Nicotine

<h2 id="uses">Uses</h2>
<h3>Medical</h3>
See also: <a href="/facts/Nicotine_replacement_therapy/NVndtPso">Nicotine replacement therapy</a>

The primary <a href="/facts/Pharmacotherapy/bEX4Xo3y">therapeutic use</a> of nicotine is treating nicotine dependence to eliminate <a href="/facts/Smoking/byhnmD0X">smoking</a> and the damage it does to health. Controlled levels of nicotine are given to patients through <a href="/facts/Nicotine_gum/3FHGcYTp">gums</a>, <a href="/facts/Nicotine_patches/kKWfYe2B">dermal patches</a>, lozenges, inhalers, or nasal sprays to wean them off their dependence. A 2018 <a href="/facts/Cochrane_Collaboration/UlmdJ1H8">Cochrane Collaboration</a> 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.<a class="footnote-ref" id="fnref:48" href="#fn:48">48</a>
Combining <a href="/facts/Nicotine_patch/kKWfYe2B">nicotine patch</a> use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success.<a class="footnote-ref" id="fnref:49" href="#fn:49">49</a>
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.<a class="footnote-ref" id="fnref:50" href="#fn:50">50</a>: 112  The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk.<a class="footnote-ref" id="fnref:51" href="#fn:51">51</a>

<h3>Pesticide</h3>
Nicotine has been used as an <a href="/facts/Insecticide/1xYL3MSD">insecticide</a> since at least 1690, in the form of tobacco extracts or as pure nicotine sulphate<a class="footnote-ref" id="fnref:52" href="#fn:52">52</a><a class="footnote-ref" id="fnref:53" href="#fn:53">53</a><a class="footnote-ref" id="fnref:54" href="#fn:54">54</a> (although other components of tobacco also seem to have pesticide effects).<a class="footnote-ref" id="fnref:55" href="#fn:55">55</a> It acts on the <a href="/facts/Nicotinic_acetylcholine_receptor/k2s2pPHr">nicotinic acetylcholine receptor</a>, and gave the receptor its name. Nicotine is in <a href="/facts/Insecticide_Resistance_Action_Committee/j72wrfn1">IRAC</a> group 4B. Nicotine insecticides have been banned in the US since 2014,<a class="footnote-ref" id="fnref:56" href="#fn:56">56</a> including use on organic crops,<a class="footnote-ref" id="fnref:57" href="#fn:57">57</a> and caution is recommended for small gardeners.<a class="footnote-ref" id="fnref:58" href="#fn:58">58</a> Nicotine pesticides have been banned in the EU since 2009.<a class="footnote-ref" id="fnref:59" href="#fn:59">59</a> Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels.<a class="footnote-ref" id="fnref:60" href="#fn:60">60</a><a class="footnote-ref" id="fnref:61" href="#fn:61">61</a> <a href="/facts/Neonicotinoids/YB6B8WdR">Neonicotinoids</a>, such as <a href="/facts/Imidacloprid/SQCcdbh0">imidacloprid</a>, which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016.<a class="footnote-ref" id="fnref:62" href="#fn:62">62</a><a class="footnote-ref" id="fnref:63" href="#fn:63">63</a>

<h3>Performance</h3>
Nicotine-containing products are sometimes used for the <a href="/facts/Performance-enhancing_substance/NydFWSGJ">performance-enhancing</a> effects of nicotine on cognition.<a class="footnote-ref" id="fnref:64" href="#fn:64">64</a> A 2010 meta-analysis of 41 <a href="/facts/Double-blind/6ALSxX8M">double-blind</a>, <a href="/facts/Placebo/3fw50t53">placebo</a>-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.<a class="footnote-ref" id="fnref:65" href="#fn:65">65</a> A 2015 review noted that stimulation of the <a href="/facts/%CE%914%CE%B22_nicotinic_receptor/qleRmw4W">α4β2 nicotinic receptor</a> is responsible for certain improvements in attentional performance;<a class="footnote-ref" id="fnref:66" href="#fn:66">66</a> among the <a href="/facts/Nicotinic_receptor/k2s2pPHr">nicotinic receptor</a> subtypes, nicotine has the highest <a href="/facts/Binding_affinity/44QLL4eU">binding affinity</a> at the α4β2 receptor (ki=1 nM), which is also the biological target that mediates nicotine's <a href="/facts/Addictive/76UrWQuT">addictive</a> properties.<a class="footnote-ref" id="fnref:67" href="#fn:67">67</a> Nicotine has potential beneficial effects, but it also has <a href="/facts/Paradoxical_reaction/nJFHqkSz">paradoxical effects</a>, which may be due to the <a href="/facts/Yerkes%E2%80%93Dodson_law/PFR3XpMQ">inverted U-shape of the dose-response curve</a> or <a href="/facts/Pharmacokinetic/x4CUUnle">pharmacokinetic</a> features.<a class="footnote-ref" id="fnref:68" href="#fn:68">68</a>

<h3>Recreational</h3>
Nicotine is used as a <a href="/facts/Recreational_drug/eoBD3vKn">recreational drug</a>.<a class="footnote-ref" id="fnref:69" href="#fn:69">69</a> It is widely used, highly addictive and hard to discontinue.<a class="footnote-ref" id="fnref:70" href="#fn:70">70</a> Nicotine is often <a href="/facts/Addiction/76UrWQuT">used compulsively</a>,<a class="footnote-ref" id="fnref:71" href="#fn:71">71</a> and <a href="/facts/Substance_dependence/x9qrReh4">dependence</a> can develop within days.<a class="footnote-ref" id="fnref:72" href="#fn:72">72</a><a class="footnote-ref" id="fnref:73" href="#fn:73">73</a> Recreational drug users commonly use nicotine for its mood-altering effects.<a class="footnote-ref" id="fnref:74" href="#fn:74">74</a> Recreational nicotine products include <a href="/facts/Chewing_tobacco/lk5UQ2PH">chewing tobacco</a>, <a href="/facts/Cigars/cuUUCR2t">cigars</a>,<a class="footnote-ref" id="fnref:75" href="#fn:75">75</a> <a href="/facts/Cigarettes/8kuVCjbr">cigarettes</a>,<a class="footnote-ref" id="fnref:76" href="#fn:76">76</a> <a href="/facts/E-cigarettes/0P3DIQWn">e-cigarettes</a>,<a class="footnote-ref" id="fnref:77" href="#fn:77">77</a> <a href="/facts/Snuff_(tobacco)/DhSKwAIB">snuff</a>, <a href="/facts/Pipe_smoking/UmeyNJ29">pipe tobacco</a>,<a class="footnote-ref" id="fnref:78" href="#fn:78">78</a> <a href="/facts/Snus/dkFq5e1k">snus</a>, and <a href="/facts/Nicotine_pouch/ywTQS3oz">nicotine pouches</a>.
<a href="/facts/Alcohol_(drug)/IeK2fVd5">Alcohol</a> infused with nicotine is called <a href="/facts/Nicotini/BaUMSqGI">nicotini</a>.<a class="footnote-ref" id="fnref:79" href="#fn:79">79</a>

<h2 id="contraindications">Contraindications</h2>
Nicotine use for tobacco cessation has few contraindications.<a class="footnote-ref" id="fnref:80" href="#fn:80">80</a>
It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014.<a class="footnote-ref" id="fnref:81" href="#fn:81">81</a> It is therefore not recommended to adolescents.<a class="footnote-ref" id="fnref:82" href="#fn:82">82</a> 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.<a class="footnote-ref" id="fnref:83" href="#fn:83">83</a><a class="footnote-ref" id="fnref:84" href="#fn:84">84</a><a class="footnote-ref" id="fnref:85" href="#fn:85">85</a>
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.<a class="footnote-ref" id="fnref:86" href="#fn:86">86</a> 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 <a href="/facts/Harm_reduction/2cAHgTu7">harm reduction</a>.<a class="footnote-ref" id="fnref:87" href="#fn:87">87</a>
<a href="/facts/Nicotine_gum/3FHGcYTp">Nicotine gum</a> is contraindicated in individuals with <a href="/facts/Temporomandibular_joint_disease/JmCeePnw">temporomandibular joint disease</a>.<a class="footnote-ref" id="fnref:88" href="#fn:88">88</a> People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays.<a class="footnote-ref" id="fnref:89" href="#fn:89">89</a> Nicotine in any form is <a href="/facts/Contraindicated/HawhU8x9">contraindicated</a> in individuals with a known <a href="/facts/Hypersensitivity/j2AWmqCD">hypersensitivity</a> to nicotine.<a class="footnote-ref" id="fnref:90" href="#fn:90">90</a><a class="footnote-ref" id="fnref:91" href="#fn:91">91</a>

<h2 id="adverse-effects">Adverse effects</h2>

Nicotine is classified as a poison,<a class="footnote-ref" id="fnref:92" href="#fn:92">92</a><a class="footnote-ref" id="fnref:93" href="#fn:93">93</a> and it is "extremely hazardous".<a class="footnote-ref" id="fnref:94" href="#fn:94">94</a> However, at doses typically used by consumers, it presents little if any hazard to the user.<a class="footnote-ref" id="fnref:95" href="#fn:95">95</a><a class="footnote-ref" id="fnref:96" href="#fn:96">96</a><a class="footnote-ref" id="fnref:97" href="#fn:97">97</a> A 2018 <a href="/facts/Cochrane_Collaboration/UlmdJ1H8">Cochrane Collaboration</a> review lists nine main adverse events related to nicotine replacement therapy: <a href="/facts/Headache/mdmmC9DP">headache</a>, <a href="/facts/Dizziness/eI8UvmS5">dizziness</a>, <a href="/facts/Lightheadedness/Gcuruugy">lightheadedness</a>, <a href="/facts/Nausea/dyhkcbeD">nausea</a>, <a href="/facts/Vomiting/R2vQkHqV">vomiting</a>, gastrointestinal symptoms, <a href="/facts/Insomnia/C1TnQTb2">insomnia</a>, abnormal <a href="/facts/Dream/BdJDoVmg">dreams</a>, non-<a href="/facts/Ischemic/ySL9xbCl">ischemic</a> <a href="/facts/Palpitations/2wACMY49">palpitations</a> and chest pain, skin reactions, oral/nasal reactions, and <a href="/facts/Hiccup/dTyQsvSn">hiccups</a>.<a class="footnote-ref" id="fnref:98" href="#fn:98">98</a> Many of these were also common in the placebo group without nicotine.<a class="footnote-ref" id="fnref:99" href="#fn:99">99</a> 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.<a class="footnote-ref" id="fnref:100" href="#fn:100">100</a> 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.<a class="footnote-ref" id="fnref:101" href="#fn:101">101</a> At low amounts, it has a mild <a href="/facts/Analgesic/xLj4XBcq">analgesic</a> effect.<a class="footnote-ref" id="fnref:102" href="#fn:102">102</a> However, at sufficiently high doses, nicotine may result in nausea, vomiting, <a href="/facts/Diarrhea/6TBHaRdA">diarrhea</a>, <a href="/facts/Salivation/RUzb41Ct">salivation</a>, <a href="/facts/Bradycardia/70msP5HD">bradycardia</a>, and possibly <a href="/facts/Seizure/zuIrQyze">seizures</a>, <a href="/facts/Hypoventilation/ruqIr4oa">hypoventilation</a>, and death.<a class="footnote-ref" id="fnref:103" href="#fn:103">103</a>

