From CNN.com Today/Eissenberg study with feedback

[dtm]

Danger of Inhaling Propylene Glycol
*from an article on e-how... sorry not enough posts to create a link*

Most interesting.

(PG), is a colorless, odorless chemical that is used as a food additive, in cosmetics and in pharmaceuticals as an inert solvent or carrier. Its industrial applications include antifreezes, hydraulic fluids, deicing liquids and coolants. PG is recognized as safe by the Food and Drug Administration (FDA).

and...

1. Electronic Cigarettes
2. Persons trying to quit smoking have recently turned to the recent invention of electronic cigarettes. Battery-powered, these devices deliver measured amounts of nicotine diluted in PG and then inhaled. A heating element within the device vaporizes the compounds, thereby allowing for easy inhalation. While many have questioned the safety of electronic cigarettes, their concerns are directed toward the inconsistent amounts of nicotine, not the PG solution in which it is delivered.

Looks like they are fishing for something here, like anything to throw a spanner in the works... well, I'll take my "inconsistent" e-cig over one I light up any day.

 

[DVap]

Dr. Eissenberg,

As a professional analytical chemist (20+ years) and amateur ecig researcher, I have done quite a bit of testing/experimentation on my own time. While my research is not validated in the sense required of a clinical or scientific study produced for submission/publication (I'm just one guy!), I have found e-cigarette vapor to contain nicotine.

Additional research done by another forum member, also with a laboratory background, who I consider to be a peer as far as his technical and experimental expertise, using an apparatus much improved over mine (cryotrap -vs- electrostatic vapor condenser) has also identified alkaloids in vaporized and subsequently condensed eliquid obtained from ecigarette models popular among members of this forum. Titrated as nicotine, he has consistently found ~ 90 - 100% transfer of nicotine from liquid to condensed vapor at eliquid nicotine concentrations of 6, 18, 36, and 70 mg/mL. Additionally, he has presented his apparatus, methodology, and results here on this forum such that anybody so inclined could reproduce his experiments.

This research, humble though it may be, demonstrates an approximately quantitative transfer of nicotine from e-cigarette liquid to vapor.

Our driving force, like yours, is curiosity and the pursuit of knowledge.

I quite understand that your study as designed and implemented generated a set of data that reflects the study design and conditions. In the same manner, the research performed by myself and improved upon by my peer here on the forum also generated a set of data that reflects the study design and conditions.

I produce my own eliquid from purified nicotine, propylene glycol (USP) and glycerin (USP). My mixed liquid contains 80% glycerin, 18.5% propylene glycol and 1.5% (15 mg/mL) nicotine. I do not smoke cigarettes (having quit completely in September 2009) nor do I use any traditional NRT, smokeless tobacco, etc, and I am not exposed with any regularity to second-hand smoke.

I consume 2 - 3 mL daily of this liquid, and I believe you would agree that if the above is accurate, then any nicotine or nicotine metabolite present in my blood or urine would with great likelihood derive from the nicotine present in my eliquid.

In short, I have to imagine that you might be (at least in passing) interested in what my blood or urine cotinine level might be? Cotinine, as you're surely quite aware, is nicotine's major metabolite possessing a much longer half-life than nicotine, and generally accepted as a proportional indicator of nicotine uptake. With my daily habitual usage being stable, I have to believe that my cotinine levels has reached a relatively steady-state.

I do appreciate that you've done the research you have, and by now, you've likely seen that many individuals here have many ideas that might, in one way or another, help you to design further ecigarette research that, we believe, will find that nicotine.

To the forum.. alright, I'm off to find a test kit.

 

[DVap]

My blood serum and urine levels are within 20% of what they were this time last year... I live alone, and work primarily from home. I'm rarely exposed to any smoker, and that only in the open-air occasionally. So if the device is delivering "little to none" - my body is doing one heck of a job synthesizing it. That, of course, would be a medical miracle, so I need to know how I can capitalize on that...

Adrenalynn, you're talking my language, and you beat me to the punch. Nice.

What was your pre-vaping cigarette usage like?

 

[mpetva]

Many of those who succeeded here with e-cigs have made e-smoking a hobby. We're like the hot rodders and custom car guys of the 50s. Yes, we can get more vapor, more nicotine, more throat hit.

But that's not the point of his reserach, or any research likely to be done.

