Nicotine: Difference between revisions

{{Short description|Chemical stimulant produced by some plants}}

{{About|the chemical|other uses|Nicotine (disambiguation)}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Use dmy dates|date=January 2024}}

{{Infobox drug

| Verifiedfields =

| imageL = Nicotine molecule ball from xtal.png

| imageR = Nicotine molecule spacefill from xtal.png

| caption =

| image2 =

| tradename = Nicorette, others

| Drugs.com = {{drugs.com|monograph|nicotine}}

| pregnancy_AU = D

| pregnancy_US = D

| legal_AU = S7

| legal_AU_comment =

| legal_CA = Unscheduled

| legal_CA_comment =

| legal_BR = Unscheduled

| legal_DE = Unscheduled

| legal_DE_comment =

| legal_NZ = Unscheduled

| legal_NZ_comment =

| legal_UK = GSL

| legal_UK_comment = <ref>{{cite web |title=The Medicines (Products Other Than Veterinary Drugs) (General Sale List) Amendment Order 2001 |url=https://www.legislation.gov.uk/uksi/2001/2068/note/made?view=plain |website=legislation.gov.uk |access-date=2 August 2022}}</ref>

| legal_US = OTC

| legal_US_comment = and [[prescription drug|prescription]]

<ref name="PubChem Nicotine">{{cite encyclopedia | title=Nicotine | url=https://pubchem.ncbi.nlm.nih.gov/compound/nicotine | series=PubChem Compound Database | publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | access-date={{CURRENTDMY}} | date=16 February 2019}}</ref>

| legal_UN = Unscheduled

| legal_UN_comment =

| legal_EU =

| legal_status = In general legal for all uses for tobacco and nicotine products as electronic cigarettes, OTC for nicotine gums and lozenges.

| dependency_liability = [[Physical dependence|Physical]]: Low–moderate<ref>{{cite book |doi=10.1007/978-3-319-13482-6_4 |chapter=Nicotine Withdrawal |title=The Neuropharmacology of Nicotine Dependence |series=Current Topics in Behavioral Neurosciences |date=2015 | vauthors = McLaughlin I, Dani JA, De Biasi M |volume=24 |pages=99–123 |pmid=25638335 |pmc=4542051 |isbn=978-3-319-13481-9 }}</ref> [[Psychological dependence|Psychological]]: High<ref name=Dependence-withdrawal/><ref>{{cite journal | vauthors = Cosci F, Pistelli F, Lazzarini N, Carrozzi L | title = Nicotine dependence and psychological distress: outcomes and clinical implications in smoking cessation | journal = Psychology Research and Behavior Management | volume = 4 | pages = 119–128 | date = 2011 | pmid = 22114542 | pmc = 3218785 | doi = 10.2147/prbm.s14243 | doi-access = free }}</ref>

| addiction_liability = Very high in susceptible individuals<ref>{{cite book | vauthors = Hollinger MA |title=Introduction to Pharmacology | edition = Third |url=https://books.google.com/books?id=qfrLBQAAQBAJ&pg=PA222|date=19 October 2007|publisher=CRC Press|location=Abingdon|isbn=978-1-4200-4742-4|pages=222–223}}</ref>

| routes_of_administration = [[Inhalation]]; [[Insufflation (medicine)|insufflation]]; [[Oral route|oral]] – buccal, sublingual, and ingestion; [[transdermal]]; [[suppository|rectal]]

| class = [[Stimulant]]; [[Nootropic]]; [[Euphoriant]]

<!--Pharmacokinetic data-->| bioavailability =

| protein_bound = <5%

| metabolism = Primarily [[hepatic]]: [[CYP2A6]], [[CYP2B6]], [[FMO3]], others

| elimination_half-life = 1–2 hours; 20 hours active metabolite

| metabolites = [[Cotinine]]

| excretion = [[Renal]], [[urine pH]]-dependent;<ref name="inchem">{{cite web | url=http://www.inchem.org/documents/pims/chemical/nicotine.htm | vauthors = Landoni JH | title=Nicotine (PIM) | website=INCHEM | publisher=International Programme on Chemical Safety | access-date=29 January 2019}}</ref><br /> {{nowrap|10–20%}} (gum), 30% (inhaled); {{nowrap|10–30%}} (intranasal)

<!--Identifiers-->| IUPAC_name = 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine

| image = File:Nikotin - Nicotine.svg

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 54-11-5

| ATC_prefix = N07

| ATC_suffix = BA01

| ATC_supplemental = {{ATCvet|P53|AX13}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 18723

| PubChem = 89594

| IUPHAR_ligand = 2585

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00184

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 80863

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D03365

| PDB_ligand = NCT

<!--Chemical data-->| C = 10

| H = 14

| N = 2

| chirality = [[Chiral]]

| smiles = c1ncccc1[C@@H]2CCCN2C

| density = 1.01

| melting_point = -79

| boiling_point = 247

{{tobacco}}

'''Nicotine''' is a [[natural product|naturally produced]] [[alkaloid]] in the [[nightshade]] family of plants (most predominantly in [[tobacco]] and ''[[Duboisia hopwoodii]]'')<ref name="FagerströmReview">{{cite journal | vauthors = Fagerström K |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 |doi-access=free }}</ref> and is widely used [[recreational drug use|recreationally]] as a [[stimulant]] and [[anxiolytic]]. 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 = 539–554 | 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 |quote=Used as an aid to smoking cessation and for the relief of nicotine withdrawal symptoms.}}</ref><ref name=Abou-Donia2015>{{cite book |vauthors = Abou-Donia M |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 = 117–124 | 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% of the dry weight of tobacco.<ref>{{cite web|url=http://dccps.nci.nih.gov/tcrb/monographs/9/m9_3.PDF |archive-url=https://ghostarchive.org/archive/20221009/http://dccps.nci.nih.gov/tcrb/monographs/9/m9_3.PDF |archive-date=2022-10-09 |url-status=live |title=Smoking and Tobacco Control Monograph No.&nbsp;9 |access-date=19 December 2012}}</ref> Nicotine is also present at [[Parts-per notation|ppb]] concentrations in edible plants in the 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 toxin]]; consequently, nicotine was widely used as an [[insecticide]] in the past,<ref>{{cite book |vauthors = Rodgman A, Perfetti TA |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 |vauthors = Ujváry I |contribution=Nicotine and Other Insecticidal Alkaloids |veditors = Yamamoto I, Casida J |title=Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor |pages=29–69 |publisher=Springer-Verlag |location=Tokyo |year=1999}}</ref> and [[neonicotinoid]]s (structurally similar to nicotine), such as [[imidacloprid]], are some of the most effective and widely used insecticides.

Nicotine is highly [[addictive]].<ref name="pmid23494236">{{cite journal |vauthors=Perkins KA, Karelitz JL |title=Reinforcement enhancing effects of nicotine via smoking |journal=[[Psychopharmacology]] |volume=228 |issue=3 |pages=479–486 |date=August 2013 |pmid=23494236 |pmc=3707934 |doi=10.1007/s00213-013-3054-4 |url= |issn=}}</ref><ref name=Grana2014/><ref name=Siqueira2016/> Slow-release forms (gums and patches, when used correctly) can be less addictive and help in quitting.<ref name="pmid17640334">{{cite journal |vauthors=Etter JF |title=Addiction to the nicotine gum in never smokers |journal=[[BMC Public Health]] |volume=7 |issue= |page=159 |date=July 2007 |pmid=17640334 |pmc=1939993 |doi=10.1186/1471-2458-7-159 |url= |issn= |doi-access=free }}</ref><ref>{{cite journal | vauthors = Olausson P, Jentsch JD, Taylor JR | title = Nicotine enhances responding with conditioned reinforcement | journal = Psychopharmacology | volume = 171 | issue = 2 | pages = 173–178 | date = January 2004 | pmid = 13680077 | doi = 10.1007/s00213-003-1575-y | s2cid = 11855403 }}</ref><ref name="assets.publishing.service.gov.uk">{{cite web | work = Public Health England. | title = Evidence Review of E-Cigarettes and Heated Tobacco Products | date = 2018 | url = 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>{{cite web|url=http://www.healthnz.co.nz/Addiction_TobNic.htm|title = Tobacco more addictive than Nicotine|archive-url=https://web.archive.org/web/20230420062215/http://www.healthnz.co.nz/Addiction_TobNic.htm|archive-date=2023-04-20}}</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 | vauthors = Smith TT, Rupprecht LE, Cwalina SN, Onimus MJ, Murphy SE, Donny EC, Sved AF | title = Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine | journal = Neuropsychopharmacology | volume = 41 | issue = 9 | pages = 2335–2343 | date = August 2016 | pmid = 26955970 | pmc = 4946064 | 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&nbsp;mg of ingested nicotine for an adult (6.5–13&nbsp;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 |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 = 175–188 | date = April 2008 | pmid = 18452252 | pmc = 2615322 | doi = 10.3349/ymj.2008.49.2.175 }}</ref> [[physical dependence]], [[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 = 477–481 | date = March 2013 | pmid = 23631239 }}</ref> and can cause 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 = 567–576 | 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">{{cite journal |vauthors=Schraufnagel DE, Blasi F, Drummond MB, Lam DC, Latif E, Rosen MJ, Sansores R, Van Zyl-Smit R |date=September 2014 |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=611–618 |doi=10.1164/rccm.201407-1198PP |pmid=25006874 |s2cid=43763340|url=https://figshare.com/articles/journal_contribution/10758143 }}</ref> Animal studies suggest that nicotine may adversely affect cognitive development in adolescence, but the relevance of these findings to human brain development is disputed.<ref name="2016 SGR">{{cite web |title=E-Cigarette Use Among Youth and Young Adults. 2016 Surgeon General's report.lts |url=https://e-cigarettes.surgeongeneral.gov/documents/2016_SGR_Full_Report_508.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://e-cigarettes.surgeongeneral.gov/documents/2016_SGR_Full_Report_508.pdf |archive-date=2022-10-09 |url-status=live |website=surgeongeneral.gov}}</ref><ref name="RCP" /> 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> According to the [[International Agency for Research on Cancer]], "nicotine is not generally considered to be a carcinogen".<ref>[[International Agency for Research on Cancer|IARC]] Working Group on the Evaluation of Carcinogenic Risks to Humans. Personal Habits and Indoor Combustions. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No.&nbsp;100E.) [https://www.ncbi.nlm.nih.gov/books/NBK304395/ TOBACCO SMOKING].</ref><ref name=IARCCancerStatement/>

