Nicotine: Difference between revisions

{{short description|Mild chemical stimulant naturally found in some plants}}

'''Nicotine''' is a [[chiral]] [[alkaloid]] that is [[natural product|naturally produced]] in the [[nightshade]] family of plants (most predominantly in [[tobacco]] and [[duboisia hopwoodii]]<ref name="FagerströmReview">{{cite journal |last1=Fagerström |first1=Karl |title=Nicotine: Pharmacology, Toxicity and Therapeutic use |journal=Journal of Smoking Cessation |date=December 2014 |volume=9 |issue=2 |pages=53–59 |doi=10.1017/jsc.2014.27 |url=https://www.cambridge.org/core/services/aop-cambridge-core/content/view/15D8BBF6393C6093C2076546E6515457/S1834261214000279a.pdf/nicotine-pharmacology-toxicity-and-therapeutic-use.pdf |access-date=6 December 2020}}</ref>) and is widely used as a [[stimulant]]. As a [[pharmaceutical drug]], it is used for smoking cessation to relieve [[drug withdrawal|withdrawal symptoms]].<ref name=SajjaRahman2016>{{cite journal | vauthors = Sajja RK, Rahman S, Cucullo L | title = Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 36 | issue = 3 | pages = 539–54 | date = March 2016 | pmid = 26661236 | pmc = 4794105 | doi = 10.1177/0271678X15616978 }}</ref><ref name="PubChem Nicotine" /><ref name="IUPHAR nicotine clinical data">{{cite web|title=Nicotine: Clinical data|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=2585|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date={{CURRENTDMY}}|quote=Used as an aid to smoking cessation and for the relief of nicotine withdrawal symptoms.}}</ref><ref name=Abou-Donia2015>{{cite book| first = Mohamed | last = Abou-Donia | name-list-style = vanc |title=Mammalian Toxicology|url=https://books.google.com/books?id=3mGRBgAAQBAJ&pg=PA587|date=5 February 2015|publisher=John Wiley & Sons|isbn=978-1-118-68285-2|pages=587–}}</ref> Nicotine acts as a [[receptor agonist]] at most [[nicotinic acetylcholine receptor]]s (nAChRs),<ref name=IUPHAR/><ref name=MalenkaNicotine/><ref name="Kishioka_2014">{{cite journal | vauthors = Kishioka S, Kiguchi N, Kobayashi Y, Saika F | title = Nicotine effects and the endogenous opioid system | journal = Journal of Pharmacological Sciences | volume = 125 | issue = 2 | pages = 117–24 | date = 2014 | pmid = 24882143 | doi = 10.1254/jphs.14R03CP | doi-access = free }}</ref> except at two [[nicotinic receptor subunits]] ([[nAChRα9]] and [[nAChRα10]]) where it acts as a [[receptor antagonist]].<ref name=IUPHAR/>

Nicotine constitutes approximately 0.6–3.0[[percentage|%]] of the dry weight of tobacco.<ref>{{cite web|url=http://dccps.nci.nih.gov/tcrb/monographs/9/m9_3.PDF |title=Smoking and Tobacco Control Monograph No. 9 |access-date=19 December 2012}}</ref> Nicotine is also present at concentrations of millionths of a percent in the edible family [[Solanaceae]], including [[potato]]es, [[tomato]]es, and [[eggplant]]s,<ref name=SiegmundLeitner1999/> though sources disagree on whether this has any biological significance to human consumers.<ref name=SiegmundLeitner1999/> It functions as an [[plant defense against herbivory|antiherbivore chemical]]; consequently, nicotine was widely used as an [[insecticide]] in the past{{when|date=May 2020}},<ref>{{cite book|last1=Rodgman|first1=Alan|last2=Perfetti|first2=Thomas A. |name-list-style=vanc |title=The chemical components of tobacco and tobacco smoke|place=Boca Raton, FL|publisher=CRC Press|year=2009|lccn=2008018913|isbn=978-1-4200-7883-1}}{{page needed|date=December 2013}}</ref><ref name=Ujvary>{{Cite book|first=István|last=Ujváry| name-list-style=vanc |contribution=Nicotine and Other Insecticidal Alkaloids|editor-first=Izuru|editor-last=Yamamoto|editor2-first=John|editor2-last=Casida|title=Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor|pages=29–69|publisher=Springer-Verlag|location=Tokyo|year=1999}}</ref> and [[neonicotinoids]], such as [[imidacloprid]], are widely used.

Nicotine is highly [[addictive]],<ref name=Grana2014/><ref name=Siqueira2016/> unless used in slow-release forms.<ref name="assets.publishing.service.gov.uk">Public Health England. Evidence Review of E-Cigarettes and Heated Tobacco Products 2018. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/684963/Evidence_review_of_e-cigarettes_and_heated_tobacco_products_2018.pdf</ref><ref>http://www.healthnz.co.nz/Addiction_TobNic.htm</ref> Animal research suggests that [[monoamine oxidase inhibitors]] present in tobacco smoke may enhance nicotine's addictive properties.<ref name="RCP" /><ref name="SmithMAO">{{cite journal |last1=Smith |first1=Tracy T |last2=Rupprecht |first2=Laura E |last3=Cwalina |first3=Samantha N |last4=Onimus |first4=Matthew J |last5=Murphy |first5=Sharon E |last6=Donny |first6=Eric C |last7=Sved |first7=Alan F |title=Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine |journal=Neuropsychopharmacology |date=August 2016 |volume=41 |issue=9 |pages=2335–2343 |doi=10.1038/npp.2016.36}}</ref> An average [[cigarette]] yields about 2&nbsp;mg of absorbed nicotine.<ref name=MayerNewLethalDose2013/>  

