Microdosing nicotine increases NAD levels and rejuvenates old mice

[Mauritio]

This study has some commonalities and some differences from the original study of this thread.

It showed that low dose nicotine resulted in worse reproductive health in male rats.

However the dosage was about 3-4 times higher, about 7,5mg per day and since it was IP the oral dose to achieve that level would be around 10mg.

The dose was given intraperitoneally, all ot once , as opposed to the slow and steady approach from the OP-study, so that might be another reason why these studies had a different outcome.
Plus, I doubt intraperitoneal administration has the same first pass metabolism than oral admin has. The nicotine metabolites like cotinine might play a role in its benefits.

" A low-dose nicotine exposure at 0.6 mg/kg caused detrimental effects on sperm characteristics and induced oxidative stress in the testes and prostate."

Low-dose Nicotine Exposure Induced the Oxidative Damage of Reproductive Organs and Altered the Sperm Characteristics of Adolescent Male Rats - PubMed

A low-dose nicotine exposure at 0.6 mg/kg caused detrimental effects on sperm characteristics and induced oxidative stress in the testes and prostate.

pubmed.ncbi.nlm.nih.gov

 

[GTW]

Nicotine content of Rustica tobacco claimed to be 5-10% dry weight. ie, not much to get 2 mg!
I grew many Nicotiana/tobacco species. My nephew smoked several of them. He said Rustica was great. Because only a few puffs to get a satisfying dose.

 

[Mauritio]

This one shows that an HED of 3,75mg twice per day helped with stroke recovery in rats.

"Behavioral results demonstrated that by the end of the testing stroke+nicotine animals showed significant behavioral improvement relative to stroke+saline animals. Stroke+nicotine animals showed an increase in dendritic length and branching in pyramidal cells of the forelimb and cingulate areas. The results suggest that the behavioral enhancement in the stroke+nicotine group might be attributable to the enhanced dendritic growth in residual cortical motor regions."

Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats - PubMed

The current study examines the effects of chronic administration of nicotine on motor behavior after focal stroke in rats. Animals were trained in a tray-reaching task for 2weeks and then they were divided into: (1) control+saline (2) control+nicotine (3) stroke+saline, and (4) stroke+nicotine...

pubmed.ncbi.nlm.nih.gov

 

[Tarmander]

This is pretty interesting and connects some dots I have observed.

Most problems with nicotine I have seen others have, and I have had, all come from quickly absorbing nicotine. Either through vaping or sublingual etc. I love nicotine, but I only use it once and awhile because it will make me angry afterwards.

I tried yesterday just swallowing a bit of a lozenge instead of letting it absorb sublingually. I had a nice even energy boost that lasted much longer then normal.

Maybe slow absorbing nicotine is the way?

 

[Mauritio]

This is pretty interesting and connects some dots I have observed.

Most problems with nicotine I have seen others have, and I have had, all come from quickly absorbing nicotine. Either through vaping or sublingual etc. I love nicotine, but I only use it once and awhile because it will make me angry afterwards.

I tried yesterday just swallowing a bit of a lozenge instead of letting it absorb sublingually. I had a nice even energy boost that lasted much longer then normal.

Maybe slow absorbing nicotine is the way?

I tried it today too. And it feels a lot more natural and gradual than topically. Not a huge peak in dopamine followed by a crash.
It also does soemthing in my gut, I think it has anti-fungal effects and it helps to speed up transit time. I also noticed less water retention, but i also get that with topical application.

 

[Tarmander]

I tried it today too. And it feels a lot more natural and gradual than topically. Not a huge peak in dopamine followed by a crash.
It also does soemthing in my gut, I think it has anti-fungal effects and it helps to speed up transit time. I also noticed less water retention, but i also get that with topical application.

Yeah maybe the anti fungal effects are significant. Nicotine sometimes pops up as a recommendation on my microbiome report.

 

[GTW]

Tobacco was used topically to treat ringworm.

 

[SonOfEurope]

Saturated fat is the only one welcomed by the lungs.


Amazing thing of nicotine.

We got a hell of a discussion in the near future.

