Nicotine: Difference between revisions

NFPA 704
*safety square*
NFPA 704; safety square
	4 1 0

Nicotine
Clinical data
Trade names	Nicorette, Nicotrol
AHFS/Drugs.com	Monograph
Pregnancy; category	AU: D; ;
Dependence; 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: S4 (Prescription only); UK: General sales list (GSL, OTC); US: WARNINGOTC;
Pharmacokinetic data
Bioavailability	20 to 45% (oral), 53% (intranasal), 68% (transdermal)
Protein binding	<5%
Metabolism	Hepatic
Elimination half-life	1-2 hours; 20 hours active metabolite (cotinine)
Excretion	Urine (10-20% (gum), pH-dependent; 30% (inhaled); 10-30% (intranasal))
Identifiers
	IUPAC name 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 ;
CompTox Dashboard (EPA)	DTXSID1020930 ;
ECHA InfoCard	100.000.177
Chemical and physical data
Formula	C10H14N2
Molar mass	162.12 g/mol g·mol−1
3D model (JSmol)	Interactive image;
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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Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae) and a stimulant drug. It is a nicotinic acetylcholine receptor agonist. It is made in the roots and accumulates in the leaves of the plants. It constitutes approximately 0.6–3.0% of the dry weight of tobacco^[2] and is present in the range of 2–7 µg/kg of various edible plants.^[3] It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past^[4]^[5] and nicotine analogs such as imidacloprid are currently widely used.

In smaller doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.^[6]^[7]^[8] This stimulant effect is likely a major contributing factor to the dependence-forming properties of tobacco smoking, nicotine patches, nicotine gum, nicotine inhalers and liquid nicotine vapourizers.^{[citation needed]} According to the American Heart Association, nicotine addiction has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine nicotine addiction are similar to those determining addiction to heroin and cocaine. 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. This was found for all major market categories of cigarettes.^[9]

Research in 2011 found that nicotine inhibits chromatin-modifying enzymes (class I and II histone deacetylases); this inhibition has been shown to increase the ability of cocaine to cause an addiction.^[10]

Psychoactive effects

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.^[11] 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.^[12] Like any stimulant, it may very rarely cause the often uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.^[13]^[14]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, arginine vasopressin, serotonin, dopamine, and beta-endorphin.^[15] ^[16] This release of neurotransmitters and hormones is responsible for most of nicotine's psychoactive effects. Nicotine appears to enhance concentration^[17] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine^[18] and increases sensitivity in brain reward systems.^[19] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.^[20]

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.^[21] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation^[22] and subsequently referred to as "Nesbitt's Paradox."

Medical uses

A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that NRT increases a quitter's chance of success by 50 to 70%.^[23] But in 1990, researchers found that 93% of users returned to smoking within six months.^[24]

Although population level effectiveness has not been demonstrated,^[25]^[26]^[27] 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.

However, in a few situations, smoking has been observed to be of therapeutic value. These are often referred to as "Smoker’s Paradoxes".^[28] Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other substances found in tobacco.

For instance, studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention(PCI).^[28] Risk of ulcerative colitis has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.^[29]^[30] Smoking also appears to interfere with development of Kaposi's sarcoma in patients with HIV.^[31]

Nicotine reduces the chance of preeclampsia,^[32] and atopic disorders such as allergic asthma.^[33]^{[dubious – discuss]} A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.^[34]

Tobacco smoke has been shown to contain compounds capable of inhibiting monoamine oxidase, which is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.^[35]

While tobacco smoking is associated with an increased risk of Alzheimer's disease,^[36] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.^[37] Nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.^[38]^[39]^[40] A study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.^[41]

Studies have indicated that nicotine can be used to help adults suffering from autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are responsible for processing nicotine in the brain.^[42]

Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.^[43]^[44] Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.^[45]

Research at Duke University Medical Center found that nicotine may improve the symptoms of depression.^[46] Nicotine appears to improve ADHD symptoms. Some studies have focused on benefits of nicotine therapy in adults with ADHD.^[47]

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.^[48]

Nicotine (in the form of chewing gum or a transdermal patch) has been explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.^[49]^[50]^[51]

The relationship between smoking and inflammatory bowel disease has been firmly established, but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease.^[52]^[53]

Side effects

Nicotine increases blood pressure and heart rate in humans.^[54] 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]

A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus,^[57] an estrogen-sensitive region of the brain involved in memory formation and retention.