The estimated lower dose limit for fatal outcomes is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg).<ref name="RCP">{{cite web |author1=Royal College of Physicians |title=Nicotine without smoke: Tobacco harm reduction |url=https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction |access-date=16 September 2020 |pages=57 |date=28 April 2016}}</ref><ref name=MayerNewLethalDose2013/> Nicotine [[addiction]] involves drug-reinforced behavior, compulsive use, and relapse following abstinence.<ref name=Caponnetto2012>{{cite journal | vauthors = Caponnetto P, Campagna D, Papale G, Russo C, Polosa R | title = The emerging phenomenon of electronic cigarettes | journal = Expert Review of Respiratory Medicine | volume = 6 | issue = 1 | pages = 63–74 | date = February 2012 | pmid = 22283580 | doi = 10.1586/ers.11.92 | s2cid = 207223131 }}</ref> Nicotine [[drug dependence|dependence]] involves tolerance, sensitization,<ref name=JainMukherjee2008>{{cite journal | vauthors = Jain R, Mukherjee K, Balhara YP | title = The role of NMDA receptor antagonists in nicotine tolerance, sensitization, and physical dependence: a preclinical review | journal = Yonsei Medical Journal | volume = 49 | issue = 2 | pages = 175–88 | date = April 2008 | pmid = 18452252 | pmc = 2615322 | doi = 10.3349/ymj.2008.49.2.175 }}</ref> [[physical dependence]], and [[psychological dependence]].<ref>{{cite journal | vauthors = Miyasato K | title = [Psychiatric and psychological features of nicotine dependence] | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 71 | issue = 3 | pages = 477–81 | date = March 2013 | pmid = 23631239 }}</ref> Nicotine dependence causes distress.<ref name=Parrott2015/><ref name=psych_addiction>{{cite journal | vauthors = Parrott AC | title = Nicotine psychobiology: how chronic-dose prospective studies can illuminate some of the theoretical issues from acute-dose research | journal = Psychopharmacology | volume = 184 | issue = 3–4 | pages = 567–76 | date = March 2006 | pmid = 16463194 | doi = 10.1007/s00213-005-0294-y | s2cid = 11356233 | url = http://psy.swansea.ac.uk/staff/parrott/Parrott2006NicotineReviewArticleInPsychopharmacology.pdf }}</ref> Nicotine withdrawal symptoms include depressed mood, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances.<ref name=Dependence-withdrawal/> Mild nicotine withdrawal symptoms are measurable in unrestricted smokers, who experience normal moods only as their blood nicotine levels peak, with each cigarette.<ref name=Parrott2003/> On quitting, withdrawal symptoms worsen sharply, then gradually improve to a normal state.<ref name=Parrott2003/>

Nicotine use as a tool for [[quitting smoking]] has a good safety history.<ref name=Schraufnage2014/> Nicotine itself is associated with some health harms.<ref name=Edgar2013>{{cite web|url=https://www.webmd.com/smoking-cessation/news/20131112/e-cigarettes-cdc#1|title=E-Cigarettes: Expert Q&A With the CDC|last=Edgar|first=Julie | name-list-style = vanc |publisher=[[WebMD]]|date=12 November 2013}}</ref> Nicotine is potentially harmful to non-users.<ref name=Schraufnagel2015/> At low amounts, it has a mild [[analgesic]] effect.<ref name=Schraufnagel2015>{{cite journal | vauthors = Schraufnagel DE | title = Electronic Cigarettes: Vulnerability of Youth | journal = Pediatric Allergy, Immunology, and Pulmonology | volume = 28 | issue = 1 | pages = 2–6 | date = March 2015 | pmid = 25830075 | pmc = 4359356 | doi = 10.1089/ped.2015.0490 }}</ref> The [[Surgeon General of the United States]] indicates that nicotine does not cause cancer.<ref name=SGUS2014/> Nicotine has been shown to produce birth defects in some animal species, but not others.<ref name="TOXNET Nicotine entry">{{cite web | title=Nicotine | url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+1107 | work=United States National Library of Medicine&nbsp;– Toxicology Data Network | publisher=Hazardous Substances Data Bank |date=20 August 2009}}</ref> It is considered a [[teratogen]] in humans.<ref name=Kohlmeier2015>{{cite journal | vauthors = Kohlmeier KA | title = Nicotine during pregnancy: changes induced in neurotransmission, which could heighten proclivity to addict and induce maladaptive control of attention | journal = Journal of Developmental Origins of Health and Disease | volume = 6 | issue = 3 | pages = 169–81 | date = June 2015 | pmid = 25385318 | doi = 10.1017/S2040174414000531 }}</ref> The [[median lethal dose]] of nicotine in humans is unknown,<ref name="ECHA nicotine monograph"/> but high doses are known to cause [[nicotine poisoning]].<ref name=SGUS2014/>

{{Main|Nicotine replacement therapy}}<!-- https://www.ncbi.nlm.nih.gov/books/NBK195719/ -->

Nicotine is being researched in clinical trials for possible benefit in treating [[Parkinson's disease]], [[dementia]], [[ADHD]], [[Depression (mood)|depression]] and [[sarcoma]]. <ref name="MIND Study">{{cite web |last1=The MIND Study |title=Why Nicotine? |url=http://mindstudy.org/nicotine |website=MIND |access-date=6 December 2020}}</ref>

Nicotine-containing products are sometimes used for the [[performance-enhancing substance|performance-enhancing]] effects of nicotine on cognition. <ref>{{cite journal | vauthors = Valentine G, Sofuoglu M | title = Cognitive Effects of Nicotine: Recent Progress | journal = Current Neuropharmacology | publisher = Bentham Science Publishers | date=May 2018 | volume = 16 | issue = 4 | pages = 403–414 | doi=10.2174/1570159X15666171103152136 | pmid = 29110618| pmc = 6018192 }}</ref> A 2010 meta-analysis of 41&nbsp;[[double-blind]], [[placebo]]-controlled studies concluded that nicotine or smoking had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory.<ref>{{cite journal | vauthors = Heishman SJ, Kleykamp BA, Singleton EG | title = Meta-analysis of the acute effects of nicotine and smoking on human performance | journal = Psychopharmacology | volume = 210 | issue = 4 | pages = 453–69 | date = July 2010 | pmid = 20414766 | pmc = 3151730 | doi = 10.1007/s00213-010-1848-1 }}</ref> A 2015 review noted that stimulation of the [[α4β2 nicotinic receptor]] is responsible for certain improvements in attentional performance;<ref>{{cite journal | vauthors = Sarter M | title = Behavioral-Cognitive Targets for Cholinergic Enhancement | journal = Current Opinion in Behavioral Sciences | volume = 4 | pages = 22–26 | date = August 2015 | pmid = 28607947 | pmc = 5466806 | doi = 10.1016/j.cobeha.2015.01.004 }}</ref> among the [[nicotinic receptor]] subtypes, nicotine has the highest [[binding affinity]] at the α4β2 receptor (k_i=1&nbsp;{{abbr|nM|nanomolar}}), which is also the biological target that mediates nicotine's [[addictive]] properties.<ref name="Nicotine IUPHAR">{{cite web|title=Nicotine: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2585|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date=7 February 2016|quote=K_is as follows; α2β4=9900nM [5], α3β2=14nM [1], α3β4=187nM [1], α4β2=1nM [4,6]. Due to the heterogeneity of nACh channels we have not tagged a primary drug target for nicotine, although the α4β2 is reported to be the predominant high affinity subtype in the brain which mediates nicotine addiction}}</ref> Nicotine has potential beneficial effects, but it also has [[paradoxical reaction|paradoxical effects]], which may be due to the [[Yerkes–Dodson law|inverted U-shape of the dose-response curve]] or [[pharmacokinetic]] features.<ref>{{cite journal | vauthors = Majdi A, Kamari F, Vafaee MS, Sadigh-Eteghad S | title = Revisiting nicotine's role in the ageing brain and cognitive impairment | journal = Reviews in the Neurosciences | volume = 28 | issue = 7 | pages = 767–781 | date = October 2017 | pmid = 28586306 | doi = 10.1515/revneuro-2017-0008 | s2cid = 3758298 | url = https://findresearcher.sdu.dk:8443/ws/files/140909555/Revisiting_nicotine_s_role_in_the_ageing_brain_and_cognitive_impairment.pdf }}</ref>

