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Nicotine is an alkaloid originally found in the nightshade family of plants (predominantly in tobacco and Duboisia hopwoodii). In addition to natural extraction it can be synthesized and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve drug withdrawal. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist. Nicotine exists in free-base and protonated (Nicotine salt) forms, influencing absorption and sensory effects in delivery systems.
Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco. 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. Nicotine, an antiherbivore toxin, was historically used as an insecticide; (2025). 9781420078831, CRC Press. ISBN 9781420078831 Neonicotinoid, 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 and levamisole, a veterinary antihelminthic.
Nicotine is highly addictive. Slow-release forms (gums and patches, when used correctly) can be less addictive and help in quitting. Animal research suggests that monoamine oxidase inhibitors present in tobacco smoke may enhance nicotine's addictive properties. An average cigarette yields about 2 mg of absorbed nicotine. The estimated lower dose limit for fatal outcomes is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg), but the median lethal dose in humans remains unknown. High doses are known to cause nicotine poisoning, organ failure, and death through paralysis of respiratory muscles, though serious or fatal overdoses are rare.
Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence. Nicotine dependence involves Drug tolerance, sensitization, physical dependence, and psychological dependence, which can cause distress. Nicotine withdrawal symptoms include depression, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances. Mild nicotine withdrawal symptoms are measurable in unrestricted smokers, who experience normal moods only as their blood nicotine levels peak, with each cigarette. 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.
Nicotine use for quitting smoking, as part of engineered nicotine delivery systems to reduce tobacco's harms, has a good safety history. It is a teratogen, causing birth defects in humans. Animal studies suggest nicotine may impair adolescent cognitive development, but its relevance to human brain development is debated. At low doses, it has a mild analgesic effect. Recent research indicates that nicotine exerts broad, mostly immunosuppressive effects on immune function—from aggravating cancers to treating autoimmune diseases—and mixed CNS effects, from disruption to neuroprotection. "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.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.
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 , regardless of setting.
Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.
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. The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.
Alcohol infused with nicotine is called nicotini.
It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014. It is therefore not recommended to adolescents. 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.
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. 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.
Nicotine gum is contraindicated in individuals with temporomandibular joint disease. People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays. Nicotine in any form is contraindicated in individuals with a known hypersensitivity to nicotine.
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.
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."
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.
Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms. These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette. Smokers have a worse mood than they typically would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking. Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers.
In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels. The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal. Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar.
Nicotine activates the mesolimbic pathway and Inducible gene long-term ΔFosB expression (i.e., produces phosphorylated ΔFosB ) in the nucleus accumbens when inhaled or injected frequently or at high doses, but not necessarily when ingested. Consequently, high daily exposure (possibly excluding oral route) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.
Although nicotine is classified as a non-carcinogenic substance, it can still promote tumor growth and metastasis. It induces several processes, some of them via nicotine's effects on immune function, that contribute to cancer progression in both smoking-related and non-smoking-related cancers, including cell cycle progression, epithelial-to-mesenchymal transition, migration, invasion, angiogenesis, and evasion of apoptosis. These effects are primarily mediated through nicotinic acetylcholine receptors (nAChRs), particularly the α7 subtype, and to a lesser extent, β-adrenergic receptors (β-ARs). Activation of these receptors triggers several signaling cascades crucial in cancer biology, notably the MAPK/ERK pathway, PI3K/AKT pathway, and JAK-STAT signaling.
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. Additionally, nicotine-induced EMT contributes to drug resistance in cancer cells.
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, a known type 1 carcinogen, suggesting that consumption of non-tobacco forms of nicotine may still play a role in carcinogenesis.
Nicotine exposure uterus 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 . 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.
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). An increased respiratory rate (i.e., tachypnea) is one of the primary medical sign of nicotine poisoning. At sufficiently high doses, somnolence (sleepiness or drowsiness), confusion, syncope (loss of consciousness from fainting), shortness of breath, marked weakness, , and coma may occur. Lethal nicotine poisoning rapidly produces seizures, and death – which may occur within minutes – is believed to be due to respiratory paralysis.
