There is no evidence whatsoever that nicotine can cause dependence without exposure to tobacco, and considerable evidence that it can't. This is a controversial issue because of the significant commercial, regulatory and reputational implications, and this article examines the relevant issues.
There are no published clinical trials of pure nicotine administered to never-smokers examining dependence issues (or lack of them): therefore there is no evidence that nicotine can, by itself, create dependence. Because there are multiple clinical trials of this type, involving hundreds of subjects in total, for various other purposes such as investigation of nicotine's benefits for certain medical conditions, and no subject has ever been reported as exhibiting any signs of dependence, it now appears extremely unlikely that nicotine has any potential for independent creation of dependence; 'boosters' of some kind are apparently needed (more correctly termed potentiators or synergens). On completion of these trials there were no signs of reinforcement, withdrawal, or continued use in the test subjects: these are the markers for dependence, and none were seen, ever, in any subject - despite large quantities of nicotine being administered daily for several months to never-smokers.
As a result of this growing body of evidence, and from extensive personal experience, several experts in this field have clearly stated that nicotine has no potential for dependence outside of tobacco exposure, and some quotes are listed below.
In case the implications of this are not clear: it is regarded by nicotine administration experts (those with extensive experience of working with nicotine and never-smokers) as impossible to create nicotine dependence clinically, and as being a very rare event when reported anecdotally. Therefore it is not seen as likely that even the most efficient consumer nicotine delivery devices such as the latest types of EV (electronic vapouriser / ecig) will produce any clinically significant measure of dependence in persons unexposed to tobacco.
There is no published clinical trial examining the potential of nicotine for 'addiction'. That is to say, there is no published trial of the administration of pure nicotine to never-smokers for the purpose of investigating any potential for dependence.
There are multiple clinical trials where nicotine has been administered to never-smokers, for other purposes such as investigating its beneficial effects in treating certain medical conditions. The eight published trials located so far involved hundreds of never-smokers in total. In some trials, high doses of nicotine were administered daily for several months. No subject, ever, in any trial, was reported to have experienced any sign of reinforcement, or withdrawal, or continued nicotine use after (and this was both examined and commented on). It was noted that nicotine had no potential for dependence in any of these trials.
The trials were variously for investigation of nicotine therapy in cognitive dysfunction, degenerative and auto-immune diseases where there had been reports that supplementation of the alkaloid (normally present in the average diet) may have some benefit. We need not examine these trials or their results: you will find several of them listed on the References page. Because the trials were not specifically for the examination of dependence potential, but were specifically for examining some other factor, only that factor is allowable in the results and the evidence obtained. 'Side effects' (or lack of them) are not an evidentiary effect in a trial for another purpose. Therefore, no matter the weight of evidence supplied by the inability to create any dependence or even the least sign of it in hundreds of people administered high doses of a compound for months on end, since it was not the designed goal then it is deemed anecdotal.
On the other hand, although evidence from an individual trial is regarded as anecdotal, there may come a point when such a weight of evidence exists that it can no longer be regarded as anecdotal. We certainly see this elsewhere: for example the millions of vapers who are successful ex-smokers have been described as 'anecdotes', and such a description reveals that something can be a fact but not accepted by those sections of industry and the medical community who would be harmed financially by the fact being recognised.
"The risk of addiction to nicotine alone is virtually nil."
- Dr. Paul Newhouse
Director, Vanderbilt University Center for Cognitive Medicine
"Nicotine is not addictive."
- Prof Peter Killeen
Emeritus Professor of Psychology, ASU
"There is very little to no evidence for the abuse of nicotine when not delivered in a tobacco vehicle."
- Prof K Fagerstrom
(creator of the Fagerstrom Test for Smoking Dependence)
"...decades of research and use have shown that NRT products sold OTC do not appear to have significant potential for abuse or dependence."
See, for more detail:
You will also be immediately aware, if you have any connection with the world of clinical trials, that there are several rather important ethics issues here:
It is abundantly clear that what might be called the private medical profile of nicotine, and its public profile, are completely different.
