User:QuackGuru/Sand 1

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green apple flavor

Flavors Enhance Nicotine Vapor Self-administration in Male Mice Cited by and Cited by reviews. wait for review

Some prior investigators have emphasized that even very low levels of second-hand smoke exposure (serum cotinine concentrations below 0.1 ng/mL) can cause adverse effects on cognitive outcomes among children and this could be also attributed to the higher lead concentrations found in children exposed to second-hand smoke compared to those unexposed.[1]

QuackGuru/Sand 1
Top: Concentrated nicotine liquid

Bottom left: Skeleton representation of a nicotine molecule

Bottom right: Ball-and-stick model of a nicotine molecule
Trade namesNicorette, Nicotrol
  • 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine
Clinical data
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Dependence riskPhysical: Low–moderate[4] Psychological: Moderate–High[5][6]
Addiction riskVery high[7]
  • AU: D
  • US: D (Evidence of risk)
Routes of
Inhalation; insufflation; oral – buccal, sublingual, and ingestion; transdermal; rectal
External links
Legal status
Protein binding<5%
MetabolismPrimarily hepatic: CYP2A6, CYP2B6, FMO3, others
Elimination half-life1–2 hours; 20 hours active metabolite
ExcretionRenal, urine pH-dependent;[8]
10–20% (gum), 30% (inhaled); 10–30% (intranasal)
CAS Number
  • 54-11-5 checkY
PubChem CID
PDB ligand
ATC code
Chemical and physical data
Molar mass162.236 g·mol−1
3D model (JSmol)
Density1.01 g/cm3
Melting point−79 °C (−110 °F)
Boiling point247 °C (477 °F)
  • c1ncccc1[C@@H]2CCCN2C
  • InChI=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 checkY


  1. Mourino, Nerea; Ruano-Raviña, Alberto; Varela Lema, Leonor; Fernández, Esteve; López, María José; Santiago-Pérez, María Isolina; Rey-Brandariz, Julia; Giraldo-Osorio, Alexandra; Pérez-Ríos, Mónica (5 May 2022). "Serum cotinine cut-points for secondhand smoke exposure assessment in children under 5 years: A systemic review". PLOS ONE. 17 (5): e0267319. doi:10.1371/journal.pone.0267319. PMC 9070924. PMID 35511766. This article incorporates text by Nerea Mourino, Alberto Ruano-Raviña, Leonor Varela Lema, Esteve Fernández, María José López, María Isolina Santiago-Pérez, Julia Rey-Brandariz, Alexandra Giraldo-Osorio, and Mónica Pérez-Ríos available under the CC BY 4.0 license.
  2. "The Medicines (Products Other Than Veterinary Drugs) (General Sale List) Amendment Order 2001". Retrieved 2 August 2022.
  3. Nicotine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. 16 February 2019. Retrieved 19 April 2024.
  4. McLaughlin I, Dani JA, De Biasi M (2015). "Nicotine Withdrawal". The Neuropharmacology of Nicotine Dependence. Current Topics in Behavioral Neurosciences. Vol. 24. pp. 99–123. doi:10.1007/978-3-319-13482-6_4. ISBN 978-3-319-13481-9. PMC 4542051. PMID 25638335.
  5. Cite error: Invalid <ref> tag; no text was provided for refs named Dependence-withdrawal
  6. Cosci F, Pistelli F, Lazzarini N, Carrozzi L (2011). "Nicotine dependence and psychological distress: outcomes and clinical implications in smoking cessation". Psychology Research and Behavior Management. 4: 119–28. doi:10.2147/prbm.s14243. PMC 3218785. PMID 22114542.
  7. Hollinger MA (19 October 2007). Introduction to Pharmacology (Third ed.). Abingdon: CRC Press. pp. 222–223. ISBN 978-1-4200-4742-4.
  8. Landoni JH. "Nicotine (PIM)". INCHEM. International Programme on Chemical Safety. Retrieved 29 January 2019.

QuackGuru/Sand 1
Top: Skeleton representation of a nicotine molecule Bottom : Ball-and-stick model of a nicotine molecule
Trade namesNicorette, Nicotrol
  • 3-(1-Methylpyrrolidin-2-yl)pyridine
Clinical data
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Dependence riskPhysical: Varies[3]
Psychological: Mild to severe and from short-lasting to continuous[4]
Addiction riskVery high[5]
  • AU: D
  • US: D (Evidence of risk)
Routes of
Inhalation; insufflation; oral – buccal, sublingual, and ingestion; transdermal; rectal
External links
Legal status
Protein binding<5%
MetabolismPrimarily hepatic: CYP2A6, CYP2B6, FMO3, others
Elimination half-life1–2 hours; 20 hours active metabolite
ExcretionRenal, urine pH-dependent;[6]
10–20% (gum), 30% (inhaled); 10–30% (intranasal)
CAS Number
  • 54-11-5 checkY
PubChem CID
PDB ligand
ATC code
Chemical and physical data
Molar mass162.236 g·mol−1
3D model (JSmol)
Density1.01 g/cm3
Melting point−79 °C (−110 °F)
Boiling point247 °C (477 °F)
  • c1ncccc1[C@@H]2CCCN2C
  • InChI=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 checkY

Nicotine is a stimulant and potent parasympathomimetic alkaloid that is produced in the nightshade family of plants.[7] It is the nicotine in tobacco that makes it popular.[8] The tobacco species Nicotiana tabacum is a major, non-food industrial crop that is extensively cultivated in several countries.[9] It is this species of tobacco that is mainly associated with consumer products.[8] Nicotine is one of the most widely used recreational drugs[10] and has a damaging impact on public health worldwide.[11] Prolonged drug abuse leads to reliance and consequently withdrawal symptoms upon discontinuing use.[12] Nicotine replacement products are used for smoking cessation to curtail the desire to smoke and to relieve withdrawal symptoms, thereby helping to maintain complete smoking abstinence.[13] Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs),[14] except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist.[15]

Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco.[16] Usually consistent concentrations of nicotine varying from 2–7 μg/kg (20–70 millionths of a percent wet weight) are found in edible plants in the family Solanaceae, such as potatoes, tomatoes, and eggplant.[17] Nicotine obtained from food is generally trivial unless exceedingly high amounts of certain vegetables are eaten.[17] It functions as an antiherbivore toxin; consequently, nicotine was widely used as an insecticide[18][19] and the Environmental Protection Agency banned its use in the US in 2014.[20] Neonicotinoids (structurally similar to nicotine[21]) such as imidacloprid are widely used, and have been associated with an array of issues to the environment.[22] Outdoor use of three neonicotinoid insecticides were banned in the European Union in 2018.[23]

