Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco.[16] Nicotine also occurs in trace amounts (parts per billion) in edible Solanaceae plants, such as potatoes, tomatoes, and eggplants, and in tea leaves, at levels far too low to cause significant pharmacological or addictive effects.[17] Nicotine, an antiherbivore toxin, was historically used as an insecticide;[18][19]neonicotinoids, like imidacloprid, are structurally similar and highly effective, widely used insecticides. Synthetic mimetics of nicotine also include FDA-approved therapeutic agents varenicline for smoking cessation[20] and levamisole, a veterinary antihelminthic.[21]
Nicotine is highly addictive.[22][23][24] Slow-release forms (gums and patches, when used correctly) can be less addictive and help in quitting.[25][26][27][28] Animal research suggests that monoamine oxidase inhibitors present in tobacco smoke may enhance nicotine's addictive properties.[29][30] An average cigarette yields about 2mg of absorbed nicotine.[31] The estimated lower dose limit for fatal outcomes is 500–1,000mg of ingested nicotine for an adult (6.5–13mg/kg), but the median lethal dose in humans remains unknown.[29][31][32] High doses are known to cause nicotine poisoning, organ failure, and death through paralysis of respiratory muscles,[33][34] though serious or fatal overdoses are rare.[35]
Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence.[36]Nicotine dependence involves tolerance, sensitization,[37]physical dependence, and psychological dependence,[38] which can cause distress.[39][40]Nicotine withdrawal symptoms include depression, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances.[2] Mild nicotine withdrawal symptoms are measurable in unrestricted smokers, who experience normal moods only as their blood nicotine levels peak, with each cigarette.[41] On quitting, withdrawal symptoms worsen sharply, then gradually improve to a normal state, with some long-lasting molecular effects reverting to normal after 1-3 months or longer.[42][43][44][45][41]
Nicotine use for quitting smoking, as part of engineered nicotine delivery systems to reduce tobacco's harms, has a good safety history.[46][47] It is a teratogen, causing birth defects in humans.[48][49] Animal studies suggest nicotine may impair adolescent cognitive development, but its relevance to human brain development is debated.[50][29] At low doses, it has a mild analgesic effect.[51] Recent research indicates that nicotine exerts broad, mostly immunosuppressive effects on immune function—potentially aggravating cancers while treating autoimmune diseases—and mixed CNS effects, from disruption to neuroprotection.[52][53][54][55] "Nicotine is not generally considered to be a carcinogen," and the causal link between exposure to nicotine and risk for cancer cannot be established due to lack of evidence, per IARC and US Surgeon General.[33][56][57]
The primary therapeutic use of nicotine is treating nicotine dependence to eliminate smoking and the damage it does to health. Nicotine itself is not a standalone cessation tool; its efficacy in smoking cessation relies on nicotine replacement therapy (NRT) delivery systems, which vary formulations (e.g., transdermal patches and lozenges for steady release versus oral gum, inhalers, and nasal sprays for acute relief) to control and modify how much nicotine is delivered and absorbed, and to mimic tobacco pharmacokinetics without harmful byproducts.[47]
A 2018 Cochrane Collaboration review found high-quality evidence that all current forms of nicotine replacement therapy (gum, patch, lozenges, inhaler, and nasal spray) increase the chances of successfully quitting smoking by 50–60%, regardless of setting.[47]
Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.[58]
In contrast to recreational nicotine products, which have been designed to maximize the likelihood of addiction, nicotine replacement products (NRTs) are designed to minimize addictiveness.[33]:112 The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.[39]
Pesticide
Nicotine has been used as an insecticide since at least 1690, in the form of tobacco extracts or as pure nicotine sulphate[19][59][60] (although other components of tobacco also seem to have pesticide effects).[61] It acts on the nicotinic acetylcholine receptor, and gave the receptor its name. Nicotine is in IRAC group 4B. Nicotine insecticides have been banned in the US since 2014,[62] including use on organic crops,[63] and caution is recommended for small gardeners.[64] Nicotine pesticides have been banned in the EU since 2009.[65] Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels.[65][66]Neonicotinoids, such as imidacloprid, which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016.[67][59]
Performance
Nicotine-containing products are sometimes used for the performance-enhancing effects of nicotine on cognition.[68] A 2010 meta-analysis of 41double-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.[69] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;[70] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (ki=1nM), which is also the biological target that mediates nicotine's addictive properties.[71] Nicotine has potential beneficial effects, but it also has paradoxical effects, which may be due to the inverted U-shape of the dose-response curve or pharmacokinetic features.[72]
Nicotine use for tobacco cessation has few contraindications.[79]
It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014.[80] It is therefore not recommended to adolescents.[81] It is not safe to use nicotine during pregnancy or breastfeeding, although it is safer than smoking. The desirability of NRT use in pregnancy is therefore debated.[82][83][84]
Randomized trials and observational studies of nicotine replacement therapy in cardiovascular patients show no increase in adverse cardiovascular events compared to those treated with placebo.[85] Using nicotine products during cancer treatment may be contraindicated, as nicotine may promote tumour growth, but temporary use of NRTs to quit smoking may be advised for harm reduction.[86]
Nicotine is classified as a poison,[89][90] and it is "extremely hazardous".[91] The CDC says it is "toxic to developing fetuses and is a health danger for pregnant women." It can harm brain development up to age twenty-five, and early use of nicotine can predispose young people to smoking and drug use.[92] However, at doses typically used by consumers, it presents little if any hazard to adult users.[93][94][95] Although at low amounts nicotine has a mild analgesic effect,[51] at sufficiently high doses nicotine may result in nausea, vomiting, diarrhea, salivation, bradycardia, and possibly seizures, hypoventilation, and death.[96]
Sleep
Nicotine reduces the amount of rapid eye movement (REM) sleep, slow-wave sleep (SWS), and total sleep time in healthy nonsmokers given nicotine via a transdermal patch, and the reduction is dose-dependent.[97] Acute nicotine intoxication has been found to significantly reduce total sleep time and increase REM latency, sleep onset latency, and non-rapid eye movement (NREM) stage 2 sleep time.[97][98] Depressive non-smokers experience mood and sleep improvements under nicotine administration; however, subsequent nicotine withdrawal has a negative effect on both mood and sleep.[99]
Cardiovascular system
