Editing Nicotine (section)

==Adverse effects==
[[File:Side effects of nicotine.png|thumb|330px|Possible [[side effect]]s of nicotine<ref>Detailed reference list is located on a [[:File:Side effects of nicotine.png#Summary|separate image page]].</ref>]]
Nicotine is classified as a poison,<ref>{{cite book |title=Textbook of Forensic Medicine & Toxicology: Principles & Practice |edition=5th | vauthors = Vij K |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 |date=8 July 2021|url=https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750028.html}}</ref> and it is "extremely hazardous".<ref name=":4">{{Citation |title=Nicotine |date=2024 |work=Dictionary of Toxicology |pages=691 |url=https://link.springer.com/10.1007/978-981-99-9283-6_1860 |access-date=2024-10-19 |place=Singapore |publisher=[[Springer Nature]] |language=en |doi=10.1007/978-981-99-9283-6_1860 |isbn=978-981-99-9282-9 |quote=Nicotine is a colorless, water-soluble, and extremely hazardous alkaloid. It also has a terrible taste. |via=<!--[[WP:TWL]]-->|url-access=subscription }}</ref> However, at doses typically 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 |page=125 |quote=Use of nicotine alone, in the doses used by smokers, represents little if any hazard to the user.}}</ref><ref>{{cite journal | vauthors = Douglas CE, Henson R, Drope J, Wender RC | title = The American Cancer Society public health statement on eliminating combustible tobacco use in the United States | journal = CA | volume = 68 | issue = 4 | pages = 240–245 | date = July 2018 | pmid = 29889305 | doi = 10.3322/caac.21455 | quote = It is the smoke from combustible tobacco products—not nicotine—that injures and kills millions of smokers. | s2cid = 47016482 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dinakar C, O'Connor GT | title = The Health Effects of Electronic Cigarettes | journal = The New England Journal of Medicine | volume = 375 | issue = 14 | pages = 1372–1381 | date = October 2016 | pmid = 27705269 | doi = 10.1056/NEJMra1502466 | 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 nine main adverse events related to nicotine replacement therapy: [[headache]], [[dizziness]], [[lightheadedness]], [[nausea]], [[vomiting]], gastrointestinal symptoms, [[insomnia]], abnormal [[dream]]s, non-[[ischemic]] [[palpitations]] and chest pain, skin reactions, oral/nasal reactions, and [[hiccup]]s.<ref name="Cochrane NRT 2018_AEs">{{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 | issue = 5 | pmid = 29852054 | pmc = 6353172 | doi = 10.1002/14651858.CD000146.pub5 }}</ref> Many of these were also common in the placebo group without nicotine.<ref name="Cochrane NRT 2018_AEs" /> 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" /> However, at sufficiently high doses, nicotine may result in nausea, vomiting, [[diarrhea]], [[salivation]], [[bradycardia]], and possibly [[seizure]]s, [[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 = 286–293 | date = August 2015 | pmid = 25794473 | pmc = 4594223 | doi = 10.1016/j.amepre.2015.01.015 }}</ref>
{| class="wikitable sortable"
|+ ''Common'' side effects of nicotine use according to route of administration and dosage form
! class="sortable"   | [[Route of administration]]
! class="sortable"   | [[Dosage form]]
! class="unsortable" | Associated side effects of nicotine
! class="unsortable" | <small>Sources</small>
|-
| style="text-align:center" rowspan="2" | [[Buccal administration|Buccal]]
| style="text-align:center" | [[Nicotine gum]]
| [[Indigestion]], nausea, hiccups, traumatic injury to oral mucosa or teeth, irritation or [[tingling]] of the mouth and throat, [[mouth ulcer|oral mucosal ulceration]], jaw-[[muscle ache]], burping, gum sticking to teeth, unpleasant taste, dizziness, lightheadedness, headache, and [[insomnia]].
| style="text-align:center" | <ref name="Cochrane NRT 2018" /><ref name="Nicotine AHFS monograph" />
|-
| style="text-align:center" | [[Nicotine lozenge|Lozenge]]
| Nausea, [[dyspepsia]], [[flatulence]], headache, [[upper respiratory tract infection]]s, irritation (i.e., a burning sensation), hiccups, sore throat, coughing, dry lips, and oral mucosal ulceration.
| style="text-align:center" | <ref name="Cochrane NRT 2018" /><ref name="Nicotine AHFS monograph" />
|-
| style="text-align:center" | [[Transdermal]]
| style="text-align:center" | [[Nicotine patch|Transdermal<br />patch]]
| [[Application site reaction]]s (i.e., [[pruritus]], burning, or [[erythema]]), diarrhea, dyspepsia, abdominal pain, dry mouth, nausea, dizziness, nervousness or restlessness, headache, vivid dreams or other sleep disturbances, and irritability.
| style="text-align:center" | <ref name="Cochrane NRT 2018" /><ref name="Nicotine AHFS monograph" /><ref name="FDA transdermal patch">{{cite web | title = Nicotine Transdermal Patch |url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020076Orig1s045lbl.pdf |  website = United States Food and Drug Administration | access-date=24 January 2019}}</ref>
|-
| style="text-align:center" | [[Intranasal]]
| style="text-align:center" | [[Nicotine nasal spray|Nasal spray]]
| Runny nose, nasopharyngeal and ocular irritation, watery eyes, sneezing, and coughing.
| style="text-align:center" | <ref name="Cochrane NRT 2018" /><ref name="Nicotine AHFS monograph" /><ref name="Nicotrol NS">{{cite web | title = Nicotrol NS | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020385s010lbl.pdf | website = United States Food and Drug Administration | access-date = 24 January 2019 }}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref>
|-
| style="text-align:center" | Oral inhalation
| style="text-align:center" | [[Nicotine inhaler|Inhaler]]
| Dyspepsia, oropharyngeal irritation (e.g., coughing, irritation of the mouth and throat), [[rhinitis]], and headache.
| style="text-align:center" | <ref name="Cochrane NRT 2018" /><ref name="Nicotine AHFS monograph">{{cite web | title = Nicotine | url = https://www.drugs.com/monograph/nicotine.html | publisher = American Society of Health-System Pharmacists | website = Drugs.com | access-date = 24 January 2019 }}</ref><ref name="Nicotrol">{{cite web| title = Nicotrol | website = Pfizer | url = https://www.pfizer.com/files/products/uspi_nicotrol_inhaler.pdf | access-date = 24 January 2019 }}</ref>
|-
| style="text-align:center" colspan="2" | All (nonspecific)
| Peripheral [[vasoconstriction]], [[tachycardia]] (i.e., fast heart rate), elevated [[blood pressure]], increased [[alertness]] and [[#Performance|cognitive performance]].
| style="text-align:center" | <ref name="Nicotine AHFS monograph" /><ref name="Nicotrol NS" />
|}