 

[Mauritio]

Tobacco was used topically to treat ringworm.

It's also been used against the plague historically:

""Those employed in the collection of bodies frequently smoked tobacco to avoid catching the plague.”
“For personal disinfections, nothing enjoyed such favor as tobacco; the belief in it was widespread, and even children were made to light up a reaf in pipes. Thomas Hearnes remembers one Tom Rogers telling him that when he was a scholar at Eton in the year that the great plague raged, all the boys smoked in school by order and that he was never whipped so much in his life as he was one morning for not smoking. It was long afterward a tradition that none who kept a tobacconist shop in London had the plague.”
- Nicotine & Testosterone: Is Smoking Tobacco Bad for Men?

 

[Mauritio]

The exact same dosage as in the original study has been shown to alleviate fatty liver (NASH) in mice. Although the dose was given through injection and not via drinking water.

"The results of our investigation demonstrated that nicotine could reduce significantly the levels of IL-6, and TNF-α in serum (P<0.05). The expression of p-NF-κB protein in the group which was NASH model mice injected with nicotine declined significantly as compared with the group which was NASH model mice injected with saline (P<0.05)."
- [Nicotine alleviates the liver inflammation of non-alcoholic steatohepatitis induced by high-fat and high-fructose in mice] - PubMed

 

[Mauritio]

Today is day 3 of doing 1mg/day in my water bottle.

Here's what I noticed:

- an anti-fungal/anti-microbial effect , it's definitely doing something in mg gut, lots of rumbling

- better liver function --> less water retention ,fuller muscles , lost some weight

- more BMs , faster transit time

- relatively sustained and stable energy

- mood sometimes a little low, seems to be related to BMs though , after a BM felt normal again

- slightly higher adrenergic feeling, decided not to take it after 4PM

- feeling cold less often

- hair and skin definitely looks better ,hair loss is greatly reduced, probably due to less endotoxin/gut problems

I'll stop now for a few days and see if the effects stick and how my gut feels without nicotine.
Overall I really like it, and it seems very beneficial for gut and liver.
Since I did 1V-LSD 2 weeks ago I had a slight pinch in my liver that almost completely went away after taking nicotine.

 

[cs3000]

This study looked at the effect of microdoses (2 μg/mL drinking water) of nicotine on mice.

Nicotine was able to rescue the rate limiting enzyme for NAD synthesis, NAMPT, and improve NAD levels.
This comes of course with all the goodies of a higher NAD/NADH ration, in this case: increase in anti-oxidant enzymes, lowering of inflammation and oxidative stress, improvement of cognition and neurogenesis, etc...

Nicotine restores the NAMPT to levels to those of young mice. In some organs even above that.

The interesting thing about nicotine was that higher or lower doses were not as effective or even ineffective.
So there seems to be a sweet spot at a tissue level of about 10ng/ml of nicotine.

In the in-vivo study the oral dose was about 8mcg /day/rat (2mcg/ml drinking water). A mouse weighs about 20g, so 0.4mcg/1g or 400mcg/kg.
Divided by 12 for the usual conversion to humans equals 33,33mcg/kg. Multiplied by 75 for average human weight equals a HED of almost exactly 2.5mg/day.
(I might have screwed up the calculation, so correct me if I'm wrong.)

As it is completely water-soluble, it should be relatively easy to dilute nicotine and take microdoses. Worth a try.

- Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity

great effect thanks
it looks like a low end typical dose rather than microdose (about the amount in 1.5 cigarettes, but taken orally)
but in the peer review they say they showed the effect was independent of effect on nicotine receptors.

