Nicotine: Difference between revisions

NFPA 704
*fire diamond*
NFPA 704; fire diamond
	4 1 0 The fire diamond hazard sign for nicotine.

Nicotine
Clinical data
Trade names	Nicorette, Nicotrol
AHFS/Drugs.com	Monograph
Pregnancy; category	AU: D; ;
Dependence; liability	Physical: low–moderate; Psychological: moderate–high
Addiction; liability	High
Routes of; administration	Inhalation; insufflation; oral – buccal, sublingual, and ingestion; transdermal; rectal
ATC code	N07BA01 (WHO) QP53AX13 (WHO);
Legal status
Legal status	AU: Unscheduled; CA: Unscheduled; NZ: Unscheduled; UK: Unscheduled; US: WARNINGUnscheduled; UN: Unscheduled; EU: Unscheduled;
Pharmacokinetic data
Bioavailability	20 to 45% (oral), 53% (intranasal), 68% (transdermal)
Protein binding	<5%
Metabolism	Primarily hepatic: CYP2A6, CYP2B6, FMO3, others
Metabolites	Cotinine
Elimination half-life	1-2 hours; 20 hours active metabolite
Excretion	Urine (10-20% (gum), pH-dependent; 30% (inhaled); 10-30% (intranasal))
Identifiers
	IUPAC name (S)-3-[1-Methylpyrrolidin-2-yl]pyridine;
CAS Number	54-11-5 ;
PubChem CID	89594;
IUPHAR/BPS	2585;
DrugBank	DB00184 ;
ChemSpider	80863 ;
UNII	6M3C89ZY6R;
KEGG	D03365 ;
ChEBI	CHEBI:18723 ;
ChEMBL	ChEMBL3 ;
PDB ligand	NCT (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID1020930 ;
ECHA InfoCard	100.000.177
Chemical and physical data
Formula	C10H14N2
Molar mass	162.23 g/mol g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
Density	1.01 g/cm3
Melting point	−79 °C (−110 °F)
Boiling point	247 °C (477 °F)
	SMILES CN(CCC1)[C@@H]1C2=CC=CN=C2;
	InChI 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 ; Key:SNICXCGAKADSCV-JTQLQIEISA-N ;
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Revision as of 21:42, 6 November 2016

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,^[5]^[6] except at nAChRα9 and nAChRα10 where it acts as an antagonist.^[5] Nicotine is found in the leaves of Nicotiana rustica in amounts of 2–14%, the tobacco plant Nicotiana tabacum, Duboisia hopwoodii and Asclepias syriaca.^[7]

It constitutes approximately 0.6–3.0% of the dry weight of tobacco^[8] and is present in the range of 2–7 µg/kg of various edible plants.^[9] It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past^[10]^[11] and neonicotinoids such as imidacloprid are currently widely used.

Nicotine is highly addictive.^[12]^[13] An average cigarette yields about 2 mg of absorbed nicotine, and in lesser doses of that order, the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.^[14]^[15]^[16] 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.^[17]

The health effects of long-term nicotine use is unknown.^[18] The general medical position is that nicotine itself poses few health risks, except among certain vulnerable groups.^[19] Nicotine in the form of nicotine replacement products is less of a risk than smoking.^[20] Nicotine is associated with a range of harmful effects, including potential birth defects.^[21] In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.^[21] There is inadequate research to demonstrate that nicotine is associated with cancer in humans.^[20] As medicine, nicotine is used to help with quitting smoking and has good safety in this form.^[22] During pregnancy, there are risks to the child later in life for type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.^[22] At high-enough doses, nicotine is associated with poisonings,^[20] and at high-enough doses,^[16] it is potentially lethal.^[23] The use of electronic cigarettes, which are designed to be refilled with nicotine-containing e-liquid, has raised concerns over nicotine overdoses, especially with regard to the possibility of young children ingesting the liquids.^[24]

Psychoactive effects

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.^[26] 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.^[27] 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.^[28]^[29]

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.^[30]^[31] Nicotine also extends the duration of positive effects of dopamine and increases the sensitivity of the brain's reward system to rewarding stimuli.^[32]^[33] Most cigarettes contain 1–3 milligrams of inhalable nicotine.^[34] Studies suggest that when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.^[35]

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.^[36]^[37]

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%.^[38]

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%,^[38] though reductions in the population as a whole have not been demonstrated.^[39]

Enhancing performance

Nicotine is frequently used for its performance-enhancing effects on cognition, alertness, and focus.^[40] 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.^[41] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;^[42] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (k_i=1 nM), which is also the biological target that mediates nicotine's addictive properties.^[43]

Recreational

Nicotine is commonly consumed as a recreational drug for its stimulant effects.^[44] Recreational nicotine products include chewing tobacco, cigars, cigarettes, e-cigarettes, snuff, pipe tobacco, and snus.

Adverse effects

Nicotine has a negative impact on public health worldwide.^[45] Limited data exists on the health effects of continued use of nicotine because the majority of nicotine used is in products containing tobacco.^[46] The health effects of long-term nicotine use is unknown.^[18] The long-term adverse effects of nicotine in the form of snus were reported in studies to incur a slight risk of cardiovascular disease in comparison to tobacco.^[46] The complex effects of nicotine is not entirely understood.^[21] A 2016 Royal College of Physicians report found "nicotine alone in the doses used by smokers represents little if any hazard to the user. ... Questions remain about the safety of nicotine in pregnancy and potential effects on fetal development and mortality".^[47] Some studies of continued use of nicotine replacement products in those who have stopped smoking found no adverse effects from months to several years.^[46] Other studies suggest that people with cardiovascular disease are able to tolerate nicotine replacement products for up to 12 weeks.^[46] A 2013 report Cancer Research UK found that "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".^[19] Experimental research suggests that adolescent nicotine use may harm brain development.^[20] Children exposed to nicotine may have a number of lifelong health issues.^[13] Nicotine in the form of nicotine replacement products is less of a risk than compared to smoking.^[20]