It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014.<ref name="pharmacotherapy">{{cite journal | vauthors = Aubin HJ, Luquiens A, Berlin I | title = Pharmacotherapy for smoking cessation: pharmacological principles and clinical practice | journal = British Journal of Clinical Pharmacology | volume = 77 | issue = 2 | pages = 324–36 | date = February 2014 | pmid = 23488726 | pmc = 4014023 | doi = 10.1111/bcp.12116 }}</ref> It is therefore not recommended to adolescents.<ref name="adolescents">{{cite journal | vauthors = Bailey SR, Crew EE, Riske EC, Ammerman S, Robinson TN, Killen JD | title = Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents | journal = Paediatric Drugs | volume = 14 | issue = 2 | pages = 91–108 | date = April 2012 | pmid = 22248234 | pmc = 3319092 | doi = 10.2165/11594370-000000000-00000 }}</ref> It is not safe to use nicotine during pregnancy or breastfeeding, although it is safer than smoking; the desirability of NRT use in pregnancy is therefore debated.<ref>{{cite web|url=https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/Electronic-Cigarettes-Infographic-508.pdf|title=Electronic Cigarettes – What are the health effects of using e-cigarettes?|publisher=Centers for Disease Control and Prevention|date=22 February 2018|quote=Nicotine is a health danger for pregnant women and their developing babies.}}</ref><ref>{{cite journal | vauthors = Bruin JE, Gerstein HC, Holloway AC | title = Long-term consequences of fetal and neonatal nicotine exposure: a critical review | journal = Toxicological Sciences | volume = 116 | issue = 2 | pages = 364–74 | date = August 2010 | pmid = 20363831 | pmc = 2905398 | doi = 10.1093/toxsci/kfq103 | quote = there is no safe dose of nicotine during pregnancy... The general consensus among clinicians is that more information is needed about the risks of NRT use during pregnancy before well-informed definitive recommendations can be made to pregnant women... Overall, the evidence provided in this review overwhelmingly indicates that nicotine should no longer be considered the ‘‘safe’’ component of cigarette smoke. In fact, many of the adverse postnatal health outcomes associated with maternal smoking during pregnancy may be attributable, at least in part, to nicotine alone. }}</ref><ref name="pregnancy_controversy">{{cite journal | vauthors = Forest S | title = Controversy and evidence about nicotine replacement therapy in pregnancy | journal = MCN. The American Journal of Maternal/Child Nursing | volume = 35 | issue = 2 | pages = 89–95 | date = March 1, 2010 | pmid = 20215949 | doi = 10.1097/NMC.0b013e3181cafba4 | s2cid = 27085986 }}</ref>

Precautions are needed when using NRT in people who have had a [[myocardial infarction]] within two weeks, a serious or worsening [[angina pectoris]], and/or a serious underlying arrhythmia.<ref name="adolescents"/> Using nicotine products during cancer treatment is counterrecommended, as nicotine promotes tumour growth, but temporary use of NRTs to quit smoking may be advised for [[harm reduction]].<ref name="carcinogenicity">{{cite journal | vauthors = Sanner T, Grimsrud TK | title = Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment - A Review | journal = Frontiers in Oncology | volume = 5 | pages = 196 | date = 2015 | pmid = 26380225 | pmc = 4553893 | doi = 10.3389/fonc.2015.00196 }}</ref>

Nicotine is classified as a poison.<ref>{{cite book |title=Textbook of Forensic Medicine & Toxicology: Principles & Practice |edition=5th |first1=Krishan |last1=Vij |publisher=Elsevier Health Sciences |year=2014 |isbn=978-81-312-3623-9 |page=525 |url=https://books.google.com/books?id=Ip1rAwAAQBAJ}} [https://books.google.com/books?id=Ip1rAwAAQBAJ&pg=PA525 Extract of page 525]</ref><ref>{{cite web |title=NICOTINE : Systemic Agent |url=https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750028.html}}</ref> However, at doses used by consumers, it presents little if any hazard to the user.<ref name="RCP_report">{{cite web |last1=Royal College of Physicians |title=Nicotine Without Smoke -- Tobacco Harm Reduction |url=https://www.rcplondon.ac.uk/file/3563/download?token=Mu0K_ZR0 |access-date=30 September 2020 |pages=125 |quote=Use of nicotine alone, in the doses used by smokers, represents little if any hazard to the user.}}</ref><ref>{{cite journal |last1=Douglas |first1=Clifford E. |last2=Henson |first2=Rosie |last3=Drope |first3=Jeffrey |last4=Wender |first4=Richard C. |title=The American Cancer Society public health statement on eliminating combustible tobacco use in the United States: Eliminating Combustible Tobacco Use |url=https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21455 |journal=CA: A Cancer Journal for Clinicians |access-date=30 September 2020 |pages=240–245 |doi=10.3322/caac.21455 |date=July 2018 |volume=68 |issue=4 |pmid=29889305 |s2cid=47016482 |quote=It is the smoke from combustible tobacco products—not nicotine—that injures and kills millions of smokers.|doi-access=free }}</ref><ref>{{cite journal |last1=Dinakar |first1=Chitra |last2=O’Connor |first2=George T. |title=The Health Effects of Electronic Cigarettes |journal=New England Journal of Medicine |date=6 October 2016 |volume=375 |issue=14 |pages=1372–1381 |doi=10.1056/NEJMra1502466 |pmid=27705269 |quote=Beyond its addictive properties, short-term or long-term exposure to nicotine in adults has not been established as dangerous}}</ref> A 2018 [[Cochrane Collaboration]] review lists 9 main adverse events related to nicotine replacement therapy: headache, dizziness/light‐headedness, nausea/vomiting, gastro‐intestinal symptoms, sleep/dream problems, non‐[[ischemic]] [[palpitations]] and chest pain, skin reactions, oral/nasal reactions and hiccups.<ref name="Cochrane NRT 2018_AEs">{{cite journal |last1=Hartmann-Boyce |first1=Jamie |last2=Chepkin |first2=Samantha C |last3=Ye |first3=Weiyu |last4=Bullen |first4=Chris |last5=Lancaster |first5=Tim |title=Nicotine replacement therapy versus control for smoking cessation |journal=Cochrane Database of Systematic Reviews |date=31 May 2018 |volume=5 |page=Appendix 3 |doi=10.1002/14651858.CD000146.pub5 |pmid=29852054 |pmc=6353172 |url=https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD000146.pub5/appendices#CD000146-sec-0077}}</ref> Many of these were also common in the placebo group without nicotine.<ref name="Cochrane NRT 2018_AEs" /> The palpitations and chest pain were deemed "rare" and there was no evidence of an increased number of serious cardiac problems compared to the placebo group, even in people with established cardiac disease.<ref name="Cochrane NRT 2018" /> The common side effects from nicotine exposure are listed in the table below. Serious adverse events due to the use of nicotine replacement therapy are extremely rare.<ref name="Cochrane NRT 2018" /> At low amounts, it has a mild [[analgesic]] effect.<ref name="Schraufnagel2015" /> At sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures, hypoventilation, and death.<ref name="England2015">{{cite journal | vauthors = England LJ, Bunnell RE, Pechacek TF, Tong VT, McAfee TA | title = Nicotine and the Developing Human: A Neglected Element in the Electronic Cigarette Debate | journal = American Journal of Preventive Medicine | volume = 49 | issue = 2 | pages = 286–93 | date = August 2015 | pmid = 25794473 | pmc = 4594223 | doi = 10.1016/j.amepre.2015.01.015 }}</ref>

