From CNN.com Today/Eissenberg study with feedback

[slybootz]

Assuming those of us who decide to test our cotinine levels (who are not exposed to 2nd hand smoke, and who do not supplement vaping with smokeless tobacco, etc) find cotinine at levels generally accepted by the medical community to be indicative of regular smoking, then there is a paradox to be solved, "How is a device that is said to deliver insignicant nicotine able to yield significant cotinine?"

I intend to continue using only 15 mg/mL eliquid (mixed quantitatively and confirmed by titration) while aggressively avoiding any other form of nicotine or 2nd hand smoke. When my nicalert comes in a few days, I should have an interesting result.

(and yes, I'm tempted to run it on hi-res mass spec right now, but somehow I don't think my employer would approve of me figuratively ...... into or otherwise fooling around with a half million dollar instrument, so I won't be doing that!)

i wish i could be of help by testing my cotinine levels...but i am a snuff-taker, and the occasional snus. i hope that those that do test themselves come up with results that will make the researches consider that cotinine levels need to be tested as well as plasma nicotine levels

 

[chrisl317]

well as they say there will always be a critic. Besides even if we arn't getting all the nicotine as before it still works. And his study will be used but so will others in the defence. So dont worry about it. It's going to take a long time to get what ever there trying to do in the works....

If we aren't getting the nicotine that we think we are, then wouldn't that be a good thing to them? Then with that thinking, they would ban something that's really no different from sucking air through a straw, right?

 

[Belletrist]

So, are we considering a longer-term study for e-cigs? Of course! You need to realize, however, that these studies are not at all cheap, and I need to convince unbiased funding sources to provide the necessary resources. It is on my "to do" list, I promise you. I have found many of the suggestions on this thread very useful on planning that and other studies. I will continue to listen.

Last night I spent some time researching Dr. E's previous work, and ran across some longer term studies of other nicotine-delivery related devices... I'm glad to see he is planning to pursue that type of study with e-cigs.

 

[OutWest]

News from the lab:

First, and most important, I've just completed an analysis that should put this issue of primer to rest. We had a total of 7 atomizers of (NJOY calls them vaporizers) of each brand in use throughout the study. By the end of the first 16 subjects, every atomizer had been used more than once (that is, *at least* 40 puffs). Now, the hypothesis being advanced by some in this thread is that the first use was all primer, explaining the low nicotine delivery in the Tobacco Control paper that many of you have looked at.

From my experience, 40 puffs is not enough to clear out the primer. The best way to clear out primer is to assemble the ecig without a cartridge and to puff on it until no more vapor, whatsoever, comes out. Then, reprime the atomizer with eliquid by adding 2-3 drops (note: do this with battery removed). Puff on it (again without cartridge attached) to get it going and then attach cartridge.

Either that, or ask the mfg of the test units to prime the atomizers with nicotine liquid rather than the normal primer.

 

[kai kane]

I respect Dr. E very much now as he has demonstrated his possession of a ten-pound pair via his willingness to wade into this hornet's nest of besieged crankiness.

Well put Dvap!

 

[Bill Godshall]

In contrast to Tom Eissenberg's "no-nicotine" claims in the CNN article, his new study reported finding that both e-cigarette products (NJOY 16mg and Crown Seven 16mg) delivered nicotine to users at levels similar to various low-nitrosamine smokeless tobacco products and nicotine gums, lozenges and patches.

The study also found that, as with cigarette smoking, plasma nicotine levels peak quickly (about five minutes) after e-cigarette usage, unlike oral tobacco/nicotine products that typically take 30-60 minutes to peak, while transdermal nicotine products (i.e. skin patches) can take even longer to peak.

Smokers in the study, all of which were first time e-cigarette users, also reported that e-cigarettes reduced cigarette/nicotine cravings.

Five minutes after use, mean plasma nicotine levels of users increased to 3.0-3.4 ng/ml for the NJOY e-cigarette, and to 2.5ng/ml for the Crown Seven e-cigarette.

Fifteen minutes after use, mean plasma nicotine levels of users had declined to 2.8-3.1 ng/ml for the NJOY e-cigarette, and to 2.3 ng/ml for the Crown Seven e-cigarette.

Thirty minutes after use, mean plasma nicotine levels of users had declined to 2.6-2.9 ng/ml for the NJOY e-cigarette, and to 2.2-2.3 ng/ml for the Crown Seven e-cigarette.