Vascular system

Human epidemiology studies show that nicotine use is not a significant cause of cardiovascular disease.^[48]^[49] A 2016 review suggests that "the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease."^[50] Some studies in people show the possibility that nicotine contributes to acute cardiovascular events in smokers with established cardiovascular disease, and induces pharmacologic effects that might contribute to increased atherosclerosis.^[50] A 2015 review found that nicotine is associated with cardiovascular disease.^[21] A 2015 review found "Nicotine in vitro and in animal models can inhibit apoptosis and enhance angiogenesis, effects that raise concerns about the role of nicotine in promoting the acceleration of atherosclerotic disease."^[51] A 2012 Cochrane review found no evidence of an increased risk of cardiovascular disease with nicotine replacement products.^[52] A 1996 randomized controlled trial using nicotine patches found that serious adverse events were not more frequent among smokers with cardiovascular disease.^[52] A meta-analysis shows that snus consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not associated with heart attacks.^[53] Hence, it is not nicotine, but tobacco smoke's other components which seem to be implicated in ischemic heart disease.^[53] Nicotine increases blood pressure and induces abnormal heart rhythms.^[54] Nicotine affects the heart’s rhythm.^[21] Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.^[55] Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).^[56] Nicotine does not adversely affect serum cholesterol levels,^[48] but may elevate serum cholesterol levels.^[21] Nicotine supports clot formation and aids in plaque formation by enhancing vascular smooth muscle.^[21]

Cancer

Although there is insufficient evidence to classify nicotine as a carcinogen, there is an ongoing debate about whether it functions as a tumor promoter.^[58] In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.^[21] 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.^[20] Nicotine replacement products has not been shown to be associated with cancer in the real world.^[21] Nicotine as a tool to quitting smoking has a good safety history.^[22]

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.^[59]^[60]^[61] Nicotine increases cholinergic signalling and adrenergic signalling in the case of colon cancer,^[62] 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.^[63]^[64] 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).^[65] 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.^[66] The IARC has not evaluated pure nicotine or assigned it to an official carcinogenic classification.

In cancer cells, nicotine promotes the epithelial–mesenchymal transition which makes the cancer cells more resistant to drugs that treat cancer.^[67]

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.^[68]

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.^[69]

Nicotine negatively affects pregnancy outcomes and fetal brain development.^[20] Risks to the child later in life via nicotine exposure during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.^[22] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.^[70]

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.^[71] 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.^[71]

Nicotine is highly addictive.^[12]^[13]^[70] 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.^[72]^[73]^[74] Consequently, repeated daily exposure (possibly excluding oral route) to nicotine can result in accumbal ΔFosB overexpression, in turn causing nicotine addiction.^[72]^[73]

In dependent smokers, smoking during withdrawal returns cognitive abilities to pre-withdrawal levels, but chronic use may not offer cognitive benefits over not smoking.^[20]^[75]

Connections to the use of other substances

In animals it is relatively simple to determine if consumption of a certain drug increases the later attraction of another drug. In humans, where such direct experiments are not possible, longitudinal studies can show if the probability of a substance use is related to earlier use of other substances.^[76]

In mice nicotine increased the probability of later consumption of cocaine and the experiments permitted concrete conclusions on the underlying molecular biological alteration in the brain.^[77] The biological changes in mice correspond to the epidemiological observations in humans that nicotine consumption is coupled to an increased probability of later use of cannabis and cocaine.^[78]

In rats cannabis consumption – earlier in life – increased the later self-administration of nicotine.^[79] A study of drug use of 14,577 US 12th graders showed that alcohol consumption was associated with an increased probability of later use of tobacco, cannabis, and other illegal drugs.^[80]

Overdose

Nicotine is regarded as a potentially lethal poison.^[23] 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.^[14]^[81] 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.^[16] 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.^[82]

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.^[83]^[84]^[85] 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.^[83]^[86] 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.^[87]

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 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."^[88]

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 raised concerns over nicotine overdoses, especially in the possibility of young children ingesting the liquids.^[24] A 2015 Public Health England report 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.^[24] They also noted case reports of suicides by nicotine.^[24] 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.^[24] 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."^[24]

Pharmacology

Pharmacodynamics

Central nervous system

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.^[89] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.^[90]

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.^[91]^[92] This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area.^[92] 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.^[91] These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of euphoria;^[91] however, mild euphoria from nicotine use can occur in some individuals.^[91] Chronic nicotine use inhibits class I and II histone deacetylases in the striatum, where this effect plays a role in nicotine addiction.^[93]^[94]

Sympathetic nervous system

Nicotine also activates the sympathetic nervous system,^[95] 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. 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.^[96]

Adrenal medulla

By binding to ganglion type nicotinic receptors in the adrenal medulla, nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.^[97]

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.^[98]

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.^[99] The elimination half-life of nicotine in the body is around two hours.^[100]

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,^[101] 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) 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.^[102] Under some conditions, other substances may be formed such as myosmine.^[103]

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.^[104]

Chemistry

Nicotine is a hygroscopic, colorless^{[citation needed]} 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.^[106]

Nicotine is readily volatile (vapor pressure 5.5 ㎩ at 25 ℃) and dibasic (K_b1 = 1×10⁻⁶, K_b2 = 1×10⁻¹¹).^[7]

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.^[107] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.^[108]

On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.^[108]

Occurrence and biosynthesis

Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety.^[109] Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae (such as potatoes, tomatoes, and eggplant).^[110]

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.^[111]^[112] 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.^[113]

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.^[114]^[115] Nicotine use is not regulated in competitive sports programs.^[116]

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,^[117] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.^[117]

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.^[11]

Currently, nicotine, even in the form of tobacco dust, is prohibited as a pesticide for organic farming in the United States.^[118]^[119]

