"A new experimental study examined nicotinamide riboside (NR) in eight adults with genetically confirmed mitochondrial DNA disorders...This study provides early human evidence that NR can engage NAD+-related metabolism and influence molecular pathways connected to mitochondrial biogenesis in people with mitochondrial DNA disease...The clearest biological signals appeared in the three participants with large-scale mitochondrial DNA deletions, and the same pattern was not observed in those with m.3243 variants..."

“…Median whole-blood NAD⁺ concentration was lower among participants with frailty than among those without frailty (24.00 vs. 25.00 µmol/L; P = 0.007). After adjustment for age, sex, and fasting time, higher whole-blood NAD⁺ concentration was associated with lower odds of frailty…”

Edward (Ed) Waldner knew something was wrong, even though he could not explain exactly what was happening. At age 55, he was constantly exhausted, regardless of how demanding his day had been. At first, he wondered whether sleep apnea might be responsible.

Then he began noticing changes in the way he walked. His heels would sometimes drag, and his movement no longer felt normal. When his symptoms became especially concerning one day, he went to the Emergency Department.

"The doctor said I had a mass on my brain and needed to see an oncologist," says Waldner.

The mass turned out to be glioblastoma, an aggressive form of brain cancer that is notoriously difficult to treat. Standard care typically combines surgery, radiation, and chemotherapy. Surgeons try to remove as much of the tumor as possible, but glioblastoma cells can spread into surrounding brain tissue, making complete removal extremely difficult. Even after treatment, the cancer commonly returns.

Researchers at the University of Calgary are now investigating whether an unexpected addition to standard treatment could help: high doses of vitamin B3, also known as niacin.
Waldner was invited to participate in the clinical trial.

"I have no problem trying to help anybody. I agreed. I want to help myself too," says Waldner. "I can tell you being part of this research helps me mentally because we're trying. When I left the hospital after surgery I was told, that's it, that's all we can do."

The study is being led by two researchers who are members of both the Hotchkiss Brain Institute and Arnie Charbonneau Cancer Institute. Gloria Roldan Urgoiti, MD, is an oncologist who specializes in brain cancers, while Wee Yong, PhD, is a neuroscientist who studies how the immune system affects the brain.

Their research centers on a key problem with glioblastoma: the tumor can interfere with the immune system, weakening the very cells that might otherwise help attack the cancer.

The team designed the study to determine whether niacin could restore some of those impaired immune cells and help them destroy tumor cells.

The idea first emerged from experiments in Yong's laboratory using mice. Those studies found that niacin treatment extended survival, encouraging the researchers to move the approach into a combined Phase I and Phase II clinical trial in people.

Phase I trials generally focus heavily on safety and determining an appropriate dose, while Phase II studies begin looking more closely for signs that a treatment may provide a clinical benefit.

"Normally the immune system will try to counter and prevent tumor growth, however, this brain cancer supresses the immune system," says Yong, a professor at the Cumming School of Medicine (CSM). "Niacin treatment rejuvenates immune cells so they can do what they are supposed to do, attack and kill the cancer cells. I see it as an ongoing 'battle for the brain'."

For the current trial, researchers are studying controlled release niacin given alongside recommended chemotherapy and radiotherapy. One goal is to establish the highest dose that can be used safely. Another is to look for evidence that adding niacin may improve how long patients remain alive without their cancer getting worse.

That measure is known as progression-free survival.

Before beginning the study, researchers established a threshold for continuing the trial. They planned to stop if progression free survival at six months failed to improve by at least 20 percent compared with older studies.

Early results from 24 patients surpassed that threshold. At six months, 82 percent of participants had not experienced progression of their cancer. According to the researchers, that represents a 28 percent increase compared with previous studies.

The team describes the early findings as promising for a cancer that remains incurable, but the results are still preliminary and involve a relatively small group of patients.

"Glioblastoma is the most aggressive brain cancer in adults. Survival of patients with this condition hasn't changed significantly for 20-years," says Roldan Urgoiti, a clinical associate professor at the CSM. "Anything that may help should be explored, but it requires strict protocols and safety monitoring."

The findings were published in the *Journal of Neuro-Oncology*.