Common side effects of nicotine use according to route of administration and dosage form<table><tbody><tr><th><a href="/facts/Route_of_administration/LsyoHTzH">Route of administration</a></th><th><a href="/facts/Dosage_form/ahtNIMrF">Dosage form</a></th><th>Associated side effects of nicotine</th><th>Sources</th></tr><tr><td rowspan="2"><a href="/facts/Buccal_administration/FKqbyvYS">Buccal</a></td><td><a href="/facts/Nicotine_gum/3FHGcYTp">Nicotine gum</a></td><td><a href="/facts/Indigestion/axnCu0gn">Indigestion</a>, nausea, hiccups, traumatic injury to oral mucosa or teeth, irritation or <a href="/facts/Tingling/hRBAxluk">tingling</a> of the mouth and throat, <a href="/facts/Mouth_ulcer/TSQ0UCqS">oral mucosal ulceration</a>, jaw-<a href="/facts/Muscle_ache/AbVybHB8">muscle ache</a>, burping, gum sticking to teeth, unpleasant taste, dizziness, lightheadedness, headache, and <a href="/facts/Insomnia/C1TnQTb2">insomnia</a>.</td><td><a class="footnote-ref" id="fnref:104" href="#fn:104">104</a><a class="footnote-ref" id="fnref:105" href="#fn:105">105</a></td></tr><tr><td><a href="/facts/Nicotine_lozenge/reXp8USf">Lozenge</a></td><td>Nausea, <a href="/facts/Dyspepsia/axnCu0gn">dyspepsia</a>, <a href="/facts/Flatulence/XMAcIUru">flatulence</a>, headache, <a href="/facts/Upper_respiratory_tract_infection/DL59KLz4">upper respiratory tract infections</a>, irritation (i.e., a burning sensation), hiccups, sore throat, coughing, dry lips, and oral mucosal ulceration.</td><td><a class="footnote-ref" id="fnref:106" href="#fn:106">106</a><a class="footnote-ref" id="fnref:107" href="#fn:107">107</a></td></tr><tr><td><a href="/facts/Transdermal/zFITIEjd">Transdermal</a></td><td><a href="/facts/Nicotine_patch/kKWfYe2B">Transdermalpatch</a></td><td><a href="/facts/Application_site_reaction/GVUGP0n5">Application site reactions</a> (i.e., <a href="/facts/Pruritus/MBWq6SPc">pruritus</a>, burning, or <a href="/facts/Erythema/VUsgXRlB">erythema</a>), diarrhea, dyspepsia, abdominal pain, dry mouth, nausea, dizziness, nervousness or restlessness, headache, vivid dreams or other sleep disturbances, and irritability.</td><td><a class="footnote-ref" id="fnref:108" href="#fn:108">108</a><a class="footnote-ref" id="fnref:109" href="#fn:109">109</a><a class="footnote-ref" id="fnref:110" href="#fn:110">110</a></td></tr><tr><td><a href="/facts/Intranasal/W0hvb0gd">Intranasal</a></td><td><a href="/facts/Nicotine_nasal_spray/QGS0733R">Nasal spray</a></td><td>Runny nose, nasopharyngeal and ocular irritation, watery eyes, sneezing, and coughing.</td><td><a class="footnote-ref" id="fnref:111" href="#fn:111">111</a><a class="footnote-ref" id="fnref:112" href="#fn:112">112</a><a class="footnote-ref" id="fnref:113" href="#fn:113">113</a></td></tr><tr><td>Oral inhalation</td><td><a href="/facts/Nicotine_inhaler/XIHBTKbV">Inhaler</a></td><td>Dyspepsia, oropharyngeal irritation (e.g., coughing, irritation of the mouth and throat), <a href="/facts/Rhinitis/VYf2UR8U">rhinitis</a>, and headache.</td><td><a class="footnote-ref" id="fnref:114" href="#fn:114">114</a><a class="footnote-ref" id="fnref:115" href="#fn:115">115</a><a class="footnote-ref" id="fnref:116" href="#fn:116">116</a></td></tr><tr><td colspan="2">All (nonspecific)</td><td>Peripheral <a href="/facts/Vasoconstriction/9hdY0aR2">vasoconstriction</a>, <a href="/facts/Tachycardia/ycmyzP7q">tachycardia</a> (i.e., fast heart rate), elevated <a href="/facts/Blood_pressure/VtqqSM2J">blood pressure</a>, increased <a href="/facts/Alertness/F1SDanRA">alertness</a> and cognitive performance.</td><td><a class="footnote-ref" id="fnref:117" href="#fn:117">117</a><a class="footnote-ref" id="fnref:118" href="#fn:118">118</a></td></tr></tbody></table>
<h3>Sleep</h3>
Nicotine reduces the amount of <a href="/facts/Rapid_eye_movement_sleep/ySwdAgfK">rapid eye movement</a> (REM) sleep, <a href="/facts/Slow-wave_sleep/HIN4tW2y">slow-wave sleep</a> (SWS), and total sleep time in healthy nonsmokers given nicotine via a <a href="/facts/Transdermal_patch/GR3Pel6S">transdermal patch</a>, and the reduction is <a href="/facts/Dose%E2%80%93response_relationship/DLcuLdHc">dose-dependent</a>.<a class="footnote-ref" id="fnref:119" href="#fn:119">119</a> Acute nicotine intoxication has been found to significantly reduce total sleep time and increase REM latency, <a href="/facts/Sleep_onset_latency/Hggc86rQ">sleep onset latency</a>, and <a href="/facts/NREM/zYWgLzXd">non-rapid eye movement</a> (NREM) stage 2 sleep time.<a class="footnote-ref" id="fnref:120" href="#fn:120">120</a><a class="footnote-ref" id="fnref:121" href="#fn:121">121</a> Depressive non-smokers experience mood and sleep improvements under nicotine administration; however, subsequent nicotine withdrawal has a negative effect on both mood and sleep.<a class="footnote-ref" id="fnref:122" href="#fn:122">122</a>

<h3>Cardiovascular system</h3>
Nicotine exerts several significant effects on the <a href="/facts/Cardiovascular_system/WXwudzzc">cardiovascular system</a>. Primarily, it stimulates the <a href="/facts/Sympathetic_nervous_system/hs8psNRd">sympathetic nervous system</a>, leading to the release of <a href="/facts/Catecholamine/hHFrCMgM">catecholamines</a>. This activation results in an increase in <a href="/facts/Heart_rate/YngB0bzg">heart rate</a> and <a href="/facts/Blood_pressure/VtqqSM2J">blood pressure</a>, as well as enhanced <a href="/facts/Myocardial_contractility/0BdQPIsv">myocardial contractility</a>, which raises the workload on the heart. Additionally, nicotine causes systemic <a href="/facts/Vasoconstriction/9hdY0aR2">vasoconstriction</a>, including constriction of coronary arteries, which can reduce blood flow to the heart. Long-term exposure to nicotine may impair <a href="/facts/Endothelial/L4ENFVnw">endothelial</a> function, potentially contributing to <a href="/facts/Atherosclerosis/WIS8QQ6v">atherosclerosis</a>. Furthermore, nicotine has been associated with the development of <a href="/facts/Cardiac_arrhythmia/ooEpr46Q">cardiac arrhythmias</a>, particularly in individuals who already have underlying heart disease.<a class="footnote-ref" id="fnref:123" href="#fn:123">123</a>
The effects of nicotine can be differentiated between short-term and long-term use. Short-term nicotine use, such as that associated with <a href="/facts/Nicotine_replacement_therapy/NVndtPso">nicotine replacement therapy</a> (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 <a href="/facts/Carbon_monoxide/CKuLtEMJ">carbon monoxide</a> and oxidant gases.<a class="footnote-ref" id="fnref:124" href="#fn:124">124</a>
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 class="footnote-ref" id="fnref:125" href="#fn:125">125</a>
A 2018 <a href="/facts/Cochrane_(organisation)/UlmdJ1H8">Cochrane</a> review found that, in rare cases, nicotine replacement therapy can cause non-<a href="/facts/Ischemic/ySL9xbCl">ischemic</a> chest pain (i.e., chest pain that is unrelated to a <a href="/facts/Myocardial_infarction/xoGw0qcG">heart attack</a>) and <a href="/facts/Heart_palpitation/2wACMY49">heart palpitations</a>, but does not increase the incidence of serious cardiac adverse events (i.e., myocardial infarction, <a href="/facts/Stroke/DwpjdzY0">stroke</a>, and <a href="/facts/Cardiac_death/HIAm9AWX">cardiac death</a>) relative to controls.<a class="footnote-ref" id="fnref:126" href="#fn:126">126</a>

<h4>Blood pressure</h4>
In the short term, nicotine causes a transient increase in <a href="/facts/Blood_pressure/VtqqSM2J">blood pressure</a>. Long term, epidemiological studies generally show increased blood pressure and <a href="/facts/Hypertension/wlAvBfcf">hypertension</a> among nicotine users.<a class="footnote-ref" id="fnref:127" href="#fn:127">127</a>

<h3>Reinforcement disorders</h3>
See also: <a href="/facts/Nicotine_withdrawal/9XzN3D6M">Nicotine withdrawal</a> and <a href="/facts/Smoking_cessation/DDddp1SQ">Smoking cessation</a>
<table><tbody><tr><td></td></tr></tbody></table>
Nicotine is highly <a href="/facts/Addictive/76UrWQuT">addictive</a> but paradoxically has quite weak reinforcing property compared to other drugs of abuse in various animals.<a class="footnote-ref" id="fnref:128" href="#fn:128">128</a><a class="footnote-ref" id="fnref:129" href="#fn:129">129</a><a class="footnote-ref" id="fnref:130" href="#fn:130">130</a><a class="footnote-ref" id="fnref:131" href="#fn:131">131</a> Its addictiveness depends on how it is administered and also depends upon form in which nicotine is used.<a class="footnote-ref" id="fnref:132" href="#fn:132">132</a> Animal research suggests that <a href="/facts/Monoamine_oxidase_inhibitors/obewT56a">monoamine oxidase inhibitors</a>, <a href="/facts/Acetaldehyde/QllLbSUe">acetaldehyde</a><a class="footnote-ref" id="fnref:133" href="#fn:133">133</a><a class="footnote-ref" id="fnref:134" href="#fn:134">134</a> and other constituents in tobacco smoke may enhance its addictiveness.<a class="footnote-ref" id="fnref:135" href="#fn:135">135</a><a class="footnote-ref" id="fnref:136" href="#fn:136">136</a> <a href="/facts/Nicotine_dependence/UUKFVcSc">Nicotine dependence</a> involves aspects of both <a href="/facts/Psychological_dependence/9M3oLRP5">psychological dependence</a> and <a href="/facts/Physical_dependence/y2rzJnfB">physical dependence</a>, since discontinuation of extended use has been shown to produce both <a href="/facts/Affect_(psychology)/jEQ6IWSm">affective</a> (e.g., anxiety, irritability, craving, <a href="/facts/Anhedonia/SMPHrCon">anhedonia</a>) and <a href="/facts/Somatic_nervous_system/wEIqqhg9">somatic</a> (mild motor dysfunctions such as <a href="/facts/Tremor/rD6ogM7X">tremor</a>) withdrawal symptoms.<a class="footnote-ref" id="fnref:137" href="#fn:137">137</a> Withdrawal symptoms peak in one to three days<a class="footnote-ref" id="fnref:138" href="#fn:138">138</a> and can persist for several weeks.<a class="footnote-ref" id="fnref:139" href="#fn:139">139</a> Even though other drugs of dependence can have withdrawal states lasting 6 months or longer, this does not appear to occur with cigarette withdrawal.<a class="footnote-ref" id="fnref:140" href="#fn:140">140</a>
Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms.<a class="footnote-ref" id="fnref:141" href="#fn:141">141</a> These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette.<a class="footnote-ref" id="fnref:142" href="#fn:142">142</a> Smokers have a worse mood than they typically would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking.<a class="footnote-ref" id="fnref:143" href="#fn:143">143</a> Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers.<a class="footnote-ref" id="fnref:144" href="#fn:144">144</a><a class="footnote-ref" id="fnref:145" href="#fn:145">145</a>
In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels.<a class="footnote-ref" id="fnref:146" href="#fn:146">146</a> The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal.<a class="footnote-ref" id="fnref:147" href="#fn:147">147</a> Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar.<a class="footnote-ref" id="fnref:148" href="#fn:148">148</a>
Nicotine activates the <a href="/facts/Mesolimbic_pathway/pkEaYUNf">mesolimbic pathway</a> and <a href="/facts/Inducible_gene/alCPohLR">induces</a> long-term <a href="/facts/%CE%94FosB/KHElvauK">ΔFosB</a> expression (i.e., produces <a href="/facts/Phosphorylated/LXUEEeIL">phosphorylated</a> ΔFosB <a href="/facts/Isoform/oWmzfg4l">isoforms</a>) in the <a href="/facts/Nucleus_accumbens/2M43u5X4">nucleus accumbens</a> when inhaled or injected frequently or at high doses, but not necessarily when ingested.<a class="footnote-ref" id="fnref:149" href="#fn:149">149</a><a class="footnote-ref" id="fnref:150" href="#fn:150">150</a><a class="footnote-ref" id="fnref:151" href="#fn:151">151</a> Consequently, high daily exposure (possibly excluding <a href="/facts/Oral_route/vNQcvLVx">oral route</a>) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction.<a class="footnote-ref" id="fnref:152" href="#fn:152">152</a><a class="footnote-ref" id="fnref:153" href="#fn:153">153</a>

