Nicotine

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Nicotine
Nicotine.svg
Nicotine-3D-vdW.png
Clinical data
Trade namesNicorette, Nicotrol
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Dependence
liability
Physical: low–moderate
Psychological: moderate–high[1][2]
Addiction
liability
High[3]
Routes of
administration
Inhalation; insufflation; oral – buccal, sublingual, and ingestion; transdermal; rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding<5%
MetabolismPrimarily hepatic: CYP2A6, CYP2B6, FMO3, others
MetabolitesCotinine
Elimination half-life1-2 hours; 20 hours active metabolite
ExcretionRenal, urine pH-dependent;[5]
10–20% (gum), 30% (inhaled); 10–30% (intranasal)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.000.177 Edit this at Wikidata
Chemical and physical data
FormulaC10H14N2
Molar mass162.23 g/mol g·mol−1
3D model (JSmol)
ChiralityChiral
Density1.01 g/cm3
Melting point−79 °C (−110 °F)
Boiling point247 °C (477 °F)

Nicotine is a stimulant and potent parasympathomimetic alkaloid that is naturally produced in the nightshade family of plants. It is used for the treatment of tobacco use disorders as a smoking cessation aid and nicotine dependence for the relief of withdrawal symptoms.[4][6][7] Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs),[8][9][10] except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist.[8]

Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco.[11] Usually consistent concentrations of nicotine varying from 2–7 µg/kg (20–70 millionths of a percent wet weight) are found in the edible family Solanaceae, such as potatoes, tomatoes, and eggplant.[12] Some research indicates that the contribution of nicotine obtained from food is substantial in comparison to inhalation of second-hand smoke.[12] Others consider nicotine obtained from food to be trivial unless exceedingly high amounts of certain vegetables are eaten.[12] It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past,[13][14] and neonicotinoids, such as imidacloprid, are widely used.

Nicotine is highly addictive.[15][16][17] It is one of the most commonly abused drugs.[18] An average cigarette yields about 2 mg of absorbed nicotine; high amounts can be more harmful.[19] Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence.[20] Nicotine dependence involves tolerance, sensitization,[21] physical dependence, and psychological dependence.[22] Nicotine dependence causes distress.[23][24] Nicotine withdrawal symptoms include depressed mood, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances.[1] Mild nicotine withdrawal symptoms are measurable in unrestricted smokers, who experience normal moods only as their blood nicotine levels peak, with each cigarette.[25] On quitting, withdrawal symptoms worsen sharply, then gradually improve to a normal state.[25]

Nicotine use as a tool for quitting smoking has a good safety history.[26] The general medical position is that nicotine itself poses few health risks, except among certain vulnerable groups[27] such as youth.[28] Nicotine is potentially harmful to non-users.[28] At low amounts, it has a mild analgesic effect.[28] The International Agency for Research on Cancer indicates that nicotine does not cause cancer.[29] Nicotine has been shown to produce birth defects in some animal species, but not others;[30] consequently, it is considered to be a possible teratogen in humans.[30] The median lethal dose of nicotine in humans is unknown,[31] but high doses are known to cause nicotine poisoning.[32]

Uses[edit]

Medical[edit]

A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that nicotine replacement therapy increases a quitter's chance of success by 50–60%, regardless of setting.[33]

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, electronic/substitute cigarettes 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) therapies increase the chances of successfully quitting smoking by 50–60%, regardless of setting.[33]

Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.[34] 4 mg versus 2 mg nicotine gum also increase the chances of success.[34]

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.[32]:112 The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.[23]

Pesticide[edit]

Nicotine has been used as an insecticide since at least the 1690s, in the form of tobacco extracts[35] (although other components of tobacco also seem to have pesticide effects).[36] Nicotine pesticides have not been commercially available in the US since 2014,[37] and homemade pesticides are banned on organic crops[38] and counterrecommended for small gardeners.[39] Nicotine pesticides have been banned in the EU since 2009.[40] Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels.[40][41] Neonicotinoids, which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016.[42][35]

In nicotine-producing plants, nicotine functions as an antiherbivory chemical; consequently, nicotine has been widely used as an insecticide,[43][14] and neonicotinoids, such as imidacloprid, are widely used.

