Nicotine

This article is about the chemical. For other uses, see Nicotine (disambiguation).
Nicotine
Systematic (IUPAC) name
(S)-3-[1-Methylpyrrolidin-2-yl]pyridine
Clinical data
Trade names Nicorette, Nicotrol
AHFS/Drugs.com monograph
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
Legal status
Legal status
  • AU: Unscheduled
  • CA: Unscheduled
  • NZ: Unscheduled
  • UK: Unscheduled
  • US: Unscheduled
  • UN: Unscheduled
  • EU: Unscheduled
Pharmacokinetic data
Bioavailability 20 to 45% (oral), 53% (intranasal), 68% (transdermal)
Protein binding <5%
Metabolism Hepatic
Metabolites Cotinine
Biological half-life 1-2 hours; 20 hours active metabolite
Excretion Urine (10-20% (gum), pH-dependent; 30% (inhaled); 10-30% (intranasal))
Identifiers
CAS Number 54-11-5 YesY
ATC code N07BA01 (WHO) QP53AX13 (WHO)
PubChem CID 89594
IUPHAR/BPS 2585
DrugBank DB00184 YesY
ChemSpider 80863 YesY
UNII 6M3C89ZY6R YesY
KEGG D03365 YesY
ChEBI CHEBI:18723 N
ChEMBL CHEMBL3 YesY
PDB ligand ID NCT (PDBe, RCSB PDB)
Chemical data
Formula C10H14N2
Molar mass 162.23 g/mol
Physical data
Density 1.01 g/cm3
Melting point −79 °C (−110 °F)
Boiling point 247 °C (477 °F)
 NYesY (what is this?)  (verify)

Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae) and is a stimulant drug. Nicotine is a nicotinic acetylcholine receptor (nAChR) agonist,[4][5] except at nAChRα9 and nAChRα10 where it acts as an antagonist.[4] It is made in the roots of and accumulates in the leaves of the nightshade family of plants. Nicotine is found in the leaves of Nicotiana rustica in amounts of 2–14%, the tobacco plant Nicotiana tabacum, Duboisia hopwoodii and Asclepias syriaca.[6]

It constitutes approximately 0.6–3.0% of the dry weight of tobacco[7] and is present in the range of 2–7 µg/kg of various edible plants.[8] It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past[9][10] and neonicotinoids such as imidacloprid are currently widely used.

Nicotine is addictive.[11] In lesser doses (an average cigarette yields about 2 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.[12][13][14] This stimulant effect is a contributing factor to the addictive properties of tobacco smoking. Nicotine's addictive nature includes psychoactive effects, drug-reinforced behavior, compulsive use, relapse after abstinence, physical dependence and tolerance.[15]

It is widely held that nicotine, delivered as a drug in regulated nicotine replacement therapy devices at recommended doses, itself poses few health risks, except among certain vulnerable groups.[16] Nicotine is associated with potential birth defects and at high enough-doses, poisonings.[17][18] In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.[18] There is inadequate research to demonstrate that nicotine is associated with cancer in humans.[19] As medicine, nicotine is used to help with quitting smoking and has good safety in this form.[20] During pregnancy, there are risks to the child later in life for type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.[20] At high enough doses, nicotine is lethal.[21] It is unlikely that a person would overdose on nicotine through smoking alone.[22] The use of electronic cigarettes, which are designed to be refilled with nicotine-containing e-liquid, has renewed interest in nicotine overdoses, especially with regard to the possibility of young children ingesting the liquids.[23]

Psychoactive effects

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[24] First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[25] Like any stimulant, it may very rarely cause the often uncomfortable akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[26][27]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates nicotinic acetylcholine receptors; this indirectly promotes the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, arginine vasopressin, serotonin, dopamine, and beta-endorphin in parts of the brain.[28][29] Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems.[30][31] Most cigarettes contain 1–3 milligrams of inhalable nicotine.[32] Studies suggest that when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[33]

Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative with increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation[34] and subsequently referred to as "Nesbitt's paradox."[35]

Uses

Medical

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% to 70%.[36]