| Peripheral [[vasoconstriction]], [[tachycardia]] (i.e., fast heart rate), elevated [[blood pressure]], and increased [[alertness]] and [[#Enhancing performance|cognitive performance]].

A 2018 [[Cochrane review]] found that, in rare cases, nicotine replacement therapy can cause non-[[ischemic]] chest pain (i.e., chest pain that is unrelated to a [[myocardial infarction]]) and [[heart palpitation]]s.<ref name="Cochrane NRT 2018" /> The same review indicated that nicotine replacement therapy does not increase the incidence of serious cardiac adverse events (i.e., myocardial infarction, [[stroke]], and [[cardiac death]]) relative to controls.<ref name="Cochrane NRT 2018">{{cite journal | vauthors = Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T | title = Nicotine replacement therapy versus control for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 5 | pages = CD000146 | date = May 2018 | pmid = 29852054 | pmc = 6353172 | doi = 10.1002/14651858.CD000146.pub5 | quote = There is high-quality evidence that all of the licensed forms of NRT (gum, transdermal patch, nasal spray, inhalator and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50% to 60%, regardless of setting, and further research is very unlikely to change our confidence in the estimate of the effect. The relative effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual.&nbsp;...<br /><br />A meta-analysis of adverse events associated with NRT included 92&nbsp;RCTs and 28&nbsp;observational studies, and addressed a possible excess of chest pains and heart palpitations among users of NRT compared with placebo groups (Mills 2010). The authors report an OR of 2.06 (95%&nbsp;CI 1.51 to 2.82) across 12&nbsp;studies. We replicated this data collection exercise and analysis where data were available (included and excluded) in this review, and detected a similar but slightly lower estimate, OR 1.88 (95%&nbsp;CI 1.37 to 2.57; 15&nbsp;studies; 11,074&nbsp;participants; OR rather than RR calculated for comparison; Analysis 6.1). Chest pains and heart palpitations were an extremely rare event, occurring at a rate of 2.5% in the NRT groups compared with 1.4% in the control groups in the 15&nbsp;trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21&nbsp;RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR&nbsp;2.29 95%&nbsp;CI 1.39 to 3.82). However, when only serious adverse cardiac events (myocardial infarction, stroke and cardiovascular death) were considered, the finding was not statistically significant (RR&nbsp;1.95 95%&nbsp;CI 0.26 to 4.30). }}</ref>

A 2016 review of the cardiovascular toxicity of nicotine concluded, “Based on current knowledge, we believe that the cardiovascular risks of nicotine from e-cigarette use in people without cardiovascular disease are quite low. We have concerns that nicotine from e-cigarettes could pose some risk for users with cardiovascular disease.”<ref>{{cite journal | vauthors = Benowitz NL, Burbank AD | title = Cardiovascular toxicity of nicotine: Implications for electronic cigarette use | journal = Trends in Cardiovascular Medicine | volume = 26 | issue = 6 | pages = 515–23 | date = August 2016 | pmid = 27079891 | doi = 10.1016/j.tcm.2016.03.001 | pmc = 4958544 }}</ref>

{{see also|Nicotine withdrawal|Smoking cessation}}

| caption = Top: this depicts the initial effects of high dose exposure to an addictive drug on [[gene expression]] in the [[nucleus accumbens]] for various Fos family proteins (i.e., [[c-Fos]], [[FosB]], [[ΔFosB]], [[Fra1]], and [[Fra2]]).<br />Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these [[phosphorylated]] (35–37&nbsp;[[kilodalton]]) ΔFosB [[isoform]]s persist in the [[D1-type]] [[medium spiny neurons]] of the nucleus accumbens for up to 2&nbsp;months.<ref name="pmid11572966">{{cite journal | vauthors = Nestler EJ, Barrot M, Self DW | title = DeltaFosB: a sustained molecular switch for addiction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11042–6 | date = September 2001 | pmid = 11572966 | pmc = 58680 | doi = 10.1073/pnas.191352698 | quote = Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal&nbsp;... Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well. | bibcode = 2001PNAS...9811042N }}</ref><ref name="Nestler2">{{cite journal | vauthors = Nestler EJ | title = Transcriptional mechanisms of drug addiction | journal = Clinical Psychopharmacology and Neuroscience | volume = 10 | issue = 3 | pages = 136–43 | date = December 2012 | pmid = 23430970 | pmc = 3569166 | doi = 10.9758/cpn.2012.10.3.136 | quote = The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives.&nbsp;... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure.&nbsp;... ΔFosB overexpression in nucleus accumbens induces NFκB }}</ref>