In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.^[120] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.^[121]

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.^[122]^[123] Its chemical empirical formula was described by Melsens in 1843,^[124] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,^[125]^[126]^[127]^{[clarification needed]} and it was first synthesized by Amé Pictet and A. Rotschy in 1904.^[128]

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.^[129]

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.^[130] 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."^[131]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,^[132] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.^[133]

Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.^[134]^[135]

Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson's disease.^[136]

There is tentative evidence that nicotinamides may improve depression.^[137]

References

^ ^a ^b 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.
^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Introduction to Pharmacology Third Edition. Abingdon: CRC Press. 2007. pp. 222–223. ISBN 9781420047424.
^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ ^a ^b "Nicotinic acetylcholine receptors: Introduction". IUPHAR Database. International Union of Basic and Clinical Pharmacology. Retrieved 1 September 2014.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 9: Autonomic Nervous System". In Sydor A, Brown RY (eds.). 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 ...
^ ^a ^b Robert L. Metcalf (2007), "Insect Control", Ullmann's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, p. 9
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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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External links

Description of nicotine mechanisms
Erowid Nicotine Vault : Nicotine Material Safety Data Sheet
Thomas, Gareth AO; Rhodes, John; Ingram, John R (2005). "Mechanisms of Disease: Nicotine—a review of its actions in the context of gastrointestinal disease". Nature Clinical Practice Gastroenterology & Hepatology. 2 (11): 536–544. doi:10.1038/ncpgasthep0316.
CDC - NIOSH Pocket Guide to Chemical Hazards

