View source for Nicotine

{{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
| image_classR = bg-transparent
| 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 | date = 16 February 2019 | 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}}}}</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 | vauthors = McLaughlin I, Dani JA, De Biasi M | chapter = Nicotine Withdrawal | title = The Neuropharmacology of Nicotine Dependence | volume = 24 | pages = 99–123 | date = 2015 | pmid = 25638335 | pmc = 4542051 | doi = 10.1007/978-3-319-13482-6_4 | series = Current Topics in Behavioral Neurosciences | isbn = 978-3-319-13481-9 }}</ref> [[Psychological dependence|Psychological]]: High<ref name="DSouza_2011" /><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<ref>{{cite book | vauthors = Hollinger MA | title = Introduction to Pharmacology | location = Abingdon | pages = 222–223 | date = 19 October 2007 | edition = Third | url = https://books.google.com/books?id=qfrLBQAAQBAJ&pg=PA222 | publisher = CRC Press | isbn = 978-1-4200-4742-4 }}</ref>
| routes_of_administration = [[Inhalation]], [[Insufflation (medicine)|insufflation]], [[Oral administration|oral]], [[Buccal administration|buccal]], [[Sublingual administration|sublingual]], [[transdermal]], [[Rectal administration|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 | vauthors = Landoni JH | title = Nicotine (PIM) | url = http://www.inchem.org/documents/pims/chemical/nicotine.htm | 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
| image_class = skin-invert-image
| 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
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6M3C89ZY6R
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03365
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 3
| PDB_ligand = NCT
<!--Chemical data-->| C = 10
| H = 14
| N = 2
| chirality = [[Chiral]]
| smiles = c1ncccc1[C@@H]2CCCN2C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H14N2/c1-12-7-3-5-10(12)9-4-2-6-11-8-9/h2,4,6,8,10H,3,5,7H2,1H3/t10-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SNICXCGAKADSCV-JTQLQIEISA-N
| density = 1.01
| melting_point = -79
| boiling_point = 247
}}
{{tobacco}}
'''Nicotine''' is an [[alkaloid]] found primarily in plants of the [[nightshade]] family, notably in [[tobacco]] and ''[[Duboisia hopwoodii]]''.<ref name="Fagerstrom_2014">{{cite journal | vauthors = Fagerström K | title = Nicotine: Pharmacology, Toxicity and Therapeutic use | journal = Journal of Smoking Cessation | volume = 9 | issue = 2 | pages = 53–59 | date = December 2014 | doi = 10.1017/jsc.2014.27 | doi-access = free }}</ref> In addition to extraction from tobacco, it is synthesized. Nicotine is used [[recreational drug use|recreationally]] for its [[stimulant]] and [[anxiolytic]] effects. In tobacco leaves, nicotine constitutes about 0.6–3.0% of the dry weight,<ref>{{cite book | vauthors = Hoffmann D, Hoffmann I | chapter = Chemistry and toxicology. | veditors = Shopland DR | date = 1998 | pages = 55–104 | isbn = 978-0-7881-7301-1 | title = Smoking and Tobacco Control Monograph No. 9 | publisher = U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute | chapter-url = https://cancercontrol.cancer.gov/sites/default/files/2020-06/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 | access-date = 19 December 2012 }}</ref> and smaller, trace quantities occur in other [[Solanaceae]] crops such as tomatoes, potatoes, and eggplants. In pure form, nicotine is a colorless to yellowish, oily liquid that readily penetrates biological membranes and acts as a potent [[neurotoxin]] in insects, where it serves as a [[Plant defense against herbivory|antiherbivore]] toxin. Historically, it was widely used as an [[insecticide]], and its structure provided the basis for synthetic [[neonicotinoid]] pesticides.<ref name="Ujvary_1999">{{cite book |vauthors=Ujváry I |veditors=Yamamoto I, Casida J | title = Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor | chapter = Nicotine and Other Insecticidal Alkaloids |publisher=Springer-Verlag |year=1999 |location=Tokyo |pages=29–69 | isbn = 978-4-431-67933-2 | doi = 10.1007/978-4-431-67933-2_2 }}</ref>

In humans, nicotine acts primarily as a [[stimulant]] by binding to and activating [[nicotinic acetylcholine receptor|nicotinic acetylcholine receptors]] (nAChRs) in the [[central nervous system]] and peripheral tissues. This results in the release of [[neurotransmitter]]s such as [[dopamine]], [[acetylcholine]], and [[norepinephrine]], producing effects including increased alertness, reduced anxiety, and mild euphoria.<ref name="Sajja_2016">{{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> Nicotine is typically consumed through [[tobacco smoking]], [[vaping]], or other [[nicotine delivery system]]s. An average cigarette yields about 2 mg of absorbed nicotine, a dose sufficient to produce reinforcement and dependence while remaining far below toxic levels.<ref name="Mayer_2014" />

Nicotine is highly addictive, and [[nicotine dependence]] is characterized by [[Drug tolerance|tolerance]], [[physical dependence]], [[psychological dependence]], and [[nicotine withdrawal]] symptoms such as irritability, anxiety, and difficulty concentrating.<ref name="Perkins_2013">{{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 }}</ref> [[Nicotine replacement therapy]] (NRT) products, including gums, patches, and lozenges, deliver the compound in slower, lower doses that are less addictive and are used medically to help people quit smoking.<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="Etter_2007">{{cite journal | vauthors = Etter JF | title = Addiction to the nicotine gum in never smokers | journal = [[BMC Public Health]] | volume = 7 | date = July 2007 | pmid = 17640334 | pmc = 1939993 | doi = 10.1186/1471-2458-7-159 | article-number = 159 | doi-access = free }}</ref> Synthetic derivatives of nicotine, such as [[varenicline]], act as partial agonists at nicotinic receptors and are also used as smoking cessation aids.<ref>{{cite journal | vauthors = Coe JW et al. | title = Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 10 | pages = 3474–3477 | date = May 2005 | pmid = 15887955 | doi = 10.1021/jm050069n }}</ref>

Although nicotine itself is not classified as a [[carcinogen]] by either the [[International Agency for Research on Cancer]] or the [[Surgeon General of the United States]],<ref name="NCCDPHP_2014" /> high doses can cause [[nicotine poisoning]] and respiratory paralysis. Chronic exposure may also affect the [[immune system|immune]], [[cardiovascular system|cardiovascular]], and [[central nervous system|nervous]] systems.<ref name="Effah_2022">{{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><ref name="Mahmoudzadeh_2023" /> Nicotine is also a known [[teratogen]], associated with adverse developmental effects during pregnancy,<ref name="Kohlmeier_2015">{{cite journal | vauthors = Kohlmeier KA | date = June 2015 | 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 | doi = 10.1017/S2040174414000531 | pmid = 25385318 | s2cid = 29298949 }}</ref> and may impair adolescent neurodevelopment, though the extent of this effect in humans remains debated.<ref name="2016 SGR">{{cite book | author = U.S. Department of Health and Human Services. | title = E-Cigarette Use Among Youth and Young Adults. A Report of the Surgeon General. | location = Atlanta, GA | publisher = U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic, Disease Prevention and Health Promotion, Office on Smoking and Health | date = 2016 | 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 }}</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. Nicotine itself is not a standalone cessation tool; its efficacy in smoking cessation relies on nicotine replacement therapy (NRT) delivery systems, which vary formulations (e.g., transdermal patches and lozenges for steady release versus oral gum, inhalers, and nasal sprays for acute relief) to control and modify how much nicotine is delivered and absorbed, and to mimic tobacco pharmacokinetics without harmful byproducts.<ref name="Cochrane NRT 2018" />

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="Theodoulou_2023">{{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 | date = June 2023 | pmid = 37335995 | pmc = 10278922 | doi = 10.1002/14651858.CD013308.pub2 | article-number = CD013308 }}</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="NCCDPHP_2014" />{{rp|112}} The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.<ref name="Parrott_2015" />

===Pesticide===
Nicotine has been used as an insecticide since at least 1690, in the form of tobacco extracts or as pure nicotine sulfate<ref name="Ujvary_1999" /><ref name="Tomizawa_2005">{{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 = 247–268 | date = 2005 | pmid = 15822177 | doi = 10.1146/annurev.pharmtox.45.120403.095930 }}</ref><ref>{{cite book | vauthors = Rodgman A, Perfetti TA | title = The chemical components of tobacco and tobacco smoke | year = 2009 | publisher = CRC Press | 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> It acts on the [[nicotinic acetylcholine receptor]], and gave the receptor its name. Nicotine is in [[Insecticide Resistance Action Committee#Table of modes of action and classes of insecticide|IRAC]] group 4B. Nicotine insecticides have been banned in the US since 2014,<ref name="USEPA_2009">{{cite journal | vauthors = USEPA | title = Nicotine; Product Cancellation Order | journal = Federal Register | pages = 26695–26696 | date = 3 June 2009 | url = https://federalregister.gov/a/E9-12561 | access-date = 8 April 2012 }}</ref> including use 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="Tharp_2014">{{cite web | vauthors = Tharp C | title = Safety for Homemade Remedies for Pest Control | date = 5 September 2014 | 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 | 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?] | journal = Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | volume = 60 | issue = 7 | pages = 768–773 | date = July 2017 | pmid = 28508955 | doi = 10.1007/s00103-017-2556-3 | language = de | s2cid = 22662492 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Authority EF | title = Potential risks for public health due to the presence of nicotine in wild mushrooms | journal = EFSA Journal | volume = 7 | issue = 5 | pages = 286r | date = 7 May 2009 | doi = 10.2903/j.efsa.2009.286r | 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="Tomizawa_2005" />