Nicotine is highly [[addictive]].<ref name=Grana2014>{{cite journal | vauthors = Grana R, Benowitz N, Glantz SA | title = E-cigarettes: a scientific review | journal = Circulation | volume = 129 | issue = 19 | pages = 1972–86 | date = May 2014 | pmid = 24821826 | pmc = 4018182 | doi = 10.1161/circulationaha.114.007667 }}</ref><ref name=Siqueira2016/> Its addictiveness depends on how it is administered.<ref name="assets.publishing.service.gov.uk"/> [[Nicotine dependence]] involves aspects of both [[psychological dependence]] and [[physical dependence]], since discontinuation of extended use has been shown to produce both [[affect (psychology)|affective]] (e.g., anxiety, irritability, craving, [[anhedonia]]) and [[somatic nervous system|somatic]] (mild motor dysfunctions such as [[tremor]]) withdrawal symptoms.<ref name="Dependence-withdrawal">{{cite journal | vauthors = D'Souza MS, Markou A | title = Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments | journal = Addiction Science & Clinical Practice | volume = 6 | issue = 1 | pages = 4–16 | date = July 2011 | pmid = 22003417 | pmc = 3188825 | quote = Withdrawal symptoms upon cessation of nicotine intake: Chronic nicotine use induces neuroadaptations in the brain’s reward system that result in the development of nicotine dependence. Thus, nicotine-dependent smokers must continue nicotine intake to avoid distressing somatic and affective withdrawal symptoms. Newly abstinent smokers experience symptoms such as depressed mood, anxiety, irritability, difficulty concentrating, craving, bradycardia, insomnia, gastrointestinal discomfort, and weight gain (Shiffman and Jarvik, 1976; Hughes et al., 1991). Experimental animals, such as rats and mice, exhibit a nicotine withdrawal syndrome that, like the human syndrome, includes both somatic signs and a negative affective state (Watkins et al., 2000; Malin et al., 2006). The somatic signs of nicotine withdrawal include rearing, jumping, shakes, abdominal constrictions, chewing, scratching, and facial tremors. The negative affective state of nicotine withdrawal is characterized by decreased responsiveness to previously rewarding stimuli, a state called anhedonia. }}</ref> Withdrawal symptoms peak in one to three days<ref name=DasProchaska2017>{{cite journal | vauthors = Das S, Prochaska JJ | title = Innovative approaches to support smoking cessation for individuals with mental illness and co-occurring substance use disorders | journal = Expert Review of Respiratory Medicine | volume = 11 | issue = 10 | pages = 841–850 | date = October 2017 | pmid = 28756728 | pmc = 5790168 | doi = 10.1080/17476348.2017.1361823 }}</ref> and can persist for several weeks.<ref name="HKS2010">{{cite journal | vauthors = Heishman SJ, Kleykamp BA, Singleton EG | title = Meta-analysis of the acute effects of nicotine and smoking on human performance | journal = Psychopharmacology | volume = 210 | issue = 4 | pages = 453–69 | date = July 2010 | pmid = 20414766 | pmc = 3151730 | doi = 10.1007/s00213-010-1848-1 | quote = The significant effects of nicotine on motor abilities, attention, and memory likely represent true performance enhancement because they are not confounded by withdrawal relief. The beneficial cognitive effects of nicotine have implications for initiation of smoking and maintenance of tobacco dependence. }}</ref> Some people experience symptoms for 6 months or longer.<ref name=BaraonaLovelace2017>{{cite journal | vauthors = Baraona LK, Lovelace D, Daniels JL, McDaniel L | title = Tobacco Harms, Nicotine Pharmacology, and Pharmacologic Tobacco Cessation Interventions for Women | journal = Journal of Midwifery & Women's Health | volume = 62 | issue = 3 | pages = 253–269 | date = May 2017 | pmid = 28556464 | doi = 10.1111/jmwh.12616 | s2cid = 1267977 }}</ref>

Nicotine activates the [[mesolimbic pathway]] and [[Inducible gene|induces]] long-term [[ΔFosB]] expression (i.e., produces [[phosphorylated]] ΔFosB [[isoform]]s) in the [[nucleus accumbens]] when inhaled or injected frequently or at high doses, but not necessarily when ingested.<ref name="Nestler 2013Rev">{{cite journal | vauthors = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues in Clinical Neuroscience | volume = 15 | issue = 4 | pages = 431–43 | date = December 2013 | pmid = 24459410 | pmc = 3898681 | doi =  10.31887/DCNS.2013.15.4/enestler}}</ref><ref name="Addiction molecular neurobiology">{{cite journal | vauthors = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = The American Journal of Drug and Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–37 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | s2cid = 19157711 | quote = The knowledge of ΔFosB induction in chronic drug exposure provides a novel method for the evaluation of substance addiction profiles (i.e. how addictive they are). Xiong et al. used this premise to evaluate the potential addictive profile of propofol (119). Propofol is a general anaesthetic, however its abuse for recreational purpose has been documented (120). Using control drugs implicated in both ΔFosB induction and addiction (ethanol and nicotine),&nbsp;...<br /><br />Conclusions<br />ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). }}</ref><ref name="RouteDFosB Primary">{{cite journal | vauthors = Marttila K, Raattamaa H, Ahtee L | title = Effects of chronic nicotine administration and its withdrawal on striatal FosB/DeltaFosB and c-Fos expression in rats and mice | journal = Neuropharmacology | volume = 51 | issue = 1 | pages = 44–51 | date = July 2006 | pmid = 16631212 | doi = 10.1016/j.neuropharm.2006.02.014 | s2cid = 8551216 }}</ref> Consequently, high daily exposure (possibly excluding [[oral route]]) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.<ref name="Nestler 2013Rev"/><ref name="Addiction molecular neurobiology"/>

Although nicotine itself does not cause cancer in humans,<ref name=IARCCancerStatement>{{cite web |title=Does nicotine cause cancer? |url=https://cancer-code-europe.iarc.fr/index.php/en/ecac-12-ways/tobacco/199-nicotine-cause-cancer |website=European Code Against Cancer |publisher=World Health Organization&nbsp;– International Agency for Research on Cancer |access-date=23 January 2019}}</ref> it is unclear whether it functions as a [[tumor promoter]] {{as of|2012|lc=y}}.<ref>{{cite journal | vauthors = Cardinale A, Nastrucci C, Cesario A, Russo P | title = Nicotine: specific role in angiogenesis, proliferation and apoptosis | journal = Critical Reviews in Toxicology | volume = 42 | issue = 1 | pages = 68–89 | date = January 2012 | pmid = 22050423 | doi = 10.3109/10408444.2011.623150 | s2cid = 11372110 }}</ref> A 2018 report by the [[National Academies of Sciences, Engineering, and Medicine]] concludes, "[w]hile it is biologically plausible that nicotine can act as a tumor promoter, the existing body of evidence indicates this is unlikely to translate into increased risk of human cancer."<ref>{{cite book|title=Public Health Consequences of E-Cigarettes|chapter=Chapter 4: Nicotine|authors=National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems|veditors=Eaton DL, Kwan LY, Stratton K|isbn=9780309468343|publisher=National Academies Press|year=2018|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK507191}}</ref>  