Template:Nootropics

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[Addiction_molecular_neurobiology-73] Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am J Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. 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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@@ Line 79: / Line 79: @@
 Nicotine is highly [[addictive]].<ref name=Grana2014/><ref name=Holbrook2016/> An average [[cigarette]] yields about 2&nbsp;mg of absorbed nicotine, and in lesser doses of that order, the substance acts as a [[stimulant]] in [[mammal]]s, while high amounts (50–100&nbsp;mg) can be harmful.<ref name=inchem>{{cite web|url=http://www.inchem.org/documents/pims/chemical/nicotine.htm#PartTitle:7.%20TOXICOLOGY |title=Nicotine (PIM) |publisher=Inchem.org |accessdate=2012-12-19}}</ref><ref name=overdose>{{cite web | author = Genetic Science Learning Center | title = How Drugs Can Kill | url = http://learn.genetics.utah.edu/content/addiction/drugskill/ }}</ref><ref name=MayerNewLethalDose2013/> 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.<ref name=Caponnetto2012>{{cite journal|last1=Caponnetto|first1=Pasquale|last2=Campagna|first2=Davide|last3=Papale|first3=Gabriella|last4=Russo|first4=Cristina|last5=Polosa|first5=Riccardo|title=The emerging phenomenon of electronic cigarettes|journal=Expert Review of Respiratory Medicine|volume=6|issue=1|year=2012|pages=63–74|issn=1747-6348|doi=10.1586/ers.11.92|pmid=22283580}}</ref>
-The general medical position is that nicotine itself poses few health risks, except among certain vulnerable groups.<ref name=CancerResearch2013/> Nicotine in the form of [[nicotine replacement products]] is less of a risk than [[smoking]].<ref name=SGUS2014/> Nicotine is associated with potential birth defects<ref name=Jerry2015/> and at high-enough doses, [[nicotine poisoning|poisonings]].<ref name=SGUS2014/> ''[[In vitro]]'' studies have associated it with cancer, but carcinogenicity has not been demonstrated ''[[in vivo]]''.<ref name=Jerry2015/> There is inadequate research to demonstrate that nicotine is associated with cancer in humans.<ref name=SGUS2014/> As medicine, nicotine is used to help with [[quitting smoking]] and has good safety in this form.<ref name=Schraufnage2014/> During pregnancy, there are risks to the child later in life for type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.<ref name=Schraufnage2014/> The use of [[electronic cigarette]]s, which are designed to be refilled with nicotine-containing [[e-liquid]], has raised concerns over nicotine overdoses, especially with regard to the possibility of young children ingesting the liquids.<ref name=McNeill2015/>
+The [[health effect]]s of long-term nicotine use is unknown.<ref name=FranckFilion2016/> The general medical position is that nicotine itself poses few health risks, except among certain vulnerable groups.<ref name=CancerResearch2013/> Nicotine in the form of [[nicotine replacement products]] is less of a risk than [[smoking]].<ref name=SGUS2014/> Nicotine is associated with a range of harmful effects, including potential birth defects.<ref name=Jerry2015/> ''[[In vitro]]'' studies have associated it with cancer, but carcinogenicity has not been demonstrated ''[[in vivo]]''.<ref name=Jerry2015/> There is inadequate research to demonstrate that nicotine is associated with cancer in humans.<ref name=SGUS2014/> As medicine, nicotine is used to help with [[quitting smoking]] and has good safety in this form.<ref name=Schraufnage2014/> During pregnancy, there are risks to the child later in life for type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.<ref name=Schraufnage2014/> At high-enough doses, nicotine is associated with [[nicotine poisoning|poisonings]],<ref name=SGUS2014/> and at high-enough doses,<ref name=MayerNewLethalDose2013/> it is potentially lethal.<ref name=Brandon2015/> The use of [[electronic cigarette]]s, which are designed to be refilled with nicotine-containing [[e-liquid]], has raised concerns over nicotine overdoses, especially with regard to the possibility of young children ingesting the liquids.<ref name=McNeill2015/>
 {{TOC limit|3}}
@@ Line 108: / Line 108: @@
 ==Adverse effects==
-According to a 2016 report by the [[Royal College of Physicians]], "nicotine alone in the doses used by smokers represents little if any hazard to the user. ... Questions remain about the safety of nicotine in pregnancy and potential effects on fetal development and mortality".<ref name="RCP">{{cite web|last1=Royal College of Physicians|title=Nicotine without smoke: Tobacco harm reduction|url=https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction-0|website=rcplondon.ac.uk|accessdate=8 May 2016|ref=RCP2016}}</ref> Some studies of continued use of [[nicotine replacement products]] in those who have stopped smoking found no [[adverse effect]]s from months to several years.<ref name=BhatnagarWhitsel2014/> Other studies suggest that people with [[cardiovascular disease]] are able to tolerate nicotine replacement products for up to 12 weeks.<ref name=BhatnagarWhitsel2014>{{cite journal|last1=Bhatnagar|first1=A.|last2=Whitsel|first2=L. P.|last3=Ribisl|first3=K. M.|last4=Bullen|first4=C.|last5=Chaloupka|first5=F.|last6=Piano|first6=M. R.|last7=Robertson|first7=R. M.|last8=McAuley|first8=T.|last9=Goff|first9=D.|last10=Benowitz|first10=N.|title=Electronic Cigarettes: A Policy Statement From the American Heart Association|journal=Circulation|volume=130|issue=16|year=2014|pages=1418–1436|issn=0009-7322|doi=10.1161/CIR.0000000000000107|pmid=25156991}}</ref> A 2013 report [[Cancer Research UK]] found that "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".<ref name=CancerResearch2013>{{cite web|last1=de Andrade|first1=Marisa|last2=Hastings|first2=Gerald|title=Tobacco Harm Reduction and Nicotine Containing Products|url=http://www.cancerresearchuk.org/sites/default/files/tobacco-harm-reduction.pdf|website=Cancer Research UK|pages=8|publisher=Cancer Research UK|accessdate=10 March 2016}}</ref> Experimental research suggests that adolescent nicotine use may harm [[brain development]].<ref name=SGUS2014/> Children exposed to nicotine may have a number of lifelong health issues.<ref name=Holbrook2016>{{cite journal|last1=Holbrook|first1=Bradley D.|title=The effects of nicotine on human fetal development|journal=Birth Defects Research Part C: Embryo Today: Reviews|volume=108|issue=2|pages=181–92|year=2016|issn=1542-975X|doi=10.1002/bdrc.21128|pmid=27297020}}</ref> Nicotine in the form of nicotine replacement products is less of a risk than compared to [[smoking]].<ref name=SGUS2014/>