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence (though electronic cigarettes are only able to be licensed as medical products in a few jurisdictions, such as the European Union). Studies have found that these therapies increase the chance of success of quitting by 50 to 70%,[36] though reductions in the population as a whole have not been demonstrated.[37]

Enhancing performance

Nicotine is frequently used for its performance-enhancing effects on cognition, alertness, and focus.[38] 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.[39] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;[40] 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.[41]

Recreational

Nicotine is commonly consumed as a recreational drug for its stimulant effects.[42] Recreational nicotine products include chewing tobacco, cigars, cigarettes, e-cigarettes, snuff, and snus.

Adverse effects

According to a 2013 report by Cancer Research UK in a discussion of nicotine when delivered as a drug in regulated nicotine replacement therapy devices at recommended doses: "The accepted medical position is that while nicotine is highly addictive and comparable to drugs such as heroin or cocaine, it poses little health risks except in certain vulnerable groups".[16] A large number of randomized controlled trials show that nicotine replacement products do not cause serious adverse events among smokers, even in patients with established cardiovascular disease.[43] The 2014 US Surgeon General's Report concluded that nicotine negatively affects pregnancy outcomes and fetal brain development, and that experimental research suggests that adolescent nicotine use may harm brain development.[17] It noted that evidence is inadequate to infer whether nicotine plays any role in causing cancer, but "clearly the risk, if any, is less than continued smoking".[17]

Vascular system

Human epidemiology studies show that nicotine is not a significant cause of cardiovascular disease.[44][45] Evidence is contradictory on whether nicotine is harmful among those who had previously suffered a heart attack.[46] Randomized trials show that nicotine replacement products are not associated with cardiovascular events, even among those with established cardiovascular disease.[43] A meta-analysis shows that snus consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not associated with heart attacks.[47] Hence, it is not nicotine, but tobacco smoke's other components which are implicated in ischemic heart disease.[47] Nicotine increases blood pressure and heart rate as well as constricts pupils in some individuals.[48] Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.[49] Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).[50] Nicotine elevates serum cholesterol levels, supports clot formation, and aids in plaque formation by enhancing vascular smooth muscle.[18]

Carcinogen

Possible side effects of nicotine.[51]

Although there is insufficient evidence to classify nicotine as a carcinogen, there is an ongoing debate about whether it functions as a tumor promoter.[52] In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.[18] There is inadequate research to demonstrate that nicotine is associated with cancer in humans, but there is evidence indicating possible oral, esophageal, or pancreatic cancer risks.[19] Nicotine replacement therapy has not been shown to be associated with cancer in the real world.[18] Medicinal nicotine as a tool to quitting smoking has a good safety history.[20]

While no epidemiological evidence directly supports the notion that nicotine acts as a carcinogen in the formation of human cancer, research has identified nicotine's indirect involvement in cancer formation in animal models and cell cultures.[53][54][55] Nicotine increases cholinergic signalling and adrenergic signalling in the case of colon cancer,[56] 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.[57][58] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).[59] N-Nitrosonornicotine (NNN), classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen, has been shown to form in vitro in amounts less than 0.01% of the active substance, when human saliva is incubated with nornicotine.[60] The IARC has not evaluated pure nicotine or assigned it to an official carcinogenic classification.

Fetal development

In pregnancy, a 2013 review noted that "nicotine is only 1 of more than 4000 compounds to which the fetus is exposed through maternal smoking. Of these, ∼30 compounds have been associated with adverse health outcomes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role. Nicotine also has been shown to have significant deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development." It also notes that "abnormalities of newborn neurobehavior, including impaired orientation and autonomic regulation and abnormalities of muscle tone, have been identified in a number of prenatal nicotine exposure studies" and that there is weak data associating fetal nicotine exposure with newborn facial clefts, and that there is no good evidence for newborns suffering nicotine withdrawal from fetal exposure to nicotine.[61]

Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.[62]

Risks to the child later in life via nicotine exposure during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.[20] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.[11]

