On the benefits and lack of demerits of nicotine
psychology, biology, nootropics
created: 09 May 2011
modified: 26 Apr 2015
status:
in progress

belief:
likely

On the benefits and lack of demerits of nicotine
psychology, biology, nootropics
created: 09 May 2011; modified: 26 Apr 2015
status:
in progress

belief:
likely

On the benefits and lack of demerits of nicotine (psychology, biology, nootropics)
created: 09 May 2011; modified: 26 Apr 2015
status: in progress; belief: likely
On the benefits and lack of demerits of nicotine (psychology, biology, nootropics)
created: 09 May 2011; modified: 26 Apr 2015; status: in progress; belief: likely

One of the reasons tobacco became so popular in the 1600s, along with tea & coffee (for their caffeine), was that nicotine is a powerful stimulant. Obvious enough; it affects tons of systems. Less obvious is that nicotine has many beneficial effects (and these benefits may be related to anomalous smoking results1); the infamous deadliness of smoking would seem to be almost solely from the smoke, not the nicotine. Even less obvious is that nicotine itself may not be especially addictive, and its addictiveness is genetically modulated2.

All of the harm seems to stem from tobacco, and tobacco smoking in particular; this is not necessarily obvious because almost everyone casually conflates tobacco with nicotine (especially public education programs3), treating them as a single synonymous evil I dub “nicbacco”. When someone or something says that “nicotine” is harmful and you drill down to the original references for their claims, the references often turn out to actually be talking about tobacco rather than nicotine gums or patches45. Other methodological issues include comparing to current smokers rather than former smokers or failing to control for the subjects being the sort of people who would begin such a societally-disapproved activity like smoking; the studies typically aren’t designed properly even for showing an effect: you need a study which finds deficits in smokers but not in non-smokers or former smokers (eg. Heffernan et al 2011 or Sabia et al 2008/Sabia et al 2012 although neither enables nicotine inferences since there was no nicotine-only control group).

Since it’s the main concern, we’ll address it up front.

Wikipedia summarizes Guillem et al 2005 as “Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties” - the addictiveness coming from MAOIs (eg. Khalil et al 2000, Khalil et al 2006) & possibly other compounds present in tobacco; while there don’t seem to many human studies aside from the Amsterdam et al 2006 review on the observed inhibition in smokers (consistent with the MAOIs playing a role in addiction), there are a number of significant animal studies:

Reviews or discussion of human smoking & MAOIs include Fowler et al 2003 & Berlin & Anthenelli 20016.

Another thorough and contrarian piece is Frenk & Dar’s 2002 book, A Critique of Nicotine Addiction. I don’t entirely agree with their take-no-prisoners arguments, since additional work since 2002 has clearly shown that nicotine alone does have some addictive properties: for example, Le Foll et al 2007, “High Reinforcing Efficacy of Nicotine in Non-Human Primates” found that given enough development, squirrel monkeys would push levers up to 600 times for an injection. But on the other hand, as Le Foll et al comment:

Surprisingly, reinforcing effects of nicotine alone have often been difficult to demonstrate directly in controlled laboratory studies with both animals and humans as experimental subjects. Consequently, there has been continuing controversy in the literature about the validity of previous findings of reinforcing effects of nicotine in experimental animals and human subjects [3], [4], [5], [6], [7], [8].

Or “Brain science, addiction and drugs” 2008:

The results showed that 40% of smokers receiving the [anti-nicotine] vaccine gave up smoking for nearly six months of follow-up; the highest smoking cessation rate (57%) was associated with the highest antibody response. These results are better than those seen in most nicotine replacement trials, but it is interesting that an unusually high proportion (31%) of the smokers receiving placebo also quit smoking for up to six months [Holman J (2005). “Helping patients kick the habit”. American Diabetes Association, DOC News 2, 1-2].

My take away is that there is addiction but it’s drastically overestimated by almost everyone and may been conflated with the habit-formation capability; the latter makes nicotine doubly valuable, but the former means we will want to be more careful with the nicotine than with modafinil or caffeine, where the main consequence of carelessness is tolerance rendering the stimulant useless or messing up our sleep for a few days.

For example, snus, a sort of chewing tobacco, has been studied extensively in Sweden where it is very popular and has been credited with large reductions in the smoking rate7, and with little hard evidence of harm from snus use8. Smokeless tobacco in general is hugely more safe than smoking (“Smokeout: Not as easy as ABC”, Washington Times):

Modern smokeless tobacco products contain nicotine in addictive doses to satisfy smokers’ cravings. University research has documented that smokers who switch to smokeless tobacco reduce their risk for all smoking-related illnesses, including oral cancer. On average, smokers live 8 years less than those who never used tobacco; smokeless users lose just 15 days. Statistically, smokeless users have about the same risk of dying as automobile users.

Or “The Nicotine Patch Didn’t Work? You May Not Have Used It Enough”, The New York Times:

“People are unreasonably afraid of nicotine”, Dr. Shiffman said. “The majority of smokers believe that nicotine causes cancer and is a big player in the harm caused by cigarettes.” In fact, carbon monoxide, tar and the countless toxic particles in cigarette smoke are what promote illness. Although smokers may become dependent on nicotine, it does not appear to raise the risk of cancer, lung disease or heart disease. Early reports that people who smoked cigarettes while wearing a patch stood an increased risk of heart attack proved unfounded years ago.

Dr. Siegel, whose graduate school manuscripts Dr. Glantz used to read, says e-cigarette pessimists are stuck on the idea that anything that looks like smoking is bad. “They are so blinded by this ideology that they are not able to see e-cigarettes objectively,” he said. Dr. Glantz disagrees. “E-cigarettes seem like a good idea,” he said, “but they aren’t.”…Public health experts like to say that people smoke for the nicotine but die from the tar. And the reason e-cigarettes have caused such a stir is that they take the deadly tar out of the equation while offering the nicotine fix and the sensation of smoking. For all that is unknown about the new devices - they have been on the American market for only seven years - most researchers agree that puffing on one is far less harmful than smoking a traditional cigarette…E-cigarette skeptics have also raised concerns about nicotine addiction. But many researchers say that the nicotine by itself is not a serious health hazard. Nicotine-replacement therapies like lozenges and patches have been used for years. Some even argue that nicotine is a lot like caffeine: an addictive substance that stimulates the mind. “Nicotine may have some adverse health effects, but they are relatively minor,” said Dr. Neal L. Benowitz, a professor of medicine at the University of California, San Francisco, who has spent his career studying the pharmacology of nicotine…“Part of the furniture for us is that the tobacco industry is evil and everything they do has to be opposed,” said John Britton, a professor of epidemiology at the University of Nottingham in England, and the director for the U.K. Center for Tobacco and Alcohol Studies. “But one doesn’t want that to get in the way of public health.”

