Nicotine

On the benefits and lack of demerits of nicotine (research up to 2015)
psychology, biology, nootropics, survey, IQ
2011-05-092016-03-06 in progress certainty: likely importance: 9


In 2011, I be­came cu­ri­ous about nico­tine gum/­patches as a pos­si­ble al­ter­na­tive stim­u­lant to modafinil: its much shorter half-life makes it more use­ful for evenings or sce­nar­ios like need­ing a quick alert on a long dri­ve. I looked briefly into the nicotine/­to­bacco re­search to see whether there was con­vinc­ing ev­i­dence that nico­tine on its own, with­out any to­bacco or smoke-re­lated de­liv­ery mech­a­nism, is ei­ther more harm­ful than most stim­u­lants or likely to lead to se­vere ad­dic­tion to to­bacco as a ‘gate­way drug’.

The psy­cho­log­i­cal effects of nico­tine as a stim­u­lant are long es­tab­lished by a scat­ter­shot lit­er­a­ture, so there are pos­si­ble ben­e­fits.

Cost-wise, much of the nicotine/­to­bacco lit­er­a­ture will­fully con­flates the two, lead­ing to mis­lead­ing at­tri­bu­tion of the harm of to­bacco to nicotine; many as­so­ci­a­tions with harm are con­founded by past or present to­bacco use, but when pure nico­tine is ex­am­ined, as in patch/GUM NRT, the harms ap­peared min­i­mal: like all stim­u­lants, nico­tine may raise blood pres­sure some­what, and is ad­dic­tive to some de­gree, but the risks do not ap­pear much more strik­ingly harm­ful than caffeine or modafinil (and cer­tainly ap­pear less than the many com­mon­ly-used am­phet­a­mi­nes). An­i­mal ex­per­i­ments are, like usu­al, highly am­bigu­ous, of low qual­i­ty, and of doubt­ful rel­e­vance to hu­mans. There is lit­tle ev­i­dence from the NRT lit­er­a­ture that ‘nev­er-smok­ers’ like my­self are all that likely to be­come highly ad­dict­ed, and min­i­mal epi­demi­o­log­i­cal ev­i­dence of harm from NRT use over the past 3 decades it has been avail­able.

‘Va­p­ing’ is an­other sto­ry: few ex­per­i­ments have been done, and its pop­u­lar­ity is re­cent enough that any harms are poorly un­der­stood other than it can’t pos­si­bly be re­motely as harm­ful as to­bacco smok­ing, and its de­liv­ery mech­a­nism plau­si­bly is much more ad­dic­tive than gum/­patch de­liv­ery would be.

Over­all, I am per­son­ally com­fort­able us­ing nico­tine gum (but not va­p­ing) once in a while, and have done so since 2011 with­out any no­tice­able prob­lems or es­ca­la­tion in us­age fre­quen­cy.

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). The offers a case in point of this prej­u­dice: de­spite every sign point­ing to adul­ter­ants added to il­le­gal THC/marijuana va­p­ing flu­ids by fly­-by-night op­er­a­tors rather than nico­tine (such as the decades of nico­tine va­p­ing by mil­lions of peo­ple not caus­ing them to land overnight in hos­pi­tal ICUs), the out­break has been used as an ex­cuse to ban le­gal nico­tine va­p­ing flu­ids in­stead­—which is like ban­ning as­pirin as a re­sponse to the opi­ate cri­sis be­cause they’re both used for pain re­lief and they both come in pill form, and some OD vic­tims also used as­pirin re­cent­ly, so that makes them pretty much the same thing, right?

Addictiveness

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, 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 , , [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.

On the e-ci­g­a­rette reg­u­la­tion con­tro­versy:

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, 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.”

Wedri­fid 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

Romeo Stevens:

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 ). 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 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 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 & ? 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; 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 []. 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; ), 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; ; 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]).

Siegel et al 2011 found new e-ci­g­a­rette users claimed large re­duc­tions in smok­ing due to e-ci­g­a­rette use.

Et­ter & Bullen 2011 found their e-ci­g­a­rette users like­wise used it as a smok­ing sub­sti­tute.

Dawkins et al 2013 ran an on­line sur­vey of 1347 e-ci­g­a­rette users; only 2 re­spon­dents were nev­er-smok­ers and were not an­a­lyzed fur­ther. The cur­rent & ex-smoker re­spon­dents in­di­cated less crav­ings & de­pen­dence on e-ci­g­a­rettes than cig­a­rettes, and to use them long-term as a sub­sti­tute.

A 2016 sur­vey by Scott Alexan­der of the on­line nootrop­ics com­mu­ni­ties (pri­mar­ily Red­dit’s /r/nootrop­ics) had ~342 re­spon­dents on its nicotine-effi­cacy ques­tion and a sub­set an­swered ques­tions about nico­tine source & whether they con­sid­ered them­selves ad­dict­ed, but not nev­er-smoker sta­tus:

About 35% of users re­ported be­com­ing ad­dict­ed, but this was heav­ily de­pen­dent upon va­ri­ety of nico­tine. Among users who smoked nor­mal to­bacco cig­a­rettes, 65% re­ported ad­dic­tion. Among those who smoked e-ci­g­a­rettes, only 25% re­ported ad­dic­tion (and again, since there’s no time data, it’s pos­si­ble these peo­ple switched to e-ci­g­a­rettes be­cause they were ad­dicted and not vice ver­sa). Among users of nico­tine gum and lozenges, only 7% re­ported ad­dic­tion, and only 1% re­ported ma­jor ad­dic­tion. Al­though cig­a­rettes are a known gi­gan­tic health/ad­dic­tion risk, the nootropic com­mu­ni­ty’s use of iso­lated nico­tine as a stim­u­lant seems from this sur­vey (sub­ject to the above caveat) to be com­par­a­tively but not com­pletely safe.