Reinforcement disorders

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 can persist for several weeks.[63] Nicotine has clinically significant cognitive-enhancing effects at low doses, particularly in fine motor skills, attention, and memory. These beneficial cognitive effects may play a role in the maintenance of tobacco dependence.[63]

Nicotine is addictive.[11][64][65] Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression in the nucleus accumbens when inhaled or injected at sufficiently high doses, but not necessarily when ingested.[64][65][66] Consequently, repeated daily exposure (possibly excluding oral route) to nicotine can result in accumbal ΔFosB overexpression, in turn causing nicotine addiction.[64][65]

In dependent smokers, smoking during withdrawal returns cognitive abilities to pre-withdrawal levels, but chronic use may not offer cognitive benefits over not smoking.[17][67]

Overdose

Main article: Nicotine poisoning

Nicotine is regarded as a potentially lethal poison.[21] The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.[12][68] However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally.[14] 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.[69]

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 or due to accidental ingestion of tobacco or tobacco products or ingestion of nicotine containing plants.[70][71][72] 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.[70][73] 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 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 levels of 5 mg/m3, nicotine is immediately dangerous to life and health.[74]

It is unlikely that a person would overdose on nicotine through smoking alone, the US Food and Drug Administration (FDA) states in 2013 "There are no significant safety concerns associated with using more than one OTC NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette."[22]

The recent rise in the use of electronic cigarettes, many forms of which are designed to be refilled with nicotine-containing e-liquid supplied in small plastic bottles, has renewed interest in nicotine overdoses, especially in the possibility of young children ingesting the liquids.[23] A 2015 report on e-cigarettes by Public Health England noted an "unconfirmed newspaper report of a fatal poisoning of a two-year old child" and two published case reports of children of similar age who had recovered after ingesting e-liquid and vomiting.[23] They also noted case reports of suicides by nicotine.[23] Where adults drank liquid containing up to 1,500 mg of nicotine they recovered (helped by vomiting), but an ingestion apparently of about 10,000 mg was fatal, as was an injection.[23] They commented that "Serious nicotine poisoning seems normally prevented by the fact that relatively low doses of nicotine cause nausea and vomiting, which stops users from further intake."[23]

Pharmacology

Pharmacodynamics

Central nervous system

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." 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.[75] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[76]

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.[77][78] This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link, which is mediated by the neuropeptide ghrelin in the ventral tegmental area.[78] Nicotine also appears to activate opioid pathways in the reward system, since naltrexone – an opioid receptor antagonist – blocks nicotine self-administration.[77] These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of euphoria;[77] however, mild euphoria from nicotine use can occur in some individuals.[77] Chronic nicotine use inhibits class I and II histone deacetylases in the striatum, where this effect plays a role in nicotine addiction.[79][80]

Sympathetic nervous system

Nicotine also activates the sympathetic nervous system,[81] 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 noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.[82]

Adrenal medulla

Effect of nicotine on chromaffin cells.

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.[83]

Nicotine has a half-life of 1–2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18–20 hours, making it easier to analyze due to its longer half-life.[84]

Pharmacokinetics

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.[85] The elimination half-life of nicotine in the body is around two hours.[86]

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,[87] 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 is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.[88] Under some conditions, other substances may be formed such as myosmine.[89]

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.[90]

Physical and chemical properties

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 oil Health code 4: Very short exposure could cause death or major residual injury. E.g., VX gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
1
4
0
The fire diamond hazard sign for nicotine.[91]

Nicotine is a hygroscopic, colorless 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.[92]

Nicotine is readily volatile (vapor pressure 5.5 ㎩ at 25 ℃) and dibasic (Kb1 = 1×10⁻⁶, Kb2 = 1×10⁻¹¹).[6]

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.[93] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.[94]

On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.[94]

Occurrence and biosynthesis

Nicotine biosynthesis

Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety.[95] Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae (such as potatoes, tomatoes, and eggplant).[96]

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.[97][98] 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.

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.