The [[Surgeon General of the United States]] indicates that evidence is inadequate to infer the presence or absence of a causal relationship between exposure to nicotine and risk for cancer.<ref name=SGUS2014/> Nicotine has been shown to produce birth defects in humans and is considered a [[teratogen]].<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 = 169–181 | date = June 2015 | pmid = 25385318 | doi = 10.1017/S2040174414000531 | s2cid = 29298949 }}</ref><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> The [[median lethal dose]] of nicotine in humans is unknown.<ref name="ECHA nicotine monograph"/> High doses are known to cause [[nicotine poisoning]], organ failure, and death through paralysis of respiratory muscles,<ref name=SGUS2014/><ref name="Effah2022">{{cite journal | vauthors = Effah F, Taiwo B, Baines D, Bailey A, Marczylo T | title = Pulmonary effects of e-liquid flavors: a systematic review | journal = Journal of Toxicology and Environmental Health Part B: Critical Reviews | volume = 25 | issue = 7 | pages = 343–371 | date = October 2022 | pmid = 36154615 | pmc = 9590402 | doi = 10.1080/10937404.2022.2124563 | bibcode = 2022JTEHB..25..343E }}</ref> though serious or fatal overdoses are rare.<ref name="Lavoie">{{cite journal | vauthors = Lavoie FW, Harris TM | title = Fatal nicotine ingestion | journal = The Journal of Emergency Medicine | volume = 9 | issue = 3 | pages = 133–136 | year = 1991 | pmid = 2050970 | doi = 10.1016/0736-4679(91)90318-a }}</ref>

{{TOC limit|3}}

==Uses==

===Medical===

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

[[Image:Nicoderm.JPG|thumb|right|A [[nicotine patch]] applied to the left arm. The [[Cochrane Collaboration]] finds that [[nicotine replacement therapy]] increases a quitter's chance of success by {{nowrap|50–60%}}, regardless of setting.<ref name="Cochrane NRT 2018" />]]

The primary [[Pharmacotherapy|therapeutic use]] of nicotine is treating nicotine dependence to eliminate [[smoking]] and the damage it does to health. Controlled levels of nicotine are given to patients through [[nicotine gum|gums]], [[nicotine patches|dermal patches]], lozenges, inhalers, or nasal sprays to wean them off their dependence. A 2018 [[Cochrane Collaboration]] review found high-quality evidence that all current forms of nicotine replacement therapy (gum, patch, lozenges, inhaler, and nasal spray) increase the chances of successfully quitting smoking by {{nowrap|50–60%}}, regardless of setting.<ref name="Cochrane NRT 2018" />

Combining [[nicotine patch]] use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.<ref name=":3">{{cite journal | vauthors = Theodoulou A, Chepkin SC, Ye W, Fanshawe TR, Bullen C, Hartmann-Boyce J, Livingstone-Banks J, Hajizadeh A, Lindson N | title = Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 6 | pages = CD013308 | date = June 2023 | pmid = 37335995 | pmc = 10278922 | doi = 10.1002/14651858.CD013308.pub2 }}</ref>

In contrast to recreational nicotine products, which have been designed to maximize the likelihood of addiction, nicotine replacement products (NRTs) are designed to minimize addictiveness.<ref name="SGUS2014" />{{rp|112}} The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.<ref name="Parrott2015" />

'''Investigative'''

Nicotine is being researched in clinical trials for possible benefit in treating [[Parkinson's disease]], [[dementia]], [[attention deficit hyperactivity disorder]], and [[Depression (mood)|depression]].<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 may partly attenuate [[sensory gating]] and attentional deficits associated with [[schizophrenia]]. Short-term use of Nicotine was found to improve subjects’ reaction time and [[Vigilance (psychology)|alertness]] in given tasks, according to research. Nicotine was not found to improve [[Negative symptoms of schizophrenia|negative]], [[Psychosis|positive]], or other cognitive symptoms of schizophrenia.<ref>{{cite journal | vauthors = Harris JG, Kongs S, Allensworth D, Martin L, Tregellas J, Sullivan B, Zerbe G, Freedman R | title = Effects of nicotine on cognitive deficits in schizophrenia | journal = Neuropsychopharmacology | volume = 29 | issue = 7 | pages = 1378–1385 | date = July 2004 | pmid = 15138435 | doi = 10.1038/sj.npp.1300450 }}</ref>

===Pesticide===

Nicotine has been used as an [[insecticide]] since at least 1690, in the form of tobacco extracts<ref name="Ujvary" /><ref name=neonic_mechanisms>{{cite journal | vauthors = Tomizawa M, Casida JE | title = Neonicotinoid insecticide toxicology: mechanisms of selective action | journal = Annual Review of Pharmacology and Toxicology | volume = 45 | pages = 247–68 | date = 2005 | pmid = 15822177 | doi = 10.1146/annurev.pharmtox.45.120403.095930 }}</ref><ref>{{cite book |title=The chemical components of tobacco and tobacco smoke |vauthors=Rodgman A, Perfetti TA |publisher=CRC Press |year=2009 |isbn=978-1-4200-7883-1 |place=Boca Raton, FL |lccn=2008018913}}{{page needed|date=December 2013}}</ref> (although other components of tobacco also seem to have pesticide effects).<ref name=modern_pesticide>{{cite web |title=Tobacco and its evil cousin nicotine are good as a pesticide – American Chemical Society |url=https://www.acs.org/content/acs/en/pressroom/presspacs/2010/acs-presspac-october-27-2010/tobacco-and-its-evil-cousin-nicotine-are-good-as-a-pesticide.html |website=American Chemical Society |access-date=29 October 2018 |language=en}}</ref> Nicotine pesticides have not been commercially available in the US since 2014,<ref name=epacancel2>{{cite journal|author=USEPA|title=Nicotine; Product Cancellation Order|journal=Federal Register|pages=26695–26696|url=https://federalregister.gov/a/E9-12561|date=3 June 2009|access-date=8 April 2012}}</ref> homemade pesticides are banned on organic crops,<ref name=prohibited_dust>US Code of Federal Regulations. [https://www.law.cornell.edu/cfr/text/7/205.602 7 CFR 205.602 – Nonsynthetic substances prohibited for use in organic crop production]</ref> and caution is recommended for small gardeners.<ref name="homemade_pesticide">{{cite web | vauthors = Tharp C |title=Safety for Homemade Remedies for Pest Control |url=http://www.pesticides.montana.edu/documents/mt-pesticide-bulletins/2009_05_MPB.pdf |website=Montana Pesticide Bulletin |publisher=Montana State University |access-date=21 September 2020 |date=5 September 2014|archive-url=https://web.archive.org/web/20140905021334/http://www.pesticides.montana.edu/news/Bulletins/MT%20Pest%20Bulletin-May.pdf |archive-date=5 September 2014 }}</ref> Nicotine pesticides have been banned in the EU since 2009.<ref name=pesticide_contam/> Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels.<ref name=pesticide_contam>{{cite journal | vauthors = Michalski B, Herrmann M, Solecki R | title = [How does a pesticide residue turn into a contaminant?] | language = de | journal = Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | volume = 60 | issue = 7 | pages = 768–773 | date = July 2017 | pmid = 28508955 | doi = 10.1007/s00103-017-2556-3| s2cid = 22662492 }}</ref><ref>{{cite journal |author=European Food Safety Authority|title=Potential risks for public health due to the presence of nicotine in wild mushrooms |journal=EFSA Journal |volume=7 |issue=5 |pages=286r |doi=10.2903/j.efsa.2009.286r |date=7 May 2009|doi-access=free }}</ref> [[Neonicotinoids]], such as [[imidacloprid]], which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016.<ref>{{cite journal | vauthors = Abreu-Villaça Y, Levin ED | title = Developmental neurotoxicity of succeeding generations of insecticides | journal = Environment International | volume = 99 | pages = 55–77 | date = February 2017 | pmid = 27908457 | pmc = 5285268 | doi = 10.1016/j.envint.2016.11.019 | bibcode = 2017EnInt..99...55A }}</ref><ref name=neonic_mechanisms/>

===Performance===

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/ws/files/140909555/Revisiting_nicotine_s_role_in_the_ageing_brain_and_cognitive_impairment.pdf }}</ref>