Dependence and withdrawal

Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, research examining its addictive nature has been found to show that nicotine activates the mesolimbic pathway ("reward system") – the circuitry within the brain that regulates feelings of pleasure and euphoria.^[58]

Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be as addictive as cocaine and heroin when used in the form of tobacco.^[59]^[60]^[61] Like other physically addictive drugs,^{[citation needed]} nicotine withdrawal causes downregulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine regulates the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors,^[62] in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity.^[19] This alteration in neuronal chemistry can persist for months following the last administration.

Immunology prevention

Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle operates under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.

These include attaching the nicotine molecule as a hapten to a protein carrier such as keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.

Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over-the-counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.^[63]

Toxicology

NFPA 704

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.^[6]^[64] 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 an oral LD50 of 6.5–13 mg/kg .^[8] Nevertheless nicotine has a relatively high toxicity in comparison to many other alkaloids such as cocaine, which has an LD₅₀of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotine through smoking alone, although overdose can occur through combined use of nicotine patches or nicotine gum and cigarettes at the same time.^[7]^{[unreliable source?]} Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.^[65]

Historically, nicotine has not been regarded as a carcinogen.^{[citation needed]} The IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture.^[66]^[67] Nicotine has been noted to directly cause cancer through a number of different mechanisms such as the activation of MAP Kinases.^[68] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer^[69]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.^[70]^[71] 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).^[72] N-Nitrosonornicotine (NNN), classified by the IARC as a Group 1 carcinogen, is produced endogenously from nitrite in saliva and nicotine.

The teratogenic properties of nicotine have been investigated. According to a study of about 77,000 pregnant women in Denmark,^{[citation needed]} women who used nicotine gum and patches during the early stages of pregnancy were found to face an increased risk of having babies with birth defects. The study showed that women who used nicotine-replacement therapy in the first 12 weeks of pregnancy had a 60% greater risk of having babies with birth defects compared to women who were non-smokers.^{[citation needed]}

Tobacco use among pregnant women has also been correlated to increased frequency of ADHD. Children born to mothers who used tobacco were two and a half times more likely to be diagnosed with ADHD.^[73] Froelich estimated that "exposure to higher levels of lead and prenatal tobacco each accounted for 500,000 additional cases of ADHD in U.S. children".^[74]

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.^[75]

Chemistry

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. 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.^[76]

Optical activity

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.^[77] The salts of (+)-nicotine are usually dextrorotatory.

Biosynthesis

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ¹-pyrrollidium cation.^[78]^[79] 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.^[80]

Pharmacology

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.^[81] The elimination half-life of nicotine in the body is around two hours.^[82]

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,^[83] 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.^[84] Under some conditions, other substances may be formed such as myosmine.^[85]

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.^[86]

Detection of use

Medical detection

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.^[87]^[88] Nicotine use is not regulated in competitive sports programs.^[89]

Pharmacodynamics

Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.

In the central nervous system

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain one of the major contributors of the apparent euphoria and relaxation, and addiction caused by nicotine consumption. This release of dopamine induced by nicotine is thought to occur via a cholinergic–dopaminergic link, mediated by a neuropeptide, ghrelin, in the ventral tegmentum.^[90] Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.^[91] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.^[92]

Tobacco smoke contains anabasine, anatabine, and nornicotine. It also contains the monoamine oxidase inhibitors harman and norharman.^[93] These beta-carboline compounds significantly decrease MAO activity in smokers.^[93]^[94] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOIs and the nicotine is responsible for most of the addictive properties of tobacco smoking.^[95] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.^[96]