<h3>Cancer</h3>
Contrary to <a href="/facts/List_of_common_misconceptions/rxSqIHvF">popular belief</a>, nicotine itself does not cause cancer in humans,<a class="footnote-ref" id="fnref:154" href="#fn:154">154</a><a class="footnote-ref" id="fnref:155" href="#fn:155">155</a> although it is unclear whether it functions as a <a href="/facts/Tumor_promoter/YRIoXPUx">tumor promoter</a> as of 2012<a href="https://en.wikipedia.org/w/index.php?title=Nicotine&action=edit">[update]</a>.<a class="footnote-ref" id="fnref:156" href="#fn:156">156</a> A 2018 report by the US <a href="/facts/National_Academies_of_Sciences,_Engineering,_and_Medicine/AdYmBBGV">National Academies of Sciences, Engineering, and Medicine</a> 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."<a class="footnote-ref" id="fnref:157" href="#fn:157">157</a>
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 <a href="/facts/Cell_cycle/nLMT7K4r">cell cycle</a> progression, <a href="/facts/Epithelial-to-mesenchymal_transition/7fTxEBlb">epithelial-to-mesenchymal transition</a>, <a href="/facts/Cellular_migration/5ySAMquQ">migration</a>, invasion, <a href="/facts/Angiogenesis/h0HF9IUd">angiogenesis</a>, and evasion of <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a>.<a class="footnote-ref" id="fnref:158" href="#fn:158">158</a> These effects are primarily mediated through <a href="/facts/Nicotinic_acetylcholine_receptor/k2s2pPHr">nicotinic acetylcholine receptors</a> (nAChRs), particularly the <a href="/facts/Alpha-7_nicotinic_receptor/Q4hcBmDE">α7 subtype</a>, and to a lesser extent, <a href="/facts/%CE%92-adrenergic_receptor/uoAeJbcN">β-adrenergic receptors</a> (β-ARs). Activation of these receptors triggers several <a href="/facts/Signaling_cascade/1bs0Me6w">signaling cascades</a> crucial in cancer biology, notably the <a href="/facts/MAPK/ERK_pathway/jfpd0YvE">MAPK/ERK pathway</a>, <a href="/facts/PI3K/AKT_pathway/bgWlgxQJ">PI3K/AKT pathway</a>, and <a href="/facts/JAK-STAT_signaling/t31RBT3X">JAK-STAT signaling</a>.<a class="footnote-ref" id="fnref:159" href="#fn:159">159</a>
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.<a class="footnote-ref" id="fnref:160" href="#fn:160">160</a> Additionally, nicotine-induced EMT contributes to drug resistance in cancer cells.<a class="footnote-ref" id="fnref:161" href="#fn:161">161</a>
Nicotine in tobacco can form carcinogenic <a href="/facts/Tobacco-specific_nitrosamines/KYz39wwU">tobacco-specific nitrosamines</a> through a <a href="/facts/Nitrosation/Psk5HkH0">nitrosation</a> reaction. This occurs mostly in the curing and processing of tobacco. However, nicotine in the mouth and stomach can react to form <a href="/facts/N-Nitrosonornicotine/aY85uW7p">N-nitrosonornicotine</a>,<a class="footnote-ref" id="fnref:162" href="#fn:162">162</a> a known type 1 carcinogen,<a class="footnote-ref" id="fnref:163" href="#fn:163">163</a> suggesting that consumption of non-tobacco forms of nicotine may still play a role in carcinogenesis.<a class="footnote-ref" id="fnref:164" href="#fn:164">164</a>

<h3>Genotoxicity</h3>
Nicotine causes <a href="/facts/DNA_damage_(naturally_occurring)/CjGTLKGl">DNA damage</a> in several types of human cells as judged by assays for <a href="/facts/Genotoxicity/fRUJaqxo">genotoxicity</a> such as the <a href="/facts/Comet_assay/jctPYYYu">comet assay</a>, cytokinesis-block <a href="/facts/Micronucleus_test/dF0YAnrd">micronucleus test</a> and <a href="/facts/Chromosome_abnormality/6hL7p0cP">chromosome aberrations</a> test. In humans, this damage can happen in primary <a href="/facts/Parotid_gland/H4tPjP4D">parotid gland</a> cells,<a class="footnote-ref" id="fnref:165" href="#fn:165">165</a> <a href="/facts/Lymphocyte/pS2pv2Ma">lymphocytes</a>,<a class="footnote-ref" id="fnref:166" href="#fn:166">166</a> and respiratory tract cells.<a class="footnote-ref" id="fnref:167" href="#fn:167">167</a>

<h3>Pregnancy and breastfeeding</h3>
Nicotine has been shown to produce birth defects in some animal species, but not others;<a class="footnote-ref" id="fnref:168" href="#fn:168">168</a> consequently, it is considered to be a possible <a href="/facts/Teratogen/j4BN6lsB">teratogen</a> in humans.<a class="footnote-ref" id="fnref:169" href="#fn:169">169</a> In <a href="/facts/Animal_studies/fdTuHKgk">animal studies</a> that resulted in birth defects, researchers found that nicotine negatively affects fetal <a href="/facts/Brain_development/hSjrUxCn">brain development</a> and pregnancy outcomes;<a class="footnote-ref" id="fnref:170" href="#fn:170">170</a><a class="footnote-ref" id="fnref:171" href="#fn:171">171</a> the negative effects on early brain development are associated with abnormalities in <a href="/facts/Brain_metabolism/EKla9NkJ">brain metabolism</a> and <a href="/facts/Neurotransmitter_system/LlpYFSU3">neurotransmitter system</a> function.<a class="footnote-ref" id="fnref:172" href="#fn:172">172</a> Nicotine crosses the <a href="/facts/Placenta/7XUoks1b">placenta</a> and is found in the breast milk of mothers who smoke as well as mothers who inhale <a href="/facts/Passive_smoke/Ar7w91W8">passive smoke</a>.<a class="footnote-ref" id="fnref:173" href="#fn:173">173</a>
Nicotine exposure <a href="/facts/Uterus/LIrApMXs">in utero</a> is responsible for several complications of pregnancy and birth: pregnant women who smoke are at greater risk for both <a href="/facts/Miscarriage/sFq0vdnU">miscarriage</a> and <a href="/facts/Stillbirth/x3UcW2P7">stillbirth</a> and infants exposed to nicotine in utero tend to have lower <a href="/facts/Birth_weight/rJuI7u42">birth weights</a>.<a class="footnote-ref" id="fnref:174" href="#fn:174">174</a> A <a href="/facts/McMaster_University/XmAxtS9z">McMaster University</a> research group observed in 2010 that rats exposed to nicotine in the womb (via parenteral infusion) later in life had conditions including <a href="/facts/Type_2_diabetes/zCMXksmt">type 2 diabetes</a>, <a href="/facts/Obesity/RBF9y5Vl">obesity</a>, <a href="/facts/Hypertension/wlAvBfcf">hypertension</a>, neurobehavioral defects, respiratory dysfunction, and <a href="/facts/Infertility/emky9q8L">infertility</a>.<a class="footnote-ref" id="fnref:175" href="#fn:175">175</a>

<h2 id="overdose">Overdose</h2>
Main article: <a href="/facts/Nicotine_poisoning/JpsMcE2X">Nicotine poisoning</a>
It is unlikely that a person would overdose on nicotine through smoking alone. The US <a href="/facts/Food_and_Drug_Administration/rCEnh9WB">Food and Drug Administration</a> (FDA) stated in 2013 that there are no significant safety concerns associated with the use of more than one form of <a href="/facts/Over-the-counter_drug/QI3FcgRf">over-the-counter</a> (OTC) <a href="/facts/Nicotine_replacement_therapy/NVndtPso">nicotine replacement therapy</a> at the same time, or using OTC NRT at the same time as another nicotine-containing product, like cigarettes.<a class="footnote-ref" id="fnref:176" href="#fn:176">176</a> The <a href="/facts/Median_lethal_dose/PSTer8Wv">median lethal dose</a> of nicotine in humans is unknown.<a class="footnote-ref" id="fnref:177" href="#fn:177">177</a><a class="footnote-ref" id="fnref:178" href="#fn:178">178</a> Nevertheless, nicotine has a relatively high <a href="/facts/Toxicity/qa96rs60">toxicity</a> in comparison to many other alkaloids such as <a href="/facts/Caffeine/Hx6E2QC5">caffeine</a>, which has an LD50 of 127 mg/kg when administered to mice.<a class="footnote-ref" id="fnref:179" href="#fn:179">179</a> At sufficiently high doses, it is associated with nicotine poisoning,<a class="footnote-ref" id="fnref:180" href="#fn:180">180</a> which, while common in children (in whom poisonous and lethal levels occur at lower doses per kilogram of body weight<a class="footnote-ref" id="fnref:181" href="#fn:181">181</a>) rarely results in significant morbidity or death.<a class="footnote-ref" id="fnref:182" href="#fn:182">182</a> The estimated lower dose limit for fatal outcomes is 500–1,000 mg of ingested nicotine for an adult (6.5–13 mg/kg).<a class="footnote-ref" id="fnref:183" href="#fn:183">183</a><a class="footnote-ref" id="fnref:184" href="#fn:184">184</a>
The initial symptoms of a nicotine overdose typically include <a href="/facts/Nausea/dyhkcbeD">nausea</a>, vomiting, diarrhea, <a href="/facts/Hypersalivation/fjDlJ6tj">hypersalivation</a>, abdominal pain, <a href="/facts/Tachycardia/ycmyzP7q">tachycardia</a> (rapid heart rate), <a href="/facts/Hypertension/wlAvBfcf">hypertension</a> (high blood pressure), <a href="/facts/Tachypnea/G220HYhe">tachypnea</a> (rapid breathing), headache, dizziness, <a href="/facts/Pallor/bHpLxohY">pallor</a> (pale skin), auditory or visual disturbances, and perspiration, followed shortly after by marked <a href="/facts/Bradycardia/70msP5HD">bradycardia</a> (slow heart rate), <a href="/facts/Bradypnea/M6JHJUS0">bradypnea</a> (slow breathing), and <a href="/facts/Hypotension/BhrdVVRS">hypotension</a> (low blood pressure).<a class="footnote-ref" id="fnref:185" href="#fn:185">185</a> An increased respiratory rate (i.e., <a href="/facts/Tachypnea/G220HYhe">tachypnea</a>) is one of the primary <a href="/facts/Medical_sign/BzP6MrTN">signs</a> of nicotine poisoning.<a class="footnote-ref" id="fnref:186" href="#fn:186">186</a> At sufficiently high doses, <a href="/facts/Somnolence/mIlFhyf0">somnolence</a> (sleepiness or drowsiness), <a href="/facts/Confusion/Pcvw6deb">confusion</a>, <a href="/facts/Syncope_(medicine)/AqU1whYh">syncope</a> (loss of consciousness from fainting), <a href="/facts/Shortness_of_breath/1jBfFzxU">shortness of breath</a>, marked <a href="/facts/Weakness/U9wAgeLn">weakness</a>, <a href="/facts/Seizure/zuIrQyze">seizures</a>, and <a href="/facts/Coma/N9oQ7g7R">coma</a> may occur.<a class="footnote-ref" id="fnref:187" href="#fn:187">187</a><a class="footnote-ref" id="fnref:188" href="#fn:188">188</a> Lethal nicotine poisoning rapidly produces seizures, and death – which may occur within minutes – is believed to be due to <a href="/facts/Respiratory_paralysis/R3GcdkJ1">respiratory paralysis</a>.<a class="footnote-ref" id="fnref:189" href="#fn:189">189</a>

<h3>Toxicity</h3>
Today nicotine is less commonly used in agricultural <a href="/facts/Insecticide/1xYL3MSD">insecticides</a>, which was a main source of poisoning. More recent cases of poisoning typically appear to be in the form of <a href="/facts/Green_Tobacco_Sickness/B3kw1ECM">Green Tobacco Sickness</a> (GTS),<a class="footnote-ref" id="fnref:190" href="#fn:190">190</a> accidental ingestion of <a href="/facts/Tobacco/bTD4RUPQ">tobacco</a> or <a href="/facts/Tobacco_products/jVCn4CEC">tobacco products</a>, or ingestion of nicotine-containing plants.<a class="footnote-ref" id="fnref:191" href="#fn:191">191</a><a class="footnote-ref" id="fnref:192" href="#fn:192">192</a><a class="footnote-ref" id="fnref:193" href="#fn:193">193</a> 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.<a class="footnote-ref" id="fnref:194" href="#fn:194">194</a><a class="footnote-ref" id="fnref:195" href="#fn:195">195</a> People can be exposed to nicotine in the workplace by breathing it in, skin absorption, swallowing it, or eye contact. The <a href="/facts/Occupational_Safety_and_Health_Administration/dCGbW5Ax">Occupational Safety and Health Administration</a> (OSHA) has set the legal limit (<a href="/facts/Permissible_exposure_limit/IrQeETWy">permissible exposure limit</a>) for nicotine exposure in the workplace as 0.5 mg/m3 skin exposure over an 8-hour workday. The US <a href="/facts/National_Institute_for_Occupational_Safety_and_Health/5WjdDNMN">National Institute for Occupational Safety and Health</a> (NIOSH) has set a <a href="/facts/Recommended_exposure_limit/nexWYeNv">recommended exposure limit</a> (REL) of 0.5 mg/m3 skin exposure over an 8-hour workday. At environmental levels of 5 mg/m3, nicotine is <a href="/facts/IDLH/ektUbSdQ">immediately dangerous to life and health</a>.<a class="footnote-ref" id="fnref:196" href="#fn:196">196</a>