Nicotine exerts several significant effects on the cardiovascular system. Primarily, it stimulates the sympathetic nervous system, leading to the release of catecholamines. This activation results in an increase in heart rate and blood pressure, as well as enhanced myocardial contractility, which raises the workload on the heart. Additionally, nicotine causes systemic vasoconstriction, including constriction of coronary arteries, which can reduce blood flow to the heart. Long-term exposure to nicotine may impair endothelial function, potentially contributing to atherosclerosis. Furthermore, nicotine has been associated with the development of cardiac arrhythmias, particularly in individuals who already have underlying heart disease.[100]
The effects of nicotine can be differentiated between short-term and long-term use. Short-term nicotine use, such as that associated with nicotine replacement therapy (NRT) for smoking cessation, appears to pose little cardiovascular risk, even for patients with known cardiovascular conditions. In contrast, longer-term nicotine use may not accelerate atherosclerosis but could contribute to acute cardiovascular events in those with pre-existing cardiovascular disease. Many severe cardiovascular effects traditionally associated with smoking may not be solely attributable to nicotine itself. Cigarette smoke contains numerous other potentially cardiotoxic substances, including carbon monoxide and oxidant gases.[100]
A 2016 review of the cardiovascular toxicity of nicotine concluded, "Based on current knowledge, we believe that the cardiovascular risks of nicotine from e-cigarette use in people without cardiovascular disease are quite low. We have concerns that nicotine from e-cigarettes could pose some risk for users with cardiovascular disease."[100]
A 2018 Cochrane review found that, in rare cases, nicotine replacement therapy can cause non-ischemic chest pain (i.e., chest pain that is unrelated to a heart attack) and heart palpitations, but does not increase the incidence of serious cardiac adverse events (i.e., myocardial infarction, stroke, and cardiac death) relative to controls.[47]
Blood pressure
In the short term, nicotine causes a transient increase in blood pressure. Long term, epidemiological studies generally show increased blood pressure and hypertension among nicotine users.[100]
Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2). Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37kilodalton) ΔFosB isoforms persist in the D1-typemedium spiny neurons of the nucleus accumbens for up to 2months.[101][102]
Nicotine is highly addictive but paradoxically has quite weak reinforcing property compared to other drugs of abuse in various animals.[23][24][103][104] Its addictiveness depends on how it is administered and also depends upon form in which nicotine is used.[27] Animal research suggests that monoamine oxidase inhibitors, acetaldehyde[104][105] and other constituents in tobacco smoke may enhance its addictiveness.[29][30]Nicotine dependence involves aspects of both psychological dependence and physical dependence, since discontinuation of extended use has been shown to produce both affective (e.g., anxiety, irritability, craving, anhedonia) and somatic (mild motor dysfunctions such as tremor) withdrawal symptoms.[2] Withdrawal symptoms peak in one to three days[106] and can persist for several weeks.[107] Even though other drugs of dependence can have withdrawal states lasting 6 months or longer, this does not appear to occur with cigarette withdrawal.[108]
Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms.[41] These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette.[41] Smokers have a worse mood than they typically would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking.[41] Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers.[109][110]
In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels.[111] The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal.[41] Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar.[41]
Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression (i.e., produces phosphorylated ΔFosB isoforms) in the nucleus accumbens when inhaled or injected frequently or at high doses, but not necessarily when ingested.[112][113][114] Consequently, high daily exposure (possibly excluding oral route) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.[112][113]
Cancer
Contrary to popular belief, nicotine itself does not cause cancer in humans,[57][115] although it is unclear whether it functions as a tumor promoteras of 2012[update].[116] A 2018 report by the US National Academies of Sciences, Engineering, and Medicine concludes, "[w]hile it is biologically plausible that nicotine can act as a tumor promoter, the existing body of evidence indicates this is unlikely to translate into increased risk of human cancer."[117]
Nicotine promotes lung cancer development by enhancing proliferation, angiogenesis, migration, invasion, and epithelial–mesenchymal transition (EMT) via nAChRs, which are present in lung cancer cells.[119] Additionally, nicotine-induced EMT contributes to drug resistance in cancer cells.[120]
Nicotine in tobacco can form carcinogenic tobacco-specific nitrosamines through a nitrosation reaction. This occurs mostly in the curing and processing of tobacco. However, nicotine in the mouth and stomach can react to form N-nitrosonornicotine,[121] a known type 1 carcinogen,[122] suggesting that consumption of non-tobacco forms of nicotine may still play a role in carcinogenesis.[123]
Nicotine has been shown to produce birth defects in some animal species, but not others;[49] consequently, it is considered to be a possible teratogen in humans.[49] In animal studies that resulted in birth defects, researchers found that nicotine negatively affects fetal brain development and pregnancy outcomes;[49][33] the negative effects on early brain development are associated with abnormalities in brain metabolism and neurotransmitter system function.[127] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.[128]
Nicotine exposure in utero is responsible for several complications of pregnancy and birth: pregnant women who smoke are at greater risk for both miscarriage and stillbirth and infants exposed to nicotine in utero tend to have lower birth weights.[129] A McMaster University research group observed in 2010 that rats exposed to nicotine in the womb (via parenteral infusion) later in life had conditions including type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.[130]
It is unlikely that a person would overdose on nicotine through smoking alone. The US Food and Drug Administration (FDA) stated in 2013 that there are no significant safety concerns associated with the use of more than one form of over-the-counter (OTC) nicotine replacement therapy at the same time, or using OTC NRT at the same time as another nicotine-containing product, like cigarettes.[131] The median lethal dose of nicotine in humans is unknown.[32][31] Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50 of 127mg/kg when administered to mice.[132] At sufficiently high doses, it is associated with nicotine poisoning,[33] which, while common in children (in whom poisonous and lethal levels occur at lower doses per kilogram of body weight[51]) rarely results in significant morbidity or death.[49] The estimated lower dose limit for fatal outcomes is 500–1,000mg of ingested nicotine for an adult (6.5–13mg/kg).[29][31]
The initial symptoms of a nicotine overdose typically include nausea, vomiting, diarrhea, hypersalivation, abdominal pain, tachycardia (rapid heart rate), hypertension (high blood pressure), tachypnea (rapid breathing), headache, dizziness, pallor (pale skin), auditory or visual disturbances, and perspiration, followed shortly after by marked bradycardia (slow heart rate), bradypnea (slow breathing), and hypotension (low blood pressure).[49] An increased respiratory rate (i.e., tachypnea) is one of the primary signs of nicotine poisoning.[49] At sufficiently high doses, somnolence (sleepiness or drowsiness), confusion, syncope (loss of consciousness from fainting), shortness of breath, marked weakness, seizures, and coma may occur.[7][49] Lethal nicotine poisoning rapidly produces seizures, and death– which may occur within minutes– is believed to be due to respiratory paralysis.[49]