Nicotine is highly addictive[24][25][26] and is one of the most difficult addictions to do away with.[27] An average cigarette yields about 2 mg of absorbed nicotine; high amounts can be more harmful.[28] Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence.[29] Nicotine dependence involves tolerance, sensitization,[30] physical dependence, psychological dependence,[31] and dependence can cause distress.[32][33] Nicotine withdrawal symptoms include depressed mood, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances.[34] Mild nicotine withdrawal symptoms are measurable in unrestricted smokers, who experience normal moods only as their blood nicotine levels peak, with each cigarette.[35] On quitting, withdrawal symptoms worsen sharply, then gradually improve to a normal state.[35]

Nicotine itself is associated with a variety of health harms.[36][37] This includes an elevated risk of cardiovascular, respiratory, and gastrointestinal disease.[36] Children, youth,[38] and young adults are especially sensitive to the effects of nicotine[39] and it can harm adolescent brain development.[40][41][42] It also damages other growing organs during this period.[43] Nicotine is potentially harmful to non-users.[44][45][46] The International Agency for Research on Cancer does not consider nicotine to be a carcinogen, though several studies demonstrate it is carcinogenic.[36] Nicotine causes birth defects in humans (e.g., alters typical progression of brain development[47]) and is considered a teratogen.[48] The median lethal dose of nicotine in humans is unknown.[49] At low amounts, it has a mild analgesic effect.[50] High doses are known to cause nicotine poisoning,[51] organ failure, and death through paralysis of respiratory muscles,[52] though serious or fatal overdoses are rare.[53]



A nicotine patch applied to the left arm. A Cochrane Collaboration finds that nicotine replacement products increases a quitter's chance of success by 50–60%, regardless of setting.[13]

The primary therapeutic use of nicotine is treating nicotine dependence to eliminate smoking and the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, inhalers, or nasal sprays to wean them off their dependence. A 2018 Cochrane Collaboration review found high-quality evidence that all current forms of nicotine replacement therapy (gum, patch, lozenges, inhaler, and nasal spray) increase the chances of successfully quitting smoking by 50–60%, regardless of setting.[13]

Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.[54] Studies indicate that opting for 4 mg of nicotine gum increases the chances of successfully quitting versus a 2 mg dosage.[54]

Nicotine is being researched in studies for possible benefit in treating Parkinson's disease, dementia, ADHD, depression, and sarcoma.[55] The available evidence suggests that nicotine (or nicotinic receptor drugs) have a potential for treating Parkinson's disease, although the detailed courses of treatment have not been established.[56] Studies in 2001 and 2007 found a benefit for administering transdermal nicotine to a limited number of elderly people with advanced dementia and considerable behavioral issues.[57] Under certain conditions, nicotine may improve symptoms of depression.[58] Two studies conducted in 1996 of adults with ADHD were administered a nicotine patch or a nicotine-free patch.[57] Although it is hard to interpret acute drug supervised studies, the results showed no improvement associated with irritability or aggression.[57] 7 mg of transdermal nicotine compared to placebo was administered over a week period to young adults with autism spectrum disorder and aggressive behavior in a 2018 study.[57] Although aggression continued in the nicotine group, there was a decrease in aggression.[57] The decrease in aggression was not statistically meaningful.[57] Nicotine can cause muscle sarcomas in A/J mice.[59] Long-term nicotine use in A/J mice causes leiomyosarcomas and rhabdomyosarcomas.[59] This suggests nicotine directly participates in initiating cancer.[59]

In contrast to recreational nicotine products, which have been designed to maximize the likelihood of addiction, nicotine replacement products are designed to minimize addictiveness.[51]: 112  The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.[32]


In nicotine-producing plants, nicotine functions as an antiherbivory chemical.[60] Nicotine has been used as an insecticide since at least the 1690s, in the form of tobacco extracts[61] (although other components of tobacco also seem to have pesticide effects).[62] The Environmental Protection Agency banned its use in the US in 2014.[20] Nicotine pesticides have not been commercially available in the US since 2014.[63] Homemade pesticides are banned on organic crops[64] and caution is recommended with using nicotine in a pesticide formulation for small gardeners.[65] Nicotine pesticides have been banned in the EU since 2009.[66] Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels.[66][67] Neonicotinoids, such as imidacloprid, which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016.[68][61] Neonicotinoids such as imidacloprid have been associated with an array of impacts to the environment.[22] Outdoor use of three neonicotinoid insecticides were banned in the European Union in 2018.[23]

Metal accumulation

The tobacco plant can accumulate potentially toxic elements from soil contaminated with heavy metals.[9] Certain potentially toxic elements such as arsenic, cadmium, and lead have been demonstrated to be potential dangers to end-users.[9]


Nicotine-containing products are sometimes used for the performance-enhancing effects of nicotine on cognition.[69] A 2010 meta-analysis of 41 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.[70] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;[71] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (ki=1 nM), which is also the biological target that mediates nicotine's addictive properties.[72] Nicotine has potential beneficial effects, but it also has paradoxical effects, which may be due to the inverted U-shape of the dose-response curve or pharmacokinetic features.[73]


Nicotine is used as a recreational drug.[74] It is widely used, highly addictive and hard to discontinue.[25] This commonly abused drug has a damaging impact on public health worldwide.[11] Nicotine is often used compulsively,[75] and dependence can develop within days.[75][76] Recreational drug users commonly use nicotine for its mood-altering effects.[32] Recreational nicotine products include chewing tobacco,[citation needed], cigars,[77] cigarettes,[77] e-cigarettes,[78] snuff,[citation needed] pipe tobacco,[77] nicotine pouches,[79] and snus.[citation needed] Alcohol infused with tobacco is called nicotini.[80] It may include undisclosed ingredients.[81]


Nicotine use for tobacco cessation has few contraindications.[82]

It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014.[83] It is therefore not recommended to adolescents.[84] 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.[85][86][87]

Precautions are needed when using NRT in people who have had a myocardial infarction within two weeks, a serious or worsening angina pectoris, and/or a serious underlying arrhythmia.[84] Using nicotine products during cancer treatment is contraindicated, as nicotine promotes tumor growth, but temporary use of NRTs to quit smoking may be advised for harm reduction.[88]

