Nicotinamide adenine dinucleotide (NAD) replenishment therapy using nicotinamide riboside (NR) shows promise for Parkinson’s disease (PD) and other neurodegenerative disorders.
However, the optimal dose of NR remains unknown, and doses exceeding 2000 mg daily have not been tested in humans. To evaluate the safety of high-dose NR therapy, we conducted a single-center, randomized, placebo-controlled, double-blind, phase I trial on 20 individuals with PD, randomized 1:1 on NR 1500 mg twice daily (n = 10) or placebo (n = 10) for four weeks.
The trial was conducted at the Department of Neurology, Haukeland University Hospital, Bergen, Norway. The primary outcome was safety, defined as the frequency of moderate and severe adverse events. Secondary outcomes were tolerability defined as frequency of mild adverse events, change in the whole blood and urine NAD metabolome, and change in the clinical severity of PD, measured by MDS-UPDRS.
All 20 participants completed the trial. The trial met all prespecified outcomes. NR therapy was well tolerated with no moderate or severe adverse events, and no significant difference in mild adverse events. NR therapy was associated with clinical improvement of total MDS-UPDRS scores.
NR greatly augmented the blood NAD metabolome with up to 5-fold increase in blood NAD+ levels.
Our results support extending the dose range of NR in phase II clinical trials to 3000 mg per day, with appropriate safety monitoring.
3 grams of NR per day could end up being a bit pricey, but well worth it if it works. They found an 11 point improvement in the UPDRS score in the test arm but not in the placebo arm, which is big. This was confounded by the fact that patients in the test arm ended up taking levodopa more frequently at the end of the study than at the beginning. So the good results cannot be definitively attributed to the NR supplementation. But worth a try if one is so inclined
I’m on 900 mg a day of TriNiagen the last few weeks. Doing slightly better. Walking easier, arm swing improved and less fatigue. 3 g/day would be a chunk a’ change. But if safe and effective…
As someone else mentioned the TruNiagen company has started to distribute larger bottles with 2 x 500mg doses (as opposed to my 3 x 300mg). They did an email blast about a month ago (1 November 23) linking to their site, extract follows:
“Tru Niagen Pro 1,000mg is our most potent offering—the serving size made for longtime Tru Niagen customers, physicians, pro athletes, and health enthusiasts in the know. It’s also the serving administered in the majority of clinical studies using Niagen. Taken daily, Tru Niagen 1,000mg increases levels of nicotinamide adenine dinucleotide (NAD+) by up to 150% in as little as three weeks, and keeps them elevated with ongoing supplementation. ”
If you use Tru Niagen, it would take 10 capsules per day to reach 3 grams. About $120 for 9 days if you buy the 90 capsule jar. That's $13.33 x30 = $400 per month. A little less if you buy a larger bottle.
I don't think TruNiagen has the patent on NR anymore. I see this: 2000 MG Liposomal Nicotinamide Riboside Supplement, High Absorption, NAD+ Boosting Supplement with TMG and Pterostilbene, Superior to Niacinamide for Cellular Energy, and Age Resist, 120 Softgels for $30.
ChromaDex just recently intro'd Tru Niagen 1000mg tablets to the general population, whereas before ( and still available ) you could only get the 300mg tabs.
expensive in the usa -- i bought mine in China ... but like so many other supplements I've tried (I take about 30 daily) --- didn't seem to make any difference ... but i didn't take it very long
I take 900mg of Tru Niagen a day for about 6 months. I also take an NAD supplement. I have noticed a big difference. I also have had NAD IVs that are very expensive but worth it!
Tru Niagen is the one they use on the studies. It’s expensive but definitely worth it. The rest is a crapshoot, so I chose this. I started them at the same time, so I’m not sure which one. is working or both?
In my opinion a small dose of vitamin B3 NA will provide all the NAD needed safely at the cost of a tenth. We PwPs are not decathlon athletes, even if we think we are, we need gradualness and long-term security. I don't like sudden vitamin boosts especially if they are new untested things. This is an old discussion, do your research on HUCP too.
IMHO it could be dangerous boosts NAD in such a short time as it could trigger unwanted cell apostosis. See the Lou T. comments and Simon's response, here at the end:
I completely agree with you. In my opinion, a B-complex with bioactive B vitamins and reasonable dosages should be sufficient for most of us. It's important to prioritize gradualness and long-term safety, rather than relying on sudden boosts of untested substances. Thank you for sharing your thoughts on this.
More than ever this is the case with the b3 and I quote:
“Lou T.
JULY 6, 2018 AT 12:41 AM
Very helpful article. I’ve been considering NR for a relative who has PD, but have a few concerns regarding safety, specifically for someone who has PD.
Looking at the chart that shows how NR enables increased production of NAD+ from its breakdown products (i.e., “recycling” of NAD+), I see that one by-product of this increased NAD+ production is additional ADP-ribose.
This article from 2014 is titled “Poly (ADP-ribose) in the pathogenesis of Parkinson’s disease.”