Low levels of nicotine stimulate cell proliferation<ref>{{cite journal | vauthors = Dasgupta P | title = Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines | journal = International Journal of Cancer | publisher = The Journal of Clinical Endocrinology & Metabolism | date=January 2009 | volume = 124 | issue = 1 | pages = 36–45 | doi=10.1002/ijc.23894 | pmid = 18844224 | pmc = 2826200 }}</ref>, while high levels are cytotoxic.{{citation needed|date=November 2019}} Nicotine increases [[Nicotinic acetylcholine receptor|cholinergic]] signaling and [[adrenergic receptor|adrenergic]] signaling in colon cancer cells,<ref>{{cite journal | vauthors = Wong HP, Yu L, Lam EK, Tai EK, Wu WK, Cho CH | title = Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation | journal = Toxicological Sciences | volume = 97 | issue = 2 | pages = 279–87 | date = June 2007 | pmid = 17369603 | doi = 10.1093/toxsci/kfm060 | doi-access = free }}</ref> thereby impeding apoptosis ([[programmed cell death]]), promoting tumor growth, and activating [[growth factors]] and cellular [[mitogenic]] factors such as [[5-lipoxygenase]] (5-LOX), and [[epidermal growth factor]] (EGF). Nicotine also promotes cancer growth by stimulating [[angiogenesis]] and [[neovascularization]].<ref>{{cite journal | vauthors = Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi M | title = Nicotine enhances neovascularization and promotes tumor growth | journal = Molecules and Cells | volume = 16 | issue = 2 | pages = 143–6 | date = October 2003 | pmid = 14651253 | url = http://www.molcells.org/journal/view.html?year=2003&volume=16&number=2&spage=143 }}</ref><ref>{{cite journal | vauthors = Ye YN, Liu ES, Shin VY, Wu WK, Luo JC, Cho CH | title = Nicotine promoted colon cancer growth via epidermal growth factor receptor, c-Src, and 5-lipoxygenase-mediated signal pathway | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 308 | issue = 1 | pages = 66–72 | date = January 2004 | pmid = 14569062 | doi = 10.1124/jpet.103.058321 | s2cid = 9774853 | url = https://semanticscholar.org/paper/03f0d8d3e6705a8fc06c46e5455b7916dc4c50b5 }}</ref> Nicotine promotes lung cancer development and accelerates its proliferation, angiogenesis, migration, invasion and epithelial–mesenchymal transition (EMT), via its influence on nAChRs receptors, whose presence has been confirmed in lung cancer cells.<ref name=Merecz-SadowskaSitarek2020>{{cite journal | vauthors = Merecz-Sadowska A, Sitarek P, Zielinska-Blizniewska H, Malinowska K, Zajdel K, Zakonnik L, Zajdel R | title = A Summary of In Vitro and In Vivo Studies Evaluating the Impact of E-Cigarette Exposure on Living Organisms and the Environment | journal = International Journal of Molecular Sciences | volume = 21 | issue = 2 | pages = 652 | date = January 2020 | pmid = 31963832 | pmc = 7013895 | doi = 10.3390/ijms21020652 }}{{CC-notice|cc=by4|url=https://www.mdpi.com/1422-0067/21/2/652/htm|author(s)=Anna Merecz-Sadowska, Przemyslaw Sitarek, Hanna Zielinska-Blizniewska, Katarzyna Malinowska, Karolina Zajdel, Lukasz Zakonnik, and Radoslaw Zajdel}}</ref> In cancer cells, nicotine promotes the [[epithelial–mesenchymal transition]] which makes the cancer cells more resistant to drugs that treat cancer.<ref>{{cite journal | vauthors = Kothari AN, Mi Z, Zapf M, Kuo PC | title = Novel clinical therapeutics targeting the epithelial to mesenchymal transition | journal = Clinical and Translational Medicine | volume = 3 | pages = 35 | date = 2014 | pmid = 25343018 | pmc = 4198571 | doi = 10.1186/s40169-014-0035-0 }}</ref>

Nicotine can form carcinogenic [[Tobacco-specific nitrosamines]] (TSNAs) through a [[nitrosation]] reaction. This occurs mostly in the curing and processing of tobacco. However, nicotine in the mouth and stomach can react to form [[N-Nitrosonornicotine]]<ref name=":1">{{cite journal | vauthors = Knezevich A, Muzic J, Hatsukami DK, Hecht SS, Stepanov I | title = Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans | journal = Nicotine & Tobacco Research | volume = 15 | issue = 2 | pages = 591–5 | date = February 2013 | pmid = 22923602 | pmc = 3611998 | doi = 10.1093/ntr/nts172 }}</ref>, a known type 1 carcinogen,<ref name=":2">{{Cite web|title=List of Classifications – IARC Monographs on the Identification of Carcinogenic Hazards to Humans|url=https://monographs.iarc.fr/list-of-classifications|access-date=2020-07-22|website=monographs.iarc.fr}}</ref> suggesting that consumption of non-tobacco forms of nicotine may still play a role in carcinogenesis.<ref>{{cite journal | vauthors = Sanner T, Grimsrud TK | title = Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment - A Review | journal = Frontiers in Oncology | volume = 5 | pages = 196 | date = 2015-08-31 | pmid = 26380225 | pmc = 4553893 | doi = 10.3389/fonc.2015.00196 }}</ref>

Nicotine has been shown to produce birth defects in some animal species, but not others;<ref name="TOXNET Nicotine entry" /> consequently, it is considered to be a possible [[teratogen]] in humans.<ref name="TOXNET Nicotine entry"/> In [[animal studies]] that resulted in birth defects, researchers found that nicotine negatively affects fetal [[brain development]] and pregnancy outcomes;<ref name="TOXNET Nicotine entry"/><ref name=SGUS2014>{{cite book|url=https://stacks.cdc.gov/view/cdc/21569/Share|title=The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General, Chapter 5 - Nicotine|year=2014|pages=107–138|publisher=[[Surgeon General of the United States]]|pmid=24455788|author1=National Center for Chronic Disease Prevention Health Promotion (US) Office on Smoking Health}}</ref> the negative effects on early brain development are associated with abnormalities in [[brain metabolism]] and [[neurotransmitter system]] function.<ref>{{cite journal | vauthors = Behnke M, Smith VC | title = Prenatal substance abuse: short- and long-term effects on the exposed fetus | journal = Pediatrics | volume = 131 | issue = 3 | pages = e1009-24 | date = March 2013 | pmid = 23439891 | doi = 10.1542/peds.2012-3931 | doi-access = free }}</ref> Nicotine crosses the [[placenta]] and is found in the breast milk of mothers who smoke as well as mothers who inhale [[passive smoke]].<ref name=Chapman2015>{{cite web|url=https://www.cdph.ca.gov/Programs/CCDPHP/DCDIC/CTCB/CDPH%20Document%20Library/Policy/ElectronicSmokingDevices/StateHealthEcigReport.pdf|title=State Health Officer's Report on E-Cigarettes: A Community Health Threat|publisher=California Department of Public Health|date=January 2015}}</ref>