Nicotine gum is contraindicated in individuals with temporomandibular joint disease.[89] People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays.[84] Nicotine in any form is contraindicated in individuals with a known hypersensitivity to nicotine.[89][84]

Adverse effects

Although it is safer than inhaled tobacco smoke,[36] nicotine itself is associated with a variety of health harms.[36][37] Strong evidence shows that nicotine contributes to disease processes in the lungs, kidneys, heart, liver, and other organs.[90] Nicotine influences fibrosis in various bodily systems by modifying fibroblast activity.[90] Nicotine use substantially elevates catecholamine levels and other hormonal concentrations in the blood, which could lead to profound effects on several organ systems.[90] The maximum harm reduction attainable for smokers is to quit all nicotine use.[91] It is linked to serious morbidity and mortality globally[27] and also poses health risks to certain vulnerable groups such as pregnant women and fetuses, children, and adolescents.[92] Any significant favorable effect of nicotine on people has not been demonstrated.[36]

A 2018 Cochrane Collaboration review lists nine main adverse events related to nicotine replacement therapy: headache, dizziness/light-headedness, nausea/vomiting, gastro-intestinal symptoms, sleep/dream problems, non-ischemic palpitations and chest pain, skin reactions, oral/nasal reactions and hiccups.[93] Many of these were also common in the placebo group without nicotine.[93] Palpitations and chest pain were deemed "rare" and there was no evidence of an increased number of serious cardiac problems compared to the placebo group, even in people with established cardiac disease.[13] Nicotine replacement therapy is often used in smoking cessation, although there is little evidence on the safety and efficacy of their long-term use.[94]

The common side effects from nicotine exposure are listed in the table below. Serious adverse events due to the use of nicotine replacement therapy are extremely rare.[13] At low amounts, it has a mild analgesic effect.[50] At sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures and hypoventilation.[92]

Common side effects of nicotine use according to route of administration and dosage form
Route of administration Dosage form Associated side effects of nicotine Sources
Buccal Nicotine gum Indigestion, nausea, hiccups, traumatic injury to oral mucosa or teeth, irritation or tingling of the mouth and throat, oral mucosal ulceration, jaw-muscle ache, burping, gum sticking to teeth, unpleasant taste, dizziness, lightheadedness, headache, and insomnia. [13][89]
Lozenge Nausea, dyspepsia, flatulence, headache, upper respiratory tract infections, irritation (i.e., a burning sensation), hiccups, sore throat, coughing, dry lips, and oral mucosal ulceration. [13][89]
Transdermal Transdermal
Application site reactions (i.e., pruritus, burning, or erythema), diarrhea, dyspepsia, abdominal pain, dry mouth, nausea, dizziness, nervousness or restlessness, headache, vivid dreams or other sleep disturbances, and irritability. [13][89][95]
Intranasal Nasal spray Runny nose, nasopharyngeal and ocular irritation, watery eyes, sneezing, and coughing. [13][89][96]
Oral inhalation Inhaler Dyspepsia, oropharyngeal irritation (e.g., coughing, irritation of the mouth and throat), rhinitis, and headache. [13][89][97]
All (nonspecific) Peripheral vasoconstriction, tachycardia (i.e., fast heart rate), elevated blood pressure, increased alertness and cognitive performance. [89][96]


Nicotine reduces the amount of 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-dependent.[98] Acute nicotine intoxication has been found to significantly reduce total sleep time and increase REM latency, sleep onset latency, and non-rapid eye movement (NREM) stage 2 sleep time.[98][99] Depressive non-smokers experience mood and sleep improvements under nicotine administration; however, subsequent nicotine withdrawal has a negative effect on both mood and sleep.[100]

Cardiovascular system

Potential side effects of nicotine include increased clotting tendency, atherosclerosis, enlargement of the aorta, bronchospasm, muscular tremor and pain, gastrointestinal nausea, dry mouth, dyspepsia, diarrhea, heartburn, peptic ulcer, cancer, lightheadedness, headache, sleep disturbances, abnormal dreams, irritability, dizziness, blood restriction, increased or decreased heart rate, increased blood pressure, tachycardia, more (or less) arrhythmias, coronary artery constriction, coronary artery disease, high insulin, insulin resistance, and risks to child later in life during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.
Potential side effects of nicotine[101]

Some researchers, particularly those supporting tobacco harm reduction, hold the position that "most of the harm caused by tobacco use is derived from exposure to combustion products of tobacco".[102] Others disagree, "the relative contributions of nicotine versus non-nicotine components of TC [tobacco cigarette] smoke are unknown".[102] The effects of inhaled nicotine are difficult to isolate from the smoke constituents (oral nicotine delivery has been studied) and "understanding the role of nicotine in cardiopulmonary disease is extraordinarily difficult".[102]

Research has shown that nicotine activates the sympathetic nervous system, constricting coronary arteries, reducing coronary blood flow reserve, and causing transient increases in heart rate, blood pressure, and myocardial contractability.[102] The adverse events of nicotine can be attributed to its dose-dependent effects, with the toxic cardiovascular effects at higher doses.[94] Nicotine use is associated with unfavorable cardiac effects.[103] Because of this, the use of nicotine replacement products should be used cautiously.[103]

The known effects of nicotine on the cardiovascular system are numerous and complex.[104] In favor of a continuous effect on blood pressure is the awareness that muscle sympathetic stimulation is recurrently elevated in smokers, thought to be a result of nicotine.[105] Nicotine may help cause chronic hypertension to lead to accelerated or malignant hypertension by worsening vasoconstriction.[105] Heart rate and blood pressure becomes elevated irrespective of the type of nicotine product used.[105] Elevated heart rate causes a rise in cardiac output.[105] Nicotine can increase serum cholesterol levels,[106] lower coronary blood flow,[105] and constrict blood vessels.[107]

Nicotine is the key component of tobacco smoke causing an increased chance of the cardiovascular disease and cardiac arrest connected with smoking which is thought to be triggered by arrhythmias.[108] A 2018 Cochrane review found that, in rare cases, nicotine replacement therapy can cause non-ischemic chest pain (i.e., chest pain that is unrelated to a heart attack) and heart palpitations, but does not increase the incidence of serious cardiac adverse events (i.e., myocardial infarction, stroke, and cardiac death) relative to controls.[13]