Interestingly, nicotine is a secondary metabolite of the NAD+ biosynthesis and the NAD+ pathway is also coordinately regulated with nicotine biosynthesis20,21. Consequently, we hypothesized that nicotine may play a role in the NAD+ salvage pathway. It has been discovered that minuscule amounts of nicotine, as an activator of NAD+ biogenesis, can markedly improve NAMPT activity and NAD+ synthesis, leading to improved glucose metabolism and cognitive function, as well as aging symptoms, in male mice.

clear anti aging effect & survival boost. lowered tumor incidence also

did not effect feed or water intake like higher usual doses
lowered blood sugar (guess it was elevated?)


it increased neurogenesis in the hippocampus a lot , like 2x higher in these aged mice. rly nice effect

To examine the effect of nicotine on NAMPT activity in different tissues of aging mice, we tested NAMPT activity in the hippocampus, cortex, heart, liver, muscle, and kidney at 2, 6, and 12 months of age. We found that the activity of NAMPT in mouse tissues gradually decreased with increasing age. After nicotine administration in drinking water (2 μg/mL) from 6 to 12 months, nicotine significantly restored the NAMPT activity in all the tissues (Fig. 1a–g). Consistently, we detected β-NMN levels in brain and liver tissues by LC-MS and found that β-NMN levels were significantly increased after nicotine administration (Supplementary Fig. 9c).

specific for dose ,
2 micrograms/ml
They show their bodyweight & water intake in the supplementary materials - drank 350ml / week (up to 375ml)

so 50ml a day * 2mcg = 100 micrograms a day

body weight is say 30.5g
so 3.2mg / kg mice dose , taken orally
= human dose 16mg - 20mg depending on bodyweight

but plus side is it worked by drinking in water through the day. so the dose is split up into low doses,
activating choline receptors maybe not great but spread out I wonder if this gets around the stimulation / addictive potential
also considering orally (not chewed as gum but swallowed) the dose is about 20% - 44% as effective vs 80%-90% as cigarretes so should give half the effect. and unlike cigarettes you can avoid the toxic metals.

https://biomedres.us/pdfs/BJSTR.MS.ID.002343.pdf 4mg human dose in this one worked to increase hippocampus BDNF also. so might have benefits for the rest of this too.
though on the other side another study using 1mg/kg i.p in rats , showed a 80% decrease in PSA-NCAM+ and NeuN+ cells

 

[cs3000]

= human dose 16mg - 20mg depending on bodyweight

but plus side is it worked by drinking in water through the day. so the dose is split up into low doses,
activating choline receptors maybe not great but spread out I wonder if this gets around the stimulation / addictive potential
also considering orally (not chewed as gum but swallowed) the dose is about 20% - 44% as effective vs 80%-90% as cigarretes so should give half the effect. and unlike cigarettes you can avoid the toxic metals.

https://biomedres.us/pdfs/BJSTR.MS.ID.002343.pdf 4mg human dose in this one worked to increase hippocampus BDNF also. so might have benefits for the rest of this too.
though on the other side another study using 1mg/kg i.p in rats , showed a 80% decrease in PSA-NCAM+ and NeuN+ cells

Correction on that , the dose and relating it to cigarettes (which only have 1mg nicotine actually absorbed as most of its burned 4. Does development of nicotine addiction depend on the dose?)

"It has been reported that nicotine, when ingested in drinking water, is slowly absorbed through the gastrointestinal tract and is rapidly metabolized in the liver63–66, which might explain why the concentration of nicotine in the body is extremely low (Supplementary Figs. 1a and 3c)."

Btw I'm not 100% sure if I calculated the HED right ,so if anyone could confirm me on that, that'd be great. I can't find a flaw myself, the thing that makes me suspicious is, the authors keep talking about how tiny the dose is in mice but 2.5mg for a human actually isn't really a microdose anymore. So I hope the HED is right.

confused me too why they say mg amounts are a low dose in the study.

350ml water intake / 50ml a day for mice has to be an error surely?
maybe they added a 0 by mistake? so 35ml a week / 5ml a day. which is ~ the usual estimated intake for 6 month mice
by usual calculation, 3/37 * human bodyweight * dose per kg,
gives 1.6mg - 2mg human dose for their bodyweight close to what you got
which is about 1 - 2 cigarettes (but orally)

found another study that shows 20mcg/ml is 5mg/kg for the bodyweight of their mice . so 2mcg/ml would be 2.5mg - 3.2mg from 60kg - 80kg bodyweight humans. both combined = somewhere around 2mg

