In smaller doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful. This stimulant effect is likely to be a major contributing factor to the dependence-forming properties of tobacco smoking, nicotine patches, nicotine gum, nicotine inhalers and liquid nicotine vaporizers. According to the American Heart Association, nicotine addiction has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine nicotine addiction are similar to those determining addiction to heroin and cocaine. The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.
Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine. This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation and subsequently referred to as "Nesbitt's Paradox".
A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that NRT increases a quitter's chance of success by 50 to 70%. But in 1990, researchers found that 93% of users returned to smoking within six months.
Although population level effectiveness has not been demonstrated, the primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.
However, in a few situations, smoking has been observed to be of therapeutic value. These are often referred to as "Smoker’s Paradoxes". Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other substances found in tobacco.
Tobacco smoke has been shown to contain compounds capable of inhibiting monoamine oxidase, which is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.
While tobacco smoking is associated with an increased risk of Alzheimer's disease, there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease. Nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans. A study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.
Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine. Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.
Research at Duke University Medical Center found that nicotine may improve the symptoms of depression. Nicotine appears to improve ADHD symptoms. Some studies have focused on benefits of nicotine therapy in adults with ADHD.
While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers.
Nicotine (in the form of chewing gum or a transdermal patch) has been explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.
The relationship between smoking and inflammatory bowel disease has been firmly established, but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease.
Nicotine increases blood pressure and heart rate and primarily causes a light head in humans. Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells. Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).
A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus, an estrogen-sensitive region of the brain involved in memory formation and retention.
Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, research examining its addictive nature has been found to show that nicotine activates the mesolimbic pathway ("reward system") – the circuitry within the brain that regulates feelings of pleasure and euphoria.
Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be as addictive as cocaine and heroin when used in the form of tobacco. Like other physically addictive drugs,nicotine withdrawal causes downregulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine is downregulated, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors, in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity. This alteration in neuronal chemistry can persist for months following the last administration.
Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle operates under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.
Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over-the-counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.
The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 g/kg) can be a lethal dosage for adult humans. However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to an oral LD50 of 6.5–13 mg/kg . Nevertheless nicotine has a relatively high toxicity in comparison to many other alkaloids such as cocaine, which has an LD50of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotine through smoking alone, although overdose can occur through combined use of nicotine patches or nicotine gum and cigarettes at the same time.[unreliable source?] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.
Historically, nicotine has not been regarded as a carcinogen. The IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture. Nicotine has been noted to directly cause cancer through a number of different mechanisms such as the activation of MAP Kinases. Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization. In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).N-Nitrosonornicotine (NNN), classified by the IARC as a Group 1 carcinogen, is produced endogenously from nitrite in saliva and nicotine.
The teratogenic properties of nicotine have been investigated. According to a study of about 77,000 pregnant women in Denmark, women who used nicotine gum and patches during the early stages of pregnancy were found to face an increased risk of having babies with birth defects. The study showed that women who used nicotine-replacement therapy in the first 12 weeks of pregnancy had a 60% greater risk of having babies with birth defects compared to women who were non-smokers.
Tobacco use among pregnant women has also been correlated to increased frequency of ADHD. Children born to mothers who used tobacco were two and a half times more likely to be diagnosed with ADHD. Froelich estimated that "exposure to higher levels of lead and prenatal tobacco each accounted for 500,000 additional cases of ADHD in U.S. children".
The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation. Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.
The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.
The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.
The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (–)-nicotine.
The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine, suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".
Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide. Under some conditions, other substances may be formed such as myosmine.
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids. Nicotine use is not regulated in competitive sports programs.
By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain one of the major contributors of the apparent euphoria and relaxation, and addiction caused by nicotine consumption. This release of dopamine induced by nicotine is thought to occur via a cholinergic–dopaminergic link, mediated by a neuropeptide, ghrelin, in the ventral tegmentum. Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis. Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.
Nicotine also activates the sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.
Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.
Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide (waste from the tobacco industry) were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.
In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States. This request was granted, and since 1 January 2014, this pesticide has not been available for sale.
