Nicotine
Thursday, September 04, 2025 11:10AM
Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and Duboisia hopwoodii)[8] and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve withdrawal symptoms.[9][6][10][11] Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs),[12][13][14] except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist.[12]
Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco.[15] Nicotine is also present in trace amounts — measured in parts per billion — in edible plants in the family Solanaceae, including potatoes, tomatoes, and eggplants,[16] and sources disagree on whether this has any biological significance to human consumers.[16] It functions as an antiherbivore toxin; consequently, nicotine was widely used as an insecticide in the past,[17][18] and neonicotinoids (structurally similar to nicotine), such as imidacloprid, are some of the most effective and widely used insecticides.
Nicotine is highly addictive.[19][20][21] Slow-release forms (gums and patches, when used correctly) can be less addictive and help in quitting.[22][23][24][25] Animal research suggests that monoamine oxidase inhibitors present in tobacco smoke may enhance nicotine's addictive properties.[26][27] An average cigarette yields about 2 mg of absorbed nicotine.[28] The estimated lower dose limit for fatal outcomes is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg).[26][28] Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence.[29] Nicotine dependence involves tolerance, sensitization,[30] physical dependence, and psychological dependence,[31] which can cause distress.[32][33] 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.[34] On quitting, withdrawal symptoms worsen sharply, then gradually improve to a normal state.[34]
Nicotine use as a tool for quitting smoking has a good safety history.[35] Animal studies suggest that nicotine may adversely affect cognitive development in adolescence, but the relevance of these findings to human brain development is disputed.[36][26] At low amounts, it has a mild analgesic effect.[37] According to the International Agency for Research on Cancer, "nicotine is not generally considered to be a carcinogen".[38][39] The Surgeon General of the United States indicates that evidence is inadequate to infer the presence or absence of a causal relationship between exposure to nicotine and risk for cancer.[40] Nicotine has been shown to produce birth defects in humans and is considered a teratogen.[41][42] The median lethal dose of nicotine in humans is unknown.[43] High doses are known to cause nicotine poisoning, organ failure, and death through paralysis of respiratory muscles,[40][44] though serious or fatal overdoses are rare.[45]
USES:
The primary therapeutic use of nicotine is treating nicotine dependence to eliminate smoking and the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, inhalers, or nasal sprays to wean them off their dependence. 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.[46]
Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.[47]
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.[40]: 112 The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.[32]
Pesticide
Nicotine has been used as an insecticide since at least 1690, in the form of tobacco extracts or as pure nicotine sulphate[18][48][49] (although other components of tobacco also seem to have pesticide effects).[50] 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,[51] including use on organic crops,[52] and caution is recommended for small gardeners.[53] Nicotine pesticides have been banned in the EU since 2009.[54] Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels.[54][55] Neonicotinoids, such as imidacloprid, which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016.[56][48]
Performance
Nicotine-containing products are sometimes used for the performance-enhancing effects of nicotine on cognition.[57] A 2010 meta-analysis of 41 double-blind, placebo-controlled studies concluded that nicotine or smoking had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory.[58] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;[59] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (ki=1 nM), which is also the biological target that mediates nicotine's addictive properties.[60] 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.[61]
Recreational
Nicotine is used as a recreational drug.[62] It is widely used, highly addictive and hard to discontinue.[21] Nicotine is often used compulsively,[63] and dependence can develop within days.[63][64] Recreational drug users commonly use nicotine for its mood-altering effects.[32] Recreational nicotine products include chewing tobacco, cigars,[65] cigarettes,[65] e-cigarettes,[66] snuff, pipe tobacco,[65] snus, and nicotine pouches.
Alcohol infused with nicotine is called nicotini.[67]
Contraindications
Nicotine use for tobacco cessation has few contraindications.[68]
It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014.[69] It is therefore not recommended to adolescents.[70] 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.[71][72][73]
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.[74] 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.[75]
Nicotine gum is contraindicated in individuals with temporomandibular joint disease.[76] People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays.[70] Nicotine in any form is contraindicated in individuals with a known hypersensitivity to nicotine.[76][70]
Adverse effects
Possible side effects of nicotine[77]
Nicotine is classified as a poison,[78][79] and it is "extremely hazardous".[80] However, at doses typically used by consumers, it presents little if any hazard to the user.[81][82][83] A 2018 Cochrane Collaboration review lists nine main adverse events related to nicotine replacement therapy: headache, dizziness, lightheadedness, nausea, vomiting, gastrointestinal symptoms, insomnia, abnormal dreams, non-ischemic palpitations and chest pain, skin reactions, oral/nasal reactions, and hiccups.[84] Many of these were also common in the placebo group without nicotine.[84] Palpitations and chest pain were deemed "rare" and there was no evidence of an increased number of serious cardiac problems compared to the placebo group, even in people with established cardiac disease.[46] The common side effects from nicotine exposure are listed in the table below. Serious adverse events due to the use of nicotine replacement therapy are extremely rare.[46] At low amounts, it has a mild analgesic effect.[37] However, at sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradycardia, and possibly seizures, hypoventilation, and death.[85]
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.[89] 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.[89][90] Depressive non-smokers experience mood and sleep improvements under nicotine administration; however, subsequent nicotine withdrawal has a negative effect on both mood and sleep.[91]
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.[92]
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.[92]
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."[92]
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.[46]
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.[92]
Cancer
Contrary to popular belief, nicotine itself does not cause cancer in humans,[39][107] although it is unclear whether it functions as a tumor promoter as of 2012.[108] 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."[109]
Although nicotine is classified as a non-carcinogenic substance, it can still promote tumor growth and metastasis. It induces several processes that contribute to cancer progression, including cell cycle progression, epithelial-to-mesenchymal transition, migration, invasion, angiogenesis, and evasion of apoptosis.[110] These effects are primarily mediated through nicotinic[12][13] except at two [nicotinic receptor subunits acetylcholine receptors](https://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor) (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.[110]
