Nicotine

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)
This article is about the chemical. For other uses, see Nicotine (disambiguation).

Nicotine
Top: Concentrated nicotine liquid

Bottom left: Skeleton representation of a nicotine molecule

Bottom right: Ball-and-stick model of a nicotine molecule
Clinical data
Trade namesNicorette, Nicotrol
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: D
QP53AX13 (WHO)
Legal status
Legal status
urine pH-dependent;[8]

10–20% (gum), 30% (inhaled); 10–30% (intranasal)
Identifiers
  • 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine
Chiral
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
  • Key:SNICXCGAKADSCV-JTQLQIEISA-N checkY
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Production

Nicotine is a

nAChRα10) where it acts as a receptor antagonist.[13]

Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco.[16] Nicotine is also present at ppb-concentrations in edible plants in the family Solanaceae, including potatoes, tomatoes, and eggplants,[17] though sources disagree on whether this has any biological significance to human consumers.[17] It functions as an antiherbivore toxin; consequently, nicotine was widely used as an insecticide in the past,[18][19] and neonicotinoids (structurally similar to nicotine), such as imidacloprid, are some of the most effective and widely used insecticides.

Nicotine is highly

monoamine oxidase inhibitors present in tobacco smoke may enhance nicotine's addictive properties.[27][28] An average cigarette yields about 2 mg of absorbed nicotine.[29]
The estimated lower dose limit for fatal outcomes is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg).
dependence involves tolerance, sensitization,[31] physical dependence, psychological dependence,[32] and can cause distress.[33][34] Nicotine withdrawal symptoms include depressed mood, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances.[2] 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 use as a tool for

quitting smoking has a good safety history.[36] Animal studies suggest that nicotine may adversely affect cognitive development in adolescence, but the relevance of these findings to human brain development is disputed.[37][27] At low amounts, it has a mild analgesic effect.[38] According to the International Agency for Research on Cancer, "nicotine is not generally considered to be a carcinogen."[39][40]
The
teratogen.[42][43] The median lethal dose of nicotine in humans is unknown.[44] High doses are known to cause nicotine poisoning, organ failure, and death through paralysis of respiratory muscles,[41][45] though serious or fatal overdoses are rare.[46]

Uses

Medical

See also: Nicotine replacement therapy
Cochrane Collaboration finds that nicotine replacement therapy increases a quitter's chance of success by 50–60%, regardless of setting.[47]

The primary

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.[47]

Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.[48]

Nicotine is being researched in clinical trials for possible benefit in treating

ADHD, depression and sarcoma.[49]

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.[41]: 112  The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.[33]

Pesticide

Nicotine has been used as an

Neonicotinoids, such as imidacloprid, which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016.[58][50]

Performance

Nicotine-containing products are sometimes used for the

pharmacokinetic features.[63]

Recreational

Nicotine is used as a

e-cigarettes,[68] snuff, pipe tobacco,[67] snus, and nicotine pouches
.

Alcohol infused with nicotine is called nicotini.[69]

Contraindications

Nicotine use for tobacco cessation has few contraindications.[70]

It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014.[71] It is therefore not recommended to adolescents.[72] 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.[73][74][75]

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.[76] 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.[77]

contraindicated in individuals with a known hypersensitivity to nicotine.[78][72]

Adverse effects

Possible side effects of nicotine[79]

Nicotine is classified as a poison.

ischemic palpitations and chest pain, skin reactions, oral/nasal reactions and hiccups.[85] Many of these were also common in the placebo group without nicotine.[85] 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.[47] 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.[47] At low amounts, it has a mild analgesic effect.[38] At sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures, hypoventilation, and death.[86]

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
muscle ache, burping, gum sticking to teeth, unpleasant taste, dizziness, lightheadedness, headache, and insomnia
. 		[47][78]
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. 		[47][78]
Transdermal Transdermal
patch
pruritus, burning, or erythema
), diarrhea, dyspepsia, abdominal pain, dry mouth, nausea, dizziness, nervousness or restlessness, headache, vivid dreams or other sleep disturbances, and irritability. 		[47][78][87]
Intranasal
 Nasal spray Runny nose, nasopharyngeal and ocular irritation, watery eyes, sneezing, and coughing. [47][78][88]
Oral inhalation
Inhaler
 Dyspepsia, oropharyngeal irritation (e.g., coughing, irritation of the mouth and throat), rhinitis, and headache. [47][78][89]
All (nonspecific) Peripheral vasoconstriction, tachycardia (i.e., fast heart rate), elevated blood pressure, increased alertness and cognitive performance. [78][88]