Nicotine appears to increase oxidative stress and the inflammatory burden and accelerate atherosclerosis to increase the risk for cardiovascular disease.[109] However, it is unclear whether nicotine and cotinine affect vascular smooth muscle cell phenotypic switching to a proliferative, migratory phenotype and atherosclerosis development and vascular smooth muscle cell senescence, characteristic of a more advanced plaque.[109] The summation of these events is relevant in the context of atherosclerosis severity as they promote an unstable atherosclerotic cap prone to rupture.[109] A ruptured plaque may block an artery and lead to ischemia, restricted tissue blood flow, which impairs tissue oxygenation and pathological endpoints, such as a heart attack or stroke, by blocking arteries in the heart or brain.[109]

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 CVD are quite low. We have concerns that nicotine from e-cigarettes could pose some risk for users with CVD."[105] Twenty-five tobacco smokers were exposed to vaping with and without nicotine, and sham vaping (with the e-cigarette turned off) under specific vaping conditions (25 puffs with puff duration of 4 seconds every 30 seconds) in a 2018 randomized crossover trial.[110] No modifications of cardiovascular parameters or oxidative stress were observed with sham vaping and no-nicotine vaping.[110] Instead, vaping with nicotine resulted in the modification of cardiovascular parameters and increased plasma myeloperoxidase.[110] Thus, based on these results, it seems that e-cigarettes' effects on cardiovascular and oxidative stress are due to nicotine and not to high-temperature e-cigarette vehicle vaporization.[110]

Reinforcement disorders

ΔFosB accumulation from excessive drug use
ΔFosB accumulation graph
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).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.[111][112]

Nicotine is highly addictive[24][25][26] and is one of the most difficult addictions to do away with.[27] Nicotine replacement products provide lower amounts of nicotine at a slower speed and are generally less addictive than smoking.[113] US FDA-endorsed nicotine replacement products raise blood nicotine levels more slowly and at decreased amounts relative to traditional cigarettes.[114] As a result, these products exhibit a reduced likelihood of addiction.[114] Its addictiveness depends on the form[115] and in the manner in which it was used.[116]

The potential for nicotine addiction is greater in the brains of children and adolescents.[50] First-time nicotine users develop a dependence reportedly 32% of the time.[117] There may be other substances in cigarette smoke other than nicotine that may enhance its addictiveness.[115] While nicotine is clearly the primary reinforcer in tobacco and e-cigarettes, added flavors may also act as rewards and/or reinforcers in their own right.[118] A 2022 study demonstrated how vaping-related reinforcement behavior is elevated in male mice when self-administering menthol or green-apple flavored e-liquid compared to no flavor e-liquids.[119] Farnesol, a component of green apple flavor, has been shown to significantly increase nicotine-reward related behavior by altering baseline firing of GABA neurons and upregulating nAChR function, especially in male mice.[119]

Nicotine dependence involves aspects of both psychological dependence and physical dependence, since discontinuation of extended use has been shown to produce both affective (e.g., anxiety, irritability, craving, anhedonia) and somatic (mild motor dysfunctions such as tremor) withdrawal symptoms.[34] Psychological disorders can vary from being relatively low in intensity to severe and from being short-lasting to continuous.[4] Withdrawal symptoms peak in one to three days[120] and can persist for several weeks.[121] Some people experience symptoms for 6 months or longer.[122]

Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms.[35] These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette.[35] Smokers have a worse mood than they typically would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking.[35] Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers.[123][124]

In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels.[125] The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal.[35] Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar.[35]

Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression (i.e., produces phosphorylated ΔFosB isoforms) in the nucleus accumbens when inhaled or injected frequently or at high doses, but not necessarily when ingested.[126][127][128] Consequently, high daily exposure (possibly excluding oral route) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.[126][127]


Figure shows differential effects of different nicotinic acetylcholine receptors subtypes on cell growth. Chronic exposure to nicotine causes selective activation of the cancer stimulatory nicotinic acetylcholine receptors in the cell.
Figure shows differential effects of different nicotinic acetylcholine receptors subtypes on cell growth.[129] Chronic exposure to nicotine causes selective activation of the cancer stimulatory nicotinic acetylcholine receptors in the cell.[129]
(a) Schematic model of nicotine action of YAP1. (b) Nicotine activates the positive feedback loop of protein kinase C mediated phosphorylation of nicotinic acetylcholine receptor.
(a) Schematic model of nicotine action of YAP1.[129] (b) Nicotine activates the positive feedback loop of protein kinase C mediated phosphorylation of nicotinic acetylcholine receptor.[129]

Although the International Agency for Research on Cancer does not consider nicotine to be a carcinogen, several studies demonstrate it is carcinogenic.[36] Nicotine is reportedly directly associated with causing the following cancers: small-cell and non-small-cell lung carcinomas, in addition to head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, bladder, and kidney cancers.[130] Nicotine is known to the state of California to cause cancer.[131] It has a strong tumor-inducing effect on several kinds of cancers.[37] This is because nicotinic receptors are present on the surfaces of both tumor and immune cells, which allows nicotine to directly impact the "tumor microenvironment".[37]

Low levels of nicotine stimulate cell proliferation,[132] while high levels are cytotoxic.[88] In cancer cells, nicotine promotes the epithelial–mesenchymal transition which makes the cancer cells more resistant to drugs that treat cancer.[133] Nicotine may inhibit the antitumor immune response.[88] It has also been reported that exposure to nicotine adversely affects dendritic cells, a cell type that has an important role in anticancer immunosurveillance.[88]

Tobacco-specific nitrosamines are formed through the nitrosation of tobacco alkaloids during the tobacco curing and fermentation process.[134] Nicotine in the mouth and stomach can react to form the tobacco-specific nitrosamine N-Nitrosonornicotine (NNN),[135] a known group 1 carcinogen.[136] The potential for nicotine to facilitate cancer development and progression may extend to non-tobacco forms of nicotine delivery such as nicotine patch, nicotine gum, and nicotine lozenge.[37]

Because it can form nitrosamine compounds (particularly NNN and nicotine-derived nitrosamine ketone (NNK)) through a conversion process, nicotine itself exhibits a strong potential for causing cancer.[137] About 10% of breathed in nicotine is estimated to convert to these nitrosamine compounds.[137] Nitrosamine carcinogenicity is thought to be a result of enhanced DNA methylation and may lead to an agonist response on the nicotinic acetylcholine receptors, which acts to encourage tumors to grow, stay alive, and penetrate into neighboring tissues.[137]