as u mentioned , they mean its low dose when taken orally because its metabolized different , so basically none of the nicotine shows up in mice

https://juniperpublishers.com/oajt/pdf/OAJT.MS.ID.555552.pdf

They show orally nicotine is rapidly metabolized by the liver before it enters circulation , at least in mice . 20mcg/ml didnt increase blood levels in 4 out of 5 mice.
(so low nicotine receptor effects - mainly geting the metabolite cotinine which doesnt bind nicotine receptors as strongly and has a long half life without causing addiction . and like the first study mentioned u dont need nicotine receptor impact for the health boost)
in humans maybe its higher at 20%-40% of the nicotine making it through? Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor
spread out maybe ok

wonder if theres a decent way to increase cyp2a6 (cyp2a5 in mice) to metabolise more of it
also i wonder about the lozenges over going through off brand vendors (feels shady) , but if can find one without a bunch of shitty additives the lozenges use nicotine bitartrate dihydrate. so i wonder if its the same in this form

 

[Mauritio]

great effect thanks
it looks like a low end typical dose rather than microdose (about the amount in 1.5 cigarettes, but taken orally)
but in the peer review they say they showed the effect was independent of effect on nicotine receptors.



clear anti aging effect & survival boost. lowered tumor incidence also
View attachment 49002
did not effect feed or water intake like higher usual doses
lowered blood sugar (guess it was elevated?)


it increased neurogenesis in the hippocampus a lot , like 2x higher in these aged mice. rly nice effect



specific for dose ,
2 micrograms/ml
They show their bodyweight & water intake in the supplementary materials - drank 350ml / week (up to 375ml)
View attachment 49003
so 50ml a day * 2mcg = 100 micrograms a day

body weight is say 30.5g
so 3.2mg / kg mice dose , taken orally
= human dose 16mg - 20mg depending on bodyweight

but plus side is it worked by drinking in water through the day. so the dose is split up into low doses,
activating choline receptors maybe not great but spread out I wonder if this gets around the stimulation / addictive potential
also considering orally (not chewed as gum but swallowed) the dose is about 20% - 44% as effective vs 80%-90% as cigarretes so should give half the effect. and unlike cigarettes you can avoid the toxic metals.

https://biomedres.us/pdfs/BJSTR.MS.ID.002343.pdf 4mg human dose in this one worked to increase hippocampus BDNF also. so might have benefits for the rest of this too.
though on the other side another study using 1mg/kg i.p in rats , showed a 80% decrease in PSA-NCAM+ and NeuN+ cells

I see somebody else took a look at the supplementary data:)
I wasnt particularly impressed by the life extending effects but it is significant non the less.

The data on water intake of the mice is almost certainly wrong.
This study looked at the median water intake of 28 different species of mice and they found:

"Mean daily unadjusted water intakes ranged from 3.9 ± 0.2 ml/mouse (RIIIS/J) to 8.2 ± 0.3 ml/mouse (SEA/GnJ)..."
- Food Intake, Water Intake, and Drinking Spout Side Preference of 28 Mouse Strains

So drinking 50ml/day is like a human that drinks 20L per day.

Maybe they were off by a decimal...that would make more sense.

 

[Mauritio]

They show orally nicotine is rapidly metabolized by the liver before it enters circulation , at least in mice . 20mcg/ml didnt increase blood levels in 4 out of 5 mice.
(so low nicotine receptor effects - mainly geting the metabolite cotinine which doesnt bind nicotine receptors as strongly and has a long half life without causing addiction . and like the first study mentioned u dont need nicotine receptor impact for the health boost)
in humans maybe its higher at 20%-40% of the nicotine making it through? Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor
spread out maybe ok

I was thinking maybe the effects we saw were more due to cotinine and not nicotine . The supplementary data also showed that cotinine levels were through the roof.
So I should look more on cotinine's effect on metabolism ,specifically on NAD.

On the other hand the authors hypothesize that nicotine was the cause of these benefits through activating the salvage pathway and increasing NAMPT (and thus increasing NAD) .

in humans maybe its higher at 20%-40% of the nicotine making it through?