(Specifically, the main carcinogens in tobacco seem to be the nitrosamines, polycyclic aromatic hydrocarbons, radium-226, polonium-210, and the nanoparticles like carbon created in combustion; see Marmorstein 1986, Rodu & Jansson 2004 & National Cancer Institute. That is, smoking is bad for you for much the same reason that fireplaces kill; see Naeher et al 2007.)

Which would seem to suggest the following line of thought: if the research on actual smoking is equivocal, and then the demonstrated harm of non-smoking tobacco is so minimal (even if we ignore equivocalness), then how much safer would be just nicotine on its own as a patch/pill? Let’s ignore the general issue of tobacco (about as harmful as TV watching?910) and focus on just nicotine.

# Effects

## Benefits

### Performance

If you’ve read through this page and also read the Wikipedia page on nicotine, your eye was probably caught by the mention that nicotine affects the cholinergic system - the same system piracetam affects. (This might make nicotine redundant with piracetam or other nootropics that affect acetylcholine or acetylcholinesterase, such as huperzine-A, but it’s been argued against.11)

Indeed, the research literature is full of results connecting nicotine with improved mental performance:

Notice that many of these results are recent, and postdate the victorious war on tobacco. The question of whether positive results are tainted by tobacco money has been examined; Anders Sandberg notes that there is pretty clear evidence of funding bias - but the independent researchers still turned up their fair share of positive results.

Anecdotally, a great many Imminst posters report a positive experience which is similar to, but better than, the extremely popular amphetamine formulation Adderall; a few also favorably compare it to caffeine. (These anecdotes are supported by a historical survey which reports that the 2 highest rates of hourly consumption were during work hours, and that “Of these three groups [surveyed], 86% of the clinic group, 83% of the students, and 59% of the hospital workers agreed with the statement that ‘smoking helps me think and concentrate’.”)

### Habit-formation

Besides the nootropic effects, nicotine can be used as an relatively precise self-reward - faster acting than other stimulants like caffeine and modafinil, but with a combination of weak addictiveness and habit formation which is seems to be neural23 and epigenetic24 and affecting sensitivity of the reward system. This use of nicotine to strengthen habits is in accord with at least some research into nicotine; from “Nicotine Creates Stronger Memories, Cues To Drug Use”, Science Daily, describing “Dopamine enables in vivo synaptic plasticity associated with the addictive drug nicotine” (Tang & Dani 2009; see also Davis & Gould 2008 and Levine et al 2011):

“Our brains normally make these associations between things that support our existence and environmental cues so that we conduct behaviors leading to successful lives. The brain sends a reward signal when we act in a way that contributes to our well being,” said Dr. John A. Dani, professor of neuroscience at BCM and co-author of the study. “However, nicotine commandeers this subconscious learning process in the brain so we begin to behave as though smoking is a positive action.” Dani said that environmental events linked with smoking can become cues that prompt the smoking urge. Those cues could include alcohol, a meal with friends, or even the drive home from work. To understand why these associations are so strong, Dani and Dr. Jianrong Tang, instructor of neuroscience at BCM and co-author of the report, decided to record brain activity of mice as they were exposed to nicotine, the addictive component of tobacco.

…“The brain activity change was just amazing,” Dani said. “Compared to injections of saline, nicotine strengthened neuronal connections-sometimes up to 200 percent. This strengthening of connections underlies new memory formation.”…“We found that nicotine could strengthen neuronal synaptic connections only when the so called reward centers sent a dopamine signal. That was a critical process in creating the memory associations even with bad behavior like smoking.”

LessWrong user Wedrifid, has a fascinating series of comments:

I have had success working around ‘Ugh’ reactions to various activities. I took the direct approach. I (intermittently) use nicotine lozenges as a stimulant while exercising. Apart from boosting physical performance and motivation it also happens to be the most potent substance I am aware of for increasing habit formation in the brain…

And I do use nicotine for studying at times (usually patches that I have cut into the desired dose). Partly for learning mental habits and partly for enhanced focus and motivation without the agitation that comes (with methamphetamine (at least, for me)). Again, I don’t swear by it but it works…25

I have never smoked a cigarette. Nor have I ever had a remote tendency towards addiction to any substance. That is even one of the reasons I gave when describing why this is an effective technique for me personally. I am more at risk of becoming addicted to discussing substances on the Internet than the substances themselves….

I should note that the role nicotine lozenges are taking here is not primarily as a training reward, like giving the rat electronically stimulated orgasms when it presses the lever. Nicotine isn’t particularly strong in that role compared to alternatives (such as abusing Ritalin), at least when it is not administered by a massive hit straight into the brain via the lungs. No, the particular potency of nicotine is that it potentates the formation of habits for activities undertaken while under the influence by means more fundamental than a ‘mere’ stimulus-reward mechanism. Habits that are found to be harder to extinct than an impulse to take a drug. This is what makes smoking so notoriously hard to quit even with patches and makes the use of fake cigarettes to suck on useful.26

E-cigarettes are a really cheap nicotine delivery system. Like pennies per cigarette equivalent cheap if you mix juice yourself. I don’t see how taking advantage of the effects of nicotine is any worse than caffeine. I started vaping while I study and have seen huge productivity improvements from the reduction in ugh fields.

Dose-wise:

My lozenges (when I had them) were 4mg… which I would consider almost too much. About equivalent to a full double-dose can of energy drink. If I use nicotine as a stimulant now I tend to go with about 4mg of 16 hour patch. (That is, I cut the 24mg 16 hour patches into small pieces).

