This result is the complete opposite of what we expected, and it's quite worrying for people who are taking NR and NMN supplements. And what I find difficult as a medical doctor, not to get frustrated by, is that the NR and NMN supplement companies, as well as their influencers, will not surface this study to you, because it's not going to be good for their sales, or their affiliate commissions [1].
And this comes from someone who was optimistic about NMN back in 2019 and 2020, and made a lot of videos about it. Since then, more data has come in that's starting to make me concerned about the strategy of megadosing vitamin B3, which is what NR and NMN supplements are.
In Norway, 410 people with early Parkinson's disease took either nicotinamide riboside, NR, or a placebo every day for a year. NR is one of the best-known NAD supplements, and the doctors running this trial had seen hints in smaller studies that it might help.
After a year, the people on NR were doing worse than the people on placebo [2]. We'll dive into the details later in this article.
And I think it's important to go through how the supplement companies and associated influencers will try and trick you into buying these supplements. So that you know what to watch out for, and so that you've got a full picture. Because I'm not here to tell you what to do, I'm just here to present you the research, and you can make up your own decision.
Table of Contents
- "It worked in mice"
- "Your NAD falls with age"
- "It raises your NAD"
- "It's just a vitamin"
- The Parkinson's trial
- Why would more NAD make things worse?
- "But I feel better on it"
- My take
- References
"It worked in mice"
But to understand why this result is so surprising, we need to go back to where all the excitement came from.
So the excitement for NR and NMN supplements came from a few mouse studies, as well as the idea that a molecule central to our metabolism, called NAD, declines with age. And if we can support our NAD levels, then in theory we can support our metabolism, and our cells should be more resilient to stress and damage.
And in 2016, that looked like it might work. Old mice given NR had more NAD in their muscles, their muscle stem cells behaved more like young ones, and they lived a little longer [3].
But the excitement really kicked off in January 2019, when David Sinclair, a geneticist at Harvard, appeared on the Joe Rogan podcast.
"…if we give our latest molecule called NMN to a mouse and we exercise it, it'll run even further than it could with either of those alone." David Sinclair, The Joe Rogan Experience, January 2019 [4]
"…so what NMN does, and this other molecule called NR, which both you can get on the internet, they boost the body's levels of NAD back up to youthful levels again. And if we give them to mice… they live longer and they're super healthy… so I take a gram of NMN in the morning, based on clinical trials, has been shown that that will raise NAD." David Sinclair, The Joe Rogan Experience, January 2019 [4]
Now, there's just one problem.
Notice he says "based on clinical trials". There were a handful of small studies showing NR could raise NAD in people. But at that point, there wasn't a single published human trial of NMN. Not one [5].
And even the mouse research wasn't as solid as it looked, because a lot of exciting mouse results don't hold up when other labs try to repeat them. So the most reliable mouse data we have comes from something called the Interventions Testing Program. It runs the same experiment at three separate labs at the same time, in genetically mixed mice, so a result has to show up more than once. And when they tested NR, the mice didn't live any longer [6].
But what about the idea underneath all of this, that our NAD levels go down as we get older?
"Your NAD falls with age"
So let's have a look at that, because it's the idea this whole category of supplements rests on.
In 2022, researchers took muscle biopsies from younger and older adults. And on average, the older adults had less NAD in their muscles. But the older adults who did structured exercise, at least three times a week, had NAD levels comparable to the younger adults. It was the older adults who struggled on a basic test of physical function who had the lowest levels [7].
And then this year, a study measured NAD in the blood very carefully, across seven separate groups of people. And it found that blood NAD stays remarkably stable as we get older [8, 9].
Now, there are some small studies that do find lower NAD in older skin and brain tissue. But the idea that we all run low on NAD as we age, and need to top it back up, just isn't well supported in humans. So the entire premise of taking NR and NMN supplements is kind of not robust.
So what happens when you actually give these supplements to people?
"It raises your NAD"
Well, one place researchers have tested this is long COVID. So what's the link? When the body fights an infection, the recovery puts a lot of strain on our NAD metabolism. So in theory, NR should help. And in this trial, they gave 58 people NR or a placebo, and their blood NAD went up about three-fold. But did that actually help with any of their symptoms? Unfortunately, it didn't show any benefit. It was a small trial, and quite a few people dropped out, but compared with placebo, there was no difference in their thinking, their fatigue, their sleep or their mood [10].
