Nicotine absorbtion from vaping research

[need_2quit]

I've noticed when I'm wondering about my blood nic level at any given time, I ask myself, "do I want a cig?". if the answer is no, then i kick it down to zero mg homebrew juice. When the answer is yes, I hit the 36 juice.

Helps keep me leveled off throughout the day without increasing my desire for nic (worse than cigs)

I find I'm sucking this thing like a paccy though cause of the flavors. I do miss hanging a cig from my mouth though. These things are too heavy.

 

[TropicalBob]

Kate, others: I've done some calculations on e-liquid and nicotine, because as sure as I'm sitting at my laptop, the FDA will dramatically regulate e-liquid if they allow it at all. It will not be allowed to be more effective than existing NRT. I consider that a given. So here's what I came up with:

If the FDA allows nicotine to be delivered in vapor, it's likely limits will be placed on the nicotine strength. We can look at approved NRT products for guidance:

With a nicotine inhaler, most similar to our devices, each puff is said to contain about 10 times less nicotine than a puff from a cigarette. That is exactly the measurement for e-cigs using 16mg liquid. Look at 16mg liquid as the absolute upper strength the FDA would allow -- if in a good mood. The actual inhaler plug has 10mg of nicotine, but can deliver only 4mg.

Nicotine gum comes in 2mg or 4mg pieces that is recommended for use every 30 minutes, with a maximum of 30 pieces a day. Each piece delivers 1mg; that's 2mg per hour, about like smoking a cigarette at 30-minute intervals.

The nicotine patch strength is 21mg for the 24-hour one, or less than 1mg per hour.

Nicotine nasal spray delivers 0.5mg per use and can be used up to twice each hour, 40 times each day. About 2mg per hour of absorption.

The nicotine lozenge's top strength is 4mg, and it now comes in delicious cappucino flavor, something children will surely love as they begin their nicotine addiction. A user is allowed 20 pieces per day, and absorbs 2mg per hour. Candy tobacco?

Now consider e-liquid. The average user seems to vaporize about 2ml per day. That's 0.05ml volume per waking hour. If it's 36mg liquid, that's 4.5mg of nicotine per hour. No way the FDA will allow that. Far above any approved NRT.

At 26mg, 2ml over 16 hours still comes to a high 3.25mg per hour. Not acceptable.

So what is likely to be the ceiling on any FDA-approved e-liquid? 8mg. If a user constantly vapes 8mg liquid for 16 hours, that user gets 1mg per hour. That's on target. If the FDA is in a great mood, maybe 16mg as the ceiling. But don't bet on it.

Whatever they decide, it will be on a total time-strength basis. That's been the case for NRT products, where even Big Pharma argued the strength wasn't high enough (we know it isn't!). But virtually all risk to anyone from pregnant 14-year-olds to 79-year-old cardiac cases must be taken into consideration and minimized or eliminated. That's why we'll end up with really wimpy e-liquid.

If we get it at all, even on prescription from Big Pharma.

 

[Kate]

Thanks very much for the calculations TBob. I tend to agree that wimpy levels of nicotine will be all we're officially allowed eventually.

The thing I'm thinking is that if we're being successful because of a placebo effect at the moment then it won't matter how little nicotine is delivered with vaping as long as we think it's replacing tobacco levels.

 

[TropicalBob]

I agree. I really cannot tell a difference between 36mg and 16mg liquids. I've even used 8mg and still can't tell any difference. The new 48mg did tighten my chest, however, and I stopped dripping that.

A ringer here is that the FDA will soon have the authority to order cigarette makers to lower nicotine levels. At present, a cig has about 10mg -- and nearly 90% wifts away as second-hand or sidestream smoke. A smoker gets about 1mg per cig. But what if the FDA ordered raw nicotine content cut in half?

Then we have to recalculate what might be allowed in e-liquid. I once wrote that we could find a limitation of 2mg or 4mg liquid. That might still hold true.

 

[Atreides Ghola]

Okay,

After reading over this thread for awhile now, I've got to correct a few misconceptions that folks seem to have about the nicotine molecule itself, what blood levels mean, and the comparisons to vaping.

First off:

Propelyne Glycol: This is a hygroscopic substance, and readily dissolves in water. It is highly unlikely that it will accumulate in the lungs as undissolved particles, and like other low molecular weight alcohols, will easily cross any mucosa it comes in contact with. What this means practically for vaping is that the theory that accumulated PG + Nicotine particles slow releasing nicotine in the lungs over a long period of time is probably false. If you're ill after a day of heavy vaping, it's likely not due to nicotine poisoning from ever-increasing levels of nicotine being released from the lungs.