Nicotine inherently possesses properties that encourages the growth of tumors.[138] Several lines of evidence indicate that nicotine may contribute to the development of cancer.[88] Evidence from experimental in vitro studies on cell cultures, in vivo studies on rodents as well as studies on humans inclusive of epidemiological studies indicate that nicotine itself, independent of other tobacco constituents, may stimulate a number of effects of importance in cancer development.[88] Nicotine promotes lung cancer development and accelerates its proliferation, angiogenesis, migration, invasion and epithelial–mesenchymal transition (EMT), via its influence on nAChRs receptors, whose presence has been confirmed in lung cancer cells.[44] A 2019 study showed that mice exposed to nicotine delivered by means of electronic cigarette aerosol develop lung adenocarcinoma.[139] This suggests the need for caution when using nicotine replacement therapies and e-cigarettes.[139]

Strong evidence shows that nicotine encourages the development of cancer.[90] Nicotine, one of the primary cancer-causing agents in cigarettes, affects the angiogenic process.[140] Nicotine acts as a powerful activator of angiogenesis.[141] In experimental and animal models of cancer, nicotine promotes angiogenesis and accelerates tumor growth.[142] For instance, in mice with colon cancer tumors (HT-29), nicotine leads to elevated vascular endothelial growth factor expression and increased microvascular density.[142] Additionally, nicotine induces angiogenesis in lung cancer, where its systemic administration to mice bearing LLC tumors enhances tumor growth by accelerating tumor angiogenesis.[142] Nicotine also promotes angiogenesis in gastric tumors through the upregulation of cytochrome c oxidase subunit 2 and vascular endothelial growth factor receptor 2.[142] In addition, nicotine also accelerated the growth of syngenic colon CMT93 tumor cells by inducing angiogenesis through the recruitment of bone marrow derived EPCs within the tumor.[142] Nicotine also interacts with β2-adrenergic receptors and activates the downstream COX 2 pathway, which can cause cell proliferation in gastric carcinoma and colon cancer.[143]

Nicotine exposure promotes anchorage-independent growth of A549, MDA-MB-468 and MCF-7 cell lines by downregulation of anoikis.[144] Nicotine treatment induces changes in gene expression associated with EMT in lung and breast cancer cells.[144] In colon tumor tissues from HT-29 cell-bearing BALB/c mice, vascular endothelial growth factor expression is elevated by nicotine which correlates with enhanced microvessel density.[144] Nicotine stimulation of nicotinic acetylcholine receptor (nAChRs) enhances SW620 and LOVO colorectal cancer cell invasion and metastasis in vitro via the activation of p38 mitogen-activated protein kinases signaling pathway.[144] Similarly, nicotine pretreatment stimulates the activation of alpha-9 nicotinic receptor which mediates MCF-7 and MDA-MB-231 breast cancer cell migration via the expression of epithelial mesenchymal transition markers.[144] Furthermore, implantation of CD18/HPAF pancreatic cancer cells into immuno-deficient mice, demonstrates that nicotine treatment activates alpha-7 nicotinic receptor and mediates tumor metastasis via Janus kinase 2 (JAK2)/STAT3 signaling in synergy with mitogen activated protein kinase (Ras/Raf/MEK/ERK1/2) signaling pathway.[144]

Studies indicated nicotine is able to induce cancer directly via promoting proliferation, inhibiting apoptosis of cancer cells, and stimulating tumor angiogenesis.[129] These findings suggest that nicotinic acetylcholine receptors are the central regulatory module of multiple downstream oncogenic signaling pathways in mediating the cellular responses of nicotine and its derivatives.[129] And nicotinic acetylcholine receptors mediated effects of nicotine function in coalition with the mutagenic effects of the cancerogenic nitrosamine derivatives and reactive oxygen species activated by intracellular nicotine to promote tumor development and progression in tobacco related cancers.[129]

The affinity of NNK for alpha-7 nicotinic receptor is 1,300 times higher than that of nicotine, whereas the affinity of NNN for heteromeric α–β nAChRs is 5,000 times higher than that of nicotine.[129] Thus NNK and NNN can cause displacement of nicotine from these receptors as a result of their higher affinity for nicotinic acetylcholine receptors.[129] Therefore nitrosamines may cause many of the cardiovascular, neuropsychological, and cancer-stimulating effects similar to nicotine.[129] Thus, nicotine, NNK, and NNN bind to nicotinic acetylcholine receptors and other receptors, leading to activation of the serine/threonine kinase AKT, protein kinase A (PKA), and other factors.[129] Accelerated tumor growth was observed after systemic administration of nicotine in xenograft mouse model.[129]

Nicotine and NNK promote the synthesis and release of adrenaline and noradrenaline to promote the proliferation and migration of pancreatic cancer cells.[129] Nicotine promotes metastasis of pancreatic cancer through alpha-7 nicotinic receptor mediated Mucin-4 (MUC4) upregulation.[129] Chronic exposure to nicotine leads to increased expression of MUC4 in pancreatic cancer through activation of the alpha-7 nicotinic receptor/JAK2/STAT3 and the MEK/ERK1/ERK2 signaling cascade.[129] And tobacco smoking induces chronic inflammation to trigger the development of pancreatic cancer.[129] The oncogenic effects of nicotinic acetylcholine receptor signaling in pancreatic cancer are also supported by the animal experiments, and N-nitroso compounds, formed from nicotine by nitrosation during the processing of tobacco plants, can cause pancreatic cancer in Syrian golden hamsters.[129]

Nicotinic acetylcholine receptors mediated the nicotine activation of the oncogenic YAP1 of the Hippo signaling pathway in esophageal cancer.[129] The upregulation of YAP1 in esophageal cancer samples is significantly associated with the smoking history of the patients, and the effects are regulated by protein kinase C signaling, as protein kinase C specific inhibitor can abolish the activation of YAP1 by nicotine treatment.[129] Nicotine promotes head and neck cancer through activation of endogenous FOXM1 activity by loss of heterozygosity involving the whole of chromosome 13 and copy number abnormality in oral keratinocytes.[129] Cellular and molecular studies on nicotinic acetylcholine receptors indicate that chronic exposure to nicotine or nicotine-derived carcinogenic nitrosamines upregulates the alpha-7 nicotinic receptor and alpha-9 nicotinic receptor and desensitizes the heteromeric alpha-4 beta-2 nicotinic receptor to activate the oncogenic pathways, promotes tumor angiogenesis, and inhibits drug induced apoptosis in multiple types of cancers.[129]