===Recreational===

Nicotine is used as a [[recreational drug]].<ref name=UbanHorton2018>{{cite journal | vauthors = Uban KA, Horton MK, Jacobus J, Heyser C, Thompson WK, Tapert SF, Madden PA, Sowell ER | title = Biospecimens and the ABCD study: Rationale, methods of collection, measurement and early data | journal = Developmental Cognitive Neuroscience | volume = 32 | pages = 97–106 | date = August 2018 | pmid = 29606560 | pmc = 6487488 | doi = 10.1016/j.dcn.2018.03.005 }}</ref> It is widely used, highly addictive and hard to discontinue.<ref name="Siqueira2016">{{cite journal | vauthors = Siqueira LM | title = Nicotine and Tobacco as Substances of Abuse in Children and Adolescents | journal = Pediatrics | volume = 139 | issue = 1 | pages = e20163436 | date = January 2017 | pmid = 27994114 | doi = 10.1542/peds.2016-3436 | doi-access = free }}</ref> Nicotine is often [[addiction|used compulsively]],<ref name=addictive>{{cite journal | vauthors = Stolerman IP, Jarvis MJ | title = The scientific case that nicotine is addictive | journal = Psychopharmacology | volume = 117 | issue = 1 | pages = 2–10; discussion 14–20 | date = January 1995 | pmid = 7724697 | doi = 10.1007/BF02245088 | s2cid = 8731555 }}</ref> and [[substance dependence|dependence]] can develop within days.<ref name=addictive/><ref name="Wilder2016">{{cite web|url=https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction-0|title=Nicotine without smoke: Tobacco harm reduction | vauthors = Wilder N, Daley C, Sugarman J, Partridge J |date=April 2016 |publisher=Royal College of Physicians |location=UK |pages=58, 125}}</ref><!--no access to fulltext of former, but cited by latter source and seems more reliable than same--> Recreational drug users commonly use nicotine for its mood-altering effects.<ref name=Parrott2015>{{cite journal | vauthors = Parrott AC | title = Why all stimulant drugs are damaging to recreational users: an empirical overview and psychobiological explanation | journal = Human Psychopharmacology | volume = 30 | issue = 4 | pages = 213–24 | date = July 2015 | pmid = 26216554 | doi = 10.1002/hup.2468 | s2cid = 7408200 }}</ref> Recreational nicotine products include [[chewing tobacco]], [[cigars]],<ref name=ElSayedSylvester2007/> [[cigarettes]],<ref name=ElSayedSylvester2007/> [[e-cigarettes]],<ref name=Rahman2014>{{cite journal | vauthors = Rahman MA, Hann N, Wilson A, Worrall-Carter L | title = Electronic cigarettes: patterns of use, health effects, use in smoking cessation and regulatory issues | journal = Tobacco Induced Diseases | volume = 12 | issue = 1 | page = 21 | year = 2014 | pmid = 25745382 | pmc = 4350653 | doi = 10.1186/1617-9625-12-21 | doi-access = free }}</ref> [[Snuff (tobacco)|snuff]], [[pipe smoking|pipe tobacco]],<ref name=ElSayedSylvester2007>{{cite journal | vauthors = El Sayed KA, Sylvester PW | title = Biocatalytic and semisynthetic studies of the anticancer tobacco cembranoids | journal = Expert Opinion on Investigational Drugs | volume = 16 | issue = 6 | pages = 877–87 | date = June 2007 | pmid = 17501699 | doi = 10.1517/13543784.16.6.877 | s2cid = 21302112 }}</ref> [[snus]], and [[nicotine pouch]]es.

[[Alcohol (drug)|Alcohol]] infused with nicotine is called [[nicotini]].<ref>{{cite web |title=2003: The 3rd Annual Year In Ideas; Nicotini, The |url=https://www.nytimes.com/2003/12/14/magazine/2003-the-3rd-annual-year-in-ideas-nicotini-the.html |website=www.nytimes.com |publisher=The New York Times Magazine |access-date=28 March 2024 |archive-url=https://web.archive.org/web/20150527232744/https://www.nytimes.com/2003/12/14/magazine/2003-the-3rd-annual-year-in-ideas-nicotini-the.html |archive-date=27 May 2015 |url-status=live }}</ref>

==Contraindications==

Nicotine use for tobacco cessation has few contraindications.<ref name="nrt_safety">{{cite journal | vauthors = Little MA, Ebbert JO | title = The safety of treatments for tobacco use disorder | journal = Expert Opinion on Drug Safety | volume = 15 | issue = 3 | pages = 333–41 | date = 2016 | pmid = 26715118 | doi = 10.1517/14740338.2016.1131817 | s2cid = 12064318 }}</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 |archive-url=https://ghostarchive.org/archive/20221009/https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/Electronic-Cigarettes-Infographic-508.pdf |archive-date=2022-10-09 |url-status=live|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 = 1 March 2010 | pmid = 20215949 | doi = 10.1097/NMC.0b013e3181cafba4 | s2cid = 27085986 }}</ref>

Randomized trials and observational studies of nicotine replacement therapy in cardiovascular patients show no increase in adverse cardiovascular events compared to those treated with placebo.<ref name="ACC Consensus">{{cite journal | vauthors = Barua RS, Rigotti NA, Benowitz NL, Cummings KM, Jazayeri MA, Morris PB, Ratchford EV, Sarna L, Stecker EC, Wiggins BS | title = 2018 ACC Expert Consensus Decision Pathway on Tobacco Cessation Treatment: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents | journal = Journal of the American College of Cardiology | volume = 72 | issue = 25 | pages = 3332–3365 | date = December 2018 | pmid = 30527452 | doi = 10.1016/j.jacc.2018.10.027 | doi-access = free }}</ref> Using nicotine products during cancer treatment may be contraindicated, as nicotine may promote 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 | page = 196 | date = 2015 | pmid = 26380225 | pmc = 4553893 | doi = 10.3389/fonc.2015.00196 | doi-access = free }}</ref>

[[Nicotine gum]] is contraindicated in individuals with [[temporomandibular joint disease]].<ref name="Nicotine AHFS monograph" /> People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays.<ref name="adolescents"/> Nicotine in any form is [[contraindicated]] in individuals with a known [[hypersensitivity]] to nicotine.<ref name="Nicotine AHFS monograph" /><ref name="adolescents"/>

==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]]-->}}</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 }}</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>

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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, "[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>

==Overdose==

{{Main|Nicotine poisoning}}

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 | bibcode = 2014ArTox..88....5M }}</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" /> The estimated lower dose limit for fatal outcomes is 500–1,000&nbsp;mg of ingested nicotine for an adult (6.5–13&nbsp;mg/kg).<ref name="RCP"/><ref name=MayerNewLethalDose2013/>

The initial symptoms of a nicotine overdose typically include [[nausea]], vomiting, diarrhea, [[hypersalivation]], abdominal pain, [[tachycardia]] (rapid heart rate), [[hypertension]] (high blood pressure), [[tachypnea]] (rapid breathing), headache, dizziness, [[pallor]] (pale skin), auditory or visual disturbances, and perspiration, followed shortly after by marked [[bradycardia]] (slow heart rate), [[bradypnea]] (slow breathing), and [[hypotension]] (low blood pressure).<ref name="TOXNET Nicotine entry" /> An increased respiratory rate (i.e., [[tachypnea]]) is one of the primary [[medical sign|signs]] of nicotine poisoning.<ref name="TOXNET Nicotine entry" /> At sufficiently high doses, [[somnolence]] (sleepiness or drowsiness), [[confusion]], [[syncope (medicine)|syncope]] (loss of consciousness from fainting), [[shortness of breath]], marked [[weakness]], [[seizure]]s, and [[coma]] may occur.<ref name="inchem" /><ref name="TOXNET Nicotine entry" /> Lethal nicotine poisoning rapidly produces seizures, and death&nbsp;– which may occur within minutes&nbsp;– is believed to be due to [[respiratory paralysis]].<ref name="TOXNET Nicotine entry" />