Nicotine activates nicotinic receptors (particularly α4β2 nicotinic receptors, but also α5 nAChRs) on neurons that innervate the ventral tegmental area and within the mesolimbic pathway where it appears to cause the release of dopamine. (2025). 9780071481274, McGraw-Hill Medical. ISBN 9780071481274 This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area. Nicotine can modulate the firing rate of the ventral tegmental area neurons. These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of euphoria; however, mild euphoria from nicotine use can occur in some individuals.
Nicotine binds to presynaptic and postsynaptic nAChRs, leading to initial activation followed by desensitization—a conformational shift rendering receptors temporarily unresponsive. 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. Human imaging studies show this upregulation is temporary and returns to baseline levels in nonsmokers by approximately 21 days after smoking cessation.
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. 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.
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. 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.
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, 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 18–20 hours, making it easier to analyze due to longer half-life than that of nicotine itself.
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. Under some conditions, other substances may be formed such as myosmine.
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.
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. For example, 2% benzoate salt produced 3x higher Cmax in human puffing trials. Notably, Cmax of protonated Nicotine salt appears independent of the composition and identity of the counter anions (e.g., benzoate, lactate, levulinate) forming the salts for higher administered nicotine Formulation.
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.
Nicotine is chiral and hence optically active, having two forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of αD=–166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (−)-nicotine. (−)-nicotine is more toxic than (+)-nicotine. The salts of (−)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids. The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180 °C. Anabasine is a structural isomer of nicotine, as both compounds have the molecular formula .
Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer. Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers. 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. 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. Pod mod electronic cigarettes use nicotine in the form of a nicotine salt, rather than free base nicotine found in earlier generations.
The starting material was an N-substituted pyrrole derivative, which was heated to convert it by a [Sigmatropic 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. Many other syntheses of nicotine, in both racemic and chiral forms have since been published.
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.
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.
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 pure (−)-nicotine. (2011). 9780470747032, Wiley. ISBN 9780470747032
Nicotine occurs in smaller amounts (varying from 2–7 microgram/kilogram, or 20–70 millionths of a percent wet weight) in other plants, including some crop species such as , , eggplant, and capsicum, as well as non-crop species such as Duboisia hopwoodii. The amounts of nicotine in tomatoes lowers substantially as the fruit ripens. 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 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." The amount of nicotine eaten per day is roughly around 1.4 and 2.25 microgram/day at the 95th percentile. These numbers may be low due to insufficient food intake data. The concentrations of nicotine in vegetables are difficult to measure accurately, since they are very low (parts per billion range). Pure nicotine tastes "terrible".
Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the France ambassador in Portugal, Jean Nicot, who sent tobacco and seeds to Paris in 1560, presented to the French King,9780808923541, Churchill Livingstone. ISBN 9780808923541 and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague. However, the "holy herb", tobacco, had first reached Europe by the early 1530s, brought by Spanish explorers.
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 colony, 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. (2025). 9780415116695, Taylor and Francis. ISBN 9780415116695 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.
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 .
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.
Although methods of production of synthetic nicotine have existed for decades, it was believed that the cost of making nicotine by laboratory synthesis was cost prohibitive compared to extracting nicotine from tobacco. However, recently synthetic nicotine started to be found in different brands of e-cigarettes and oral pouches and marketed as "tobacco-free."
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. 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 European Union, the minimum age to purchase nicotine products is 18. However, there is no minimum age requirement to use tobacco or nicotine products.
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.
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.
Though tobacco smoking is associated with an increased risk of Alzheimer's disease, there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease. (2025). 9783540692461 ISBN 9783540692461
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 Neuroprotection, or other compounds in cigarette smoke acting as neuroprotective agents.
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, Psychosis, or other cognitive symptoms of schizophrenia.
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.
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 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 .
Although some of its effects are pro-inflammatory (e.g. inducing prostaglandinE2 production), nicotine effects are mostly anti-inflammatory. 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 cell, and suppressing the activation of Dendritic cell. As a result, cell-mediated immunity against infection and neoplastic diseases is downregulated. In vitro and animal studies also showed that nicotine reduces T-cell receptor (TCR) signaling and suppresses the production and secretion of Antibody.
Nicotine effects on immune system function can aggravate Tumor (growth and metastases) in cancer patients and is found to have many positive effects in the treating autoimmune disease (e.g. inflammatory bowel disease/ulcerative colitis, arthritis), requiring further studies.
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