<h2 id="drug-interactions">Drug interactions</h2>
<h3>Pharmacodynamic</h3>
<ul><li>Potential interaction with <a href="/facts/Sympathomimetic_drug/IEYU5ERW">sympathomimetic drugs</a> (<a href="/facts/Adrenergic_agonist/fJ8XuRaQ">adrenergic agonists</a>) and <a href="/facts/Sympatholytic_drug/aXHpgfPs">sympatholytic drugs</a> (<a href="/facts/Alpha-blocker/MqNLhfS9">alpha-blockers</a> and <a href="/facts/Beta-blockers/PRsWgpLV">beta-blockers</a>).<a class="footnote-ref" id="fnref:197" href="#fn:197">197</a></li></ul>
<h3>Pharmacokinetic</h3>
Nicotine and cigarette smoke both <a href="/facts/Inducible_gene/alCPohLR">induce</a> the <a href="/facts/Gene_expression/alCPohLR">expression</a> of liver enzymes (e.g., certain <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> proteins) which metabolize drugs, leading to the potential for alterations in <a href="/facts/Drug_metabolism/I5nQ28Ma">drug metabolism</a>.<a class="footnote-ref" id="fnref:198" href="#fn:198">198</a>

<ul><li>Smoking cessation may decrease the metabolism of <a href="/facts/Acetaminophen/SNDfQWcf">acetaminophen</a>, <a href="/facts/Beta-blockers/PRsWgpLV">beta-blockers</a>, <a href="/facts/Caffeine/Hx6E2QC5">caffeine</a>, <a href="/facts/Oxazepam/UGeD4Utb">oxazepam</a>, <a href="/facts/Pentazocine/DuoNIw3f">pentazocine</a>, <a href="/facts/Propoxyphene/wjh8HcC2">propoxyphene</a>, <a href="/facts/Theophylline/qJzjQVB2">theophylline</a>, and <a href="/facts/Tricyclic_antidepressants/vpBLER2Q">tricyclic antidepressants</a>, leading to higher <a href="/facts/Blood_plasma/oHuwwugG">plasma</a> concentrations of these drugs.<a class="footnote-ref" id="fnref:199" href="#fn:199">199</a></li>
<li>Possible alteration of nicotine <a href="/facts/Drug_absorption/LCezQPJK">absorption</a> through the skin from the transdermal nicotine patch by drugs that cause <a href="/facts/Vasodilation/cjzrU8Ro">vasodilation</a> or <a href="/facts/Vasoconstriction/9hdY0aR2">vasoconstriction</a>.<a class="footnote-ref" id="fnref:200" href="#fn:200">200</a></li>
<li>Possible alteration of nicotine absorption through the nasal cavity from the nicotine nasal spray by nasal vasoconstrictors (e.g., <a href="/facts/Xylometazoline/bLSBCzou">xylometazoline</a>).<a class="footnote-ref" id="fnref:201" href="#fn:201">201</a></li>
<li>Possible alteration of nicotine absorption through <a href="/facts/Oral_mucosa/uJyDj6c0">oral mucosa</a> from nicotine gum and lozenges by food and drink that modify <a href="/facts/Saliva/gK4nvayc">salivary</a> <a href="/facts/PH/RnSv8D7y">pH</a>.<a class="footnote-ref" id="fnref:202" href="#fn:202">202</a></li></ul>
<h2 id="pharmacology">Pharmacology</h2>
<h3>Pharmacodynamics</h3>
Nicotine acts as a <a href="/facts/Receptor_agonist/nz8U5NNp">receptor agonist</a> at most <a href="/facts/Nicotinic_acetylcholine_receptor/k2s2pPHr">nicotinic acetylcholine receptors</a> (nAChRs),<a class="footnote-ref" id="fnref:203" href="#fn:203">203</a><a class="footnote-ref" id="fnref:204" href="#fn:204">204</a> except at two <a href="/facts/Nicotinic_receptor_subunits/k2s2pPHr">nicotinic receptor subunits</a> (<a href="/facts/NAChR%CE%B19/KXxv09uv">nAChRα9</a> and <a href="/facts/NAChR%CE%B110/Ru6E9B5e">nAChRα10</a>) where it acts as a <a href="/facts/Receptor_antagonist/PuXHVNdV">receptor antagonist</a>.<a class="footnote-ref" id="fnref:205" href="#fn:205">205</a> Such antagonism results in mild <a href="/facts/Analgesic/xLj4XBcq">analgesia</a>.

<h4>Central nervous system</h4>

By binding to <a href="/facts/Nicotinic_acetylcholine_receptor/k2s2pPHr">nicotinic acetylcholine receptors</a> in the brain, nicotine elicits its psychoactive effects and increases the levels of several <a href="/facts/Neurotransmitter/LlpYFSU3">neurotransmitters</a> in various brain structures – acting as a sort of "volume control".<a class="footnote-ref" id="fnref:206" href="#fn:206">206</a><a class="footnote-ref" id="fnref:207" href="#fn:207">207</a> Nicotine has a higher affinity for nicotinic receptors in the brain than those in <a href="/facts/Skeletal_muscle/en1tVYFN">skeletal muscle</a>, though at toxic doses it can induce contractions and respiratory paralysis.<a class="footnote-ref" id="fnref:208" href="#fn:208">208</a> Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.<a class="footnote-ref" id="fnref:209" href="#fn:209">209</a> Nicotine is unusual in comparison to most drugs, as its profile changes from <a href="/facts/Stimulant/nmBdAXM5">stimulant</a> to <a href="/facts/Sedative/JWzvq66P">sedative</a> with increasing <a href="/facts/Dose_(biochemistry)/Gez72mSn">dosages</a>, a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969.<a class="footnote-ref" id="fnref:210" href="#fn:210">210</a><a class="footnote-ref" id="fnref:211" href="#fn:211">211</a> At very high doses it dampens <a href="/facts/Neuronal_activity/9H38LExu">neuronal activity</a>.<a class="footnote-ref" id="fnref:212" href="#fn:212">212</a> Nicotine induces both behavioral stimulation and anxiety in animals.<a class="footnote-ref" id="fnref:213" href="#fn:213">213</a> Research into nicotine's most predominant metabolite, <a href="/facts/Cotinine/5hesUlxJ">cotinine</a>, suggests that some of nicotine's psychoactive effects are mediated by cotinine.<a class="footnote-ref" id="fnref:214" href="#fn:214">214</a>
Nicotine activates nicotinic receptors (particularly <a href="/facts/%CE%914%CE%B22_nicotinic_receptor/qleRmw4W">α4β2 nicotinic receptors</a>, but also <a href="/facts/Alpha5_Nicotinic_Acetylcholine_Receptor/0cICJ5PR">α5 nAChRs</a>) on neurons that innervate the <a href="/facts/Ventral_tegmental_area/f1rcxshF">ventral tegmental area</a> and within the <a href="/facts/Mesolimbic_pathway/pkEaYUNf">mesolimbic pathway</a> where it appears to cause the release of <a href="/facts/Dopamine/5gNy8Xkd">dopamine</a>.<a class="footnote-ref" id="fnref:215" href="#fn:215">215</a><a class="footnote-ref" id="fnref:216" href="#fn:216">216</a> This nicotine-induced dopamine release occurs at least partially through activation of the <a href="/facts/Cholinergic%E2%80%93dopaminergic_reward_link/0uWqCQsX">cholinergic–dopaminergic reward link</a> in the <a href="/facts/Ventral_tegmental_area/f1rcxshF">ventral tegmental area</a>.<a class="footnote-ref" id="fnref:217" href="#fn:217">217</a><a class="footnote-ref" id="fnref:218" href="#fn:218">218</a> Nicotine can modulate the firing rate of the ventral tegmental area neurons.<a class="footnote-ref" id="fnref:219" href="#fn:219">219</a> These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of <a href="/facts/Euphoria/u4cnbWC4">euphoria</a>;<a class="footnote-ref" id="fnref:220" href="#fn:220">220</a> however, mild euphoria from nicotine use can occur in some individuals.<a class="footnote-ref" id="fnref:221" href="#fn:221">221</a> Chronic nicotine use inhibits class I and II <a href="/facts/Histone_deacetylases/P38q78aV">histone deacetylases</a> in the <a href="/facts/Striatum/MjNnTjSd">striatum</a>, where this effect plays a role in nicotine addiction.<a class="footnote-ref" id="fnref:222" href="#fn:222">222</a><a class="footnote-ref" id="fnref:223" href="#fn:223">223</a>

<h4>Sympathetic nervous system</h4>

Nicotine also activates the <a href="/facts/Sympathetic_nervous_system/hs8psNRd">sympathetic nervous system</a>,<a class="footnote-ref" id="fnref:224" href="#fn:224">224</a> acting via <a href="/facts/Splanchnic_nerves/atDFXxVV">splanchnic nerves</a> 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 <a href="/facts/Bloodstream/WXwudzzc">bloodstream</a>.

<h4>Adrenal medulla</h4>
By binding to <a href="/facts/Ganglion_type_nicotinic_receptor/3m4rqQdN">ganglion type nicotinic receptors</a> in the adrenal medulla, nicotine increases flow of <a href="/facts/Adrenaline/k7vvMI7E">adrenaline</a> (epinephrine), a stimulating <a href="/facts/Hormone/WFnBnINJ">hormone</a> and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of <a href="/facts/Calcium/hf252CC0">calcium</a> through voltage-gated calcium channels. Calcium triggers the <a href="/facts/Exocytosis/4P4oQdtA">exocytosis</a> of <a href="/facts/Chromaffin_cell/ydWmHLLo">chromaffin granules</a> and thus the release of <a href="/facts/Epinephrine/k7vvMI7E">epinephrine</a> (and norepinephrine) into the <a href="/facts/Bloodstream/WXwudzzc">bloodstream</a>. The release of <a href="/facts/Epinephrine/k7vvMI7E">epinephrine</a> (adrenaline) causes an increase in <a href="/facts/Heart_rate/YngB0bzg">heart rate</a>, <a href="/facts/Blood_pressure/VtqqSM2J">blood pressure</a> and <a href="/facts/Breathing/92Wov2gk">respiration</a>, as well as higher <a href="/facts/Blood_glucose/I4SkNzrm">blood glucose</a> levels.<a class="footnote-ref" id="fnref:225" href="#fn:225">225</a>

<h3>Pharmacokinetics</h3>

As nicotine enters the body, it is distributed quickly through the <a href="/facts/Blood/03zEulkj">bloodstream</a> and crosses the <a href="/facts/Blood%E2%80%93brain_barrier/xYzvVwdu">blood–brain barrier</a> reaching the <a href="/facts/Human_brain/qfSwSB8K">brain</a> within 10–20 seconds after inhalation.<a class="footnote-ref" id="fnref:226" href="#fn:226">226</a> The <a href="/facts/Elimination_half-life/7nB2JtMr">elimination half-life</a> of nicotine in the body is around two hours.<a class="footnote-ref" id="fnref:227" href="#fn:227">227</a><a class="footnote-ref" id="fnref:228" href="#fn:228">228</a> Nicotine is primarily <a href="/facts/Excretion/mspsTfnv">excreted</a> in <a href="/facts/Urine/oNUYVtvX">urine</a> and urinary concentrations vary depending upon <a href="/facts/Urine_flow_rate/8eXDcCr2">urine flow rate</a> and <a href="/facts/Urine_pH/oNUYVtvX">urine pH</a>.<a class="footnote-ref" id="fnref:229" href="#fn:229">229</a>
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,<a class="footnote-ref" id="fnref:230" href="#fn:230">230</a> 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. <a href="/facts/Cotinine/5hesUlxJ">Cotinine</a> is an active metabolite of nicotine that remains in the blood with a half-life of 18–20 hours, making it easier to analyze.<a class="footnote-ref" id="fnref:231" href="#fn:231">231</a>
Nicotine is <a href="/facts/Metabolized/WxDrm8k5">metabolized</a> in the <a href="/facts/Liver/Rtp4Fk2b">liver</a> by <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> enzymes (mostly <a href="/facts/CYP2A6/rcK5p3HT">CYP2A6</a>, and also by <a href="/facts/CYP2B6/gkM9tRSJ">CYP2B6</a>) and <a href="/facts/FMO3/SIPG8pAd">FMO3</a>, which selectively metabolizes (S)-nicotine. A major metabolite is <a href="/facts/Cotinine/5hesUlxJ">cotinine</a>. Other primary metabolites include nicotine N-oxide, <a href="/facts/Nornicotine/8Ho3ozbo">nornicotine</a>, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.<a class="footnote-ref" id="fnref:232" href="#fn:232">232</a> Under some conditions, other substances may be formed such as <a href="/facts/Myosmine/PuGM0mbx">myosmine</a>.<a class="footnote-ref" id="fnref:233" href="#fn:233">233</a><a class="footnote-ref" id="fnref:234" href="#fn:234">234</a>
<a href="/facts/Glucuronidation/G5qfwsFb">Glucuronidation</a> and oxidative metabolism of nicotine to cotinine are both inhibited by <a href="/facts/Menthol/Pdg9F3pS">menthol</a>, an additive to <a href="/facts/Menthol_cigarettes/QEGTfNYy">mentholated cigarettes</a>, thus increasing the half-life of nicotine <a href="/facts/In_vivo/kWcWyl6f">in vivo</a>.<a class="footnote-ref" id="fnref:235" href="#fn:235">235</a>