In addition to promoting angiogenesis, nicotine could recruit alpha-7 nicotinic receptors to boost vasculogenesis.[145] A 2011 study shows that nicotine induced proliferation, migration and tube formation also in ECFCs and that this effect was inhibited by mecamylamine or α-bungarotoxin.[145] Moreover, nicotine triggered EPC mobilization from bone marrow in a cohort of mice xenografted with colorectal cancer cells, thereby fostering tumor growth and vascularization.[145] The pro-angiogenic effect of nicotine was, therefore, likely to be mediated by nicotinic acetylcholine receptors.[145]


Nicotine causes 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 aberrations test. In humans, this damage can happen in primary parotid gland cells,[146] lymphocytes,[147] and respiratory tract cells.[148]


Youth are especially vulnerable as a consequence of the impact of nicotine on the growing neural tissue, possibility of being addicted for life, aggressive industry promotion, and the ease of obtaining nicotine products.[50] Nicotine can harm adolescent brain development, which continues into the early to mid-20s.[42] Exposure to nicotine during adolescence also damages other growing organs.[43] Young people who use nicotine products in any form, including e-cigarettes, are uniquely at risk for long-lasting effects.[149] It leads to irreversible alterations in the growing brains of youth and young adults.[150] Nicotine exposure during adolescence adversely affects cognitive development.[92] Nicotine consumption during adolescence is associated with cognitive impairment post-adolescent with diminished attention span and increased impulsivity.[40] Adolescent nicotine consumption is associated with the long-term neurochemical and behavioral altercations which suggests that nicotine is capable of exerting epigenetic alterations in the neural genome.[40]

In such a critical phase of human development, nicotine exposure may prime the brain's reward system increasing pleasing effects of other substances of abuse.[151] As evidence of this, youngsters vaping e-cigarettes display a greater risk of co-occurring alcohol and/or marijuana use.[151]

Pregnancy and breastfeeding

Nicotine has been shown to produce birth defects in some animal species, but not others.[152] It is considered a teratogen.[48] In animal studies that resulted in birth defects, researchers found that nicotine negatively affects fetal brain development and pregnancy outcomes;[152][51] the negative effects on early brain development are associated with abnormalities in brain metabolism and neurotransmitter system function.[153] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.[131]

Nicotine exposure in utero is responsible for several complications of pregnancy and birth: pregnant women who smoke are at greater risk for both miscarriage and stillbirth and infants exposed to nicotine in utero tend to have lower birth weights.[47] Some evidence suggests that in utero nicotine exposure influences the occurrence of certain conditions later in life, including type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.[154]

Children exposed to nicotine before birth are susceptible to having several long-long health issues such as reduced function of the endocrine, reproductive, respiratory, cardiovascular, and nervous systems.[47]

Multigenerational effects

The multigenerational epigenetic effect of nicotine on lung function has been demonstrated.[155] The use of any nicotine-infused product during pregnancy or during pregnancy and during the breastfeeding, postpartum period leads to the "concurrent exposure of three generations to nicotine".[156]


One in four people who do not smoke are exposed to [second-hand smoke in the US.
One in four people who do not smoke are exposed to second-hand smoke in the US.[157]

People are involuntarily exposed to nicotine from second-hand and third-hand aerosol, as well as second-hand and third-hand smoke.[26] The majority of review articles concluding that second-hand smoking does not represent a health risk are written by authors who have an association with the tobacco industry.[158] There is about a 20% increase in the risk of developing lung cancer among never-smokers who are exposed to second-hand smoke.[159] A 2014 study has shown that non-users absorb nicotine from exhaled e-cigarette aerosol at amounts comparable with exposure to second-hand smoke as assessed by salivary cotinine levels.[160] The impacts on health from inadvertent or second-hand and third-hand exposure to nicotine from nicotine products that do not involve combustion are not clearly understood.[161]

Nicotine is potentially harmful to non-users.[44][45][46] A 2019 analyses of the health risk of e-cigarette use for bystanders indicate that exposure may be associated with systemic effects of nicotine action and increased risk of tumors.[44] Second-hand exposure to nicotine and other chemicals in indoor places may result in serious adverse effects.[50] Exhaled nicotine from an e-cigarette can deposit onto surfaces and subsequently negatively affect the health of those exposed (third-hand exposure).[162] There is evidence that nicotine metabolites in serum, as well as saliva and urine cotinine levels, are superimposable among non-using adults secondhandedly exposed to e-cigarettes and conventional cigarettes.[151] The health impacts of exposure to nicotine in infants and children are not clear.[92]

The carcinogenic tobacco-specific n-nitrosamines are known risk factors for head and neck cancers.[163] Nicotine from e-cigarette aerosol or e-liquid may remain on the surface for several weeks or even months and react with the environment to form tobacco-specific n-nitrosamines compounds along with nitric acid, which can result in inhalation, ingestion, or dermal exposure to carcinogens.[163]

The tobacco industry financed independent organizations to create research that seemed not connected to the tobacco industry and would bolster its image.[164] The tobacco industry documents indicated the tobacco industry rejected scholarly research that did not agree with their view that environmental tobacco smoke is a minor risk to health.[164] In 1981, Takeshi Hirayama's paper was published in The BMJ which become a historic study on environmental tobacco smoke and lung cancer in cohabiting partners.[164] The tobacco industry publicly denounced Hirayama's paper, but privately it knew that some of its own advisors had determined the research was sound.[164] Tobacco industry documents showed that as soon as 1975 the tobacco industry knew that environmental tobacco smoke can be damaging to health.[164] A 2001 review concluded that the "Industry documents illustrate a deliberate strategy to use scientific consultants to discredit the science on ETS [environmental tobacco smoke]".[164] The tobacco industry acknowledged that it could not state that environmental tobacco smoke is safe and recognized the concern would have a “devastating effect on sales”.[164]


Undiluted liquid nicotine in solid grey bottle and clear glass container.
Liquid nicotine in plastic bottle and glass container