^ abUjváry, István (1999). "Nicotine and Other Insecticidal Alkaloids". In Yamamoto, Izuru; Casida, John. Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Tokyo: Springer-Verlag. pp. 29–69.
^ abMayer B (October 2013). "How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century". Arch. Toxicol.88 (1): 5–7. doi:10.1007/s00204-013-1127-0. PMID24091634.
^Lagrue, Gilbert; Cormier, Anne (June 2001). "Des récepteurs nicotiniques à la dépendance tabagique : Perspectives thérapeutiques" [From nicotinic receptors to smoking dependence: Therapeutic prospects]. Alcoologie et addictologie (in French) 23 (2): 39S–42S. ISSN1620-4522. INIST:1081618.Cite uses deprecated parameters (help)
^Orsini, Jean-Claude (June 2001). "Dépendance tabagique et contrôle central de la glycémie et de l'appétit" [Dependence on tobacco smoking and brain systems controlling glycemia and appetite]. Alcoologie et addictologie (in French) 23 (2 Suppl): 28S–36S. ISSN1620-4522. INIST:1081638.Cite uses deprecated parameters (help)
^Chen, Hui; Vlahos, Ross; Bozinovski, Steve; Jones, Jessica; Anderson, Gary P; Morris, Margaret J (2004). "Effect of Short-Term Cigarette Smoke Exposure on Body Weight, Appetite and Brain Neuropeptide Y in Mice". Neuropsychopharmacology30 (4). doi:10.1038/sj.npp.1300597. PMID15508020. Lay summary – The University of Melbourne (1 November 2004).
^Pomerleau OF, Pomerleau CS (1984). Neuroregulators and the reinforcement of smoking: Towards a biobehavioral explanation. Neuroscience and Biobehavioral Reviews, 8:503-513.
^Doran, Christopher M.; Valenti, Lisa; Robinson, Maxine; Britt, Helena; Mattick, Richard P. (2006). "Smoking status of Australian general practice patients and their attempts to quit". Addictive Behaviors31 (5): 758–66. doi:10.1016/j.addbeh.2005.05.054. PMID16137834.
^Pierce, John P.; Cummins, Sharon E.; White, Martha M.; Humphrey, Aimee; Messer, Karen (2012). "Quitlines and Nicotine Replacement for Smoking Cessation: Do We Need to Change Policy?". Annual Review of Public Health33: 341–56. doi:10.1146/annurev-publhealth-031811-124624. PMID22224888.
^ abCohen DJ, Doucet M, Cutlip DE, Ho KK, Popma JJ, Kuntz RE (August 2001). "Impact of smoking on clinical and angiographic restenosis after percutaneous coronary intervention: another smoker's paradox?". Circulation104 (7): 773–8. doi:10.1161/hc3201.094225. PMID11502701.
^Longmore, M., Wilkinson, I., Torok, E. Oxford Handbook of Clinical Medicine (5th ed.). p. 232.
^Green JT, Richardson C, Marshall RW, Rhodes J, McKirdy HC, Thomas GA, Williams GT (November 2000). "Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis". Aliment. Pharmacol. Ther.14 (11): 1429–34. doi:10.1046/j.1365-2036.2000.00847.x. PMID11069313.
^Goedert JJ, Vitale F, Lauria C, Serraino D, Tamburini M, Montella M, Messina A, Brown EE, Rezza G, Gafà L, Romano N (November 2002). "Risk factors for classical Kaposi's sarcoma". J. Natl. Cancer Inst.94 (22): 1712–8. doi:10.1093/jnci/94.22.1712. PMID12441327. Lay summary – United Press International (March 29, 2001).
^Lain KY, Powers RW, Krohn MA, Ness RB, Crombleholme WR, Roberts JM (November 1999). "Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure". Am. J. Obstet. Gynecol.181 (5 Pt 1): 1192–6. doi:10.1016/S0002-9378(99)70107-9. PMID10561644.