===Toxicity===

Today nicotine is less commonly used in agricultural [[insecticide]]s, which was a main source of poisoning. More recent cases of poisoning typically appear to be in the form of [[Green Tobacco Sickness]] (GTS),<ref name="TOXNET Nicotine entry" /> accidental ingestion of [[tobacco]] or [[tobacco products]], or ingestion of nicotine-containing plants.<ref name="Schep"/><ref name="Smolinske">{{cite journal | vauthors = Smolinske SC, Spoerke DG, Spiller SK, Wruk KM, Kulig K, Rumack BH | title = Cigarette and nicotine chewing gum toxicity in children | journal = Human Toxicology | volume = 7 | issue = 1 | pages = 27–31 | date = January 1988 | pmid = 3346035 | doi = 10.1177/096032718800700105 | s2cid = 27707333 }}</ref><ref name="Furer">{{cite journal | vauthors = Furer V, Hersch M, Silvetzki N, Breuer GS, Zevin S | title = Nicotiana glauca (tree tobacco) intoxication--two cases in one family | journal = Journal of Medical Toxicology | volume = 7 | issue = 1 | pages = 47–51 | date = March 2011 | pmid = 20652661 | pmc = 3614112 | doi = 10.1007/s13181-010-0102-x }}</ref> People who harvest or cultivate tobacco may experience GTS, a type of nicotine poisoning caused by dermal exposure to wet tobacco leaves. This occurs most commonly in young, inexperienced tobacco harvesters who do not consume tobacco.<ref name=Schep>{{cite journal | vauthors = Schep LJ, Slaughter RJ, Beasley DM | title = Nicotinic plant poisoning | journal = Clinical Toxicology | volume = 47 | issue = 8 | pages = 771–81 | date = September 2009 | pmid = 19778187 | doi = 10.1080/15563650903252186 | s2cid = 28312730 }}</ref><ref>{{cite journal | vauthors = Gehlbach SH, Williams WA, Perry LD, Woodall JS | title = Green-tobacco sickness. An illness of tobacco harvesters | journal = JAMA | volume = 229 | issue = 14 | pages = 1880–3 | date = September 1974 | pmid = 4479133 | doi = 10.1001/jama.1974.03230520022024 }}</ref> People can be exposed to nicotine in the workplace by breathing it in, skin absorption, swallowing it, or eye contact. The [[Occupational Safety and Health Administration]] (OSHA) has set the legal limit ([[permissible exposure limit]]) for nicotine exposure in the workplace as 0.5&nbsp;mg/m³ skin exposure over an 8-hour workday. The US [[National Institute for Occupational Safety and Health]] (NIOSH) has set a [[recommended exposure limit]] (REL) of 0.5&nbsp;mg/m³ skin exposure over an 8-hour workday. At environmental levels of 5&nbsp;mg/m³, nicotine is [[IDLH|immediately dangerous to life and health]].<ref>{{cite web|title=CDC – NIOSH Pocket Guide to Chemical Hazards – Nicotine|url =https://www.cdc.gov/niosh/npg/npgd0446.html|website=www.cdc.gov|access-date=20 November 2015}}</ref>

{{clear right}}

==Drug interactions==

===Pharmacodynamic===

* Potential interaction with [[sympathomimetic drug]]s ([[adrenergic agonist]]s) and [[sympatholytic drug]]s ([[alpha-blocker]]s and [[beta-blockers]]).<ref name="Nicotine AHFS monograph"/>

===Pharmacokinetic===

Nicotine and cigarette smoke both [[inducible gene|induce]] the [[Gene expression|expression]] of liver enzymes (e.g., certain [[cytochrome P450]] proteins) which metabolize drugs, leading to the potential for alterations in [[drug metabolism]].<ref name="Nicotine AHFS monograph" />

* ''Smoking cessation'' may decrease the metabolism of [[acetaminophen]], [[beta-blockers]], [[caffeine]], [[oxazepam]], [[pentazocine]], [[propoxyphene]], [[theophylline]], and [[tricyclic antidepressants]], leading to higher [[blood plasma|plasma]] concentrations of these drugs.<ref name="Nicotine AHFS monograph" />

* Possible alteration of nicotine [[drug absorption|absorption]] through the skin from the transdermal nicotine patch by drugs that cause [[vasodilation]] or [[vasoconstriction]].<ref name="Nicotine AHFS monograph" />

* Possible alteration of nicotine absorption through the nasal cavity from the nicotine nasal spray by nasal vasoconstrictors (e.g., [[xylometazoline]]).<ref name="Nicotine AHFS monograph" />

* Possible alteration of nicotine absorption through [[oral mucosa]] from nicotine gum and lozenges by food and drink that modify [[saliva]]ry [[pH]].<ref name="Nicotine AHFS monograph"/>

==Pharmacology==

Nicotine acts as a [[receptor agonist]] at most [[nicotinic acetylcholine receptor]]s (nAChRs),<ref name="IUPHAR"/><ref name=MalenkaNicotine>{{cite book|vauthors=Malenka RC, Nestler EJ, Hyman SE|veditors=Sydor A, Brown RY|title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience|year=2009|publisher=McGraw-Hill Medical|location=New York|isbn=978-0-07-148127-4|page=234|edition=2nd|chapter=Chapter 9: Autonomic Nervous System|quote=Nicotine&nbsp;... is a natural alkaloid of the tobacco plant. Lobeline is a natural alkaloid of Indian tobacco. Both drugs are agonists are nicotinic cholinergic receptors&nbsp;...}}</ref> except at two [[nicotinic receptor subunits]] ([[nAChRα9]] and [[nAChRα10]]) where it acts as a [[receptor antagonist]].<ref name=IUPHAR>{{cite web|title=Nicotinic acetylcholine receptors: Introduction|url=http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=76&familyType=IC|website=IUPHAR Database|publisher=International Union of Basic and Clinical Pharmacology|access-date=1 September 2014|archive-date=29 June 2017|archive-url=https://web.archive.org/web/20170629235725/http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=76&familyType=IC}}</ref> Such antagonism results in mild [[analgesic|analgesia]].

====Central nervous system====

By binding to [[nicotinic acetylcholine receptor]]s in the brain, nicotine elicits its psychoactive effects and increases the levels of several [[neurotransmitter]]s in various brain structures&nbsp;– acting as a sort of "volume control".<ref name=Pomerleau1984>{{cite journal | vauthors = Pomerleau OF, Pomerleau CS | title = Neuroregulators and the reinforcement of smoking: towards a biobehavioral explanation | journal = Neuroscience and Biobehavioral Reviews | volume = 8 | issue = 4 | pages = 503–13 | year = 1984 | pmid = 6151160 | doi = 10.1016/0149-7634(84)90007-1 | s2cid = 23847303 }}</ref><ref>{{cite journal | vauthors = Pomerleau OF, Rosecrans J | title = Neuroregulatory effects of nicotine | journal = Psychoneuroendocrinology | volume = 14 | issue = 6 | pages = 407–23 | year = 1989 | pmid = 2560221 | doi = 10.1016/0306-4530(89)90040-1 | hdl = 2027.42/28190 | s2cid = 12080532 | hdl-access = free }}</ref> Nicotine has a higher affinity for nicotinic receptors in the brain than those in [[skeletal muscle]], though at toxic doses it can induce contractions and respiratory paralysis.<ref>{{cite book | vauthors = Katzung BG |title=Basic and Clinical Pharmacology |publisher=McGraw-Hill Medical |location=New York |year=2006 |pages=99–105 }}</ref> Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.<ref name="pmid19252481">{{cite journal | vauthors = Xiu X, Puskar NL, Shanata JA, Lester HA, Dougherty DA | title = Nicotine binding to brain receptors requires a strong cation-pi interaction | journal = Nature | volume = 458 | issue = 7237 | pages = 534–7 | date = March 2009 | pmid = 19252481 | pmc = 2755585 | doi = 10.1038/nature07768 | bibcode = 2009Natur.458..534X }}</ref> Nicotine is unusual in comparison to most drugs, as its profile changes from [[stimulant]] to [[sedative]] with increasing [[dose (biochemistry)|dosages]], a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969.<ref>Nesbitt P <!-- note: not [[Paul Nesbitt]] -->(1969). Smoking, physiological arousal, and emotional response. Unpublished doctoral dissertation, Columbia University.</ref><ref name=Parrott1998>{{cite journal | vauthors = Parrott AC | title = Nesbitt's Paradox resolved? Stress and arousal modulation during cigarette smoking | journal = Addiction | volume = 93 | issue = 1 | pages = 27–39 | date = January 1998 | pmid = 9624709 | doi = 10.1046/j.1360-0443.1998.931274.x | citeseerx = 10.1.1.465.2496 }}</ref> At very high doses it dampens [[neuronal activity]].<ref name=Wadgave2016>{{cite journal | vauthors = Wadgave U, Nagesh L | title = Nicotine Replacement Therapy: An Overview | journal = International Journal of Health Sciences | volume = 10 | issue = 3 | pages = 425–35 | date = July 2016 | pmid = 27610066 | pmc = 5003586 | doi=10.12816/0048737}}</ref> Nicotine induces both behavioral stimulation and anxiety in animals.<ref name="inchem" /> Research into nicotine's most predominant metabolite, [[cotinine]], suggests that some of nicotine's psychoactive effects are mediated by cotinine.<ref>{{cite journal | vauthors = Grizzell JA, Echeverria V | title = New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine | journal = Neurochemical Research | volume = 40 | issue = 10 | pages = 2032–46 | date = October 2015 | pmid = 24970109 | doi = 10.1007/s11064-014-1359-2 | s2cid = 9393548 }}</ref>