Nicotine is a harmful poison.[36] 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 (OTC) nicotine replacement therapy at the same time, or using OTC NRT at the same time as another nicotine-containing product, like cigarettes.[165] The median lethal dose of nicotine in humans is unknown.[49][28] Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50 of 127 mg/kg when administered to mice.[166] At sufficiently high doses, it is associated with nicotine poisoning,[51] which, while common in children, rarely results in significant morbidity or death.[152] Fatal dose outcomes is 0.5–1.0 mg per kg body weight for an adult and likely as low as 0.1–0.2 mg per kg body weight for a child.[50] As low as 2 mg of nicotine has resulted in toxicity in children.[167]

Undiluted liquid nicotine in solid grey bottle and clear glass container.
A rare case of death resulting from intravenous injection of undiluted nicotine.[168] Macropathologic findings in the injection mark on the right upper arm.[168] a There is subcutaneous hemorrhage on the right upper arm.[168] b The injection marks are along the blood vessel.[168]

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).[152] An increased respiratory rate (i.e., tachypnea) is one of the primary signs of nicotine poisoning.[152] At sufficiently high doses, somnolence (sleepiness or drowsiness), confusion, syncope (loss of consciousness from fainting), shortness of breath, marked weakness, seizures, and coma may occur.[6][152] Lethal nicotine poisoning rapidly produces seizures, and death – which may occur within minutes – is believed to be due to respiratory paralysis.[152]

There has been several reports on cases of poisoning from intraperitoneal nicotine and nicotine-containing products, mainly in infants.[168] However, few have reported about poisoning from intravenous nicotine in adults.[168]


Today nicotine is less commonly used in agricultural insecticides, which was a main source of poisoning. More recent cases of poisoning typically appear to be in the form of green tobacco sickness,[152] accidental ingestion of tobacco or tobacco products, or ingestion of nicotine-containing plants.[169][170][171] People who harvest or cultivate tobacco may experience green tobacco sickness, 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.[169][172] 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 mg/m3 skin exposure over an 8-hour workday. The US National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 0.5 mg/m3 skin exposure over an 8-hour workday. At environmental levels of 5 mg/m3, nicotine is immediately dangerous to life and health.[173]

Drug interactions



Nicotine and cigarette smoke both induce the expression of liver enzymes (e.g., certain cytochrome P450 proteins) which metabolize drugs, leading to the potential for alterations in drug metabolism.[89]



Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs),[15][174] except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist.[15] Such antagonism results in mild analgesia.

Central nervous system

Diagram showing effect of nicotine on dopaminergic neurons
Effect of nicotine on dopaminergic neurons

By binding to nicotinic acetylcholine receptors in the brain, nicotine elicits its psychoactive effects and increases the levels of several neurotransmitters in various brain structures – acting as a sort of "volume control".[175][176] 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.[177] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[178] Nicotine is unusual in comparison to most drugs, as its profile changes from stimulant to sedative with increasing dosages, a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969.[179][180] At very high doses it dampens neuronal activity.[181] Nicotine induces both behavioral stimulation and anxiety in animals.[6] Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.[182]

Nicotine activates nicotinic receptors (particularly α4β2 nicotinic receptors, but also α5 nAChRs) on neurons that innervate the ventral tegmental area and within the mesolimbic pathway where it appears to cause the release of dopamine.[183][184] This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area.[184][185] Nicotine can modulate the firing rate of the ventral tegmental area neurons.[185] Nicotine also appears to induce the release of endogenous opioids that activate opioid pathways in the reward system.[183] These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of euphoria;[183] however, mild euphoria from nicotine use can occur in some individuals.[183] Chronic nicotine use inhibits class I and II histone deacetylases in the striatum, where this effect plays a role in nicotine addiction.[186][187]

Sympathetic nervous system

Effect of nicotine on chromaffin cells

Nicotine also activates the sympathetic nervous system,[188] acting via splanchnic nerves to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream.

Adrenal medulla

By binding to ganglion type nicotinic receptors 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 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 respiration, as well as higher blood glucose levels.[189]


Diagram showing urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine[190]
Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine

As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.[191] The elimination half-life of nicotine in the body is around two hours.[192] Nicotine is primarily excreted in urine and urinary concentrations vary depending upon urine flow rate and urine pH.[6]

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,[193] suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".

Nicotine has a half-life of 1–2 hours. Cotinine is an active metabolite of nicotine that remains in the blood with a half-life of 18–20 hours, making it easier to analyze.[194]

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.[195] Under some conditions, other substances may be formed such as myosmine.[196][197]

Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.[198]


Nicotine decreases hunger and as a consequence food consumption,[199] alongside increasing energy expenditure.[200] 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.[199] Nicotine effect on weight appears to result from nicotine's stimulation of α3β4 nAChR receptors located in the POMC neurons in the arcuate nucleus and subsequently the melanocortin system, especially the melanocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus, thus modulating feeding inhibition.[185][199] POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.[199]


NFPA 704
fire diamond
The fire diamond hazard sign for nicotine

Nicotine is a hygroscopic, colorless to yellow-brown, oily liquid, that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its neutral amine base form between 60 °C and 210 °C. It is a dibasic nitrogenous base, having Kb1=1×10−6, Kb2=1×10−11.[201] It readily forms ammonium salts with acids that are usually solid and water-soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C.[202] Nicotine is readily volatile (vapor pressure 5.5 Pa at 25 °C)[201] On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (niacin, vitamin B3), and methylamine.[203]

Nicotine is chiral and hence optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D=–166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (−)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[204] The salts of (+)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids.[203] The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180 °C.[203] Anabasine is a structural isomer of nicotine, as both compounds have the molecular formula {{chem2|auto=1|C10H14N2}.

Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer.[205] Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers.[206] This suggests that tobacco-derived and synthetic nicotine can be determined by measuring the ratio of the two different enantiomers, although means exist for adjusting the relative levels of the enantiomers or performing a synthesis that only leads to the S-enantiomer. There is limited data on the relative physiological effects of these two enantiomers, especially in people. However, the studies to date indicate that (S)-nicotine is more potent than (R)-nicotine and (S)-nicotine causes stronger sensations or irritation than (R)-nicotine. To date, studies are not adequate to determine the relative addictiveness of the two enantiomers in people.

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.