+Nicotine has a negative impact on [[public health]] worldwide.<ref name=SajjaRahman2016>{{cite journal|author=Sajja RK, Rahman S, Cucullo L| title=Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress.|journal=J Cereb Blood Flow Metab|year=2016|volume=36|issue=3|pages=539-54|doi=10.1177/0271678X15616978|pmc=4794105|pmid=26661236}}</ref> Limited data exists on the [[health effect]]s of continued use of nicotine because the majority of nicotine used is in products containing [[tobacco]].<ref name=BhatnagarWhitsel2014/> The health effects of long-term nicotine use is unknown.<ref name=FranckFilion2016>{{cite journal|last1=Franck|first1=Caroline|last2=Filion|first2=Kristian B.|last3=Kimmelman|first3=Jonathan|last4=Grad|first4=Roland|last5=Eisenberg|first5=Mark J.|title=Ethical considerations of e-cigarette use for tobacco harm reduction|journal=Respiratory Research|volume=17|issue=1|year=2016|issn=1465-993X|doi=10.1186/s12931-016-0370-3|pmc=4869264|pmid=27184265}}</ref> The long-term adverse effects of nicotine in the form of snus were reported in studies to incur a slight risk of cardiovascular disease in comparison to tobacco.<ref name=BhatnagarWhitsel2014/> The complex effects of nicotine is not entirely understood.<ref name=Jerry2015/> A 2016 [[Royal College of Physicians]] report found "nicotine alone in the doses used by smokers represents little if any hazard to the user. ... Questions remain about the safety of nicotine in pregnancy and potential effects on fetal development and mortality".<ref name=Wilder2016>{{cite web|last1=Wilder|first1=Natalie|last2=Daley|first2=Claire|last3=Sugarman|first3=Jane|last4=Partridge|first4=James|title=Nicotine without smoke: Tobacco harm reduction|url=https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction-0|page=125|location=UK|publisher=Royal College of Physicians|date=April 2016}}</ref> Some studies of continued use of [[nicotine replacement products]] in those who have stopped smoking found no [[adverse effect]]s from months to several years.<ref name=BhatnagarWhitsel2014/> Other studies suggest that people with [[cardiovascular disease]] are able to tolerate nicotine replacement products for up to 12 weeks.<ref name=BhatnagarWhitsel2014>{{cite journal|last1=Bhatnagar|first1=A.|last2=Whitsel|first2=L. P.|last3=Ribisl|first3=K. M.|last4=Bullen|first4=C.|last5=Chaloupka|first5=F.|last6=Piano|first6=M. R.|last7=Robertson|first7=R. M.|last8=McAuley|first8=T.|last9=Goff|first9=D.|last10=Benowitz|first10=N.|title=Electronic Cigarettes: A Policy Statement From the American Heart Association|journal=Circulation|volume=130|issue=16|year=2014|pages=1418–1436|issn=0009-7322|doi=10.1161/CIR.0000000000000107|pmid=25156991}}</ref> A 2013 report [[Cancer Research UK]] found that "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".<ref name=CancerResearch2013>{{cite web|last1=de Andrade|first1=Marisa|last2=Hastings|first2=Gerald|title=Tobacco Harm Reduction and Nicotine Containing Products|url=http://www.cancerresearchuk.org/sites/default/files/tobacco-harm-reduction.pdf|website=Cancer Research UK|pages=8|publisher=Cancer Research UK|accessdate=10 March 2016}}</ref> Experimental research suggests that adolescent nicotine use may harm [[brain development]].<ref name=SGUS2014/> Children exposed to nicotine may have a number of lifelong health issues.<ref name=Holbrook2016>{{cite journal|last1=Holbrook|first1=Bradley D.|title=The effects of nicotine on human fetal development|journal=Birth Defects Research Part C: Embryo Today: Reviews|volume=108|issue=2|pages=181–92|year=2016|issn=1542-975X|doi=10.1002/bdrc.21128|pmid=27297020}}</ref> Nicotine in the form of nicotine replacement products is less of a risk than compared to [[smoking]].<ref name=SGUS2014/>
 ===Vascular system===
-Human epidemiology studies show that nicotine use is not a significant cause of cardiovascular disease.<ref name=FarsalinosPolosa2014>{{cite journal|last1=Farsalinos|first1=K. E.|last2=Polosa|first2=R.|title=Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review|journal=Therapeutic Advances in Drug Safety|volume=5|issue=2|year=2014|pages=67–86|issn=2042-0986|doi=10.1177/2042098614524430|pmid=25083263|pmc=4110871}}</ref><ref name=Fagerström2014>{{cite journal|last1=Fagerström|first1=Karl|title=Nicotine: Pharmacology, Toxicity and Therapeutic use|url=http://www.clivebates.com/documents/nicotinescience.pdf|journal=Journal of Smoking Cessation|volume=9|issue=2|year=2014|pages=53–59|issn=1834-2612|doi=10.1017/jsc.2014.27}}</ref> A 2016 review concluded{{FV|date=November 2016}} that "the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease."<ref name=BenowitzBurbank2016>{{cite journal|last1=Benowitz|first1=Neal L.|last2=Burbank|first2=Andrea D.|title=Cardiovascular toxicity of nicotine: Implications for electronic cigarette use|journal=Trends in Cardiovascular Medicine|volume=26|issue=6|year=2016|pages=515–523|issn=1050-1738|doi=10.1016/j.tcm.2016.03.001|pmc=4958544|pmid=27079891}}</ref> A 2015 review found "Nicotine ''in vitro'' and in animal models can inhibit [[apoptosis]] and enhance [[angiogenesis]], effects that raise concerns about the role of nicotine in promoting the acceleration of [[Atherosclerosis|atherosclerotic]] disease."<ref name=MorrisFerence2015>{{cite journal|last1=Morris|first1=Pamela B.|last2=Ference|first2=Brian A.|last3=Jahangir|first3=Eiman|last4=Feldman|first4=Dmitriy N.|last5=Ryan|first5=John J.|last6=Bahrami|first6=Hossein|last7=El-Chami|first7=Mikhael F.|last8=Bhakta|first8=Shyam|last9=Winchester|first9=David E.|last10=Al-Mallah|first10=Mouaz H.|last11=Sanchez Shields|first11=Monica|last12=Deedwania|first12=Prakash|last13=Mehta|first13=Laxmi S.|last14=Phan|first14=Binh An P.|last15=Benowitz|first15=Neal L.|title=Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic Cigarettes|journal=Journal of the American College of Cardiology|volume=66|issue=12|year=2015|pages=1378â€“1391|issn=0735-1097|doi=10.1016/j.jacc.2015.07.037|pmid=26383726}}</ref> A 2012 [[Cochrane review]] found no evidence of an increased risk of cardiovascular disease with nicotine replacement products.<ref name=Cochrane2012>{{Cite journal | author = [[Lindsay F. Stead]], [[Rafael Perera]], [[Chris Bullen]], [[David Mant]], [[Jamie Hartmann-Boyce]], [[Kate Cahill]] & [[Tim Lancaster]]  | title = Nicotine replacement therapy for smoking cessation | journal = [[The Cochrane database of systematic reviews]] | volume = 11 | pages = CD000146 | year = 2012 | month =  | doi = 10.1002/14651858.CD000146.pub4 | pmid = 23152200}}</ref> A 1996 [[randomized controlled trial]] using [[nicotine patch]]es found that [[serious adverse event]]s were not more frequent among smokers with cardiovascular disease.<ref name=Cochrane2012/> A [[meta-analysis]] shows that [[snus]] consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not associated with [[heart attacks]].<ref name=HanssonGalanti2012>{{cite journal|last1=Hansson|first1=Jenny|last2=Galanti|first2=Maria Rosaria|last3=Hergens|first3=Maria-Pia|last4=Fredlund|first4=Peeter|last5=Ahlbom|first5=Anders|last6=Alfredsson|first6=Lars|last7=Bellocco|first7=Rino|last8=Eriksson|first8=Marie|last9=Hallqvist|first9=Johan|last10=Hedblad|first10=Bo|last11=Jansson|first11=Jan-Håkan|last12=Nilsson|first12=Peter|last13=Pedersen|first13=Nancy|last14=Trolle Lagerros|first14=Ylva|last15=Östergren|first15=Per-Olof|last16=Magnusson|first16=Cecilia|title=Use of snus and acute myocardial infarction: pooled analysis of eight prospective observational studies|journal=European Journal of Epidemiology|volume=27|issue=10|year=2012|pages=771–779|issn=0393-2990|doi=10.1007/s10654-012-9704-8|pmid=22722951}}</ref> Hence, it is not nicotine, but tobacco smoke's other components which seem to be implicated in [[ischemic heart disease]].<ref name=HanssonGalanti2012/> Nicotine affects the heart’s rhythm.<ref name=Jerry2015/> Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.<ref name=pmid11166759>{{cite journal |authors=Zhang S, Day I, Ye S |title=Nicotine induced changes in gene expression by human coronary artery endothelial cells |journal=Atherosclerosis |volume=154 |issue=2 |pages=277–83 |date=February 2001 |pmid=11166759 |doi=10.1016/S0021-9150(00)00475-5}}</ref> Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).<ref name=pmid11830264>{{cite journal |authors=Hawkins BT, Brown RC, Davis TP |title=Smoking and ischemic stroke: a role for nicotine? |journal=Trends in Pharmacological Sciences |volume=23 |issue=2 |pages=78–82 |date=February 2002 |doi=10.1016/S0165-6147(02)01893-X |pmid=11830264}}</ref> Nicotine does not adversely affect serum cholesterol levels,<ref name=FarsalinosPolosa2014/> but may elevate serum cholesterol levels.<ref name=Jerry2015/> Nicotine supports clot formation and aids in plaque formation by enhancing [[vascular smooth muscle]].<ref name=Jerry2015/>