For comparison, a previous study by Eissenberg at http://static.mgnetwork.com/rtd/pdfs/20090712_toba.pdf found mean plasma nicotine levels fifteen minutes after product use at 2.9 ng/ml for Altria's Marlboro Snus, 3.4 ng/ml for Star's Ariva tobacco lozenge, 4.6 ng/ml for GlaxoSmithKline's 2mg Commit nicotine lozenge, and 7.6 ng/ml for RJ Reynolds' Camel Snus, all of which were significantly higher than levels five minutes after product use.

Other studies (1,2) have similarly found plasma nicotine levels peaking at fifteen, thirty or sixty minutes following usage of smokefree oral tobacco/nicotine products ranging from 2-7 ng/ml for Star's Ariva and Stonewall tobacco lozenges, UST's Revel snus, GSK's 2mg Commit nicotine lozenge, and 2mg nicotine gums, while UST's Copenhagen moist snuff and Swedish snus can increase plasma nicotine levels to 10-16 ng/ml. Meanwhile, cigarettes increase plasma nicotine levels to 15-25 ng/ml within five minutes after usage, which declines rapidly thereafter.

(1) Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge, M Kotlyar, MI Mendoza-Baumgart, ZZ Li, PR Pentel, BC Barnett RM Feuer, EA Smith, DK Hatsukami, Tob Control 2007;16:138-142. Sign In

(2) Effect of smokeless tobacco (snus) on smoking and public health in Sweden, J Foulds, L Ramstrom, M Burke, K Fagerström Tob Control 2003;12:349-359. Sign In

Although I cannot understand why Tom Eissenberg chose to tell the news media that e-cigarettes deliver "no-nictione (when his research found otherwise), I strongly agree with his statement in the discussion part of his letter/study that states: "Taken together, the well known lethality of nicotine, variability in cartridge/vapour content, and the results reported hereall support the notion that electronic nicotine delivery devices (E-cigarettes) and their nicotine-containing soution should be evaluated, regulated, labelled and packaged in a manner consistent with cartidge content and product effect."

But I strongly disagree with (and think it misrepresents the available evidence, including his own research findings) with Tom's next (and final) sentence of his letter/study when he states "At the least, consumers should be aware that, unlike several regulated nicotine products (e.g. gum, patch), these putative drug delivery ststems to not delivery nicotine effectively after acute administration."

Thanks to Tropical Bob for posting plasma nicotine levels following usage of various tobacco/nicotine products

Bill Godshall
Smokefree Pennsylvania
412-351-5880
smokefree@compuserve.com

 

[teissenb]

As Mr. Godshall has been informed elsewhere, his comments show an unfortunate disregard of the published statistical method and results. I won't belabor the same points here, except to say that the "increases" he discusses for the e-cigs are not statistically significant (hence the lack of filled symbols/asterisks, as is seen for the own brand condition). I have responded to this issue earlier in this thread: if the observed result is not statistically significant it is measurement error and not reliable. Because the plasma nicotine assay will not return a negative result (i.e., we could never see a -5 ng/ml nicotine value), all measurement error must be positive, so there can always be positive blips on a plasma nicotine curve when no nicotine is present. If the "blip" is not statistically significant, it is error. These are the facts. I have published nearly 100 peer-reviewed scientific works, and these same principles have operated in every one of them. I stand by the conclusions discussed here and in the paper and deplore Mr. Godshall's misrepresentation of the statistics and the facts.

Tom E.

 

[kai kane]

Hi all: Sorry for the slow responses.

No worries! Pardon my long response.

Dr. Dean Edell said (recently 1/15/2010, see transcript) "It's complicated from the point of view of the law but I'm not so sure why we're such tight-butts about electronic cigarettes."

Well, I'd say it boils down to money, political power, and drugs (nicotine)!

You need to realize, however, that these studies are not at all cheap, and I need to convince unbiased funding sources to provide the necessary resources. It is on my "to do" list, I promise you. I have found many of the suggestions on this thread very useful on planning that and other studies. I will continue to listen.

Great! as you can tell we are delighted by your participation.

The term "unbiased funding resources" instantly reminds me of metaphors we used to joke about like "postal service" and "military intelligence" and modern ones like "toxic assets" and "perfect storm". (and not being snide here - saying this respectfully but honestly)

...about abuse liability. Short answer: When a new drug is considered for FDA approval, the question is asked (by the FDA) how likely is this drug to be abused instead of used therapeutically?... In other cases, like a novel stimulant or narcotic,...