And this is the first trick to watch out for. Niagen, the company that sells the NR brand Tru Niagen, helped fund that trial. And on a call with its investors in March, the company described it as showing "significant within group improvements" in fatigue, sleep and depression [11]. Now, within-group just means people felt better than when they started, and the paper itself called those results exploratory. People often feel better after starting any pill, which is why trials have a placebo group. Against placebo, which is the whole point of the trial, there was no difference. This is just company spin, trying to desperately protect their sales.
And it's a similar story for the NMN and NR trials I've gone through in previous videos. When they're pooled, there's no meaningful benefit for muscle, and NMN didn't help blood sugar or cholesterol [12, 13]. There are just a few small signals, like a slightly longer walk in one NR trial in people with poor leg circulation, and slightly lower blood pressure in some NMN trials, that still need confirming [14, 15].
So yes, NR and NMN raise NAD in the blood. But so far, that just hasn't translated into people actually feeling or functioning any better. So is there any harm in trying?
"It's just a vitamin"
The usual answer is that even if NR or NMN doesn't help, it's just a vitamin, so what's the harm? But we've actually been here before with another form of vitamin B3. For decades, doctors prescribed high-dose niacin to improve cholesterol [16]. But in modern trials, in people already on a statin, it didn't reduce heart attacks or strokes. And in the biggest one, with over 25,000 people, where niacin was given with a second drug to stop the flushing, that combination caused more serious side effects, including problems with diabetes control, infections and bleeding [17, 18].
And there's another reason to be cautious. In 2024, researchers looked at what's left over when the body breaks down excess vitamin B3. And people with the highest levels of one of these breakdown products, called 4PY, had about twice the risk of a heart attack, stroke or death over the next three years. In mice, 4PY inflamed the lining of the blood vessels. And NR and NMN raise 4PY as well [19, 20].
Now, this is an association, so it doesn't prove that 4PY causes heart disease, and no NR or NMN trial has measured heart attacks. But it's one more reason I don't think megadosing vitamin B3 is completely risk-free. And to really know whether NR helps or harms, you need a big randomised trial. And now we finally have one.
The Parkinson's trial
So if there's one disease where boosting NAD should help, it's Parkinson's. The brain cells that die in Parkinson's use a lot of energy, and their power stations, the mitochondria, are under strain [21]. So in theory, NAD metabolism should be under significant stress, and that's why a team at Haukeland University Hospital in Bergen, led by the neurologist Charalampos Tzoulis, decided to test NR.
Back in 2022, they gave NR or a placebo to 30 newly diagnosed people for a month. NAD went up in the brain, signs of inflammation fell in the fluid around the brain and spinal cord, and the people whose brain NAD went up showed a mild improvement. And the team concluded that NR deserved a bigger trial [22].
So things were sounding good, and they ran the big one. The NOPARK trial enrolled 410 people at 11 centres across Norway, all diagnosed within the previous two years, with brain scans confirming the diagnosis. Half of them took 500 milligrams of NR twice a day for a year, which is roughly 25 times the vitamin B3 an adult needs each day. And the other half took a placebo that looked identical [2].
Now, Tzoulis and one of his colleagues hold patents on using NR to treat Parkinson's, and those patents are licensed to Niagen. Niagen supplied the capsules, and in 2025 it took out an exclusive licence to develop NR as a Parkinson's drug [2, 23]. So if anyone wanted a positive result, it was them. And they published the negative result anyway, in one of the biggest medical journals in the world. And I really respect that.
So what happened? Over the first three months, both groups improved a little, although the NR group improved less. And then the lines split. The NR group got steadily worse, while the placebo group kept improving until about six months, and only then started to slip.
After a year, on the standard Parkinson's rating scale, where a higher score is worse, the NR group had scored 2.7 points worse than the placebo group [2].
Now, 2.7 points sounds small, and it is. On its own, a patient probably wouldn't notice it, because the point where people tend to notice they're worse is about five points. But this was supposed to slow the disease down, and it went the wrong way. And the result held up when the researchers re-ran the numbers in different ways. The overall score for non-movement symptoms, things like mood, sleep and pain, got worse on NR as well. And in every subgroup they looked at, the result pointed the same way.
NR vs placebo after 1 year (higher = worse):
- Total Parkinson's score: +2.7 points (P = .02)
- Non-movement symptoms: +4.2 points (P = .009)
- Quality-of-life score: lower on NR (exploratory)
- Every prespecified subgroup: pointed toward placebo
Now, to be fair to NR, a couple of things went the other way. Serious side effects, so things like hospital admissions, were actually less common on NR, 8% versus 14%, although that gap could easily be down to chance. And the brain scans didn't show the dopamine cells dying any faster. So this trial doesn't show that NR damaged people's brains. What it shows is that people felt and functioned worse on it [2].
