benefits & Considerations

  • Reduced Methyl Drain: Because NAR produces NA instead of NAM, it bypasses nicotinamide methylation, a process that consumes methyl donors such as S-adenosylmethionine (SAMe). This may help preserve overall methyl pool availability in the body.
  • Flushing Risk: High doses of nicotinic acid (niacin) cause prostaglandin-mediated vasodilation (“niacin flush”). NAR appears to cause less flushing at equivalent molar doses, likely due to differences in pharmacokinetics and tissue distribution.
  • Efficacy: Preclinical rodent studies demonstrate that NAR supplementation (around 300 mg/kg/day) increases hepatic NAD⁺ levels by up to 60% without significantly altering lipid profiles. Human clinical trials are limited but ongoing, and initial reports suggest bioavailability comparable to NMN.

Dihydronicotinamide Riboside (NRH)

Biochemistry & Mechanism
NRH is the reduced form of nicotinamide riboside (NR) and is transported into cells via equilibrative nucleoside transporters (ENTs). Once inside the cytosol, NRH is phosphorylated by adenosine kinase (ADK) into reduced nicotinamide mononucleotide (NMNH), bypassing the NRK-dependent step used by NR. The metabolic pathway proceeds as follows:

  • NRH → NMNH (via adenosine kinase)
  • NMNH → NADH (via NMN adenylyltransferase, NMNAT)
  • NADH → NAD⁺ (via mitochondrial Complex I or other oxidoreductases)

Benefits & Considerations

  • Rapid NAD⁺ Boost: Preclinical studies show that NRH increases NAD⁺ levels faster and more robustly than NR or NMN, often doubling intracellular NAD⁺ concentrations within an hour after administration.
  • Safety Profile: Human pharmacokinetic data are limited, but rodent studies suggest a favorable safety profile at doses up to 500 mg/kg, with no significant toxicity observed. Long-term human safety remains under study.
  • ROS Generation: Because NRH elevates NADH pools rapidly, it can transiently increase reactive oxygen species (ROS), particularly if mitochondrial oxidative phosphorylation is not well matched. Supporting antioxidant systems (e.g. N-acetylcysteine) may help balance redox homeostasis.

Nicotinamide Mononucleotide Conjugates & Prodrugs

Overview
To improve bioavailability and targeted tissue delivery, researchers have developed various prodrugs and conjugates of nicotinamide mononucleotide (NMN), including:

  • Esterified NMN (e.g., NMN-HCl vs. NMN-OTf): Changing the salt form can improve chemical stability and cellular uptake, potentially enhancing bioavailability.
  • Lipophilic NMN esters (e.g., triacetylated NMN): These modifications increase NMN’s lipid solubility, facilitating better membrane permeability. Once inside cells, nonspecific intracellular esterases cleave the ester groups, releasing bioactive NMN.
  • Biotin-NMN Conjugates: Leveraging biotin’s affinity for mitochondrial biotin receptors, these conjugates are designed to target mitochondria selectively, aiming to boost mitochondrial NAD⁺ pools more effectively than unmodified NMN.

Benefits & Considerations

  • Enhanced Tissue Penetration: Lipophilic and conjugated forms of NMN may achieve higher NAD⁺ concentrations in tissues with selective barriers, such as neuronal and muscle tissues, supporting improved brain function, muscle endurance, and mitochondrial health.
  • Cost & Availability: Many of these NMN prodrugs and conjugates are in early research or development stages and are often costly. Clinical-grade, well-validated formulations are currently limited and not widely available.

Inhibiting NADases: Preserving Endogenous NAD⁺

CD38 Inhibitors

Role of CD38
CD38 is a membrane-bound NADase enzyme that hydrolyzes NAD⁺ into nicotinamide (NAM) and ADP-ribose, producing cyclic ADP-ribose (cADPR) as a by-product. CD38 expression increases with age, chronic inflammation, and in certain senescent cells, accelerating NAD⁺ depletion and contributing to metabolic decline.