===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 | volume = 16 | issue = 4 | pages = 403–414 | date = May 2018 | pmid = 29110618 | pmc = 6018192 | doi = 10.2174/1570159X15666171103152136 | publisher = Bentham Science Publishers }}</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 = 453–469 | 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<sub>i</sub>=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<sub>i</sub>s 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===
{{See also|Tobacco smoking|Electronic cigarette|Nicotine pouch}}

Nicotine is used as a [[recreational drug]].<ref name="Uban_2018">{{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="Siqueira_2017">{{cite journal | vauthors = Siqueira LM | title = Nicotine and Tobacco as Substances of Abuse in Children and Adolescents | journal = Pediatrics | volume = 139 | issue = 1 | date = January 2017 | pmid = 27994114 | doi = 10.1542/peds.2016-3436 | article-number = e20163436 | doi-access = free }}</ref> Nicotine is often [[addiction|used compulsively]],<ref name="Stolerman_1995">{{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="Stolerman_1995" /><ref name="Wilder2016">{{cite web | vauthors = Wilder N, Daley C, Sugarman J, Partridge J | title = Nicotine without smoke: Tobacco harm reduction | location = UK | pages = 58, 125 | date = April 2016 | url = https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction-0 | publisher = Royal College of Physicians }}</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="Parrott_2015">{{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 = 213–224 | date = July 2015 | pmid = 26216554 | doi = 10.1002/hup.2468 | s2cid = 7408200 }}</ref> Recreational nicotine products include [[chewing tobacco]], [[cigars]],<ref name="El_Sayed_2007" /> [[cigarettes]],<ref name="El_Sayed_2007" /> [[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="El_Sayed_2007">{{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 = 877–887 | date = June 2007 | pmid = 17501699 | doi = 10.1517/13543784.16.6.877 | s2cid = 21302112 }}</ref> [[snus]], and [[nicotine pouch]]es.<ref>{{cite journal | vauthors = Travis N, Warner KE, Goniewicz ML, Oh H, Ranganathan R, Meza R, Hartmann-Boyce J, Levy DT | title = The Potential Impact of Oral Nicotine Pouches on Public Health: A Scoping Review | journal = Nicotine & Tobacco Research | volume = 27 | issue = 4 | pages = 598–610 | date = March 2025 | pmid = 38880491 | pmc = 11931220 | doi = 10.1093/ntr/ntae131 }}</ref>

[[Alcohol (drug)|Alcohol]] infused with nicotine is called [[nicotini]].<ref>{{cite web | vauthors = Sella M | title = 2003: The 3rd Annual Year In Ideas; Nicotini, The | date = 14 December 2003 | 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="Little_2016">{{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 = 333–341 | 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="Aubin_2014">{{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 = 324–336 | date = February 2014 | pmid = 23488726 | pmc = 4014023 | doi = 10.1111/bcp.12116 }}</ref> It is therefore not recommended to adolescents.<ref name="Bailey_2012">{{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 | title = Electronic Cigarettes – What are the health effects of using e-cigarettes? | date = 22 February 2018 | 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 | publisher = Centers for Disease Control and Prevention | 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 = 364–374 | 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="Forest_2010">{{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="Sanner_2015">{{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">{{cite web | title = Nicotine | url = https://www.drugs.com/monograph/nicotine.html | access-date = 24 January 2019 | website = Drugs.com | publisher = American Society of Health-System Pharmacists }}</ref> People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays.<ref name="Bailey_2012" /> Nicotine in any form is [[contraindicated]] in individuals with a known [[hypersensitivity]] to nicotine.<ref name="Nicotine AHFS monograph" /><ref name="Bailey_2012" />

==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 | vauthors = Vij K | title = Textbook of Forensic Medicine & Toxicology: Principles & Practice | page = 525 | year = 2014 | edition = 5th | publisher = Elsevier Health Sciences | isbn = 978-81-312-3623-9 | 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="DoT_2024">{{cite book | chapter = Nicotine |date=2024 | title =Dictionary of Toxicology |page=691 |chapter-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]]-->|chapter-url-access=subscription }}</ref> The CDC says it is "toxic to developing fetuses and is a health danger for pregnant women." It can harm brain development up to age twenty-five, and early use of nicotine can predispose young people to smoking and drug use.<ref>{{Cite web | title = Health Effects of Vaping | date = 2025-01-31 | last = CDC | url = https://www.cdc.gov/tobacco/e-cigarettes/health-effects.html | access-date = 2025-09-17 | website = Smoking and Tobacco Use | language = en-us }}</ref> However, at doses typically used by consumers, it presents little if any hazard to adult users.<ref name="RCP_report">{{cite web | title = Nicotine Without Smoke -- Tobacco Harm Reduction | page = 125 | last1 = Royal College of Physicians | url = https://www.rcplondon.ac.uk/file/3563/download?token=Mu0K_ZR0 | access-date = 30 September 2020 | quote = Use of nicotine alone, in the doses used by smokers, represents little if any hazard to the user. | archive-date = 1 November 2020 | archive-url = https://web.archive.org/web/20201101131716/https://www.rcplondon.ac.uk/file/3563/download?token=Mu0K_ZR0 }}</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> Although at low amounts nicotine has a mild [[analgesic]] effect,<ref name="Schraufnagel_2015">{{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> at sufficiently high doses nicotine may result in nausea, vomiting, diarrhea, salivation, [[bradycardia]], and possibly seizures, [[hypoventilation]], and death.<ref name="England_2015">{{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>

===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="Jaehne_2009">{{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 | pmc = 4958544 | doi = 10.1016/j.tcm.2016.03.001 }}</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 | issue = 5 | date = May 2018 | pmid = 29852054 | pmc = 6353172 | doi = 10.1002/14651858.CD000146.pub5 | article-number = CD000146 | 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="Nestler_2001">{{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 = 11042–11046 | 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="Nestler_2012">{{cite journal | vauthors = Nestler EJ | title = Transcriptional mechanisms of drug addiction | journal = Clinical Psychopharmacology and Neuroscience | volume = 10 | issue = 3 | pages = 136–143 | date = December 2012 | pmid = 23430970 | pmc = 3569166 | doi = 10.9758/cpn.2012.10.3.136 | quote = The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives.&nbsp;... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure.&nbsp;... ΔFosB overexpression in nucleus accumbens induces NFκB }}</ref>
| header = ΔFosB accumulation from excessive drug use
| header_background = light-dark(aliceblue,var(--background-color-neutral))
| class = skin-invert-image
| image-bg-color = light-dark(white,transparent)
| annot-color = var(--color-base,#202122)  
| alt = ΔFosB accumulation graph
| image = ΔFosB accumulation.svg
| align = right
| icon = none
| image-width = 400
| image-left = 0
| image-top = 0
| width = 400
| height = 440
| annotations =
}}