So you're saying humans have lower expression of these enzymes and thus more nicotine gets through the liver unmetabolized ? That would mean humans could get away with even lower doses ,if the effects were due to nicotine and not one of the metabolites .

 

[cs3000]

I see somebody else took a look at the supplementary data:)
I wasnt particularly impressed by the life extending effects but it is significant non the less.

The data on water intake of the mice is almost certainly wrong.
This study looked at the median water intake of 28 different species of mice and they found:

"Mean daily unadjusted water intakes ranged from 3.9 ± 0.2 ml/mouse (RIIIS/J) to 8.2 ± 0.3 ml/mouse (SEA/GnJ)..."
- Food Intake, Water Intake, and Drinking Spout Side Preference of 28 Mouse Strains

So drinking 50ml/day is like a human that drinks 20L per day.

Maybe they were off by a decimal...that would make more sense.

yep . the bdnf effects are nice around that dose (adjusted for extra 0) as long as its not response to damage, wouldnt think so.
should also raise neurogenesis in the nucleus accumbens Nicotine sensitization and analysis of brain-derived neurotrophic factor in adolescent beta-arrestin-2 knockout mice - PubMed
those pictures show a nice difference in aging .
by other studies may help ulcerative colitis a bit but over 4mg cant be taken orally due to it being irritating to the gut Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor
cheers

I was thinking maybe the effects we saw were more due to cotinine and not nicotine . The supplementary data also showed that cotinine levels were through the roof.
So I should look more on cotinine's effect on metabolism ,specifically on NAD.

On the other hand the authors hypothesize that nicotine was the cause of these benefits through activating the salvage pathway and increasing NAMPT (and thus increasing NAD) .


So you're saying humans have lower expression of these enzymes and thus more nicotine gets through the liver unmetabolized ? That would mean humans could get away with even lower doses ,if the effects were due to nicotine and not one of the metabolites .

this is a long winded way to say theres a different study that showed nicotine rising in mice unlike the other one. so it probably is nicotine responsible for the effects, in the same amount for humans :

thought either one would work based on the study showing in vitro nicotine works , and a study showing blood levels of nicotine not rising in mice only cotinine,
(if only cotidine levels rise then has to be this responsible for effects through a different mechanism than SIRT1,
unless its one of the other minor metabolites. but most of nicotine goes to cotinine, and cotinine is studied for a bunch of benefits so it would likely be that) -
- but another study does show nicotine levels rising in mice so probably not

they said they think the effect is nicotine enhancing SIRT1 interaction with NAMPT to boost NAD+, without effecting SIRT1 expression.
and cotinine didnt have this effect in vitro on SIRT1 , where nicotine does

We compared the effect of nicotine with these two SIRT1 activators and found that SRT1720 and resveratrol were required much higher concentrations for promoting SIRT1-NAMPT interaction than nicotine (Fig. 5g, h). In contrast, nicotine neither directly inhibits/activates SIRT1 nor affects SIRT1 expression (Supplementary Fig. 4f, g). Hence, nicotine might solely enhance SIRT1 interaction with NAMPT to boost NAD+ synthesis, and the increased NAD+ in turn enhances SIRT1 activity and regulates NAMPT activity in a positive feedback manner.

Cotinine is the main metabolic product of nicotine26. To investigate whether cotinine could regulate the SIRT1-NAMPT interaction, we directly measured the content of cotinine was about 14.7 ng/g in the aged brain with LC-MS (Supplementary Fig. 4h). Based on this concentration, the HT22 cells were treated with cotinine at 1, 10, 100 ng/mL, and we found that cotinine did not affect the SIRT1-NAMPT interaction (Fig. 5g).

thought humans get more nicotine orally because in this mice study https://juniperpublishers.com/oajt/pdf/OAJT.MS.ID.555552.pdf at 25mg or 150mg human equivalent dose orally it didnt raise blood nicotine levels over the 2ng/ml threshold,
where cotinine levels increased. if that was being metabolised 60% like in humans then you'd think the miligrams of remaining nicotine would show up even if its spread out.