Nicotine activates nicotinic receptors (particularly [[α4β2 nicotinic receptor]]s, but also [[Alpha5 Nicotinic Acetylcholine Receptor|α5 nAChRs]]) on neurons that innervate the [[ventral tegmental area]] and within the [[mesolimbic pathway]] where it appears to cause the release of [[dopamine]].<ref name="Nicotine reinforcement and euphoria">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |pages=369, 372–373 |edition=2nd }}</ref><ref name="Cholinergic-dopaminergic reward link" /> This nicotine-induced dopamine release occurs at least partially through activation of the [[cholinergic–dopaminergic reward link]] in the [[ventral tegmental area]].<ref name="Cholinergic-dopaminergic reward link">{{cite journal | vauthors = Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E | title = The role of the central ghrelin system in reward from food and chemical drugs | journal = Molecular and Cellular Endocrinology | volume = 340 | issue = 1 | pages = 80–7 | date = June 2011 | pmid = 21354264 | doi = 10.1016/j.mce.2011.02.017 | url = https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf | quote = This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. | hdl = 2077/26318 | s2cid = 206815322 | access-date = 23 September 2019 | archive-date = 4 August 2020 | archive-url = https://web.archive.org/web/20200804221721/https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf }}</ref><ref name="Picciotto2014">{{cite journal | vauthors = Picciotto MR, Mineur YS | title = Molecules and circuits involved in nicotine addiction: The many faces of smoking | journal = Neuropharmacology | volume = 76 | issue = Pt B | pages = 545–53 | date = January 2014 | pmid = 23632083 | pmc = 3772953 | doi = 10.1016/j.neuropharm.2013.04.028 | quote = Rat studies have shown that nicotine administration can decrease food intake and body weight, with greater effects in female animals (Grunberg et al., 1987). A similar nicotine regimen also decreases body weight and fat mass in mice as a result of β4* nAChR-mediated activation of POMC neurons and subsequent activation of MC4 receptors on second order neurons in the paraventricular nucleus of the hypothalamus (Mineur et al., 2011). | type = Review }}</ref> Nicotine can modulate the firing rate of the ventral tegmental area neurons.<ref name="Picciotto2014"/> These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of [[euphoria]];<ref name="Nicotine reinforcement and euphoria" /> however, mild euphoria from nicotine use can occur in some individuals.<ref name="Nicotine reinforcement and euphoria" /> Chronic nicotine use inhibits class I and II [[histone deacetylases]] in the [[striatum]], where this effect plays a role in nicotine addiction.<ref>{{cite journal | vauthors = Levine A, Huang Y, Drisaldi B, Griffin EA, Pollak DD, Xu S, Yin D, Schaffran C, Kandel DB, Kandel ER | title = Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine | journal = Science Translational Medicine | volume = 3 | issue = 107 | pages = 107ra109 | date = November 2011 | pmid = 22049069 | pmc = 4042673 | doi = 10.1126/scitranslmed.3003062 }}</ref><ref>{{cite journal | vauthors = Volkow ND | title = Epigenetics of nicotine: another nail in the coughing | journal = Science Translational Medicine | volume = 3 | issue = 107 | pages = 107ps43 | date = November 2011 | pmid = 22049068 | pmc = 3492949 | doi = 10.1126/scitranslmed.3003278 }}</ref>

====Sympathetic nervous system====

[[File:NicotineChromaffinCells WP1603.png|thumb|right|300px|Effect of nicotine on chromaffin cells]]

Nicotine also activates the [[sympathetic nervous system]],<ref>{{cite journal | vauthors = Yoshida T, Sakane N, Umekawa T, Kondo M | title = Effect of nicotine on sympathetic nervous system activity of mice subjected to immobilization stress | journal = Physiology & Behavior | volume = 55 | issue = 1 | pages = 53–7 | date = January 1994 | pmid = 8140174 | doi = 10.1016/0031-9384(94)90009-4 | s2cid = 37754794 }}</ref> acting via [[splanchnic nerves]] to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the [[bloodstream]].

====Adrenal medulla====

By binding to [[ganglion type nicotinic receptor]]s in the adrenal medulla, nicotine increases flow of [[adrenaline]] (epinephrine), a stimulating [[hormone]] and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of [[calcium]] through voltage-gated calcium channels. Calcium triggers the [[exocytosis]] of [[Chromaffin cell|chromaffin granules]] and thus the release of [[epinephrine]] (and norepinephrine) into the [[bloodstream]]. The release of [[epinephrine]] (adrenaline) causes an increase in [[heart rate]], [[blood pressure]] and [[breathing|respiration]], as well as higher [[blood glucose]] levels.<ref name="Marieb" >{{cite book | vauthors = Marieb EN, Hoehn K |title=Human Anatomy & Physiology (7th Ed.) | url = https://archive.org/details/humananatomyphys00mari_4 | url-access = registration |publisher=Pearson |pages=? |year=2007 |isbn=978-0-8053-5909-1}}{{page needed|date=December 2013}}</ref>

===Pharmacokinetics===

[[File:Nicotine metabolism.png|thumb|upright=1.5|600px|Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine<ref>{{cite book| vauthors = Henningfield JE, Calvento E, Pogun S |title=Nicotine Psychopharmacology |series=Handbook of Experimental Pharmacology |date=2009 |volume=192 |publisher=Springer|isbn=978-3-540-69248-5|pages=35, 37 |doi=10.1007/978-3-540-69248-5 }}</ref>]]

<!--Summarize this: "Nicotine undergoes first-pass metabolism in the liver, reducing the overall bioavailability of swallowed nicotine pills. A pill that could reliably produce high enough nicotine levels in the central nervous system would risk causing adverse gastrointestinal effects. To avoid this problem, nicotine replacement products are formulated for absorption through the oral or nasal mucosa (chewing gum, lozenges, sublingual tablets, inhalator, spray) or through the skin (transdermal patches)."<ref name="Cochrane NRT 2018" /> -->

As nicotine enters the body, it is distributed quickly through the [[blood]]stream and crosses the [[blood–brain barrier]] reaching the [[human brain|brain]] within 10–20 seconds after inhalation.<ref name="pmid12971663">{{cite journal | vauthors = Le Houezec J | title = Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review | journal = The International Journal of Tuberculosis and Lung Disease | volume = 7 | issue = 9 | pages = 811–9 | date = September 2003 | pmid = 12971663 }}</ref> The [[elimination half-life]] of nicotine in the body is around two hours.<ref>{{cite journal | vauthors = Kolli AR, Calvino-Martin F, Kuczaj AK, Wong ET, Titz B, Xiang Y, Lebrun S, Schlage WK, Vanscheeuwijck P, Hoeng J | title = Deconvolution of Systemic Pharmacokinetics Predicts Inhaled Aerosol Dosimetry of Nicotine | journal = European Journal of Pharmaceutical Sciences | volume = 180 | pages = 106321 | date = January 2023 | pmid = 36336278 | doi = 10.1016/j.ejps.2022.106321 | doi-access = free }}</ref><ref name="pmid7077531">{{cite journal | vauthors = Benowitz NL, Jacob P, Jones RT, Rosenberg J | title = Interindividual variability in the metabolism and cardiovascular effects of nicotine in man | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 221 | issue = 2 | pages = 368–72 | date = May 1982 | pmid = 7077531 }}</ref> Nicotine is primarily [[Excretion|excreted]] in [[urine]] and urinary concentrations vary depending upon [[urine flow rate]] and [[urine pH]].<ref name="inchem" />

The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine,<ref name="Russell_1980">{{cite journal | vauthors = Russell MA, Jarvis M, Iyer R, Feyerabend C | title = Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers | journal = British Medical Journal | volume = 280 | issue = 6219 | pages = 972–976 | date = April 1980 | pmid = 7417765 | pmc = 1601132 | doi = 10.1136/bmj.280.6219.972 }}</ref> suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".

Nicotine has a half-life of 1–2&nbsp;hours. [[Cotinine]] is an active metabolite of nicotine that remains in the blood with a half-life of 18–20&nbsp;hours, making it easier to analyze.<ref>{{cite journal| vauthors = Bhalala O |title=Detection of Cotinine in Blood Plasma by HPLC MS/MS |journal=MIT Undergraduate Research Journal |volume=8 |date=Spring 2003 |pages=45–50 |url=http://www.docstoc.com/docs/89426297/Detection-of-Cotinine-in-Blood-Plasma-by-HPLC-MS-MS |archive-url=https://web.archive.org/web/20131224105112/http://www.docstoc.com/docs/89426297/Detection-of-Cotinine-in-Blood-Plasma-by-HPLC-MS-MS |archive-date=24 December 2013 }}</ref>

Nicotine is [[metabolized]] in the [[liver]] by [[cytochrome P450]] enzymes (mostly [[CYP2A6]], and also by [[CYP2B6]]) and [[FMO3]], which selectively metabolizes (''S'')-nicotine. A major metabolite is [[cotinine]]. Other primary metabolites include nicotine ''N''-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.<ref name="pmid15734728">{{cite journal | vauthors = Hukkanen J, Jacob P, Benowitz NL | title = Metabolism and disposition kinetics of nicotine | journal = Pharmacological Reviews | volume = 57 | issue = 1 | pages = 79–115 | date = March 2005 | pmid = 15734728 | doi = 10.1124/pr.57.1.3 | s2cid = 14374018 }}</ref> Under some conditions, other substances may be formed such as [[myosmine]].<ref name="Petrick_2011">{{cite journal | vauthors = Petrick LM, Svidovsky A, Dubowski Y | title = Thirdhand smoke: heterogeneous oxidation of nicotine and secondary aerosol formation in the indoor environment | journal = Environmental Science & Technology | volume = 45 | issue = 1 | pages = 328–33 | date = January 2011 | pmid = 21141815 | doi = 10.1021/es102060v | bibcode = 2011EnST...45..328P | s2cid = 206939025 }}</ref><ref>{{cite news |title=''The danger of third-hand smoke: Plain language summary'' – Petrick et al., "Thirdhand smoke: heterogeneous oxidation of nicotine and secondary aerosol formation in the indoor environment" in ''Environmental Science & Technology'' |url=http://www.chromatographyonline.com/danger-third-hand-smoke |work=The Column |issue=3 |publisher=Chromatography Online |date=22 February 2011 |volume=7 |language=en}}</ref>