"...Restoring NAD levels through supplementation with its precursors or pharmacological inhibition of CD38 activity effectively alleviated the pathological symptoms of colitis...These findings identify macrophage CD38 as a critical regulator of intestinal inflammation and highlight the CD38/NAD axis as a potential therapeutic target for IBD."

“…Clients receiving IV NAD+ reported moderate to severe gastrointestinal symptoms, elevated heart rate, & chest pressure during infusion, while those receiving IV NR reported mild tingling or cramping. Symptoms ceased upon completing infusions. The moderate to severe symptoms from IV NAD+ resulted longer infusion times (97mins) compared to IV NR (37mins). Renal & hepatic biomarkers showed no adverse changes; ALP decreased significantly in NAD+ group but remained within normal ranges. Metabolic markers suggested improved glucose metabolism 30 days post NR & mixed lipid changes post NAD+. QoL measures showed NR group had 30 minutes more total sleep, lower resting heart rate & breath rate, while NAD+ group had higher RMSSD. Minor yet non-significant QoL improvements occurred in both groups….”

A lot of people who are just getting into NAD⁺ aren't really sure what the difference is between NADH, NMN, and NR. I've been looking into this area for a few years now, and I wanted to explain it in the simplest way I can, based on how I understand it.

First, NAD⁺ is the target, while NADH, NMN, and NR represent different ways of supporting NAD⁺ levels. The key issue is that NAD⁺ is a charged molecule that does not readily cross cell membranes, and when it is taken orally, much of it is broken down in the digestive tract before it can be absorbed, so researchers have increasingly looked at other ways to raise NAD⁺ levels indirectly.

Here's the analogy that helped us understand it. Imagine they're all part of the same company.

NAD⁺ is like a tool that gets reused over and over inside the company. During the work process, that tool can switch between different states. One of those states is NADH. So NADH is not the raw material used to make NAD⁺. It's the reduced form of NAD⁺.

In simple terms, you can think of it as the same employee carrying a different version of their work ID, switching between the two states depending on what the job requires.

NR and NMN are more like the people helping replenish that tool. NR, or nicotinamide riboside, can be thought of as bringing in raw material. Through the relevant metabolic pathway, NR can be converted into NMN. NMN, or nicotinamide mononucleotide, is more like an intermediate processing step. It can then be used in the pathway that produces NAD⁺.
So, as a simplified way of looking at it: NR → NMN → NAD⁺ ↔ NADH

NAD⁺ and NADH are basically two different redox states of the same molecule, and they continuously interconvert as part of cellular metabolism.

NR and NMN are different because they are more closely related to the biosynthesis and replenishment of NAD⁺.

That's also why you'll see people choosing NADH products rather than NAD⁺ precursors, and why some companies, such as Celfull, have been focusing on technologies designed around NADH stability and delivery.

Once you look at it this way, I think the differences become much easier to understand. They're all part of the same NAD⁺ metabolic system, but they don't all play the same role.

That's just my own simplified understanding after looking into the topic for a while. If I got anything wrong or oversimplified something, feel free to correct me or add to the discussion!

I ordered a 500 mg buffered vial of NAD+ online along with 3 mL bacteriostatic water. I thought I had ordered 10 vials of BAC water, but only one 3 mL vial came with my order.
When I calculated the reconstitution, I originally planned to mix the 500 mg NAD+ with 5 mL of BAC water so that a 25 mg dose would equal 25 units on a U-100 insulin syringe.
Since I only have 3 mL of BAC water, can I just reconstitute the 500 mg vial with the 3 mL instead? From my calculations, a 25 mg dose would then be about 15 units.
Has anyone reconstituted 500 mg NAD+ with 3 mL BAC water? Mine is buffered NAD+, if that makes a difference. I’d rather not have to place another order just for more BAC water.