Toxicity
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 (GTS),[49] accidental ingestion of tobacco or tobacco products, or ingestion of nicotine-containing plants.[133][134][135] People who harvest or cultivate tobacco may experience 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.[133][136] 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 0.5mg/m3 skin exposure over an 8-hour workday. The US National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 0.5mg/m3 skin exposure over an 8-hour workday. At environmental levels of 5mg/m3, nicotine is immediately dangerous to life and health.[137]
Nicotine and cigarette smoke both induce the expression of liver enzymes (e.g., certain cytochrome P450 proteins) which metabolize drugs, leading to the potential for alterations in drug metabolism.[87]
Possible alteration of nicotine absorption through the nasal cavity from the nicotine nasal spray by nasal vasoconstrictors (e.g., xylometazoline).[87]
Possible alteration of nicotine absorption through oral mucosa from nicotine gum and lozenges by food and drink that modify salivarypH.[87]
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".[138][139] 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.[140] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[141] 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.[142][143] At very high doses it dampens neuronal activity.[144] Nicotine induces both behavioral stimulation and anxiety in animals.[7] Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.[145]
Chronic exposure to nicotine induces several molecular changes in neuronal systems, particularly within the mesolimbic dopamine pathway and associated circuits. These adaptations include desensitization and upregulation of nAChRs and downregulation of related enzymes (e.g. class I and II histone deacetylases in the striatum), alterations in transcription factors, and modifications to dopamine synthesis and release.[149][150]
Nicotine binds to presynaptic and postsynaptic nAChRs, leading to initial activation followed by desensitization—a conformational shift rendering receptors temporarily unresponsive.[151][152] With repeated exposure, this promotes upregulation, an increase in receptor density, observed in brain regions such as the ventral tegmental area and striatum within 3-7 days after chronic nicotine exposure in animal models.[153] Human imaging studies show this upregulation is temporary and returns to baseline levels in nonsmokers by approximately 21 days after smoking cessation.[154]
Chronic nicotine also leads to accumulation of the transcription factor ΔFosB in dopamine D1-type medium spiny neurons of the nucleus accumbens, a process implicated in sustained reward pathway modifications.[42] This elevation is longer-lasting and persists for 1–2 months following cessation in animal models before becoming undetectable.
Additionally, positron emission tomography (PET) studies indicate reduced presynaptic dopamine synthesis capacity in the striatum of chronic smokers, as measured by 18F-DOPA uptake. This deficit, approximately 15–20% lower than in nonsmokers, normalizes after about 3 months of abstinence.[43][44]
A 2016 study found that nicotine exposure creates long-lasting malleable circuits 7 months after the initial exposure to nicotine and 6 months after stopping its administration.[45] Other studies suggest broader neuronal recovery, such as normalization of dopamine transporter (DAT) levels in reward centers, may extend up to 12–14 months in some cases of substance dependence affecting dopamine levels, though specific data for nicotine are limited.[155]
Sympathetic nervous system
Effect of nicotine on chromaffin cells
Nicotine also activates the sympathetic nervous system,[156] 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.[citation needed]
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,[162] 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".
Cotinine is an active metabolite of nicotine that remains in the blood with a half-life of 18–20hours, making it easier to analyze due to longer half-life than that of nicotine itself.[163]
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.[164] Under some conditions, other substances may be formed such as myosmine.[165][166]
Nicotine's absorption is modulated by its ionization state, governed by pH relative to pKa values (8.10 for pyrrolidine nitrogen, 3.41 for pyridine). At physiological pH (~7.4), it's mostly monoprotonated (cationic); above pH 8, it becomes unprotonated free-base, which is lipophilic and volatile[15]. The distribution of nicotine among its free-base and protonated forms in aerosolised nicotine affects inhalability; it has been manipulated in tobacco smoke and now in electronic cigarettes by the use of acids to de-freebase nicotine and form 'nicotine salts'[168].
Free-base nicotine enables rapid membrane diffusion and higher bioavailability in early tobacco/oral studies. Yet, recent e-cigarette research contradicts this: protonated salts (e.g., nicotine benzoate, lactate, levulinate from acid addition) yield higher Cmax and faster onset than equivalent free-base[15]. For example, 2% benzoate salt produced 3x higher Cmax in human puffing trials. Notably, Cmax of protonated nicotine salts appears independent of the composition and identity of the counter anions (e.g., benzoate, lactate, levulinate) forming the salts for higher administered nicotine formulations[169].
These effects stem from aerosol dynamics—salts form low-volatility submicron particles for deeper lung deposition and less exhalation loss, versus free-base's superficial deposition. Sensorily, free-base delivers a harsh throat hit, while salts allow smoother high-dose inhalation, boosting appeal and intake[15].
Metabolism
Nicotine decreases hunger and as a consequence food consumption, alongside increasing energy expenditure.[170][171] The majority of research shows that nicotine reduces body weight, but some researchers have found that nicotine may result in weight gain under specific types of eating habits in animal models.[171] Nicotine effect on weight appears to result from nicotine's stimulation of α3β4 nAChR receptors located in the POMC neurons in the arcuate nucleus and subsequently the melanocortin system, especially the melanocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus, thus modulating feeding inhibition.[148][171] POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.[171]
Nicotine is a hygroscopic, colorless[91] to yellow-brown, oily liquid, that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its neutral amine base form between 60°C and 210°C. It is a dibasic nitrogenous base, having Kb1=1×10−6, Kb2=1×10−11.[173] It readily forms ammonium salts with acids that are usually solid and water-soluble. Its flash point is 95°C and its auto-ignition temperature is 244°C.[174] Nicotine is volatile (vapor pressure 5.5 Pa at 25°C)[173] On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (niacin, a B3 vitamer), and methylamine.[175]
Nicotine is chiral and hence 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.[176] (−)-nicotine is more toxic than (+)-nicotine.[177] The salts of (−)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids.[175] The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180°C.[175]Anabasine is a structural isomer of nicotine, as both compounds have the molecular formulaC10H14N2.
Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer.[178] Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers.[179] This suggests that tobacco-derived and synthetic nicotine can be determined by measuring the ratio of the two different enantiomers, although strategies exist for adjusting the relative levels of the enantiomers or performing a synthesis that only leads to the S-enantiomer, and synthetic stereospecific nicotine has now arrived on the market to consumers of electronic cigarette products.[180] There is limited data on the relative physiological effects of these two enantiomers, especially in people. However, the studies to date indicate that (S)-nicotine is more potent than (R)-nicotine and (S)-nicotine causes stronger sensations or irritation than (R)-nicotine. Studies have not been adequate to determine the relative addictiveness of the two enantiomers in people.
Structure of protonated nicotine (left) and structure of the counterion benzoate (right). This combination is used in some vaping products to increase nicotine delivery to the lung.
The first laboratory preparation of nicotine (as its racemate) was described in 1904.[182]
The starting material was an N-substituted pyrrole derivative, which was heated to convert it by a [1,5] sigmatropic shift to the isomer with a carbon bond between the pyrrole and pyridine rings, followed by methylation and selective reduction of the pyrrole ring using tin and hydrochloric acid.[182][183] Many other syntheses of nicotine, in both racemic and chiral forms have since been published.[184]
Biosynthesis
Nicotine biosynthesis
The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that comprise nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from nicotinic acid the pyrrolidine is derived from N-methyl-Δ1-pyrrollidium cation.[185][186] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for nicotinic acid 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-amino 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 phosphoribosyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form nicotinic acid mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce nicotinic acid via the conversion of nicotinamide by the enzyme nicotinamidase.[citation needed]
The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methyl putrescine then undergoes deamination into 4-methylaminobutanal by the N-methyl putrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[citation needed]
The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and nicotinic acid. 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 nicotinic acid 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.[187]
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.[188][189] Nicotine use is not regulated in competitive sports programs.[190]
Methods for analysis of enantiomers
Methods for measuring the two enantiomers are straightforward and include normal-phase liquid chromatography,[178] liquid chromatography with a chiral column.[191] However, since methods can be used to alter the two enantiomers, it may not be possible to distinguish tobacco-derived from synthetic nicotine simply by measuring the levels of the two enantiomers. A new approach uses hydrogen and deuterium nuclear magnetic resonance to distinguish tobacco-derived and synthetic nicotine based on differences the substrates used in the natural synthetic pathway performed in the tobacco plant and the substrates most used in synthesis.[192] Another approach measures the carbon-14 content which also differs between natural and laboratory-based tobacco.[193] These methods remain to be fully evaluated and validated using a wide range of samples.
Analogues and derivatives
Analogues and derivatives of nicotine are known.[194][195][196][197][198] These compounds, often structurally similar and sharing affinity for nicotinic acetylcholine receptors, have applications in pharmacology (e.g., smoking cessation), pest control, and neuroscience research (e.g., multiple domain cognitive enhancement, neuroprotection).[199][200]
Nicotine is a secondary metabolite produced in a variety of plants in the family Solanaceae, most notably in tobacco Nicotiana tabacum, where it can be found at high concentrations of 0.5 to 7.5%.[202] Nicotine is also present in other tobacco species, such as Nicotiana rustica (in amounts of 2–14%).[173] Nicotine production is strongly induced in response to wounding as part of a jasmonate-dependent reaction.[203] Specialist insects on tobacco, such as the tobacco hornworm (Manduca sexta), have a number of adaptations to the detoxification and even adaptive re-purposing of nicotine.[204] Nicotine is also found at low concentrations in the nectar of tobacco plants, where it may promote outcrossing by affecting the behavior of hummingbird pollinators.[205]
Nicotine occurs in smaller amounts (varying from 2–7μg/kg, or 20–70 millionths of a percent wet weight[17]) in other Solanaceaeous plants, including some crop species such as potatoes, tomatoes, eggplant, and peppers,[17][206] as well as non-crop species such as Duboisia hopwoodii.[173] The amounts of nicotine in tomatoes lowers substantially as the fruit ripens.[17] A 1999 report found "In some papers it is suggested that the contribution of dietary nicotine intake is significant when compared with exposure to ETS [environmental tobacco smoke] or by active smoking of small numbers of cigarettes. Others consider the dietary intake to be negligible unless inordinately large amounts of specific vegetables are consumed."[17] The amount of nicotine eaten per day is roughly around 1.4 and 2.25μg/day at the 95th percentile.[17] These numbers may be low due to insufficient food intake data.[17] The concentrations of nicotine in vegetables are difficult to measure accurately, since they are very low (parts per billion range).[207] Pure nicotine tastes "terrible".[91]
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,[215] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.[215] However, the "holy herb", tobacco, had first reached Europe by the early 1530s, brought by Spanish explorers.[216]
Since then, tobacco quickly gained traction in Europe for its stimulating effects, driven by nicotine's now-known addictive and pharmacological properties. By the early 17th century, this allure fueled its mercilessly laborious cultivation as a cash crop in the Virginia colonies, where John Rolfe's introduction in 1612 rescued Jamestown from economic collapse and famine, transforming it into a prosperous export hub with over 20,000 pounds shipped by 1619 and laying the groundwork for transatlantic trade.[217] From the 17th century onward, tobacco smoking became virtually central to European social, economic, and cultural history and beyond, entrenching itself in daily rituals, trade networks, and even international conflicts.[217]
By the late 17th century, tobacco was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[19]
The nicotine content of popular American-brand cigarettes has increased over time, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.[218]
Although methods of production of synthetic nicotine have existed for decades,[219] it was believed that the cost of making nicotine by laboratory synthesis was cost prohibitive compared to extracting nicotine from tobacco.[220] However, recently synthetic nicotine started to be found in different brands of e-cigarettes and oral pouches and marketed as "tobacco-free."[221]
The US FDA is tasked with reviewing tobacco products such as e-cigarettes and determining which can be authorized for sale. In response to the likelihood that FDA would not authorize many e-cigarettes to be marketed, e-cigarette companies began marketing products that they claimed to contain nicotine that were not made or derived from tobacco, but contained synthetic nicotine instead, and thus, would be outside FDA's tobacco regulatory authority.[222] Similarly, nicotine pouches that claimed to contain non-tobacco (synthetic) nicotine were also introduced. The cost of synthetic nicotine has decreased as the market for the product increased. In March 2022, the U.S. Congress passed a law (the Consolidated Appropriations Act, 2022) that expanded FDA's tobacco regulatory authority to include tobacco products containing nicotine from any source, thereby including products made with synthetic nicotine.