Buyers of an alternative to a cigarette should know that an off-the-shelf product will deliver a known, safe quantity of needed nicotine to satisfy their addiction. It must be manufactured under known quality control conditions, have the same amount of nicotine as stated on the contents, and should be every bit as easy to use as a tobacco cigarette.

Pick it up, suck, inhale to lungs, exhale.

All of the fiddling and garage modifications mean nothing to anyone but hobbyists. Don't expect or even ask a university researcher to follow your modifications down a dark alley to a speakeasy with a peephole. We are getting far afield from reality in some posts here. Whatever works for you, do it. But testing will involve a stock product that either works, or doesn't work, with no learning curve or product modification needed. That's the real world of the non-hobbyist.

Good post! I think the same way. The average new user will buy it and will start using the ecig and it should work without a large learning curve. Vaping should be easy, consistent and convenient in order for the average smoker to change over to it.

 

[slybootz]

DVap, I was WAITING for you to make a post! Very nice, I look forward to seeing the results from your cotinine tests! If I had a twitter, I would tweet your post.

DVaps post

 

[TropicalBob]

I sent the study to researchers I maintain email contact with in other parts of the world. It's morning in New Zealand, where Dr. Murrary Laugesen of Health New Zealand read the PDF study and wrote me back:

dont think ecigs contain sufficient nicotine. (And is probably why vapers use bottled nicotine ) But then I dont think Nicotrol inhalers do either.

He said he felt the graph presented with the study was inaccurate. And he ended with this:

Note that Tobacco Control is insisting that ecigs be primarily named as Electronic Nicotine Delivery Devices, which is what TobReg Committee of WHO want them to be called. This frames them neatly in pharmaceutical territory, rather than as lifestyle drugs for addicted smokers to enjoy.

Laugesen studied electronic smoking for more than a year as head of Health New Zealand. The study was funded by Ruyan, the company which claims to have invented the e-cig. He has issued three lengthy reports of his findings, which are only applicable to Ruyan cartridges and devices, with nicotine no higher than 16mg per ml.

His initial conclusion that e-cigs don't deliver adequate nicotine, particularly in comparison to tobacco cigarettes, has led him to say vapor contains only 1/10th the nicotine of the same volume of smoke.

I spoke by phone with the CEO of another company moving into liquid production for e-cigs and he said a lab test he ordered showed only "pathetic" levels of nicotine, not nearly enough to be effective. His goal is to market liquids that pack the same punch as cigarette smoke. And he said he's ready to do that, and will bring some with him on his next visit to Florida, where I reside. Look forward to that. I'm one of those who feel there's "something missing" with vaping, and I could not remain smokefree without snus, nasal snuff and dissolvable tobacco pelllets to use concurently with vaping.

 

[Belletrist]

In short, I have to imagine that you might be (at least in passing) interested in what my blood or urine cotinine level might be? Cotinine, as you're surely quite aware, is nicotine's major metabolite possessing a much longer half-life than nicotine, and generally accepted as a proportional indicator of nicotine uptake. With my daily habitual usage being stable, I have to believe that my cotinine levels has reached a relatively steady-state.

I do appreciate that you've done the research you have, and by now, you've likely seen that many individuals here have many ideas that might, in one way or another, help you to design further ecigarette research that, we believe, will find that nicotine.

To the forum.. alright, I'm off to find a test kit.

i'm interested--in fact, i'm doing the same thing. i just linked to three kits that test cotinine in a semi-quantitative way (i'm not a scientist, please be gentle. )... what do you think of these ? i'd love to have others post their results on my blog as well (or just pm me here, and i can link back to ECF posts that show results).

obviously, this isn't 'hard science' but it's something, and i'd hate for people to be put off even trying to vape because "CNN said they don't work."

 

[leaford]

To be fair to some of the negative studies, why anyone would use the juices made in China is beyond me.. As many reports of toxic substances in other products coming out of there are I wouldn't be surprised if their juices were extracted from soylent green and mixed with cyanide and liquefied puppies.

It's easy to imagine the worst, but as someone who's over here in China now, let me assure you that's not the case.

Perhaps you would be interested in seeing what the liquid factories actually look like:

Leaford – An E-Smoker Forever! -|- Leaford’s reviews, E-Cigs, E-cigarettes, electronic cigarettes, e-pipes Blog Archive A trip to Vapor4Life’s liquid manufacturer.

