Chapter 191
Nicotinamide (NAM)
There are a number of rare genetic defects that can lead to the disease mitochondrial myopathy, for which a low NAD+ level in blood and muscle is characteristic. In 2020, researchers showed that these levels can be replenished with 750 to 1000 milligrams of NA per day, which significantly increased muscle strength. This was the first and only study ever to show, of any NAD+ booster, that it improved levels in muscle and improved muscle strength. In a control group of people without the genetic defect, NA did increase the NAD+ level in blood, but not in muscle, suggesting that the NAD+ level in normal, healthy muscle is already "maxed out." You will see that this is a recurring theme with NAD+ boosters.
We know that high doses of NA can increase the NAD+ level in human blood, but evidence of correspondingly greater sirtuin activity is still lacking. Why not just try it? Because of the side effects that emerged in the cholesterol-lowering studies. NA increases blood sugar and increases diabetes risk. Based on data from studies with tens of thousands of participants who had taken high doses of NA for years, it is to be expected that 1 in 43 of those who took NA for five years and otherwise would not have become ill will get diabetes. It is not clear whether this risk is limited to sustained-release preparations.
The safety margin, the ratio between the highest tolerable upper limit and the recommended daily amount, is the smallest for NA compared to half a dozen other common vitamins. However, this upper limit is based on the hot flashes as a reaction, which are unpleasant but are considered harmless and mostly subside on their own. Long-term use can also lead to other complaints, such as stomach ulcers, vomiting, abdominal pain, diarrhea, jaundice, and other signs of liver damage (especially with sustained-release preparations). In addition, there are theoretical considerations as to whether excessive intake of NA leads to Parkinson's disease. Because of the unpleasant hot flashes and the risk of more serious side effects, interest has shifted to other NAD+ precursor substances.
Nicotinamide (NAM)
Ever since it has been known that nicotinamide (NAM) also cures pellagra, NA and NAM have been referred to together as niacin or vitamin B3, even though they are different compounds. For example, NAM does not cause the same kind of hot flashes. (Facial flushing that was attributed to niacinamide in older studies probably came from a not fully purified preparation that was contaminated with residual NA.)
Whether NA can produce more NAD+ than NAM is not clear. Neither has been shown to increase sirtuin activity, but both extend the lifespan of C. elegans. For NA I have found no longevity studies, but NAM has been studied and did not extend the life of mice. What clinical effects are to be expected in humans?
I have examined the proven anti-aging effects of topically applied nicotinamide, as well as the remarkable ability of orally administered nicotinamide to counteract skin cancer. Despite promising results in mice, it did not prevent type 1 diabetes, but it helps preserve the remaining function in newly diagnosed type 1 diabetes, just apparently not enough to affect blood sugar regulation. And can it be used as an NAD+ booster?
In people with mitochondrial myopathy, NA increased the NAD+ level in muscle and improved mitochondrial and muscle function, but in healthy people the NAD+ level in muscle did not budge. However, the average age in the control group was 50 years. What about older adults, whose muscle NAD+ level may be lower? In older adults, four NAD+ precursors were tested: tryptophan, NA, NAM, and NR. None of them could improve muscle strength or muscle function, did not affect mitochondrial function, and did not even nudge NAD+ in muscle. But why not try NAM anyway? Here too: side effects.
Like NA, NAM can also cause gastrointestinal disturbances and signs of liver toxicity at high dosages. In addition, NAM can cause more problems through methylation. The most important first step in breaking down excess NAM is the addition of a methyl group, forming MeNAM. MeNAM can cross the blood-brain barrier and was toxic to nerve cells in vitro. That could explain why NAM can produce Parkinson's-disease-like symptoms in rats and why Parkinson's patients may have higher levels of the NAM-methylating enzyme in the brain. Excess NAM can also deplete the body's supply of methyl groups.
You may recall from the chapter "Epigenetics" that DNA methylation is indispensable for regulating gene expression. Epigenetic changes caused by NAM-induced methyl deficiency were held responsible for rats suffering from fatty liver and kidney swelling when they had eaten NAM in extremely high doses, but converted, that would go far beyond what a human normally eats. Is there any indication that a lower NAM supplementation could affect methylation in humans? Yes, even a single 100-milligram dose.
Methylation also plays a key role in breaking down fight-or-flight hormones such as norepinephrine and neurotransmitters such as serotonin and histamine. Within a few hours after a 100-milligram dose of NAM, levels of all three hormones rose, suggesting that their metabolism was impaired because methyl groups were shifted to cope with the additional NAM. In addition, a significant increase in homocysteine was found, a byproduct of methylation reactions and a cardiovascular as well as dementia risk factor.
Another possible problem with NAM is its property as a sirtuin inhibitor. Wasn't the whole point of taking NAD+ precursors to boost sirtuin activity? The sirtuin enzymes consume NAD+ and spit out NAM. This allows the body to recycle the NAM into NAD+, and the sirtuins can reuse it. But it also means that the body can use NAM as part of a negative feedback loop. Like a thermostat that shuts off the furnace in winter when it gets too warm, the body turns down the sirtuins' use of NAD+ when it registers too much NAM. As our bodies developed, there were no NAM pills. So if it finds that it is suddenly flooded with NAM, it thinks the sirtuins are spitting out too much and prevents them from doing so. Perhaps that explains why NAM did not extend the life of mice. When NAM's sirtuin-inhibiting effect was first described 20 years ago, scientists warned that "long-term nicotinamide therapy in humans" could have "harmful consequences."
Nicotinamide riboside (NR)
NR and NMN are more promising NAD+ precursors than NA or NAM, because they do not cause hot flashes and do not directly inhibit sirtuins. In mice, both NR and NMN increase the NAD+ level in the liver, but only NR increases the NAD+ level in muscle. In addition, NR is so far the only NAD+ booster that extends the lifespan of mice.
There are at least ten clinical studies on NR showing that it can increase the NAD+ level in human blood by up to 168 percent. However, the doses were mostly above 300 milligrams, the daily dose that the FDA and the European Food Safety Authority classified as safe for health. At the approved dose, the NAD+ level increases by 50 to 60 percent, but compared to a placebo, no dosage influenced the NAD+ level in human muscle.
The larger body of data on the bioavailability and safety of NR compared to NMN led some to declare NR the preferred NAD+ precursor. And by "some" I mean employees of a chemical company that manufactures NR for supplements. The question that arises after all the NR studies with humans is: Has any of them shown a clinical benefit? No, unfortunately not.