but this study is different Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor
15mg/kg so ~80mg human dose orally, gave high 64 ng/ml plasma levels of nicotine

in humans 5mg dose orally gives ~ 5ng/ml

Nicotine Population Pharmacokinetics in Healthy Smokers After Intravenous, Oral, Buccal and Transdermal Administration - Clinical Pharmacokinetics

Background In 4 decades, numerous nicotine replacement therapy products have been developed. Population pharmacokinetic models can support exposure–response modeling and inform nicotine replacement therapy product development, but only limited model-based cross-study population pharmacokinetic...

link.springer.com

A randomised study to assess the nicotine pharmacokinetics of an oral nicotine pouch and two nicotine replacement therapy products - Scientific Reports

Nicotine replacement therapies (NRTs) are intended for short-term use to help cigarette smokers to quit. Some smokers find NRTs ineffective or seek a more satisfactory source of nicotine. Tobacco-free oral nicotine pouch (NP) products have emerged as a potential reduced risk product compared...

www.nature.com

so assuming linear then that shows mice and humans are close to the same , if you disregard the first study that showed no response over 2ng/ml
would have been nice if cotinine had the effect too as it has a way longer half life in humans & might cross BBB more. but probably just the nicotine

*edit: actually looking at it nicotine has much longer half life in humans too. so u might be onto something still with needing lower dose. if this plays a role

The plasma half-life of nicotine in mice is 6–7 min, in rats 1 h, and in humans 2 h

 

[Tarmander]

Today is day 3 of doing 1mg/day in my water bottle.

Here's what I noticed:

- an anti-fungal/anti-microbial effect , it's definitely doing something in mg gut, lots of rumbling

- better liver function --> less water retention ,fuller muscles , lost some weight

- more BMs , faster transit time

- relatively sustained and stable energy

- mood sometimes a little low, seems to be related to BMs though , after a BM felt normal again

- slightly higher adrenergic feeling, decided not to take it after 4PM

- feeling cold less often

- hair and skin definitely looks better ,hair loss is greatly reduced, probably due to less endotoxin/gut problems

I'll stop now for a few days and see if the effects stick and how my gut feels without nicotine.
Overall I really like it, and it seems very beneficial for gut and liver.
Since I did 1V-LSD 2 weeks ago I had a slight pinch in my liver that almost completely went away after taking nicotine.

I get the same stomach gurgles and I have definitely had faster transit time.

I am down to around 0.3-0.5mg twice per day of the lozenges, swallowed. Even that may be too much, but I am really liking this. Sleep is better, muscles are bigger. I even seem more patient which is not a thing I usually experience on nicotine. If anything its usually opposite.

 

[Mauritio]

they said they think the effect is nicotine enhancing SIRT1 interaction with NAMPT to boost NAD+, without effecting SIRT1 expression.
and cotinine didnt have this effect in vitro on SIRT1 , where nicotine does

Oh yeah right , so it was nicotine after all!

Theres surprisingly little data on the effect of nicotine on NAD .

I get the same stomach gurgles and I have definitely had faster transit time.

I am down to around 0.3-0.5mg twice per day of the lozenges, swallowed. Even that may be too much, but I am really liking this. Sleep is better, muscles are bigger. I even seem more patient which is not a thing I usually experience on nicotine. If anything its usually opposite.

Interesting, I also suspect that even 1mg might be a bit too much. I felt a little anxious. Maybe I'll try just 0.5mg/day when I'll resume taking it.
Now that I've stopped my hair looks significantly worse again ,I'm more bloated towards the evening, but I fell calmed .
I think I'll restart again soon, it really seems to be doing soemthing for my gut. I suspect it kills candida.

 

[jasieltego]

Very interesting topic. A quick search on pubmed with keywords nicotine liver, majority of what I see is it causing liver injury and fatty liver. Just from looking at titles, I,ll do more research later. Thanks

 

[cremes]

I agree that this is interesting. A 1mg (or less) dose for a 90kg person seems incredible.

Where does one procure nicotine like this? I searched my usual places and just found the gum in 2mg or 4mg sizes which are apparently too big.