NAD+ IV Therapy vs. NR IV Therapy: What Clinical Research Reveals About Safety, Efficacy, and Why It Matters

Key Takeaways

• New peer-reviewed pilot research puts NAD+ IV therapy under the microscope: A newly published study is the first to compare NR IV and NAD+ IV across multiple days in a real-world clinical setting at Restore Hyper Wellness.
• NR IV was far better tolerated than IV NAD+: In the Reyna et al. study conducted by Restore Hyper Wellness, every single participant who received NAD+ IV reported moderate to severe symptoms, including cramping, nausea, vomiting, elevated heart rate, and chest pressure. NR IV participants reported only mild, transient effects, allowing infusions to be completed 60% faster.
• NR IV was also associated with improved blood glucose control: At 30 days post-infusion, NR IV significantly reduced HbA1c compared to baseline and the NAD+ IV group, while NAD+ IV was associated with a reduction in HDL (“good”) cholesterol.
• Findings replicate earlier clinical observations: These results build on the Hawkins et al. pilot study—the first clinical comparison of NR IV and NAD+ IV—which also found reduced tolerability, longer infusion times, and signs of inflammatory potential with NAD+ IV. 

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule found in every living cell. It is involved in over 500 enzymatic reactions throughout the body, playing a central role in energy metabolism, DNA repair, and cellular resilience.¹ Simply put, without adequate NAD+, cells cannot function optimally. 

Yet, NAD+ levels naturally decline with age² and exposure to various metabolic stressors, such as alcohol consumption,³ a sedentary lifestyle,⁴ and viral infections.⁵ As levels fall, so can the cells’ capacity to repair damage and meet the energy demands required to maintain normal biological function.

In response, interest in restoring NAD+ levels has grown rapidly. While oral supplements have been the most widely used approach, intravenous delivery has recently gained popularity as a novel method. However, simply administering NAD+ itself is far less effective than most assume, and newly published pilot clinical research is making that increasingly clear.

New Pilot Clinical Research: NR IV Outperforms NAD+ IV on Safety, Speed, and Metabolic Outcomes

A newly published pilot peer-reviewed study by Reyna et al. is the first to directly compare intravenously administered nicotinamide riboside (NR)–a vitamin B3 derivative and NAD+ precursor, commercially available as Niagen® IV–with intravenous NAD+ across a multi-day protocol with a 30-day follow-up.⁶* 

The study included 14 healthy men and women treated at Restore Hyper Wellness in Austin, Texas, who received 500 mg infusions on four consecutive days. Both the NR and NAD+ powder were lyophilized (freeze-dried) and reconstituted in 500 mL of normal saline prior to administration.

Key Findings From the Study:

• Tolerability: Participants who received NR IV experienced only mild adverse effects, including temporary tingling of the tongue, jaw, or arm, and cramping that was later attributed to menstruation. In contrast, every participant who received NAD+ IV reported moderate to severe symptoms during infusion. These included gastrointestinal distress such as abdominal cramping, vomiting, and diarrhea, as well as elevated heart rate, throat pain, nausea, and chest pressure.
• Infusion Time: Because of the symptoms experienced during NAD+ IV, infusion rates had to be slowed to manage discomfort. As a result, the average infusion time over the four-day protocol was substantially shorter for NR IV–37 minutes compared with 97 minutes for NAD+ IV, a difference of roughly 60%.
• Exploratory Metabolic Outcomes: At the 30-day follow-up, the NR IV group demonstrated a statistically significant reduction in HbA1c, a measure of average blood sugar over the past 2–3 months, compared with both baseline and the NAD+ IV group, suggesting potential improvement in blood sugar regulation. These findings should be interpreted cautiously, given the study’s retrospective design, small sample size, and lack of matched controls or standardized lifestyle measures. Meanwhile, the NAD+ IV group showed a significant reduction in high-density lipoprotein (HDL), often referred to as “good” cholesterol because of its role in cardiovascular protection, as well as a decrease in alkaline phosphatase (ALP), an enzyme commonly used as a marker of liver and bone health; however, both markers remained within their respective reference ranges. Because these analyses were exploratory and the study was not powered to detect metabolic outcomes, the results should be considered preliminary. 

It is important to note that this was a retrospective analysis rather than a prospective clinical trial, meaning the researchers evaluated existing clinical data rather than conducting a controlled experiment. Accordingly, the findings are intended to inform future research rather than provide definitive conclusions.