Nicotine is highly [[addictive]] but paradoxically has quite weak reinforcing property compared to other drugs of abuse in various animals.<ref name="Grana_2014">{{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="Siqueira_2017" /><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="PHE_2018">{{cite web | title = Evidence Review of E-Cigarettes and Heated Tobacco Products | date = 2018 | work = Public Health England. | 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> Animal research suggests that [[monoamine oxidase inhibitors]], [[acetaldehyde]]<ref name="Belluzzi Wang Leslie 2005"/><ref>{{cite web | title = Acetaldehyde | work = Rijksinstituut voor Volksgezondheid en Milieu (RIVM) | trans-work = National Institute for Public Health and the Environment | location = Netherlands | url = https://www.rivm.nl/en/tobacco/harmful-substances-in-tobacco-smoke/acetaldehyde }}</ref> and other constituents in tobacco smoke may enhance its addictiveness.<ref name="RCP">{{cite web | vauthors = ((Royal College of Physicians)) | title = Nicotine without smoke: Tobacco harm reduction | date = 28 April 2016 | work = RCP London | url = https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction | access-date = 16 September 2020 | archive-date = 7 August 2023 | archive-url = https://web.archive.org/web/20230807092505/https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction }}</ref><ref name="Smith_2016">{{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> [[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="DSouza_2011">{{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="Das_2017">{{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="Heishman_2010">{{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 = 453–469 | 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 = 486–496 | 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="Bruijnzeel_2012">{{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 = 1418–1441 | 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 = 428–437 | 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 | title = The Promise of Vaping and the Rise of Juul | date = May 7, 2018 | url = https://www.newyorker.com/magazine/2018/05/14/the-promise-of-vaping-and-the-rise-of-juul | access-date = June 29, 2024 | magazine = [[The New Yorker]] }}</ref> although it is unclear whether it functions as a [[tumor promoter]] {{as of|2012|lc=y}}.<ref>{{cite journal | vauthors = Cardinale A, Nastrucci C, Cesario A, Russo P | title = Nicotine: specific role in angiogenesis, proliferation and apoptosis | journal = Critical Reviews in Toxicology | volume = 42 | issue = 1 | pages = 68–89 | date = January 2012 | pmid = 22050423 | doi = 10.3109/10408444.2011.623150 | s2cid = 11372110 | type = Review }}</ref> A 2018 report by the US [[National Academies of Sciences, Engineering, and Medicine]] concludes, "{{wj}}[w]hile it is biologically plausible that nicotine can act as a tumor promoter, the existing body of evidence indicates this is unlikely to translate into increased risk of human cancer."<ref>{{cite book | 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 | chapter = Chapter 4: Nicotine | title = Public Health Consequences of E-Cigarettes | year = 2018 | isbn = 978-0-309-46834-3 | publisher = National Academies Press | 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 theoretically promote tumor growth and metastasis as evidenced from alterations. Nicotine induces several processes, some of them via nicotine's effects on immune function, that contribute to cancer progression in both smoking-related and non-smoking-related cancers, 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><ref name="Mahmoudzadeh_2023" /> 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 potentially 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="MereczSadowska_2020">{{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 | date = 2014 | pmid = 25343018 | pmc = 4198571 | doi = 10.1186/s40169-014-0035-0 | article-number = e35 | 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="Knezevich_2013">{{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 = 591–595 | date = February 2013 | pmid = 22923602 | pmc = 3611998 | doi = 10.1093/ntr/nts172 | type = Primary }}</ref> a known type 1 carcinogen,<ref name="IARC_2020">{{cite book | chapter = List of Classifications: N'-Nitrosonornicotine | title = IARC Monographs on the Identification of Carcinogenic Hazards to Humans | chapter-url = https://monographs.iarc.fr/list-of-classifications | access-date = 2020-07-22 | publisher = The International Agency for Research on Cancer (IARC); World Health Organization }}</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 | bibcode = 2012ToxL..208...23G }}</ref>

===Pregnancy and breastfeeding===
Nicotine has been shown to produce birth defects in some animal species, but not others;<ref name="TOXNET Nicotine entry">{{cite web |date=20 August 2009 |title=Nicotine |url=https://www.nlm.nih.gov/toxnet/index.html |work=United States National Library of Medicine&nbsp;– Toxicology Data Network |publisher=Hazardous Substances Data Bank}}</ref> 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="NCCDPHP_2014">{{cite book | vauthors = Lushniak BD, Samet JM, Pechacek TF, Norman LA, Taylor PA, ((National Center for Chronic Disease Prevention Health Promotion (US) Office on Smoking Health)) | title = The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General | chapter = Chapter 5 - Nicotine | pages = 107–138 | year = 2014 | pmid = 24455788 | chapter-url = https://stacks.cdc.gov/view/cdc/21569/Share | archive-url = http://web.archive.org/web/20250717043527/https://stacks.cdc.gov/view/cdc/21569/Share | archive-date = 17 July 2025 | publisher = [[Surgeon General of the United States]] }}</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 | pmc = 8194464 | doi = 10.1542/peds.2012-3931 | doi-access = free }}</ref> Nicotine crosses the [[placenta]] and is found in the breast milk of mothers who smoke as well as mothers who inhale [[passive smoke]].<ref name="Chapman2015">{{cite web | title = State Health Officer's Report on E-Cigarettes: A Community Health Threat | date = January 2015 | 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 | publisher = California Department of Public Health }}</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="Holbrook_2016">{{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 | date = 1 April 2013 | url = https://www.fda.gov/forconsumers/consumerupdates/ucm345087.htm | archive-url = https://web.archive.org/web/20130404003416/http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm345087.htm? | archive-date = 4 April 2013 | publisher = FDA }}</ref> The [[median lethal dose]] of nicotine in humans is unknown.<ref name="ECHA nicotine monograph">{{cite web | title = Nicotine | date = September 2015 | 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 }}</ref><ref name="Mayer_2014">{{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 LD<sub>50</sub> 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="NCCDPHP_2014" /> which, while common in children (in whom poisonous and lethal levels occur at lower doses per kilogram of body weight<ref name="Schraufnagel_2015" />) 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="Mayer_2014" />

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_2009" /><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 | bibcode = 1988HETox...7...27S | s2cid = 27707333 }}</ref><ref name="Furer_2011">{{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_2009">{{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/m<sup>3</sup> 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/m<sup>3</sup> skin exposure over an 8-hour workday. At environmental levels of 5&nbsp;mg/m<sup>3</sup>, 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==
===Pharmacodynamics===
Nicotine acts as a [[receptor agonist]] at most [[nicotinic acetylcholine receptor]]s (nAChRs),<ref name="IUPHAR" /><ref name="Malenka_2009">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | chapter = Chapter 9: Autonomic Nervous System | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | location = New York | year = 2009 | publisher = McGraw-Hill Medical | isbn = 978-0-07-148127-4 | page = 234 | edition = 2nd | 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="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><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]].

The stereochemistry of nicotine is crucial to its biological effects. Due to the chiral nature of its receptors in the body, the (S)-enantiomer is substantially more active. For this reason, nearly all pharmacological and toxicological data is based on studies of (S)-nicotine. (S)-Nicotine is 4–28 times more potent than (R)-nicotine in standard nicotinic receptor binding and functional assays and elicits stronger nasal irritation, stinging, and mucosal responses at lower detection thresholds—yet smokers rated it as more pleasant in the only human sensory study.<ref name=":1" /><ref name=":0">{{cite journal |vauthors=Salam S, El-Hajj Moussa F, El-Hage R, El-Hellani A, Aoun Saliba N |date=March 2023 |title=A Systematic Review of Analytical Methods for the Separation of Nicotine Enantiomers and Evaluation of Nicotine Sources |journal=Chemical Research in Toxicology |volume=36 |issue=3 |pages=334–341 |doi=10.1021/acs.chemrestox.2c00310 |pmc=10031562 |pmid=36897818}}</ref> The pharmacological, metabolic, and toxicological effects of (R)-nicotine and of racemic (R)/(S)-nicotine mixtures in humans remain poorly understood, with data largely limited to animal studies.<ref name=":1" />

====Central nervous system====

===== Acute effects on CNS =====
[[File:NicotineDopaminergic WP1602.png|thumb|right|class=skin-invert-image|Effect of nicotine on dopaminergic neurons]]
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="Pomerleau_1984">{{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 | location = New York | pages = 99–105 | year = 2006 | publisher = McGraw-Hill Medical }}</ref> Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.<ref name="Xiu_2009">{{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="Parrott_1998">{{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="Wadgave_2016">{{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 | location = New York | pages = 369, 372–373 | year = 2009 | publisher = McGraw-Hill Medical | isbn = 978-0-07-148127-4 | 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="Picciotto_2014">{{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="Picciotto_2014" /> 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" /> 

===== Long-term effects on CNS =====
Chronic exposure to nicotine induces several molecular changes in neuronal systems, particularly within the [[Mesolimbic dopamine pathway|mesolimbic dopamine]] pathway and associated circuits. These adaptations include [[Downregulation and upregulation|desensitization]] and [[Downregulation and upregulation|upregulation]] of nAChRs and [[Downregulation and upregulation|downregulation]] of related enzymes (e.g. class I and II [[histone deacetylases]] in the [[striatum]]), alterations in transcription factors, and modifications to dopamine synthesis and release.<ref>{{cite journal | vauthors = Cadet JL | title = Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications | journal = Molecular Neurobiology | volume = 53 | issue = 1 | pages = 545–560 | date = January 2016 | pmid = 25502297 | pmc = 4703633 | doi = 10.1007/s12035-014-9040-y }}</ref><ref>{{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 = 545–553 | date = January 2014 | pmid = 23632083 | pmc = 3772953 | doi = 10.1016/j.neuropharm.2013.04.028 }}</ref>