Sleep

Nicotine reduces the amount of

non-rapid eye movement (NREM) stage 2 sleep time.[90][91] Depressive non-smokers experience mood and sleep improvements under nicotine administration; however, subsequent nicotine withdrawal has a negative effect on both mood and sleep.[92]

Cardiovascular system

A 2018

cardiac death) relative to controls.[47]

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."[93]

Blood pressure

In the short term, nicotine causes a transient increase in blood pressure, but in the long term, epidemiological studies generally do not show increased blood pressure or hypertension among nicotine users.[93]

Reinforcement disorders

See also: Nicotine withdrawal and Smoking cessation
ΔFosB accumulation from excessive drug use
ΔFosB accumulation graph
Top: this depicts the initial effects of high dose exposure to an addictive drug on
medium spiny neurons of the nucleus accumbens for up to 2 months.[94][95]

Nicotine is highly

monoamine oxidase inhibitors, acetaldehyde[97][98] and other constituents in tobacco smoke may enhance its addictiveness.[27][28] 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.[2] Withdrawal symptoms peak in one to three days[99] and can persist for several weeks.[100] Some people experience symptoms for 6 months or longer.[101]

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.[102][103]

In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels.[104] 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

oral route) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.[105][106]

Cancer

Although nicotine itself does not cause cancer in humans,

tumor promoter as of 2012.[108] A 2018 report by the US National Academies of Sciences, Engineering, and Medicine concludes, "[w]hile it is biologically plausible that nicotine can act as a tumor promoter, the existing body of evidence indicates this is unlikely to translate into increased risk of human cancer."[109]

Low levels of nicotine stimulate cell proliferation,

5-lipoxygenase (5-LOX), and epidermal growth factor (EGF). Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[112][113] 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.[114] In cancer cells, nicotine promotes the epithelial–mesenchymal transition which makes the cancer cells more resistant to drugs that treat cancer.[115]

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,[116] a known type 1 carcinogen,[117] suggesting that consumption of non-tobacco forms of nicotine may still play a role in carcinogenesis.[118]

Genotoxicity

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,[119] lymphocytes,[120] and respiratory tract cells.[121]

Pregnancy and breastfeeding

Nicotine has been shown to produce birth defects in some animal species, but not others;

passive smoke.[123]

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.[124] 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.[125]

Overdose

Main article: 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 (OTC) nicotine replacement therapy at the same time, or using OTC NRT at the same time as another nicotine-containing product, like cigarettes.[126] The median lethal dose of nicotine in humans is unknown.[44][29] 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.[127] At sufficiently high doses, it is associated with nicotine poisoning,[41] which, while common in children (in whom poisonous and lethal levels occur at lower doses per kilogram of body weight[38]) rarely results in significant morbidity or death.[43] The estimated lower dose limit for fatal outcomes is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg).[27][29]

The initial symptoms of a nicotine overdose typically include

respiratory paralysis.[43]

Toxicity

Today nicotine is less commonly used in agricultural

immediately dangerous to life and health.[132]

Drug interactions

Pharmacodynamic

Pharmacokinetic

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.[78]

Pharmacology

Pharmacodynamics

Nicotine acts as a

nAChRα10) where it acts as a receptor antagonist.[13] Such antagonism results in mild analgesia
.

Central nervous system

Effect of nicotine on dopaminergic neurons

By binding to

neuronal activity.[139] Nicotine induces both behavioral stimulation and anxiety in animals.[8] Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.[140]

Nicotine activates nicotinic receptors (particularly

histone deacetylases in the striatum, where this effect plays a role in nicotine addiction.[144][145]

Sympathetic nervous system

Effect of nicotine on chromaffin cells

Nicotine also activates the

bloodstream
.

Adrenal medulla

By binding to

blood glucose levels.[147]

Pharmacokinetics

Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine[148]

As nicotine enters the body, it is distributed quickly through the

urine pH.[8]

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,[151] 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.[152]

Nicotine is

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.[153] Under some conditions, other substances may be formed such as myosmine.[154][155]

mentholated cigarettes, thus increasing the half-life of nicotine in vivo.[156]

Metabolism

Nicotine decreases hunger and as a consequence food consumption, alongside increasing energy expenditure.[157][158] 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.[158] 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.[143][158] POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.[158]

Chemistry

NFPA 704
fire diamond
NFPA 704 four-colored diamondHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
4
1
0
The fire diamond hazard sign for nicotine[159]

Nicotine is a

nicotinic acid (niacin, vitamin B3), and methylamine.[162]

Nicotine is

molecular formula C10H14N
2.

Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer.[164]  Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers.[165] 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 electronic cigarettes use nicotine in the form of a protonated nicotine, rather than free-base nicotine found in earlier generations.[166]

Preparation

The first laboratory preparation of nicotine (as its

racemate) was described in 1904.[167]

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.[167][168] Many other syntheses of nicotine, in both racemic and chiral forms have since been published.[169]

Biosynthesis

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.[170][171] 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

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-methyl putrescine then undergoes deamination into 4-methylaminobutanal by the N-methyl putrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[citation needed]

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.[172]

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.[173][174] Nicotine use is not regulated in competitive sports programs.[175]

Methods for analysis of enantiomers

Methods for measuring the two enantiomers are straightforward and include normal-phase liquid chromatography,[164] liquid chromatography with a chiral column.[176] 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.[177] Another approach measures the carbon-14 content which also differs between natural and laboratory-based tobacco.[178] These methods remain to be fully evaluated and validated using a wide range of samples.

Natural occurrence

Nicotine is a secondary metabolite produced in a variety of plants in the family Solanaceae, most notably in tobacco Nicotiana tabacum, where it can be found at high concentrations of 0.5 to 7.5%.[179] Nicotine is also found in the leaves of other tobacco species, such as Nicotiana rustica (in amounts of 2–14%). Nicotine production is strongly induced in response to wounding as part of a jasmonate-dependent reaction.[180] 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.[181] 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.[182]

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][183] as well as non-crop species such as Duboisia hopwoodii.[160] The amounts of nicotine in tomatoes lowers substantially as the fruit ripens.[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] 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).[184]

History, society and culture

See also: History of tobacco
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.[185][186] Its chemical empirical formula was described by Melsens in 1843,[187] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[188][189][190][clarification needed] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[167][191]

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,[192] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.[192]

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.[193]

Although methods of production of synthetic nicotine have existed for decades,[194] it was believed that the cost of making nicotine by laboratory synthesis was cost prohibitive compared to extracting nicotine from tobacco.[195] However, recently synthetic nicotine started to be found in different brands of e-cigarettes and oral pouches and marketed as "tobacco-free."[196]

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.[197] Similarly, nicotine pouches that claimed to contain non-tobacco (synthetic) nicotine were also introduced. The cost of synthetic nicotine has decreased as the market for the product increased. In March 2022, the U.S. Congress passed a law (the Consolidated Appropriations Act, 2022) that expanded FDA's tobacco regulatory authority to include tobacco products containing nicotine from any source, thereby including products made with synthetic nicotine.

Legal status

Further information: Smoking in the United Kingdom and Tobacco in the United States

In the United States, nicotine products and nicotine replacement therapy products like Nicotrol are only available to people 18 and above; proof of age is required; not for sale in vending machine or from any source where proof of age cannot be verified. As of 2019, the minimum age to sell tobacco in the US is 21 at the federal level.[198]

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.[199]

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

In media

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

In some

public service announcements in which he tries to get kids addicted to cigarettes before being foiled by the DC Comics character Superman.[200]

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.[201]

Research

Central nervous system

While acute/initial nicotine intake causes activation of neuronal nicotine receptors, chronic low doses of nicotine use leads to desensitization of those receptors (due to the development of tolerance) and results in an antidepressant effect, with early research showing low dose nicotine patches could be an effective treatment of major depressive disorder in non-smokers.[202]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[203] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[204]

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.[205]

Immune system

Immune cells of both the

immune function.[206]

Optopharmacology

A

ultraviolet light with certain conditions, has been developed for studying nicotinic acetylcholine receptors in brain tissue.[207]

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.[208] 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.[209]

See also

References

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    .
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    . 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.
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    A meta-analysis of adverse events associated with NRT included 92 RCTs and 28 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% CI 1.51 to 2.82) across 12 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% CI 1.37 to 2.57; 15 studies; 11,074 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 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 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 95% 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 1.95 95% CI 0.26 to 4.30).
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    . 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.
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    . It is the smoke from combustible tobacco products—not nicotine—that injures and kills millions of smokers.
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    . The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB
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    . 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
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    . 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), ...

    Conclusions
    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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External links

Wikimedia Commons has media related to Nicotine.
Wikisource has the text of the 1911 Encyclopædia Britannica article "Nicotine".