Nicotinamide riboside supplements are basically ineffective!
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Nicotinamide riboside supplements are basically ineffective!
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The most comprehensive review of clinical trial results so far shows that nicotinamide riboside supplements are basically ineffective!
Even people who don’t pay attention to beauty makeup and health care products, I think they should have heard of the name of niacinamide. Whether it is nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), the ultimate goal is to increase the level of nicotinamide adenine dinucleotide (NAD) in the body.
NAD is the number one auxiliary in almost all types of cells. It participates in the mitochondrial energy supply chain and also acts as a substrate for multiple enzymes. It plays an important role in regulating cell aging and maintaining normal body functions. With age, the level of NAD in the human body will gradually decrease, and animal experiments have also shown that low levels of NAD are related to obesity and aging-related metabolic abnormalities.
People see the light of hope for health and longevity from NAD.
Correspondingly, various health care products added with NMN and NR are also available, and the prices are quite high. Before spending big bucks on “elixirs of life,” shouldn’t we ask the question—what good do we really get from supplementing them?
Recently, the journal “Science Progress” published a review.
Researchers from the University of Copenhagen sorted out the results of 25 clinical trials of NR supplements for us, and several of them were participated by the author himself.
We have to say that the two are very ruthless in their evaluation of their scientific research fields.
They directly commented that there is almost no evidence of clinical effects on NR supplements, and the relevant researchers tend to exaggerate the research results and credulously believe in the “magic power” of NR. .
Before we start pointing clinical research, let’s first understand the relationship between NR and NAD. The metabolism of NAD in the human body is a bit complicated. It has three main biosynthetic pathways.
You can refer to the figure below for a brief overview. One is the Preiss-Handler pathway starting with NA, and the other is tryptophan (Trp).
The third is the rescue synthesis pathway in which the NAD metabolite NAM is transformed into NMN and then re-turned into NAD.
Green is the metabolite, blue is the key enzyme, red is the main metabolic enzyme of NAD
In the case of oral administration of a large amount of NR, NR will be converted into NAM through CD157 in the intestine, and converted into NA under the action of intestinal microorganisms, in which the presence of enterobacteria is very important .
Only a small amount of orally administered NR can enter the blood in its natural form, and quickly changes to NAM in the blood (with a half-life of about 3 minutes), so the concentration of NR in the blood is very low.
The following are the clinical trials of NR supplements since 2016. All the studies listed here are NR as the main intervention method. After all, it is difficult to say who works when more drugs are used. All the following clinical trials used oral NR.
Overview of Clinical Trials for NR
Next, we will discuss separately according to the design of clinical trials.
The first is a trial with no placebo control . The ugly words must be said first, and the design without placebo is acceptable, but it will definitely have an unpredictable impact on the test results.
Any changes observed during such a trial would be confounded, such as the behavior of the study stressing out participants to make lifestyle changes, whether consciously or unconsciously.
Results from non-placebo-controlled trials are useful, but differences are difficult to attribute directly to the treatment itself.
The first trial of human supplementation with NR was carried out by Trammel et al. in 2016. The test subjects continued to ingest NR 1000mg/d within a week, and blood and urine samples were sampled and tested multiple times.
The results of the trial showed increased levels of NAD metabolites in peripheral blood mononuclear cells (PBMCs) and increased levels of NAD-related excretions in urine.
Airhart et al subsequently conducted a similar study, taking 250-2000 mg/d within 8 days, and concluded that oral administration of NR can increase the steady-state levels of NR and NAD in whole blood.
However, since the steady-state calculation method is only the average value of the compound in the first 12 hours after the last dose, the review authors believe that this cannot indicate that the NR level in the blood is at a steady state.
The study authors noted that blood NR levels varied widely between participants, suggesting that there may be active transport of NR or differences in intestinal metabolism.
We now know that differences in gut bacteria can explain this very well. During the trial, no changes in the participants’ body weight, blood pressure, blood sugar, and various markers of liver and kidney damage were observed.
Another study by Zhou et al. tested the effect of increasing doses of NR in 4 patients with heart failure. 500-2000mg/d, after 5-9 days of intervention, blood and PBMC NAD levels increased, and the expression levels of two inflammatory markers, IL-6 and IL-18, in PBMCs decreased.
The review author pointed out that the data processing in this study was not rigorous, and there may be errors in the p value, but considering that the performance of all participants in the small sample is in the same direction, it should also be meaningful.
In a larger study by Veenhuis et al., 25 mg/kg/d NR was administered orally, up to a maximum dose of 900 mg/d, for 4 months in 24 children over 2 years of age and adults with ataxia telangiectasia.
Results showed no changes in disease-associated biomarkers, quality of life assessments, HbA1c, or hepatic and renal function measures, although disease scores improved slightly, but no control and little understanding of disease progression in ataxia telangiectasia , it is also difficult to say that NR has a meaningful therapeutic effect on the disease.
The study by Lapatto et al. was divided into two parts, in which the data of the non-placebo control group could not be meaningfully explained, and the placebo control group also had certain data analysis problems.
Collectively, these studies confirm that oral NR is safe and can also increase NAD metabolite levels in the blood .
Look at the placebo-controlled parallel design trial .