# Costs

## Price

The price is not an issue. Nicotine in the US is not as expensive as one might intuitively guess from sky-high cigarette prices & widespread tobacco smuggling; perhaps due to the intrinsic low cost of nicotine or because it is politically unpalatable to tax products which are largely used by people quitting smoking, prices for a 2mg dose of nicotine is easily in the 15-20 cents range:

• for example, one Nicorette gum product offers 100 4mg gums for $38.56, or 39 cents a gum, or if you split one in half to get a 2mg dose, 18 cents a dose. • a random nicotine lozenge product is 144 4mg lozenges for$42.68, 30 cents per lozenge, and 15 cents per 2mg.

2mg may be too much for a non-smoker like me, in which case prices per dose drop further. Nor have I looked hard27 for low prices; just grabbed random hits on Amazon. You could probably drive it down to the 5-10 cents range with canny shopping and buying in bulk (nicotine is an insecticide, not a perishable foodstuff, so you could buy years’ worth - just like with melatonin). One difficulty with gum, however, is that it’s hard to subdivide: nicotine evaporates from gum and so cutting up a 4mg piece of gum into 4 1mg pieces forces you to either use them all within a few hours, waste some pieces, or store them in some sort of air-tight wrapper for later use.

Further, the rise of e-cigarettes which use nicotine dissolved in water means that if you are willing to have the nicotine absorbed quickly (which would seem to slightly increase addiction risks), the price for a 2mg dose plummets even further; consider one liter of fluid for e-cigarettes ($232 as of 2012, but down to$160 as of October 2013). The concentration is 100 mg of nicotine per ml, there are 1000 ml per liter, one wants 2 mg per dose, so $\frac{100×1000}{2}=50000$ doses for $232, or a (very) small fraction of a cent per dose ## Health issues So, what are the gotchas? 1. Tolerance may be a problem. Posters report (like with most stimulants, and perhaps modafinil); their anecdotes are supported by general observations that smokers tend to escalate their smoking habit and by findings that nicotine down-regulates its receptors in mice. On the other hand, even if one does develop tolerance to nicotine, that simply suggests spacing it out or rotating with other stimulants. One could imagine a 3-day cycle: nicotine, caffeine, and modafinil. 2. Nicotine is well-known to cause vasoconstriction (higher blood pressure) which concerns people But the increase may not be all that large, especially at a low non-smoker dose; and if there is blood pressure increase, it may be perfectly tolerable.28 3. Though patches are generally found to be safe29 and not abused30, research on nicotine turns up all sorts of possible ways nicotine could be net-unhealthy (perhaps it metabolizes to a carcinogen among other things or cause mutations31 ) But nicotine has been so intensively studied that we ought to expect a lot of scary looking correlations and possibilities even if nicotine were the bee’s knees, and it can be difficult to interpret the overall mass of studies - what does it actually mean if in mice nicotine increases lung cancer resistance but in female rats nicotine plus estrogen weakens resistance to brain trauma? Does this work in humans? Does it make the cancer more deadly? Is that offset by benefits elsewhere? Is this even a real result given the small sample sizes & lack of replication? If we read of massive carcinogenesis in mice being given LD50-size doses of nicotine for 2 years, is that evidence against nicotine’s safety or for? What does it mean when one can cause cytotoxicity in mouse cells in a petri dish using 100% undiluted nicotine (and no more dilute) while 4/5 cigarette smoke extracts caused cytotoxicity? There are a lot of links in this page, but only a fraction of the ones I’ve seen. Cherry-picking and unjustified leaps are a problem in any review; “Cigarette smoking: an underused tool in high-performance endurance training” makes the point humorously. One forumite illustrates the problem: “Consider acne. Nicotine increases keratinocyte differentiation, increases sebum production, etc. It seems like it would induce acne. Yet, overall studies show nicotine use is associated with significantly less acne, purportedly due to other anti-inflammatory mechanisms…nicotine is unfortunately far more complex and difficult to understand.” There are other grab-bags of pros and cons to nicotine32. 4. Nicotine has been shown to impair neurogenesis in the hippocampus in rats at high doses. But the impairment was only shown at the higher doses33, and it’s unclear how it would generalize to humans. (As well, many stimulants impair the hippocampus in mice & rats; caffeine, for example.) 5. there may be an interaction with diabetes: a small correlational study found a long-term correlation between nicotine gum and hyperinsulinemia & insulin resistance (an experimental rat study found the opposite); and Axelsson et al 2001 found a short-term effect but only in diabetics, similar to Morgan et al 2004’s no acute effect in its (all-healthy) volunteers. (Unfortunately, most studies published since 1996 citing Eliasson et al 1996 in Google Scholar are focused on tobacco products or smoking.) 6. You could become addicted despite everything. Hypothetically, this could then lead to tobacco use with all the attendant ills. This is a truly subjective one. Former smokers probably should not be monkeying about with nicotine. Some people are scared this might happen; others aren’t worried at all. Given what I’ve read about nicotine not being addictive but strengthening habits (see previous quotes from Wedrifid), I think this fear might be overblown. ## Dependence Nicotine gum or patch use seems to be extremely rare among people who have not previously smoked (“never smokers”), which makes it hard to judge the risk of developing dependence, or the risk of developing dependence and then moving on to tobacco. An example of the rarity comes from Gerlach et al 2008: the authors examined a survey of n=28,000; 8 never-smokers claimed use of nicotine-replacement therapy, but 6 self-reported tobacco use or had blood-levels too high or low - leaving just 2 (probably) valid examples. Etter 2007 ran an online (self-selected) survey on a smoking cessation website, receiving 848 responses; the 5 never-smokers (1 had smoked cigarettes before), reported dependence and one described it as self-medication for depression (see also Caldirola et al 2013). Etter 2007 described the background information on the rarity of never smokers, apparent absence of nicotine gum abuse, and generally low levels of dependence on former or current smokers: People who were addicted to the nicotine gum could easily find our questionnaire, because it was listed on top of the list in Google. In spite of this effective enrolment strategy, we identified only two never-users of tobacco among daily gum users, which suggests that NRT use in never-users of tobacco is a rare phenomenon. Similarly, a previous survey in people who responded to a newspaper ad that read: “Are you addicted to nicotine gum?” could not enrol any never smoker [5]. Furthermore, there was no report of subsequent nicotine dependence in never smokers who were treated with nicotine for ulcerative colitis, aphtous ulcers and sleep-disordered