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First Human Trial of I.V. NAD+: You Pee it Out

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#1 Michael

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Posted 03 September 2019 - 10:56 PM


All:
 
I find this very surprising:
 

Front. Aging Neurosci. | doi: 10.3389/fnagi.2019.00257
A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 hour intravenous infusion of NAD+
Ross Grant, Jade Berg, Richard Mestayer, Nady Braidy, James Bennett, Susan Broom and James Watson
 
... no data are currently available on the fate of directly infused NAD+ in a human cohort. This study therefore documented changes in plasma and urine levels of NAD+ and its metabolites during and after a 6 hour 3 μmol/min NAD+ intravenous infusion.

Surprisingly, no change in plasma NAD+ or metabolites (nicotinamide, methylnicotinamide, ADP ribose and nicotinamide mononucleotide) were observed until after 2 hours. Increased urinary excretion of methylnicotinamide and NAD+ were detected at 6 hours, however no significant rise in urinary nicotinamide was observed.

This study revealed for the first time that i) at an infusion rate of 3 μmol/min NAD+ is rapidly and completely removed from the plasma for at least the first 2 hours, ii) the profile of metabolites is consistent with NAD+ glycohydrolase and NAD+ pyrophosphatase activity and iii) urinary excretion products arising from an NAD+ infusion include NAD+ itself and meNAM but not NAM.


The full text is not available, and their phrasing is a bit odd: "no change in plasma NAD+ or metabolites ... observed until after 2 hours" implies that such elevations were seen from that point onward, but if so, why not put that (with the numbers) in the abstract?

 

They looked at plasma NAD+ (etc), not eg. whole blood or RBC, so one might speculate that it's rapidly absorbed into RBC — but there's no evidence that this happens AFAIK, and if that happened, you'd expect to see it rise in plasma first and slowly be taken up. OTOH, they saw "increased urinary excretion of ... NAD+ ... at 6 hours," so it doesn't seem to have just been broken down (especially since there was (initially?) no rise in plasma NAM or NMN, and no increase in urinary NAM either. There was a rise in urinary MeNAM, consistent with conversion to NAM and then methylation to detoxify it, but how did it get there? Again, what happened in the "missing" 4 hours in plasma?

 

"the profile of metabolites is consistent with NAD+ glycohydrolase and NAD+ pyrophosphatase activity" might answer some of this, but it's not clear how: NAD glycohydrolase catalyzes hydrolysis of NAD+ to ADP-ribose, and NAD+ pyrophosphatase hydrloyzes NAD+ to ADP and NMN, but they saw "no change in plasma ... ADP ribose and nicotinamide mononucleotide ... until after 2 hours." It would, however, at least partially explain there was no NAM anywhere to be seen, with perhaps some NAM being produced and converted to MeNAM.

 

Certainly, it doesn't seem that IV NAD+ is used much, since its use by SIRTs or PARPs leads directly to NAM production. Amounts matter, however: if there was a ton of MeNAM and little ADPR or NMN at any time point, that might imply significant consumption of NAD+ by these enzymes (and/or CD38 and/or CD73). But, again, silence, and no numbers.

 

Very odd. And these investigators are NAD+ enthusiasts (albeit not necesarily intravenous NAD+ enthusiasts).

 

By the way, NPR recently did an exposé on IV NAD+ addiction scammers clinics.

 

 


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#2 MikeDC

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Posted 04 September 2019 - 10:54 PM

This abstract from a recent conference says otherwise

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#3 able

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Posted 05 September 2019 - 01:26 AM

yes, the title of this thread seems a bit unfair.

 

The conference paper shows improvement in some of the same inflammation markers Dr Brenner noted in his recent clinical trial of NR, plus improvement in CRP, which wasn't found

in the NR study.

 

 

Will certainly be interesting to see the details of both studies.



