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 . Less obvi­ous is that nico­tine has many (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 s (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, , 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 , s, , , 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 or other nootrop­ics that affect or , such as , 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; 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 ; 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 24 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 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 (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 -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 in the 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 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 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 ” (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 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 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. lists 9 stud­ies cor­re­lat­ing nico­tine use with var­i­ous genes & .↩︎

  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.”

    ↩︎
  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.

    ↩︎
  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
    ↩︎
  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 s 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 (: 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.

    (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?↩︎