<h3>Metabolism</h3>
Nicotine decreases hunger and as a consequence food consumption, alongside increasing <a href="/facts/Energy_expenditure/0quwmrbc">energy expenditure</a>.<a class="footnote-ref" id="fnref:236" href="#fn:236">236</a><a class="footnote-ref" id="fnref:237" href="#fn:237">237</a> 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.<a class="footnote-ref" id="fnref:238" href="#fn:238">238</a> Nicotine effect on weight appears to result from nicotine's stimulation of α3β4 nAChR receptors located in the <a href="/facts/Proopiomelanocortin/M5qudCoQ">POMC neurons</a> in the arcuate nucleus and subsequently the <a href="/facts/Central_melanocortin_system/zVMCpyNn">melanocortin system</a>, especially the melanocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus, thus modulating feeding inhibition.<a class="footnote-ref" id="fnref:239" href="#fn:239">239</a><a class="footnote-ref" id="fnref:240" href="#fn:240">240</a> POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.<a class="footnote-ref" id="fnref:241" href="#fn:241">241</a>

<h2 id="chemistry">Chemistry</h2>

Nicotine is a <a href="/facts/Hygroscopy/1NBGewXv">hygroscopic</a>, colorless<a class="footnote-ref" id="fnref:242" href="#fn:242">242</a> to yellow-brown, oily liquid, that is readily soluble in alcohol, ether or light petroleum. It is <a href="/facts/Miscible/HwQaolbQ">miscible</a> with <a href="/facts/Water_(molecule)/FFsl65l1">water</a> in its neutral amine <a href="/facts/Base_(chemistry)/M9wA7qeM">base</a> form between 60 °C and 210 °C. It is a dibasic <a href="/facts/Nitrogenous_base/zj1Vl9Qh">nitrogenous base</a>, having Kb1=1×10−6, Kb2=1×10−11.<a class="footnote-ref" id="fnref:243" href="#fn:243">243</a> It readily forms ammonium <a href="/facts/Salt_(chemistry)/lsSKwGpn">salts</a> with <a href="/facts/Acid/FySU18n1">acids</a> that are usually solid and water-soluble. Its <a href="/facts/Flash_point/97JQP35E">flash point</a> is 95 °C and its auto-ignition temperature is 244 °C.<a class="footnote-ref" id="fnref:244" href="#fn:244">244</a> Nicotine is readily volatile (<a href="/facts/Vapor_pressure/whrEr96T">vapor pressure</a> 5.5 Pa at 25 °C)<a class="footnote-ref" id="fnref:245" href="#fn:245">245</a> On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, <a href="/facts/Nicotinic_acid/UAAqPpk6">nicotinic acid</a> (niacin, a B3 vitamer), and <a href="/facts/Methylamine/srMMDp0D">methylamine</a>.<a class="footnote-ref" id="fnref:246" href="#fn:246">246</a>
Nicotine is <a href="/facts/Chirality_(chemistry)/p5a9pftB">chiral</a> and hence <a href="/facts/Optically_active/XQ3q2R3R">optically active</a>, having two <a href="/facts/Enantiomer/wjPv5J3y">enantiomeric</a> forms. The naturally occurring form of nicotine is <a href="/facts/Levorotatory/XQ3q2R3R">levorotatory</a> with a <a href="/facts/Specific_rotation/XGLNP7U3">specific rotation</a> of [α]D=–166.4° ((−)-nicotine). The <a href="/facts/Dextrorotatory/XQ3q2R3R">dextrorotatory</a> form, (+)-nicotine is physiologically less active than (−)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.<a class="footnote-ref" id="fnref:247" href="#fn:247">247</a> The salts of (−)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids.<a class="footnote-ref" id="fnref:248" href="#fn:248">248</a> The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180 °C.<a class="footnote-ref" id="fnref:249" href="#fn:249">249</a> <a href="/facts/Anabasine/CtjVGdUb">Anabasine</a> is a <a href="/facts/Structural_isomer/vEQEBbWQ">structural isomer</a> of nicotine, as both compounds have the <a href="/facts/Molecular_formula/hghUtthl">molecular formula</a> <a href="/facts/Carbon/ukrgQexo">C</a>10<a href="/facts/Hydrogen/BoYHjl0J">H</a>14<a href="/facts/Nitrogen/Nf1QpGDz">N</a>2.
Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer.<a class="footnote-ref" id="fnref:250" href="#fn:250">250</a>  Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers.<a class="footnote-ref" id="fnref:251" href="#fn:251">251</a> 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.

<a href="/facts/Construction_of_electronic_cigarettes/pzCC8IXK">Pod mod</a> electronic cigarettes use nicotine in the form of a <a href="/facts/Nicotine_salt/TIDDBHR9">protonated nicotine</a>, rather than <a href="/facts/Free_base/bLMkVbTk">free-base</a> nicotine found in earlier generations.<a class="footnote-ref" id="fnref:252" href="#fn:252">252</a>

<h3>Preparation</h3>
The first laboratory preparation of nicotine (as its <a href="/facts/Racemate/STEagtrD">racemate</a>) was described in 1904.<a class="footnote-ref" id="fnref:253" href="#fn:253">253</a>

The starting material was an N-substituted <a href="/facts/Pyrrole/7c7AbyN8">pyrrole</a> derivative, which was heated to convert it by a <a href="/facts/Sigmatropic_reaction/aWMl8GPd">[1,5] sigmatropic shift</a> to the <a href="/facts/Isomer/PXlvDVdg">isomer</a> with a carbon bond between the pyrrole and pyridine rings, followed by <a href="/facts/Methylation/EvDMWVW5">methylation</a> and selective reduction of the pyrrole ring using tin and hydrochloric acid.<a class="footnote-ref" id="fnref:254" href="#fn:254">254</a><a class="footnote-ref" id="fnref:255" href="#fn:255">255</a> Many other syntheses of nicotine, in both racemic and chiral forms have since been published.<a class="footnote-ref" id="fnref:256" href="#fn:256">256</a>

<h3>Biosynthesis</h3>

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that comprise nicotine. Metabolic studies show that the <a href="/facts/Pyridine/X817hCch">pyridine</a> ring of nicotine is derived from <a href="/facts/Nicotinic_acid/UAAqPpk6">nicotinic acid</a> the <a href="/facts/Pyrrolidine/YPVKcwyT">pyrrolidine</a> is derived from N-methyl-Δ1-pyrrollidium cation.<a class="footnote-ref" id="fnref:257" href="#fn:257">257</a><a class="footnote-ref" id="fnref:258" href="#fn:258">258</a> 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 <a href="/facts/Nicotiana/Bfh1JnE0">Nicotiana</a> begins with the oxidation of aspartic acid into α-amino succinate by aspartate oxidase (AO). This is followed by a condensation with <a href="/facts/Glyceraldehyde-3-phosphate/Wy3FMLzJ">glyceraldehyde-3-phosphate</a> and a cyclization catalyzed by quinolinate synthase (QS) to give <a href="/facts/Quinolinic_acid/8FfG8CzE">quinolinic acid</a>. 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 <a href="/facts/Nicotinamide/5GQcLC5K">nicotinamide</a> by the enzyme <a href="/facts/Nicotinamidase/014MdPWs">nicotinamidase</a>.
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 <a href="/facts/Decarboxylation/Uugc18fz">decarboxylation</a> of <a href="/facts/Ornithine/BtnkQfmk">ornithine</a> by <a href="/facts/Ornithine_decarboxylase/kAKxbPJE">ornithine decarboxylase</a> (ODC) to produce <a href="/facts/Putrescine/jvkcXtHY">putrescine</a>. Putrescine is then converted into N-methyl putrescine via <a href="/facts/Methylation/EvDMWVW5">methylation</a> by SAM catalyzed by <a href="/facts/Putrescine_N-methyltransferase/K06MQ5oU">putrescine N-methyltransferase</a> (PMT). N-methyl putrescine then undergoes <a href="/facts/Deamination/aBIhMC23">deamination</a> 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 <a href="/facts/Enantiomer/wjPv5J3y">enantiomerically</a> pure (−)-nicotine.<a class="footnote-ref" id="fnref:259" href="#fn:259">259</a>

<h3>Detection in body fluids</h3>
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.<a class="footnote-ref" id="fnref:260" href="#fn:260">260</a><a class="footnote-ref" id="fnref:261" href="#fn:261">261</a> Nicotine use is not regulated in competitive sports programs.<a class="footnote-ref" id="fnref:262" href="#fn:262">262</a>

<h3>Methods for analysis of enantiomers</h3>
Methods for measuring the two enantiomers are straightforward and include normal-phase liquid chromatography,<a class="footnote-ref" id="fnref:263" href="#fn:263">263</a> liquid chromatography with a chiral column.<a class="footnote-ref" id="fnref:264" href="#fn:264">264</a> 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.<a class="footnote-ref" id="fnref:265" href="#fn:265">265</a> Another approach measures the carbon-14 content which also differs between natural and laboratory-based tobacco.<a class="footnote-ref" id="fnref:266" href="#fn:266">266</a> These methods remain to be fully evaluated and validated using a wide range of samples.

<h3>Analogues and derivatives</h3>
<a href="/facts/Structural_analog/3aysWSVG">Analogues</a> and <a href="/facts/Chemical_derivative/JYcbLkbm">derivatives</a> of nicotine are known.<a class="footnote-ref" id="fnref:267" href="#fn:267">267</a><a class="footnote-ref" id="fnref:268" href="#fn:268">268</a><a class="footnote-ref" id="fnref:269" href="#fn:269">269</a><a class="footnote-ref" id="fnref:270" href="#fn:270">270</a><a class="footnote-ref" id="fnref:271" href="#fn:271">271</a> Examples include <a href="/facts/Altinicline/5R2KuNLK">altinicline</a>, <a href="/facts/Anabasine/CtjVGdUb">anabasine</a>, <a href="/facts/Anatabine/jI9ygmWu">anatabine</a>, <a href="/facts/Altinicline/5R2KuNLK">altinicline</a>, <a href="/facts/Arecoline/vGlVj3UJ">arecoline</a>, <a href="/facts/6-chloronicotine/BJcjUKf5">6-chloronicotine</a>, <a href="/facts/Cotinine/5hesUlxJ">cotinine</a>, <a href="/facts/Cytisine/zPop523E">cytisine</a>, <a href="/facts/Dianicline/1vkaEbhc">dianicline</a>, <a href="/facts/Epibatidine/hqFyHg8u">epibatidine</a>, <a href="/facts/Levamisole/1XGQzV6c">levamisole</a>, <a href="/facts/RJR-2429/RklykuJG">RJR-2429</a>, <a href="/facts/TC-1698/pRC2LJIK">TC-1698</a>, <a href="/facts/UB-165/DSLYvSXt">UB-165</a>, and <a href="/facts/Varenicline/DdJwFBbY">varenicline</a>, among others.<a class="footnote-ref" id="fnref:272" href="#fn:272">272</a><a class="footnote-ref" id="fnref:273" href="#fn:273">273</a>