breathing [18,19,20,21]. The short-term effect of the nasal spray was also tested in never smokers, with no report of never smokers getting addicted to this fast delivery product [22,23,24]. In a previous survey, 0.3% of adolescent never smokers reported past daily use of NRT, but none was reported as being addicted to NRT [25]. However, some adolescents will endorse using any product when a list is presented to them, e.g. 0.4% said they used a fictitious nicotine “Nic-T” product [26]. In two surveys in the USA, 2.7% and 4.6% of school drug counsellors indicated that nicotine patches and gums were abused by adolescents, but these “NRT abusers” were mainly smokers who used NRT while smoking, and only 7% to 16% of these “NRT abusers” were never smokers [27]. The latter study did not report any case of NRT dependence in adolescent never smokers [27]. Similarly, studies in representative samples of the UK and Swedish general populations found no never-user of tobacco among users of NRT [28]. A review of post-marketing surveillance data in the USA found no report of primary dependence to the nicotine gum and patch,[29] and only 39 cases of dependence on the nicotine gum were reported per million prescriptions to smokers, in surveillance data [30]. Therefore, addiction to nicotine gum in never smokers is probably very rare. Furthermore, there may be few adverse consequences of being addicted to the nicotine gum, except for the financial cost and the inconvenience of permanent chewing. In particular, NRT products are safe even in patients with heart disease, [31,32] and there was no untoward effect of 5 years of nicotine gum use in the Lung Health Study [33]. Thus, long-term use of NRT is not known to be harmful. Etter 2009 yielded additional information: For instance, in U.S. national samples, 5 to 6% of nicotine gum users used it for more than the recommended duration of 3 months (Shiffman et al., 2000; Shiffman, Hughes, Pillitteri, & Burton, 2003a), and in the UK, 9% of gum users in smoking cessation clinics used the gum for one year or more (Hajek, McRobbie, & Gillison, 2007). In a survey of 805 households that purchased the nicotine gum, 2% purchased it continuously for 6 months or more (Shiffman et al., 2000). In clinical trials, up to 30% of patients use NRT products beyond the recommended 3-month period (Hajek, Jackson, & Belcher, 1988; Shiffman, Hughes, Di Marino, & Sweeney, 2003b; Hughes et al., 1991a; Steinberg, Foulds, Richardson, Burke, & Shah, 2006; Johnson, Hollis, Stevens, & Woodson, 1991; Hatsukami, Huber, Callies, & Skoog, 1993; Hughes, 1989). However, participants in clinical trials usually receive the gum for free, and having to pay for it decreases utilization (Hughes, Wadland, Fenwick, Lewis, & Bickel, 1991b). …Taking a substance over a longer time than intended is a criterion for drug dependence (American Psychiatric Association, 1994), but long-term use does not necessarily imply dependence, because dependence requires other criteria, in particular unsuccessful attempts to quit and withdrawal symptoms upon cessation. Post-marketing data from the U.S., reported by the manufacturers, indicated that only 39 cases of dependence on the nicotine gum were reported per million prescriptions (Spyker et al., 1996). However, the limitations of post-marketing surveillance data are well known (Brewer & Colditz, 1999), and survey data indicate that the prevalence of dependence on the nicotine gum in over-the-counter settings is substantially higher than that, at about 1% of ever users (Hughes et al., 2004). About one third of smokers report having ever used NRT products (Al-Delaimy, Gilpin, & Pierce, 2005). Thus, even if only 1% of users became dependent on the gum, this would still represent tens of thousands of people…Even though some users may be dependent on the gum, it must be emphasized that there is no known adverse consequence of long-term use of NRT, except for the financial cost, and that the potential benefits (i.e., prevent late relapse) far outweigh the drawbacks. This is probably why dependence on the nicotine gum has been generally downplayed in the literature (West et al., 2000 [see also Hughes et al 2005]). One approach to estimating addictiveness of nicotine gum or patches is to borrow a strategy from Fagerstrom & Eissenberg 2012 in looking at the success of various studies’ control groups (using nicotine gums or patches) in quitting during those studies: The intention here was not to estimate the effect of the treatment but rather its placebo to determine how difficult it is to stop using a certain form of tobacco/nicotine product. Therefore, the success rate in the placebo group is used as indicators for difficulty abstaining. Table 2 shows that cigarette smokers, independent of treatment, show a success rate of roughly 10% with little variation (range 9.8-11.2). Those seeking to stop ST use have roughly more than double the success rate of cigarette smokers (range 19.1-33.0). In the study (Tønnesen & Mikkelsen, 2012), where 69 long-term users of pure nicotine mostly in the form of gum, in average seven years, a success rate of 36% was observed. Those who become long-term users of nicotine replacement therapy (NRT) are recognized as heavy dependent smokers (Hajek, Jackson, & Belcher, 1988), which also seemed to be true in this study. Their cigarette consumption before quitting was 24.5 per day and their recalled FTCD score from when they were smoking was a high 6.7. It can be hypothesized that this type of smoker would have had no better success rate in stopping than the 10% seen normally but when coming off long-term NRT, it was 36%. The 36% was obtained from a 1-year follow-up. Several of the smokeless studies reported success rates from 6 months. It is of interest to note that the authors excluded long-term patch users since it would have been unlikely to see a difference between active and placebo treatment due to the ease by which they normally can stop. Moreover, it is much more infrequent to observe long-term patch use (Shiffman, Hughes, Pillitteri, & Burton, 2003). It seems as a patch is not very likely to be able to support a compulsive use pattern due to its little behavioral involvement and or pharmacokinetic nicotine uptake pattern. The data in Table 2 lead us to conclude that quitting cigarette smoking is more difficult than quitting ST (Fagerström, Gilljam, Metcalfe, Tonstad, & Messig, 2010) and, although there is only one study from the NR category, that quitting these products may be easiest (Tønnesen & Mikkelsen, 2012). What does this imply for any never-smoker (not predisposed to tobacco use) using nicotine gum/patches judiciously and self-monitoring for signs of dependence, well aware of the dangers of tobacco use? Given the lack of observations despite large datasets, the low rates of dependence in smokers, the ease of quitting nicotine gum, and so on, my personal opinion is that the risk of dependency should be much lower than the smoker risks of 1-20% and then the risk even lower of then progressing to tobacco use. (In considering cost-benefit, it’s worth remembering that tobacco use has been quit successfully by many millions despite the notorious difficulty, and that the health outcomes of quitters gradually heal to the baseline of non-smokers.) # Conclusion So what’s the upshot? My reading has convinced me to at