 

[slybootz]

It's easy to imagine the worst, but as someone who's over here in China now, let me assure you that's not the case.

Perhaps you would be interested in seeing what the liquid factories actually look like:

Leaford – An E-Smoker Forever! -|- Leaford’s reviews, E-Cigs, E-cigarettes, electronic cigarettes, e-pipes Blog Archive A trip to Vapor4Life’s liquid manufacturer.

Leaford! Glad to see you're still paying attention to the USA posts all the way from the Shenzhen factory in China! Great pictures from the V4L factory. I hope you're still enjoying it over there!

 

[slybootz]

I've read that blog post of yours back in December, but I thought I would quote a particularly good excerpt:

First off, while sanitation is, and should be, a reasonable concern with ANY consumable goods, the particular paranoia over Chinese goods is at least a little xenophobic, and even a bit racist. Sure there have been high profile cases of contaminated goods, but compared to the sheer VOLUME of consumable goods made in China for the US, they are such a MINUTE fraction as to be almost inconsiderable. And it’s not as if the US has never had serious incidents of contaminated goods or foods before. Salmonella salad, anyone?

Very nicely put, I hope that your blog post, as well as the pictures you've included, should ease the minds of those who are in doubt about Chinese manufacturing procedures.

 

[Vocalek]

Teissenb:

You should also be aware that you are being misquoted:

that's at: DailyTech - Study: E-Cigarettes Fail at Nicotine Delivery, No Better Than Unlit Cigarette

Wow! I had to jump in to defend Dr. Eissenberg:

To state that the test subjects were inhaling a "toxic vapor" borders on slanderous toward Dr. Eissenberg. He would not knowingly expose test subjects to potential harm. Furthermore, his research, sponsored by the National Cancer Institute, was required to undergo approval by an Institutional Review Board. The IRB knew ahead of time that test subjects would not be exposed to anything more toxic than the cigarette smoke they inhaled on a daily basis. Indeed, the vapor is thousands of times less toxic than cigarette smoke.

I was particularly bothered by these two statements:

"At least one manufacturer used diethylene glycol as a key ingredient , a chemical commonly used in antifreeze and toxic to humans."

"...instead users were actually inhaling a nicotine-devoid toxic vapor of compounds like diethylene glycol or nitrosamines, a family of cancer-causing nitrogen compounds."

I'm afaid I let the author have it with both barrels. It was late. I was tired. I'm nice most of the time...

 

[DVap]

i'm interested--in fact, i'm doing the same thing. i just linked to three kits that test cotinine in a semi-quantitative way (i'm not a scientist, please be gentle. )... what do you think of these ? i'd love to have others post their results on my blog as well (or just pm me here, and i can link back to ECF posts that show results).

obviously, this isn't 'hard science' but it's something, and i'd hate for people to be put off even trying to vape because "CNN said they don't work."

The principle looks sound enough (immunochromatography... highly glorified paper chromatography using a cotinine-specific antibody), I guess it all depends on the implementation. Any of them should be good for a decent semi-quantitative result assuming they're not... blowing smoke.


TBob, very interesting the various opinions you've heard that vapor doesn't contain appreciable nicotine. The FDA report itself found 43.2, 34.9, and 26.8 micrograms (average ~ 35 micrograms) of nicotine per 100 mL puff from NJoy 18 mg carts. Using this average, and recalling my experiment last year that found a 1 microliter/second liquid consumption (based on 5 place balance weighing after 10 puffs of 5 seconds each).

So, using the FDA's own data, and filtering it through this 1 microliter/second experimental finding, we get the maximum nicotine in the vapor per 1 microliter of liquid consumed:

1 uL = 18 ug (194% recovery)
2 uL = 36 ug (97% recovery)
3 uL = 54 ug (65% recovery)

This is to say that the nicotine found in the vapor by the FDA would be at 100% of the available nicotine if the volume of liquid consumed per puff was 1.94 microliters (which I believe represents an ~ 2 second puff from a well-functioning ecig).

I'm not interested in making the nicotine be there or not be there, I only assert what I believe to really be the case, and I believe that it is there, and apparently, so does the FDA.

On the other hand, if every researcher around seems to insist it's not there, maybe I shouldn't argue? They can all leave us alone with our placebos.

 

[Belletrist]

thanks for replying dvap! i'm going to get as much feedback as i can before i do my li'l ol' test, so that the results are as accurate as they can be.

like you, though, it's not that i want the nic "to be there" or "not be there"... it'd be just as intriguing to discover i'm somehow getting by without the nic... and without withdrawal.

