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description: On the benefits and lack of demerits of nicotine
tags: psychology, biology, nootropics
...
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](!Wikipedia "Nicotine#Psychoactive effects"). Less obvious is that nicotine has many [beneficial effects](!Wikipedia "Nicotine#Therapeutic uses") (and these benefits may be related to [anomalous](http://www.overcomingbias.com/2009/12/animal-smoking-studies.html) [smoking](http://www.overcomingbias.com/2009/12/smoking-followup.html) [results](http://www.overcomingbias.com/2009/12/what-anti-smoking-evidence.html)[^fisher]); 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[^addiction], and its addictiveness is genetically modulated^[[SNPedia](!Wikipedia) lists [9 studies](http://www.snpedia.com/index.php/Nicotine_dependence) correlating nicotine use with various genes & [SNPs](!Wikipedia "Single-nucleotide polymorphism").].
[^addiction]: Wikipedia summarizes [Guillem 2005](http://www.jneurosci.org/content/25/38/8593) as "Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties." - the addictiveness coming from [MAOI](!Wikipedia)s present in tobacco. (See also Villégier et al 2003, ["Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors"](http://www.ncbi.nlm.nih.gov/pubmed/14592678).)
Another thorough and contrarian piece is Frenk & Dar's 2002 book, [_A Critique of Nicotine Addiction_](/docs/2002-frenkdar.pdf). 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"](http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000230) 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]](http://tobaccodocuments.org/rjr/512051954-1964.pdf), [[4]](http://legacy.library.ucsf.edu/documentStore/k/q/v/kqv04d00/Skqv04d00.pdf), [[5]](http://informahealthcare.com/doi/abs/10.1080/1606635021000041753), [[6]](http://www.ncbi.nlm.nih.gov/pubmed/15004737), [[7]](http://www.springerlink.com/content/vacdjfxdnka8aj7n/), [[8]](http://www.springerlink.com/content/8ydu1kypuekq741w/)."
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 overestimated and may be 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.
[^fisher]: 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](DNB FAQ#fn51). The great statistician [Ronald Fisher](!Wikipedia) 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](http://www.york.ac.uk/depts/maths/histstat/fisher274.pdf) his arguments ([background](http://members.iinet.net.au/~ray/TSSOASb.html)):
> "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"](http://ije.oxfordjournals.org/content/38/5/1175.full.pdf).
For example, [snus](!Wikipedia "Snus#Health consequences"), 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 rate[^hurrah-snus], and with little hard evidence of significant harm from snus use[^snus-harm]. Smokeless tobacco in general is hugely more safe than smoking (["Smokeout: Not as easy as ABC"](http://www.washingtontimes.com/news/2005/nov/12/20051112-102753-2328r/), _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."
[^hurrah-snus]: ["Brain science, addiction and drugs: An Academy of Medical Sciences working group report chaired by Professor Sir Gabriel Horn FRS FRCP"](http://www.acmedsci.ac.uk/download.php?file=/images/publication/Report.pdf) (May 2008):
> "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
[^snus-harm]: "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](http://www.ncbi.nlm.nih.gov/pubmed/17498797)). 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](http://info.cancerresearchuk.org/cancerstats/types/pancreas/incidence/)). 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)."
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[^argument] (about as harmful as TV watching[^upperbound]) and focus on just nicotine.
[^argument]: [Some](http://www.longecity.org/forum/topic/38868-smoking-is-good-for-you/) [people](http://wispofsmoke.net/goodforyou.html) do try to argue that smoking is *good* for you. Are they right? I don't know. It's not a subject I'm interested in tackling. In philosophy, on is taught to not 'try to prove too much', 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. 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 etc. 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](http://lesswrong.com/lw/gw/politics_is_the_mindkiller/) [politics](http://lesswrong.com/lw/gt/a_fable_of_science_and_politics/) & revisionist history. It is challenging beliefs that are, rightly or wrongly, deeply entrenched. Most 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 my one Nicotine 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](!Wikipedia "Pareto distribution") 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, it's a very [bad use of time](http://lesswrong.com/lw/85x/value_of_information_four_examples/) to investigate tobacco.
[^upperbound]: These are only correlational studies, of course, randomized controlled studies being shamefully lacking, but offered for your consideration; ["Daily TV quota of 6 hours could shorten life expectancy by 5 years"](http://www.eurekalert.org/pub_releases/2011-08/bmj-dtq081511.php):
> "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_](http://bjsm.bmj.com/content/early/2011/08/01/bjsm.2011.085662.abstract). 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."