In the United States, nicotine products and nicotine replacement therapy products like Nicotrol are only available to people 18 and above; proof of age is required; not for sale in vending machine or from any source where proof of age cannot be verified. As of 2019, the minimum age to purchase tobacco in the US is 21 at the federal level.[223]
In the European Union, the minimum age to purchase nicotine products is 18. However, there is no minimum age requirement to use tobacco or nicotine products.[224]
In the United Kingdom, the Tobacco and Related Products Regulations 2016 implemented the European directive 2014/40/EU, amended by Tobacco Products and Nicotine Inhaling Products (Amendment etc.) (EU Exit) Regulations 2019 and the Tobacco Products and Nicotine Inhaling Products (Amendment) (EU Exit) Regulations 2020. Additionally other regulations limit advertising, sale and display of tobacco products and other products containing nicotine for human consumption. The Sunak government proposed banning disposable vapes to limit their appeal and affordability for children and to reduce the amount of waste generated.
In some anti-smoking literature, the harm that tobacco smoking and nicotine addiction does is personified as Nick O'Teen, represented as a humanoid with some aspect of a cigarette or cigarette butt about him or his clothes and hat.[225] Nick O'Teen was a villain that was created for the Health Education Council. The character was featured in three animated anti-smoking public service announcements in which he tries to get kids addicted to cigarettes before being foiled by the DC Comics character Superman.[225]
Nicotine was often compared to caffeine in advertisements in the 1980s by the tobacco industry, and later in the 2010s by the electronic cigarettes industry, in an effort to reduce the stigmatization and the public perception of the risks associated with nicotine use.[226]
Research
Central nervous system
While acute/initial nicotine intake causes activation of neuronal nicotinic receptors, chronic low doses of nicotine use leads to desensitization of those receptors (due to the development of tolerance) and results in an antidepressant effect, with early research showing low dose nicotine patches could be an effective treatment of major depressive disorder in non-smokers.[227] Nicotine anti-depressant effects have been documented in murine research.[54]
Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[228] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[229]
Smoking is associated with a decreased risk of Parkinson's disease; however, it is unknown whether this is due to people with healthier brain dopaminergic reward centers (the area of the brain affected by Parkinson's) being more likely to enjoy smoking and thus pick up the habit, nicotine directly acting as a neuroprotective agent, or other compounds in cigarette smoke acting as neuroprotective agents.[230]
Nicotine may partly attenuate sensory gating and attentional deficits associated with schizophrenia. Short-term use of transdermal nicotine was found to improve subjects' reaction time and alertness in given tasks. Nicotine was not found to improve negative, positive, or other cognitive symptoms of schizophrenia.[231]
Nicotine dependence pathophysiology in heavy smokers suggests less efficient network architecture in the brain and disruptions in the topological organization of brain networks, with the altered brain network metrics correlated with the duration of cigarette use and the severity of nicotine dependence.[232]
Some long-term effects of nicotine may be irreversible because "it is entirely possible that doses of nicotine achieved in the brains of human smokers can damage or kill mHb [medial habenula] neurons that regulate nicotine avoidance behaviors", but more studies are needed to elucidate this underlying mechanism of nicotine-induced degeneration of the mHb-IPn circuit .[233]
Although some of its effects are pro-inflammatory (e.g. inducing prostaglandinE2 production), nicotine effects are mostly anti-inflammatory.[176][235] Nicotine suppresses the innate and adaptive immune response by reducing the secretion of pro-inflammatory cytokines (IL-1, IL-6, TNF-α, IL-17, IL-21, and IL-22), reducing proliferation and activation of T-cells, and suppressing the activation of dendritic cells.[176] As a result, cell-mediated immunity against infection and neoplastic diseases is downregulated.[176] In vitro and animal studies also showed that nicotine reduces T cell receptor (TCR) signaling and suppresses the production and secretion of antibodies.[176]
A photoactivatable form of nicotine, which releases nicotine when exposed to ultraviolet light with certain conditions, has been developed for studying nicotinic acetylcholine receptors in brain tissue.[236]
Oral health
Many studies have shown the pro-inflammatory effect of nicotine on oral diseases.[53] Nicotine promotes and aggravates some diseases such as periodontitis and gingivitis, especially when there are harmful microorganisms in the oral cavity, however, the data are insufficient, especially in vivo.[53] Understanding the potential role of nicotine in oral health has become increasingly important given the recent introduction of novel nicotine products and their potential role in helping smokers quit.[237]
1 2 3 D'Souza MS, Markou A (July 2011). "Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments". Addiction Science & Clinical Practice. 6 (1): 4–16. PMC3188825. PMID22003417. 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.
1 2 Nicotine. PubChem Compound Database. United States National Library of Medicine– National Center for Biotechnology Information. 16 February 2019. Retrieved 12 October 2025.
1 2 3 4 Landoni JH. "Nicotine (PIM)". INCHEM. International Programme on Chemical Safety. Retrieved 29 January 2019.
↑ "Nicotine: Clinical data". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Used as an aid to smoking cessation and for the relief of nicotine withdrawal symptoms.
1 2 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 (2nded.). New York: McGraw-Hill Medical. p.234. ISBN978-0-07-148127-4. 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...
1 2 3 4 5 6 7 Siegmund B, Leitner E, Pfannhauser W (August 1999). "Determination of the nicotine content of various edible nightshades (Solanaceae) and their products and estimation of the associated dietary nicotine intake". Journal of Agricultural and Food Chemistry. 47 (8): 3113–20. Bibcode:1999JAFC...47.3113S. doi:10.1021/jf990089w. PMID10552617.
1 2 3 Ujváry I (1999). "Nicotine and Other Insecticidal Alkaloids". In Yamamoto I, Casida J (eds.). Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Tokyo: Springer-Verlag. pp.29–69.
↑ Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, etal. (May 2005). "Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation". Journal of Medicinal Chemistry. 48 (10): 3474–3477. doi:10.1021/jm050069n. PMID15887955.