Pod mod e-cigarettes use nicotine in the form of a protonated nicotine, rather than free-base nicotine found in earlier generations.[207]


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%.[208] Nicotine is also found in the leaves of other tobacco species, such as Nicotiana rustica.[8] Nicotine production is strongly induced in response to wounding as part of a jasmonate-dependent reaction.[209] 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.[210] 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.[211]

Nicotine occurs in smaller amounts (varying from 2–7 μg/kg, or 20–70 millionths of a percent wet weight[17]) in other Solanaceaeous plants, including some crop species such as potatoes, tomatoes, eggplant, and peppers,[17][212] as well as non-crop species such as Duboisia hopwoodii.[201] The amounts of nicotine in tomatoes lowers substantially as the fruit ripens.[17] Nicotine content in tea leaves is greatly inconsistent and in some cases considerably greater than in the Solanaceae fruits.[17] Nicotine content in tea leaves is greatly inconsistent and in some cases considerably greater than in the Solanaceae fruits.[17]

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."[17] Whilst food consumption levels of dietary nicotine are insignificant compared with moderate second-hand smoke exposure, the consumption of high quantities might contribute to low-level elevations in serum cotinine (e.g. 80 g of eggplant is equivalent to approximately 0.01 ng/ml of serum cotinine).[213] The amount of nicotine eaten per day is roughly around 1.4 and 2.25 μg/day at the 95th percentile.[17] These numbers may be low due to insufficient food intake data.[17] The concentrations of nicotine in vegetables are difficult to measure accurately, since they are very low (parts per billion range).[214]


The first laboratory preparation of nicotine (as its racemate) was described in 1904.[215]

The starting material was an N-substituted pyrrole derivative, which was heated to convert it by a [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.[215][216] Many other syntheses of nicotine, in both racemic and chiral forms have since been published.[217]


Nicotine biosynthesis

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that comprise nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidine is derived from N-methyl-Δ1-pyrrollidium cation.[218][219] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.

The NAD pathway in the genus Nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoribosyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.[citation needed]

The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[citation needed]

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (−)-nicotine.[220]

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.[221][222] Nicotine use is not regulated in competitive sports programs.[223]

Methods for analysis of enantiomers

Methods for measuring the two enantiomers are straightforward and include normal-phase liquid chromatography,[205] liquid chromatography with a chiral column.[224] 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.[225] Another approach measures the carbon-14 content which also differs between natural and laboratory-based tobacco.[226] These methods remain to be fully evaluated and validated using a wide range of samples.

History, society, and culture

Cigarette ad featuring baseball player Joe DiMaggioo 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.[227][228] Its chemical empirical formula was described by Melsens in 1843,[229] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[230][231][232][clarification needed] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[215][233]

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, presented to the French King,[234] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.[234] In 1610, Francis Bacon noted that trying to give up tobacco use was very hard.[235]

Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[19]

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.[236]

Although methods of production of synthetic nicotine have existed for decades,[237] it was believed that the cost of making nicotine by laboratory synthesis was cost prohibitive compared to extracting nicotine from tobacco.[238] However, recently synthetic nicotine started to be found in different brands of e-cigarettes and oral pouches and marketed as "tobacco-free."[239]

The US FDA is tasked with reviewing tobacco products such as e-cigarettes and determining which can be authorized for sale. In response to the likelihood that FDA would not authorize many e-cigarettes to be marketed, e-cigarette companies began marketing products that they claimed to contain nicotine that were not made or derived from tobacco, but contained synthetic nicotine instead, and thus, would be outside FDA's tobacco regulatory authority.[240] Similarly, nicotine pouches that claimed to contain non-tobacco (synthetic) nicotine were also introduced. The cost of synthetic nicotine has decreased as the market for the product increased. In March 2022, the U.S. Congress passed a law (the Consolidated Appropriations Act, 2022) that expanded FDA's tobacco regulatory authority to include tobacco products containing nicotine from any source, thereby including products made with synthetic nicotine.

Legal status

In the US, nicotine products and nicotine replacement therapy products like Nicotrol are only available to people 21 and above; proof of age is required; not for sale in vending machine or from any source where proof of age cannot be verified. In some states[where?], these products are only available to persons over the age of 21.[medical citation needed][where?] Many states in the US have implemented a Tobacco 21 law for tobacco products, raising the minimum age from 18 to 21.[241] As of December 2019, the minimum age to sell any tobacco product is in the US is 21 at the federal level.[242] This law is not applicable to nicotine-free e-liquids or to the devices themselves.[243]

In the European Union, the minimum age to purchase nicotine products is 18. However, there is no minimum age requirement to use tobacco or nicotine products.[244]

Following the United Kingdom's withdrawal from the European Union, The Tobacco Products and Nicotine Inhaling Products (Amendment) (EU Exit) Regulations 2020 took the place of the EU's Tobacco Products Directive (TPD) as the governing regulatory instrument.[245]

In media

External image
An image showing Nick O'Teen fleeing from Superman, Comic Vine

In some anti-smoking literature, the harm that tobacco smoking and nicotine addiction does is personified as Nick O'Teen, represented as a humanoid with some aspect of a cigarette or cigarette butt about him or his clothes and hat.[246] Nick O'Teen was a villain that was created for the Health Education Council.[246] 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.[246]

Nicotine was often compared to caffeine in advertisements in the 1980s by the tobacco industry, and later in the 2010s by the e-cigarette industry, in an effort to reduce the stigmatization and the public perception of the risks associated with nicotine use.[247]


Central nervous system

While acute/initial nicotine intake causes activation of neuronal nicotine receptors, chronic low doses of nicotine use leads to desensitization of those receptors (due to the development of tolerance) and results in an antidepressant effect, with early research showing low dose nicotine patches could be an effective treatment of major depressive disorder in non-smokers.[248]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[249] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[250]

Smoking is associated with a decreased risk of Parkinson's Disease; however, it is unknown whether this is due to people with healthier brain dopaminergic reward centers (the area of the brain affected by Parkinson's) being more likely to enjoy smoking and thus pick up the habit, nicotine directly acting as a neuroprotective agent, or other compounds in cigarette smoke acting as neuroprotective agents.[251]

Immune system

Immune cells of both the Innate immune system and adaptive immune systems frequently express the α2, α5, α6, α7, α9, and α10 subunits of nicotinic acetylcholine receptors.[252] Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of immune function.[252]


A 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.[253]

Oral health

Several in vitro studies have investigated the potential effects of nicotine on a range of oral cells. A recent systematic review concluded that nicotine was unlikely to be cytotoxic to oral cells in vitro in most physiological conditions but further research is needed.[254] 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.[255]

See also



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    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).
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