[[Glucuronidation]] and oxidative metabolism of nicotine to cotinine are both inhibited by [[menthol]], an additive to [[menthol cigarettes|mentholated cigarettes]], thus increasing the half-life of nicotine ''[[in vivo]]''.<ref>{{cite journal | vauthors = Benowitz NL, Herrera B, Jacob P | title = Mentholated cigarette smoking inhibits nicotine metabolism | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 3 | pages = 1208–15 | date = September 2004 | pmid = 15084646 | doi = 10.1124/jpet.104.066902 | s2cid = 16044557 }}</ref>

===Metabolism===

Nicotine decreases hunger and as a consequence food consumption, alongside increasing [[energy expenditure]].<ref>{{cite journal |title=Nicotine' actions on energy balance: Friend or foe? |journal=[[Pharmacology & Therapeutics]] |date=March 2021 |volume=219}}</ref><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 melanocortin-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/>

==Chemistry==

{{NFPA 704|Health=4|Flammability=1|Reactivity=0|caption=The fire diamond hazard sign for nicotine<ref>{{cite web|url=http://www.nmsu.edu/safety/programs/chem_safety/NFPA-ratingJ-R.htm|title=NFPA Hazard Rating Information for Common Chemicals |access-date=15 March 2015|archive-url=https://web.archive.org/web/20150217040510/http://www.nmsu.edu/safety/programs/chem_safety/NFPA-ratingJ-R.htm|archive-date=17 February 2015}}</ref>}}

Nicotine is a [[hygroscopy|hygroscopic]], colorless<ref name=":4" /> 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 Pa at 25&nbsp;°C)<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"/>

Nicotine is [[Chirality (chemistry)|chiral]] and hence [[optically active]], having two [[enantiomer]]ic forms. The naturally occurring form of nicotine is [[levorotatory]] with a [[specific rotation]] of [α]_D=–166.4° ((−)-nicotine). The [[dextrorotatory]] form, (+)-nicotine is physiologically less active than (−)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.<ref>{{cite book | vauthors = Gause GF |title=Optical Activity and Living Matter|chapter-url=https://archive.org/stream/opticalactivityl00gauz/opticalactivityl00gauz_djvu.txt| veditors = Luyet BJ |publisher=Biodynamica|location= Normandy, Missouri |year=1941|chapter=Chapter V: Analysis of various biological processes by the study of the differential action of optical isomers|volume=2|series= A series of monographs on general physiology}}</ref> The salts of (−)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids.<ref name="library.sciencemadness.org"/> The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180&nbsp;°C.<ref name="library.sciencemadness.org">{{cite book | vauthors = Henry TA | title = The Plant Alkaloids | publisher = The Blakiston Company | location = Philadelphia, Toronto | edition = 4th | year = 1949 | url = http://library.sciencemadness.org/library/books/the_plant_alkaloids.pdf |pages= 36–43 }}</ref> [[Anabasine]] is a [[structural isomer]] of nicotine, as both compounds have the [[molecular formula]] {{chem2|auto=1|C10H14N2}}.

Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer.<ref name="Enantiomeric composition of nicotin">{{cite journal | vauthors = Zhang H, Pang Y, Luo Y, Li X, Chen H, Han S, Jiang X, Zhu F, Hou H, Hu Q | title = Enantiomeric composition of nicotine in tobacco leaf, cigarette, smokeless tobacco, and e-liquid by normal phase high-performance liquid chromatography | journal = Chirality | volume = 30 | issue = 7 | pages = 923–931 | date = July 2018 | pmid = 29722457 | doi = 10.1002/chir.22866 }}</ref>  Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers.<ref>{{cite journal | vauthors = Hellinghausen G, Lee JT, Weatherly CA, Lopez DA, Armstrong DW | title = Evaluation of nicotine in tobacco-free-nicotine commercial products | journal = Drug Testing and Analysis | volume = 9 | issue = 6 | pages = 944–948 | date = June 2017 | pmid = 27943582 | doi = 10.1002/dta.2145 }}</ref> This suggests that tobacco-derived and synthetic nicotine can be determined by measuring the ratio of the two different enantiomers, although means exist for adjusting the relative levels of the enantiomers or performing a synthesis that only leads to the S-enantiomer. There is limited data on the relative physiological effects of these two enantiomers, especially in people. However, the studies to date indicate that (S)-nicotine is more potent than (R)-nicotine and (S)-nicotine causes stronger sensations or irritation than (R)-nicotine. Studies have not been adequate to determine the relative addictiveness of the two enantiomers in people. [[File:Nicotine benzoate.svg|thumb|Structure of protonated nicotine (left) and structure of the counterion benzoate (right). This combination is used in some vaping products to increase nicotine delivery to the lung.]]

[[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 | page = 30 | date = February 2019 | pmid = 30791645 | pmc = 6406299 | doi = 10.3390/children6020030| doi-access = free }}{{CC-notice|cc=by4|url=https://www.mdpi.com/2227-9067/6/2/30/htm|author(s)= Jenssen BP, Boykan R }}</ref>

===Preparation===

The first laboratory preparation of nicotine (as its [[racemate]]) was described in 1904.<ref name=Pictet>{{cite journal |title=Synthese des Nicotins |trans-title=Synthesis of nicotine |language=de |year=1904 | vauthors=Pictet A, Rotschy A |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=37 |issue=2 |pages=1225–1235 |doi=10.1002/cber.19040370206 |url=https://zenodo.org/record/1426104 }}</ref>

:[[File:Nicotine synthesis 1904.svg|650px]]

The starting material was an N-substituted [[pyrrole]] derivative, which was heated to convert it by a [[Sigmatropic reaction|[1,5] sigmatropic shift]] to the [[isomer]] with a carbon bond between the pyrrole and pyridine rings, followed by [[methylation]] and selective reduction of the pyrrole ring using tin and hydrochloric acid.<ref name=Pictet/><ref>{{cite journal |doi=10.1002/hlca.200490241 |title=A New Approach to Nicotine: Symmetry Consideration for Synthesis Design |year=2004 | vauthors = Ho TL, Kuzakov EV |journal=Helvetica Chimica Acta |volume=87 |issue=10 |pages=2712–2716 }}</ref> Many other syntheses of nicotine, in both racemic and chiral forms have since been published.<ref>{{cite journal |doi=10.1002/slct.202104425 |title=Research Progress in the Pharmacological Effects and Synthesis of Nicotine |year=2022 | vauthors = Ye X, Zhang Y, Song X, Liu Q |journal=ChemistrySelect |volume=7 |issue=12 |s2cid=247687372 }}</ref>

===Biosynthesis===

[[File:Nicotine biosynthesis june 2012.png|thumb|300px|Nicotine biosynthesis]]

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that comprise nicotine. Metabolic studies show that the [[pyridine]] ring of nicotine is derived from [[niacin]] (nicotinic acid) while the [[pyrrolidine]] is derived from ''N''-methyl-Δ¹-pyrrollidium cation.<ref>{{cite journal | vauthors = Lamberts BL, Dewey LJ, Byerrum RU | title = Ornithine as a precursor for the pyrrolidine ring of nicotine | journal = Biochimica et Biophysica Acta | volume = 33 | issue = 1 | pages = 22–6 | date = May 1959 | pmid = 13651178 | doi = 10.1016/0006-3002(59)90492-5 }}</ref><ref>{{cite journal |doi=10.1021/ja01495a059 |title=The Biosynthesis of Nicotine from Isotopically Labeled Nicotinic Acids |year=1960 |vauthors=Dawson RF, Christman DR, d'Adamo A, Solt ML, Wolf AP |journal=Journal of the American Chemical Society |volume=82 |issue=10 |pages=2628–2633}}</ref> Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for ''N''-methyl-Δ¹-pyrrollidium cation.

The NAD pathway in the genus ''[[Nicotiana]]'' begins with the oxidation of aspartic acid into α-amino 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 phosphoribosyl 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]].{{citation needed|date=May 2021}}

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|putrescine ''N''-methyltransferase]] (PMT). ''N''-methyl putrescine then undergoes [[deamination]] into 4-methylaminobutanal by the ''N''-methyl putrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into ''N''-methyl-Δ¹-pyrrollidium cation.{{citation needed|date=May 2021}}

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 | veditors = Ashihara H, Crozier A, Komamine A |title=Plant metabolism and biotechnology |date=7 June 2011 |publisher=Wiley |location=Cambridge |isbn=978-0-470-74703-2}}{{page needed|date=December 2013}}</ref>

===Detection in body fluids===

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| vauthors = Baselt RC |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 | doi-access = free }}</ref>