Nicotine exposure ''[[in utero]]'' is responsible for several complications of pregnancy and birth: pregnant women who smoke are at greater risk for both [[miscarriage]] and [[stillbirth]] and infants exposed to nicotine ''in utero'' tend to have lower [[birth weight]]s.<ref name=Holbrook2016>{{cite journal | vauthors = Holbrook BD | title = The effects of nicotine on human fetal development | journal = Birth Defects Research. Part C, Embryo Today | volume = 108 | issue = 2 | pages = 181–92 | date = June 2016 | pmid = 27297020 | doi = 10.1002/bdrc.21128 }}</ref> Some evidence suggests that ''in utero'' nicotine exposure influences the occurrence of certain conditions later in life, including [[type 2 diabetes]], [[obesity]], [[hypertension]], neurobehavioral defects, respiratory dysfunction, and [[infertility]].<ref name=Schraufnage2014>{{cite journal | vauthors = Schraufnagel DE, Blasi F, Drummond MB, Lam DC, Latif E, Rosen MJ, Sansores R, Van Zyl-Smit R | display-authors = 6 | title = Electronic cigarettes. A position statement of the forum of international respiratory societies | journal = American Journal of Respiratory and Critical Care Medicine | volume = 190 | issue = 6 | pages = 611–8 | date = September 2014 | pmid = 25006874 | doi = 10.1164/rccm.201407-1198PP | s2cid = 43763340 | url = https://semanticscholar.org/paper/d88b38ea2a82b144f8fcf08d462fb9e4147e26bf }}</ref>

It is unlikely that a person would overdose on nicotine through smoking alone. The US [[Food and Drug Administration]] (FDA) stated in 2013 that there are no significant safety concerns associated with the use of more than one form of [[Over-the-counter drug|over-the-counter]] (OTC) [[nicotine replacement therapy]] at the same time, or using OTC NRT at the same time as another nicotine-containing product, like cigarettes.<ref name=FDANRTLabels>{{cite web|title=Consumer Updates: Nicotine Replacement Therapy Labels May Change|url=https://www.fda.gov/forconsumers/consumerupdates/ucm345087.htm|publisher=FDA|date=1 April 2013}}</ref> The [[median lethal dose]] of nicotine in humans is unknown.<ref name="ECHA nicotine monograph">{{cite web |title=Nicotine |url=https://echa.europa.eu/documents/10162/31694def-b7c3-208d-5aaf-3db9681ec3b9 |publisher=European Chemicals Agency: Committee for Risk Assessment |access-date=23 January 2019|date=September 2015}}</ref><ref name=MayerNewLethalDose2013>{{cite journal | vauthors = Mayer B | title = How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century | journal = Archives of Toxicology | volume = 88 | issue = 1 | pages = 5–7 | date = January 2014 | pmid = 24091634 | pmc = 3880486 | doi = 10.1007/s00204-013-1127-0 }}</ref> Nevertheless, nicotine has a relatively high [[toxicity]] in comparison to many other alkaloids such as [[caffeine]], which has an LD₅₀ of 127&nbsp;mg/kg when administered to mice.<ref>''[[Toxicology and Applied Pharmacology]].'' Vol. 44, Pg. 1, 1978.</ref> At sufficiently high doses, it is associated with nicotine poisoning,<ref name=SGUS2014/> which, while common in children (in whom poisonous and lethal levels occur at lower doses per kilogram of body weight<ref name=Schraufnagel2015/>) rarely results in significant morbidity or death.<ref name="TOXNET Nicotine entry" />

Nicotine decreases hunger and food consumption.<ref name=HuYang2018>{{cite journal | vauthors = Hu T, Yang Z, Li MD | title = Pharmacological Effects and Regulatory Mechanisms of Tobacco Smoking Effects on Food Intake and Weight Control | journal = Journal of Neuroimmune Pharmacology | volume = 13 | issue = 4 | pages = 453–466 | date = December 2018 | pmid = 30054897 | doi = 10.1007/s11481-018-9800-y | s2cid = 51727199 |quote=Nicotine’s weight effects appear to result especially from the drug’s stimulation of α3β4 nicotine acetylcholine receptors (nAChRs), which are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), leading to activation of the melanocortin circuit, which is associated with body weight. Further, α7- and α4β2-containing nAChRs have been implicated in weight control by nicotine.}}</ref> The majority of research shows that nicotine reduces body weight, but some researchers have found that nicotine may result in weight gain under specific types of eating habits in animal models.<ref name=HuYang2018 /> Nicotine effect on weight appears to result from nicotine's stimulation of α3β4 nAChR receptors located in the [[Proopiomelanocortin|POMC neurons]] in the arcuate nucleus and subsequently the [[central melanocortin system|melanocortin system]], especially the melatocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus, thus modulating feeding inhibition.<ref name="Picciotto2014" /><ref name=HuYang2018/> POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.<ref name=HuYang2018/>

Nicotine is a [[hygroscopy|hygroscopic]], colorless to yellow-brown, oily liquid, that is readily soluble in alcohol, ether or light petroleum. It is [[miscible]] with [[water (molecule)|water]] in its neutral amine [[base (chemistry)|base]] form between 60&nbsp;°C and 210&nbsp;°C. It is a dibasic [[nitrogenous base]], having K_b1=1×10⁻⁶, K_b2=1×10⁻¹¹.<ref name="metcalf"/> It readily forms ammonium [[salt (chemistry)|salts]] with [[acid]]s that are usually solid and water-soluble. Its [[flash point]] is 95&nbsp;°C and its auto-ignition temperature is 244&nbsp;°C.<ref name=SLMSDS>{{cite web | url = http://www.sciencelab.com/msds.php?msdsId=9926222 | title =  L-Nicotine Material Safety Data Sheet | work = Sciencelab.com, Inc. }}</ref> Nicotine is readily volatile ([[vapor pressure]] 5.5 ㎩ at 25 ℃)<ref name="metcalf"/> On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, [[nicotinic acid]] (niacin, vitamin B3), and [[methylamine]].<ref name="library.sciencemadness.org"/>

[[Construction of electronic cigarettes#Pod mods|Pod mod]] electronic cigarettes use nicotine in the form of a [[nicotine salt|protonated nicotine]], rather than [[free base|free-base]] nicotine found in earlier generations.<ref name=JenssenBoykan2019>{{cite journal | vauthors = Jenssen BP, Boykan R | title = Electronic Cigarettes and Youth in the United States: A Call to Action (at the Local, National and Global Levels) | journal = Children | volume = 6 | issue = 2 | pages = 30 | date = February 2019 | pmid = 30791645 | pmc = 6406299 | doi = 10.3390/children6020030}}{{CC-notice|cc=by4|url=https://www.mdpi.com/2227-9067/6/2/30/htm|author(s)=Brian P. Jenssen and Rachel Boykan}}</ref>

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]].<ref>{{cite book |last1=Bell |first1=Luke |last2=Copeland |first2=Ash |date=2018 |title=Organic Chemistry |publisher=Scientific e-Resources |page=282 |isbn=978-1839472008}}</ref>

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.<ref>{{cite book |last1=Bell |first1=Luke |last2=Copeland |first2=Ash |date=2018 |title=Organic Chemistry |publisher=Scientific e-Resources |page=282-283 |isbn=978-1839472008}}</ref>