The chemical formula is C₃H₈O₂. The molecule has two hydroxyl groups. These ensure the interaction with water by what is know in chemistry/biochemistry as hydrogen bonding. Also important to note is that it is a diol alcohol. This will be important later on in this post, since the molecule will be metabolized (in the liver) by the same cellular pathways that deal with, say, ethyl alcohol, the active ingredient of spirits, wine, and beer.

Second misconception:

Nicotine blood levels reflect the efficacy of nicotine delivery to the brain.

Any measure of nicotine in the blood is going to show you (and this is VERY important) the amount of nicotine that is not engaged in metabolic processes. This means that the nicotine levels in the blood represent unused nicotine. A better measure of the amount of nicotine delivered to the brain is to quantify the receptor-ligand kinetics of vaping in comparison to smoking.

Nicotine interacts with cell surface receptors called nicotinic acetylcholine receptors in the brain. Once it bind to these receptors, it signal transduces the upregulation of a great many neurotransmiters. The one we're most interested in, however, is dopamine. The increase in dopamine levels is what we're really addicted to.

Cell biologists measure receptor engagement by measuring the dissociation constant, K_d, of a ligand (nicotine) and its receptor. This measure allows us to evaluate how much unbound ligand is present, how many unbound receptors are present, and how much ligand is actually bound to a receptor. All of these are measured in concentrations: [R], [L], and [R-L] would be the concentration of receptor on a cell surface, the concentration of free ligand (in this case, blood nicotine levels), and the concentration of ligand bound to receptor, respectively. The calculation is done as follows:

[R]_eq x [L]_eq / [R-L]_eq

Any of you familiar with equilibrium constants from your chemistry/organic chemistry/ biochemistry classes should be familiar with this. Remember, the cell surface receptors for nicotine are finite in number. Your nicotine levels may spike very high after a cigarette, but that by no means shows you how much nicotine your brain is actually using. The above calculation does. If you were to graph this out, you'd get a graph that starts low, increases rapidly, and then reaches a plateau. At this point, no matter how much nicotine you have in your blood, it's not going to bind any more receptor, and so, you're not going to get the benefits.

A cigarette gives extremely high blood levels of nicotine, which has a half life of about 2 hours in the human body. During this time, unmetabolized nicotine will bind receptor and keep the whole system at equilibrium (the plateau phase) until there's not enough left to bind all of the nicotine receptors. The reason you vape more than smoke is not because it's not effectively binding to the receptors, or that there's not enough. It's because you haven't stored up extra nicotine in your blood. Vaping perhaps delivers less nicotine per puff over time, but the absorption is probably more efficient, and the metabolism of the nicotine is probably more efficient, too. From what I can gather from the (very sparse, we really need more peer-reviewed data from scientists unconnected with the e-cig industry) data, almost all of the nicotine absorbed through vaping interacts with receptor, as opposed to nicotine levels remaining high in the blood, as with smoking. From a health/physiologic point of view, this is a good thing.

However, nicotine doesn't just wait around to meet a brain receptor...it's metabolized in other ways as well in the liver, CNS, PNS. The high levels in the blood evoked by smoking are generally metabolized and removed from the system through the kidneys. So, most of the nicotine delivered by a cigarette goes to waste.

About PG. There's a lot of talk about how safe it is on these forums, and while I'm not going to disagree outright, there really is no good data on how safe it is in a system designed to deliver it to the lungs for extended periods of time. It breaks down to a few different products in the body through the action of alcohol dehydrogenase in the liver. You get pyruvate as the major product (not lactic acid); pyruvate can be converted to lactic acid under anaerobic conditions (exercising, high stress). Pyruvate is the major product of glycolysis, and is converted to Acetyl-CoA for delivery to the tricarboxcylic acid cycle in aerobic respiration, and those products are then passed on to the electron transport chain for further energy production. These are basic cellular reactions that contribute to both energy production and CO₂ production. Artifically altered levels of these substances are absolutely going to cause changes in metabolism, and in heavy users or sensitive systems will almost certainly lead to mild ketoacidosis...i.e. nausea and headache in the user. This is probably what's causing the side effects, not nicotine overdoses.

I could go on forever, but there's the gist of it in a nutshell.

And I'm going to rant a bit about folks who are so adamant that these products are perfectly safe, and all of the appropriate testing has been done, and why doesn't the government just leave us be. The truth of the matter is that e-cigs haven't been evaluated for their health effects. No one knows what kinds of problems a 20 year vaper is going to have.

For example, since PG is an alcohol, and is metabolized very much like ethanol, how do you know that extended heavy use isn't going to cause liver damage like cirrhosis? It also can interfere, theoretically, with glycolysis...how does anyone know what extended use is going to do to the body?