Enhancing performance[edit]

Nicotine-containing products are sometimes used for the performance-enhancing effects of nicotine on cognition.[citation needed] A 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.[44] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;[45] 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.[46] 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.[47]

Recreational[edit]

Nicotine is used as a recreational drug.[48] It is widely used because it is highly addictive and hard to discontinue using it.[49] Nicotine is often used compulsively,[50] and dependence can develop within days.[50][51] Recreational drug users commonly use nicotine for its mood-altering effects.[23] Other recreational nicotine products include chewing tobacco,[citation needed] cigars,[52] cigarettes,[52] e-cigarettes,[53] snuff,[citation needed][54] pipe tobacco,[52] and snus.[citation needed]

Contraindications[edit]

Nicotine use for tobacco cessation has few contraindications.[55]

It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014.[56] It is therefore not recommended to adolescents.[57] 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.[58][59][60]

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.[57] Using nicotine products during cancer treatment is counterrecommended, as nicotine promotes tumour growth, but temporary use of NRTs to quit smoking may be advised for harm reduction.[61]

Nicotine gum is contraindicated in individuals with temporomandibular joint disease.[62] People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays.[57] Nicotine in any form is contraindicated in individuals with a known hypersensitivity to nicotine.[62][57]

Side effects[edit]

Nicotine may not be harmless,[63] but it is safer than inhaled tobacco smoke.[64] As medicine, nicotine is used to help with quitting smoking and has good safety in this form.[26] The accepted medical position in 2013 was that nicotine itself poses few health risks, except among certain vulnerable groups[27] such as youth,[28] but the ideal course of action for smokers is to quit all nicotine use.[65]

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.[33] At low amounts, it has a mild analgesic effect.[28] At sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures and hypoventilation.[66]

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. [33][62]
Buccal 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. [33][62]
Transdermal Transdermal
patch
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. [33][62][67]
Intranasal Nasal spray Runny nose, nasopharyngeal and ocular irritation, watery eyes, sneezing, and coughing. [33][62][68]
Oral inhalation Inhaler Dyspepsia, oropharyngeal irritation (e.g., coughing, irritation of the mouth and throat), rhinitis, and headache. [33][62][69]
All (nonspecific) Peripheral vasoconstriction, tachycardia (i.e., fast heart rate), elevated blood pressure, and increased alertness and cognitive performance. [62][68]

Sleep[edit]

Possible side effects of nicotine.[70]

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.[71] 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.[71][72]

Cardiovascular system[edit]

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 myocardial infarction) and heart palpitations.[33] The same review indicated that nicotine replacement therapy does not increase the incidence of serious cardiac adverse events (i.e., myocardial infarction, stroke, and cardiac death) relative to controls.[33]

Cancer[edit]

Although nicotine does not cause cancer in humans,[29] it is unclear whether it functions as a tumor promoter as of 2012.[73] A 2018 report by the 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.”[74]

Low levels of nicotine stimulate cell proliferation, while high levels are cytotoxic.[75] Nicotine increases cholinergic signaling and adrenergic signaling in colon cancer cells,[76] thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-lipoxygenase (5-LOX), and epidermal growth factor (EGF). Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[77][78] In cancer cells, nicotine promotes the epithelial–mesenchymal transition which makes the cancer cells more resistant to drugs that treat cancer.[79]

Fetal development and breastfeeding[edit]

Nicotine has been shown to produce birth defects in some animal species, but not others;[30] consequently, it is considered to be a possible teratogen in humans.[30] In animal studies that resulted in birth defects, researchers found that nicotine negatively affects fetal brain development and pregnancy outcomes;[30][32] the negative effects on early brain development are associated with abnormalities in brain metabolism and neurotransmitter system function.[80] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.[81]

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.[26]

Overdose[edit]

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.[82] The median lethal dose of nicotine in humans is unknown.[31][19] 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.[83] At sufficiently high doses, it is associated with nicotine poisoning,[32] which, while common in children, rarely results in significant morbidity or death.[30]

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).[30] Respiratory stimulation (i.e., tachypnea) is one of the primary signs of nicotine poisoning.[30] 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.[5][30] Lethal nicotine poisoning rapidly produces seizures, and death – which may occur within minutes – is believed to be due to respiratory paralysis.[30]

Reinforcement disorders[edit]

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.[84][85]

Nicotine is highly addictive.[15][16][17] 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.[1] Withdrawal symptoms peak in one to three days[86] and can persist for several weeks.[87] Some people experience symptoms for 6 months or longer.[88]

Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms.[89] These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette.[89] Smokers have worse mood than they would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking.[25] Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers.[90][91]

In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels.[92] The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal.[89] Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar.[89]

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.[93][94][95] Consequently, high daily exposure (possibly excluding oral route) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.[93][94]

Toxicity[edit]

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,[30] accidental ingestion of tobacco or tobacco products, or ingestion of nicotine-containing plants.[96][97][98] People who harvest or cultivate tobacco may experience Green Tobacco Sickness (GTS), a type of nicotine poisoning caused by dermal exposure to wet tobacco leaves. This occurs most commonly in young, inexperienced tobacco harvesters who do not consume tobacco.[96][99] 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.[100]