Nicotine binds to presynaptic and postsynaptic [[Nicotinic acetylcholine receptor|nAChRs]], leading to initial activation followed by desensitization—a conformational shift rendering receptors temporarily unresponsive.<ref>{{cite journal | vauthors = Buisson B, Bertrand D | title = Chronic exposure to nicotine upregulates the human (alpha)4((beta)2 nicotinic acetylcholine receptor function | journal = The Journal of Neuroscience | volume = 21 | issue = 6 | pages = 1819–1829 | date = March 2001 | pmid = 11245666 | pmc = 6762627 | doi = 10.1523/JNEUROSCI.21-06-01819.2001 }}</ref><ref>{{cite journal | vauthors = Wills L, Kenny PJ | title = Addiction-related neuroadaptations following chronic nicotine exposure | journal = Journal of Neurochemistry | volume = 157 | issue = 5 | pages = 1652–1673 | date = June 2021 | pmid = 33742685 | doi = 10.1111/jnc.15356 }}</ref> Chronic nicotine exposure promotes [[upregulation]] of [[Nicotinic acetylcholine receptor|nAChRs]] in brain regions like the [[ventral tegmental area]] and [[striatum]], with increased receptor density observed within 1–7 days and peaking after 10–14 days in rodent models.<ref>{{cite journal | vauthors = Henderson BJ, Lester HA | title = Inside-out neuropharmacology of nicotinic drugs | journal = Neuropharmacology | volume = 96 | issue = Pt B | pages = 178–193 | date = September 2015 | pmid = 25660637 | pmc = 4486611 | doi = 10.1016/j.neuropharm.2015.01.022 | series = The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition }}</ref> Human imaging studies show this upregulation is temporary and returns to baseline levels in nonsmokers by approximately 21 days after smoking cessation but full recovery taking 6-12 weeks.<ref>{{cite journal | vauthors = Cosgrove KP, Batis J, Bois F, Maciejewski PK, Esterlis I, Kloczynski T, Stiklus S, Krishnan-Sarin S, O'Malley S, Perry E, Tamagnan G, Seibyl JP, Staley JK | title = beta2-Nicotinic acetylcholine receptor availability during acute and prolonged abstinence from tobacco smoking | journal = Archives of General Psychiatry | volume = 66 | issue = 6 | pages = 666–676 | date = June 2009 | pmid = 19487632 | pmc = 2796827 | doi = 10.1001/archgenpsychiatry.2009.41 }}</ref><ref>{{cite journal | vauthors = Jackson KJ, Muldoon PP, De Biasi M, Damaj MI | title = New mechanisms and perspectives in nicotine withdrawal | journal = Neuropharmacology | volume = 96 | issue = Pt B | pages = 223–234 | date = September 2015 | pmid = 25433149 | pmc = 4444410 | doi = 10.1016/j.neuropharm.2014.11.009 | series = The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition }}</ref>

Chronic nicotine use also leads to accumulation of the transcription factor ΔFosB in [[dopamine]] D1-type medium spiny neurons of the [[nucleus accumbens]], a process implicated in sustained [[reward pathway]] modifications.<ref>{{cite journal | vauthors = Robison AJ, Nestler EJ | title = ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression | journal = ACS Chemical Neuroscience | volume = 13 | issue = 3 | pages = 296–307 | date = February 2022 | pmid = 35020364 | pmc = 8879420 | doi = 10.1021/acschemneuro.1c00723 }}</ref> This elevation is longer-lasting and persists "for weeks and months even when substance use has ceased."<ref>{{cite journal | vauthors = Arjmand S, Ilaghi M, Shafie'ei M, Gobira PH, Grassi-Oliveira R, Wegener G | title = Exploring the potential link between ΔFosB and <i>N</i>-acetylcysteine in craving/relapse dynamics: can <i>N</i>-acetylcysteine stand out as a possible treatment candidate? | journal = Acta Neuropsychiatrica | volume = 37 | pages = e31 | date = October 2024 | pmid = 39415655 | doi = 10.1017/neu.2024.38 }}</ref>

Additionally, positron emission tomography (PET) studies indicate reduced presynaptic dopamine synthesis capacity in the striatum of chronic smokers, as measured by 18F-DOPA uptake. This deficit, approximately 15–20% lower than in nonsmokers, normalizes after about 3 months of abstinence.<ref name="Ashok_2019">{{cite journal | vauthors = Ashok AH, Mizuno Y, Howes OD | title = Tobacco smoking and dopaminergic function in humans: a meta-analysis of molecular imaging studies | journal = Psychopharmacology | volume = 236 | issue = 4 | pages = 1119–1129 | date = April 2019 | pmid = 30887059 | pmc = 6591186 | doi = 10.1007/s00213-019-05196-1 }}</ref><ref name="Rademacher_2016">{{cite journal | vauthors = Rademacher L, Prinz S, Winz O, Henkel K, Dietrich CA, Schmaljohann J, Mohammadkhani Shali S, Schabram I, Stoppe C, Cumming P, Hilgers RD, Kumakura Y, Coburn M, Mottaghy FM, Gründer G, Vernaleken I | title = Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers | journal = Biological Psychiatry | volume = 80 | issue = 3 | pages = 198–206 | date = August 2016 | pmid = 26803340 | doi = 10.1016/j.biopsych.2015.11.009 }}</ref>

A 2016 study found that nicotine exposure creates long-lasting malleable circuits 7 months after the initial exposure to nicotine and 6 months after stopping its administration.<ref name="Morud_2016">{{cite journal | vauthors = Morud J, Adermark L, Perez-Alcazar M, Ericson M, Söderpalm B | title = Nicotine produces chronic behavioral sensitization with changes in accumbal neurotransmission and increased sensitivity to re-exposure | journal = Addiction Biology | volume = 21 | issue = 2 | pages = 397–406 | date = March 2016 | pmid = 25581387 | doi = 10.1111/adb.12219 }}</ref> Other studies suggest broader neuronal recovery, such as normalization of dopamine transporter (DAT) levels in reward centers, may extend up to 12–14 months in some cases of substance dependence affecting dopamine levels, though specific data for nicotine are limited.<ref>{{cite journal | vauthors = Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J | title = Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence | journal = The Journal of Neuroscience | volume = 21 | issue = 23 | pages = 9414–9418 | date = December 2001 | pmid = 11717374 | doi = 10.1523/JNEUROSCI.21-23-09414.2001 | pmc = 6763886 }}</ref>

==== Sympathetic nervous system ====

[[File:NicotineChromaffinCells WP1603.png|thumb|right|300px|class=skin-invert-image|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]].{{citation needed|date=July 2025}}

====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_2007">{{cite book | vauthors = Marieb EN, Hoehn K | title = Human Anatomy & Physiology (7th Ed.) | pages = ? | year = 2007 | url = https://archive.org/details/humananatomyphys00mari_4 | url-access = registration | publisher = Pearson | isbn = 978-0-8053-5909-1 }}{{page needed|date=December 2013}}</ref>

===Pharmacokinetics===
[[File:Nicotine metabolism.png|thumb|upright=1.5|600px|class=skin-invert-image|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 | volume = 192 | pages = 35, 37 | date = 2009 | doi = 10.1007/978-3-540-69248-5 | series = Handbook of Experimental Pharmacology | publisher = Springer | isbn = 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="Le_Houezec_2003">{{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 | date = January 2023 | pmid = 36336278 | doi = 10.1016/j.ejps.2022.106321 | article-number = 106321 | doi-access = free }}</ref><ref name="Benowitz_1982">{{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 | doi = 10.1016/S0022-3565(25)33068-5 }}</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".

[[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 due to longer half-life than that of nicotine itself.<ref>{{cite journal | vauthors = Bhalala O | title = Detection of Cotinine in Blood Plasma by HPLC MS/MS | journal = MIT Undergraduate Research Journal | volume = 8 | pages = 45–50 | date = Spring 2003 | 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="Hukkanen_2005">{{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 | volume = 7 | issue = 3 | date = 22 February 2011 | url = http://www.chromatographyonline.com/danger-third-hand-smoke | work = The Column | publisher = Chromatography Online | language = en | archive-date = 19 January 2019 | access-date = 18 January 2019 | archive-url = https://web.archive.org/web/20190119121328/http://www.chromatographyonline.com/danger-third-hand-smoke }}</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>