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions^[97]^[98] but not habenulopeduncular structures.^[99] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.^[100]

In the sympathetic nervous system

Nicotine also activates the sympathetic nervous system,^[101] acting via splanchnic nerves to the adrenal medulla, stimulates 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.^[102]

In 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.^[103]

Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.^[104]

History and name

Name

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, 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.^{[citation needed]}

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.^[105]^[106] Its chemical empirical formula was described by Melsens in 1843,^[107] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,^[108]^[109]^[110]^{[clarification needed]} and it was first synthesized by Amé Pictet and A. Rotschy in 1904.^[111]

As an insecticide

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 (waste from the tobacco industry) 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.^[5]

Currently, nicotine, even in the form of tobacco dust, is prohibited as a pesticide for organic farming in the United States.^[112]^[113]^{[dead link]}

In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.^[114] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.^[115]

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External links

Nicotine bound to proteins in the PDB
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. doi:10.1038/ncpgasthep0316.
CDC - NIOSH Pocket Guide to Chemical Hazards

Template:Nootropics

Template:Link FA

[FDA-AllBoxedWarnings-1] "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.

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[4] 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.^{[page needed]}

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[overdose-7] Genetic Science Learning Center. "How Drugs Can Kill".

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[pmid19020025-100] Pons S, Fattore L, Cossu G; et al. (November 2008). "Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration". J. Neurosci. 28 (47): 12318–27. doi:10.1523/JNEUROSCI.3918-08.2008. PMC 2819191. PMID 19020025. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

[101] Yoshida T, Sakane N, Umekawa T, Kondo M (Jan 1994). "Effect of nicotine on sympathetic nervous system activity of mice subjected to immobilization stress". Physiol. Behav. 55 (1): 53–7. doi:10.1016/0031-9384(94)90009-4. PMID 8140174.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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[Marieb-103] Elaine N. Marieb and Katja Hoehn (2007). Human Anatomy & Physiology (7th Ed.). Pearson. pp. ?. ISBN 0-8053-5909-5.^{[page needed]}

[104] Bhalala, Oneil (Spring 2003). "Detection of Cotinine in Blood Plasma by HPLC MS/MS". MIT Undergraduate Research Journal. 8: 45–50.

[105] Posselt, W.; Reimann, L. (1828). "Chemische Untersuchung des Tabaks und Darstellung eines eigenthümlich wirksamen Prinzips dieser Pflanze". Magazin für Pharmacie (in German). 6 (24): 138–161. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)CS1 maint: multiple names: authors list (link)

[pmid16463054-106] Henningfield JE, Zeller M (March 2006). "Nicotine psychopharmacology research contributions to United States and global tobacco regulation: a look back and a look forward". Psychopharmacology (Berl.). 184 (3–4): 286–91. doi:10.1007/s00213-006-0308-4. PMID 16463054.

[107] Melsens, Louis-Henri-Frédéric (1843) "Note sur la nicotine," Annales de chimie et de physique, third series, vol. 9, pages 465-479; see especially page 470. [Note: The empirical formula that Melsens provides is incorrect because at that time, chemists used the wrong atomic mass for carbon (6 instead of 12).]

[108] Pinner, A.; Wolffenstein, R. (1891). "Ueber Nicotin". Berichte der deutschen chemischen Gesellschaft. 24: 1373. doi:10.1002/cber.189102401242.

[109] Pinner, A. (1893). "Ueber Nicotin. Die Constitution des Alkaloïds". Berichte der deutschen chemischen Gesellschaft. 26: 292. doi:10.1002/cber.18930260165.

[110] Pinner, A. (1893). "Ueber Nicotin. I. Mitteilung". Archiv der Pharmazie. 231 (5–6): 378. doi:10.1002/ardp.18932310508.

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[112] US Code of Federal Regulations. 7 CFR 205.602 - Nonsynthetic substances prohibited for use in organic crop production

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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 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 JJC8-088 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)