+Human epidemiology studies show that nicotine use is not a significant cause of cardiovascular disease.<ref name=FarsalinosPolosa2014>{{cite journal|last1=Farsalinos|first1=K. E.|last2=Polosa|first2=R.|title=Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review|journal=Therapeutic Advances in Drug Safety|volume=5|issue=2|year=2014|pages=67–86|issn=2042-0986|doi=10.1177/2042098614524430|pmid=25083263|pmc=4110871}}</ref><ref name=Fagerström2014>{{cite journal|last1=Fagerström|first1=Karl|title=Nicotine: Pharmacology, Toxicity and Therapeutic use|url=http://www.clivebates.com/documents/nicotinescience.pdf|journal=Journal of Smoking Cessation|volume=9|issue=2|year=2014|pages=53–59|issn=1834-2612|doi=10.1017/jsc.2014.27}}</ref> A 2016 review suggests that "the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease."<ref name=BenowitzBurbank2016>{{cite journal|last1=Benowitz|first1=Neal L.|last2=Burbank|first2=Andrea D.|title=Cardiovascular toxicity of nicotine: Implications for electronic cigarette use|journal=Trends in Cardiovascular Medicine|volume=26|issue=6|year=2016|pages=515–523|issn=1050-1738|doi=10.1016/j.tcm.2016.03.001|pmc=4958544|pmid=27079891}}</ref> Some studies in people show the possibility that nicotine contributes to acute cardiovascular events in smokers with established cardiovascular disease, and induces pharmacologic effects that might contribute to increased [[atherosclerosis]].<ref name=BenowitzBurbank2016/> A 2015 review found that nicotine is associated with cardiovascular disease.<ref name=Jerry2015/> A 2015 review found "Nicotine ''in vitro'' and in animal models can inhibit [[apoptosis]] and enhance [[angiogenesis]], effects that raise concerns about the role of nicotine in promoting the acceleration of atherosclerotic disease."<ref name=MorrisFerence2015>{{cite journal|last1=Morris|first1=Pamela B.|last2=Ference|first2=Brian A.|last3=Jahangir|first3=Eiman|last4=Feldman|first4=Dmitriy N.|last5=Ryan|first5=John J.|last6=Bahrami|first6=Hossein|last7=El-Chami|first7=Mikhael F.|last8=Bhakta|first8=Shyam|last9=Winchester|first9=David E.|last10=Al-Mallah|first10=Mouaz H.|last11=Sanchez Shields|first11=Monica|last12=Deedwania|first12=Prakash|last13=Mehta|first13=Laxmi S.|last14=Phan|first14=Binh An P.|last15=Benowitz|first15=Neal L.|title=Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic Cigarettes|journal=Journal of the American College of Cardiology|volume=66|issue=12|year=2015|pages=1378â€“1391|issn=0735-1097|doi=10.1016/j.jacc.2015.07.037|pmid=26383726}}</ref> A 2012 [[Cochrane review]] found no evidence of an increased risk of cardiovascular disease with nicotine replacement products.<ref name=Cochrane2012>{{Cite journal | author = [[Lindsay F. Stead]], [[Rafael Perera]], [[Chris Bullen]], [[David Mant]], [[Jamie Hartmann-Boyce]], [[Kate Cahill]] & [[Tim Lancaster]]  | title = Nicotine replacement therapy for smoking cessation | journal = [[The Cochrane database of systematic reviews]] | volume = 11 | pages = CD000146 | year = 2012 | month =  | doi = 10.1002/14651858.CD000146.pub4 | pmid = 23152200}}</ref> A 1996 [[randomized controlled trial]] using [[nicotine patch]]es found that [[serious adverse event]]s were not more frequent among smokers with cardiovascular disease.<ref name=Cochrane2012/> A [[meta-analysis]] shows that [[snus]] consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not associated with [[heart attacks]].<ref name=HanssonGalanti2012>{{cite journal|last1=Hansson|first1=Jenny|last2=Galanti|first2=Maria Rosaria|last3=Hergens|first3=Maria-Pia|last4=Fredlund|first4=Peeter|last5=Ahlbom|first5=Anders|last6=Alfredsson|first6=Lars|last7=Bellocco|first7=Rino|last8=Eriksson|first8=Marie|last9=Hallqvist|first9=Johan|last10=Hedblad|first10=Bo|last11=Jansson|first11=Jan-Håkan|last12=Nilsson|first12=Peter|last13=Pedersen|first13=Nancy|last14=Trolle Lagerros|first14=Ylva|last15=Östergren|first15=Per-Olof|last16=Magnusson|first16=Cecilia|title=Use of snus and acute myocardial infarction: pooled analysis of eight prospective observational studies|journal=European Journal of Epidemiology|volume=27|issue=10|year=2012|pages=771–779|issn=0393-2990|doi=10.1007/s10654-012-9704-8|pmid=22722951}}</ref> Hence, it is not nicotine, but tobacco smoke's other components which seem to be implicated in [[ischemic heart disease]].<ref name=HanssonGalanti2012/> Nicotine increases blood pressure and induces abnormal heart rhythms.<ref name=WLF2014>{{cite web|title=WHO Right to Call for E-Cigarette Regulation|url=http://www.worldlungfoundation.org/ht/d/ReleaseDetails/i/32757|publisher=World Lung Federation|date=26 August 2014}}</ref> Nicotine affects the heart’s rhythm.<ref name=Jerry2015/> Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.<ref name=pmid11166759>{{cite journal |authors=Zhang S, Day I, Ye S |title=Nicotine induced changes in gene expression by human coronary artery endothelial cells |journal=Atherosclerosis |volume=154 |issue=2 |pages=277–83 |date=February 2001 |pmid=11166759 |doi=10.1016/S0021-9150(00)00475-5}}</ref> Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).<ref name=pmid11830264>{{cite journal |authors=Hawkins BT, Brown RC, Davis TP |title=Smoking and ischemic stroke: a role for nicotine? |journal=Trends in Pharmacological Sciences |volume=23 |issue=2 |pages=78–82 |date=February 2002 |doi=10.1016/S0165-6147(02)01893-X |pmid=11830264}}</ref> Nicotine does not adversely affect serum cholesterol levels,<ref name=FarsalinosPolosa2014/> but may elevate serum cholesterol levels.<ref name=Jerry2015/> Nicotine supports clot formation and aids in plaque formation by enhancing [[vascular smooth muscle]].<ref name=Jerry2015/>
 ===Cancer===
@@ Line 239: / Line 239: @@
 Little research is available in humans but animal research suggests there is potential benefit from nicotine in [[Parkinson's disease]].<ref>{{cite journal|last1=Barreto|first1=GE|last2=Iarkov|first2=A|last3=Moran|first3=VE|title=Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease|journal=Front Aging Neuroscience|date=Jan 2015|volume=9|issue=6|page=340|doi=10.3389/fnagi.2014.00340|pmc=4288130|pmid=25620929}}</ref>
-There is tentative evidence that [[nicotinamide]]s may improve depression.<ref>{{Cite web|title = http://www.sciencedaily.com/releases/2006/09/060912225448.htm|url = http://www.sciencedaily.com/releases/2006/09/060912225448.htm|website = www.sciencedaily.com|accessdate = 2015-06-11}}</ref>
+There is tentative evidence that [[nicotinamide]]s may improve depression.<ref>{{Cite web|title=Nicotine Lessens Symptoms Of Depression In Nonsmokers|url=http://www.sciencedaily.com/releases/2006/09/060912225448.htm|work=[[Science Daily]]|date=13 September 2006}}</ref>
 ==See also==