least give it a try and it has been useful (see the nicotine section of Nootropics). The negatives universally seem to be long-term negatives, and even if nicotine turns out to be something I haul out only in a crisis or every few weeks, it would still have been worth investigating. # Appendix: On proving too much Some people do try to argue that smoking is good for you. Are they right? I don’t know. As deliciously contrarian as it would be to go around shocking people by seriously advocating tobacco use, it’s not a subject I’m interested in tackling. In philosophy, one is taught to not “try to prove too much” (inviting people to modus tollens your modus ponens), to not do more philosophy than one has to; in programming, you learn to not become an “architecture astronaut” solving some hugely abstract version of your actual problem - such overreach invites disaster. It’s much easier for me to defend use of nicotine, so that’s all I try to do: nicotine is pretty much harmless, the studies are clear, the relevant areas & studies comprehensible with not too much work, and I feel I can discuss it with a clean conscience. Really, about the worst you can say about pure nicotine use is that it might be a gateway to tobacco or that one’s blood pressure might increase a tad, which are issues that can be easily addressed empirically via additional studies/surveys or by eg. measuring one’s own blood pressure after taking nicotine, respectively. But if I wanted to defend tobacco itself, I have abruptly expanded my task by orders of magnitude: now I need to deal with all the anti-smoking correlational studies, I need to defend an idiosyncratic interpretation of how the tobacco industry’s products have evolved over the last century, I need to defend not just nicotine but all the other substances in tobacco which might override its benefits, I need to explain why the nigh-universal consensus against tobacco is wrong and to give a historical account of how such an error could come into exist and then expand to be universal. This is an incredible amount of work; any one of these points represents more work than this entire article and plausibly more work than this entire site. One could (and men have) spent entire careers working on small parts of the puzzle just outlined. It’s also bad from the rhetorical point of view: defending tobacco requires me to engage in what looks like partisan politics & revisionist history. It is challenging beliefs that are, rightly or wrongly, deeply entrenched. Many people have enough flexibility to think, even if a relative died horribly of lung cancer, that nicotine was only the addictive stimulating agent and the real killer was the smoke or the tar or something, and so are willing to consider that nicotine - on its own - might be useful. They are not willing to consider the whole package. You can see the difference in the tasks by comparing this one page to the multiple threads in Imminst alone with scores of pages in each. One is short and clear and easily evaluated on its own terms (I hope), and has met with neutral or positive reactions from everyone I’ve asked to read it; the other comes off as a crank laying out an entire worldview, filled with ad hominems, bad faith, and clearly has not changed anyone’s minds. Remember Pareto’s observation about where most of the value in a subject comes from, and the value of your time! Without reason to believe tobacco has absolutely massive gains compared to nicotine alone (which there isn’t, even taking pro-tobacco claims at face value), it’s a very bad use of time to investigate tobacco. One should let sleeping fags lie. 1. It’s generally assumed that the tobacco industry held off regulation for so many decades simply because it spent so very much on lobbying; but lobbying isn’t omnipotent (look at Prohibition). I think at least part of it is that the evidence is not as strong as one would expect; the main case comes from epidemiology, which has an execrable track record and many problems. The great statistician Ronald Fisher has often been excoriated for testifying in favor of the tobacco industry and implied to have sold his soul for blood-money, but can we really be that critical when we read his arguments (background): There were fewer inhalers among the cancer patients than among the non-cancer patients. That, I think, is an exceedingly important finding. Of course, that could be true and also smoking still harmful. One major attempt to refute Fisher was Cornfield et al’s 1959 paper, “Smoking and lung cancer: recent evidence and a discussion of some questions”. 2. SNPedia lists 9 studies correlating nicotine use with various genes & SNPs. 3. Nuance is not a goal of anti-smoking campaigns; hence a California Department of Public Health campaign defined its goals as The program combines an aggressive media campaign with community programs emphasizing three themes: • That the tobacco industry lies; • That nicotine is addictive; • That secondhand smoke kills. and produces advertisements like 4. ^nicbacco-1 5. “I understand that smoking is bad”, said Maryka Quik, director of the Neurodegenerative Diseases Program at SRI International, a nonprofit research institute based in California’s Silicon Valley. “My father died of lung cancer. I totally get it.” Yet for years Quik has endured the skepticism and downright hostility of many of her fellow neuroscientists as she has published some three dozen studies revealing the actions of nicotine within the mammalian brain. “The whole problem with nicotine is that it happens to be found in cigarettes”, she told me. “People can’t disassociate the two in their mind, nicotine and smoking. It’s not the general public that annoys me, it’s the scientists. When I tell them about the studies, they should say, ‘Wow.’ But they say, ‘Oh well, that might be true, but I don’t see the point.’ It’s not even ignorance. It’s their preconceived ideas and inflexibility.” 6. A popularization is provided by Salon: A study involving sixty-seven people with mild cognitive impairment, in which memory is slightly impaired but decision-making and other cognitive abilities remain within normal levels, found “significant nicotine-associated improvements in attention, memory, and psychomotor speed,” with excellent safety and tolerability….“…And we’ve seen absolutely no withdrawal symptoms. There doesn’t seem to be any abuse liability whatsoever in taking nicotine by patch in nonsmokers. That’s reassuring.” That’s not reassuring: it’s totally bizarre. Nicotine has routinely been described in news accounts as among the most addictive sub­stances known. As the New York Times Magazine famously put it in 1987, “nicotine is as addictive as heroin, cocaine or amphetamines, and for most people more addictive than alcohol.” But that’s just wrong. Tobacco may well be as addictive as heroin, crack, alcohol, and Cherry Garcia combined into one giant crazy sundae. But as laboratory scientists know, getting mice or other ani­mals hooked on nicotine all by its lonesome is dauntingly difficult. As a 2007 paper in the journal Neuropharmacology put it, “Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer.” That same study, like many others, found that other ingredients in tobacco smoke are necessary to amp up nicotine’s addictiveness. Those other chemical ingredients - things like acetaldehyde, anab­asine, nornicotine, anatabine, cotinine, and myosmine - help to keep people hooked on tobacco. On its own, nicotine isn’t enough. 