Promising Inhibitors

  • Apigenin & Quercetin: These flavonoids inhibit CD38 activity in vitro at micromolar concentrations. In aged mice, quercetin administered at 100 mg/kg/day reduced CD38 expression in adipose tissue, resulting in elevated NAD⁺ levels and improved metabolic function.
  • 78c (A Small-Molecule CD38 Inhibitor):Preclinical studies show that 78c restored tissue NAD⁺ levels by approximately 50% in aged mice, enhanced mitochondrial function, and lowered inflammatory cytokine levels. This compound remains investigational.
  • Nicotinamide (NAM) as Feedback Inhibitor: At high concentrations, NAM can inhibit PARPs and sirtuins. It also competes for CD38 binding, indirectly preserving NAD⁺. However, excessive dosing (>500 mg/day) may deplete methyl donors, posing a risk for methylation imbalance.

Benefits & Considerations

  • Synergy with Precursors: Combining CD38 inhibitors with NAD⁺ precursors such as NR or NMN can produce a more sustained and robust increase in NAD⁺ levels compared to precursors alone.
  • Tissue Specificity: CD38 is highly expressed on immune cells. Inhibiting CD38 may modulate immune responses, so monitoring for potential immunosuppressive effects is important, especially in vulnerable or immunocompromised patients.
  • Dosing & Safety: Flavonoid-based inhibitors, like quercetin at doses of 500–1,000 mg/day, are generally considered safe. Synthetic inhibitors like 78c are still under research and not yet approved for clinical use.

PARP Inhibitors

Role of PARPs
PARPs (especially PARP1) are enzymes that play a critical role in detecting and repairing DNA damage. PARPs use NAD⁺ as a substrate to catalyze ADP-ribosylation of target proteins involved in the DNA repair process. When DNA damage is extensive or persistent, such as during chronic oxidative or genotoxic stress, PARP activation becomes excessive, rapidly depleting cellular NAD⁺ pools. This NAD⁺ depletion can impair energy production, ultimately leading to cellular energy crisis and cell death.

Clinically Used Agents

  • Olaparib, Rucaparib, Niraparib: FDA-approved PARP inhibitors for BRCA-mutated cancers. These agents work by blocking PARP activity, thereby preventing tumor cells, especially those with deficient DNA repair, from surviving DNA damage.
  • Use in Non-Oncologic Settings: Low-dose PARP inhibitors (e.g., 10–50 mg olaparib) theoretically reduce NAD⁺ consumption without fully blocking DNA repair. Small pilot studies with low-dose olaparib (10–50 mg) have shown that partial inhibition of PARP can increase NAD⁺ concentrations in peripheral blood cells of elderly volunteers, without fully suppressing DNA repair mechanisms.

Benefits & Considerations

  • Careful Dosing is Critical: Complete PARP blockade in healthy tissue can severely impair DNA repair, raising the risk for genomic instability and related complications. When PARP inhibitors are considered outside of oncology, dosing must be carefully titrated to preserve essential DNA repair while reducing excess NAD⁺ loss.
  • Potential Side Effects: Even at low doses, PARP inhibitors can cause side effects such as anemia, fatigue, and gastrointestinal upset. Therefore, all regimens require close clinical supervision and monitoring.
  • Patient Selection: Candidates for this approach are typically individuals with documented high PARP activity, such as those with chronic inflammation, high oxidative stress, or age-associated increases in poly-ADP-ribose (PAR) levels in immune cells.

Managing Methylation & Thus NAD⁺ Precursor Efficacy

Methyl Donor Depletion Risk

High-dose supplementation with NAD⁺ precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) can elevate tissue levels of nicotinamide (NAM) as NAD⁺ is consumed by processes like sirtuin and PARP activity. Excess NAM is metabolized by nicotinamide N-methyltransferase (NNMT), which uses S-adenosylmethionine (SAMe) as a methyl donor, producing 1-methylnicotinamide (MeNAM) and S-adenosylhomocysteine. With ongoing high-dose precursor use, this pathway can draw down stores of SAMe, folate, and vitamin B₁₂, leading to impaired methylation-dependent functions such as: DNA methylation, neurotransmitter synthesis & phosphatidylcholine production. This is what leads to “methyl donor depletion”.

