Risks and Benefits of Nicotinamide Riboside (NR), a NAD+ Booster

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The suppression of NAD+ synthesis by NR in humans may explain the disparate rodent results.

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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

NR and NMN seem to be more promising NAD+ precursors than NA or NAM, since they don’t cause flushing. Nor do they directly inhibit sirtuins. In mice, NR and NMN both raised liver NAD+ levels, but of the two, only NR significantly raised NAD+ in the muscles. Also, NR is so far the only NAD+ booster shown to prolong the lifespan of mice.

There have been at least 10 clinical trials of NR, most showing it can boost human blood levels of NAD+ by up to 168 percent. Note, though, that most doses used exceeded 300 mg, which is the daily dose approved as safe by the U.S. Food and Drug Administration and European Food Safety Authority. At the approved dose, blood NAD+ is boosted more on the order of 50 to 60 percent, but no dose was found to affect NAD+ levels in human muscle (compared to placebo).

The greater preponderance of human bioavailability and safety data for NR compared to NMN has led some to proclaim NR as the preferred NAD+ precursor. And, by some, I mean employees of a chemical company that produces NR for supplements. The question after all of these human NR trials is: have any of them shown clinical benefit? Sadly, no. Let’s go through the alphabet.

After accounting for multiple testing, randomized, double-blind, placebo-controlled trials of NR in middle-aged or older adults failed to find any significant benefit over placebo for artery stiffness or artery function, BAT activation, blood pressure, blood sugar control, body weight, cardiac energy or ejection fraction, fat burning, fatty liver, exercise capacity, fatigue, insulin sensitivity, metabolic flexibility, metabolic health, metabolic rate, mitochondrial function or biogenesis, muscle blood flow, upper or lower body muscle strength, pancreatic function or the release of metabolic hormones, the treatment of Parkinson’s disease symptoms, or physical performance.

NR-hawking companies claim NR is anti-inflammatory, but in their own study, only three out of 10 markers of inflammation were affected compared to placebo, and a subsequent independent study using the same dose for twice as long found zero of 12 markers affected.

Remarkably, the opposite was found for many of these outcomes in rats and mice. In rodents, NR does raise NAD+ levels in muscle, improving insulin sensitivity and mitochondrial biogenesis, and on down much of the list. Why does NR work in rodents but appear to almost entirely flop in people? Some have suggested inadequate dosing. The typical dose used in mouse studies was about twice that used in many human studies. But a double dose has been tried in people, to no avail.

Another possibility is sirtuin inhibition by NAM, the main degradation product of NR. In fact, based on mouse studies, NR may metabolize in the gut into NAM or NA before it even makes it in the bloodstream. Either way, unlike in mice, NR can’t seem to elevate NAD+ in human muscle; so, no wonder there’s no alteration of human sirtuin activity. Maybe that explains the disparate results. In fact, the key NAD+ synthesizing enzyme in human muscle biopsies was actually suppressed by NR supplementation. This doesn’t happen in mice, but it does in people. Presumably this downregulation is an adaptive response to the unnaturally large flood of NR coming into the system. So, what happens when you stop taking the supplement? How quickly does your enzyme activity bounce back?

In mice, not only may their microbiome affect NR, but the NR may affect their microbiome, too. Some of the benefits of NR can then be transferred between mice via fecal transplants. So, at least in mice, some of the benefits of NR may be due to modulating the mouse microbiome. The distinct differences between the gut flora of humans and rodents may offer another explanation why NR works in them, but not us.

Unlike NAM, supplementation with NR did not increase homocysteine levels. But one study of a combination of NR plus a resveratrol analogue called pterostilbene raised LDL cholesterol high enough to kill as many as one in 40 long-term users. However, this effect is presumed to be due to the pterostilbene, as NR alone has not been shown to raise LDL, whereas pterostilbene has.

One study did find that NR seems to cause a small reduction in hematocrit, hemoglobin, and platelet count in people within a week of starting it. This shift towards a more anemic state was suggested to account for impaired exercise performance seen in rats given NR. However, the 35 percent drop in performance did not reach statistical significance. NR did cause a significant increase in systemic oxidative stress, however, and another rodent study found a worsening of inflammation and deterioration of metabolic health. But if positive effects in rodents don’t translate to people, perhaps we shouldn’t expect that negative ones will either.

Regulatory authorities from Australian, Canada, Europe, and the United States have all authorized NR as safe, at least up to 300 mg a day (or 230 in pregnant and lactating women). But the lack of demonstrable clinical benefit would seem to preclude NR supplementation.