Since nicotine itself has been shown to be a stimulant (dopamine release, etc?) and "hot rodders" apparently claim they are getting it, even if just via the colloquial "hot rodding", is it fair to say that this practice fits into the "abuse liability" study you are interested in researching?

Regulators use the results of such studies to determine how easy it will be for people to obtain the drug (i.e., over-the-counter, by prescription, etc.).

Since one can already buy OTC nicotine, and NRT products have already been studied for liability abuse thus far, what would the value of additional research with this device (ecig) provide? That the ecig vehicle may or may not encourage abuse? (as claimed by ASH, FDA, etc, ie; kid-bait flavors)

DVap makes some very cogent remarks about reporters. I think we need to be cognizant of a reporters job, which is (at least in part) to help sell their ...I try very hard to detail the methods and all of the caveats. But you know what?... the details ... rarely make it into the paper...What gets in are the few sound bites.

Thanks for recognizing this. And since you are the "voice" to media and media wields such heavy power, you also have a "power" in this arena, and still can influence the reporter in summarizing what a research report does NOT prove. Can a scientist "ethically" provide accurate "sound bites" to the media? Could this help constrain the reporter to a more accurate report? Does that make sense?

Many mahalos - and if you ever visit Hawaii, lemme know, I'd love to buy you a Kona Pale Ale (or it's non-alcohol equiv. if you abstain)!
kai

 

[eVaporizing]

e-cigs don't deliver any nicotine huh, really.

Well if this is all just placebo it sure is the best one that ever worked on me as I stopped smoking analogs within a week of my intro to e-cigs over 2 years ago.

(I guess it would be hard as hell for me to know how to prove it, but I can certainly tell subjectively- hell, I can tell the dif. between a 10mg and 20mg mix let along whether it has any or not).

Come on, this clinical study and much other spin in my honest opinion is being created by big tobacco who are scared s**t-less about e-cigs accelerating the end of their dying industry.... my two cents.

 

[Thulium]

As Mr. Godshall has been informed elsewhere, his comments show an unfortunate disregard of the published statistical method and results. I won't belabor the same points here, except to say that the "increases" he discusses for the e-cigs are not statistically significant (hence the lack of filled symbols/asterisks, as is seen for the own brand condition). I have responded to this issue earlier in this thread: if the observed result is not statistically significant it is measurement error and not reliable. Because the plasma nicotine assay will not return a negative result (i.e., we could never see a -5 ng/ml nicotine value), all measurement error must be positive, so there can always be positive blips on a plasma nicotine curve when no nicotine is present. If the "blip" is not statistically significant, it is error. These are the facts. I have published nearly 100 peer-reviewed scientific works, and these same principles have operated in every one of them. I stand by the conclusions discussed here and in the paper and deplore Mr. Godshall's misrepresentation of the statistics and the facts.

Tom E.

Perhaps I am misunderstanding, but it seems to me that "measurement error must be positive" would only apply to physical testing of the constituent ingredients and not to the testing of of the body's absorption and elimination of nicotine over time. Further, doesn't "measurement errors must be positive" mean that any negative measurement is not in error?

It also seems to me that you are failing to accurately determine the efficacy of electronic cigarettes at acute nicotine delivery if you are only testing the usage by a neophyte. Not only are there potential for "usage" issues (ie. learning "how" to vape), there are physiological factors as well: We know that smoking tobacco is especially addictive because it is especially effective at acute nicotine delivery--does it not follow that an addicted body might become accostomed to a certain method of nicotine delivery and respond faster over time?

Is it not then possible that cigarettes quickly trigger higher nicotine plasma levels specifically because of a Pavlovian response? Certainly psychological theories like Pavlov's would be considered when considerign placebo effects, is it terribly far-fetched to suspect the body absorbing and/or eliminating the nicotine might be similarly effected? Cigarettes contain more than just nicotine and studies have already shown that ingredients such as MAO inhibitors have a synergistic effect on nicotine's addictiveness, should we not also expect the additional ingredients to have a measurable effect on other physiological systems as well?

 

[kai kane]

Is it not then possible that cigarettes quickly trigger higher nicotine plasma levels specifically because of a Pavlovian response?...Certainly psychological theories like Pavlov's would be considered when considerign placebo effects ...