And here's the second trick to watch out for. Back in March, before the paper came out, Niagen told its investors that NOPARK "did not show a clear benefit". Now, "did not show a clear benefit" is technically true. But it leaves out that people actually did worse. And now the company says the next step, together with Tzoulis, is to try NR as a way to prevent Parkinson's. And no trial has ever tested that [11].
So why would more NAD make people worse?
Why would more NAD make things worse?
Well, nobody knows yet. But there's a surprising clue. In that earlier one-month trial, NR had raised NAD in the brain. But after a year, the brain scans in NOPARK found no clear rise, even though NAD in the blood had gone way up. The researchers think the brain may adjust to a constant supply, either by making less NAD or by breaking it down faster, or the scans may just not be sensitive enough to pick it up [2].
And as for why people got worse, the researchers offer two possibilities. Keeping NAD high for a long time might do something unhelpful in Parkinson's that we just don't understand yet. Or NR might be interfering with Parkinson's medication. In mice, NR has been shown to turn down dopamine production over time. But the authors are clear that both of these ideas are unproven [2, 24].
Now, this was a trial in people with Parkinson's, so it doesn't prove that NR harms healthy people. And NMN wasn't tested. But in the largest head-to-head trial in humans, NR and NMN raised blood NAD by about the same amount, and as I covered in my last video on this, animal studies suggest gut bacteria break both of them down into the same cheap form of vitamin B3 [25, 26]. So I'd be surprised if NMN behaved very differently. And what this trial does do is undercut the idea that, at worst, these supplements are harmless.
"But I feel better on it"
Now, a lot of the influencers promoting these supplements will tell you that they feel much better when they're taking them. And some of you will have taken NR or NMN and felt more energetic. I don't think you imagined it. But often, people start one of these supplements when they've decided to get serious about their health. So they're exercising more, they're improving their diet, they're sleeping better, and then the supplement gets the credit.
Add the placebo effect on top of that, and it's easy to feel better, even on something that, in this trial, left people worse off than a placebo [2].
My take
So here's my take. I would not take NR or NMN. After years of human trials, I just don't see a benefit, and now we've got a big trial where people did worse. If you have Parkinson's and you're taking NR, the researchers themselves don't recommend it, so it's worth raising with your neurologist [27].
And when someone's selling you an NAD supplement, ask them whether they told you about this trial.
And remember those older adults with about the same muscle NAD as young people? They were the ones who exercised. That study can't prove the exercise did it, but exercise does so much for us as we get older.
References
1. https://www.casestudies.com/company/partnercentric/case-study/tru-niagen-customer-case-study
2. https://jamanetwork.com/journals/jama/fullarticle/2855023
3. https://www.science.org/doi/10.1126/science.aaf2693
4. https://podm8.com/episodes/the-joe-rogan-experience/1234-david-sinclair
5. https://www.jstage.jst.go.jp/article/endocrj/67/2/67_EJ19-0313/_article
6. https://pmc.ncbi.nlm.nih.gov/articles/PMC8135004/
7. https://www.nature.com/articles/s43587-022-00174-3
8. https://www.nature.com/articles/s42255-026-01537-5
9. https://pmc.ncbi.nlm.nih.gov/articles/PMC8747183/
10. https://pmc.ncbi.nlm.nih.gov/articles/PMC12675013/
12. https://pmc.ncbi.nlm.nih.gov/articles/PMC12022230/
13. https://pmc.ncbi.nlm.nih.gov/articles/PMC11557618/
14. https://www.nature.com/articles/s41467-024-49092-5
15. https://doi.org/10.3390/nu18060890
16. https://doi.org/10.1111/j.1365-2796.2005.01528.x
17. https://www.nejm.org/doi/full/10.1056/NEJMoa1300955
18. https://www.nejm.org/doi/full/10.1056/NEJMoa1107579
19. https://pmc.ncbi.nlm.nih.gov/articles/PMC11841810/
20. https://pmc.ncbi.nlm.nih.gov/articles/PMC6702140/
21. https://doi.org/10.1016/j.cub.2015.07.050
22. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00052-0
23. https://www.businesswire.com/news/home/20250708472670/en
24. https://doi.org/10.1016/j.heliyon.2024.e34355
25. https://pmc.ncbi.nlm.nih.gov/articles/PMC12855009/