# 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](!Wikipedia) or other nootropics that affect [acetylcholine](!Wikipedia) or [acetylcholinesterase](!Wikipedia), such as [huperzine-A](!Wikipedia), but it's been argued against.^[One [Imminst.org](!Wikipedia) [poster](http://www.longecity.org/forum/topic/46040-ex-smoker-using-nicotine/page__view__findpost__p__447780) 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](http://www.ncbi.nlm.nih.gov/pubmed/15610934), [Pasquini 2005](http://www.ncbi.nlm.nih.gov/pubmed/15610960), and [Salín-Pascual 2003](http://www.ncbi.nlm.nih.gov/pubmed/15011734) among others.])
Indeed, the research literature is full of results connecting nicotine with improved mental performance:
- nicotine [boosts IQ scores](http://www.springerlink.com/content/f43533n81707641r/) (specifically scores on the [RAPM](!Wikipedia "Raven's Progressive Matrices"); see also [N-back FAQ](DNB FAQ))
- [reaction time](!Wikipedia) [is improved](http://cercor.oxfordjournals.org/content/19/9/1990.abstract), [as](http://www.springerlink.com/content/f43533n81707641r/) [is](http://www.springerlink.com/content/f43533n81707641r/) [inspection time](!Wikipedia) and [visual](http://legacy.library.ucsf.edu/tid/xnl04d00) [search](http://eprints.lib.sussex.ac.uk/600/01/nic&VS2004_final_4_IP.pdf) (but perhaps [due solely](http://www.springerlink.com/content/u033qg104ph117wv/) to [faster motor reaction](http://legacy.library.ucsf.edu/tid/bsj04d00)?)
- [pilots' performance enhanced](http://www.nature.com/?file=/npp/journal/v28/n7/full/1300202a.html) 4/5 as much as [donepezil](!Wikipedia) does; improves [late-day piloting](http://www.springerlink.com/content/br7x10795uqm5aqm/)
- [driving performance enhanced](http://content.karger.com/ProdukteDB/produkte.asp?Doi=119229)
- [overnight performance](http://www.springerlink.com/content/f6gxhlj63peeytlr) on various memory & attention[^attention] tasks ("These data suggest that when performance is being measured overnight, smokers show little or no impairment, whilst the performance of non-smokers showed performance decrements.")
- [faster performance](http://www.springerlink.com/content/5mmg0gmtg69g6978/) on Stroop and word classification
- ["acute nicotine administration may exert direct beneficial effects on novelty detection and subsequent memory recognition"](http://www.springerlink.com/content/mrn6232427w6269q/)
- in smokers, improved 'prospective memory' (things one intends to do); [Rusted et al 2005](http://dept.wofford.edu/neuroscience/neuroseminar/pdffall2006/rusted-mem3.pdf "Nicotine improves memory for delayed intentions")
- can improve [handwriting](http://www.springerlink.com/content/w4r53b9cglwt8jqp)
- helps ADHD ([Connors et al 1996](http://www.ncbi.nlm.nih.gov/pubmed/8927677); or [Levin et al 1996](http://www.ncbi.nlm.nih.gov/pubmed/8741955) - as well as OCD, see previous footnote) : "Results indicate significant clinician-rated global improvement, self-rated vigor and concentration, and improved performance on chronometric measures of attention and timing accuracy."
- may [help symptoms](http://web.as.uky.edu/Biology/faculty/cooper/Bio401G/nicotineSchiz.pdf) of schizophrenia (see [Wikipedia](!Wikipedia "Schizophrenia and smoking")), and protect against [Parkinson's & Alzheimers](http://www.ncbi.nlm.nih.gov/pubmed/10942038)[^review2]
- A [meta-analysis](http://www.ncbi.nlm.nih.gov/pubmed/20414766) ([PDF](http://dengulenegl.dk/blog/wp-content/uploads/2011/02/meta-analysis-acute-effects-of-nicotine-and-smoking-on-human-performance.pdf)) of nicotine studies reports results similar to [older literature reviews](http://legacy.library.ucsf.edu/tid/lmd29e00) (eg. [Warburton 1992](/docs/1992-warburton.pdf "Nicotine as a cognitive enhancer"), [Newhouse et al 2004](/docs/2004-newhouse.pdf "Effects of nicotinic stimulation on cognitive performance")):
> "There were sufficient effect size data to conduct meta-analyses on nine performance domains, including motor abilities, alerting and orienting attention, and episodic and working memory. We found significant positive effects of nicotine or smoking on six domains: fine motor, alerting attention-accuracy and response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT (effect size range = 0.16 to 0.44)."