#4 Michael

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Posted 06 September 2019 - 07:37 PM

This abstract from a recent conference says otherwise

 
Actually, no, it doesn't. Read it carefully: it says nothing at all about IV NAD+ raising circulating NAD+, instead saying only that it elevated the "NAD+ metabolome." As in the case of the NR muscle study, this needn't imply any elevation in NAD+ itself.
 

yes, the title of this thread seems a bit unfair.


How so? Or just on the same misreading as MikeDC?
 

Will certainly be interesting to see the details of both studies.

 MikeDC: here, as in many cases, you attached a screenshot (in this case, a particularly blurry one) without attribution or a link. It would be a lot more helpful and credible to directly link and quote the source.

 

With a little digging, I found the conference paper here:

 

 

 We evaluated repeat dose IV NAD+ (1000 mg) for 6 days in a population of 8 healthy adults between the ages of 70 and 80 years. Our data is the first to show that IV NAD+ increases the blood NAD+ metabolome in elderly humans. We found increased concentrations of glutathione peroxidase -3 and paraoxonase-1, and decreased concentrations of 8-iso-prostaglandin F2α, advanced oxidative protein products, protein carbonyl, C-reactive protein and interleukin 6. We report significant increases in mRNA expression and activity of SIRT1, and Forkhead box O1, and reduced acetylated p53 in peripheral blood mononuclear cells isolated from these subjects. No major adverse effects were reported in this study.

 

Notably this is a longer-term, repeat-dose study than the published paper, and specifically in elderly subjects, and does seem to show some benefits. Hopefully this too will be published.As noted, the NR muscle study found no effects on CRP or some other inflammatory mediators, tho' others were favorably moderated (and it had a placebo control). It would be interesting to run a 2x2 study with placebo vs. verum for both IV NAD+ and oral NR on the same parameters.

 

.


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#5 MikeDC

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Posted 06 September 2019 - 09:05 PM

You got to be kidding. IV NAD+ will obviously raise NAD+ in the blood.
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#6 Michael

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Posted 16 September 2019 - 11:32 PM

Well, I'll be darned ... talk about burying the lede ...!
 


fnagi-11-00257-g001.jpg

 

From the barest of skims, the only caveats I will immediately mention are that (a) as you can see, the molar increase in NAM is even greater than that of NAD+, and those of MeNAM, ADPR, and NMN are each about half as much, which is quantitatively curious and in the case of MeNAM a potential hazard; and (b) "On the day prior to the NAD+ IV infusion participants consumed an identical niacin-reduced diet and drank only water," which would tend to lower the baseline and control NAD+ level and thus potentially overstate the effect on NAD+ and the -olome relative to people eating a normal diet or those taking even One-A-Day levels of  NAM/NA.


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#7 mitoMAN

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Posted 27 August 2020 - 05:36 PM

Any more thoughts on this or updated studies?

#8 Oakman

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Posted 27 August 2020 - 07:39 PM

The study mentioned by the OP is not paywalled, it was readily available in its entirety to me. Don't know why.

 

A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 hour intravenous infusion of NAD+

 

In summary, this study revealed for the first time that: (a) at a flow rate of 3 μmole/min all exogenously infused NAD+ was rapidly and completely removed from the plasma for at least the first 2 h; (b) the increase in metabolic bi-products analyzed is consistent with NAD+ glycohydrolases and NAD+ pyrophosphatase activity; and © the urinary excretion products arising from NAD+ infusion include native NAD+ and meNAM but not NAM.

 

AFAICS, the results are both expected and seeming common sense. Give NAD+ IV, the body absorbs as much as it can handle and/or needs to correct for latent deficits, then any excess is discarded from the body. Stop the IV and it all goes back to relative normal shortly.

 

Couple things seems fairly obvious from these results, one, the body that is deficient enjoys an excess of NAD+ for a time as it comes to homeostasis, then not so much.

IV NAD+ is not useful for >2 hours (in this case), and therefore longer therapies do not make sense, depending on the state of the subject at the onset of the treatment.

Perhaps some type of testing should be done on those attempting NAD+ IV to determine their base level of something (metabolites?) before starting.

 


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