v t e Stimulants
Adamantanes	Adapromine Amantadine Bromantane Memantine Rimantadine
Adenosine antagonists	8-Chlorotheophylline 8-Cyclopentyltheophylline 8-Phenyltheophylline Aminophylline Caffeine CGS-15943 Dimethazan Istradefylline Paraxanthine SCH-58261 Theobromine Theophylline
Alkylamines	Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Levopropylhexedrine Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane
Ampakines	CX-516 CX-546 CX-614 CX-691 CX-717 IDRA-21 LY-404,187 LY-503,430 Nooglutyl Org 26576 PEPA S-18986 Sunifiram Unifiram
Arylcyclohexylamines	Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine
Benzazepines	6-Br-APB SKF-77434 SKF-81297 SKF-82958
Cathinones	3-Fluoromethcathinone 3,4-DMMC 4-BMC 4-CMC 4-Methylbuphedrone 4-Methylcathinone 4-MEAP 4-Methylpentedrone Amfepramone Benzedrone Buphedrone Bupropion Butylone Cathinone Dimethylcathinone Ethcathinone Ethylone Flephedrone Hexedrone Isoethcathinone Mephedrone Methcathinone Methedrone Methylenedioxycathinone Methylone Mexedrone N-Ethylbuphedrone N-Ethylhexedrone Pentedrone Pentylone Phthalimidopropiophenone
Cholinergics	A-84,543 A-366,833 ABT-202 ABT-418 AR-R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine PHA-543,613 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A SIB-1553A SSR-180,711 TC-1698 TC-1827 TC-2216 Tebanicline UB-165 Varenicline WAY-317,538
Convulsants	Anatoxin-a Bicuculline DMCM Flurothyl Gabazine Pentetrazol Picrotoxin Strychnine Thujone
Eugeroics	Adrafinil Armodafinil CRL-40,940 CRL-40,941 Fluorenol Modafinil
Oxazolines	4-Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone
Phenethylamines	1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fluoroamphetamine 2-Fluoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fluoroamphetamine 3-Fluoroethamphetamine 3-Methoxyamphetamine 3-Methylamphetamine 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-MMA 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Camfetamine Cathine Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D-Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dobutamine DOPA (Dextrodopa, Levodopa) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethylnorepinephrine Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Feprosidnine Fludorex Formetorex Furfenorex Gepefrine Hexapradol HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine Indanylamphetamine Iofetamine Isoetarine Isoprenaline L-Deprenyl (Selegiline) Lefetamine Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA (midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxamine Methoxyphenamine MMA Methoxyphenamine MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L-Norpseudoephedrine Octopamine Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol (Levosalbutamol) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine
Phenylmorpholines	3-Fluorophenmetrazine Fenbutrazate Fenmetramide G-130 Manifaxine Morazone Morforex Oxaflozane PD-128,907 Phendimetrazine Phenmetrazine 2-Phenyl-3,6-dimethylmorpholine Pseudophenmetrazine Radafaxine
Piperazines	2C-B-BZP 3C-PEP BZP CM156 DBL-583 GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 MeOPP MBZP oMPP Vanoxerine
Piperidines	1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine 2-Benzylpiperidine 2-Methyl-3-phenylpiperidine 3,4-Dichloromethylphenidate 4-Benzylpiperidine 4-Fluoromethylphenidate 4-Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate JZ-IV-10 Methylphenidate (Dexmethylphenidate) Nocaine Phacetoperane Pipradrol Propylphenidate Serdexmethylphenidate SCH-5472
Pyrrolidines	2-Diphenylmethylpyrrolidine 4-Cl-PVP 5-DBFPV α-PPP α-PBP α-PCYP α-PHiP α-PHP α-PHPP α-PVP α-PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone
Racetams	Oxiracetam Phenylpiracetam Phenylpiracetam hydrazide
Tropanes	4-fluorotropacocaine 4'-Fluorococaine Altropane (IACFT) Brasofensine CFT (WIN 35,428) β-CIT (RTI-55) Cocaethylene Cocaine Dichloropane (RTI-111) Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (¹²³I) Norcocaine PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-120 RTI-121 (IPCIT) RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 RTI-354 RTI-371 RTI-386 Salicylmethylecgonine Tesofensine Troparil (β-CPT, WIN 35,065-2) Tropoxane WF-23 WF-33
Tryptamines	4-HO-αMT 4-Methyl-αET 4-Methyl-αMT 5-Chloro-αMT 5-Fluoro-αMT 5-MeO-αET 5-MeO-αMT 5-MeO-DIPT 6-Fluoro-αMT 7-Methyl-αET αET αMT
Others	2-MDP 3,3-Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D-161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI-52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ-7925476 Lazabemide Leptacline Lomevactone LR-5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O-2172 Oxaprotiline PNU-99,194 PRC200-SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH-232 Yohimbine
ATC code: N06B