7. The European Union ban on the sale of “snus” (a moist snuff product) is an example where regulation appears to have prevented access to an effective treatment for cigarette smoking. Snus has become widely used in Sweden, and has been attributed to causing a drop in cigarette smoking: only 17% of Swedish men smoke, whereas 19% of adult men are daily users of snus (Fagerstrom & Schildt, 2003). The use of snus has helped Sweden to become the only European country to reach the WHO goal of less than 20% daily smoking prevalence among adults by 2000. • Fagerstrom K & Schildt E (2003). “Should the European union lift the ban on snus? Evidence from the Swedish experience”. Addiction 98, 1191-1195 8. “Brain science, addiction and drugs” 2008: Concerns about links between snus and increased risk of oral cancer or cardiovascular have not been confirmed by a large-scale epidemiological study (Luo et al 2007). However, their data suggested that snus may be associated with an increased risk of pancreatic cancer - with an odds ratio of 2.0, suggesting a lifetime risk increased from 1% to 2% (Luo et al., 2007). In 2004 the number of new cases of pancreatic cancer in the UK was 7,398 (Cancer Research UK, 2008). This increase is still much lower than the 15-fold increase in the risk of lung cancer attributable to cigarette smoking (38,313 new cases in 2004) (ibid). See also Foulds et al 2003, Roth et al 2005, 9. RCTs are shamefully lacking, but offered for your consideration is “Daily TV quota of 6 hours could shorten life expectancy by 5 years”: Watching TV for an average of six hours a day could shorten the viewer’s life expectancy by almost five years, indicates research published online in the British Journal of Sports Medicine. The impact rivals that of other well known behavioural risk factors, such as smoking and lack of exercise, the study suggests. Sedentary behaviour - as distinct from too little exercise - is associated with a higher risk of death, particularly from heart attack or stroke. Watching TV accounts for a substantial amount of sedentary activity, but its impact on life expectancy has not been assessed, say the authors. They used previously published data on the relationship between TV viewing time and death from analyses of the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), as well as Australian national population and mortality figures for 2008, to construct a lifetime risk framework. …Based on these figures, and expected deaths from all causes, the authors calculated that an individual who spends a lifetime average of six hours a day watching TV can expect to live just under five fewer years than someone who does not watch TV. These figures compare with the impact of other well known lifestyle factors on the risk of death from cardiovascular disease after the age of 50, including physical activity and obesity. For example, other research has shown that lifelong smoking is associated with the shortening of life expectancy by more than 4 years after the age of 50, with the average loss of life from one cigarette calculated to be 11 minutes - equivalent to half an hour of TV watching, according to the authors’ risk framework. 10. The above TV risk may be from sitting; in another Australian study, 8-11 or 11+ hours of sitting lead to mortality hazard ratios of 1.15-1.40 compared to the 0-4 hours of sitting group. 11. One Imminst.org poster argues that “I don’t think that’s all there is to nicotine’s mode of action. Choline is counter-indicated for OCD and can make it worse, yet there’s many studies showing nicotine’s efficacy in treating even refractory Obsessive Compulsive Disorder.” For the OCD studies, see Lundberg 2004, Pasquini et al 2005, and Salín-Pascual & Basañez-Villa 2003 among others. 12. I am generally a skeptic of any claims to boost IQ in healthy adults. I am a strong believer that fixing deficits like iodine can lead to real IQ gains, but almost always an initially promising intervention like creatine fades out with additional studies and reverts to no net effect - as has happened to dual n-back. So I take this unreplicated study as being more evidence for the stimulating effect of nicotine rather than any genuine peak intelligence boost, in the same way that monetary payment can increase peoples’ scores on IQ tests - you wouldn’t say “the promise of money makes people smarter”, but rather, “the promise of money ‘enables’ people to work harder”. 13. Attention is a recurring keyword; seems to be how it exerts many of its effects - “Cognitive effects of nicotine in humans: an fMRI study”, Kumari et al 2003: To elucidate the neural correlates of cognitive effects of nicotine, we examined behavioral performance and blood oxygenation level-dependent regional brain activity, using functional magnetic resonance imaging, during a parametric “n-back” task in healthy nonsmoking males after the administration of nicotine (12 ␮g/kg body weight) or saline. Nicotine, compared to placebo, improved accuracy (P ϭ 0.008) in all active conditions (2%-11%), and had a load-specific effect on latency (P ϭ 0.004; 43.78% decrease at the highest memory load). Within a network of parietal and frontal areas activated by the task (P Ͻ 0.05, corrected at the voxel level), nicotine produced an increased response (P Ͻ 0.05; uncorrected within the regions of interest) in the anterior cingulate, superior frontal cortex, and superior parietal cortex. It also produced an increased response in the midbrain tectum in all active conditions and in the parahippocampal gyrus, cerebellum, and medial occipital lobe during rest (P ϭ 0.05; uncorrected). The present observations point to altered neuronal activity in a distributed neural network associated with on-line task monitoring and attention and arousal systems as underlying nicotine-related enhancement of attention and working memory in human subjects. 14. Nicotine’s relationship to depression is complicated by the fact that much of the research focuses not on how this stimulant may help depressive symptoms, but on how to get the depressed to stop smoking. Extracts from “Smoking and depression: A review”: …Smokers with depression can achieve long term abstinence in many cases and success rates could be greatly enhanced by evidence based therapies,6 although they are more nicotine dependent and may experience more challenges when attempting to quit.4 • 6. Wilhelm K, Wedgwood L, Niven H, Kay-Lambkin F. “Smoking cessation and depression: current knowledge and future directions”. Drug Alcohol Rev 2006;25:97-107. • 4. Gierisch JM, Bastian LA, Calhoun PS, McDuffie JR, Williams JW Jr. “Comparative effectiveness of smoking cessation treatments for patients with depression: a systematic review and meta-analysis of the evidence”. VA-ESP Project #09-010; 2010 …self medication: nicotine has central antidepressant properties and depressed patients could be using it as a form of self-medication to relieve symptoms.8 Nicotine releases dopamine in the mesolimbic reward pathway, elevating mood and improving wellbeing. It also increases the bioavailability of serotonin, acting in a similar manner to some antidepressant drugs. Nicotine has some positive effects, which may be of benefit in depression. It can improve attention and cognitive function, reduce stress and act as a distraction • 8. Fergusson DM, Goodwin RD, Horwood LJ. “Major depression and cigarette smoking: results of a 21-year longitudinal study”. Psychol Med 2003;33:1357-67. …Conversely, there is also evidence that chronic smoking increases a person’s risk of depression as a result of changes in neurophysiology.10 • 10. Markou A, Kenny PJ. “Neuroadaptations to chronic exposure to drugs of abuse: relevance to depressive symptomatology seen across psychiatric diagnostic categories”. Neurotox Res 2002;4:297-313. 