104 replies to this topic

[able]

Thank you for posting. I watched the video and Amy Boileau Vice president of R & D at Chromadex said nothing about sublingual delivery of NR in that video. Transcribing freely:

”The oral bioavailability of NR is high, very high and the crystalline form in the capsules can be formulated as a powder and we are also interested in topical forms”.

 

You're right.  I  had just read the article that mentioned giving a powder to older people which I thought meant sublingual.  

 

After watching the video I see she mentions it a few times, one of which she says could be a powder added to a beverage.  So it is not quite clear and may be just early investigations at this point.

 

But I'm not really buying her assertion that the "oral bioavailability of NR is high".  

 

Topical formulation may be a winner.

Edited by able, 03 November 2018 - 08:01 AM.

[Oakman]

You're right.  I  had just read the article that mentioned giving a powder to older people which I thought meant sublingual.  

 

After watching the video I see she mentions it a few times, one of which she says could be a powder added to a beverage.  So it is not quite clear and may be just early investigations at this point.

 

But I'm not really buying her assertion that the "oral bioavailability of NR is high".  

 

Topical formulation may be a winner.

 

In reality, I'd have to say she's nearly 100% wrong, as least according to the definition of 'Bioavailability'. First pass metabolism in the liver takes it down almost entirely.

 

"Bioavailability (F): Bioavailability is a measure of the amount of an administered dose that reaches the bloodstream."

 

https://www.scienced...bioavailability

 

or

 

"n pharmacology, bioavailability is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs."

 

https://en.wikipedia...Bioavailability

 

What saves her is this, since NR is not classified as a drug......

 

"For dietary supplements, herbs and other nutrients in which the route of administration is nearly always oral, bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed.^[2]

 

Bioavailability is defined slightly differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food and Drug Administration regulations."

[Harkijn]

Also, let's not forget that both NR and NMN at rather moderate dosages  were demonstrated to raise NAD considerably though over time this effect abated. And I  think we all agree that at least preventing chronically low NAD+ is a very good thing.

So not detracting from the Liu study and other indications I can understand  that neither Chromadex nor Sinclair seem very concerned about the bioavailibility issue.

As far as NR is concerned , a  number of studies confirm a positive role in many conditions. A survey of these studies can be found at AboutNAD.com.

 

[aaaaaaal]

They keep saying that the best way to take NMN is sublingually.

Has this been proved scientifically?

Thanks

Edited by aaaaaaal, 13 March 2019 - 12:54 PM.

[able]

It has been proven that NR and NMN are almost entirely metabolized in the GI tract and liver.

 

There is a lot of research on sublingual delivery of other molecules and it is known what is required for a successful sublingual product, and what a typical absorption rate is.

 

Of course there have been no human studies yet showing if NMN is actually absorbed sublingually.  

 

I personally have zero doubt NMN is absorbed sublingually, as I have said here many times.  Taking 250 mg of NMN powder at once and I get a huge energy rush with measurable elevated heart rate.  It is even more pronounced with NAD+.  

 

But you might say that it is speculation, not proven fact, as there are no human clinical trials yet that prove it.

 

If you actually have reason to  believe that NMN, NR, or NAD+ is definitely NOT absorbed at all sublingually, then you might say they are spreading misinformation.

 

Otherwise, I would suggest it is  marketing claims that have not been proven.

Edited by able, 13 March 2019 - 03:37 PM.

[aaaaaaal]

 

It has been proven that NR and NMN are almost entirely metabolized in the GI tract and liver.

 

There is a lot of research on sublingual delivery of other molecules and it is known what is required for a successful sublingual product, and what a typical absorption rate is.

 

Of course there have been no human studies yet showing if NMN is actually absorbed sublingually.  

 

I personally have zero doubt NMN is absorbed sublingually, as I have said here many times.  Taking 250 mg of NMN powder at once and I get a huge energy rush with measurable elevated heart rate.  It is even more pronounced with NAD+.  

 

But you might say that it is speculation, not proven fact, as there are no human clinical trials yet that prove it.

 

If you actually have reason to  believe that NMN, NR, or NAD+ is definitely NOT absorbed at all sublingually, then you might say they are spreading misinformation.

 

Otherwise, I would suggest it is  marketing claims that have not been proven.

 

 

 

 

Fair enough.

 

I don't mean to be funny... but in Dr. Sinclair's latest study, the mice were fed their NMN in their drinking water? As they don't drink with a glass (at least I don't think they do!) maybe a lot of NMN was absorbed sublingually?