The aforementioned trial in patients with heart failure has a follow-up. Wang et al. conducted a more detailed analysis. Patients received 500-2000mg/d dose-escalation therapy for 12 weeks.
The results showed that potassium, glucose, insulin resistance, blood pressure, body weight, hematocrit Blood volume, hemoglobin and platelet counts, liver and kidney markers were unchanged, and blood NAD levels increased steadily, but the review authors believe that this study did not analyze the inflammatory and metabolic data well.
Brakdal et al. conducted research on Parkinson’s disease. Thirty newly diagnosed patients were treated with NR 1000mg/d for 30 days, and the results showed that it could increase the level of NAD in the brain and the level of related metabolite Me2PY in the cerebrospinal fluid, and reduce the inflammatory markers in the cerebrospinal fluid.
The study authors suggested that NR-associated changes in brain metabolism could be extrapolated to Parkinson’s therapeutic potential, but the review authors felt that such extrapolation was inappropriate.
The largest human NR trial to date was conducted by Conze et al., testing the safety of 100, 300, and 1000 mg/d doses for 8 weeks in 100 healthy middle-aged participants.
The results showed a dose-dependent increase in blood NA levels and increased plasma and urine metabolites. But there were no differences in liver or kidney function, potassium levels, triglycerides, or cholesterol levels between the two groups, and blood pressure and heart rate remained unchanged.
A study by Dollerup et al. published several papers related to metabolism. The participants of this study were obese, insulin-resistant male participants who received 2000mg/d NR for 12 weeks.
The results showed that NR treatment did not affect insulin sensitivity. , fasting blood glucose, HbA1c, cholesterol, and alanine aminotransferase (ALT) levels did not affect glucose tolerance or insulin, glucagon, C-peptide, and glucagon-like peptide 1 levels in the glucose tolerance test.
Muscle-centric analysis showed no changes in NAD, NADH, NADP, NADPH, etc. in muscle after NR supplementation, and did not affect mitochondrial respiration.
In addition, analysis of stool samples also showed that oral administration of NR did not affect the abundance of intestinal bacteria.
Finally, look at placebo-controlled crossover designs .
The study by Elhassan et al. supports the above conclusions of NR regarding mitochondrial function and muscle bioavailability. In this study, 12 elderly healthy men were supplemented with NR 1000mg/d for 21 days.
The results showed that only MeNAM, Me2PY, Me4PY and NAAD levels were increased in muscle. Participants’ grip strength, glucose tolerance, levels of non-esterified fatty acids, and respiratory exchange ratio were unchanged.
The same goes for liver, kidney, thyroid function, and cholesterol levels, platelet counts, and potassium levels.
Serum levels of the inflammatory markers IL-6, IL-5, IL-2, and tumor necrosis factor alpha were reduced, consistent with several other studies.
A similar study by Remie et al. was conducted in 6 overweight/obese middle-aged individuals.
Likewise, NR did not cause changes in muscle NAD, NADH, NADP, NADPH, NAM, and NNMN levels, nor did it affect muscle mitochondrial respiration, hepatic lipid deposition, or cardiac function.
Also unaffected were a range of inflammatory markers as well as cholesterol, triglycerides and glucose in the blood.
Furthermore, the review authors felt that the effect sizes for all significant differences in this study were small and the strength of the evidence was not convincing.
Still focusing on muscles, the Stocks et al. study found broadly consistent with previous studies.
The study by Dolopikou et al. provides valuable data on the acute uptake of NR. Twelve young and 12 elderly participants in the trial received 500 mg NR 2 hours before the test. In both groups, levels of NADH and NADPH in blood cells increased significantly, as did maximal oxygen uptake from baseline, but the same phenomenon was seen in the placebo group, although the change was greater in the NR group.
In the study conducted by Martens et al., 24 middle-aged and elderly participants were supplemented with NR 1000mg/d for 6 weeks. The metabolism-related results of this study were basically consistent with previous experiments. Additional analysis of Alzheimer’s disease-related markers found that changes in NAD or NADH were not related to Aβ42, total Tau, or pTau181.
In the study by Nascimento et al., ingestion of NR failed to conceptualize the activity of brown adipose tissue.
Taking all the above studies together, we can simply conclude that human NR trials, especially those related to metabolism, have yielded few clinically meaningful results.
Since the first clinical trial in 2016, our exploration of NR has focused on safety in a small sample population, mostly healthy people.
Across all studies, the reproducible conclusions were a reduction in inflammatory markers in whole blood or immune cells, and an increase in a series of related metabolites of the NAD machinery in the blood.
Outside of blood, data on NR boosting NAD is limited to muscle and brain.
In these studies, there is also an exaggeration of the results.
For example, increased levels of NAAD, MeNAM, Me2PY, and Me4PY are often interpreted as indicators of enhanced NAD metabolism, but these metabolites are not just products of NAD.
NAM produced by oral NR can either enter the NAD cycle or be directly methylated. digestion and excretion.
Obviously, what are the benefits of oral NR to human beings? It is still difficult to simply explain those expensive health care products, let them stay on the shelf for a while.
References:
[1] https://www.science.org/doi/10.1126/sciadv.adi4862
Nicotinamide riboside supplements are basically ineffective!
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