===Sleep===
Nicotine reduces the amount of [[Rapid eye movement sleep|rapid eye movement]] (REM) sleep, [[slow-wave sleep]] (SWS), and total sleep time in healthy nonsmokers given nicotine via a [[transdermal patch]], and the reduction is [[Dose–response relationship|dose-dependent]].<ref name=GarciaSalloum2015/> Acute nicotine intoxication has been found to significantly reduce total sleep time and increase REM latency, [[sleep onset latency]], and [[NREM#Stages of NREM sleep|non-rapid eye movement]] (NREM) stage 2 sleep time.<ref name=GarciaSalloum2015>{{cite journal | vauthors = Garcia AN, Salloum IM | title = Polysomnographic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: A focused review | journal = The American Journal on Addictions | volume = 24 | issue = 7 | pages = 590–598 | date = October 2015 | pmid = 26346395 | doi = 10.1111/ajad.12291 | s2cid = 22703103 }}</ref><ref name="Neuropharmacology review">{{cite journal | vauthors = Boutrel B, Koob GF | title = What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications | journal = Sleep | volume = 27 | issue = 6 | pages = 1181–1194 | date = September 2004 | pmid = 15532213 | doi = 10.1093/sleep/27.6.1181 | doi-access = free }}</ref> Depressive non-smokers experience mood and sleep improvements under nicotine administration; however, subsequent nicotine withdrawal has a negative effect on both mood and sleep.<ref name=Jaehne2009>{{cite journal | vauthors = Jaehne A, Loessl B, Bárkai Z, Riemann D, Hornyak M | title = Effects of nicotine on sleep during consumption, withdrawal and replacement therapy | journal = Sleep Medicine Reviews | volume = 13 | issue = 5 | pages = 363–377 | date = October 2009 | pmid = 19345124 | doi = 10.1016/j.smrv.2008.12.003 | type = Review }}</ref>