So maybe the best way to take NMN is to mix it with water and just lick the water with your tongue? As I said I'm not trying to be funny. LOL

Edited by aaaaaaal, 17 March 2019 - 01:37 PM.

[LawrenceW]

 

It has been proven that NR and NMN are almost entirely metabolized in the GI tract and liver.

 

 

Are you basing your statement solely on the findings of the Liu study? 

 

If so, the Liu study is contradicted on its NMN findings by this study. 

 

https://www.nature.c...018-0009-4#Sec8

 

 

Specifically "We have previously shown that NMN is absorbed from the gut into blood circulation within 2–3 min and transported into tissues within 10–30 min (refs 5,15). NMN is then immediately utilized for NAD+biosynthesis, significantly increasing NAD+ content in tissues over 60 min. This fast pharmacokinetics has recently been confirmed by using doubly labelled isotopic NMN (C13-D-NMN), showing its rapid absorption and conversion to NAD+ in peripheral tissues15. It has also been proposed that NMN is converted extracellularly to NR, which is transported into cells and reconverted to NMN21. Recent studies, however, have shown that the analyses of in vivo kinetics of these NAD+intermediates are affected by differences in sample collection and extraction methodologies22,23 (also see Methods). Therefore, it is critical to understand the mechanism by which NMN or NR is transported into cells or tissues. The fast pharmacokinetics of NMN led us to the hypothesis that there is an effective transporter that facilitates the direct uptake of NMN into the gut and other organs. Thus, we set out to identify this presumed NMN transporter in mammals."

 

and

 

"Additionally, how to analyse the in vivo kinetics of NMN is also critical, and the results could be significantly affected by differences in sample collection and extraction methodologies22,23. For example, plasma samples need to be processed immediately after collection, as we did in this study, because freezing blood or plasma samples causes inaccurate measures of NMN levels."

 

What the author of this study is suggesting in the kindest way is that Liu didn't collect the NMN samples for testing in the correct way thereby generating bad data to base the NMN portion of their study on.

Edited by LawrenceW, 17 March 2019 - 02:46 PM.

[able]

Are you basing your statement solely on the findings of the Liu study? 

 

If so, the Liu study is contradicted on its NMN findings by this study. 

 

https://www.nature.c...018-0009-4#Sec8

 

 

Specifically "We have previously shown that NMN is absorbed from the gut into blood circulation within 2–3 min and transported into tissues within 10–30 min (refs 5,15). NMN is then immediately utilized for NAD+biosynthesis, significantly increasing NAD+ content in tissues over 60 min. This fast pharmacokinetics has recently been confirmed by using doubly labelled isotopic NMN (C13-D-NMN), showing its rapid absorption and conversion to NAD+ in peripheral tissues15. It has also been proposed that NMN is converted extracellularly to NR, which is transported into cells and reconverted to NMN21. Recent studies, however, have shown that the analyses of in vivo kinetics of these NAD+intermediates are affected by differences in sample collection and extraction methodologies22,23 (also see Methods). Therefore, it is critical to understand the mechanism by which NMN or NR is transported into cells or tissues. The fast pharmacokinetics of NMN led us to the hypothesis that there is an effective transporter that facilitates the direct uptake of NMN into the gut and other organs. Thus, we set out to identify this presumed NMN transporter in mammals."

 

and

 

"Additionally, how to analyse the in vivo kinetics of NMN is also critical, and the results could be significantly affected by differences in sample collection and extraction methodologies22,23. For example, plasma samples need to be processed immediately after collection, as we did in this study, because freezing blood or plasma samples causes inaccurate measures of NMN levels."

 

What the author of this study is suggesting in the kindest way is that Liu didn't collect the NMN samples for testing in the correct way thereby generating bad data to base the NMN portion of their study on.

 

 

Yes, that is why I said "almost".  

 

But I wouldn't say Liu is contradicted by the study on Slc12a8.  

 

Liu found that ALL NR and NMN is metabolized to NAM. But they used young, healthy mice, which wouldn't be expected to have upregulated SLC12a8 activity.  That may explain why they didn't find any double labelled NAD+ outside the liver.

 

I'm sure you have noticed there is no indication how much NMN might be processed by Slc12a8.  Is it 1%, 10%, or what?

 

The Mills 2016 research shows the speedy uptake of NMN, but also gives no indication of quantity.

 

Is the NAD+ it creates in small intestine able to reach the rest of the body?  From the study:

 

 

Therefore, increasing NMN availability or stimulating the function of the NMN transporter could effectively counteract age-associated NAD+ decline in the aged small intestine.

upregulation of Slc12a8 in the ileum contributes to the maintenance of NAD+ levels in the aged intestine.