One ap­proach to es­ti­mat­ing ad­dic­tive­ness of nico­tine gum or patches is to bor­row a strat­egy from 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 () 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 ), 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, 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 . 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

    im­age of sy­ringe  cap­tion: “Are you a nico­tine junkie?”↩︎

  4. I was read­ing the Wikipedia nico­tine ar­ti­cle and thought that the fig­ure cited for es­ti­mated Amer­i­can cases of ADHD caused by nico­tine - 500,000 - seemed re­mark­ably high and sus­pected it and the pre­vi­ous sen­tence were not about nico­tine at all, but to­bac­co. I was par­tially right: both were about to­bac­co, but also lead! Sloppy work even for Wikipedia. I don’t think that any mal­ice was in­volved, just the gen­eral as­sump­tion that ‘nicbacco’ is harm­ful and the dis­tinc­tion be­tween nico­tine and to­bacco unim­por­tant.

    An­other ex­am­ple is a breath­less me­dia ar­ti­cle “Chil­dren Ex­posed to Nico­tine in Utero Have Lower Read­ing Scores” on Cho et al 2012: here we can’t blame the me­dia or Wikipedia ed­i­tors be­cause the pa­per it­self (a lon­gi­tu­di­nal cor­re­la­tional study) has “nico­tine” in its ti­tle and ab­stract (a to­tal of 8 times), though the ab­stract qui­etly men­tions it is ac­tu­ally a study of “ma­ter­nal smok­ing”, and so of lit­tle in­ter­est to any­one in­ter­ested in nico­tine be­cause there are hun­dreds or thou­sands of con­found­ing sub­stances in to­bacco smoke (on top of what smok­ing while preg­nant says about the moth­ers in the first place, some­thing which is only par­tially con­trol­lable for); the au­thors con­struct a sort of nico­tine ex­po­sure in­dex based on daily cig­a­rette con­sump­tion & nicotine-con­tent of brands, but as far as I can tell, they never an­a­lyze whether the re­sults based on this in­dex are the same as if they had an­a­lyzed it the same way for eg. to­tal cig­a­rettes smoked or to­tal tar con­tent. This is not to say that nico­tine has no im­pact on de­vel­op­ing brains (many use­ful drugs or stim­u­lants are con­traindi­cated for non-adult­s), but their re­sults do not seem to war­rant their de­scrip­tion. I was amused in 2013 when a Pubmed alert brought me word of a 2013 pa­per led by Cho ti­tled “Pre­na­tal Ex­po­sure to Nico­tine and Im­paired Read­ing Per­for­mance”; be­sides the ti­tle, the ab­stract uses the word “nico­tine” 7 times and “ma­ter­nal smok­ing” just 1 time - and repli­cates the above pro­ce­dure yet again. With re­search like this, is it any won­der that ‘nicbacco’ is alive and well?↩︎

  5. “Sci­ence’s ob­ses­sion: The search for a”smart pill“; Sci­ence has plenty of the­o­ries about how to en­hance our brains. Jour­nal­ist Dan Hur­ley tested those the­o­ries”, Sa­lon:

    “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.”

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  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 sub­-s­tances 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 ani-mals 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, an­ab-asine, nor­ni­cotine, anatabine, co­tinine, and myos­mine - help to keep peo­ple hooked on to­bac­co. On its own, nico­tine is­n’t enough.

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  7. “Brain sci­ence, ad­dic­tion and drugs: An Acad­emy of Med­ical Sci­ences work­ing group re­port chaired by Pro­fes­sor Sir Gabriel Horn FRS FRCP (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
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  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 , 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.

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  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 can lead to real IQ gains, but al­most al­ways an ini­tially promis­ing in­ter­ven­tion like fades out with ad­di­tional stud­ies and re­verts to no net effect - as has hap­pened to . 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 ug/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 = 0.004; 43.78% de­crease at the high­est mem­ory load). Within a net­work of pari­etal and frontal ar­eas ac­ti­vated by the task (P < 0.05, cor­rected at the voxel lev­el), nico­tine pro­duced an in­creased re­sponse (P < 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 = 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.

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  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.
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  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
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  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. eg. My­ers et al 2013.↩︎

  18. “Cog­ni­tive en­hancers for the treat­ment of ADHD, Bid­well et al 2011↩︎

  19. 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.↩︎

  20. Ernst et al 2001, “Effect of nico­tine on brain ac­ti­va­tion dur­ing per­for­mance of a work­ing mem­ory task”.↩︎

  21. 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.”

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  22. 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.↩︎

  23. 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).↩︎

  24. 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.

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  25. http://­less­wrong.­com/l­w/2cv/de­feat­ing_ugh_­field­s_in_prac­tice/26lu↩︎

  26. http://­less­wrong.­com/l­w/2cv/de­feat­ing_ugh_­field­s_in_prac­tice/268a↩︎

  27. 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.↩︎

  28. 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.↩︎

  29. “A meta-analy­sis to as­sess the in­ci­dence of ad­verse effects as­so­ci­ated with the trans­der­mal nico­tine patch” 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.

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  30. See Joseph et al 1996 and .↩︎

  31. “Nicotine: Po­ten­tially a Mul­ti­func­tional Car­cino­gen?”:

    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.

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  32. 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).

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  33. 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?↩︎