Exactly. And suddenly the psycho-physical habit-patterns of 'smoking addiction' are emerging as possibly the more significant factor, in my subjective observations.

Let me explain: I accidentally broke my so called 30 yr nicotine addiction by using the ecig. I received my first ecig last month, used it AND analogs for a couple days, and dropped the analogs. It turned out the cartridges had 0% nicotine, where I had thought they were "high nicotine". I discovered this error 3 days later, when throwing out the packaging!

I was "satisfied" being able to stop my (any) regular mental/physical activity, take a "puff" of vapor (quantifiable ingestion), and relax. Nicotine reinforces the relaxing process chemically, but I have become habituated to the intake (feeding) and relaxing.

Sound weird? Dr., Dean Edell cited (1/15/2020) a report he saw in the Health section of the Wall St. Journal that reported similar psychological evidence of this, I believe. That part of the Edell transcript should be up by tonite on the Edell news post. He points out that NRT's provide the nicotine drug, but the urge to 'smoke' remains, thus raising the question as to whether the 'smoking' habit alone is an 'addiction', and is not the same as 'nicotine addiction'.

Comments?

 

[Bill Godshall]

Tom Eissenberg wrote:
"I stand by the conclusions discussed here and in the paper and deplore Mr. Godshall's misrepresentation of the statistics and the facts."

I presented only data that was reported in Eissenberg's study/letter (and other previously published studies).

 

[Mister]

Dr. Eissenberg, as Mr. Godshall has pointed out, in the study at http://static.mgnetwork.com/rtd/pdfs/20090712_toba.pdf you say that

"Neither QUEST nor SHAM increased plasma nicotine level reliably. Relative to baseline, mean CS plasma nicotine level was significantly greater 15 minutes after the second product administration (7.6 ng/ml, SEM = 1.1). At that same time point, mean plasma nicotine level for MS was 2.9 ng/ml (SEM = 0.3), for ARIVA was 3.4 ng/ml (SEM = 0.3), and for COMMIT was 4.6 ng/ml (SEM = 0.5; all n.s.)."

It seems that measured plasma nicotine levels of 2.6 (SEM=0.3) and 3.4 (SEM=0.3) were taken as reliable increases in that study.

In the current study of electronic cigarettes the highest measured level was at T=5 for NPRO, "NPRO mean=3.5 ng/ml, SEM=0.5".

Yet if I understand correctly you are stating that this higher number in the e-cigarette study is not a reliable indicator.

This appears to be a significant inconsistency, can you explain it to us?

Edit: I see at the end of the above quote from the other study there's a " all n.s.)" - does that stand for "not significant"? Yet still, there's a big difference between "significant" and "reliable", and my understanding of your reasoning in this thread is that you are saying the measured levels are not reliable, i.e. don't necessarily indicate that any nicotine was delivered.

 

[DVap]

So how can we, the unwashed masses of the ECF, know as much as we do about ecig nicotine delivery that we're perfectly comfortable gainsaying a medical professional armed with data. Simple, as a group we share information and evaluate this information based on our collective ability to observe and evaluate. All of us together are smarter than any of is individually.

Consider the following hypothetical test:

--------------------------

You are a DIY mixer, and you use some TW 54 mg PI (well known for containing highly pure pharma grade nicotine in pharma PG) to make the following liquids in PG:

- 0 mg (PG only)
- 10 mg
- 20 mg
- 30 mg

You fill 4 fresh carts identically, one for each of the above nicotine concentrations. You have an assistant mark each cart with a code a, b, c, or d (unknown to you) that indicates which concentration the cart contains. You're doing a "single blind" study.

Next, take 4 fresh atomizers, blow out the primer fluid, connect each cartridge to one of the atomizers, hook up a battery and wait several minutes for the liquid to wick.

Spend a few minutes vaping and comparing the four ecigs. Try to see if you can determine which cartridge contains 0, 10, 20, and 30 mg. Record your conclusions, and have your assistant then reveal which code corresponds to which nicotine level.
​

--------------------------

How many of you are certain that you correctly identify the nicotine level in each cart? I see a lot of hands raised... and I could correctly identify them as well.

Here's the question, WHY?

Because we can taste the nicotine and (with all due respect), we don't need a medical professional to tell us we're tasting it.