 

 

They make similar statement in several places, but nowhere say that it increases NAD+ throughout the body.

 

I switched to NMN soon after the mills research came out that made me question what Chromadex says.

 

But I don't think this research tells us if the slc12a8 transporter is a  huge benefit for utilization of NMN, or minor.  Hence, I stand by my statement that NR and NMN is ALMOST entirely metabolized.

 

If Slc12a8 was a game changer, Chromadex stock would be zero.

Edited by able, 17 March 2019 - 07:36 PM.

[Michael]

It has been proven that NR and NMN are almost entirely metabolized in the GI tract and liver.

Yes — whether delivered orally or even via injection, albeit to a lesser degree. So that's still a substantial issue even if SL delivery of NMN is very high (an unproven postulate as of today).
 

There is a lot of research on sublingual delivery of other molecules and it is known what is required for a successful sublingual product, and what a typical absorption rate is.

 
Yes, and that research would suggest that NMN and NR are poor candidates . NMN does have a favorable molecular weight (334.22 Da), but it's very hydrophilic, and hydrophilic substances are generally poor candidates for sublingual delivery: they have no ability to cross the mucosal membranes, and while a very small amount may be absorbed instead tend to just dissolve in the saliva and seep down the throat. Instead, good candidates are mildly lipophilic drugs:

"Lipids present in the oral mucous membrane offer the main barrier to the permeability of hydrophilic drugs. On the other hand, well-hydrated connective tissues provide resistance to lipophilic drugs. Thus, the potential transport path across the oral mucous membrane may be either polar or non-polar. Non-polar molecules cross through the lipid regions of the epithelium, while polar molecules travel through ionic channels present in the intercellular spaces of the epithelium, or aqueous pores present in the epithelial cells. ... For efficient absorption through the oral mucosa, the drug must be hydrophobic enough to partition into the lipid bilayer, but not so hydrophobic such that once it is in the bilayer, it will not partition out again....  For this reason, an understanding of a drug’s lipophilic or hydrophilic nature during the developmental stage of the drug product appears to be the most useful index for evaluating its suitability for absorption across the oral mucosa.
http://www.pharmtech...62556?page=full
 

"Factors affecting the sublingual absorption
Lipophilicity of drug: For a drug to be absorbed completely through sublingual route, the drug must have slightly higher lipid solubility than that required for GI absorption is necessary for passive permeation."
https://innovareacad...Suppl2/1092.pdf
 
"Lipophilic drugs  are better absorbed [via the sublingual route] than hydrophilic drugs."
https://www.scienced...k/9780120885923
 
"Sublingual administration ... takes advantage of the permeability of the oral epithelium and is the preferred route for a few potent lipophilic drugs, such as nitroglycerin and oxytocin, and even the commonly used oral sedative triazolam"
https://www.scienced...m/science/book/9780323393072

This can be a non-issue when you only need a sub-milligram quantity to be absorbed and you're willing/able to throw a massive overkill dose at the problem, but not when you're using hundreds of milligrams of something and hoping for a better result than a similarly high dose by the enteral route.
 

Of course there have been no human studies yet showing if NMN is actually absorbed sublingually.

... nor any animal studies, nor even any tissue-culture models. There is diddley-squat, AFAICS.
 

If you actually have reason to believe that NMN, NR, or NAD+ is definitely NOT absorbed at all sublingually, then you might say they are spreading misinformation.

Otherwise, I would suggest it is marketing claims that have not been proven.

The burden of proof lies on the person making the positive claim, especially when s/he has a financial interest in the claim. I think it is fair to say that it borders on misinformation or deceptive marketing to make as definitive a set of assertions as ABN currently does in the absence of any evidence.
 
They say they're looking to conduct a human absorption trial; that would be admirable, so long as they are hands-off about the design and execution and agree to publication irrespective of the results. I'd encourage all ABN customers to drop them an email expressing this.
 
Beyond the provocative headline, this thread would seem best-merged into the Sublingual NR and NMN thread. Any objections?

Edited by Michael, 19 March 2019 - 06:20 PM.

[Forever21]

What NR does Michael take? Does anyone know? What I gather from that last post is that Michael is skeptic on ABN and sticks to NR for now. So my question is, what NR? Niagen?

[able]

 

 

The burden of proof lies on the person making the positive claim, especially when s/he has a financial interest in the claim. I think it is fair to say that it borders on misinformation or deceptive marketing to make as definitive a set of assertions as ABN currently does in the absence of any evidence.
 