==== Influence of ionization state ====
Nicotine's absorption is modulated by its ionization state, governed by [[pH]] relative to [[pKa]] values (8.10 for pyrrolidine nitrogen, 3.41 for pyridine). At [[physiological pH]] (~7.4), it's mostly monoprotonated (cationic); above pH 8, it becomes unprotonated free-base, which is [[Lipophilicity|lipophilic]] and [[Volatility (chemistry)|volatile]]<ref name="Gholap_2020">{{cite journal | vauthors = Gholap VV, Kosmider L, Golshahi L, Halquist MS | title = Nicotine forms: why and how do they matter in nicotine delivery from electronic cigarettes? | journal = Expert Opinion on Drug Delivery | volume = 17 | issue = 12 | pages = 1727–1736 | date = December 2020 | pmid = 32842785 | pmc = 9361466 | doi = 10.1080/17425247.2020.1814736 }}</ref>. The distribution of nicotine among its free-base and protonated forms in aerosolised nicotine affects inhalability; it has been manipulated in tobacco smoke and now in electronic cigarettes by the use of acids to de-freebase nicotine and form '[[Nicotine salt|nicotine salts]]'<ref>{{cite journal | vauthors = Duell AK, Pankow JF, Peyton DH | title = Nicotine in tobacco product aerosols: 'It's déjà vu all over again' | journal = Tobacco Control | volume = 29 | issue = 6 | pages = 656–662 | date = November 2020 | pmid = 31848312 | pmc = 7591799 | doi = 10.1136/tobaccocontrol-2019-055275 }}</ref>. [[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="Jenssen_2019">{{cite journal |vauthors=Jenssen BP, Boykan R |date=February 2019 |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 |doi=10.3390/children6020030 |pmc=6406299 |pmid=30791645 |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>

Free-base nicotine enables rapid membrane diffusion and higher [[bioavailability]] in early tobacco/oral studies. Yet, recent e-cigarette research contradicts this: protonated salts (e.g., nicotine [[benzoate]], [[Lactic acid|lactate]], [[levulinate]] from acid addition) yield higher [[Cmax (pharmacology)|Cmax]] and faster onset than equivalent free-base<ref name="Gholap_2020" />. For example, 2% benzoate salt produced 3x higher Cmax in human puffing trials. Notably, Cmax of protonated [[Nicotine salt|nicotine salts]] appears independent of the composition and identity of the counter anions (e.g., benzoate, lactate, levulinate) forming the salts for higher administered nicotine [[Formulation|formulations]]<ref>{{cite journal | vauthors = Frosina J, McEwan M, Ebajemito J, Thissen J, Taluskie K, Baxter-Wright S, Hardie G | title = Assessing the impact of protonating acid combinations in e-cigarette liquids: a randomised, crossover study on nicotine pharmacokinetics | journal = Scientific Reports | volume = 13 | issue = 1 | date = June 2023 | pmid = 37386281 | pmc = 10310785 | doi = 10.1038/s41598-023-37539-6 | article-number = 10563 | bibcode = 2023NatSR..1310563F }}</ref>.

These effects stem from [[aerosol]] dynamics—salts form low-volatility submicron particles for deeper lung deposition and less exhalation loss, versus free-base's superficial deposition. Sensorily, free-base delivers a harsh throat hit, while salts allow smoother high-dose inhalation, boosting appeal and intake<ref name="Gholap_2020" />.

===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]] | volume = 219 | date = March 2021 }}</ref><ref name="Hu_2018">{{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="Hu_2018" /> 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="Picciotto_2014" /><ref name="Hu_2018" /> 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="Hu_2018" />

==Chemistry==
{{NFPA 704|Health=4|Flammability=1|Reactivity=0|caption=The fire diamond hazard sign for nicotine<ref>{{cite web | title = NFPA Hazard Rating Information for Common Chemicals | url = http://www.nmsu.edu/safety/programs/chem_safety/NFPA-ratingJ-R.htm | 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 very [[hygroscopy|hygroscopic]], colorless to pale yellow, oily liquid that gradually turns brown on exposure to air or light.<ref name="DoT_2024" /><ref name="O'Neil_2013">{{Cite book | veditors = O'Neil MJ | title = The Merck index: an encyclopedia of chemicals, drugs, and biologicals | location = Cambridge | pages = 1214 | date = 2013 | publisher = The Royal Society of Chemistry | isbn = 978-1-84973-670-1 | edition = 15th | language = en }}</ref><ref>{{cite report | vauthors = Panzacchi S, Belpoggi F, Bua L, Bucher JR, Cora MC, De Angelis L, Falcioni L, Gnudi F, Mandrioli D, Manservigi M, Manzoli I |title=Introduction |date=2024-10-01 |work=NIEHS Report on the Toxicity Studies of Nicotine Bitartrate Dihydrate (CASRN 6019-06-3) Administered in Drinking Water to Sprague Dawley Rats and Swiss Mice: NIEHS Report 11 [Internet] |url=https://www.ncbi.nlm.nih.gov/books/NBK608400/ |access-date=2025-10-28 |publisher=National Institute of Environmental Health Sciences |language=en | pmid = 39441944 }}</ref> It develops a characteristic pungent, fishy odor of pyridine and has an acrid burning taste.<ref name="O'Neil_2013" /> It is very soluble in [[Alcohol (chemistry)|alcohol]], [[chloroform]], [[ether]], light [[petroleum]], [[kerosene]], or [[Oil|oils]].<ref name="DoT_2024" /><ref name="O'Neil_2013" /> 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<sub>b1</sub>=1×10<sup>−6</sup>, K<sub>b2</sub>=1×10<sup>−11</sup>.<ref name="Metcalf_2007" /> 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 | title = L-Nicotine Material Safety Data Sheet | url = http://www.sciencelab.com/msds.php?msdsId=9926222 | work = Sciencelab.com, Inc. }}</ref> Nicotine is volatile ([[vapor pressure]] 5.5 Pa at 25&nbsp;°C)<ref name="Metcalf_2007" /> On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, [[nicotinic acid]] (niacin, a B3 vitamer), and [[methylamine]].<ref name="Henry_1949" />

[[Anabasine]] is a [[structural isomer]] of nicotine, as both compounds have the [[molecular formula]] {{chem2|auto=1|C10H14N2}}.

=== Stereochemistry ===
Nicotine has a [[Chirality|chiral]] center at the C2' position of the [[pyrrolidine]] ring, and therefore exists as two [[Enantiomer|enantiomers]]: (S)-nicotine and (R)-nicotine.<ref>{{cite journal | vauthors = Salam S, El-Hajj Moussa F, El-Hage R, El-Hellani A, Aoun Saliba N | title = A Systematic Review of Analytical Methods for the Separation of Nicotine Enantiomers and Evaluation of Nicotine Sources | journal = Chemical Research in Toxicology | volume = 36 | issue = 3 | pages = 334–341 | date = March 2023 | pmid = 36897818 | pmc = 10031562 | doi = 10.1021/acs.chemrestox.2c00310 }}</ref>

* (S)-Nicotine − this naturally occurring form of nicotine, found in tobacco plants at over 99% purity, is [[levorotatory]] with a [[specific rotation]] of [α]<sub>D</sub>(20°C)=–169.3°.<ref name="O'Neil_2013" /><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 |date=July 2018 |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 |doi=10.1002/chir.22866 |pmid=29722457}}</ref> 
* (R)-Nicotine − this is the [[dextrorotatory]] form that is physiologically less active and less toxic than (S)-nicotine.<ref name="Sinkevicius_2025" /><ref>{{cite book | vauthors = Gause GF | veditors = Luyet BJ | chapter = Chapter V: Analysis of various biological processes by the study of the differential action of optical isomers | title = Optical Activity and Living Matter | location = Normandy, Missouri | volume = 2 | year = 1941 | chapter-url = https://archive.org/stream/opticalactivityl00gauz/opticalactivityl00gauz_djvu.txt | publisher = Biodynamica | series = A series of monographs on general physiology }}</ref> 

The salts of (S)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids.<ref name="Henry_1949" /> The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180&nbsp;°C.<ref name="Henry_1949">{{cite book | vauthors = Henry TA | title = The Plant Alkaloids | location = Philadelphia, Toronto | pages = 36–43 | year = 1949 | publisher = The Blakiston Company | edition = 4th | url = http://library.sciencemadness.org/library/books/the_plant_alkaloids.pdf }}</ref> 

The most common chemistry synthetic methods for generating nicotine yield 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> Tobacco-derived nicotine (>99% (S)-enantiomer) is distinguishable from synthetic nicotine (typically racemic, 50:50 (S)/(R)) by enantiomeric ratio analysis, although strategies exist for adjusting the relative levels of the enantiomers or performing a synthesis that only leads to the pure S-enantiomer.<ref name="Enantiomeric composition of nicotin" /><ref name=":2" /> Synthetic stereospecific (S)-nicotine has become available on the market to consumers of electronic cigarette products.<ref name=":2">{{cite journal | vauthors = Jordt SE | title = Synthetic nicotine has arrived | journal = Tobacco Control | volume = 32 | issue = e1 | pages = e113–e117 | date = April 2023 | pmid = 34493630 | pmc = 8898991 | doi = 10.1136/tobaccocontrol-2021-056626 }}</ref><ref name=":1">{{Cite web |date=23 August 2023 |title=WHO study group on tobacco product regulation: report on the scientific basis of tobacco product regulation: ninth report of a WHO study group |url=https://www.who.int/publications/i/item/9789240079410 |access-date=2025-10-26 |website=www.who.int |language=en |format=PDF}}</ref> Nicotine enantiomers differ in their biological effects on animals.<ref name=":1" /><ref name=":0" /> 
[[File:Nicotine benzoate.svg|thumb|class=skin-invert-image|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.]]
=== Preparation ===