^de Leon J, Tracy J, McCann E, McGrory A, Diaz FJ (Jul 2002). "Schizophrenia and tobacco smoking: a replication study in another US psychiatric hospital". Schizophr Res.56 (1–2): 55–65. doi:10.1016/S0920-9964(01)00192-X. PMID12084420.
^Aguilar MC, Gurpegui M, Diaz FJ, de Leon J (Mar 2005). "Nicotine dependence and symptoms in schizophrenia: naturalistic study of complex interactions". Br J Psychiatry186 (3): 215–21. doi:10.1192/bjp.186.3.215. PMID15738502.
^McClernon, F. Joseph; Hiott, F. Berry; Westman, Eric C.; Rose, Jed E.; Levin, Edward D. (2006). "Transdermal nicotine attenuates depression symptoms in nonsmokers: A double-blind, placebo-controlled trial". Psychopharmacology189 (1): 125–33. doi:10.1007/s00213-006-0516-y. PMID16977477. Lay summary – Duke Medicine News and Communications (September 12, 2006).
^Pasquini M, Garavini A, Biondi M (January 2005). "Nicotine augmentation for refractory obsessive-compulsive disorder. A case report". Prog. Neuropsychopharmacol. Biol. Psychiatry29 (1): 157–9. doi:10.1016/j.pnpbp.2004.08.011. PMID15610960.
^Lundberg S, Carlsson A, Norfeldt P, Carlsson ML (November 2004). "Nicotine treatment of obsessive-compulsive disorder". Prog. Neuropsychopharmacol. Biol. Psychiatry28 (7): 1195–9. doi:10.1016/j.pnpbp.2004.06.014. PMID15610934.
^Tizabi Y, Louis VA, Taylor CT, Waxman D, Culver KE, Szechtman H (January 2002). "Effect of nicotine on quinpirole-induced checking behavior in rats: implications for obsessive-compulsive disorder". Biol. Psychiatry51 (2): 164–71. doi:10.1016/S0006-3223(01)01207-0. PMID11822995.
^Raval AP, Bhatt A, Saul I (July 2009). "Chronic nicotine exposure inhibits 17beta-estradiol-mediated protection of the hippocampal CA1 region against cerebral ischemia in female rats". Neurosci. Lett.458 (2): 65–9. doi:10.1016/j.neulet.2009.04.021. PMID19442878.
^Wong HP, Yu L, Lam EK, Tai EK, Wu WK, Cho CH (June 2007). "Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation". Toxicol. Sci.97 (2): 279–87. doi:10.1093/toxsci/kfm060. PMID17369603.
^Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi M (October 2003). "Nicotine enhances neovascularization and promotes tumor growth". Mol. Cells16 (2): 143–6. PMID14651253.
^Ye YN, Liu ES, Shin VY, Wu WK, Luo JC, Cho CH (January 2004). "Nicotine promoted colon cancer growth via epidermal growth factor receptor, c-Src, and 5-lipoxygenase-mediated signal pathway". J. Pharmacol. Exp. Ther.308 (1): 66–72. doi:10.1124/jpet.103.058321. PMID14569062.
^Lamberts, Burton L.; Dewey, Lovell J.; Byerrum, Richard U. (1959). "Ornithine as a precursor for the pyrrolidine ring of nicotine". Biochimica et Biophysica Acta33 (1): 22–6. doi:10.1016/0006-3002(59)90492-5. PMID13651178.
^Dawson, R. F.; Christman, D. R.; d'Adamo, A.; Solt, M. L.; Wolf, A. P. (1960). "The Biosynthesis of Nicotine from Isotopically Labeled Nicotinic Acids1". Journal of the American Chemical Society82 (10): 2628. doi:10.1021/ja01495a059.
^Le Houezec J (September 2003). "Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review". Int. J. Tuberc. Lung Dis.7 (9): 811–9. PMID12971663.
^Benowitz NL, Jacob P, Jones RT, Rosenberg J (May 1982). "Interindividual variability in the metabolism and cardiovascular effects of nicotine in man". J. Pharmacol. Exp. Ther.221 (2): 368–72. PMID7077531.
^Russell MA, Jarvis M, Iyer R, Feyerabend C. Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers. Br Med J. 1980 April 5; 280(6219): 972–976.