While the results are encouraging, longer-term studies with larger populations and varying dosage protocols will be needed to further evaluate and confirm these observations.

Building on the Evidence: What Previous Research Established About NAD+ IV

The findings from Reyna et al. are consistent with an earlier pilot study by Hawkins et al., published in 2024, which was the first clinical study to directly compare NR IV and NAD+ IV in a controlled, head-to-head setting.⁷

That study–a randomized, double-blind, placebo-controlled pilot in healthy adults–analyzed data from 37 participants in the first phase and 16 in the second. Participants received a single 500 mg dose of either NR IV or NAD+ IV and were monitored over 24 hours.

The 2024 study established several key findings that the new study now reinforces:⁷ 

• NR IV infusions were 75% faster: Likely due in part to the large size of the NAD+ molecule and the side effects experienced during administration, NR IV infusions were completed dramatically faster, on average, taking only about 25% of the time required for NAD+ IV.
• NR IV raised NAD+ levels rapidly: Whole-blood NAD+ levels increased by 20.7% after three hours post NR IV infusion, outperforming NAD+ IV. Despite being delivered directly into the bloodstream, NAD+ IV did not significantly increase blood NAD+ levels until 24 hours after infusion–and even then, levels rose by only about 2% above baseline.
• NAD+ IV showed signs of inflammatory potential: Participants receiving NAD+ IV exhibited increases in white blood cell and neutrophil counts, markers that may indicate an inflammatory response. In contrast, NR IV showed no evidence of triggering such changes.

For a molecule administered intravenously, the combination of prolonged infusion times, limited increases in circulating NAD+, and potential inflammatory effects suggests important biological limitations–ones that point directly to how the body processes NAD+ itself.

The Biological Limitations of NAD+ IV Therapy

Why NAD+ IV Is Inefficient by Design: The Role of Molecular Size

One key factor underlying the limitations of NAD+ IV is the biology of the NAD+ molecule itself. NAD+ is relatively large–more than twice the molecular weight of NR–and carries two negatively charged phosphate groups. Because of its size, polarity, and charge, NAD+ cannot easily cross cell membranes.

As a result, NAD+ delivered orally or intravenously must first be broken down into smaller precursor molecules,⁸ such as NR or nicotinamide (NAM), before cells can take it up. Only after entering the cell can these precursors be used to rebuild NAD+. This additional processing step may help explain why NAD+ IV increases blood NAD+ levels more slowly and less effectively than NR IV.

The Side Effect Profile of NAD+ IV: The Science of Extracellular NAD+

The constellation of reactions reported with NAD+ IV–nausea, vomiting, elevated heart rate, chest pressure, and throat tightness–observed across both clinical studies and widely reported anecdotally, is likely more than simple discomfort. These symptoms may reflect an underlying physiological response, and research offers a potential mechanistic explanation for what may be driving them.

Under normal physiological conditions, NAD+ is primarily an intracellular molecule. It performs its essential functions inside cells, where it is tightly regulated and present in relatively small extracellular quantities. During a high-dose IV infusion, however, large amounts of NAD+ are introduced directly into the bloodstream, flooding the extracellular environment with concentrations far beyond what the body would ever encounter naturally.

The body may interpret this surge in extracellular NAD+ as a signal of cellular trauma, similar to what occurs when injured or dying cells release their intracellular contents into the bloodstream. In response, the immune system may mobilize to address what it perceives as a threat–which could explain the elevated white blood cell and neutrophil counts observed in the Hawkins et al., 2024 study, as well as the symptoms reported by participants across both studies. The body, in essence, may be mounting an inflammatory response to remove what it perceives as foreign or dangerous material.

Some researchers have proposed that extracellular NAD+ may function as a "danger signal,"⁹ prompting enzymes to rapidly break it down into metabolites such as NAM, ADP-ribose, and possibly NR. 

Taken together, this biology offers important context for the clinical findings observed across both studies. NAD+'s inability to enter cells intact makes direct infusion inherently inefficient, requiring the body to first dismantle the molecule into smaller components before it can be rebuilt intracellularly, at the cost of time, energy, and biochemical resources. Additionally, the body’s potential immune response to extracellular NAD+ accumulation adds another layer of complexity—and may help explain the side effects of NAD+ IV.