The first laboratory preparation of nicotine (as its [[racemate]]) was described in 1904.<ref name="Pictet_1904">{{cite journal | vauthors = Pictet A, Rotschy A | title = Synthese des Nicotins | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 37 | issue = 2 | pages = 1225–1235 | year = 1904 | doi = 10.1002/cber.19040370206 | trans-title = Synthesis of nicotine | language = de | url = https://zenodo.org/record/1426104 }}</ref>

[[File:Nicotine synthesis 1904.svg|650px|class=skin-invert-image]]

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_1904" /><ref>{{cite journal | vauthors = Ho TL, Kuzakov EV | title = A New Approach to Nicotine: Symmetry Consideration for Synthesis Design | journal = Helvetica Chimica Acta | volume = 87 | issue = 10 | pages = 2712–2716 | year = 2004 | doi = 10.1002/hlca.200490241 | bibcode = 2004HChAc..87.2712H }}</ref> Many other syntheses of nicotine, in both racemic and chiral forms have since been published.<ref>{{cite journal | vauthors = Ye X, Zhang Y, Song X, Liu Q | title = Research Progress in the Pharmacological Effects and Synthesis of Nicotine | journal = ChemistrySelect | volume = 7 | issue = 12 | year = 2022 | doi = 10.1002/slct.202104425 | article-number = e202104425 | s2cid = 247687372 }}</ref>

=== Biosynthesis ===

[[File:Nicotine biosynthesis june 2012.png |thumb|300px|class=skin-invert-image| 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 [[nicotinic acid]], while the [[pyrrolidine]] is derived from ''N''-methyl-Δ<sup>1</sup>-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 | vauthors = Dawson RF, Christman DR, d'Adamo A, Solt ML, Wolf AP | title = The Biosynthesis of Nicotine from Isotopically Labeled Nicotinic Acids | journal = Journal of the American Chemical Society | volume = 82 | issue = 10 | pages = 2628–2633 | year = 1960 | doi = 10.1021/ja01495a059 | bibcode = 1960JAChS..82.2628D }}</ref> Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for nicotinic acid and the tropane pathway for ''N''-methyl-Δ<sup>1</sup>-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 nicotinic acid mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce nicotinic acid via the conversion of [[nicotinamide]] by the enzyme [[nicotinamidase]].{{citation needed|date=May 2021}}

The ''N''-methyl-Δ<sup>1</sup>-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-Δ<sup>1</sup>-pyrrollidium cation.{{citation needed|date=May 2021}}

The final step in the synthesis of nicotine is the coupling between ''N''-methyl-Δ<sup>1</sup>-pyrrollidium cation and nicotinic acid. 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 nicotinic acid into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with ''N''-methyl-Δ<sup>1</sup>-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 | location = Cambridge | date = 7 June 2011 | publisher = Wiley | 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 | chapter = Nicotine Chemistry, Metabolism, Kinetics and Biomarkers | title = Nicotine Psychopharmacology | 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 }}</ref><ref>{{cite book | vauthors = Baselt RC | title = Disposition of Toxic Drugs and Chemicals in Man | pages = 1452–6 | year = 2014 | publisher = Biomedical Publications | isbn = 978-0-9626523-9-4 | edition = 10th }}</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 <sup>2</sup>H/<sup>1</sup>H 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 | veditors = Greenlief CM | title = Analysis and differentiation of tobacco-derived and synthetic nicotine products: Addressing an urgent regulatory issue | journal = PLOS ONE | volume = 17 | issue = 4 | date = 2022-04-14 | pmid = 35421170 | pmc = 9009602 | doi = 10.1371/journal.pone.0267049 | article-number = e0267049 | bibcode = 2022PLoSO..1767049C | doi-access = free }}</ref> These methods remain to be fully evaluated and validated using a wide range of samples.

=== Analogues and derivatives ===

[[Structural analog|Analogue]]s and [[chemical derivative|derivative]]s of nicotine are known.<ref name="Breining_2004">{{cite journal | vauthors = Breining SR | title = Recent developments in the synthesis of nicotinic acetylcholine receptor ligands | journal = Curr Top Med Chem | volume = 4 | issue = 6 | pages = 609–629 | date = 2004 | pmid = 14965298 | doi = 10.2174/1568026043451131 }}</ref><ref name="Vagg_2005">{{cite journal | vauthors = Vagg R, Chapman S | title = Nicotine analogues: a review of tobacco industry research interests | journal = Addiction | volume = 100 | issue = 5 | pages = 701–712 | date = May 2005 | pmid = 15847628 | doi = 10.1111/j.1360-0443.2005.01014.x }}</ref><ref name="Pogocki_2007">{{cite journal | vauthors = Pogocki D, Ruman T, Danilczuk M, Danilczuk M, Celuch M, Wałajtys-Rode E | title = Application of nicotine enantiomers, derivatives and analogues in therapy of neurodegenerative disorders | journal = Eur J Pharmacol | volume = 563 | issue = 1–3 | pages = 18–39 | date = June 2007 | pmid = 17376429 | doi = 10.1016/j.ejphar.2007.02.038 }}</ref><ref name="Panda_2021">{{cite journal | vauthors = Panda B, Albano G | title = Synthetic Methods for the Preparation of Conformationally Restricted Analogues of Nicotine | journal = Molecules | volume = 26 | issue = 24 | date = December 2021 | pmid = 34946630 | pmc = 8706964 | doi = 10.3390/molecules26247544 | page = 7544 | doi-access = free }}</ref><ref name="Effah_2025">{{cite journal | vauthors = Effah F, Sun Y, Lin K, Rahman I | title = A comparative toxicological evaluation of emerging nicotine analogs 6-methyl nicotine and nicotinamide: a scoping review | journal = Arch Toxicol | volume = 99 | issue = 4 | pages = 1333–1340 | date = February 2025 | pmid = 39937258 | doi = 10.1007/s00204-025-03960-1 | bibcode = 2025ArTox..99.1333E }}</ref> These compounds, often structurally similar and sharing affinity for nicotinic acetylcholine receptors, have applications in pharmacology (e.g., smoking cessation), pest control, and neuroscience research (e.g., multiple domain cognitive enhancement, neuroprotection).<ref>{{cite journal | vauthors = Hone AJ, McIntosh JM | title = Nicotinic acetylcholine receptors: Therapeutic targets for novel ligands to treat pain and inflammation | journal = Pharmacological Research | volume = 190 | date = April 2023 | pmid = 36868367 | pmc = 10691827 | doi = 10.1016/j.phrs.2023.106715 | article-number = 106715 }}</ref><ref>{{cite journal | vauthors = Terry AV, Callahan PM | title = Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery | journal = Nicotine & Tobacco Research | volume = 21 | issue = 3 | pages = 383–394 | date = February 2019 | pmid = 30137518 | pmc = 6379039 | doi = 10.1093/ntr/nty166 }}</ref>

==== Natural analogues ====
Natural analogues of nicotine, often found in plants or other biological sources, include [[anabasine]] (from [[Anabasis aphylla]]), [[anatabine]] (from [[tobacco]]), [[arecoline]] (from [[betel nut]]), [[cotinine]] (major metabolite of nicotine), [[cytisine]] (from [[Laburnum]] species), and [[epibatidine]] (from [[Poison dart frog|frog skin]]), among others.<ref name="Boido_2003">{{cite journal | vauthors = Boido CC, Tasso B, Boido V, Sparatore F | title = Cytisine derivatives as ligands for neuronal nicotine receptors and with various pharmacological activities | journal = Farmaco | volume = 58 | issue = 3 | pages = 265–277 | date = March 2003 | pmid = 12620422 | doi = 10.1016/S0014-827X(03)00017-X }}</ref><ref name="Breining_2004" />

==== Synthetic analogues ====
Synthetic analogues and derivatives, typically developed for research or therapeutic purposes, include [[altinicline]], [[6-Chloronicotine|6-chloronicotine]], [[dianicline]], [[levamisole]], [[RJR-2429]], [[TC-1698]], [[UB-165]], [[GTS-21]], and [[varenicline]], among others.<ref name="Boido_2003" /><ref name="Breining_2004" />