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.[111] Additionally, nicotine-induced EMT contributes to drug resistance in cancer cells.[112]
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,[113] a known type 1 carcinogen,[114] suggesting that consumption of non-tobacco forms of nicotine may still play a role in carcinogenesis.[115]
Genotoxicity
Nicotine causes DNA damage in several types of human cells as judged by assays for genotoxicity such as the comet assay, cytokinesis-block micronucleus test and chromosome aberrations test. In humans, this damage can happen in primary parotid gland cells,[116] lymphocytes,[117] and respiratory tract cells.[118]
Pregnancy and breastfeeding
Nicotine has been shown to produce birth defects in some animal species, but not others;[42] consequently, it is considered to be a possible teratogen in humans.[42] In animal studies that resulted in birth defects, researchers found that nicotine negatively affects fetal brain development and pregnancy outcomes;[42][40] the negative effects on early brain development are associated with abnormalities in brain metabolism and neurotransmitter system function.[119] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.[120]
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.[121] 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.[122]
Overdose
Main article: Nicotine poisoning
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.[123] The median lethal dose of nicotine in humans is unknown.[43][28] Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50 of 127 mg/kg when administered to mice.[124] At sufficiently high doses, it is associated with nicotine poisoning,[40] which, while common in children (in whom poisonous and lethal levels occur at lower doses per kilogram of body weight[37]) rarely results in significant morbidity or death.[42] The estimated lower dose limit for fatal outcomes is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg).[26][28]
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).[42] An increased respiratory rate (i.e., tachypnea) is one of the primary signs of nicotine poisoning.[42] 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][42] Lethal nicotine poisoning rapidly produces seizures, and death – which may occur within minutes – is believed to be due to respiratory paralysis.[42]
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),[42] accidental ingestion of tobacco or tobacco products, or ingestion of nicotine-containing plants.[125][126][127] 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.[125][128] People can be exposed to nicotine in the workplace by breathing it in, skin absorption, swallowing it, or eye contact. The Occupational Safety and Health Administration (OSHA) has set the legal limit (permissible exposure limit) for nicotine exposure in the workplace as 0.5 mg/m3 skin exposure over an 8-hour workday. The US National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 0.5 mg/m3 skin exposure over an 8-hour workday. At environmental levels of 5 mg/m3, nicotine is immediately dangerous to life and health.[129]
Drug interactions
Pharmacodynamic
- Potential interaction with sympathomimetic drugs (adrenergic agonists) and sympatholytic drugs (alpha-blockers and beta-blockers).[76]
Pharmacokinetic
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.[76]
- Smoking cessation may decrease the metabolism of acetaminophen, beta-blockers, caffeine, oxazepam, pentazocine, propoxyphene, theophylline, and tricyclic antidepressants, leading to higher plasma concentrations of these drugs.[76]
- Possible alteration of nicotine absorption through the skin from the transdermal nicotine patch by drugs that cause vasodilation or vasoconstriction.[76]
- Possible alteration of nicotine absorption through the nasal cavity from the nicotine nasal spray by nasal vasoconstrictors (e.g., xylometazoline).[76]
- Possible alteration of nicotine absorption through oral mucosa from nicotine gum and lozenges by food and drink that modify salivary pH.[76]
Pharmacology
Pharmacodynamics
Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), (nAChRα9 and nAChRα10) where it acts as a receptor antagonist.[12] Such antagonism results in mild analgesia.
CENTRAL NERVOUS SYSTEM
By binding to nicotinic acetylcholine receptors in the brain, nicotine elicits its psychoactive effects and increases the levels of several neurotransmitters in various brain structures – acting as a sort of "volume control".[130][131] 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.[132] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[133] 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.[134][135] At very high doses it dampens neuronal activity.[136] 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.[137]
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.[138][139] This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area.[139][140] Nicotine can modulate the firing rate of the ventral tegmental area neurons.[140] These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of euphoria;[138] however, mild euphoria from nicotine use can occur in some individuals.[138] Chronic nicotine use inhibits class I and II histone deacetylases in the striatum, where this effect plays a role in nicotine addiction.[141][142]
SYMPATHETIC NERVOUS SYSTEM
Nicotine also activates the sympathetic nervous system,[143] 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]
Adrenal medulla
By binding to ganglion type nicotinic receptors in the adrenal medulla, nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.[144]
As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.[146] The elimination half-life of nicotine in the body is around two hours.[147][148] Nicotine is primarily excreted in urine and urinary concentrations vary depending upon urine flow rate and urine pH.[7]
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,[149] suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".
Nicotine has a half-life of 1–2 hours. 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.[150]
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.[151] Under some conditions, other substances may be formed such as myosmine.[152][153]
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.[154]
Metabolism
Nicotine decreases hunger and as a consequence food consumption, alongside increasing energy expenditure.[155][156] 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.[156] 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.[140][156] POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.[156]
Nicotine is a hygroscopic, colorless[80] 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.[158] 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.[159] Nicotine is volatile (vapor pressure 5.5 Pa at 25 °C)[158] On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (niacin, a B3 vitamer), and methylamine.[160]
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. (−)-nicotine is more toxic than (+)-nicotine.[161] The salts of (−)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids.[160] The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180 °C.[160] Anabasine is a structural isomer of nicotine, as both compounds have the molecular formula C10H14N2.
Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer.[162] Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers.[163] This suggests that tobacco-derived and synthetic nicotine can be determined by measuring the ratio of the two different enantiomers, although means exist for adjusting the relative levels of the enantiomers or performing a synthesis that only leads to the S-enantiomer. 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.