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.[99]

Measurement 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[100].[101] Nicotine use is not regulated in competitive sports programs.[102]

History

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,[103] and who promoted their medicinal use. The tobacco and its seeds were brought to Ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo.Smoking was believed to protect against illness, particularly the plague.[103]

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.[10]

Currently, nicotine, even in the form of tobacco dust, is prohibited as a pesticide for organic farming in the United States.[104][105]

In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.[106] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.[107]

Chemical identification

Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison.[108][109] Its chemical empirical formula was described by Melsens in 1843,[110] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[111][112][113] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[114]

Society and culture

The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.[115]

Research

While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers.[116] However, the original research concluded that: "Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine's high risk to health, nicotine patches are not recommended for clinical use in depression."[117]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[118] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[119]

Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.[120][121]

Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson's disease.[122]

There is tentative evidence that nicotinamides may improve depression.[123]

See also

References

  1. 1 2 D'Souza MS, Markou A (2011). "Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments". Addict Sci Clin Pract 6 (1): 4–16. PMC 3188825. PMID 22003417. 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.
  2. ↑ 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. PMID 22114542.
  3. ↑ Introduction to Pharmacology Third Edition. Abingdon: CRC Press. 2007. pp. 222–223. ISBN 9781420047424.
  4. 1 2 "Nicotinic acetylcholine receptors: Introduction". IUPHAR Database. International Union of Basic and Clinical Pharmacology. Retrieved 1 September 2014.
  5. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 9: Autonomic Nervous System". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 234. ISBN 9780071481274. Nicotine ... is a natural alkaloid of the tobacco plant. Lobeline is a natural alkaloid of Indian tobacco. Both drugs are agonists are nicotinic cholinergic receptors ...
  6. 1 2 Robert L. Metcalf (2007), "Insect Control", Ullmann's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, p. 9
  7. ↑ "Smoking and Tobacco Control Monograph No. 9" (PDF). Retrieved 2012-12-19.
  8. ↑ "Determination of the Nicotine Content of Various Edible Nightshades (Solanaceae) and Their Products and Estimation of the Associated Dietary Nicotine Intake". Retrieved 2008-10-05.
  9. ↑ Rodgman, Alan; Perfetti, Thomas A. (2009). The chemical components of tobacco and tobacco smoke. Boca Raton, FL: CRC Press. ISBN 1-4200-7883-6. LCCN 2008018913.
  10. 1 2 Ujváry, István (1999). "Nicotine and Other Insecticidal Alkaloids". In Yamamoto, Izuru; Casida, John. Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Tokyo: Springer-Verlag. pp. 29–69.
  11. 1 2 3 "State Health Officer’s Report on E-Cigarettes: A Community Health Threat" (PDF). California Department of Public Health, California Tobacco Control Program. January 2015.
  12. 1 2 "Nicotine (PIM)". Inchem.org. Retrieved 2012-12-19.
  13. ↑ Genetic Science Learning Center. "How Drugs Can Kill".
  14. 1 2 Mayer B (January 2014). "How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century". Archives of Toxicology 88 (1): 5–7. doi:10.1007/s00204-013-1127-0. PMC 3880486. PMID 24091634.
  15. ↑ Caponnetto, Pasquale; Campagna, Davide; Papale, Gabriella; Russo, Cristina; Polosa, Riccardo (2012). "The emerging phenomenon of electronic cigarettes". Expert Review of Respiratory Medicine 6 (1): 63–74. doi:10.1586/ers.11.92. ISSN 1747-6348. PMID 22283580.
  16. 1 2 de Andrade, Marisa; Hastings, Gerald. "Tobacco Harm Reduction and Nicotine Containing Products" (PDF). Cancer Research UK. Cancer Research UK. Retrieved 10 March 2016.
  17. 1 2 3 4 {{(2014) The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. PMID 24455788}}
  18. 1 2 3 4 5 Jerry JM, Collins GB, Streem D (2015). "E-cigarettes: Safe to recommend to patients?". Cleve Clin J Med 82 (8): 521–6. doi:10.3949/ccjm.82a.14054. PMID 26270431. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors. Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.12 Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers. However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.
  19. 1 2 "Chapter 5 - Nicotine" (PDF). Surgeon General of the United States. 2014. pp. 107–138.
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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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