==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 | title = Tobacco (leaf tobacco) | url = http://www.tis-gdv.de/tis_e/ware/genuss/tabak/tabak.htm | work = Transportation Information Service | publisher = The German Insurance Association (GDV e.V.) | location = Berlin }}</ref> Nicotine is also present in other tobacco species, such as ''[[Nicotiana rustica]]'' (in amounts of 2–14%).<ref name="Metcalf_2007" /> 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 name="Kumar_2014">{{cite journal | vauthors = Kumar P, Pandit SS, Steppuhn A, Baldwin IT | title = Natural history-driven, plant-mediated RNAi-based study reveals CYP6B46's role in a nicotine-mediated antipredator herbivore defense | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 4 | pages = 1245–1252 | date = January 2014 | pmid = 24379363 | pmc = 3910579 | doi = 10.1073/pnas.1314848111 | bibcode = 2014PNAS..111.1245K | doi-access = free }}</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="Siegmund_1999" />) in other [[Solanaceae]]ous plants, including some crop species such as [[potato]]es, [[tomato]]es, [[eggplant]], and [[capsicum|peppers]],<ref name="Siegmund_1999" /><ref name="Domino_1993">{{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 | date = August 1993 | pmid = 8326992 | doi = 10.1056/NEJM199308053290619 | page = 437 | doi-access = free }}</ref> as well as non-crop species such as ''[[Duboisia hopwoodii]]''.<ref name="Metcalf_2007">{{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="Siegmund_1999" /> 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="Siegmund_1999" /> 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="Siegmund_1999" /> These numbers may be low due to insufficient food intake data.<ref name=Siegmund_1999>{{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 | bibcode = 1999JAFC...47.3113S }}</ref> The concentrations of nicotine in vegetables are difficult to measure accurately, since they are very low (parts per billion range).<ref name="Moldoveanu_2016">{{cite journal | vauthors = Moldoveanu SC, Scott WA, Lawson DM | title = Nicotine Analysis in Several Non-Tobacco Plant Materials | journal = Beiträge zur Tabakforschung International/Contributions to Tobacco Research | volume = 27 | issue = 2 | pages = 54–59 | date = April 2016 | doi = 10.1515/cttr-2016-0008 | doi-access = free }}</ref>  Pure nicotine tastes "terrible".<ref name="DoT_2024" />

==History==
{{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 | journal = Magazin für Pharmacie | volume = 6 | issue = 24 | pages = 138–161 | year = 1828 | trans-title = Chemical investigation of tobacco and preparation of a characteristically active constituent of this plant | language = de | 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 | title = Note sur la nicotine | journal = Annales de Chimie et de Physique | volume = 9 | pages = 465–479; see especially page 470 | year = 1843 | url = https://books.google.com/books?id=j-E3AAAAMAAJ&pg=PA465 | trans-title = Note on nicotine | language = fr | series = third series }} [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 | vauthors = Pinner A, Wolffenstein R | title = Ueber Nicotin | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 24 | pages = 1373–1377 | year = 1891 | doi = 10.1002/cber.189102401242 | trans-title = About nicotine | language = de }}</ref><ref>{{cite journal | vauthors = Pinner A | title = Ueber Nicotin. Die Constitution des Alkaloïds | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 26 | pages = 292–305 | year = 1893 | doi = 10.1002/cber.18930260165 | trans-title = About nicotine: The Constitution of the Alkaloids | language = de | url = https://zenodo.org/record/1425696 }}</ref><ref>{{cite journal | vauthors = Pinner A | title = Ueber Nicotin. I. Mitteilung | journal = Archiv der Pharmazie | volume = 231 | issue = 5–6 | pages = 378–448 | year = 1893 | 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_1904" /><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"/> However, the "holy herb", [[tobacco]], had first reached Europe by the early 1530s, brought by Spanish explorers.<ref>{{Cite book | vauthors = Monardes N | title = Primera y segunda y tercera partes de la Historia medicinal de las cosas que se traen de nuestras Indias occidentales | location = Seville | year = 1580 | url = http://archive.org/details/bub_gb_eAtm3cE1smAC | publisher = en casa de Fernando Diaz | others = National Central Library of Rome | language = es }}</ref>

Following its introduction, [[tobacco]] rapidly gained popularity in Europe for its stimulating effects, fueled by nicotine's addictive and pharmacological properties and tobacco's widespread embrace as a cure-all.<ref name="Goodman_2005" /> By the early 17th century, this allure fueled its mercilessly laborious cultivation as a cash crop in the [[Virginia colony|Virginia colonies]], where [[John Rolfe]]'s introduction in 1612 rescued [[Jamestown, Virginia|Jamestown]] from economic collapse and famine, transforming it into a prosperous export hub with over 20,000 pounds shipped by 1619 and laying the groundwork for transatlantic trade.<ref name="Goodman_2005">{{Cite book | vauthors = Goodman J | title = Tobacco in History: The Cultures of Dependence | location = New York | pages = 62-102, 127-140, 171 | year = 2005 | publisher = Taylor and Francis | isbn = 978-0-415-11669-5 | publication-date = 2005 | language = en }}</ref> From the 17th century onward, tobacco smoking became virtually central to European social, economic, and cultural history and beyond, entrenching itself in daily rituals, trade networks, and even international conflicts.<ref name="Goodman_2005" />

By the late 17th century, [[tobacco]] 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_1999" />

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 | date = October 2007 | pmid = 17897974 | pmc = 2598548 | doi = 10.1136/tc.2006.019695 | article-number = e5 }}</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 | title = The Loophole That's Fueling a Return to Teenage Vaping | date = 2022-03-08 | 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 | title = The Loophole That's Fueling a Return to Teenage Vaping | date = 2022-03-08 | 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>

== Society and culture ==

===Regulation===
{{Further|Smoking in the United Kingdom|Tobacco in the United States}}In the United States, the [[Food and Drug Administration]] (FDA) regulates nicotine as a tobacco product under the 2009 Family Smoking Prevention and Tobacco Control Act.<ref name=":3">{{Cite journal | author = Center for Tobacco Products |date=2024-09-26 |title=Family Smoking Prevention and Tobacco Control Act - An Overview |url=https://www.fda.gov/tobacco-products/rules-regulations-and-guidance-related-tobacco-products/family-smoking-prevention-and-tobacco-control-act-overview |journal=FDA |language=en}}</ref> The FDA is tasked with reviewing tobacco products such as e-cigarettes and determining which can be authorized for sale. 

In March 2022, the US 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.<ref name=":3" />

On January 17, 2025, the FDA proposed a strongly endorsed rule to reduce nicotine in cigarettes and certain combusted tobacco products to minimally or non-addictive levels, capping nicotine yield at 0.7 mg per gram of tobacco, approximately a 95% reduction from current commercial levels.<ref>{{Cite web |last=Commissioner |first=Office of the |date=2025-01-15 |title=FDA Proposes Significant Step Toward Reducing Nicotine to Minimally or Nonaddictive Level in Cigarettes and Certain Other Combusted Tobacco Products |url=https://www.fda.gov/news-events/press-announcements/fda-proposes-significant-step-toward-reducing-nicotine-minimally-or-nonaddictive-level-cigarettes |access-date=2025-11-08 |website=FDA |language=en}}</ref><ref>{{Cite web |title=AACR Expresses Support for FDA's Proposed Rule to Decrease Nicotine Content in Certain Combusted Tobacco Products |url=https://www.aacr.org/about-the-aacr/newsroom/news-releases/aacr-expresses-support-for-fdas-proposed-rule-to-decrease-nicotine-content-in-certain-combusted-tobacco-products/ |access-date=2025-11-08 |website=American Association for Cancer Research (AACR) |language=en}}</ref>

In the European Union, the Tobacco Products Directive (2014/40/EU) regulates the manufacture, presentation, and sale of tobacco and related products.<ref>{{Cite web |date=2024-12-03 |title=Product regulation - Public Health - European Commission |url=https://health.ec.europa.eu/tobacco/product-regulation_en |access-date=2025-11-08 |website=health.ec.europa.eu |language=en}}</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 proposed banning disposable vapes to limit their appeal and affordability for children and to reduce the amount of waste generated.