- A 2011 ADHD review^[["Cognitive enhancers for the treatment of ADHD"](/docs/2011-bidwell-adhd.pdf), Bidwell et al 2011] covers nicotine:
> "Dozens of studies have assessed the effects of nicotine on cognition in healthy, nicotine-naïve samples including studies of memory (McClernon et al., 2003), attention (Froeliger et al., 2009) and inhibitory control (Potter and Newhouse, 2004). In a recent meta-analysis of 48 studies in which nicotine was administered to non-smokers or only minimally deprived smokers (Heishman et al., 2010), nicotine was shown to have positive effects on multiple domains including attention and working memory. Twenty-nine studies specifically assessed non-smokers and among those, positive effects were observed for reaction time on tests of sustained (or alerting) attention and working memory.
>
> Studies of the effects of nicotine on inhibitory control were not included in the meta-analysis, but a handful of studies suggest potential positive effects of nicotine on this domain. Two small studies have observed acute (Levin et al., 1998) and chronic (McClernon et al., 2006) transdermal nicotine administration to result in trends toward decreases in errors of commission on a CPT task. Moreover, nicotine has been shown to reduce CPT commission errors in nonsmokers with schizophrenia (Barr et al., 2007), non-smokers low in attentiveness (Poltavski and Petros, 2006); and decrease stop signal reaction time in adolescents nonsmokers with ADHD (Potter and Newhouse, 2004). Despite these findings, nicotine was not shown to improve response inhibition in adults with ADHD as measured with a CPT task (Levin et al., 2001)."
- nicotine [confirmed](http://www.ncbi.nlm.nih.gov/pubmed/19665344) to have short-term boosts to "attention and memory"^[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.]; similar results (with one negative^[Ernst, M., Matochik, J.A., van Horn, J.D., Jons, P.H., Henningfield, J.E., London, E.D., 2001b. ["Effect of nicotine on brain activation during performance of a working memory task"](http://www.pnas.org/content/98/8/4728.abstract). Proc. Nat. Acad. Sci. USA 98, 4728-4733]):
- Kumari et al 2003, ["Cognitive effects of nicotine in humans: an fMRI study"](http://www.cognitiongroup.com/publication/Cognitive_Effects_of_Nicotine_fMRI_published.pdf),
- Foulds, J., Stapleton, J., Swettenham, J., Bell, N., McSorley, K., Russell, M.A.H., 1996. ["Cognitive performance effects of subcutaneous nicotine in smokers and never-smokers"](http://www.ncbi.nlm.nih.gov/pubmed/8880941). _Psychopharmacology_ 127, 31-38
- Heishman, S.J., Taylor, R.C., Henningfield, J.E., 1994. ["Nicotine and smoking: a review of effects of human performance"](/docs/1994-heishman.pdf). _Exp. Clin. Psychopharmacol._ 2, 1-51
- Le Houezec, J., Halliday, R., Benowitz, N.L., Callaway, E., Naylor, H., Herzig, K., 1994. ["A low dose of subcutaneous nicotine improves information-processing in non-smokers"](http://www.ncbi.nlm.nih.gov/pubmed/7855225). _Psychopharmacology_ 114, 628-634
- during withdrawal, performance [returns to baseline](http://www.springerlink.com/content/p573k8605rm87145/) (but not below; in tension with Ernst 2011)
- In non-humans, mice [learn faster](http://www.scienceagogo.com/news/20031012195753data_trunc_sys.shtml) on low doses (see also Levin, E.D., Simon, B.B., 1998. ["Nicotinic acetylcholine involvement in cognitive function in animals"](http://www.ncbi.nlm.nih.gov/pubmed/9725745). _Psychopharmacology_ 138, 217-230)
- One amusing result - nicotine can apparently [reduce bad cholesterol](http://www.ncbi.nlm.nih.gov/pubmed/10938215) (in addition to its famous weight-loss properties)
- perhaps unsurprisingly given all this, nicotine has been found helpful in the elderly; see ["Nicotine treatment of mild cognitive impairment: A 6-month double-blind pilot clinical trial"](http://www.neurology.org/content/78/2/91.full) ([slides](http://www.fda.gov/downloads/Drugs/NewsEvents/UCM232144.pdf); mention no withdrawal symptoms)[^Newhouse] and its citations. (In keeping with our usual nicotine vs smoking dichotomy, note that *smoking* may be bad for mental functioning in the elderly[^elderly-review].)
[^attention]: Attention is a recurring keyword; seems to be how it exerts many of its effects - ["Cognitive effects of nicotine in humans: an fMRI study"](http://www.cognitiongroup.com/publication/Cognitive_Effects_of_Nicotine_fMRI_published.pdf), 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.'