15. Mendelsohn 2012 continued: …Depressed mood is part of the nicotine withdrawal syndrome and is a common symptom in the first 2 weeks after quitting.13 Research shows that smokers with depression experience more severe negative moods on quitting and this is a powerful trigger for relapse.4,14-16 Smokers with a history of depression have been reported as having twice the risk of developing a major depression in the first 12 months after quitting.17 In a review of seven studies, the incidence of major depression after quitting was 0-14% among all smokers, and 3-24% among those with a history of depression.18 • 14. Pomerleau, CS, Marks JL, Pomerleau OF. “Who gets what symptom? Effects of psychiatric cofactors and nicotine dependence on patterns of smoking withdrawal symptomatology”. Nicotine Tob Res 2000;2:275-80. • 15. Hall SM, Munoz RF, Reus VI, et al. “Nicotine, negative affect and depression”. J Consul Clin Psychol 1993;61:761-7. • 16. Killen J, Fortmann S, Schatzberg A, Hayward C, Varady A. “Onset of major depression during treatment for nicotine dependence”. Addict Behav 2003;28:461-70. • 17. Tsoh JY, Humfleet GL, Munoz RF, Reus VI, Hartz DT, Hall SM. “Development of major depression after treatment for smoking cessation”. Am J Psychiatry 2000;157:368-74. • 18. Hughes JR. “Depression during tobacco abstinence: A review”. Nicotine Tob Res 2007;9:443-6. …A meta-analysis of 26 trials found that smokers with depression had a 34% lower rate of long term abstinence (OR: 0.66).19 Patients with recurrent depression have significantly lower quit rates than those who had only a single episode.19 Smokers with depression have been shown to suffer from more intense cravings and more severe nicotine withdrawal symptoms, which make quitting more difficult.4,15,20 Quit attempts may also be undermined by the cognitive deficit caused by depression and a lowered self efficacy.12 • 19. Ziedonis D, Hitsman B, Beckham JC, et al. “Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report”. Nic Tob Res 2008;10:1691-715. • 20. Breslau N, Kilbey MM, Andreski P. “Nicotine withdrawal symptoms and psychiatric disorders: findings from an epidemiologic study of young adults”. Am J Psychiatry 1992;149:464-9. • 12. Haukkala A, UUtela A, Vartiainen E, McAlister A, Knekt P. “Depression and smoking cessation: the role of motivation and self-efficacy”. Addictive Behaviors 2000;25:311-6. Nicotine replacement therapy (NRT) appears to be effective in smokers with depression. A review of three trials found cessation rates of 14-22% at 12 months or longer,4 which are comparable to NRT quit rates in the general population. Nicotine replacement therapy has also been shown to have some antidepressant qualities.28 • 28. Salin-Pascual R, Rosas M, Jimenez-Genchi A, Rivera-Meza B, Delgado-Parra V. “Antidepressant effect of transdermal nicotine patches in nonsmoking patients with major depression”. J Clin Psychiatry 1996;57:387-9 16. Kumari et al 2003 and Gahring & Rogers 2006 cite these studies for Alzheimer’s & Parkinson’s: Other studies: They also cite a result for schizophrenia: • Newhouse, P.A., Kelton, M., 2000. “Clinical aspects of nicotinic agents: therapeutic applications in central nervous system disorders”, in: Clementi, F., Fornasari, D., Gotti, C. (Eds.), Neuronal Nicotinic Receptors. Experimental Pharmacology, vol 14, Springer, Berlin, pp. 779-812 Cotinine is also being investigated as a contributor to the cognitive benefits of smoking but with fewer concerns about addiction (Echeverria & Zeitlin 2012). 17. “Cognitive enhancers for the treatment of ADHD”, Bidwell et al 2011 18. That study does find acceleration of dementia in long-term usage, but importantly, the long-term studies are of tobacco use, not nicotine gum/lozenges/patches. This is also true of Lecacheux et al 2009. 19. The lead author tries to stave off any possible misunderstanding that they may be suggesting nicotine is useful: Paul Newhouse, M.D., professor of Psychiatry and director of the Center for Cognitive Medicine at Vanderbilt University Medical Center, who authored the study, said the results of the study should not be viewed as an endorsement of smoking or of nicotine for normal individuals. “What we and others have shown is that nicotine doesn’t do much for memory and attention in the normal population, but it does do something for those whose cognitive function is already impaired.” “People with memory loss should not start smoking or using nicotine patches by themselves because there are harmful effects of smoking and a medication such as nicotine should only be used with a doctor’s supervision,” Newhouse said. “But this study provides strong justification for further research into the use of nicotine for people with early signs of memory loss which may help us determine whether benefits persist over long periods of time and provide meaningful improvement.” 20. It is tempting to think that studies showing benefits to nicotine generalize to smoking, but we must not. In this specific case, there were early epidemiological studies showing smokers had as much as halved risks of dementia or Alzheimer’s disease compared to non-smokers, which prompted many followup studies. Quickly searching, I found these reviews/meta-analyses of those studies: The upshot is that the picture is murky, and seems to be better for Parkinson’s than Alzheimer’s. Not very encouraging after so many studies. 21. Relevant papers I’ve run into include “Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence” (Counotte 2011), and “Short- and Long-Lasting Consequences of in vivo Nicotine Treatment on Hippocampal Excitability” (Penton 2011). 22. At least in mice, in one cool study, “Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine” Levine et al 2011 (Discover blog coverage); abstract: In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and used it to study the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine, as assessed by addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective; cocaine had no effect on nicotine-induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibition of histone deacetylase, which caused global histone acetylation in the striatum. We tested this conclusion further and found that a histone deacetylase inhibitor simulated the actions of nicotine by priming the response to cocaine and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data from mice. If our findings in mice apply to humans, a decrease in smoking rates in young people would be expected to lead to a decrease in cocaine addiction. 23. Posters on Imminst.org give numbers for nicotine patches that are <$1 per day of normal use, but say they cut them up into as many as 10 pieces to reduce them to the 2-3mg dose level - which implies per dose costs of <10 cents.