==== Age limits on purchase ====
In the United States, [[Over-the-counter drug|over-the-counter]] [[nicotine replacement therapy]] products are only available to people aged 18 and above, and it is not for sale in vending machines or from any source where proof of age cannot be verified. The minimum age to purchase tobacco products in the US is 21 at the federal level.<ref>{{Cite journal |last=Products |first=Center for Tobacco |date=2025-08-07 |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 in all member states except Latvia, where it is 20.<ref>{{Cite web |title=Smoking age limit to be raised to 20 as of 2025 |url=https://eng.lsm.lv/article/society/health/11.01.2024-smoking-age-limit-to-be-raised-to-20-as-of-2025.a538525/ |access-date=2025-11-10 |website=eng.lsm.lv |language=en}}</ref> 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 | date = 3 October 2017 | 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 }}</ref>

In the United Kingdom, the minimum age to purchase tobacco products is 18.<ref>{{Cite web |title=The Children and Young Persons (Sale of Tobacco etc.) Order 2007 |url=https://www.legislation.gov.uk/ukdsi/2007/9780110757384 |archive-url=http://web.archive.org/web/20230804174335/https://www.legislation.gov.uk/ukdsi/2007/9780110757384 |archive-date=2023-08-04 |access-date=2025-11-08 |website=www.legislation.gov.uk |language=en}}</ref>

===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
}}
The public's lack of understanding regarding nicotine's biological effects frequently results in inaccurate claims disseminated by the media and general public.<ref>{{cite journal | vauthors = Sinkevicius LV, Sakalauskaite S, Bukovskis M, Lõokene M, Valvere V, Gradauskiene B, Viigimaa M | title = Nicotine from a Different Angle: Biological Effects from a Psychoneuroimmunological Perspective | journal = International Journal of Molecular Sciences | volume = 26 | issue = 13 | pages = 6437 | date = July 2025 | pmid = 40650213 | pmc = 12250386 | doi = 10.3390/ijms26136437 | doi-access = free }}</ref>

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="Jacob_1985">{{cite journal | vauthors = Jacob M | title = Superman versus Nick O'Teen — a children's anti-smoking campaign | journal = Health Education Journal | volume = 44 | issue = 1 | pages = 15–18 | date = 1 March 1985 | 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="Jacob_1985" />

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 | date = 26 April 2019 | url = https://www.theverge.com/2019/4/26/18513312/vape-tobacco-big-companies-nicotine-caffeine-comparison-drugs-chemicals | website = The Verge | language = en }}</ref>

==Research==
===Central nervous system===
While acute/initial nicotine intake causes activation of neuronal nicotinic 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="Mineur_2010">{{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> Nicotine anti-depressant effects have been documented in murine research.<ref name="Xia_2019">{{cite journal |vauthors=Xia W, Veljkovic E, Koshibu K, Peitsch MC, Hoeng J |date=December 2019 |title=Neurobehavioral effects of selected tobacco constituents in rodents following subchronic administration |journal=European Journal of Pharmacology |volume=865 |doi=10.1016/j.ejphar.2019.172809 |pmid=31738931 |article-number=172809|doi-access=free }}</ref>

Though tobacco smoking is associated with an increased risk of [[Alzheimer's disease]],<ref name="Peters_2008">{{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 | date = December 2008 | pmid = 19105840 | pmc = 2642819 | doi = 10.1186/1471-2318-8-36 | article-number = 36 | doi-access = free }}</ref> there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.<ref name="Henningfield_2009">{{cite book | vauthors = Henningfield JE, Zeller M | chapter = Nicotine Psychopharmacology: Policy and Regulatory | title = Nicotine Psychopharmacology | 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 }}</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 [[Neuroprotection|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>

Nicotine may partly attenuate [[sensory gating]] and attentional deficits associated with [[schizophrenia]]. Short-term use of [[transdermal]] nicotine was found to improve subjects' reaction time and [[Vigilance (psychology)|alertness]] in given tasks. 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>

Nicotine dependence pathophysiology in heavy smokers suggests less efficient network architecture in the brain and disruptions in the topological organization of brain networks, with the altered brain network metrics correlated with the duration of cigarette use and the severity of nicotine dependence.<ref>{{cite journal | vauthors = Lin F, Wu G, Zhu L, Lei H | title = Altered brain functional networks in heavy smokers | journal = Addiction Biology | volume = 20 | issue = 4 | pages = 809–819 | date = July 2015 | pmid = 24962385 | doi = 10.1111/adb.12155 }}</ref>

Some long-term effects of nicotine may be irreversible because "it is entirely possible that doses of nicotine achieved in the brains of human smokers can damage or kill mHb [medial habenula] neurons that regulate nicotine avoidance behaviors", but more studies are needed to elucidate this underlying mechanism of nicotine-induced degeneration of the mHb-IPn circuit .<ref>{{cite journal | vauthors = Wills L, Kenny PJ | title = Addiction-related neuroadaptations following chronic nicotine exposure | journal = Journal of Neurochemistry | volume = 157 | issue = 5 | pages = 1652–1673 | date = June 2021 | pmid = 33742685 | doi = 10.1111/jnc.15356 }}</ref> 

===Immune system===
Immune cells of both the [[innate|innate immune system]] and [[adaptive immune system]]s frequently express the α<sub>2</sub>, α<sub>5</sub>, α<sub>6</sub>, α<sub>7</sub>, α<sub>9</sub>, and α<sub>10</sub> [[Nicotinic acetylcholine receptor#Subunits|subunits of nicotinic acetylcholine receptors]].<ref name="Fujii_2017">{{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 | date = 2017 | pmid = 28932225 | pmc = 5592202 | doi = 10.3389/fimmu.2017.01085 | article-number = 1085 | doi-access = free }}</ref> Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of [[immune function]].<ref name="Fujii_2017" />

Although some of its effects are pro-inflammatory (e.g., inducing [[Prostaglandin E2|prostaglandin E<sub>2</sub>]] production), nicotine effects are mostly anti-inflammatory.<ref name="Sinkevicius_2025">{{cite journal | vauthors = Sinkevicius LV, Sakalauskaite S, Bukovskis M, Lõokene M, Valvere V, Gradauskiene B, Viigimaa M | title = Nicotine from a Different Angle: Biological Effects from a Psychoneuroimmunological Perspective | journal = International Journal of Molecular Sciences | volume = 26 | issue = 13 | page = 6437 | date = July 2025 | pmid = 40650213 | pmc = 12250386 | doi = 10.3390/ijms26136437 | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=y}}</ref><ref>{{cite journal | vauthors = Takahashi HK, Iwagaki H, Hamano R, Yoshino T, Tanaka N, Nishibori M | title = Effect of nicotine on IL-18-initiated immune response in human monocytes | journal = Journal of Leukocyte Biology | volume = 80 | issue = 6 | pages = 1388–1394 | date = December 2006 | pmid = 16966384 | doi = 10.1189/jlb.0406236 }}</ref> Nicotine suppresses the innate and adaptive immune response by reducing the secretion of pro-inflammatory cytokines ([[Interleukin-1 family|IL-1]], [[Interleukin 6|IL-6]], [[TNF-α]], [[IL-17 family|IL-17]], [[Interleukin 21|IL-21]], and [[Interleukin 22|IL-22]]), reducing proliferation and activation of [[T cell|T-cells]], and suppressing the activation of [[Dendritic cell|dendritic cells]].<ref name="Sinkevicius_2025" /> As a result, cell-mediated immunity against [[infection]] and [[Neoplastic disease|neoplastic diseases]] is downregulated.<ref name="Sinkevicius_2025" /> In vitro and animal studies also showed that nicotine reduces [[T-cell receptor|T cell receptor]] (TCR) signaling and suppresses the production and secretion of [[Antibody|antibodies]].<ref name="Sinkevicius_2025" />

Nicotine effects on immune system function can aggravate [[Tumor|tumors]] (growth and metastases) in cancer patients and is found to have many positive effects in the treating [[autoimmune disease]] (e.g. [[inflammatory bowel disease]]/[[ulcerative colitis]], [[arthritis]]), requiring further studies.<ref name="Zhang_2022">{{cite journal | vauthors = Zhang W, Lin H, Zou M, Yuan Q, Huang Z, Pan X, Zhang W | title = Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects | journal = Frontiers in Immunology | volume = 13 | date = 2022 | pmid = 35251010 | pmc = 8895249 | doi = 10.3389/fimmu.2022.826889 | article-number = 826889 | doi-access = free }}</ref><ref name="Mahmoudzadeh_2023">{{cite journal | vauthors = Mahmoudzadeh L, Abtahi Froushani SM, Ajami M, Mahmoudzadeh M | title = Effect of Nicotine on Immune System Function | journal = Advanced Pharmaceutical Bulletin | volume = 13 | issue = 1 | pages = 69–78 | date = January 2023 | pmid = 36721811 | pmc = 9871277 | doi = 10.34172/apb.2023.008 }}</ref>

===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="Banala_2018">{{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===
Many studies have shown the pro-inflammatory effect of nicotine on oral diseases.<ref name="Zhang_2022" /> Nicotine promotes and aggravates some diseases such as periodontitis and gingivitis, especially when there are harmful microorganisms in the oral cavity, however, the data are insufficient, especially ''in vivo''.<ref name="Zhang_2022" /> 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 | date = 2019-06-04 | pmid = 31171977 | pmc = 6547559 | doi = 10.1186/s40814-019-0451-4 | article-number = 74 | doi-access = free }}</ref>

==See also==
* [[6-Chloronicotine]]
* [[Nicotine marketing]]

==References==
{{Reflist}}

==External links==
{{Commons category|Nicotine}}
{{EB1911 poster|Nicotine}}
* [https://www.cdc.gov/niosh/npg/npgd0446.html Chemical Hazards monograph for Nicotine] from the [[National Institute for Occupational Safety and Health]]

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