 

[Mister]

Dr. Eissenberg, I too want to say how much we appreciate your participation on this forum.

I hesitated before writing this note because I would very much like to see your continued interaction here and my note is a critical one. Others have voiced valid concerns and it is unnecessary for me to reiterate them. Yet I have another concern and feel I should voice it.

I do hope that you are an unbiased competent researcher taking an interest in electronic cigarettes, that you can relieve the legitimate concerns in this thread, and that you can advance our understanding of these devices.

The concern I wish to voice is that the data in the study does not seem to support the conclusions that "consumers should be aware that, unlike several regulated nicotine products (eg, gum, patch), these putative drug delivery systems do not deliver nicotine effectively after acute administration" (study), and that "They are as effective at nicotine delivery as puffing on an unlit cigarette" (CNN quote.)

On this thread you have suggested that your conclusions are appropriately qualified. But that is not the case. The final statement in the study's discussion section (first quote above) is written in a context which has no qualification regarding new users and a context which is suggestive in applying to all e-cigarettes. Your second statement, a quote to CNN which you stand by, has no qualification whatsoever.

Furthermore "after acute administration" is incorrect. Earlier in this thread you explain acute to mean "acute/short-term as opposed to chronic/long-term." That is not a true definition. Acute in this context means "short and severe." The conditions you tested were far from severe and earlier in this thread you state that they were deliberately so to avoid taking unwarranted risks. If you only mean short-term you should say short-term, not say acute.

As you have stated earlier in this thread the Discussion section does say that "Importantly, these results were from two specific products tested under acute conditions in which puff number was controlled. Variability in product design may influence vapour content and chronic use and/or more intensive puffing (ie, more puffs, greater puff volume) may influence nicotine delivery." But those qualifications are incorrect ("acute conditions"), omit other important qualifications (unfamiliar users, lack of testing of cartridges), are distanced from the subsequent conclusions, and are non-existent in the quote to CNN which you stand by.

A further concern is that you found the results surprising ("I published the data on 16 because the results were so surprising") yet you don't seem to have done what a scientist would normally do when faced with surprising results, i.e. attempt to confirm or deny the results before publishing to rule out error. Two obvious and simple things which could be done before reaching a generalized conclusion from the surprising results would be to:
1) Test the product's actual nicotine content. This should have been done even before finding surprising results.
2) Test the cotinine level found in a number of non-smoking long-term vapers.

From the data presented in the study many theories are possible, e.g. that the cartridges contained little or no nicotine, that the first 10 puffs deliver no nicotine, that new users don't inhale much from the unfamiliar device, that nicotine is following a different and much slower absorption path, that e-cigarettes don't deliver nicotine to the user, etc. The data is insufficient to explain the surprising results, much less to reach the strong conclusion reported via CNN.

On a separate issue you said something earlier in this thread which I think may be important regarding a whole new area of research into cigarette addiction, as well as suggesting that nicotine is being delivered by e-cigarettes when additional data is included:

"I saw another thread on here where people describe vaping and using snus at the same time, and someone else on this thread noted (as have others elsewhere) that they vape more frequently than they used to smoke. One person reported smoking normal tobacco cigarettes when stressed, but vaping at other times. All of these observations are all consistent with a product (e cig) that may not be delivering the nicotine dose to which the user has become accustomed."

I agree that those observations are consistent with a product which may not be delivering an adequate nicotine dose.

But there's more to the story which suggests both that vaping is delivering adequate nicotine and that something else is going on here. I am one of the people using snus as a supplement. Some of us use snus in small quantities. I was a hard case cigarette addict and find it very interesting that two strong snus per day (in addition to vaping 30mg e-liquid) quell my cravings, where vaping alone did not. If I am dependent on nicotine and e-cigarettes do not deliver it then using two strong snus per day should be pure torture (maybe not, I do not know for sure what is going on here.) The half life of nicotine in the body is commonly considered to be 2 hours (there seems to be variance in practice but not significant in this context) so using two snus per day should result in nothing short of a hellish experience if e-cigarettes are not delivering nicotine. I'd have a high intake twice per day with severe withdrawal for much of the remaining time. And if I am not dependent on nicotine and e-cigarettes don't deliver nicotine, shouldn't those two snus cause overdose symptoms at the time I use them? Yet they calm me.