24. In another example of how much other factors matter, Papua New Guinean farmers with 80% smoking rates still have less heart disease and fewer strokes than Swedes.

25. The patch was clearly effective as an aid to smoking abstinence. Despite the large number of patients in the analysis, few adverse cardiovascular outcomes (myocardial infarction, stroke, tachycardia, arrhythmia, angina) were reported, and no excess of these outcomes was detected among patients assigned to nicotine-patch use. The incidences of several minor adverse effects were clearly elevated among the nicotine-patch groups, especially sleep disturbances, nausea or vomiting, localised skin irritation and respiratory symptoms, but the background rates and risk ratios varied considerably across studies. The incidence of nausea or vomiting appeared to be lowest when the patch dose was tapered. The results of this meta-analysis indicate that very large studies would be needed to assess the effect of the patch, if any, on serious, rare outcomes.

26. Although a great deal of work has been carried out on the mutagenicity of the common PAHs found in cigarettes, only a few studies have addressed the genotoxic nature of nicotine itself. Although tests examining point mutagenicity have generally been negative, the alkaloid has been shown in some cases to increase chromosome aberrations in exposed cells (Trivedi et al., 1990). However, findings in this regard have been somewhat inconsistent, thus highlighting the need for further exploration.

27. It can be entertaining to read nicotine research papers - the reviews especially resemble a bad-news-good-news comedy sketch where for every couple pieces of good news, there’s bad news. (One rather wonders, if nicotine is doing all these helpful things, what the mortality rate would be for nicotine-free cigarettes.) For example, “Neuronal Nicotinic Acetylcholine Receptor Expression and Function on Nonneuronal Cells”, Gahring & Rogers 2006:

Of the thousands of proven carcinogens and toxic agents contained within a cigarette, nicotine, while being the addictive agent, is often viewed as the least harmful of these compounds.

Subsequent studies2-4 have suggested that chronic nicotine administration might in fact play a beneficial role in slowing the progression of this disease. While this finding is controversial, there is now ample evidence supporting a therapeutic benefit from nicotine in Parkinson’s5 disease, and as a neuroprotectant to toxic insults such as excitotoxins6-10 or Beta-amyloid derived peptides.10-12 Understanding the mechanistic basis for these and other similarly interesting findings,13 including a cognitive benefit from nicotine,2 would be of obvious importance….This extended expression of nAChRs is of importance because, in addition to their regulation by endogenous agonists such as acetylcholine, choline, and the exogenous compound nicotine, their impact upon peripheral processes can be quite diverse as exemplified by their ability to in some cases enhance (Crohn’s disease) disease or in other cases diminish (ulcerative colitis) progression.17-20…While smoking is a major causative factor for lung cancer, relatively few smokers generate chronic obstructive pulmonary disease (COPD), which has an incidence rate of ~20%, even among very heavy and long-term smokers.61

…While nicotine has anti-inflammatory properties in this disease, the therapeutic value of nicotine does not exceed that of more conventional treatments such as aminosalicylates.48

Therefore, while cells are present that are primed for activation, the immune and inflammatory response may be dampened, as has been observed in many smokers.62 Expanding upon this possibility, Floto and Smith64 suggested that the inflammatory response to the stimulatory components of tobacco may be counteracted by the anti-inflammatory effects of nicotine, which offers a rational explanation for why few smokers generate pulmonary Langerhans’ cell histiocytosis. It has also been pointed out that there is a significantly lower incidence of sarcoidosis in smokers65 and decreased incidence of immunoglobulin G (IgG) precipitins that develop during allergic alveolitis as occurs both in humans and guinea pigs.66,67…A notable outcome of this effect may be that the anti-inflammatory properties of nicotine actually enhance the survival of influenza virus in mice and induce significantly higher titers of virus following infection.63 Pneumonia caused by Streptococcus pneumonia, is also more frequent in smokers.90…While nicotine may inhibit macrophage function to promote pneumonia, it has also been reported that the generation of hypersensitivity pneumonia (HP) is lower in smokers than nonsmokers. HP is caused by inhalation of antigens such as Saccharopolyspora rectivirgula, which induces farmer ’s lung (once contracted, however, smoking worsens disease).

28. Specifically, their rats self-administered nicotine, and the nicotine dose ranged from <100 to >300 µg/kg (figure 1); they give a reference that 180-320 µg/kg for rats is similar to some unspecified amount of smoking in humans. The reference is paywalled. Are the harmful doses in rats equivalent to one or two cigarettes a day and doses like 3 mg patch sections used by a 86kg man? Or more like a score of cigarettes?