[^Newhouse]: The lead author tries to [stave off](http://www.sciencenewsline.com/medicine/2012010922310082.html) 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."'
[^elderly-review]: 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:
- ["Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies"](/docs/2000-fratiglioni.pdf), Fratiglioni & Wang 2000
- ["Smoking as a Risk Factor for Dementia and Cognitive Decline: A Meta-Analysis of Prospective Studies"](http://while-science-sleeps.com/pdf/643.pdf), Anstey
et al 2007
- ["Cigarette Smoking and Parkinson's Disease"](http://www.excli.de/vol6/Das08-07proof.pdf), Miller & Das 2007
- ["Cigarette smoking and dementia: potential selection bias in the elderly"](http://www.ncbi.nlm.nih.gov/pubmed/18414087), Hernán et al 2008
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.
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](http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.1997.tb02863.x/abstract); [Anders Sandberg](!Wikipedia) [notes that](http://www.overcomingbias.com/2007/01/supping_with_th.html) there is pretty clear evidence of funding bias - but the independent researchers still turned up their fair share of positive results.
Anecdotally, [a](http://www.longecity.org/forum/topic/27759-nicotine-and-acetycholine-nootropics/page__view__findpost__p__300423) [great](http://www.longecity.org/forum/topic/8742-experimenting-with-the-nicotine-patch/page__view__findpost__p__86840) [many](http://www.longecity.org/forum/topic/9481-nicotine-patch-works-good-for-add/page__view__findpost__p__95355) [Imminst](http://www.longecity.org/forum/topic/23915-nicotine-patch-for-focus-a-log/page__view__findpost__p__258639) posters report a positive experience which is similar to, but better than, the extremely popular amphetamine formulation [Adderall](!Wikipedia); a few also favorably compare it to [caffeine](http://www.longecity.org/forum/topic/23915-nicotine-patch-for-focus-a-log/page__view__findpost__p__367943). (These anecdotes are supported by a [historical survey](http://legacy.library.ucsf.edu/tid/lmd29e00) 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](#fn2) and habit formation which is seems to be neural[^neural] and [epigenetic](!Wikipedia)[^epigenetic] . [LessWrong](http://lesswrong.com/about-less-wrong) user [Wedrifid](http://lesswrong.com/user/wedrifid/), has a [fascinating series of comments](http://lesswrong.com/lw/2cv/defeating_ugh_fields_in_practice/264j):
> "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...^[<http://lesswrong.com/lw/2cv/defeating_ugh_fields_in_practice/26lu>]
>
> 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."^[<http://lesswrong.com/lw/2cv/defeating_ugh_fields_in_practice/268a>]
[^neural]: Relevant papers I've run into include ["Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence"](http://www.nature.com/neuro/journal/v14/n4/abs/nn.2770.html) (Counotte 2011), and ["Short- and Long-Lasting Consequences of _in vivo_ Nicotine Treatment on Hippocampal Excitability"](http://www.jneurosci.org/content/31/7/2584.short) (Penton 2011).
[^epigenetic]: At least in mice, in one cool study, ["Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine"](/docs/2011-levine.pdf) Levine et al 2011 ([_Discover_ blog coverage](http://blogs.discovermagazine.com/80beats/2011/11/05/nicotine-causes-epigenetic-changes-in-mice-that-spur-cocaine-addiction/)); 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."
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)."
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"](http://www.sciencedaily.com/releases/2009/09/090909122052.htm), _Science Daily_, describing ["Dopamine enables in vivo synaptic plasticity associated with the addictive drug nicotine"](http://www.ncbi.nlm.nih.gov/pubmed/19755109) (Tang & Dani 2009; see also 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."'
## Costs
### Price
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](http://www.amazon.com/Nicorette-Coated-pieces-Fresh-Mint/dp/B00062NVVW/) 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](http://www.amazon.com/Flavor-4%252dmg%252e-Nicotine-Lozenges-ct%252e/dp/B003XLEILU/) 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 hard^[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.] 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](Melatonin)).
Further, the rise of [e-cigarettes](!Wikipedia) 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](http://www.nicvape.com/store/p/48-1-liter-of-100-mg-ml.aspx) of fluid for e-cigarettes. The concentration is 100 mg of nicotine per ml, there are 1000 ml per liter, one wants 2 mg per dose, so $\frac{100 \times 1000}{2} = 50000$ 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](http://www.longecity.org/forum/topic/46273-nicotine-patch-decreases-hdl/page__view__findpost__p__449683) [report](http://www.longecity.org/forum/topic/23915-nicotine-patch-for-focus-a-log/page__view__findpost__p__262776) (like with most stimulants, and perhaps [modafinil](Modafinil#tolerance)); their anecdotes are supported by general observations that smokers tend to escalate their smoking habit and by findings that nicotine [down-regulates its receptors](http://www.ncbi.nlm.nih.gov/pubmed/8371136) 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](!Wikipedia) (higher blood pressure) which concerns [people](http://www.longecity.org/forum/topic/38572-nicotine-and-vasoconstriction/)
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.^[In another example of how divided the nicotine research is and how much other factors matter, [Papua New Guinean farmers](http://www.ncbi.nlm.nih.gov/pubmed/8077891) with 80% smoking rates still have less heart disease and fewer strokes than the Swedish.]