Note carefully that studies carried out on smokers or ex-smokers are essentially pointless, as they have no value: they cannot provide any evidence whatsoever as to nicotine's potential for dependence. Smoking - the inhalation of many thousands of compounds - is known to create dependence on nicotine. So would the consumption of ketchup, in all probability, given the right boosters, synergens and potentiators; and since we can add around 5,000 or more  to make it fair and to level the playing field out, this would be no problem at all: it seems quite likely we could create dependence on ketchup (which of course contains nicotine).
But let's get back to why we are here. Ed West asked me: "Is there is no valuable science on nicotine?", as a result of the article on Nicotine Myths.
It appears that the article may have been construed as meaning that nicotine research does not exist. This was not the intention of the article at all - there is plenty of good research on nicotine, for example core biochemistry research and, more accessible perhaps, Benowitz' papers on these subjects collating the research. And plenty more of this kind .
None of it, though, answers the most important question of all:
"If pure nicotine is administered to nicotine-naive people - and especially those never exposed to the known dependence-forming cocktail of compounds in tobacco smoke - can it produce dependence?"
It's the $64,000 question, and the one everyone argues about.
There is a very noticeable gap here: despite huge interest in nicotine's potential for dependence-creation, there is nothing available on that topic. This is such a critical omission that, reasonably, it cannot be accidental. There is no published study with an online link, and it is reported that there is nothing available in offline libraries. There is plenty of material on dependence in smokers or ex-smokers, but of course that is irrelevant to nicotine's potential for dependence: other ordinary ingredients in the diet could almost certainly be made 'addictive' by delivery in repeated large doses over many years in a carefully-engineered cocktail of synergens. For example it seems likely that dependence on vitamin A or a precursor could be created by this method, since there are several anecdotal reports of reinforcement occurring with abuse of unboosted, unmodified, raw products (e.g. carrot juice); but no one regards vitamin A in the diet, or supplements, as 'addictive'.
Modern usage differentiates between addiction and dependence - see dependence:
The use of the term addiction to describe a harmless dependence is commonly employed now to artificially inflame the debate by adding an unscientific, emotional component.
Because it is such a crucial omission, it is worth considering whether in fact it is possible that such a study has never been carried out anywhere in the world, ever. Since the anecdotal reports on nicotine's lack of dependence potential provide hints as to the outcome (all the evidence clearly shows that nicotine has no potential for reinforcement, outside of smoking), then perhaps this provides one answer as to why such a study has not been published.
Many would welcome a clinical trial that addresses the results of administration of pure nicotine to never-smokers , as this would answer some important questions. However, it is clear that such a study is unlikely to see the light of day, for numerous reasons.
Of course it could: we have just seen that multiple such trials have been approved and completed.
There are some difficulties to be faced, though:
A trial that was authorised and produced the 'wrong' result would be buried; no prizes for guessing what would happen to a nicotine trial that announced there was zero potential for dependence outside of tobacco consumption. Considering the significant interest in this topic, though, it is probably rather naive to think such a trial has never taken place.
A trial of nicotinic acid (vitamin B3) would probably get the go-ahead without issues - but nicotine is a problem, due to the taboo but mainly for its potential to destroy medical reputations, areas of dogma, whole pharmaceutical catalogues, regulatory authorities' authority, and more of the same. For all practical purposes they are similar, and in some ways more than similar; but we might expect a trial of vitamin B3 to be approved while its sister compound would be difficult. However there are many countries, and even some in Europe, where a trial of nicotine with never-smokers could almost certainly be carried out currently without issues and without contention. The real question is probably, "Is it really tenable that a clinical trial of nicotine has never taken place?".
A modern trial that did get published would be a very interesting phenomenon anyway, given the current situation regarding the commercially-influenced 'management' of clinical trials. Allowing for the dozens of ways to rig a trial, and that the results of an unmanaged trial of nicotine's dependence potential are likely to be extremely embarrassing all round, it would be hard to see how its conclusions could be trusted. A historic trial would be of far greater interest, and surely it is reasonable to suggest that such a trial exists; such trials were commonplace. Example: the large-scale clinical trials examining the presence of nicotine in the population (in which every subject tested positive every time in every study). The CDC carried out one such study, in which 800 people all tested positive for nicotine; and now they have done their best to remove that trial from public view and undoubtedly would have removed it entirely had it not already been cited .