The article shows that poly ADP-ribose (PAR) enables a process of cell death called parthanatos (essentially, death by PAR).
From that article:
“A recent report on Parkinson’s disease animal model demonstrates that poly (ADP-ribose) (PAR) dependent cell death, also named parthanatos, is accountable for selective dopaminergic neuronal loss. Parthanatos is a programmed necrotic cell death, characterized by PARP1 activation, apoptosis inducing factor (AIF) nuclear translocation, and large scale DNA fragmentation…
“Using NAD+ as a substrate, PARP can elongate ADP-ribose chains via a (1→2) O-glycosidic bond…
“Cells can die due to excessive generation of PAR (11) which is considered as a cell death messenger. This type of cell death is termed parthanatos, as previously mentioned, by combining “PAR” and the word “Thanatos” which refers to the god of death in Greek mythology (25)…
“[P]arthanatos definitely contributes to several types of cell death including neurodegeneration…
“[A] recent study using PD mouse models suggested that PAR-dependent cell death is dominant in slowly progressing dopaminergic neurodegeneration in vivo…
“PARP1 is exceptionally abundant in nigra dopaminergic neuronal cell types compared to others (i.e., approximately three times more abundant in nigra dopaminergic neurons compared to other neurons or astrocytes). Although PARP1 is quite an abundant nuclear protein in general, the additional pool present in dopaminergic neurons may provide a broader window of PAR regulation. It is conceivable that dopaminergic neurons may be more keenly susceptible to parthanatic cell death, in response to the same PARP1 activating stimuli…
“AIMP2-PARP1 signaling pathway in vivo suggests that parthanatos could be involved in slowly progressing dopaminergic neurodegeneration in PD. Speculation on how to prevent dopaminergic cell loss in PD may now be expanded to specifically target the parthanatic cell death cascade.”
According to this other article, when NAD+ breaks down into ADP-ribose, that ADP-ribose gets aggregated into chains that then damage neurons through inducing the release of AIF (cell death effector).
Figure 2 of that article purports to show the elongation of ADP-ribose into poly ADP ribose (PARP) chains.
I have *not* found any information that specifically associates NR with any deleterious effects on PD progression, or even any articles that make a connection between NR and parthanatos. But putting two and two together (maybe getting five) I have some concerns about that possibly occurring. The several safety studies that you mention, while fine to assessing acute effects, do not seem to be of sufficient duration to assess possible negative effects upon PD progression. Although, the drosophila study that shows actual improvements in climbing ability is somewhat encouraging in thinking that, whatever the negatives, there could be an overall benefit.
A further concern is that when I read accounts from people taking NR in crowdsourced reviews of Niagen, while there are many positive reports, a significant minority report negative effects such as extreme headaches.
I’d be very interested to hear your thoughts regarding whether the above concerns seem valid.
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Reply
Simon
JULY 31, 2018 AT 4:30 PM
Hi Lou,
Thank you very much for your really interesting comment – brilliant stuff. I also appreciate and have a lot of respect for the proactive approach you are taking to help your relative.
My apologies for the delay in responding to your question, but it was one which has required some homework and consulting of NAD experts. The short answer is ‘Yes, it could be detrimental if excess PAR is not metabolised quickly’. And the second half of that sentence is key.
It is important not to view biological processes like the NAD pathway in isolation. There are checks and balances for each step in this process – enzymes that monitor each enzyme – to make sure the system is running smoothly. But this is also where variations between individuals can come into play, and it is impossible to predict how each person is going to react to a particular treatment. At present we simply do not have the methods of determining this.
PAR metabolism is mediated by PAR polymerases (PARPS) and PAR glycohydrolase (PARG). In contrast to the family of PARPs, only one gene for PARG has been detected in mammals and insects. So there could be a bit of vulnerability in the system there. Different people may have different levels of PARG (due to differences in the regulation of PARG levels). This is why it is wise (if one is inclined to do so) to gradually start NAD-based supplements in a graded fashion (and always in consultation with one’s clinician). The system should be able to adapt over time, as opposed to a sudden overload of high dose supplement.
And there has very recently been a study published that was looking at this issue of dysregulation of redox resulting from too much Nicotinamide Riboside supplementation being applied too quickly (ncbi.nlm.nih.gov/pubmed/300.... After 21 days the researchers observed problems in the treated animals, but the important thing to note in this study was the dosing of 300mg/kg in rats. That is equivalent to 48mg/kg in human which means 3400mg per day
(fda.gov/…s/ucm078932.pdf). That is a crazy amount of NR supplement. Almost 3.5 times the dose being tested in the NOPARK clinical trial mentioned above.
So long-answer-short, yes there could be PAR-associated issues with NAD-based supplements, but at present we are not sure on how to determine which dose will work for which individual. This will require more research.
”Looking at the chart that shows how NR enables increased production of NAD+ from its breakdown products (i.e., “recycling” of NAD+), I see that one by-product of this increased NAD+ production is additional ADP-ribose.”
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