Don't get me wrong here. I love vaping myself, and have kept off cigarettes because of it. But I'm not going to fool myself about vaping being an end all to the problems associated with smoking. For all we know, and because of the current lack of good studies (and I mean all kinds...right back down to animal levels...it's no good to just test nic levels in vaping humans without going back and doing the animal experiments, and the in vitro experiments, etc) we could be saving up all kinds of health problems later on.

I do believe that vaping is a MUCH healthier alternative to smoking, but it's a relative issue, at least until someone can show me the kind of evidence accumulated from years of targeted, controlled, independent experiments ruling out the health hazards of vaping.

Cheers, all!

 

[orlampagal]

Thank you Atre.... I am in Anatomy 2, and you just brought back all fear and sadness I had in Anatomy 1, when the professor droned on about neuroreceptors. Seriously though, that was quite a thorough statement, thanks.

 

[katink]

(by Kate: ) Thanks very much for the calculations TBob. I tend to agree that wimpy levels of nicotine will be all we're officially allowed eventually.

The thing I'm thinking is that if we're being successful because of a placebo effect at the moment then it won't matter how little nicotine is delivered with vaping as long as we think it's replacing tobacco levels.

Except I totally can't believe in the placebo-effect - I totally expect it still remains to be found what causes real effect in the (our) e-cig. Could be a wrong way of taking measurements or interpretating them; could be the difference in device (I think combi of both actually) - but I don't believe in the placebo-theory, unless for a minority of users...

Plus even if it were placebo - that only works, for those it does, if they believe they are getting enough (but aren't in reality). It won't work if they know it isn't enough in advance allready...

I expect if 1 or 2mg were the limit, that e-cigs would have a slightly higher success-rate then the known gum/patch/lozenge etc (IF they keep working as they do now, which I don't expect) because of the adequate likings to smoking a cig, so fulfilling the hand-mouth motion enough. But only slightly better, so lets say 3% succes instead of 1.6... yay...

@Atreides: thank you for this clarification, especially the words on nicotine bloodlevels are very enlightening, this certainly could be a piece of the (my) puzzle! (and could partially change the above words too, need some more thinking on it...)
Question: do you have any indication how many mg are needed to 'fill all the dopamine-receptors' and have enough free buffer to keep the level high enough? (forgive me if this isn't put very scientifically please)

 

[Kate]

Thanks very much Atreides, that's great information for us.

Katink, I'm not sure about the placebo theory myself. I'm fairly sure that the measurements being given are not from average use at least and are put in a way that supports whatever the funders want to say.

 

[Atreides Ghola]

Katink,

Well, there are a number of factors that influence the number of receptors your cells are expressing at any given time. The receptors are naturally occurring...they don't just come out to take care of nicotine absorbed by the lungs or mucosa.

The two greatest factors, in order of importance are:

1) The genetics of the user. This is a very, very complicated subject. Any given user may have a propensity to express more receptor than another, and this doesn't even depend entirely on the gene for the receptor itself. Differences in all of the genes/proteins involved in getting a receptor to the cell surface in the first place also play significant roles.

2) How much the user smokes/dips, etc. The more nicotine you use, the more receptor you express, up to the biological limit imposed by your genetics and cell processes themselves.

As a rule of thumb, if you're not a heavy user, you exhibit fewer receptors, and don't need as much nicotine, and light users may also just naturally express lower levels of receptor because of their genetics.

Heavy users will express more receptor, and may be genetically capable of producing more receptor, more quickly.

As for the placebo effect: don't forget, this is also governed by dopamine levels, and dopamine receptors in the brain. It's a biological process every bit as much as nicotine metabolism itself.

I'd say, placebo-effect-wise (assuming vaping delivers nicotine more effectively to the brain than cigarettes do), that it's not a placebo effect at all. You're still getting the nicotine you're used to getting...it's being turned over faster, so your blood levels are lower, and you need to vape more to keep the levels up...but you're almost assuredly getting what you're used to, but more evenly than you do when smoking analogs.

 

[Atreides Ghola]

Thank you Atre.... I am in Anatomy 2, and you just brought back all fear and sadness I had in Anatomy 1, when the professor droned on about neuroreceptors. Seriously though, that was quite a thorough statement, thanks.

Fear and sadness about neuroreceptors? But why?

Anatomy...full organisms. Yuch. That's something to be fearful of.

And that's why I do cell/molecular bio.

 

[katink]

Makes a lot of sense to me Atreides - lot of things do fit in to what you are telling. I do think that it's the heavy and 'resistant' smokers that tend to be here (except the heaviest, and comparatively still reasonable healthy, ones... they will probably be smoking on). Some lighter smokers are here too of course - they might be the ones 'passing through', come to think of it - just using the e-cig temporarily to step down to zero and out...

How do you see TB and others like him - who would seem to have too many receptors to fill by the use of e-cig, if what you are saying would be the only factors? - how are your thoughts on MAOI's in this process, can you fit that in within what you know as to what is missing for them instead or together with 'too many receptors to fill'?