===Methods for analysis of enantiomers===

Methods for measuring the two enantiomers are straightforward and include normal-phase liquid chromatography,<ref name="Enantiomeric composition of nicotin"/> liquid chromatography with a chiral column.<ref>{{cite journal | vauthors = Hellinghausen G, Roy D, Wang Y, Lee JT, Lopez DA, Weatherly CA, Armstrong DW | title = A comprehensive methodology for the chiral separation of 40 tobacco alkaloids and their carcinogenic E/Z-(R,S)-tobacco-specific nitrosamine metabolites | journal = Talanta | volume = 181 | pages = 132–141 | date = May 2018 | pmid = 29426492 | doi = 10.1016/j.talanta.2017.12.060 }}</ref> However, since methods can be used to alter the two enantiomers, it may not be possible to distinguish tobacco-derived from synthetic nicotine simply by measuring the levels of the two enantiomers. A new approach uses hydrogen and deuterium nuclear magnetic resonance to distinguish tobacco-derived and synthetic nicotine based on differences the substrates used in the natural synthetic pathway performed in the tobacco plant and the substrates most used in synthesis.<ref>{{cite journal | vauthors = Liu B, Chen Y, Ma X, Hu K | title = Site-specific peak intensity ratio (SPIR) from 1D ²H/¹H NMR spectra for rapid distinction between natural and synthetic nicotine and detection of possible adulteration | journal = Analytical and Bioanalytical Chemistry | volume = 411 | issue = 24 | pages = 6427–6434 | date = September 2019 | pmid = 31321470 | doi = 10.1007/s00216-019-02023-6 | s2cid = 197593505 }}</ref> Another approach measures the carbon-14 content which also differs between natural and laboratory-based tobacco.<ref>{{cite journal | vauthors = Cheetham AG, Plunkett S, Campbell P, Hilldrup J, Coffa BG, Gilliland S, Eckard S | title = Analysis and differentiation of tobacco-derived and synthetic nicotine products: Addressing an urgent regulatory issue | journal = PLOS ONE | volume = 17 | issue = 4 | pages = e0267049 | date = 2022-04-14 | pmid = 35421170 | pmc = 9009602 | doi = 10.1371/journal.pone.0267049 | bibcode = 2022PLoSO..1767049C | veditors = Greenlief CM | doi-access = free }}</ref> These methods remain to be fully evaluated and validated using a wide range of samples.

==Natural occurrence==

Nicotine is a [[secondary metabolite]] produced in a variety of plants in the family [[Solanaceae]], 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>{{cite journal | vauthors = Baldwin IT | title = An ecologically motivated analysis of plant-herbivore interactions in native tobacco | journal = Plant Physiology | volume = 127 | issue = 4 | pages = 1449–1458 | date = December 2001 | pmid = 11743088 | pmc = 1540177 | doi = 10.1104/pp.010762 | jstor = 4280212 }}</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>{{cite journal | vauthors = Kessler D, Bhattacharya S, Diezel C, Rothe E, Gase K, Schöttner M, Baldwin IT | title = Unpredictability of nectar nicotine promotes outcrossing by hummingbirds in Nicotiana attenuata | journal = The Plant Journal | volume = 71 | issue = 4 | pages = 529–538 | date = August 2012 | pmid = 22448647 | doi = 10.1111/j.1365-313X.2012.05008.x }}</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 | page = 437 | date = August 1993 | pmid = 8326992 | doi = 10.1056/NEJM199308053290619 | doi-access = free }}</ref> as well as non-crop species such as ''[[Duboisia hopwoodii]]''.<ref name="metcalf">{{citation| vauthors = Metcalf RL |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 |date=April 2016 |volume=27 |issue=2 |pages=54–59 |doi=10.1515/cttr-2016-0008 |doi-access=free }}</ref> Pure nicotine tastes "terrible".<ref name=":4" />

==History, society and culture==

{{See also|History of tobacco}}

[[File:Joe dimaggio camel ad.jpg|thumb|[[Cigarette advertising|Cigarette ad]] featuring baseball player [[Joe DiMaggio]] in 1941]]

Nicotine was originally isolated from the tobacco plant in 1828 by chemists Wilhelm Heinrich Posselt and Karl Ludwig Reimann from [[Germany]], who believed it was a poison.<ref>{{cite journal | vauthors = Henningfield JE, Zeller M | title = Nicotine psychopharmacology research contributions to United States and global tobacco regulation: a look back and a look forward | journal = Psychopharmacology | volume = 184 | issue = 3–4 | pages = 286–91 | date = March 2006 | pmid = 16463054 | doi = 10.1007/s00213-006-0308-4 | s2cid = 38290573 }}</ref><ref>{{cite journal| vauthors = Posselt W, Reimann L |title=Chemische Untersuchung des Tabaks und Darstellung eines eigenthümlich wirksamen Prinzips dieser Pflanze|trans-title=Chemical investigation of tobacco and preparation of a characteristically active constituent of this plant|language=de|journal=Magazin für Pharmacie|volume=6|issue=24|pages=138–161|year=1828|url=https://books.google.com/books?id=cgkCAAAAYAAJ&pg=RA1-PA138}}</ref> Its chemical [[empirical formula]] was described by [[Louis Melsens|Melsens]] in 1843,<ref>{{cite journal | vauthors = Melsens LH | year = 1843 | url = https://books.google.com/books?id=j-E3AAAAMAAJ&pg=PA465 | title = Note sur la nicotine | trans-title = Note on nicotine | language = fr | journal = Annales de Chimie et de Physique | series = third series | volume = 9 | pages = 465–479; see especially page 470 }} [Note: The empirical formula that Melsens provides is incorrect because at that time, chemists used the wrong atomic mass for carbon (6 instead of 12).]</ref> its structure was discovered by [[Adolf Pinner]] and [[Richard Wolffenstein (chemist)|Richard Wolffenstein]] in 1893,<ref>{{cite journal |title=Ueber Nicotin |trans-title=About nicotine |language=de |year=1891 | vauthors=Pinner A, Wolffenstein R |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=24 |pages=1373–1377 |doi=10.1002/cber.189102401242 }}</ref><ref>{{cite journal |title=Ueber Nicotin. Die Constitution des Alkaloïds |trans-title=About nicotine: The Constitution of the Alkaloids |language=de |year=1893| vauthors = Pinner A |journal=Berichte der Deutschen Chemischen Gesellschaft|volume=26|pages=292–305|doi=10.1002/cber.18930260165|url=https://zenodo.org/record/1425696 }}</ref><ref>{{cite journal|title=Ueber Nicotin. I. Mitteilung|year=1893| vauthors = Pinner A | journal=Archiv der Pharmazie|volume=231|issue=5–6|pages=378–448|doi=10.1002/ardp.18932310508|s2cid=83703998|url=https://zenodo.org/record/1424557}}</ref>{{Clarify|reason=It's not clear that Wolffenstein should be attributed credit for identifying the structure of nicotine. Please see the talk page.|date=March 2013}} and it was first synthesized by [[Amé Pictet]] and A. Rotschy in 1904.<ref name=Pictet/><ref>{{cite magazine | vauthors = Zhang S |title=E-Cigs Are Going Tobacco-Free With Synthetic Nicotine |language=en-US |magazine=Wired |url=https://www.wired.com/2016/06/vaping-industry-wants-go-post-tobacco-synthetic-nicotine/ |access-date=2022-10-11 |issn=1059-1028}}</ref>

Nicotine is named after the tobacco plant ''[[Nicotiana tabacum]],'' which in turn is named after the [[France|French]] ambassador in [[Portugal]], [[Jean Nicot|Jean Nicot de Villemain]], who sent tobacco and seeds to [[Paris]] in 1560, presented to the French King,<ref name="Rang H. P 2007, page 598">{{cite book | vauthors = Dale MM, Ritter JM, Fowler RJ, Rang HP |title=Rang & Dale's Pharmacology |publisher=Churchill Livingstone |isbn=978-0-8089-2354-1 |edition=6th | page = 598 }}</ref> and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.<ref name="Rang H. P 2007, page 598"/>

[[Tobacco]] was introduced to [[Europe]] in 1559, and by the late 17th century, it was used not only for [[smoking]] but also as an [[insecticide]]. After [[World War II]], over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to [[mammal]]s.<ref name=Ujvary/>

The nicotine content of popular American-brand cigarettes has increased over time, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.<ref>{{cite journal | vauthors = Connolly GN, Alpert HR, Wayne GF, Koh H | title = Trends in nicotine yield in smoke and its relationship with design characteristics among popular US cigarette brands, 1997-2005 | journal = Tobacco Control | volume = 16 | issue = 5 | pages = e5 | date = October 2007 | pmid = 17897974 | pmc = 2598548 | doi = 10.1136/tc.2006.019695 }}</ref>

Although methods of production of synthetic nicotine have existed for decades,<ref>{{cite web |title=Industry Documents Library |url=https://www.industrydocuments.ucsf.edu/tobacco/docs/ |access-date=2022-10-11 |website=www.industrydocuments.ucsf.edu}}</ref> it was believed that the cost of making nicotine by laboratory synthesis was cost prohibitive compared to extracting nicotine from tobacco.<ref>{{cite news | vauthors = Jewett C |date=2022-03-08 |title=The Loophole That's Fueling a Return to Teenage Vaping |language=en-US |work=The New York Times |url=https://www.nytimes.com/2022/03/08/health/vaping-fda-nicotine.html |access-date=2022-10-11 |issn=0362-4331}}</ref> However, recently synthetic nicotine started to be found in different brands of e-cigarettes and oral pouches and marketed as "tobacco-free."<ref>{{cite news | vauthors = Jewett C |date=2022-03-08 |title=The Loophole That's Fueling a Return to Teenage Vaping |language=en-US |work=The New York Times |url=https://www.nytimes.com/2022/03/08/health/vaping-fda-nicotine.html |access-date=2022-10-11 |issn=0362-4331}}</ref>

The US FDA is tasked with reviewing tobacco products such as e-cigarettes and determining which can be authorized for sale. In response to the likelihood that FDA would not authorize many e-cigarettes to be marketed, e-cigarette companies began marketing products that they claimed to contain nicotine that were not made or derived from tobacco, but contained synthetic nicotine instead, and thus, would be outside FDA's tobacco regulatory authority.<ref>{{cite journal | vauthors = Jordt SE | title = Synthetic nicotine has arrived | journal = Tobacco Control | pages = tobaccocontrol–2021–056626 | date = September 2021 | volume = 32 | issue = e1 | pmid = 34493630 | pmc = 8898991 | doi = 10.1136/tobaccocontrol-2021-056626 }}</ref> Similarly, nicotine pouches that claimed to contain non-tobacco (synthetic) nicotine were also introduced. The cost of synthetic nicotine has decreased as the market for the product increased. In March 2022, the U.S. Congress passed a law (the [[Consolidated Appropriations Act, 2022]]) that expanded FDA's tobacco regulatory authority to include tobacco products containing nicotine from any source, thereby including products made with synthetic nicotine.