<h2 id="natural-occurrence">Natural occurrence</h2>
Nicotine is a <a href="/facts/Secondary_metabolite/mKnQjBQp">secondary metabolite</a> produced in a variety of plants in the family <a href="/facts/Solanaceae/HQPdeAVC">Solanaceae</a>, most notably in tobacco <a href="/facts/Nicotiana_tabacum/WQKhTHHK">Nicotiana tabacum</a>, where it can be found at high concentrations of 0.5 to 7.5%.<a class="footnote-ref" id="fnref:274" href="#fn:274">274</a> Nicotine is also found in the leaves of other tobacco species, such as <a href="/facts/Nicotiana_rustica/27q0W8Mf">Nicotiana rustica</a> (in amounts of 2–14%). Nicotine production is strongly induced in response to wounding as part of a <a href="/facts/Jasmonate/zILw8Ncl">jasmonate</a>-dependent reaction.<a class="footnote-ref" id="fnref:275" href="#fn:275">275</a> Specialist insects on tobacco, such as the tobacco hornworm (<a href="/facts/Manduca_sexta/A4kdLLLb">Manduca sexta</a>), have a number of adaptations to the detoxification and even adaptive re-purposing of nicotine.<a class="footnote-ref" id="fnref:276" href="#fn:276">276</a> Nicotine is also found at low concentrations in the nectar of tobacco plants, where it may promote <a href="/facts/Outcrossing/6sAJ4Gh7">outcrossing</a> by affecting the behavior of hummingbird pollinators.<a class="footnote-ref" id="fnref:277" href="#fn:277">277</a>
Nicotine occurs in smaller amounts (varying from 2–7 <a href="/facts/Microgram/aAHxytph">μg</a>/<a href="/facts/Kilogram/lU2zbPk8">kg</a>, or 20–70 millionths of a percent wet weight<a class="footnote-ref" id="fnref:278" href="#fn:278">278</a>) in other <a href="/facts/Solanaceae/HQPdeAVC">Solanaceaeous</a> plants, including some crop species such as <a href="/facts/Potato/F8jRVExs">potatoes</a>, <a href="/facts/Tomato/3d5Xsqw7">tomatoes</a>, <a href="/facts/Eggplant/UTRtUSsd">eggplant</a>, and <a href="/facts/Capsicum/oqoEFu4F">peppers</a>,<a class="footnote-ref" id="fnref:279" href="#fn:279">279</a><a class="footnote-ref" id="fnref:280" href="#fn:280">280</a> as well as non-crop species such as <a href="/facts/Duboisia_hopwoodii/gAGALUqt">Duboisia hopwoodii</a>.<a class="footnote-ref" id="fnref:281" href="#fn:281">281</a> The amounts of nicotine in tomatoes lowers substantially as the fruit ripens.<a class="footnote-ref" id="fnref:282" href="#fn:282">282</a> 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."<a class="footnote-ref" id="fnref:283" href="#fn:283">283</a> The amount of nicotine eaten per day is roughly around 1.4 and 2.25 <a href="/facts/Microgram/aAHxytph">μg</a>/day at the 95th percentile.<a class="footnote-ref" id="fnref:284" href="#fn:284">284</a> These numbers may be low due to insufficient food intake data.<a class="footnote-ref" id="fnref:285" href="#fn:285">285</a> The concentrations of nicotine in vegetables are difficult to measure accurately, since they are very low (parts per billion range).<a class="footnote-ref" id="fnref:286" href="#fn:286">286</a> Pure nicotine tastes "terrible".<a class="footnote-ref" id="fnref:287" href="#fn:287">287</a>

<h2 id="history-society-and-culture">History, society and culture</h2>
See also: <a href="/facts/History_of_tobacco/EMtrAf0C">History of tobacco</a>

Nicotine was originally isolated from the tobacco plant in 1828 by chemists Wilhelm Heinrich Posselt and Karl Ludwig Reimann from <a href="/facts/Germany/paluuWBX">Germany</a>, who believed it was a poison.<a class="footnote-ref" id="fnref:288" href="#fn:288">288</a><a class="footnote-ref" id="fnref:289" href="#fn:289">289</a> Its chemical <a href="/facts/Empirical_formula/xd0vSIlm">empirical formula</a> was described by <a href="/facts/Louis_Melsens/0U6QXjEv">Melsens</a> in 1843,<a class="footnote-ref" id="fnref:290" href="#fn:290">290</a> its structure was discovered by <a href="/facts/Adolf_Pinner/3k1hSzeM">Adolf Pinner</a> and <a href="/facts/Richard_Wolffenstein_(chemist)/wVlJcmdW">Richard Wolffenstein</a> in 1893,<a class="footnote-ref" id="fnref:291" href="#fn:291">291</a><a class="footnote-ref" id="fnref:292" href="#fn:292">292</a><a class="footnote-ref" id="fnref:293" href="#fn:293">293</a> and it was first synthesized by <a href="/facts/Am%C3%A9_Pictet/boFYqoT0">Amé Pictet</a> and A. Rotschy in 1904.<a class="footnote-ref" id="fnref:294" href="#fn:294">294</a><a class="footnote-ref" id="fnref:295" href="#fn:295">295</a>
Nicotine is named after the tobacco plant <a href="/facts/Nicotiana_tabacum/WQKhTHHK">Nicotiana tabacum</a>, which in turn is named after the <a href="/facts/France/CxIeIKM3">French</a> ambassador in <a href="/facts/Portugal/lYzwDQ63">Portugal</a>, <a href="/facts/Jean_Nicot/bsUyVuFc">Jean Nicot de Villemain</a>, who sent tobacco and seeds to <a href="/facts/Paris/DrNHpwnA">Paris</a> in 1560, presented to the French King,<a class="footnote-ref" id="fnref:296" href="#fn:296">296</a> and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.<a class="footnote-ref" id="fnref:297" href="#fn:297">297</a>
<a href="/facts/Tobacco/bTD4RUPQ">Tobacco</a> was introduced to <a href="/facts/Europe/DTAtrKfh">Europe</a> in 1559, and by the late 17th century, it was used not only for <a href="/facts/Smoking/byhnmD0X">smoking</a> but also as an <a href="/facts/Insecticide/1xYL3MSD">insecticide</a>. After <a href="/facts/World_War_II/2efV5L1U">World War II</a>, 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 <a href="/facts/Mammal/phSwTzBo">mammals</a>.<a class="footnote-ref" id="fnref:298" href="#fn:298">298</a>
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.<a class="footnote-ref" id="fnref:299" href="#fn:299">299</a>
Although methods of production of synthetic nicotine have existed for decades,<a class="footnote-ref" id="fnref:300" href="#fn:300">300</a> it was believed that the cost of making nicotine by laboratory synthesis was cost prohibitive compared to extracting nicotine from tobacco.<a class="footnote-ref" id="fnref:301" href="#fn:301">301</a> However, recently synthetic nicotine started to be found in different brands of e-cigarettes and oral pouches and marketed as "tobacco-free."<a class="footnote-ref" id="fnref:302" href="#fn:302">302</a>
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.<a class="footnote-ref" id="fnref:303" href="#fn:303">303</a> 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 <a href="/facts/Consolidated_Appropriations_Act,_2022/yXEC6Y2c">Consolidated Appropriations Act, 2022</a>) that expanded FDA's tobacco regulatory authority to include tobacco products containing nicotine from any source, thereby including products made with synthetic nicotine.

<h3>Legal status</h3>
Further information: <a href="/facts/Smoking_in_the_United_Kingdom/GE0vy7DG">Smoking in the United Kingdom</a> and <a href="/facts/Tobacco_in_the_United_States/trhT9tbk">Tobacco in the United States</a>
In the United States, nicotine products and <a href="/facts/Nicotine_replacement_therapy/NVndtPso">nicotine replacement therapy</a> 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.<a class="footnote-ref" id="fnref:304" href="#fn:304">304</a>
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.<a class="footnote-ref" id="fnref:305" href="#fn:305">305</a>
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.

<h3>In media</h3>

In some <a href="/facts/Anti-smoking/VYgG7nls">anti-smoking</a> literature, the harm that tobacco smoking and nicotine addiction does is personified as <a href="/facts/Nick_O%27Teen/VQ6HcIrY">Nick O'Teen</a>, represented as a humanoid with some aspect of a cigarette or cigarette butt about him or his clothes and hat.<a class="footnote-ref" id="fnref:306" href="#fn:306">306</a> Nick O'Teen was a villain that was created for the Health Education Council. The character was featured in three animated anti-smoking <a href="/facts/Public_service_announcements/GvX6wcy8">public service announcements</a> in which he tries to get kids addicted to cigarettes before being foiled by the <a href="/facts/DC_Comics/gvuKz3yL">DC Comics</a> character <a href="/facts/Superman/1mQylpL6">Superman</a>.<a class="footnote-ref" id="fnref:307" href="#fn:307">307</a>
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.<a class="footnote-ref" id="fnref:308" href="#fn:308">308</a>

<h2 id="research">Research</h2>
<h3>Central nervous system</h3>
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 <a href="/facts/Major_depressive_disorder/l2lQeWqr">major depressive disorder</a> in non-smokers.<a class="footnote-ref" id="fnref:309" href="#fn:309">309</a>
Though tobacco smoking is associated with an increased risk of <a href="/facts/Alzheimer%27s_disease/w7Ad6tdg">Alzheimer's disease</a>,<a class="footnote-ref" id="fnref:310" href="#fn:310">310</a> there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.<a class="footnote-ref" id="fnref:311" href="#fn:311">311</a>
Smoking is associated with a decreased risk of <a href="/facts/Parkinson%27s_disease/xpekKj6x">Parkinson's disease</a>; 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 <a href="/facts/Neuroprotection/BcbsTfN0">neuroprotective agent</a>, or other compounds in cigarette smoke acting as neuroprotective agents.<a class="footnote-ref" id="fnref:312" href="#fn:312">312</a>
Nicotine may partly attenuate <a href="/facts/Sensory_gating/s9G9P5MA">sensory gating</a> and attentional deficits associated with <a href="/facts/Schizophrenia/FMP4lQ57">schizophrenia</a>. Short-term use of <a href="/facts/Transdermal/zFITIEjd">transdermal</a> nicotine was found to improve subjects’ reaction time and <a href="/facts/Vigilance_(psychology)/aIq1CdBl">alertness</a> in given tasks. Nicotine was not found to improve <a href="/facts/Negative_symptoms_of_schizophrenia/FMP4lQ57">negative</a>, <a href="/facts/Psychosis/cVGd7MKK">positive</a>, or other cognitive symptoms of schizophrenia.<a class="footnote-ref" id="fnref:313" href="#fn:313">313</a>

<h3>Immune system</h3>
Immune cells of both the innate immune system and <a href="/facts/Adaptive_immune_system/bc7zT1Jo">adaptive immune systems</a> frequently express the α2, α5, α6, α7, α9, and α10 <a href="/facts/Nicotinic_acetylcholine_receptor/k2s2pPHr">subunits of nicotinic acetylcholine receptors</a>.<a class="footnote-ref" id="fnref:314" href="#fn:314">314</a> Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of <a href="/facts/Immune_function/HRCTf1pb">immune function</a>.<a class="footnote-ref" id="fnref:315" href="#fn:315">315</a>

<h3>Optopharmacology</h3>
A <a href="/facts/Photoactivatable_probes/bJtu9za0">photoactivatable</a> form of nicotine, which releases nicotine when exposed to <a href="/facts/Ultraviolet_light/kncBUqn5">ultraviolet light</a> with certain conditions, has been developed for studying nicotinic acetylcholine receptors in brain tissue.<a class="footnote-ref" id="fnref:316" href="#fn:316">316</a>

<h3>Oral health</h3>
Several in vitro studies have investigated the potential effects of nicotine on a range of oral cells. A recent systematic review concluded that nicotine was unlikely to be cytotoxic to oral cells in vitro in most physiological conditions but further research is needed.<a class="footnote-ref" id="fnref:317" href="#fn:317">317</a> 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.<a class="footnote-ref" id="fnref:318" href="#fn:318">318</a>

<h2 id="see-also">See also</h2>
<ul><li><a href="/facts/6-Chloronicotine/BJcjUKf5">6-Chloronicotine</a></li>
<li><a href="/facts/Nicotine_marketing/vPtqsx7D">Nicotine marketing</a></li></ul>

<h2 id="external-links">External links</h2>

Wikimedia Commons has media related to Nicotine.

<a href="/facts/Wikisource/TrMdylNf">Wikisource</a> has the text of the <a href="/facts/Encyclop%C3%A6dia_Britannica_Eleventh_Edition/mPElbCRY">1911 Encyclopædia Britannica</a> article "Nicotine".