v t e Treatment of drug dependence (N07B)
Nicotine dependence	Bupropion^# Cytisine Lobeline Mecamylamine Varenicline AATooltip Adrenergic agonist (Clonidine)
Alcohol dependence	AD inhibitor Disulfiram Acamprosate Calcium carbimide Hydrogen cyanamide General anesthetics Nitrous oxide Opioid antagonists Naltrexone Nalmefene Topiramate AATooltip Adrenergic agonist (Clonidine) Baclofen Phenibut
Opioid dependence	AATooltip Adrenergic agonist (Clonidine Lofexidine) Ibogaine Opioids Buprenorphine (+naloxone) Levacetylmethadol Methadone Dihydrocodeine Dihydroetorphine Hydromorphone (extended-release) Morphine (extended-release) Opioid antagonists (Naltrexone Nalmefene)
Benzodiazepine dependence	AATooltip Adrenergic agonist (Clonidine) Benzodiazepines (Diazepam Lorazepam Chlordiazepoxide Oxazepam) Barbiturates (Phenobarbital)

v t e Xenobiotic-sensing receptor modulators
CARTooltip Constitutive androstane receptor	Agonists: 6,7-Dimethylesculetin Amiodarone Artemisinin Benfuracarb Carbamazepine Carvedilol Chlorpromazine Chrysin CITCO Clotrimazole Cyclophosphamide Cypermethrin DHEA (prasterone) Efavirenz Ellagic acid Griseofulvin Methoxychlor Mifepristone Nefazodone Nevirapine Nicardipine Octicizer Permethrin Phenobarbital Phenytoin Pregnanedione (5β-dihydroprogesterone) Reserpine TCPOBOP Telmisartan Tolnaftate Troglitazone Valproic acid Antagonists: 3,17β-Estradiol 3α-Androstanol 3α-Androstenol 3β-Androstanol 17-Androstanol AITC Ethinylestradiol Meclizine Nigramide J Okadaic acid PK-11195 S-07662 T-0901317
PXRTooltip Pregnane X receptor	Agonists: 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone Δ⁴-Androstenedione Δ⁵-Androstenediol Δ⁵-Androstenedione AA-861 Allopregnanediol Allopregnanedione (5α-dihydroprogesterone) Allopregnanolone (brexanolone) Alpha-Lipoic acid Ambrisentan AMI-193 Amlodipine besylate Antimycotics Artemisinin Aurothioglucose Bile acids Bithionol Bosentan Bumecaine Cafestol Cephaloridine Cephradine Chlorpromazine Ciglitazone Clindamycin Clofenvinfos Chloroxine Clotrimazole Colforsin Corticosterone Cyclophosphamide Cyproterone acetate Demecolcine Dexamethasone DHEA (prasterone) DHEA-S (prasterone sulfate) Dibunate sodium Diclazuril Dicloxacillin Dimercaprol Dinaline Docetaxel Docusate calcium Dodecylbenzenesulfonic acid Dronabinol Droxidopa Eburnamonine Ecopipam Enzacamene Epothilone B Erythromycin Famprofazone Febantel Felodipine Fenbendazole Fentanyl Flucloxacillin Fluorometholone Griseofulvin Guggulsterone Haloprogin Hetacillin potassium Hyperforin Hypericum perforatum (St John's wort) Indinavir sulfate Lasalocid sodium Levothyroxine Linolenic acid: α-Linolenic acid and γ-linolenic acid LOE-908 Loratadine Lovastatin Meclizine Metacycline Methylprednisolone Metyrapone Mevastatin Mifepristone Nafcillin Nicardipine Nicotine Nifedipine Nilvadipine Nisoldipine Norelgestromin Omeprazole Orlistat Oxatomide Paclitaxel Phenobarbital Piperine Plicamycin Prednisolone Pregnanediol Pregnanedione (5β-dihydroprogesterone) Pregnanolone Pregnenolone Pregnenolone 16α-carbonitrile Proadifen Progesterone Quingestrone Reserpine Reverse triiodothyronine Rifampicin Rifaximin Rimexolone Riodipine Ritonavir Simvastatin Sirolimus Spironolactone Spiroxatrine SR-12813 Suberoylanilide Sulfisoxazole Suramin Tacrolimus Tenylidone Terconazole Testosterone isocaproate Tetracycline Thiamylal sodium Thiothixene Thonzonium bromide Tianeptine Troglitazone Troleandomycin Tropanyl 3,5-dimethulbenzoate Zafirlukast Zeranol Antagonists: Ketoconazole Sesamin
See also Receptor/signaling modulators