Drug interactions[edit]

Pharmacodynamic[edit]

Pharmacokinetic[edit]

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.[62]

Pharmacology[edit]

Pharmacodynamics[edit]

Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs),[8][9] except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist.[8]

Central nervous system[edit]

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."[101][102] 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.[103] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[104] 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.[105][106] At very high doses it dampens neuronal activity.[107] Nicotine induces both behavioral stimulation and anxiety in animals.[5] Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.[108]

Nicotine activates nicotinic receptors (particularly α4β2 nicotinic receptors) on neurons that innervate the ventral tegmental area and within the mesolimbic pathway where it appears to cause the release of dopamine.[109][110] This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area.[110] Nicotine also appears to induce the release of endogenous opioids that activate opioid pathways in the reward system, since naltrexone – an opioid receptor antagonist – blocks nicotine self-administration.[109] These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of euphoria;[109] however, mild euphoria from nicotine use can occur in some individuals.[109] Chronic nicotine use inhibits class I and II histone deacetylases in the striatum, where this effect plays a role in nicotine addiction.[111][112]

Sympathetic nervous system[edit]

Effect of nicotine on chromaffin cells

Nicotine also activates the sympathetic nervous system,[113] 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[edit]

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.[114]

Pharmacokinetics[edit]

Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine.[115]

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.[116] The elimination half-life of nicotine in the body is around two hours.[117] Nicotine is primarily excreted in urine and urinary concentrations vary depending upon urine flow rate and urine pH.[5]

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,[118] 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.[119]

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.[120] Under some conditions, other substances may be formed such as myosmine.[121]

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.[122]

Chemistry[edit]

NFPA 704
fire diamond
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oilHealth code 4: Very short exposure could cause death or major residual injury. E.g., VX gasReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
1
4
0
The fire diamond hazard sign for nicotine.[123]

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 base form between 60 °C and 210 °C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water-soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C.[124] Nicotine is readily volatile (vapor pressure 5.5 ㎩ at 25 ℃) and dibasic (Kb1=1×10⁻⁶, Kb2=1×10⁻¹¹).[125] On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.[126]

Nicotine is 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.[127] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.[126]

Anabasine is a structural isomer of nicotine, as both compounds have the molecular formula C10H14N2.

Occurrence[edit]

Nicotine is a natural product of tobacco, occurring in the leaves of Nicotiana tabacum in a range of 0.5 to 7.5% depending on variety.[128] Nicotine is also found in the leaves of Nicotiana rustica, in amounts of 2–14%; in Duboisia hopwoodii; and in Asclepias syriaca.[125]

Nicotine also naturally occurs in smaller amounts (varying from 2–7 µg/kg, or 20–70 millionths of a percent wet weight[12]) in Solanaceaein plants from the family Solanaceae (such as potatoes, tomatoes, eggplant, and peppers[12]).[129]

The amounts of nicotine of tomato varieties lowered substantially as the fruits ripened.[12] Nicotine content in tea leaves is greatly inconsistent and in some cases considerably greater than in the Solanaceae fruits.[12] 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."[12] The amount of nicotine eaten per day is roughly around 1.4 and 2.25 µg/day at the 95th percentile.[12] These numbers may be low due to insufficient food intake data.[12] Since the amounts of nicotine from the Solanum family including potato, tomato, eggplant, and from the Capsicum family vary in the parts per billion, they are tough to measure.[130]

Biosynthesis[edit]

Nicotine biosynthesis

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[131][132] 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 phosphoriboxyl 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.[133]

Detection in body fluids[edit]

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.[134][135] Nicotine use is not regulated in competitive sports programs.[136]

History, society, and culture[edit]

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.[137][138] Its chemical empirical formula was described by Melsens in 1843,[139] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[140][141][142][clarification needed] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[143]

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,[144] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.[144]

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.[14]

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.[145]

Legal status[edit]

In the United States, nicotine products and Nicotine Replacement Therapy products like Nicotrol are only available to persons 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. In some states[where?], these products are only available to persons over the age of 21.[medical citation needed][where?]

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.[146]

In media[edit]

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.[147] Nick O'Teen was a villain that was created for the Health Education Council.[147]

Research[edit]

Central nervous system[edit]

While acute/initial nicotine intake causes activation of neuronal nicotine receptors, chronic low doses of nicotine use leads to desensitisation 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.[148]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[149] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[150]

Immune system[edit]

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.[151] Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of immune function.[151]

Optopharmacology[edit]

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.[152]

References[edit]

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    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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