<ul><li><a href="http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+1107">Toxicology monograph for Nicotine</a> from the <a href="/facts/Hazardous_Substances_Data_Bank/qbUHrjgt">Hazardous Substances Data Bank</a></li>
<li><a href="https://www.cdc.gov/niosh/npg/npgd0446.html">Chemical Hazards monograph for Nicotine</a> from the <a href="/facts/National_Institute_for_Occupational_Safety_and_Health/5WjdDNMN">National Institute for Occupational Safety and Health</a></li>
<li><a href="https://pubchem.ncbi.nlm.nih.gov/compound/nicotine#datasheet=lcss§ion=Top">Laboratory Chemical Safety Summary for Nicotine</a> from <a href="/facts/PubChem/Nw3NgIxz">PubChem</a></li></ul>

<h2 id="references">References</h2>

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<li id="fn:47">Lavoie FW, Harris TM (1991). "Fatal nicotine ingestion". The Journal of Emergency Medicine. 9 (3): 133–136. doi:10.1016/0736-4679(91)90318-a. PMID 2050970. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:47" class="footnote-back-ref">↩</a></li>
<li id="fn:48">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:48" class="footnote-back-ref">↩</a></li>
<li id="fn:49">Theodoulou A, Chepkin SC, Ye W, Fanshawe TR, Bullen C, Hartmann-Boyce J, et al. (June 2023). "Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation". The Cochrane Database of Systematic Reviews. 2023 (6): CD013308. doi:10.1002/14651858.CD013308.pub2. PMC 10278922. PMID 37335995. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278922" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278922</a> <a href="#fnref:49" class="footnote-back-ref">↩</a></li>
<li id="fn:50">National Center for Chronic Disease Prevention Health Promotion (US) Office on Smoking Health (2014). The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General, Chapter 5 - Nicotine. Surgeon General of the United States. pp. 107–138. PMID 24455788. <a href="https://stacks.cdc.gov/view/cdc/21569/Share" target="_blank">https://stacks.cdc.gov/view/cdc/21569/Share</a> <a href="#fnref:50" class="footnote-back-ref">↩</a></li>
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<li id="fn:84">Bruin JE, Gerstein HC, Holloway AC (August 2010). "Long-term consequences of fetal and neonatal nicotine exposure: a critical review". Toxicological Sciences. 116 (2): 364–74. doi:10.1093/toxsci/kfq103. PMC 2905398. PMID 20363831. 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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905398" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905398</a> <a href="#fnref:84" class="footnote-back-ref">↩</a></li>
<li id="fn:85">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. PMID 20215949. S2CID 27085986. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:85" class="footnote-back-ref">↩</a></li>
<li id="fn:86">Barua RS, Rigotti NA, Benowitz NL, Cummings KM, Jazayeri MA, Morris PB, et al. (December 2018). "2018 ACC Expert Consensus Decision Pathway on Tobacco Cessation Treatment: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents". Journal of the American College of Cardiology. 72 (25): 3332–3365. doi:10.1016/j.jacc.2018.10.027. PMID 30527452. <a href="https://doi.org/10.1016%2Fj.jacc.2018.10.027" target="_blank">https://doi.org/10.1016%2Fj.jacc.2018.10.027</a> <a href="#fnref:86" class="footnote-back-ref">↩</a></li>
<li id="fn:87">Sanner T, Grimsrud TK (2015). "Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment - A Review". Frontiers in Oncology. 5: 196. doi:10.3389/fonc.2015.00196. PMC 4553893. PMID 26380225. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553893" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553893</a> <a href="#fnref:87" class="footnote-back-ref">↩</a></li>
<li id="fn:88">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:88" class="footnote-back-ref">↩</a></li>
<li id="fn:89">Bailey SR, Crew EE, Riske EC, Ammerman S, Robinson TN, Killen JD (April 2012). "Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents". Paediatric Drugs. 14 (2): 91–108. doi:10.2165/11594370-000000000-00000. PMC 3319092. PMID 22248234. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319092" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319092</a> <a href="#fnref:89" class="footnote-back-ref">↩</a></li>
<li id="fn:90">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:90" class="footnote-back-ref">↩</a></li>
<li id="fn:91">Bailey SR, Crew EE, Riske EC, Ammerman S, Robinson TN, Killen JD (April 2012). "Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents". Paediatric Drugs. 14 (2): 91–108. doi:10.2165/11594370-000000000-00000. PMC 3319092. PMID 22248234. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319092" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319092</a> <a href="#fnref:91" class="footnote-back-ref">↩</a></li>
<li id="fn:92">Vij K (2014). Textbook of Forensic Medicine & Toxicology: Principles & Practice (5th ed.). Elsevier Health Sciences. p. 525. ISBN 978-81-312-3623-9. Extract of page 525 <a href="978-81-312-3623-9" target="_blank">978-81-312-3623-9</a> <a href="#fnref:92" class="footnote-back-ref">↩</a></li>
<li id="fn:93">"NICOTINE: Systemic Agent". 8 July 2021. <a href="https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750028.html" target="_blank">https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750028.html</a> <a href="#fnref:93" class="footnote-back-ref">↩</a></li>
<li id="fn:94">"Nicotine", Dictionary of Toxicology, Singapore: Springer Nature, p. 691, 2024, doi:10.1007/978-981-99-9283-6_1860, ISBN 978-981-99-9282-9, retrieved 19 October 2024, Nicotine is a colorless, water-soluble, and extremely hazardous alkaloid. It also has a terrible taste. <a href="978-981-99-9282-9" target="_blank">978-981-99-9282-9</a> <a href="#fnref:94" class="footnote-back-ref">↩</a></li>
<li id="fn:95">Royal College of Physicians. "Nicotine Without Smoke -- Tobacco Harm Reduction". p. 125. Retrieved 30 September 2020. Use of nicotine alone, in the doses used by smokers, represents little if any hazard to the user. <a href="https://www.rcplondon.ac.uk/file/3563/download?token=Mu0K_ZR0" target="_blank">https://www.rcplondon.ac.uk/file/3563/download?token=Mu0K_ZR0</a> <a href="#fnref:95" class="footnote-back-ref">↩</a></li>
<li id="fn:96">Douglas CE, Henson R, Drope J, Wender RC (July 2018). "The American Cancer Society public health statement on eliminating combustible tobacco use in the United States". CA. 68 (4): 240–245. doi:10.3322/caac.21455. PMID 29889305. S2CID 47016482. It is the smoke from combustible tobacco products—not nicotine—that injures and kills millions of smokers. <a href="https://doi.org/10.3322%2Fcaac.21455" target="_blank">https://doi.org/10.3322%2Fcaac.21455</a> <a href="#fnref:96" class="footnote-back-ref">↩</a></li>
<li id="fn:97">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. PMID 27705269. Beyond its addictive properties, short-term or long-term exposure to nicotine in adults has not been established as dangerous <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:97" class="footnote-back-ref">↩</a></li>
<li id="fn:98">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. PMC 6353172. PMID 29852054. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:98" class="footnote-back-ref">↩</a></li>
<li id="fn:99">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. PMC 6353172. PMID 29852054. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:99" class="footnote-back-ref">↩</a></li>
<li id="fn:100">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:100" class="footnote-back-ref">↩</a></li>
<li id="fn:101">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:101" class="footnote-back-ref">↩</a></li>
<li id="fn:102">Schraufnagel DE (March 2015). "Electronic Cigarettes: Vulnerability of Youth". Pediatric Allergy, Immunology, and Pulmonology. 28 (1): 2–6. doi:10.1089/ped.2015.0490. PMC 4359356. PMID 25830075. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359356" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359356</a> <a href="#fnref:102" class="footnote-back-ref">↩</a></li>
<li id="fn:103">England LJ, Bunnell RE, Pechacek TF, Tong VT, McAfee TA (August 2015). "Nicotine and the Developing Human: A Neglected Element in the Electronic Cigarette Debate". American Journal of Preventive Medicine. 49 (2): 286–293. doi:10.1016/j.amepre.2015.01.015. PMC 4594223. PMID 25794473. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594223" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594223</a> <a href="#fnref:103" class="footnote-back-ref">↩</a></li>
<li id="fn:104">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:104" class="footnote-back-ref">↩</a></li>
<li id="fn:105">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:105" class="footnote-back-ref">↩</a></li>
<li id="fn:106">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:106" class="footnote-back-ref">↩</a></li>
<li id="fn:107">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:107" class="footnote-back-ref">↩</a></li>
<li id="fn:108">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:108" class="footnote-back-ref">↩</a></li>
<li id="fn:109">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:109" class="footnote-back-ref">↩</a></li>
<li id="fn:110">"Nicotine Transdermal Patch" (PDF). United States Food and Drug Administration. Retrieved 24 January 2019. <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020076Orig1s045lbl.pdf" target="_blank">https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020076Orig1s045lbl.pdf</a> <a href="#fnref:110" class="footnote-back-ref">↩</a></li>
<li id="fn:111">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:111" class="footnote-back-ref">↩</a></li>
<li id="fn:112">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:112" class="footnote-back-ref">↩</a></li>
<li id="fn:113">"Nicotrol NS" (PDF). United States Food and Drug Administration. Retrieved 24 January 2019. <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020385s010lbl.pdf" target="_blank">https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020385s010lbl.pdf</a> <a href="#fnref:113" class="footnote-back-ref">↩</a></li>
<li id="fn:114">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:114" class="footnote-back-ref">↩</a></li>
<li id="fn:115">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:115" class="footnote-back-ref">↩</a></li>
<li id="fn:116">"Nicotrol" (PDF). Pfizer. Retrieved 24 January 2019. <a href="https://www.pfizer.com/files/products/uspi_nicotrol_inhaler.pdf" target="_blank">https://www.pfizer.com/files/products/uspi_nicotrol_inhaler.pdf</a> <a href="#fnref:116" class="footnote-back-ref">↩</a></li>
<li id="fn:117">"Nicotine". Drugs.com. American Society of Health-System Pharmacists. Retrieved 24 January 2019. <a href="https://www.drugs.com/monograph/nicotine.html" target="_blank">https://www.drugs.com/monograph/nicotine.html</a> <a href="#fnref:117" class="footnote-back-ref">↩</a></li>
<li id="fn:118">"Nicotrol NS" (PDF). United States Food and Drug Administration. Retrieved 24 January 2019. <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020385s010lbl.pdf" target="_blank">https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020385s010lbl.pdf</a> <a href="#fnref:118" class="footnote-back-ref">↩</a></li>
<li id="fn:119">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. PMID 26346395. S2CID 22703103. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:119" class="footnote-back-ref">↩</a></li>
<li id="fn:120">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. PMID 26346395. S2CID 22703103. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:120" class="footnote-back-ref">↩</a></li>
<li id="fn:121">Boutrel B, Koob GF (September 2004). "What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications". Sleep. 27 (6): 1181–1194. doi:10.1093/sleep/27.6.1181. PMID 15532213. <a href="https://doi.org/10.1093%2Fsleep%2F27.6.1181" target="_blank">https://doi.org/10.1093%2Fsleep%2F27.6.1181</a> <a href="#fnref:121" class="footnote-back-ref">↩</a></li>
<li id="fn:122">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. PMID 19345124. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:122" class="footnote-back-ref">↩</a></li>
<li id="fn:123">Benowitz NL, Burbank AD (August 2016). "Cardiovascular toxicity of nicotine: Implications for electronic cigarette use". Trends in Cardiovascular Medicine. 26 (6): 515–523. doi:10.1016/j.tcm.2016.03.001. PMC 4958544. PMID 27079891. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544</a> <a href="#fnref:123" class="footnote-back-ref">↩</a></li>
<li id="fn:124">Benowitz NL, Burbank AD (August 2016). "Cardiovascular toxicity of nicotine: Implications for electronic cigarette use". Trends in Cardiovascular Medicine. 26 (6): 515–523. doi:10.1016/j.tcm.2016.03.001. PMC 4958544. PMID 27079891. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544</a> <a href="#fnref:124" class="footnote-back-ref">↩</a></li>
<li id="fn:125">Benowitz NL, Burbank AD (August 2016). "Cardiovascular toxicity of nicotine: Implications for electronic cigarette use". Trends in Cardiovascular Medicine. 26 (6): 515–523. doi:10.1016/j.tcm.2016.03.001. PMC 4958544. PMID 27079891. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544</a> <a href="#fnref:125" class="footnote-back-ref">↩</a></li>
<li id="fn:126">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. PMC 6353172. PMID 29852054. 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 92 RCTs and 28 observational 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 12 studies. 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; 15 studies; 11,074 participants; 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 15 trials in which they were reported at all. A recent network meta-analysis of cardiovascular events associated with smoking cessation pharmacotherapies (Mills 2014), including 21 RCTs comparing NRT with placebo, found statistically significant evidence that the rate of cardiovascular events with NRT was higher (RR 2.29 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 (RR 1.95 95% CI 0.26 to 4.30). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353172</a> <a href="#fnref:126" class="footnote-back-ref">↩</a></li>
<li id="fn:127">Benowitz NL, Burbank AD (August 2016). "Cardiovascular toxicity of nicotine: Implications for electronic cigarette use". Trends in Cardiovascular Medicine. 26 (6): 515–523. doi:10.1016/j.tcm.2016.03.001. PMC 4958544. PMID 27079891. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958544</a> <a href="#fnref:127" class="footnote-back-ref">↩</a></li>
<li id="fn:128">Grana R, Benowitz N, Glantz SA (May 2014). "E-cigarettes: a scientific review". Circulation. 129 (19): 1972–1986. doi:10.1161/circulationaha.114.007667. PMC 4018182. PMID 24821826. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018182" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018182</a> <a href="#fnref:128" class="footnote-back-ref">↩</a></li>
<li id="fn:129">Siqueira LM (January 2017). "Nicotine and Tobacco as Substances of Abuse in Children and Adolescents". Pediatrics. 139 (1): e20163436. doi:10.1542/peds.2016-3436. PMID 27994114. <a href="https://doi.org/10.1542%2Fpeds.2016-3436" target="_blank">https://doi.org/10.1542%2Fpeds.2016-3436</a> <a href="#fnref:129" class="footnote-back-ref">↩</a></li>
<li id="fn:130">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. PMID 7322454. S2CID 10076758. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:130" class="footnote-back-ref">↩</a></li>