Heck, if you're a DIY mixer, feel free to perform this experiment if you're inclined.

 

[DVap]

Dr. Eissenberg, as Mr. Godshall has pointed out, in the study at http://static.mgnetwork.com/rtd/pdfs/20090712_toba.pdf you say that

"Neither QUEST nor SHAM increased plasma nicotine level reliably. Relative to baseline, mean CS plasma nicotine level was significantly greater 15 minutes after the second product administration (7.6 ng/ml, SEM = 1.1). At that same time point, mean plasma nicotine level for MS was 2.9 ng/ml (SEM = 0.3), for ARIVA was 3.4 ng/ml (SEM = 0.3), and for COMMIT was 4.6 ng/ml (SEM = 0.5; all n.s.)."

It seems that measured plasma nicotine levels of 2.6 (SEM=0.3) and 3.4 (SEM=0.3) were taken as reliable increases in that study.

In the current study of electronic cigarettes the highest measured level was at T=5 for NPRO, "NPRO mean=3.5 ng/ml, SEM=0.5".

Yet if I understand correctly you are stating that this higher number in the e-cigarette study is not a reliable indicator.

This appears to be a significant inconsistency, can you explain it to us?

Edit: I see at the end of the above quote from the other study there's a " all n.s.)" - does that stand for "not significant"? Yet still, there's a big difference between "significant" and "reliable", and my understanding of your reasoning in this thread is that you are saying the measured levels are not reliable, i.e. don't necessarily indicate that any nicotine was delivered.

SEM (standard error of the mean), as I understand it, is the standard deviation of the result set divided by the square root of the number of observations. I'm not entirely certain how it's used here, but I suspect that the baseline must be evaluated in a similar manner and a baseline SEM calculated. At this point, a confidence interval would have to be selected. 66%, 95%, 99%, 99.9%, etc. The higher the confidence interval selected, the wider the "error bars" must be set, and the more likely that a small rise from baseline would be considered statistically insignificant (not usefully discernable from baseline) via overlap of the error bars of the result with the error bars of the baseline. So the question becomes, statistically insignificant at what confidence interval? Pick too high a confidence interval, and you're playing statistical games to deem a result insignifcant, pick too low a confidence interval, and you're also playing statistical games to deem a result significant.

(with apologies to the decent statisticians out there, since I have to relearn this stuff every time I use it)

 

[teissenb]

Mister:

Yes, "n.s." stands for "not significant" and in my discussions here I use "reliable" and "significant" interchangeably. If it is confusing, I'll stop.

Bill: The data you cite (i.e., the means and SEMs) are correct of course. What I reject and deplore is your seemingly intentional mischaracterization of the significance testing and its interpretation. Non-significant results are not meaningful differences. They are considered chance results that would likely not recur if the study were repeated. In contrast, significant results are not considered chance results and are likely to recur 95/100 times (or more) that the study is repeated.

 

[teissenb]

KK: Thanks for the offer. I'd love a beer in Hawai'i! As for abuse liability, I did not mean to say that was a set of studies I intended to conduct, only that sometimes drug naive participants are sometimes included in such studies.

 

[teissenb]

Thulium:

I agree completely that results *may* differ with more experienced users -- that point is made in the discussion section of the study. I also agree completely that Pavlovian responses *may* play a critical role in the responses elicited by e-cigs.

Tom E.

 

[DVap]

Mister:

Yes, "n.s." stands for "not significant" and in my discussions here I use "reliable" and "significant" interchangeably. If it is confusing, I'll stop.

Bill: The data you cite (i.e., the means and SEMs) are correct of course. What I reject and deplore is your seemingly intentional mischaracterization of the significance testing and its interpretation. Non-significant results are not meaningful differences. They are considered chance results that would likely not recur if the study were repeated. In contrast, significant results are not considered chance results and are likely to recur 95/100 times (or more) that the study is repeated.

I'm quite comfortable with the 95% confidence interval... use it all the time (though again, I have to relearn every time!)

I have to wonder, at what confidence interval would the results for the ecigs become significant?

 

[jamie]

thus raising the question as to whether the 'smoking' habit alone is an 'addiction', and is not the same as 'nicotine addiction'.

There is reason to believe that is true to some degree.

ScienceDirect - Pharmacology Biochemistry and Behavior : Cue dependency of nicotine self-administration and smoking