↑ Krautmann MJ, Edmonds M, Edmonds J, Van Engen NK, Esch K, Frank RK, etal. (November 2023). "Reproductive and margin of safety of a fixed-dose combination injectable endectocide (0.2 mg/kg doramectin; 6.0 mg/kg levamisole hydrochloride) in cattle". Veterinary Parasitology. A Novel, Broad-Spectrum Fixed-Dose Combination Injectable Endectocide for Cattle. 323S 110071. doi:10.1016/j.vetpar.2023.110071. PMID37951737.
↑ Miyasato K (March 2013). "[Psychiatric and psychological features of nicotine dependence]". Nihon Rinsho. Japanese Journal of Clinical Medicine. 71 (3): 477–481. PMID23631239.
1 2 3 Parrott AC (July 2015). "Why all stimulant drugs are damaging to recreational users: an empirical overview and psychobiological explanation". Human Psychopharmacology. 30 (4): 213–224. doi:10.1002/hup.2468. PMID26216554. S2CID7408200.
1 2 Rademacher L, Prinz S, Winz O, Henkel K, Dietrich CA, Schmaljohann J, etal. (August 2016). "Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers". Biological Psychiatry. 80 (3): 198–206. doi:10.1016/j.biopsych.2015.11.009. PMID26803340.
1 2 Morud J, Adermark L, Perez-Alcazar M, Ericson M, Söderpalm B (March 2016). "Nicotine produces chronic behavioral sensitization with changes in accumbal neurotransmission and increased sensitivity to re-exposure". Addiction Biology. 21 (2): 397–406. doi:10.1111/adb.12219. PMID25581387.
1 2 3 4 5 Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T (May 2018). "Nicotine replacement therapy versus control for smoking cessation". The Cochrane Database of Systematic Reviews. 5 (5) CD000146. doi:10.1002/14651858.CD000146.pub5. PMC6353172. PMID29852054. There is high-quality evidence that all of the licensed forms of NRT (gum, transdermal patch, nasal spray, inhalator and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50% to 60%, regardless of setting, and further research is very unlikely to change our confidence in the estimate of the effect. The relative effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual. A meta-analysis of adverse events associated with NRT included 92RCTs and 28observational studies, and addressed a possible excess of chest pains and heart palpitations among users of NRT compared with placebo groups (Mills 2010). The authors report an OR of 2.06 (95%CI 1.51 to 2.82) across 12studies. We replicated this data collection exercise and analysis where data were available (included and excluded) in this review, and detected a similar but slightly lower estimate, OR 1.88 (95%CI 1.37 to 2.57; 15studies; 11,074participants; OR rather than RR calculated for comparison; Analysis 6.1). Chest pains and heart palpitations were an extremely rare event, occurring at a rate of 2.5% in the NRT groups compared with 1.4% in the control groups in the 15trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR2.29 95%CI 1.39 to 3.82). However, when only serious adverse cardiac events (myocardial infarction, stroke and cardiovascular death) were considered, the finding was not statistically significant (RR1.95 95%CI 0.26 to 4.30).
↑ Kohlmeier KA (June 2015). "Nicotine during pregnancy: changes induced in neurotransmission, which could heighten proclivity to addict and induce maladaptive control of attention". Journal of Developmental Origins of Health and Disease. 6 (3): 169–181. doi:10.1017/S2040174414000531. PMID25385318. S2CID29298949.
1 2 3 4 5 6 7 8 9 10 "Nicotine". United States National Library of Medicine– Toxicology Data Network. Hazardous Substances Data Bank. 20 August 2009.
1 2 Xia W, Veljkovic E, Koshibu K, Peitsch MC, Hoeng J (December 2019). "Neurobehavioral effects of selected tobacco constituents in rodents following subchronic administration". European Journal of Pharmacology. 865 172809. doi:10.1016/j.ejphar.2019.172809. PMID31738931.
↑ Lin F, Wu G, Zhu L, Lei H (July 2015). "Altered brain functional networks in heavy smokers". Addiction Biology. 20 (4): 809–819. doi:10.1111/adb.12155. PMID24962385.
↑ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Personal Habits and Indoor Combustions. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No.100E.) TOBACCO SMOKING.
1 2 "Does nicotine cause cancer?". European Code Against Cancer. World Health Organization– International Agency for Research on Cancer. Retrieved 23 January 2019.
↑ "Nicotine: Biological activity". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 7 February 2016. Kis as follows; α2β4=9900nM [5], α3β2=14nM [1], α3β4=187nM [1], α4β2=1nM [4,6]. Due to the heterogeneity of nACh channels we have not tagged a primary drug target for nicotine, although the α4β2 is reported to be the predominant high affinity subtype in the brain which mediates nicotine addiction
1 2 3 El Sayed KA, Sylvester PW (June 2007). "Biocatalytic and semisynthetic studies of the anticancer tobacco cembranoids". Expert Opinion on Investigational Drugs. 16 (6): 877–887. doi:10.1517/13543784.16.6.877. PMID17501699. S2CID21302112.
↑ Bruin JE, Gerstein HC, Holloway AC (August 2010). "Long-term consequences of fetal and neonatal nicotine exposure: a critical review". Toxicological Sciences. 116 (2): 364–374. doi:10.1093/toxsci/kfq103. PMC2905398. PMID20363831. there is no safe dose of nicotine during pregnancy... The general consensus among clinicians is that more information is needed about the risks of NRT use during pregnancy before well-informed definitive recommendations can be made to pregnant women... Overall, the evidence provided in this review overwhelmingly indicates that nicotine should no longer be considered the safe component of cigarette smoke. In fact, many of the adverse postnatal health outcomes associated with maternal smoking during pregnancy may be attributable, at least in part, to nicotine alone.
↑ Forest S (1 March 2010). "Controversy and evidence about nicotine replacement therapy in pregnancy". MCN: The American Journal of Maternal/Child Nursing. 35 (2): 89–95. doi:10.1097/NMC.0b013e3181cafba4. PMID20215949. S2CID27085986.
↑ Royal College of Physicians. "Nicotine Without Smoke -- Tobacco Harm Reduction". p.125. Archived from the original on 1 November 2020. Retrieved 30 September 2020. Use of nicotine alone, in the doses used by smokers, represents little if any hazard to the user.
↑ Dinakar C, O'Connor GT (October 2016). "The Health Effects of Electronic Cigarettes". The New England Journal of Medicine. 375 (14): 1372–1381. doi:10.1056/NEJMra1502466. PMID27705269. Beyond its addictive properties, short-term or long-term exposure to nicotine in adults has not been established as dangerous
1 2 Garcia AN, Salloum IM (October 2015). "Polysomnographic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: A focused review". The American Journal on Addictions. 24 (7): 590–598. doi:10.1111/ajad.12291. PMID26346395. S2CID22703103.