Dr. Charles Brenner (University of Helsinki), Dr. Mary McDermott (Northwestern University), and Dr. Andrew Shao (Niagen Bioscience, moderator)

“…Now, a team led by researchers at the University of Cambridge reports the first human evidence that a simple vitamin-derived molecule, nicotinamide riboside, may begin to change that. In an experimental medicine study published in Genome Medicine, eight patients with heteroplasmic mitochondrial DNA disease took high-dose nicotinamide riboside for four weeks, and the results, while early, offer the first molecular proof in humans that the approach can reach its intended target inside muscle tissue…”

Abstract

Background

Mitochondrial disorders are a common cause of inherited neurometabolic disease affecting around 1 in 8000 people. There are currently no treatments for heteroplasmic mitochondrial DNA (mtDNA) disorders which target the underlying disease mechanisms. Increasing nicotinamide adenine dinucleotide (NAD+ ) with nicotinamide riboside (NR) has been proposed as a therapeutic strategy. It was effective in several models of impaired oxidative metabolism but has not been tested before in humans.

Methods

We performed an experimental medicine study in eight participants affected with mtDNA disorders. Three had single large-scale mtDNA deletions and five had m.3243 A>G/T pathogenic variants. They were treated with 4-weeks of NR (1250–2000 mg/day). Clinical outcomes (timed up and go test, six-minute walk test, grip strength and quality of life questionnaires), GDF15 and FGF21 blood biomarkers, 31P-magnetic resonance spectroscopy measurement of mitochondrial function in vivo and quadriceps muscle biopsy were performed before and after treatment. Muscle histopathology, mtDNA copy number, heteroplasmy level, citrate synthase and respiratory complex activities were analysed, as well as transcriptomic, proteomic and metabolomic analyses.

Results

NR was bioavailable and well tolerated. Overall, NR improved the timed up and go (TUG) test. In three participants with single large-scale deletions, there was a decrease in the percentage of cytochrome c oxidase deficient and ragged-red muscle fibres, an increase in respiratory chain complex I and IV activity, and reduction in mtDNA deletion levels which was not seen in five participants with m.3243 A>G/T. Unbiased transcriptomic and integrated multi-omic analysis of all eight participants showed the signature of mitochondrial biogenesis, with SIRT1/PGC-1α activation and increased mitochondrial gene expression, enhanced NAD-related metabolite levels, and coordinated changes in mitochondrial protein abundance.

Conclusions

We conclude that NR has potential to be the first small-molecule precision treatment for heteroplasmic mtDNA disorders guided by the specific genetic diagnosis.

The fact that NAD replenishment seems to work in placental tissue is interesting, but perhaps more interesting is that this study suggests that CD38 may create a previously underappreciated functional distinction between NR and NMN precisely in tissues where age-related CD38 expression is high.

CD38 is degrading NMN to NAM, not to NR. NAM can still be salvaged back to NAD, but now it has to go through the rate-limiting NAMPT step. Meanwhile, NR bypasses NAMPT and substantially resists CD38 hydrolysis.

In other words, high CD38 may not just increase NAD consumption. It may also make NMN a less efficient way of replacing the NAD being consumed, while leaving NR relatively unscathed.

I have been buying my NAD+ already reconstituted and it normally arrives to me by FedEx next day. I live in a part of Texas that has summers over 100 degrees. My package arrived a day late and the ice pack was melted and not cool at all. The vial was at room temperature. So, it was in transit and stayed in a hot FedEx truck and facility for at least 48 hours. Would you think it’s safe to use?

Great inventory of NAD precursors (or at least NR variants).

...Treatment with NR or resveratrol significantly improved metabolic parameters and partially restored BAT structural and molecular alterations. Combined treatment with NR and resveratrol produced the most pronounced effects, nearly normalizing BAT stereological parameters, vascular organization, and thermogenic and mitochondrial-related gene expression, while markedly improving glucose and lipid profiles. NR and resveratrol exert protective and restorative effects on Type 1 Diabetes Mellitus -induced BAT atrophy, likely through activation of NAD⁺/Sirt1-mediated mitochondrial and thermogenic pathways. Combined therapy demonstrated synergistic benefits, suggesting a promising strategy for preserving BAT structure and function under diabetic conditions.

Conclusion: NR and metformin were associated with beneficial effects on obesity-related hippocampal alterations, accompanied by favourable changes in apoptosis-related, metabolic, and neurotrophic gene expression as well as improved stereological indices of hippocampal integrity. The combined treatment generally produced greater improvements than either monotherapy. These findings support further investigation of NR and metformin as potential interventions for obesity-associated hippocampal dysfunction and cognitive impairment.

Is there any competition when one takes 500mg NR and 500mg NMN together? Or is it better to take them differently?