We can expect that no trial similar to that of the CDC 800 will be published again, until diets are so poor that vegetable consumption has reduced to the point that some nutrients are no longer detectable in the organism among certain demographics (students seem a good prospect); perhaps, at that point, the study will be carried out again with a more positive result for the tobacco control industry and their commercial funders. We might expect that no mention will be made of the nutritional deficiencies likely to co-exist, at such a time, only that not all subjects test positive for nicotine any longer. No doubt this will be attributed to lack of ETS exposure, and promoted as a win.
We already know that factual information about nicotine is suppressed:
It is unlikely that an honest trial of nicotine's potential for dependence could be carried out at this time, since the results would likely be catastrophic for some commercial agendas and ideologies. We should be looking for historical examples that have been removed from view due to their unacceptable results, as with the CDC trial of nicotine in the population.
Points of interest
1. Clinical trial of nicotine for cognitive dysfunction
This typical clinical trial of nicotine with non-smokers and never-smokers follows what appears to be a common path: nicotine is administered to a group composed of never-smokers and non-smokers, to measure any benefit for a specific condition or activity.
Despite the subjects (who were all non-smokers and mostly never-smokers) being administered 15mg* of pure nicotine daily, for 6 months, not one single subject had any withdrawal symptoms or continued to use nicotine.
* This is equivalent to smoking about 18 tobacco cigarettes, as a cigarette delivers 0.8mg nicotine on average, in the US and UK, @2013
"There was no withdrawal syndrome and no subjects continued to use nicotine products. Thus, in this nonsmoking population, there was no evidence for abuse liability of transdermal nicotine. Only nonsmokers were utilized for this study to simplify dose-ranging. As former smoking status was not a focus of this study and the number of former smokers was small, an analysis of prior smoking status and efficacy was not performed."
(Most participants are reported, then, as never-smokers).
The study reported other aspects of nicotine use that the community is already well aware of and are therefore not news: improvements in cognitive function and associated performance (e.g. memory) for those with prior impairment, and a small loss of weight over the 6 month period (2.5kg); also a small reduction in systolic blood pressure (perhaps counter-intuitive, for some people). Regarding a specific group of people with cognitive impairment, the study concluded, "Thus it is possible that nicotinic augmentation may be a particularly appropriate choice for these individuals."
We did of course already know that supplementation of this particular active dietary ingredient is beneficial for some people, although this is not really a difficult concept. There are other interesting comments in the Conclusion, such as, "measures of attentional, memory, and psychomotor performance did show an effect of nicotine and this finding provides strong justification for further treatment studies of nicotine for patients with early evidence of cognitive dysfunction."
See References page (foot of right-hand menu): Nicotine, 2, 3.
[Thanks to: www.pronik.org of Germany]
2. FDA announces nicotine not addictive or harmful
In April 2013 the FDA announced they no longer considered nicotine to be dependence-creating, liable to abuse, or dangerous if over-consumed.
In their Consumer Updates, they proposed removing several of the warning labels from NRTs. They have now conceded that several decades of evidence from nicotine-containing meds sales demonstrates that nicotine has no measurable potential for addiction and presents no danger of harm through overdose.
See References page: Nicotine, 12.
They say, "The changes that FDA is allowing to these labels reflect the fact that although any nicotine-containing product is potentially addictive, decades of research and use have shown that NRT products sold OTC do not appear to have significant potential for abuse or dependence.
The changes being recommended by FDA include a removal of the warning that consumers should not use an NRT product if they are still smoking, chewing tobacco, using snuff or any other product that contains nicotine - including another NRT."
They have had to include a message about 'potential addiction' presumably to placate the loudest objectors, but since the evidence does not support this, and they clearly do not agree that nicotine is either dependence-forming or dangerous, they appear amenable to change. The way these things go is that they will announce it; a storm will kick up among the crackpots, junk science promoters and commercial objectors; a cooling-off period will ensue (possibly of a year or two); and then they will act.