3. Though patches are generally found to be safe[^Greenland] and not abused^[See [Joseph et al 1996](http://www.hawaii.edu/hivandaids/Safety%20of%20Transdermal%20Nicotine%20as%20an%20Aid%20to%20Smoking%20Cessation.pdf "The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease") and [Pickworth et al 1994](http://www.springerlink.com/content/p26143p057591031/ "Transdermal nicotine: reduction of smoking with minimal abuse liability").], research on nicotine turns up all sorts of possible ways nicotine could be unhealthy ([perhaps](http://www.ncbi.nlm.nih.gov/pubmed/11050152) it metabolizes to a carcinogen among other things or cause mutations[^mutant])
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](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633138/)? Does this work in humans? Does it make the cancer more deadly? Is that offset by benefits elsewhere? Is this even a real result? (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"](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001541/) makes the point humorously.) One [forumite](http://www.mindandmuscle.net/forum/topic/41608-nicotine-gum/page__view__findpost__p__593879) 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 nicotine[^review].
4. Nicotine [has been shown](http://www.jneurosci.org/content/22/9/3656.full.pdf) to impair [neurogenesis](!Wikipedia) in the [hippocampus](!Wikipedia) in rats at high doses.
But the impairment was only shown at the higher doses^[Specifically, their rats self-administered nicotine, and the nicotine dose ranged from <100 to >300 µg/kg (figure 1); they give [a reference](http://www.ncbi.nlm.nih.gov/pubmed/10353437) 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?], and it's unclear how it would generalize to humans. (As well, many stimulants impair the hippocampus in mice & rats; [caffeine](Nootropics#caffeine), for example.)
5. 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.
[^Greenland]: ["A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch"](/docs/1998-greenland.pdf) Greenland e al 1998:
> "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."
[^mutant]: ["Nicotine: Potentially a Multifunctional Carcinogen?"](http://toxsci.oxfordjournals.org/content/79/1/1.full):
> "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."
[^review]: 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"](http://www.aapsj.org/articles/aapsj0704/aapsj070486/aapsj070486.pdf), 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 studies^2-4^ 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's^5^ disease, and as a neuroprotectant to toxic insults such as excitotoxins^6-10^ 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 Smith^64^ 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 smokers^65^ 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)."
[^review2]: Kumari et al 2003 and Gahring & Rogers 2006 cite these studies for Alzheimer's & Parkinson's:
- Jones, G.M.M., Sahakian, B.J., Levy, R., Warburton, D.M., Gray, J.A., 1992. "Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer's disease". _Psychopharmacology_ 108, 485-494
- Nordberg, A., 2001. "Nicotinic receptor abnormalities in Alzheimer's disease: therapeutic interventions". _Biol. Psychiatry_ 49, 200-210.
- O'Neill MJ, Murray TK, Lakics V, Visanji NP, Duty S. ["The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration"](http://www.ncbi.nlm.nih.gov/pubmed/12769612). _Curr Drug Targets CNS Neurol Disord._ 2002; 1:399-411.
- Quik M. ["Smoking, nicotine and Parkinson's disease"](http://www.ncbi.nlm.nih.gov/pubmed/15331239). _Trends Neuroscience_ 2004; 27:561-568.
- Rezvani AH, Levin ED. ["Cognitive effects of nicotine"](http://www.ncbi.nlm.nih.gov/pubmed/11230877). _Biological Psychiatry_. 2001; 49:258-267.
- Sabbagh MN, Lukas RJ, Sparks DL, Reid RT. ["The nicotinic acetylcholine receptor, smoking, and Alzheimer's disease"](http://www.ncbi.nlm.nih.gov/pubmed/12446934). _Journal Alzheimers Disease_ 2002; 4:317-325.
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
# 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](Nootropics#nicotine)). 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.
# External links
- [Erowid](http://www.erowid.org/chemicals/nicotine/)
- ["Researchers Light Up for Nicotine, the Wonder Drug"](http://www.wired.com/science/discoveries/news/2007/06/nicotine) -(_Wired_)