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 [[enantiomer]]ically pure (−)-nicotine.<ref name=plant-meta>{{cite book |editor1-first=Hiroshi |editor1-last=Ashihara |editor2-first=Alan |editor2-last=Crozier |editor3-first=Atsushi |editor3-last=Komamine |name-list-style=vanc |title=Plant metabolism and biotechnology |publisher=Wiley |location=Cambridge |isbn=978-0-470-74703-2}}{{page needed|date=December 2013}}</ref>

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.<ref>{{cite book |vauthors=Benowitz NL, Hukkanen J, Jacob P |volume=192 |issue=192 |pages=29–60 |date=1 January 2009 |pmid=19184645 |pmc=2953858 |doi=10.1007/978-3-540-69248-5_2 |isbn=978-3-540-69246-1 |series=Handbook of Experimental Pharmacology |title=Nicotine Psychopharmacology |chapter=Nicotine Chemistry, Metabolism, Kinetics and Biomarkers }}</ref><ref>{{cite book|first=Randall Clint |last=Baselt| name-list-style=vanc  |title=Disposition of Toxic Drugs and Chemicals in Man|year=2014|publisher=Biomedical Publications|isbn=978-0-9626523-9-4|edition=10th|pages=1452–6}}</ref> Nicotine use is not regulated in competitive sports programs.<ref>{{cite journal | vauthors = Mündel T, Jones DA | title = Effect of transdermal nicotine administration on exercise endurance in men | journal = Experimental Physiology | volume = 91 | issue = 4 | pages = 705–13 | date = July 2006 | pmid = 16627574 | doi = 10.1113/expphysiol.2006.033373 | s2cid = 41954065 | url = https://semanticscholar.org/paper/3405d7e94bccd92743b621682d34dbeb24e5c0f9 | doi-access = free }}</ref>

Nicotine is a secondary metabolite produced in a variety of plants in the [[Solanaceae]] family, most notably in tobacco ''[[Nicotiana tabacum]]'', where it can be found at high concentrations of 0.5 to 7.5%.<ref>{{cite web |url=http://www.tis-gdv.de/tis_e/ware/genuss/tabak/tabak.htm |title=Tobacco (leaf tobacco) |publisher=Transportation Information Service}}</ref> Nicotine is also found in the leaves of other tobacco species, such as ''[[Nicotiana rustica]]'' (in amounts of 2–14%). Nicotine production is strongly induced in response to wounding as part of a [[jasmonate]]-dependent reaction.<ref>Baldwin, I. T. 2001. An Ecologically Motivated Analysis of Plant-Herbivore Interactions in Native Tobacco. Plant Physiology 127:1449–1458. American Society of Plant Biologists.</ref> Specialist insects on tobacco, such as the tobacco hornworm (''[[Manduca sexta]]''), have a number of adaptations to the detoxification and even adaptive re-purposing of nicotine.<ref>N.d. Natural history-driven, plant-mediated RNAi-based study reveals CYP6B46’s role in a nicotine-mediated antipredator herbivore defense | PNAS.</ref> Nicotine is also found at low concentrations in the nectar of tobacco plants, where it may promote [[outcrossing]] by affecting the behavior of hummingbird pollinators.<ref>Kessler, D., S. Bhattacharya, C. Diezel, E. Rothe, K. Gase, M. Schöttner, and I. T. Baldwin. 2012. Unpredictability of nectar nicotine promotes outcrossing by hummingbirds in Nicotiana attenuata. The Plant Journal 71:529–538.</ref>

Nicotine occurs in smaller amounts (varying from 2–7&nbsp;[[microgram|µg]]/[[kilogram|kg]], or 20–70 millionths of a percent wet weight<ref name=SiegmundLeitner1999/>) in other [[Solanaceae]]ous plants, including some crop species such as [[potato]]es, [[tomato]]es, [[eggplant]], and [[capsicum|peppers]],<ref name=SiegmundLeitner1999/>).<ref name=Domino1993>{{cite journal | vauthors = Domino EF, Hornbach E, Demana T | title = The nicotine content of common vegetables | journal = The New England Journal of Medicine | volume = 329 | issue = 6 | pages = 437 | date = August 1993 | pmid = 8326992 | doi = 10.1056/NEJM199308053290619 }}</ref> as well as non-crop species such as ''[[Duboisia hopwoodii]]''.<ref name="metcalf">{{citation| first = Robert L. | last = Metcalf | name-list-style = vanc |contribution=Insect Control|title=Ullmann's Encyclopedia of Industrial Chemistry|edition=7th|publisher=Wiley|year=2007|page=9| title-link = Ullmann's Encyclopedia of Industrial Chemistry }}</ref> The amounts of nicotine in tomatoes lowers substantially as the fruit ripens.<ref name=SiegmundLeitner1999/> A 1999 report found "In some papers it is suggested that the contribution of dietary nicotine intake is significant when compared with exposure to ETS [environmental tobacco smoke] or by active smoking of small numbers of cigarettes. Others consider the dietary intake to be negligible unless inordinately large amounts of specific vegetables are consumed."<ref name=SiegmundLeitner1999/> The amount of nicotine eaten per day is roughly around 1.4 and 2.25&nbsp;[[microgram|µg]]/day at the 95th percentile.<ref name=SiegmundLeitner1999/> These numbers may be low due to insufficient food intake data.<ref name=SiegmundLeitner1999>{{cite journal | vauthors = Siegmund B, Leitner E, Pfannhauser W | title = Determination of the nicotine content of various edible nightshades (Solanaceae) and their products and estimation of the associated dietary nicotine intake | journal = Journal of Agricultural and Food Chemistry | volume = 47 | issue = 8 | pages = 3113–20 | date = August 1999 | pmid = 10552617 | doi = 10.1021/jf990089w }}</ref> The concentrations of nicotine in vegetables are difficult to measure accurately, since they are very low (parts per billion range).<ref name=MoldoveanuScott2016>{{cite journal| vauthors = Moldoveanu SC, Scott WA, Lawson DM |title=Nicotine Analysis in Several Non-Tobacco Plant Materials|journal=Beiträge zur Tabakforschung International/Contributions to Tobacco Research|volume=27|issue=2|pages=54–59|year=2016|issn=1612-9237|doi=10.1515/cttr-2016-0008|doi-access=free}}</ref>

{{external media

Immune cells of both the [[innate|Innate immune system]] and [[adaptive immune system]]s frequently express the α2, α5, α6, α7, α9, and α10 [[Nicotinic acetylcholine receptor#Subunits|subunits of nicotinic acetylcholine receptors]].<ref name=":0">{{cite journal | vauthors = Fujii T, Mashimo M, Moriwaki Y, Misawa H, Ono S, Horiguchi K, Kawashima K | title = Expression and Function of the Cholinergic System in Immune Cells | journal = Frontiers in Immunology | volume = 8 | pages = 1085 | date = 2017 | pmid = 28932225 | pmc = 5592202 | doi = 10.3389/fimmu.2017.01085 }}</ref> Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of [[immune function]].<ref name=":0" />

{{commons category|Nicotine}}