The prevalent current theory here to explain these observations is that:
1) E-cigs are delivering nicotine. (Otherwise we'd expect madness among the people using this regimen.)
2) Tobacco consumption delivers something other than nicotine which is highly addictive to some users.
3) The "something other" has a relatively (vs. nicotine) long half-life in the body.

The current thinking (with some experimentation to support it, but not conclusive) on the forum is that the "something other" completing the need satisfaction for these users is one or more of the other alkaloids present in tobacco.

 

[leaford]

Leaford! Glad to see you're still paying attention to the USA posts all the way from the Shenzhen factory in China! Great pictures from the V4L factory. I hope you're still enjoying it over there!

Thanks, SLybootz, and yes, I am still enjoying it. Most days anyway.

 

[rothenbj]

in 2

The principle looks sound enough (immunochromatography... highly glorified paper chromatography using a cotinine-specific antibody), I guess it all depends on the implementation. Any of them should be good for a decent semi-quantitative result assuming they're not... blowing smoke.


TBob, very interesting the various opinions you've heard that vapor doesn't contain appreciable nicotine. The FDA report itself found 43.2, 34.9, and 26.8 micrograms (average ~ 35 micrograms) of nicotine per 100 mL puff from NJoy 18 mg carts. Using this average, and recalling my experiment last year that found a 1 microliter/second liquid consumption (based on 5 place balance weighing after 10 puffs of 5 seconds each).

So, using the FDA's own data, and filtering it through this 1 microliter/second experimental finding, we get the maximum nicotine in the vapor per 1 microliter of liquid consumed:

1 uL = 18 ug (194% recovery)
2 uL = 36 ug (97% recovery)
3 uL = 54 ug (65% recovery)

This is to say that the nicotine found in the vapor by the FDA would be at 100% of the available nicotine if the volume of liquid consumed per puff was 1.94 microliters (which I believe represents an ~ 2 second puff from a well-functioning ecig).

I'm not interested in making the nicotine be there or not be there, I only assert what I believe to really be the case, and I believe that it is there, and apparently, so does the FDA.

On the other hand, if every researcher around seems to insist it's not there, maybe I shouldn't argue? They can all leave us alone with our placebos.

I would suggest buying nicalert, if you are interested in testing your nicotine levels since the good doctor was involved in the approval process on 2003.

 

[bobtow]

I have a couple of questions about the Dr. tests. Did he have the eliquid used in the tests analized beforehand to make sure there was not any diethelene glycol in the test liquid? If so why was this not mentioned? If he did not? Why not? If you are to test an ingredient, should you not be sure of the contents of the subject?

 

[teissenb]

Yesterday was a snow day and VCU was closed and I was home with my kids: I had a lot of time to spend responding to your important questions and concerns. Today I do not. I'm just letting you know so you don't think I've run away.

Rothenbj recommends nicalert. I was not, to mky knowledge, involved in any "approval" process, but I did do a study on it (Acosta et al., 2004) and we still use it in the lab on a daily basis to verify smoking status. They are tricky to read but work as claimed. Although they react to cotinine they also cross-react with 3 hyrdoxy cotinine which has a much longer half-life. If you smoked a cigarette or used snus five days ago and only vaped since then, a positive result is influenced by the previous tobacco use. They are also sensitive to second hand smoke. In other words, for the purposes you describe, stay away from all non-vaping sources of nicotine for at least 5 days and do not hang out around smokers.

Mister has several concerns. I've said over and over that I stand by the comments in the paper and I have made clear what I think the conclusions are from the study. I am sorry if we disagree on this point.

Regarding the word "acute". I have seen it used it in this context (and in opposition to the word "chronic" but NOT inclduing the word severe) for many years and in many publications and you are the first to question it in this manner. Simply looking at the titles of my own peer-reviewed publications reveals that it is commonly accepted when used in this manner:

Evaluating the Acute Effects of Oral, Non-combustible Potential Reduced Exposure Products Marketed to Smokers. Cobb et al., in press.

Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology. Breland et al., 2002

Acute effects of Advance: a potential reduced exposure product for smokers. Breland et al., 2002

Acute subjective and physiological responses to smoking in adolescents. Corrigall et al., 2001

Relative potency of levo-alpha-acetylmethadol and methadone in humans under acute dosing conditions. Eissenberg et al., 1999

It is not only me -- I learned the usage from others and could cite many, many more examples.