===Legal status===

{{Further|Smoking in the United Kingdom|Tobacco in the United States}}

In the United States, nicotine products and [[nicotine replacement therapy]] products like Nicotrol are only available to people 18 and above; proof of age is required; not for sale in vending machine or from any source where proof of age cannot be verified. As of 2019, the minimum age to purchase tobacco in the US is 21 at the federal level.<ref>{{cite journal | author =Center for Tobacco Products |date=2022-09-26 |title=Tobacco 21 |url=https://www.fda.gov/tobacco-products/retail-sales-tobacco-products/tobacco-21 |journal=FDA |language=en}}</ref>

In the European Union, the minimum age to purchase nicotine products is 18. However, there is no minimum age requirement to use tobacco or nicotine products.<ref>{{cite web |title=21, 18, or 14: A look at the legal age for smoking around the world |url=https://www.straitstimes.com/world/21-18-or-14-a-look-at-the-legal-age-for-smoking-around-the-world |website=Straits Times |access-date=1 March 2019|date=3 October 2017 }}</ref>

In the United Kingdom, the [[Tobacco and Related Products Regulations 2016]] implemented the European directive 2014/40/EU, amended by [[Tobacco Products and Nicotine Inhaling Products (Amendment etc.) (EU Exit) Regulations 2019]] and the [[Tobacco Products and Nicotine Inhaling Products (Amendment) (EU Exit) Regulations 2020]]. Additionally other regulations limit advertising, sale and display of tobacco products and other products containing nicotine for human consumption. The Sunak government has proposed banning disposable vapes, to limit the appeal, and affordability, for children.

===In media===

{{External media

| float = right

| width = 300px

| image1 = [http://www.comicvine.com/nick-oteen/29-67121/ An image showing Nick O'Teen fleeing from Superman], Comic Vine

}}

In some [[anti-smoking]] literature, the harm that tobacco smoking and nicotine addiction does is personified as [[Nick O'Teen]], represented as a humanoid with some aspect of a cigarette or cigarette butt about him or his clothes and hat.<ref name="HEC">{{cite journal | vauthors = Jacob M |title=Superman versus Nick O'Teen — a children's anti-smoking campaign |journal=Health Education Journal |date=1 March 1985 |volume=44 |issue=1 |pages=15–18 |doi=10.1177/001789698504400104|s2cid=71246970 }}</ref> Nick O'Teen was a villain that was created for the [[Health Education Council]]. The character was featured in three animated anti-smoking [[public service announcements]] in which he tries to get kids addicted to cigarettes before being foiled by the [[DC Comics]] character [[Superman]].<ref name="HEC" />

Nicotine was often compared to caffeine in advertisements in the 1980s by the tobacco industry, and later in the 2010s by the electronic cigarettes industry, in an effort to reduce the stigmatization and the public perception of the risks associated with nicotine use.<ref>{{cite web | vauthors = Becker R |title=Why Big Tobacco and Big Vape love comparing nicotine to caffeine |url=https://www.theverge.com/2019/4/26/18513312/vape-tobacco-big-companies-nicotine-caffeine-comparison-drugs-chemicals |website=The Verge |language=en |date=26 April 2019}}</ref>

==Research==

===Central nervous system===

While acute/initial nicotine intake causes activation of neuronal nicotine receptors, chronic low doses of nicotine use leads to desensitization of those receptors (due to the development of tolerance) and results in an antidepressant effect, with early research showing low dose nicotine patches could be an effective treatment of [[major depressive disorder]] in non-smokers.<ref name="pmid20965579">{{cite journal | vauthors = Mineur YS, Picciotto MR | title = Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis | journal = Trends in Pharmacological Sciences | volume = 31 | issue = 12 | pages = 580–6 | date = December 2010 | pmid = 20965579 | pmc = 2991594 | doi = 10.1016/j.tips.2010.09.004 }}</ref>

Though tobacco smoking is associated with an increased risk of [[Alzheimer's disease]],<ref name="pmid19105840">{{cite journal | vauthors = Peters R, Poulter R, Warner J, Beckett N, Burch L, Bulpitt C | title = Smoking, dementia and cognitive decline in the elderly, a systematic review | journal = BMC Geriatrics | volume = 8 | page = 36 | date = December 2008 | pmid = 19105840 | pmc = 2642819 | doi = 10.1186/1471-2318-8-36 | doi-access = free }}</ref> there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.<ref name=pmid19184661>{{cite book |vauthors=Henningfield JE, Zeller M |volume=192 |issue=192 |pages=511–34 |year=2009 |pmid=19184661 |doi=10.1007/978-3-540-69248-5_18 |isbn=978-3-540-69246-1 |series=Handbook of Experimental Pharmacology |title=Nicotine Psychopharmacology |chapter=Nicotine Psychopharmacology: Policy and Regulatory }}</ref>

Smoking is associated with a decreased risk of Parkinson's disease; however, it is unknown whether this is due to people with healthier brain dopaminergic reward centers (the area of the brain affected by Parkinson's) being more likely to enjoy smoking and thus pick up the habit, nicotine directly acting as a neuroprotective agent, or other compounds in cigarette smoke acting as neuroprotective agents.<ref>{{cite journal | vauthors = Quik M, O'Leary K, Tanner CM | title = Nicotine and Parkinson's disease: implications for therapy | journal = Movement Disorders | volume = 23 | issue = 12 | pages = 1641–52 | date = September 2008 | pmid = 18683238 | pmc = 4430096 | doi = 10.1002/mds.21900 }}</ref>

===Immune system===

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 | page = 1085 | date = 2017 | pmid = 28932225 | pmc = 5592202 | doi = 10.3389/fimmu.2017.01085 | doi-access = free }}</ref> Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of [[immune function]].<ref name=":0" />

===Optopharmacology===

A [[photoactivatable probes|photoactivatable]] form of nicotine, which releases nicotine when exposed to [[ultraviolet light]] with certain conditions, has been developed for studying nicotinic acetylcholine receptors in brain tissue.<ref name="pmid29578537">{{cite journal | vauthors = Banala S, Arvin MC, Bannon NM, Jin XT, Macklin JJ, Wang Y, Peng C, Zhao G, Marshall JJ, Gee KR, Wokosin DL, Kim VJ, McIntosh JM, Contractor A, Lester HA, Kozorovitskiy Y, Drenan RM, Lavis LD | title = Photoactivatable drugs for nicotinic optopharmacology | journal = Nature Methods | volume = 15 | issue = 5 | pages = 347–350 | date = May 2018 | pmid = 29578537 | pmc = 5923430 | doi = 10.1038/nmeth.4637 }}</ref>

===Oral health===

Several ''in vitro'' studies have investigated the potential effects of nicotine on a range of oral cells. A recent systematic review concluded that nicotine was unlikely to be cytotoxic to oral cells ''in vitro'' in most physiological conditions but further research is needed.<ref>{{cite journal | vauthors = Holliday RS, Campbell J, Preshaw PM | title = Effect of nicotine on human gingival, periodontal ligament and oral epithelial cells. A systematic review of the literature | journal = Journal of Dentistry | volume = 86 | pages = 81–88 | date = July 2019 | pmid = 31136818 | doi = 10.1016/j.jdent.2019.05.030 | s2cid = 169035502 }}</ref> Understanding the potential role of nicotine in oral health has become increasingly important given the recent introduction of novel nicotine products and their potential role in helping smokers quit.<ref>{{cite journal | vauthors = Holliday R, Preshaw PM, Ryan V, Sniehotta FF, McDonald S, Bauld L, McColl E | title = A feasibility study with embedded pilot randomised controlled trial and process evaluation of electronic cigarettes for smoking cessation in patients with periodontitis | journal = Pilot and Feasibility Studies | volume = 5 | issue = 1 | page = 74 | date = 2019-06-04 | pmid = 31171977 | pmc = 6547559 | doi = 10.1186/s40814-019-0451-4 | doi-access = free }}</ref>

==See also==

* [[6-Chloronicotine]]

* [[Nicotine marketing]]

==References==

{{Reflist}}

{{Commons category|Nicotine}}

{{EB1911 poster|Nicotine}}

* [http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+1107 Toxicology monograph for Nicotine] from the [[Hazardous Substances Data Bank]]

* [https://www.cdc.gov/niosh/npg/npgd0446.html Chemical Hazards monograph for Nicotine] from the [[National Institute for Occupational Safety and Health]]

* [https://pubchem.ncbi.nlm.nih.gov/compound/nicotine#datasheet=lcss&section=Top Laboratory Chemical Safety Summary for Nicotine] from [[PubChem]]

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