<li id="fn:131">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. PMID 15496937. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:131" class="footnote-back-ref">↩</a></li>
<li id="fn:132">"Evidence Review of E-Cigarettes and Heated Tobacco Products" (PDF). Public Health England. 2018. <a href="https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/684963/Evidence_review_of_e-cigarettes_and_heated_tobacco_products_2018.pdf" target="_blank">https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/684963/Evidence_review_of_e-cigarettes_and_heated_tobacco_products_2018.pdf</a> <a href="#fnref:132" class="footnote-back-ref">↩</a></li>
<li id="fn:133">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. PMID 15496937. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:133" class="footnote-back-ref">↩</a></li>
<li id="fn:134">"Acetaldehyde | RIVM". <a href="https://www.rivm.nl/en/tobacco/harmful-substances-in-tobacco-smoke/acetaldehyde" target="_blank">https://www.rivm.nl/en/tobacco/harmful-substances-in-tobacco-smoke/acetaldehyde</a> <a href="#fnref:134" class="footnote-back-ref">↩</a></li>
<li id="fn:135">Royal College of Physicians (28 April 2016). "Nicotine without smoke: Tobacco harm reduction". Retrieved 16 September 2020. <a href="https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction" target="_blank">https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction</a> <a href="#fnref:135" class="footnote-back-ref">↩</a></li>
<li id="fn:136">Smith TT, Rupprecht LE, Cwalina SN, Onimus MJ, Murphy SE, Donny EC, et al. (August 2016). "Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine". Neuropsychopharmacology. 41 (9): 2335–2343. doi:10.1038/npp.2016.36. PMC 4946064. PMID 26955970. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946064" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946064</a> <a href="#fnref:136" class="footnote-back-ref">↩</a></li>
<li id="fn:137">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. PMC 3188825. PMID 22003417. Withdrawal symptoms upon cessation of nicotine intake: Chronic nicotine use induces neuroadaptations in the brain's reward system that result in the development of nicotine dependence. Thus, nicotine-dependent smokers must continue nicotine intake to avoid distressing somatic and affective withdrawal symptoms. Newly abstinent smokers experience symptoms such as depressed mood, anxiety, irritability, difficulty concentrating, craving, bradycardia, insomnia, gastrointestinal discomfort, and weight gain (Shiffman and Jarvik, 1976; Hughes et al., 1991). Experimental animals, such as rats and mice, exhibit a nicotine withdrawal syndrome that, like the human syndrome, includes both somatic signs and a negative affective state (Watkins et al., 2000; Malin et al., 2006). The somatic signs of nicotine withdrawal include rearing, jumping, shakes, abdominal constrictions, chewing, scratching, and facial tremors. The negative affective state of nicotine withdrawal is characterized by decreased responsiveness to previously rewarding stimuli, a state called anhedonia. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188825" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188825</a> <a href="#fnref:137" class="footnote-back-ref">↩</a></li>
<li id="fn:138">Das S, Prochaska JJ (October 2017). "Innovative approaches to support smoking cessation for individuals with mental illness and co-occurring substance use disorders". Expert Review of Respiratory Medicine. 11 (10): 841–850. doi:10.1080/17476348.2017.1361823. PMC 5790168. PMID 28756728. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790168" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790168</a> <a href="#fnref:138" class="footnote-back-ref">↩</a></li>
<li id="fn:139">Heishman SJ, Kleykamp BA, Singleton EG (July 2010). "Meta-analysis of the acute effects of nicotine and smoking on human performance". Psychopharmacology. 210 (4): 453–69. doi:10.1007/s00213-010-1848-1. PMC 3151730. PMID 20414766. 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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151730" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151730</a> <a href="#fnref:139" class="footnote-back-ref">↩</a></li>
<li id="fn:140">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. PMID 17365764. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:140" class="footnote-back-ref">↩</a></li>
<li id="fn:141">Parrott AC (April 2003). "Cigarette-derived nicotine is not a medicine". The World Journal of Biological Psychiatry. 4 (2): 49–55. doi:10.3109/15622970309167951. PMID 12692774. S2CID 26903942. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:141" class="footnote-back-ref">↩</a></li>
<li id="fn:142">Parrott AC (April 2003). "Cigarette-derived nicotine is not a medicine". The World Journal of Biological Psychiatry. 4 (2): 49–55. doi:10.3109/15622970309167951. PMID 12692774. S2CID 26903942. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:142" class="footnote-back-ref">↩</a></li>
<li id="fn:143">Parrott AC (April 2003). "Cigarette-derived nicotine is not a medicine". The World Journal of Biological Psychiatry. 4 (2): 49–55. doi:10.3109/15622970309167951. PMID 12692774. S2CID 26903942. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:143" class="footnote-back-ref">↩</a></li>
<li id="fn:144">Dugas EN, Sylvestre MP, O'Loughlin EK, Brunet J, Kakinami L, Constantin E, et al. (February 2017). "Nicotine dependence and sleep quality in young adults". Addictive Behaviors. 65: 154–160. doi:10.1016/j.addbeh.2016.10.020. PMID 27816041. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:144" class="footnote-back-ref">↩</a></li>
<li id="fn:145">Cohrs S, Rodenbeck A, Riemann D, Szagun B, Jaehne A, Brinkmeyer J, et al. (May 2014). "Impaired sleep quality and sleep duration in smokers-results from the German Multicenter Study on Nicotine Dependence". Addiction Biology. 19 (3): 486–96. doi:10.1111/j.1369-1600.2012.00487.x. hdl:11858/00-001M-0000-0025-BD0C-B. PMID 22913370. S2CID 1066283. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:145" class="footnote-back-ref">↩</a></li>
<li id="fn:146">Bruijnzeel AW (May 2012). "Tobacco addiction and the dysregulation of brain stress systems". Neuroscience and Biobehavioral Reviews. 36 (5): 1418–41. doi:10.1016/j.neubiorev.2012.02.015. PMC 3340450. PMID 22405889. 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 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340450" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340450</a> <a href="#fnref:146" class="footnote-back-ref">↩</a></li>
<li id="fn:147">Parrott AC (April 2003). "Cigarette-derived nicotine is not a medicine". The World Journal of Biological Psychiatry. 4 (2): 49–55. doi:10.3109/15622970309167951. PMID 12692774. S2CID 26903942. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:147" class="footnote-back-ref">↩</a></li>
<li id="fn:148">Parrott AC (April 2003). "Cigarette-derived nicotine is not a medicine". The World Journal of Biological Psychiatry. 4 (2): 49–55. doi:10.3109/15622970309167951. PMID 12692774. S2CID 26903942. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:148" class="footnote-back-ref">↩</a></li>
<li id="fn:149">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. doi:10.31887/DCNS.2013.15.4/enestler. PMC 3898681. PMID 24459410. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:149" class="footnote-back-ref">↩</a></li>
<li id="fn:150">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): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. 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), ...ConclusionsΔFosB 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). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:150" class="footnote-back-ref">↩</a></li>
<li id="fn:151">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. PMID 16631212. S2CID 8551216. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:151" class="footnote-back-ref">↩</a></li>
<li id="fn:152">Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. doi:10.31887/DCNS.2013.15.4/enestler. PMC 3898681. PMID 24459410. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681</a> <a href="#fnref:152" class="footnote-back-ref">↩</a></li>
<li id="fn:153">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): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. 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), ...ConclusionsΔFosB 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). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:153" class="footnote-back-ref">↩</a></li>
<li id="fn:154">"Does nicotine cause cancer?". European Code Against Cancer. World Health Organization – International Agency for Research on Cancer. Retrieved 23 January 2019. <a href="https://cancer-code-europe.iarc.fr/index.php/en/ecac-12-ways/tobacco/199-nicotine-cause-cancer" target="_blank">https://cancer-code-europe.iarc.fr/index.php/en/ecac-12-ways/tobacco/199-nicotine-cause-cancer</a> <a href="#fnref:154" class="footnote-back-ref">↩</a></li>
<li id="fn:155">Tolentino J (7 May 2018). "The Promise of Vaping and the Rise of Juul". The New Yorker. Retrieved 29 June 2024. <a href="https://www.newyorker.com/magazine/2018/05/14/the-promise-of-vaping-and-the-rise-of-juul" target="_blank">https://www.newyorker.com/magazine/2018/05/14/the-promise-of-vaping-and-the-rise-of-juul</a> <a href="#fnref:155" class="footnote-back-ref">↩</a></li>
<li id="fn:156">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. PMID 22050423. S2CID 11372110. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:156" class="footnote-back-ref">↩</a></li>
<li id="fn:157">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. ISBN 978-0-309-46834-3. <a href="978-0-309-46834-3" target="_blank">978-0-309-46834-3</a> <a href="#fnref:157" class="footnote-back-ref">↩</a></li>
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<li id="fn:215">Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 369, 372–373. ISBN 978-0-07-148127-4. <a href="978-0-07-148127-4" target="_blank">978-0-07-148127-4</a> <a href="#fnref:215" class="footnote-back-ref">↩</a></li>
<li id="fn:216">Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (June 2011). "The role of the central ghrelin system in reward from food and chemical drugs" (PDF). Molecular and Cellular Endocrinology. 340 (1): 80–7. doi:10.1016/j.mce.2011.02.017. hdl:2077/26318. PMID 21354264. S2CID 206815322. Archived from the original (PDF) on 4 August 2020. Retrieved 23 September 2019. This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. <a href="https://web.archive.org/web/20200804221721/https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf" target="_blank">https://web.archive.org/web/20200804221721/https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf</a> <a href="#fnref:216" class="footnote-back-ref">↩</a></li>
<li id="fn:217">Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (June 2011). "The role of the central ghrelin system in reward from food and chemical drugs" (PDF). Molecular and Cellular Endocrinology. 340 (1): 80–7. doi:10.1016/j.mce.2011.02.017. hdl:2077/26318. PMID 21354264. S2CID 206815322. Archived from the original (PDF) on 4 August 2020. Retrieved 23 September 2019. This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. <a href="https://web.archive.org/web/20200804221721/https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf" target="_blank">https://web.archive.org/web/20200804221721/https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf</a> <a href="#fnref:217" class="footnote-back-ref">↩</a></li>
<li id="fn:218">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. PMC 3772953. PMID 23632083. 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). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772953" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772953</a> <a href="#fnref:218" class="footnote-back-ref">↩</a></li>
<li id="fn:219">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. PMC 3772953. PMID 23632083. 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). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772953" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772953</a> <a href="#fnref:219" class="footnote-back-ref">↩</a></li>
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<li id="fn:221">Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 369, 372–373. ISBN 978-0-07-148127-4. <a href="978-0-07-148127-4" target="_blank">978-0-07-148127-4</a> <a href="#fnref:221" class="footnote-back-ref">↩</a></li>
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<li id="fn:234">"The danger of third-hand smoke: Plain language summary – Petrick et al., "Thirdhand smoke: heterogeneous oxidation of nicotine and secondary aerosol formation in the indoor environment" in Environmental Science & Technology". The Column. Vol. 7, no. 3. Chromatography Online. 22 February 2011. <a href="http://www.chromatographyonline.com/danger-third-hand-smoke" target="_blank">http://www.chromatographyonline.com/danger-third-hand-smoke</a> <a href="#fnref:234" class="footnote-back-ref">↩</a></li>
<li id="fn:235">Benowitz NL, Herrera B, Jacob P (September 2004). "Mentholated cigarette smoking inhibits nicotine metabolism". The Journal of Pharmacology and Experimental Therapeutics. 310 (3): 1208–15. doi:10.1124/jpet.104.066902. PMID 15084646. S2CID 16044557. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:235" class="footnote-back-ref">↩</a></li>
<li id="fn:236">"Nicotine' actions on energy balance: Friend or foe?". Pharmacology & Therapeutics. 219. March 2021. <a href="/wiki/Pharmacology_%26_Therapeutics" target="_blank">/wiki/Pharmacology_%26_Therapeutics</a> <a href="#fnref:236" class="footnote-back-ref">↩</a></li>
<li id="fn:237">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. PMID 30054897. S2CID 51727199. 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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:237" class="footnote-back-ref">↩</a></li>
<li id="fn:238">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. PMID 30054897. S2CID 51727199. 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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:238" class="footnote-back-ref">↩</a></li>
<li id="fn:239">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. PMC 3772953. PMID 23632083. 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). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772953" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772953</a> <a href="#fnref:239" class="footnote-back-ref">↩</a></li>
<li id="fn:240">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. PMID 30054897. S2CID 51727199. 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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:240" class="footnote-back-ref">↩</a></li>
<li id="fn:241">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. PMID 30054897. S2CID 51727199. 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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:241" class="footnote-back-ref">↩</a></li>
<li id="fn:242">"Nicotine", Dictionary of Toxicology, Singapore: Springer Nature, p. 691, 2024, doi:10.1007/978-981-99-9283-6_1860, ISBN 978-981-99-9282-9, retrieved 19 October 2024, Nicotine is a colorless, water-soluble, and extremely hazardous alkaloid. It also has a terrible taste. <a href="978-981-99-9282-9" target="_blank">978-981-99-9282-9</a> <a href="#fnref:242" class="footnote-back-ref">↩</a></li>
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