↑ Jaehne A, Loessl B, Bárkai Z, Riemann D, Hornyak M (October 2009). "Effects of nicotine on sleep during consumption, withdrawal and replacement therapy". Sleep Medicine Reviews (Review). 13 (5): 363–377. doi:10.1016/j.smrv.2008.12.003. PMID19345124.
↑ Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11042–11046. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC58680. PMID11572966. Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal... Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well.
↑ Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC3569166. PMID23430970. The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives.... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure.... ΔFosB overexpression in nucleus accumbens induces NFκB
↑ Dougherty J, Miller D, Todd G, Kostenbauder HB (December 1981). "Reinforcing and other behavioral effects of nicotine". Neuroscience and Biobehavioral Reviews. 5 (4): 487–495. doi:10.1016/0149-7634(81)90019-1. PMID7322454. S2CID10076758.
1 2 Belluzzi JD, Wang R, Leslie FM (April 2005). "Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats". Neuropsychopharmacology. 30 (4): 705–712. doi:10.1038/sj.npp.1300586. PMID15496937.
↑ Heishman SJ, Kleykamp BA, Singleton EG (July 2010). "Meta-analysis of the acute effects of nicotine and smoking on human performance". Psychopharmacology. 210 (4): 453–469. doi:10.1007/s00213-010-1848-1. PMC3151730. PMID20414766. The significant effects of nicotine on motor abilities, attention, and memory likely represent true performance enhancement because they are not confounded by withdrawal relief. The beneficial cognitive effects of nicotine have implications for initiation of smoking and maintenance of tobacco dependence.
↑ Hughes JR (March 2007). "Effects of abstinence from tobacco: valid symptoms and time course". Nicotine & Tobacco Research. 9 (3): 315–327. doi:10.1080/14622200701188919. PMID17365764.
↑ Dugas EN, Sylvestre MP, O'Loughlin EK, Brunet J, Kakinami L, Constantin E, etal. (February 2017). "Nicotine dependence and sleep quality in young adults". Addictive Behaviors. 65: 154–160. doi:10.1016/j.addbeh.2016.10.020. PMID27816041.
↑ Bruijnzeel AW (May 2012). "Tobacco addiction and the dysregulation of brain stress systems". Neuroscience and Biobehavioral Reviews. 36 (5): 1418–1441. doi:10.1016/j.neubiorev.2012.02.015. PMC3340450. PMID22405889. Discontinuation of smoking leads to negative affective symptoms such as depressed mood, increased anxiety, and impaired memory and attention...Smoking cessation leads to a relatively mild somatic withdrawal syndrome and a severe affective withdrawal syndrome that is characterized by a decrease in positive affect, an increase in negative affect, craving for tobacco, irritability, anxiety, difficulty concentrating, hyperphagia, restlessness, and a disruption of sleep. Smoking during the acute withdrawal phase reduces craving for cigarettes and returns cognitive abilities to pre-smoking cessation level
1 2 Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID25083822. S2CID19157711. 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).
↑ Marttila K, Raattamaa H, Ahtee L (July 2006). "Effects of chronic nicotine administration and its withdrawal on striatal FosB/DeltaFosB and c-Fos expression in rats and mice". Neuropharmacology. 51 (1): 44–51. doi:10.1016/j.neuropharm.2006.02.014. PMID16631212. S2CID8551216.
↑ Cardinale A, Nastrucci C, Cesario A, Russo P (January 2012). "Nicotine: specific role in angiogenesis, proliferation and apoptosis". Critical Reviews in Toxicology (Review). 42 (1): 68–89. doi:10.3109/10408444.2011.623150. PMID22050423. S2CID11372110.
↑ National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems (2018). "Chapter 4: Nicotine". In Eaton DL, Kwan LY, Stratton K (eds.). Public Health Consequences of E-Cigarettes (Review). National Academies Press. ISBN978-0-309-46834-3.
↑ Ginzkey C, Steussloff G, Koehler C, Burghartz M, Scherzed A, Hackenberg S, etal. (August 2014). "Nicotine derived genotoxic effects in human primary parotid gland cells as assessed in vitro by comet assay, cytokinesis-block micronucleus test and chromosome aberrations test". Toxicology in Vitro. 28 (5): 838–846. Bibcode:2014ToxVi..28..838G. doi:10.1016/j.tiv.2014.03.012. PMID24698733.
↑ Ginzkey C, Stueber T, Friehs G, Koehler C, Hackenberg S, Richter E, etal. (January 2012). "Analysis of nicotine-induced DNA damage in cells of the human respiratory tract". Toxicology Letters. 208 (1): 23–29. doi:10.1016/j.toxlet.2011.09.029. PMID22001448.
↑ Holbrook BD (June 2016). "The effects of nicotine on human fetal development". Birth Defects Research. Part C, Embryo Today. 108 (2): 181–192. doi:10.1002/bdrc.21128. PMID27297020.
↑ Pomerleau OF, Pomerleau CS (1984). "Neuroregulators and the reinforcement of smoking: towards a biobehavioral explanation". Neuroscience and Biobehavioral Reviews. 8 (4): 503–13. doi:10.1016/0149-7634(84)90007-1. PMID6151160. S2CID23847303.
↑ Grizzell JA, Echeverria V (October 2015). "New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine". Neurochemical Research. 40 (10): 2032–46. doi:10.1007/s11064-014-1359-2. PMID24970109. S2CID9393548.
1 2 3 Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York: McGraw-Hill Medical. pp.369, 372–373. ISBN978-0-07-148127-4.
1 2 3 Picciotto MR, Mineur YS (January 2014). "Molecules and circuits involved in nicotine addiction: The many faces of smoking". Neuropharmacology (Review). 76 (Pt B): 545–53. doi:10.1016/j.neuropharm.2013.04.028. PMC3772953. PMID23632083. Rat studies have shown that nicotine administration can decrease food intake and body weight, with greater effects in female animals (Grunberg et al., 1987). A similar nicotine regimen also decreases body weight and fat mass in mice as a result of β4* nAChR-mediated activation of POMC neurons and subsequent activation of MC4 receptors on second order neurons in the paraventricular nucleus of the hypothalamus (Mineur et al., 2011).