I'm happy to see a good explanation leaving out the placebo - that has never sat well with me as to being believable

 

[paladinx]

Well i been saying the same sort of thing for a long time, minus the scientific mumbo jumbo. But you did the smart thing and talked very scientific so people took your points more seriously.

I remember some of what you are saying from biochemistry in college. But you lost me with the equation, i dont remember that.


However, I am not so convinced about vapers getting the nicotine they need to fill in their receptors etc. That huge spike of nicotine given off by a cigarette definitely does something more than other nicotine delivery devices. Maybe I am wrong, But it sounded like you were suggesting that right off the bat whatever nicotine you absorb goes straight to your brain receptors, and the rest is just excess circulating around the blood. If that were true I would imagine E-cigs would be completely satisfying, and to many they are not. Many feel that there is something missing. With cigarettes within the first five minutes you feel the majority of its effects. When vaping this doesnt seem to be the case.

 

[Atreides Ghola]

@katink

Nicotine itself isn't responsible for breaking down dopamine. There are other MAOI's in the smoke itself that prevent dopamine degradation by monoamine oxidase. That also contributes to the kick that smokers get, as well as being addictive in and of itself. There are other chemical reactions going on in cigarette smoking besides those involving nicotine that make it an addictive habit.

I'd venture to say that the lack of monoamine oxidase inhibition is why vaping isn't as satisfying as smoking to alot of people. You're not getting that extended dopamine rush (which is what you're getting...it's not the nicotine that gives you that feeling...it's the increased dopamine production that results from active metabolism of nicotine). So, if you're vaping, you're probably getting enough nicotine, but the dopamine you're producing is being broken down at normal rates, instead of the reduced rates you get from actual cigarette smoke. This also means that you're going to need to vape more often to keep dopamine levels high enough that you feel satisfied...heavy nic users will need to vape and use snus or other supplements to keep those level up way high, regardless of engaging all of the nicotine receptors. That should answer Paladinx's question as well.

@Paladinx

Scientific reasoning and expression isn't mumbo jumbo. The devil's in the details, and science provides the details and a framework for interpreting them. If folks took me more seriously, it's because they know they can go and actually find this information in a biochem book or in peer-reviewed papers.

 

[WerkIt]

However, I am not so convinced about vapers getting the nicotine they need to fill in their receptors etc. That huge spike of nicotine given off by a cigarette definitely does something more than other nicotine delivery devices.

I believe the analog addiction is separate from the nicotine addiction. Analogs deliver far more chemicals than just nicotine. Then there is also the psychological 'hand to mouth' part of the analog addiction. I also wonder if the carbon monoxide from analogs has effects similar to other addictive substances.

 

[Atreides Ghola]

Incidentally, this is why buproprion (Zyban) has been so successful in helping smokers quit...its a dopamine reuptake inhibitor, but does not inhibit monoamine oxidase action.

That's why when you use a patch, gum, or an inhaler in conjunction with buproprion, your chances of quitting practically skyrocket.

 

[Kate]

I'm sorry but chemical names and formulas are a bit beyond my understanding. Is harmine an example of the kind of chemical that you're talking about? I've heard that it prolongs the effects of nicotine.

http://www.e-cigarette-forum.com/fo...-substitute-tobacco-smoking-7.html#post105481

 

[Atreides Ghola]

I'm sorry but chemical names and formulas are a bit beyond my understanding. Is harmine an example of the kind of chemical that you're talking about? I've heard that it prolongs the effects of nicotine.

http://www.e-cigarette-forum.com/fo...-substitute-tobacco-smoking-7.html#post105481

That's exactly the type of substance, Kate. It prevents the breakdown of dopamine by the enzyme monoamine oxidase. So, if you have it in your smoke, then the dopamine (which your brain really loves) sticks around that much longer after the nicotine from smoking has induced your cells to start pumping out dopamine.

 

[Kate]

Thanks. In that case this might be of interest to some folk - http://www.e-cigarette-forum.com/fo...39-passion-flower-has-harmine.html#post103092

 

[hgielm1]

Does anyone know if he is going to be coming out with new research results? This whole business of trying to compare analog use with ecig use is very confusing. Does anyone think we'll know any answers any time soon? IF we're only getting 1/10th as much nicotine as from analogs, I'm afraid many of us will relapse. On the other hand, I read of folks who feel they "overdose" even from low levels of the nicotine juice. I guess a lot more needs to be studied on absorption from the ecigs vs. analogs to see how much nicotine we're really getting.

 

[Kate]

I heard that Dr Eissenberg is doing tests on this Karen, if I get any information I'll post it. The Ruyan research will be scrutinised at some point too so watch out for that.