A cynic might perhaps wonder if this U-turn might possibly, just slightly, be designed to assist pharmaceutical companies. It would definitely enable them to sell more smoking cessation meds, by removing unnecessary restrictions that prevent full use being made of NRTs. Indeed, NRTs cannot achieve anything like their proper potential unless the unnecessary restrictions on their use are removed - part of the reason they are so useless (a 93% to 98% failure rate in the real world) is that they are unfairly restricted to short-course therapies and multi-use is prohibited.
NRTs are among the safest of all medicines as they basically contain dietary supplements delivered by alternative routes, and are therefore essentially just an aggressive nutritional therapy. They have never been shown to have any more risk than any other food supplements; although of course many dietary components, such as iron, can cause harm in cases of substantial overdose.
It is probably reasonable to conclude that the FDA would not be taking this step unless there were a significant economic benefit for their funders. However, since no one can demonstrate any harm from nicotine, and since it is not dependence-creating except within tobacco, there are no reasons why the FDA should not take this step. It is about ten years behind the curve but that is normal within medical practice (in fact it may be regarded as radically new, with such a short timelag behind the evidence).
It won't be popular with the ideologists, but the science does not support their view in any case. Don't expect the CDC or WHO to like it; but reality does not suit crackpot ideologists too well.
So now we know: even the FDA does not consider nicotine 'addictive' or dangerous.
 See Rodgman, Perfetti 2013: 9,600 separate compounds have been identified in tobacco and tobacco smoke.
 See, for example, the DFG nicotine research library:
 Such a trial would need to involve administration of pure nicotine in realistic supra-dietary amounts to persons who have never smoked.
For example: administration of 0.8mg and 0.4mg pure nicotine (to precisely replicate the nicotine supplied in a tobacco cigarette and e-cigarette ), from a medical nicotine inhaler with measured doses, at 1-hour intervals, for eight hours per day, for 1 month, to two groups, with a third control group receiving a placebo; followed by daily determination of dependence created or not created, for a period of 2 weeks; followed by compilation and interpretation of the data.
This will provide the required trial of pure nicotine without any MAOIs, other active alkaloids, freebasers, synergens, or pyrolytic compounds. It addresses the potential of inhaled nicotine to create dependence, not that of smoking.
It would be a very simple trial to run. It almost certainly has been in some form, already. It could probably be carried out in many countries in Europe at this time, never mind elsewhere.
 Modern cigarettes supply about 0.8mg nicotine or less. E-Cigarette vapour commonly supplies 10% (demonstrated, ) to 50% (estimated) of the nicotine supplied by cigarette smoke.
 This trial has now been located by Dr Farsalinos: see References page, Nicotine, #22.
 Laugesen demonstrated that e-cigarettes he tested supplied 10mcg nicotine per puff in the vapor, and asserted that cigarettes supply 103mcg per puff in the smoke, thus ecigs supply ~10% of the nicotine supplied by cigarettes, per puff. It is likely that we would now see a 5x improvement in his results , and therefore the figure might be improved from 10% to 50%.
 Laugesen tested 1st generation e-cigarettes (the type we refer to as 'minis' or 'cig-alikes') with average strength refills, a doubly obsolete subject for measurement and with suboptimal refills. If using 2nd-generation equipment, of the mid-size (eGo) type that have replaced minis as the benchmark, with correctly-specified refills, it might be expected that a 5x improvement in the result would be obtained. Therefore, if tests are carried out properly, we could now expect to see ecigs testing at 50% of the nicotine supplied by tobacco cigarettes per puff. So, if a current era tobacco cigarette averages a supply total of 0.8mg in the smoke, we might expect to see a current era e-cigarette supplying 0.4mg total in the vapor for an equivalent session time. (Although, if staying with a demonstrated level of nicotine supplied by an e-cigarette, then we would need to use a total of 0.08mg nicotine - 10% of the tobacco cigarette figure.)