Conclusion: Translating the Research Into Practice

The convergence of recent clinical findings carries meaningful implications for how NAD+ IV therapy is applied in both clinical and wellness settings

For practitioners, the data raises important questions about whether standard NAD+ IV protocols are achieving the results clients expect–or paying for. When the infused molecule cannot readily enter cells intact, may provoke an inflammatory response, and is largely broken down before contributing to intracellular NAD+ synthesis, the scientific justification for favoring NAD+ IV over a precursor-based approach becomes difficult to defend.

For patients and consumers, these studies highlight a crucial principle: the label on a product does not necessarily reflect its mechanism of action. NAD+ and NR are not interchangeable simply because one can be converted into the other inside cells. How a molecule is delivered, whether it can cross cell membranes, and how the body responds to its presence all play pivotal roles in its effectiveness.

Boosting NAD+ levels remains a valid, evidence-based strategy for supporting cellular energy, resilience, and healthy aging. But achieving these benefits requires aligning with the body’s biology–not working against it. Precursor-based protocols, such as NR IV, showed favorable tolerability and metabolic signals in these preliminary studies, warranting further investigation in larger, controlled trials.

*AboutNAD is curated by Niagen Bioscience, Inc., the patent owners of Niagen® IV. This article is intended for educational purposes only and is based on peer-reviewed clinical research.

References

1. Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metabolism, 27(3), 529–547. https://doi.org/10.1016/j.cmet.2018.02.011
2. Massudi, H., Grant, R., Braidy, N., Guest, J., Farnsworth, B., & Guillemin, G. J. (2012). Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue. PLoS ONE, 7(7), e42357. https://doi.org/10.1371/journal.pone.0042357
3. Guest, J., Grant, R., Mori, T. A., & Croft, K. D. (2014). Changes in Oxidative Damage, Inflammation and [NAD(H)] with Age in Cerebrospinal Fluid. PLoS ONE, 9(1), e85335. https://doi.org/10.1371/journal.pone.0085335
4. Costford, S. R., Bajpeyi, S., Pasarica, M., Albarado, D. C., Thomas, S. C., Xie, H., Church, T. S., Jubrias, S. A., Conley, K. E., & Smith, S. R. (2010). Skeletal muscle NAMPT is induced by exercise in humans. American Journal of Physiology-Endocrinology and Metabolism, 298(1), E117–E126. https://doi.org/10.1152/ajpendo.00318.2009
5. Tran, T., Pencina, K. M., Schultz, M. B., Li, Z., Ghattas, C., Lau, J., Sinclair, D. A., & Montano, M. (2022). Reduced Levels of NAD in Skeletal Muscle and Increased Physiologic Frailty Are Associated With Viral Coinfection in Asymptomatic Middle-Aged Adults. JAIDS Journal of Acquired Immune Deficiency Syndromes, 89(S1), S15–S22. https://doi.org/10.1097/qai.0000000000002852
6. Reyna, K., Heinzen, G., Patel, N., Ritter, M., Siojo, A., Legere, H., & Pojednic, R. (2026). Intravenous infusion of nicotinamide adenine dinucleotide (NAD+) versus nicotinamide riboside (NR): a retrospective tolerability pilot study in a real-world setting. Frontiers in Aging, 7, 1652582. https://doi.org/10.3389/fragi.2026.1652582
7. Hawkins, J., Idoine, R., Kwon, J., Shao, A., Dunne, E., Hawkins, E., Dawson, K., & Nkrumah-Elie, Y. (2024). Randomized, placebo-controlled, pilot clinical study evaluating acute Niagen®+ IV and NAD+ IV in healthy adults. medRxiv, 2024.06.06.24308565. https://doi.org/10.1101/2024.06.06.24308565
8. Nikiforov, A., Dölle, C., Niere, M., & Ziegler, M. (2011). Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells FROM ENTRY OF EXTRACELLULAR PRECURSORS TO MITOCHONDRIAL NAD GENERATION*. Journal of Biological Chemistry, 286(24), 21767–21778. https://doi.org/10.1074/jbc.m110.213298
9. Audrito, V., Messana, V. G., Brandimarte, L., & Deaglio, S. (2021). The Extracellular NADome Modulates Immune Responses. Frontiers in Immunology, 12, 704779. https://doi.org/10.3389/fimmu.2021.704779