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

NR and NMN seem to be more promising NAD+ precursors than NA or NAM, since they don’t cause flushing. Nor do they directly inhibit sirtuins. In mice, NR and NMN both raised liver NAD+ levels, but of the two, only NR significantly raised NAD+ in the muscles. Also, NR is so far the only NAD+ booster shown to prolong the lifespan of mice.

There have been at least 10 clinical trials of NR, most showing it can boost human blood levels of NAD+ by up to 168 percent. Note, though, that most doses used exceeded 300 mg, which is the daily dose approved as safe by the U.S. Food and Drug Administration and European Food Safety Authority. At the approved dose, blood NAD+ is boosted more on the order of 50 to 60 percent, but no dose was found to affect NAD+ levels in human muscle (compared to placebo).

The greater preponderance of human bioavailability and safety data for NR compared to NMN has led some to proclaim NR as the preferred NAD+ precursor. And, by some, I mean employees of a chemical company that produces NR for supplements. The question after all of these human NR trials is: have any of them shown clinical benefit? Sadly, no. Let’s go through the alphabet.

After accounting for multiple testing, randomized, double-blind, placebo-controlled trials of NR in middle-aged or older adults failed to find any significant benefit over placebo for artery stiffness or artery function, BAT activation, blood pressure, blood sugar control, body weight, cardiac energy or ejection fraction, fat burning, fatty liver, exercise capacity, fatigue, insulin sensitivity, metabolic flexibility, metabolic health, metabolic rate, mitochondrial function or biogenesis, muscle blood flow, upper or lower body muscle strength, pancreatic function or the release of metabolic hormones, the treatment of Parkinson’s disease symptoms, or physical performance.

NR-hawking companies claim NR is anti-inflammatory, but in their own study, only three out of 10 markers of inflammation were affected compared to placebo, and a subsequent independent study using the same dose for twice as long found zero of 12 markers affected.

Remarkably, the opposite was found for many of these outcomes in rats and mice. In rodents, NR does raise NAD+ levels in muscle, improving insulin sensitivity and mitochondrial biogenesis, and on down much of the list. Why does NR work in rodents but appear to almost entirely flop in people? Some have suggested inadequate dosing. The typical dose used in mouse studies was about twice that used in many human studies. But a double dose has been tried in people, to no avail.

Another possibility is sirtuin inhibition by NAM, the main degradation product of NR. In fact, based on mouse studies, NR may metabolize in the gut into NAM or NA before it even makes it in the bloodstream. Either way, unlike in mice, NR can’t seem to elevate NAD+ in human muscle; so, no wonder there’s no alteration of human sirtuin activity. Maybe that explains the disparate results. In fact, the key NAD+ synthesizing enzyme in human muscle biopsies was actually suppressed by NR supplementation. This doesn’t happen in mice, but it does in people. Presumably this downregulation is an adaptive response to the unnaturally large flood of NR coming into the system. So, what happens when you stop taking the supplement? How quickly does your enzyme activity bounce back?

In mice, not only may their microbiome affect NR, but the NR may affect their microbiome, too. Some of the benefits of NR can then be transferred between mice via fecal transplants. So, at least in mice, some of the benefits of NR may be due to modulating the mouse microbiome. The distinct differences between the gut flora of humans and rodents may offer another explanation why NR works in them, but not us.

Unlike NAM, supplementation with NR did not increase homocysteine levels. But one study of a combination of NR plus a resveratrol analogue called pterostilbene raised LDL cholesterol high enough to kill as many as one in 40 long-term users. However, this effect is presumed to be due to the pterostilbene, as NR alone has not been shown to raise LDL, whereas pterostilbene has.

One study did find that NR seems to cause a small reduction in hematocrit, hemoglobin, and platelet count in people within a week of starting it. This shift towards a more anemic state was suggested to account for impaired exercise performance seen in rats given NR. However, the 35 percent drop in performance did not reach statistical significance. NR did cause a significant increase in systemic oxidative stress, however, and another rodent study found a worsening of inflammation and deterioration of metabolic health. But if positive effects in rodents don’t translate to people, perhaps we shouldn’t expect that negative ones will either.

Regulatory authorities from Australian, Canada, Europe, and the United States have all authorized NR as safe, at least up to 300 mg a day (or 230 in pregnant and lactating women). But the lack of demonstrable clinical benefit would seem to preclude NR supplementation.

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Doctor's Note

​​This is the fifth video in my NAD+ series. Missed any of the previous ones? See:

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