===Cardiovascular system===

Nicotine exerts several significant effects on the [[cardiovascular system]]. Primarily, it stimulates the [[sympathetic nervous system]], leading to the release of [[catecholamine]]s. This activation results in an increase in [[heart rate]] and [[blood pressure]], as well as enhanced [[myocardial contractility]], which raises the workload on the heart.  Additionally, nicotine causes systemic [[vasoconstriction]], including constriction of coronary arteries, which can reduce blood flow to the heart. Long-term exposure to nicotine may impair [[endothelial]] function, potentially contributing to [[atherosclerosis]]. Furthermore, nicotine has been associated with the development of [[cardiac arrhythmia]]s, particularly in individuals who already have underlying heart disease.<ref name="Benowitz 2016" />

The effects of nicotine can be differentiated between short-term and long-term use. Short-term nicotine use, such as that associated with [[nicotine replacement therapy]] (NRT) for smoking cessation, appears to pose little cardiovascular risk, even for patients with known cardiovascular conditions. In contrast, longer-term nicotine use may not accelerate atherosclerosis but could contribute to acute cardiovascular events in those with pre-existing cardiovascular disease.  Many severe cardiovascular effects traditionally associated with smoking may not be solely attributable to nicotine itself. Cigarette smoke contains numerous other potentially cardiotoxic substances, including [[carbon monoxide]] and oxidant gases.<ref name="Benowitz 2016" />

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 name="Benowitz 2016">{{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 = 515–523 | date = August 2016 | pmid = 27079891 | doi = 10.1016/j.tcm.2016.03.001 | pmc = 4958544 }}</ref>

A 2018 [[Cochrane (organisation)|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|heart attack]]) and [[heart palpitation]]s, but 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 | issue = 5 | 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.<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>

====Blood pressure====
In the short term, nicotine causes a transient increase in [[blood pressure]]. Long term, epidemiological studies generally show increased blood pressure and [[hypertension]] among nicotine users.<ref name="Benowitz 2016" />

===Reinforcement disorders===
{{See also|Nicotine withdrawal|Smoking cessation}}
{{Annotated image 4
| 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 | doi-access = free }}</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 = 136–143 | 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>
| header = ΔFosB accumulation from excessive drug use
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| image-bg-color = light-dark(white,transparent)
| annot-color = var(--color-base,#202122)  
| alt = ΔFosB accumulation graph
| image = ΔFosB accumulation.svg
| align = right
| icon = none
| image-width = 400
| image-left = 0
| image-top = 0
| width = 400
| height = 440
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}}

Nicotine is highly [[addictive]] but paradoxically has quite weak reinforcing property compared to other drugs of abuse in various animals.<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 = 1972–1986 | date = May 2014 | pmid = 24821826 | pmc = 4018182 | doi = 10.1161/circulationaha.114.007667 }}</ref><ref name=Siqueira2016/><ref>{{cite journal | vauthors = Dougherty J, Miller D, Todd G, Kostenbauder HB | title = Reinforcing and other behavioral effects of nicotine | journal = Neuroscience and Biobehavioral Reviews | volume = 5 | issue = 4 | pages = 487–495 | date = December 1981 | pmid = 7322454 | doi = 10.1016/0149-7634(81)90019-1 | s2cid = 10076758 }}</ref><ref name="Belluzzi Wang Leslie 2005">{{cite journal | vauthors = Belluzzi JD, Wang R, Leslie FM | title = Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats | journal = Neuropsychopharmacology | volume = 30 | issue = 4 | pages = 705–712 | date = April 2005 | pmid = 15496937 | doi = 10.1038/sj.npp.1300586 }}</ref> Its addictiveness depends on how it is administered and also depends upon form in which nicotine is used.<ref name="assets.publishing.service.gov.uk"/> Animal research suggests that [[monoamine oxidase inhibitors]], [[acetaldehyde]]<ref name="Belluzzi Wang Leslie 2005"/><ref>{{cite web | url=https://www.rivm.nl/en/tobacco/harmful-substances-in-tobacco-smoke/acetaldehyde | title=Acetaldehyde &#124; RIVM }}</ref> and other constituents in tobacco smoke may enhance its addictiveness.<ref name="RCP" /><ref name="SmithMAO"/> [[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> Even though other drugs of dependence can have withdrawal states lasting 6 months or longer, this does not appear to occur with cigarette withdrawal.<ref>{{cite journal | vauthors = Hughes JR | title = Effects of abstinence from tobacco: valid symptoms and time course | journal = Nicotine & Tobacco Research | volume = 9 | issue = 3 | pages = 315–327 | date = March 2007 | pmid = 17365764 | doi = 10.1080/14622200701188919 }}</ref>

Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms.<ref name=Parrott2003/> These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette.<ref name=Parrott2003/> Smokers have a worse mood than they typically would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking.<ref name=Parrott2003/> Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers.<ref>{{cite journal | vauthors = Dugas EN, Sylvestre MP, O'Loughlin EK, Brunet J, Kakinami L, Constantin E, O'Loughlin J | title = Nicotine dependence and sleep quality in young adults | journal = Addictive Behaviors | volume = 65 | pages = 154–160 | date = February 2017 | pmid = 27816041 | doi = 10.1016/j.addbeh.2016.10.020 }}</ref><ref>{{cite journal | vauthors = Cohrs S, Rodenbeck A, Riemann D, Szagun B, Jaehne A, Brinkmeyer J, Gründer G, Wienker T, Diaz-Lacava A, Mobascher A, Dahmen N, Thuerauf N, Kornhuber J, Kiefer F, Gallinat J, Wagner M, Kunz D, Grittner U, Winterer G | title = Impaired sleep quality and sleep duration in smokers-results from the German Multicenter Study on Nicotine Dependence | journal = Addiction Biology | volume = 19 | issue = 3 | pages = 486–96 | date = May 2014 | pmid = 22913370 | doi = 10.1111/j.1369-1600.2012.00487.x | hdl = 11858/00-001M-0000-0025-BD0C-B | s2cid = 1066283 | hdl-access = free }}</ref>

In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels.<ref name=Bruijnzeel2012>{{cite journal | vauthors = Bruijnzeel AW | title = Tobacco addiction and the dysregulation of brain stress systems | journal = Neuroscience and Biobehavioral Reviews | volume = 36 | issue = 5 | pages = 1418–41 | date = May 2012 | pmid = 22405889 | pmc = 3340450 | doi = 10.1016/j.neubiorev.2012.02.015 | quote = Discontinuation of smoking leads to negative affective symptoms such as depressed mood, increased anxiety, and impaired memory and attention...Smoking cessation leads to a relatively mild somatic withdrawal syndrome and a severe affective withdrawal syndrome that is characterized by a decrease in positive affect, an increase in negative affect, craving for tobacco, irritability, anxiety, difficulty concentrating, hyperphagia, restlessness, and a disruption of sleep. Smoking during the acute withdrawal phase reduces craving for cigarettes and returns cognitive abilities to pre-smoking cessation level }}</ref> The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal.<ref name=Parrott2003/> Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar.<ref name=Parrott2003>{{cite journal | vauthors = Parrott AC | title = Cigarette-derived nicotine is not a medicine | journal = The World Journal of Biological Psychiatry | volume = 4 | issue = 2 | pages = 49–55 | date = April 2003 | pmid = 12692774 | doi = 10.3109/15622970309167951 | s2cid = 26903942 }}</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 = 431–443 | 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"/>

===Cancer===

Contrary to [[List of common misconceptions|popular belief]], 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><ref>{{cite magazine | vauthors = Tolentino J |date=May 7, 2018 |title=The Promise of Vaping and the Rise of Juul |url=https://www.newyorker.com/magazine/2018/05/14/the-promise-of-vaping-and-the-rise-of-juul |access-date=June 29, 2024 |magazine=[[The New Yorker]]}}</ref> although 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 | type = Review }}</ref> A 2018 report by the US [[National Academies of Sciences, Engineering, and Medicine]] concludes, "{{wj}}[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| vauthors = ((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=978-0-309-46834-3|publisher=National Academies Press|year=2018|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK507191 | type = Review }}</ref>

Although nicotine is classified as a non-carcinogenic substance, it can still promote tumor growth and metastasis. It induces several processes that contribute to cancer progression, including [[cell cycle]] progression, [[epithelial-to-mesenchymal transition]], [[cellular migration|migration]], invasion, [[angiogenesis]], and evasion of [[apoptosis]].<ref name="Schaal_2014">{{cite journal | vauthors = Schaal C, Chellappan SP | title = Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers | journal = Molecular Cancer Research | volume = 12 | issue = 1 | pages = 14–23 | date = January 2014 | pmid = 24398389 | pmc = 3915512 | doi = 10.1158/1541-7786.MCR-13-0541 | type = Review }}</ref> These effects are primarily mediated through [[nicotinic acetylcholine receptor]]s (nAChRs), particularly the [[alpha-7 nicotinic receptor|α7 subtype]], and to a lesser extent, [[β-adrenergic receptor]]s (β-ARs). Activation of these receptors triggers several [[signaling cascade]]s crucial in cancer biology, notably the [[MAPK/ERK pathway]], [[PI3K/AKT pathway]], and [[JAK-STAT signaling]].<ref name="Schaal_2014" />