They say they're looking to conduct a human absorption trial; that would be admirable, so long as they are hands-off about the design and execution and agree to publication irrespective of the results. I'd encourage all ABN customers to drop them an email expressing this.
 
Beyond the provocative headline, this thread would seem best-merged into the Sublingual NR and NMN thread. Any objections?

 

I agree they should be less definitive in some of their statements.

 

I just had a problem with the title of this thread.  

 

I hope they are able to publish some results soon, but personally I don't need any clinical trials to know that some NMN is absorbed sublingual, as I get elevated heart rate within a few minutes.  

 

Maybe it is a small % that gets through that way, but is enough to have an effect.  To  me, that means they are right and it is better than a capsule.  But certainly that is no proof that the FDA would recognize. 

[WinnieBeeRich]

Instead, good candidates are mildly lipophilic drugs:

"Lipids present in the oral mucous membrane offer the main barrier to the permeability of hydrophilic drugs. On the other hand, well-hydrated connective tissues provide resistance to lipophilic drugs. Thus, the potential transport path across the oral mucous membrane may be either polar or non-polar. Non-polar molecules cross through the lipid regions of the epithelium, while polar molecules travel through ionic channels present in the intercellular spaces of the epithelium, or aqueous pores present in the epithelial cells. ... For efficient absorption through the oral mucosa, the drug must be hydrophobic enough to partition into the lipid bilayer, but not so hydrophobic such that once it is in the bilayer, it will not partition out again....  For this reason, an understanding of a drug’s lipophilic or hydrophilic nature during the developmental stage of the drug product appears to be the most useful index for evaluating its suitability for absorption across the oral mucosa.
 

Thanks a lot for sharing, Michael. Pity I didn't bump into your post earlier. Been on the wrong track for a whole  year.

 

At the risk of sounding stupid(Sorry but I'm not a biology pro), does the same apply to nasal mucous membranes ? I mean, does a drug  also have to be moderately lipophilic to be absorbed nasally? Are there lots of lipids present in nasal mucous membranes? ( Actually I wanna know if lipids are predominantly present in all mucous membranes?)

 

From what I heard from some NMN users, nasal spray has an instant refreshing effect. (Maybe they got a point because nasal NMN spray makes one sneeze.           ）

[WinnieBeeRich]

Just read that ABN released liposomal sublingual NMN gel in Feb. They must have read your post, Mike.   

 

So, the absorbtion issue is resolved?  If NMN can be made liposomal, so can everything, NAD+ included?(Do I understand it correctly?)

 

How about a liposomal NAD+ nasal or subligual gel? Now that the hydrophilicity problem has been resolved , why don't we just take NAD+ instead? NAD+ molecules are small enough(molecular weight :663.4)  for nasal and sublingual absorbtion.

 

Would love to hear your opinion, Michael. 

[able]

I really doubt liposomes are required to absorb NMN or NAD+.  As I have posted many times, you can feel a caffeine like response when taking sublingually, especially from NAD+ powder.  

 

If fact,  Dr Brenner keeps tweeting that NMN products must be adultered with caffeine, as so many people report such an immediate stimulating effect.

 

NR capsules do not have such an effect as it takes 4 hours to make it throught the stomach and liver, while NR taste nasty so doesnt work sublingually for most people.

 

The nasal spray is even more energizing. I don't know if the mucose membranes in the nose absorb it better, or, more likely because it has a direct path to the brain.

Edited by able, 16 August 2020 - 08:18 PM.

[WinnieBeeRich]

I really doubt liposomes are required to absorb NMN or NAD+.  As I have posted many times, you can feel a caffeine like response when taking sublingually, especially from NAD+ powder.  

 

If fact,  Dr Brenner keeps tweeting that NMN products must be adultered with caffeine, as so many people report such an immediate stimulating effect.

 

NR capsules do not have such an effect as it takes 4 hours to make it throught the stomach and liver, while NR taste nasty so doesnt work sublingually for most people.

 

The nasal spray is even more energizing. I don't know if the mucose membranes in the nose absorb it better, or, more likely because it has a direct path to the brain.

I've tried both sublingual and nasal delivery. Felt okay but not half as stimulating as other NMN users said. But I also doubt that liposomes are needed to absorb NAD+ precursors in mucosal delivery because from what I BINGed， most liposomes are too big  for mucosal absorbtion. The only "qualified" ones might be SUL:small, unilamellar liposomes.  SULs are smaller but when mixed with NAD+ precursors the overall dimensions might exceed the requirement (“molecular weight ＜1000”) for mucosal delivery.

Edited by WinnieBeeRich, 17 August 2020 - 04:58 PM.