^Hukkanen J, Jacob P, Benowitz NL (March 2005). "Metabolism and disposition kinetics of nicotine". Pharmacol. Rev.57 (1): 79–115. doi:10.1124/pr.57.1.3. PMID15734728.
^Dickson, Suzanne L.; Egecioglu, Emil; Landgren, Sara; Skibicka, Karolina P.; Engel, Jörgen A.; Jerlhag, Elisabet (2011). "The role of the central ghrelin system in reward from food and chemical drugs". Molecular and Cellular Endocrinology340 (1): 80–7. doi:10.1016/j.mce.2011.02.017. PMID21354264.
^Katzung, Bertram G. (2006). Basic and Clinical Pharmacology. New York: McGraw-Hill Medical. pp. 99–105.
^Wüllner U, Gündisch D, Herzog H, Minnerop M, Joe A, Warnecke M, Jessen F, Schütz C, Reinhardt M, Eschner W, Klockgether T, Schmaljohann J (January 2008). "Smoking upregulates alpha4beta2* nicotinic acetylcholine receptors in the human brain". Neurosci. Lett.430 (1): 34–7. doi:10.1016/j.neulet.2007.10.011. PMID17997038.
^Walsh H, Govind AP, Mastro R, et al. (2008). "Up-regulation of nicotinic receptors by nicotine varies with receptor subtype". J. Biol. Chem.283 (10): 6022–32. doi:10.1074/jbc.M703432200. PMID18174175.
^Nguyen HN, Rasmussen BA, Perry DC (2003). "Subtype-selective up-regulation by chronic nicotine of high-affinity nicotinic receptors in rat brain demonstrated by receptor autoradiography". J. Pharmacol. Exp. Ther.307 (3): 1090–7. doi:10.1124/jpet.103.056408. PMID14560040.
^Amir Levine et al. (2011). "Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine". Sci Transl Med3 (107): 107ra109. doi:10.1126/scitranslmed.3003062.
^Yoshida T, Sakane N, Umekawa T, Kondo M (Jan 1994). "Effect of nicotine on sympathetic nervous system activity of mice subjected to immobilization stress". Physiol. Behav.55 (1): 53–7. doi:10.1016/0031-9384(94)90009-4. PMID8140174.
^King G, Yerger VB, Whembolua GL, Bendel RB, Kittles R, Moolchan ET (June 2009). "Link between facultative melanin and tobacco use among African Americans". Pharmacol. Biochem. Behav.92 (4): 589–96. doi:10.1016/j.pbb.2009.02.011. PMID19268687.
^Henningfield JE, Zeller M (March 2006). "Nicotine psychopharmacology research contributions to United States and global tobacco regulation: a look back and a look forward". Psychopharmacology (Berl.)184 (3–4): 286–91. doi:10.1007/s00213-006-0308-4. PMID16463054.
^Melsens, Louis-Henri-Frédéric (1843) "Note sur la nicotine,"Annales de chimie et de physique, third series, vol. 9, pages 465-479; see especially page 470. [Note: The empirical formula that Melsens provides is incorrect because at that time, chemists used the wrong atomic mass for carbon (6 instead of 12).]
Bilkei-Gorzo A, Rácz I, Michel K, Darvas M, Rafael Maldonado López, Zimmer A. (2008). "A common genetic predisposition to stress sensitivity and stress-induced nicotine craving". Biol. Psychiatry63 (2): 164–71. doi:10.1016/j.biopsych.2007.02.010. PMID17570348.
Gorrod, John W.; Peyton, Jacob,III, eds. (November 16, 1999). Analytical Determination of Nicotine and Related Compounds and their Metabolites. Amsterdam: Elsevier. ISBN978-0-08-052551-8.
Thomas, Gareth AO; Rhodes, John; Ingram, John R (2005). "Mechanisms of Disease: Nicotine—a review of its actions in the context of gastrointestinal disease". Nature Clinical Practice Gastroenterology & Hepatology2 (11): 536. doi:10.1038/ncpgasthep0316.