Nicotine promotes lung cancer development by enhancing proliferation, angiogenesis, migration, invasion, and epithelial–mesenchymal transition (EMT) via nAChRs, which are present 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 | page = 652 | date = January 2020 | pmid = 31963832 | pmc = 7013895 | doi = 10.3390/ijms21020652 | doi-access = free | type = Review }}{{CC-notice|cc=by4|url=https://www.mdpi.com/1422-0067/21/2/652/htm| author(s) = Merecz-Sadowska A, Sitarek P, Zielinska-Blizniewska H, Malinowska K, Zajdel K, Zakonnik L, Zajdel R }}</ref> Additionally, nicotine-induced EMT contributes to drug resistance in cancer cells.<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 | page = 35 | date = 2014 | pmid = 25343018 | pmc = 4198571 | doi = 10.1186/s40169-014-0035-0 | doi-access = free | type = Review }}</ref>

Nicotine in tobacco can form carcinogenic [[tobacco-specific nitrosamines]] 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|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 | type = Primary }}</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 | page = 196 | date = 2015-08-31 | pmid = 26380225 | pmc = 4553893 | doi = 10.3389/fonc.2015.00196 | doi-access = free | type = Review }}</ref>

===Genotoxicity===

Nicotine causes [[DNA damage (naturally occurring)|DNA damage]] in several types of human cells as judged by assays for [[genotoxicity]] such as the [[comet assay]], cytokinesis-block [[micronucleus test]] and [[chromosome abnormality|chromosome aberrations]] test. In humans, this damage can happen in primary [[parotid gland]] cells,<ref>{{cite journal | vauthors = Ginzkey C, Steussloff G, Koehler C, Burghartz M, Scherzed A, Hackenberg S, Hagen R, Kleinsasser NH | title = Nicotine derived genotoxic effects in human primary parotid gland cells as assessed in vitro by comet assay, cytokinesis-block micronucleus test and chromosome aberrations test | journal = Toxicology in Vitro | volume = 28 | issue = 5 | pages = 838–846 | date = August 2014 | pmid = 24698733 | doi = 10.1016/j.tiv.2014.03.012 | bibcode = 2014ToxVi..28..838G }}</ref> [[lymphocyte]]s,<ref>{{cite journal | vauthors = Ginzkey C, Friehs G, Koehler C, Hackenberg S, Hagen R, Kleinsasser NH | title = Assessment of nicotine-induced DNA damage in a genotoxicological test battery | journal = Mutation Research | volume = 751 | issue = 1 | pages = 34–39 | date = February 2013 | pmid = 23200805 | doi = 10.1016/j.mrgentox.2012.11.004 | bibcode = 2013MRGTE.751...34G }}</ref> and respiratory tract cells.<ref>{{cite journal | vauthors = Ginzkey C, Stueber T, Friehs G, Koehler C, Hackenberg S, Richter E, Hagen R, Kleinsasser NH | title = Analysis of nicotine-induced DNA damage in cells of the human respiratory tract | journal = Toxicology Letters | volume = 208 | issue = 1 | pages = 23–29 | date = January 2012 | pmid = 22001448 | doi = 10.1016/j.toxlet.2011.09.029 }}</ref>

===Pregnancy and breastfeeding===
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 | pmc = 8194464 | 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 |archive-url=https://ghostarchive.org/archive/20221009/https://www.cdph.ca.gov/Programs/CCDPHP/DCDIC/CTCB/CDPH%20Document%20Library/Policy/ElectronicSmokingDevices/StateHealthEcigReport.pdf |archive-date=2022-10-09 |url-status=live|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 ''[[uterus|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 = 181–192 | date = June 2016 | pmid = 27297020 | doi = 10.1002/bdrc.21128 }}</ref> A [[McMaster University]] research group observed in 2010 that rats exposed to nicotine in the womb (via parenteral infusion) later in life had conditions including [[type 2 diabetes]], [[obesity]], [[hypertension]], neurobehavioral defects, respiratory dysfunction, and [[infertility]].<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 = 364–374 | date = August 2010 | pmid = 20363831 | pmc = 2905398 | doi = 10.1093/toxsci/kfq103 }}</ref>