↑ Yoshida T, Sakane N, Umekawa T, Kondo M (January 1994). "Effect of nicotine on sympathetic nervous system activity of mice subjected to immobilization stress". Physiology & Behavior. 55 (1): 53–7. doi:10.1016/0031-9384(94)90009-4. PMID8140174. S2CID37754794.
↑ Le Houezec J (September 2003). "Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review". The International Journal of Tuberculosis and Lung Disease. 7 (9): 811–9. PMID12971663.
↑ Benowitz NL, Jacob P, Jones RT, Rosenberg J (May 1982). "Interindividual variability in the metabolism and cardiovascular effects of nicotine in man". The Journal of Pharmacology and Experimental Therapeutics. 221 (2): 368–72. doi:10.1016/S0022-3565(25)33068-5. PMID7077531.
1 2 3 4 Hu T, Yang Z, Li MD (December 2018). "Pharmacological Effects and Regulatory Mechanisms of Tobacco Smoking Effects on Food Intake and Weight Control". Journal of Neuroimmune Pharmacology. 13 (4): 453–466. doi:10.1007/s11481-018-9800-y. PMID30054897. S2CID51727199. Nicotine's weight effects appear to result especially from the drug's stimulation of α3β4 nicotine acetylcholine receptors (nAChRs), which are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), leading to activation of the melanocortin circuit, which is associated with body weight. Further, α7- and α4β2-containing nAChRs have been implicated in weight control by nicotine.
1 2 Zhang H, Pang Y, Luo Y, Li X, Chen H, Han S, etal. (July 2018). "Enantiomeric composition of nicotine in tobacco leaf, cigarette, smokeless tobacco, and e-liquid by normal phase high-performance liquid chromatography". Chirality. 30 (7): 923–931. doi:10.1002/chir.22866. PMID29722457.
↑ Hellinghausen G, Lee JT, Weatherly CA, Lopez DA, Armstrong DW (June 2017). "Evaluation of nicotine in tobacco-free-nicotine commercial products". Drug Testing and Analysis. 9 (6): 944–948. doi:10.1002/dta.2145. PMID27943582.
↑ Ye X, Zhang Y, Song X, Liu Q (2022). "Research Progress in the Pharmacological Effects and Synthesis of Nicotine". ChemistrySelect. 7 (12) e202104425. doi:10.1002/slct.202104425. S2CID247687372.
↑ Lamberts BL, Dewey LJ, Byerrum RU (May 1959). "Ornithine as a precursor for the pyrrolidine ring of nicotine". Biochimica et Biophysica Acta. 33 (1): 22–6. doi:10.1016/0006-3002(59)90492-5. PMID13651178.
↑ Dawson RF, Christman DR, d'Adamo A, Solt ML, Wolf AP (1960). "The Biosynthesis of Nicotine from Isotopically Labeled Nicotinic Acids". Journal of the American Chemical Society. 82 (10): 2628–2633. Bibcode:1960JAChS..82.2628D. doi:10.1021/ja01495a059.
↑ Ashihara H, Crozier A, Komamine A, eds. (7 June 2011). Plant metabolism and biotechnology. Cambridge: Wiley. ISBN978-0-470-74703-2.[pageneeded]
↑ Hellinghausen G, Roy D, Wang Y, Lee JT, Lopez DA, Weatherly CA, etal. (May 2018). "A comprehensive methodology for the chiral separation of 40 tobacco alkaloids and their carcinogenic E/Z-(R,S)-tobacco-specific nitrosamine metabolites". Talanta. 181: 132–141. doi:10.1016/j.talanta.2017.12.060. PMID29426492.
↑ Liu B, Chen Y, Ma X, Hu K (September 2019). "Site-specific peak intensity ratio (SPIR) from 1D 2H/1H NMR spectra for rapid distinction between natural and synthetic nicotine and detection of possible adulteration". Analytical and Bioanalytical Chemistry. 411 (24): 6427–6434. doi:10.1007/s00216-019-02023-6. PMID31321470. S2CID197593505.
1 2 3 Breining SR (2004). "Recent developments in the synthesis of nicotinic acetylcholine receptor ligands". Curr Top Med Chem. 4 (6): 609–629. doi:10.2174/1568026043451131. PMID14965298.
↑ Pogocki D, Ruman T, Danilczuk M, Danilczuk M, Celuch M, Wałajtys-Rode E (June 2007). "Application of nicotine enantiomers, derivatives and analogues in therapy of neurodegenerative disorders". Eur J Pharmacol. 563 (1–3): 18–39. doi:10.1016/j.ejphar.2007.02.038. PMID17376429.
↑ Effah F, Sun Y, Lin K, Rahman I (February 2025). "A comparative toxicological evaluation of emerging nicotine analogs 6-methyl nicotine and nicotinamide: a scoping review". Arch Toxicol. 99 (4): 1333–1340. Bibcode:2025ArTox..99.1333E. doi:10.1007/s00204-025-03960-1. PMID39937258.
↑ 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. 184 (3–4): 286–91. doi:10.1007/s00213-006-0308-4. PMID16463054. S2CID38290573.
↑ Melsens LH (1843). "Note sur la nicotine"[Note on nicotine]. Annales de Chimie et de Physique. third series (in French). 9: 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).]
↑ Pinner A, Wolffenstein R (1891). "Ueber Nicotin" [About nicotine]. Berichte der Deutschen Chemischen Gesellschaft (in German). 24: 1373–1377. doi:10.1002/cber.189102401242.
↑ Harris JG, Kongs S, Allensworth D, Martin L, Tregellas J, Sullivan B, etal. (July 2004). "Effects of nicotine on cognitive deficits in schizophrenia". Neuropsychopharmacology. 29 (7): 1378–1385. doi:10.1038/sj.npp.1300450. PMID15138435.
↑ Lin F, Wu G, Zhu L, Lei H (July 2015). "Altered brain functional networks in heavy smokers". Addiction Biology. 20 (4): 809–819. doi:10.1111/adb.12155. PMID24962385.
↑ Takahashi HK, Iwagaki H, Hamano R, Yoshino T, Tanaka N, Nishibori M (December 2006). "Effect of nicotine on IL-18-initiated immune response in human monocytes". Journal of Leukocyte Biology. 80 (6): 1388–1394. doi:10.1189/jlb.0406236. PMID16966384.
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