Strategies to Preserve Methyl Balance

  1. Supplement Methyl Donors Concurrently
    • SAMe (S-adenosylmethionine): 200–400mg daily can directly support transmethylation processes and bolster the body’s pool of active methyl donors.
    • Trimethylglycine (Betaine): 2–5g daily acts as a methyl donor in the remethylation of homocysteine, thereby reducing reliance on folate and B₁₂ for this process.
    • Vitamin B₁₂ (Methylcobalamin) & Folate (5-MTHF): Supplementing with 1,000mcg B₁₂ and 800–1,000mcg 5-MTHF daily ensures optimal functioning of the methionine cycle, supporting methylation and preventing homocysteine accumulation.
  2. Pulse Dosing of NAD⁺ Precursors
    • Instead of daily high-dose administration, consider cyclic supplementation such as NMN 250mg twice daily for two weeks followed by a one-week break. This approach can minimize continuous methyl donor drain and allow recovery of methylation capacity.
    • Monitor serum homocysteine: levels should ideally remain below 10µmol/L. If levels rise, adjust methyl donor supplementation accordingly.
  3. Use of NAMPT Activation
    • Nicotinamide phosphoribosyltransferase (NAMPT) converts NAM to NMN, preserving NAD⁺ salvage without depleting methyl groups. Compounds like P7C3-A20 (a NAMPT activator) can promote endogenous NAD⁺ salvage, reducing reliance on exogenous precursors.

Dr. Seeds’ Unique Take on Supporting Methylation

Methylation is one of Dr. Seeds’ favorite and most foundational topics at Redox Medical Group. With every patient, he asks, “How are you methylating?” because, no matter the health concern, methylation plays a vital role. As he explains to patients, methylation essentially determines how efficiently your body transports and uses energy.

Dr. Seeds rarely reaches for typical methylation precursors as a first line. Instead, his favorite supplement to support methylation is creatine, 5 grams per day. While many associate creatine primarily with muscle health, Dr. Seeds values it most for its powerful effects on the brain and methylation pathways. Supplementing creatine for methylation helps optimize energy metabolism at the cellular level, giving patients a foundational boost for overall vitality and cognitive function.

Combination Protocols: Optimizing NAD⁺ Restoration

Protocol A: NR + CD38 Inhibition + Methyl Support

  • Weeks 1–4:
    • NR 250 mg orally, twice daily (total 500 mg/day).
    • Quercetin 500 mg, three times daily (CD38 inhibitor).
    • SAMe 200 mg, once daily; Betaine 2 g, once daily; Methylcobalamin 1,000 mcg, once daily; 5-MTHF 800 mcg, once daily.
  • Weeks 5–8:
    • Continue NR 250 mg twice daily.
    • Reduce quercetin to 500 mg daily.
    • Maintain methyl support.
  • Monitoring:
    • Monthly serum NAD⁺ assay (e.g., via mass spectrometry).
    • Serum homocysteine at baseline, Week 4, and Week 8, adjust methyl donors as needed.
    • Functional outcomes: mitochondrial function via VO₂ max or OXPHOS markers in muscle biopsy (optional).

Protocol B: NMN + PARP Modulation + Redox Cofactors

  • Weeks 1–2:
    • NMN 300 mg orally, twice daily (total 600 mg/day).
    • Olaparib 25 mg, once daily (subclinical PARP inhibition).
    • N-acetylcysteine (NAC) 600 mg, twice daily; Alpha-lipoic acid 300 mg, twice daily.
  • Weeks 3–4:
    • NMN 300 mg once daily.
    • Olaparib paused (to allow DNA repair capacity).
    • Continue NAC and ALA.
  • Weeks 5–6:
    • NMN 300 mg twice daily.
    • Resume olaparib 25 mg daily.
    • Add PQQ 20 mg daily to promote PGC-1α–mediated mitochondrial biogenesis.
  • Monitoring:
    • CBC and liver function tests at baseline and after each two-week cycle to detect cytopenias or hepatic enzyme elevations.
    • NAD⁺ levels monthly.
    • Oxidative stress markers (e.g., GSH:GSSG ratio) to evaluate redox balance.