With regard to the surprising nature of the results and subsequent publication, there are at least three points: 1) the raw data are so compelling as to eliminate any question of some statistical fluke that would be likely to disappear with more participants. When every one of 16 participants in a within-subject design shows the same pattern of results, the overwhelming probability is that subsequent participants will also show it. To simplify, if you threw a coin 16 times and it came up heads 16 times in a row, the best bet on the 17th toss would be heads. 2) When we submitted the paper based on 16 participants, we were well into completing all 32 participants as we said we would at ClinicalTrials[dot]Gov. Plasma nicotine analyses take a while to complete, but heart rate data are a nice proxy for nicotine exposure (as a stimulant, nicotine makes the heart beat faster). Heart rate data are available immediately after a session. Absolutely nothing in the heart rate data from the total data set suggested any reason to doubt the results from the first 16 participants. 3) Before the paper was published we had the plasma nicotine data from all 32 participants. As I said, we will be presenting them at SRNT in a few weeks. Again, absolutely nothing in the nicotine data from the total data set suggested any reason to doubt the results from the first 16 participants. Given these circumstances, the absence of data on these products demanded that the results be made public as quickly as possible. My only regret is that it took so long.

I would like to note that, with regard to the issue of atomizers producing nicotine-free vapor upon initial puffing, I have heard opinions but seen no data. Can someone please provide *objective* proof of the claim? In any case, if we have only 4 devices, and we have 32 participants, this effect (if it is an effect) could only have influenced 4 of the 32 people (i.e., the first person who used each of the four devices). As I said, the raw data are too compelling for that to be a meaningful factor.

With regard to analyzing cartridge or vapor nicotine content, I agree it would have been nice to do so. However, having done so would not change the conclusions -- it would only suggest WHY the products I tested failed to deliver any measurable nicotine under the conditions under which I tested them. I tested off-the-shelf products that were reported to deliver nicotine to users. Whether they failed to do so (under the conditions in which we tested them) because the product came to us with no nicotine (very difficult to believe that each of two manufacturers managed to send us separate shipments of 16 mg cartridges that actually contained no nicotine!) or because the product cannot vaporize nicotine (but FDA and Laugesen both show that at least some of these types of products do vaporize nicotine, albeit in very low doses), or because the nicotine-containing vapor does not allow absorption of the drug to the user will not change the conclusion that they failed to do so under the conditions in which we tested them. Tropical Bob's post on hobbyists addresses this point nicely. In this study I wanted to know what the first-time user of the off the shelf product is likely to experience, not what the expert in the field who modifies the device and/or drips liquid directly onto the atomizer experiences. Again, that study is an interesting one, but a different one.

Thanks,

Tom E

 

[hifistud]

In this study I wanted to know what the first-time user of the off the shelf product is likely to experience, not what the expert in the field who modifies the device and/or drips liquid directly onto the atomizer experiences. Again, that study is an interesting one, but a different one.

To take my hand saw/chain saw analogy on a stage here, what the study appears to have tested is how an experienced hand saw user would fare with a chain saw having had no training in its use and not even knowing that you have to start the engine to make it work. And perhaps even having put diesel in the fuel tank instead of petrol (because the diesel was in a can labelled "Petrol").

While I fully accept that the results you have obtained are valid for your methodology, and to pick up on your coin toss analogy, after the 16th toss I'd be checking the coin for weight bias - while 16 straight heads is not impossible, it's improbable, and experience tells me that the same applies here.

 

[CES]

I keep thinking that I'm going to jump off this thread, but then I find myself responding again...

"To simplify, if you threw a coin 16 times and it came up heads 16 times in a row, the best bet on the 17th toss would be heads."

That's a bit of an oversimplification. A coin toss has independent probabilities, It's 50% likely that you'll get heads the first time and the 17th time. The results of tossing a single coin 17 times, or 17 coins 1 time each are unrelated to other.

I assume/hope that you'll continue to test PVs. It needs to be done. Perhaps naive subjects might do better with a manual two-piece unit. Since there appears to be slightly less of a learning curve. There is also a learning curve with FDA approved NRTs- directions on how frequently to chew and use the gum, and how to use the nasal spray (is nasal spray still available? it HURT to use. if I remember correctly the placebo when testing it was a mild solution of pepper spray)