At Redox Medical Group, we don’t rely on standard protocols or routinely use NAD⁺ precursors like NMN or NR. Instead, we focus on identifying and addressing the underlying causes of NAD⁺ depletion through targeted peptide therapies and personalized care. While we may occasionally use supportive nutrients like NAC or alpha-lipoic acid based on individual needs, supplementation is never one-size-fits-all. We also don’t measure NAD⁺ levels routinely, as these tests often lack clinical relevance. Our approach centers on restoring true cellular function by treating the root cause, not just supplementing downstream markers.

Practical Takeaways & Cautions

  1. Personalize Based on Baseline NAD⁺ & Methyl Markers
    • Before initiating NAD⁺ precursors, measure baseline plasma or whole-blood NAD⁺ and homocysteine levels. Tailor dosing to individual needs, higher baseline NAD⁺ may require lower precursor doses to avoid oversaturation.
  2. Integrate With Lifestyle Interventions
  3. Monitor Methyl Balance Closely
    • High-dose NR or NMN can rapidly deplete methyl donors. Maintain robust supplementation of SAMe, betaine, B₁₂, and 5-MTHF, especially during intensive NAD⁺ restoration phases.
  4. Beware of Drug Interactions & Contraindications
    • CD38 inhibitors (quercetin, apigenin) may alter drug metabolism (CYP450).
    • PARP inhibitors can cause cytopenias; avoid or dose-adjust in patients with baseline anemia or thrombocytopenia.
    • Monitor kidney and liver function when using high-dose antioxidants (NAC, ALA).
  5. Long-Term Maintenance vs. Pulsing
    • For general anti-aging, consider maintenance dosing (NR/NMN 250 mg daily) combined with lifestyle.
    • For targeted cellular repair (e.g., post–chemotherapy, recovery from severe COVID-19), use pulsed high-dose protocols with adjunctive CD38/PARP modulation.

Conclusion & Call to Action

NAD⁺ (nicotinamide adenine dinucleotide) is essential for cellular energy, DNA repair, and longevity but its recent popularity has spurred a wave of trends that risk overshadowing both scientific facts and patient safety. NAD⁺ is fundamental for healthy metabolism, brain function, and cellular resilience. Supporting NAD⁺ homeostasis is crucial for overall vitality and aging well.

IV NAD⁺ infusions have become popular but lack strong clinical evidence and carry risks like severe nausea, chest tightness, and irregular heart rhythms. When given intravenously or intramuscularly, NAD⁺ is quickly used by CD38-expressing “bad” cells, which can fuel unhealthy processes in the body. Symptoms like nausea and chest tightness often result from this nonspecific fueling of harmful cells.Focusing on high-dose NAD⁺ (or infusions) often ignores the actual drivers of NAD⁺ depletion, such as chronic stress, metabolic dysfunction, or underlying medical issues. Addressing these upstream causes is safer and more effective in restoring cellular health.

Every plan at Redox Medical Group is personalized, intentional, and evidence informed, with a strong focus on addressing root causes to restore true wellness. We believe lasting results come from understanding why your NAD⁺ levels are low and supporting your entire system, rather than relying on generic supplement protocols or lab tests that may not capture your individual needs. Our goal is to enhance your body’s own NAD⁺ production, allowing your cells to regulate their needs intelligently. This way, healthy cells receive the energy they require, while harmful cells are not inadvertently fueled.

Ready to elevate your cellular energy and resilience with optimized NAD⁺? Book a consultation with Dr. Seeds today. With an approach grounded in evidence and personalized care, you’ll learn how to safely and effectively support your NAD⁺ levels in a way that meets your unique cellular needs, not just passing health trends. Take the next step toward lasting vitality and well-being, guided by medical expertise you can trust.