Effects of nicotine on human brain development

The health effects of long-term nicotine use is unknown.{{cite journal|last1=Franck|first1=Caroline|last2=Filion|first2=Kristian B.|last3=Kimmelman|first3=Jonathan|last4=Grad|first4=Roland|last5=Eisenberg|first5=Mark J.|title=Ethical considerations of e-cigarette use for tobacco harm reduction|journal=Respiratory Research|volume=17|issue=1|page=53|year=2016|issn=1465-993X|doi=10.1186/s12931-016-0370-3|pmc=4869264|pmid=27184265 |doi-access=free }}{{CC-notice|cc=by4|url=https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-016-0370-3|author(s)=Caroline Franck, Kristian B. Filion, Jonathan Kimmelman, Roland Grad and Mark J. Eisenberg}} It may be decades before the long-term health effects of nicotine e-cigarette aerosol (vapor) inhalation is known.{{cite journal|last1=Golub|first1=Justin S.|last2=Samy|first2=Ravi N.|title=Preventing or reducing smoking-related complications in otologic and neurotologic surgery|journal=Current Opinion in Otolaryngology & Head and Neck Surgery|volume=23|issue=5|year=2015|pages=334–340|issn=1068-9508|doi=10.1097/MOO.0000000000000184|pmid=26339963|s2cid=205830424}} Short-term nicotine use excites the autonomic ganglia nerves and autonomic nerves, but chronic use seems to induce negative effects on endothelial cells.{{cite journal|last1=Toda|first1=Noboru|last2=Toda|first2=Hiroshi|title=Nitric oxide-mediated blood flow regulation as affected by smoking and nicotine|journal=European Journal of Pharmacology|volume=649|issue=1–3|year=2010|pages=1–13|issn=0014-2999|doi=10.1016/j.ejphar.2010.09.042|pmid=20868673}} Nicotine may result in neuroplasticity modifications in the brain.{{cite journal|last1=SA|first1=Meo|last2=SA|first2=Al Asiri|title=Effects of electronic cigarette smoking on human health|url=http://www.europeanreview.org/wp/wp-content/uploads/3315-3319.pdf|journal=Eur Rev Med Pharmacol Sci|volume=18|issue=21|year=2014|pages=3315–9|pmid=25487945}} Nicotine has been demonstrated to alter the amounts of brain-derived neurotrophic factor in humans.{{cite journal|last1=Machaalani|first1=Rita|last2=Chen|first2=Hui|title=Brain derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB) and nicotine|journal=NeuroToxicology|volume=65|year=2018|pages=186–195|issn=0161-813X|doi=10.1016/j.neuro.2018.02.014|pmid=29499216|hdl=10453/122789|s2cid=3688206 |hdl-access=free}} Side effects of nicotine include mild headache, headache, dysphoria, depressed mood, irritability, aggression, frustration, impatience, anxiety, sleep disturbances, abnormal dreams, irritability, and dizziness.{{cite web|title=Nicotine Side Effects|url=https://www.drugs.com/sfx/nicotine-side-effects.html|publisher=Drugs.com|date=21 January 2019}}

The neuroregulation and structural interactions in the brain and lungs from nicotine may interfere with an array of reflexes and responses. These alterations may raise the risk of hypoxia. Continued use of nicotine may result in harmful effects to women's brains because it restricts estrogen signaling. This could lead to making the brain more vulnerable to ischemia.{{cite journal|last1=Schraufnagel|first1=Dean E.|last2=Blasi|first2=Francesco|last3=Drummond|first3=M. Bradley|last4=Lam|first4=David C. L.|last5=Latif|first5=Ehsan|last6=Rosen|first6=Mark J.|last7=Sansores|first7=Raul|last8=Van Zyl-Smit|first8=Richard|title=Electronic Cigarettes. A Position Statement of the Forum of International Respiratory Societies|journal=American Journal of Respiratory and Critical Care Medicine|volume=190|issue=6|year=2014|pages=611–618|issn=1073-449X|doi=10.1164/rccm.201407-1198PP|pmid=25006874|s2cid=43763340 |url=https://figshare.com/articles/journal_contribution/10758143 }} A 2015 review concluded that "Nicotine acts as a gateway drug on the brain, and this effect is likely to occur whether the exposure is from smoking tobacco, passive tobacco smoke or e-cigarettes."{{cite journal|last1=Kandel|first1=Denise|last2=Kandel|first2=Eric|title=The Gateway Hypothesis of substance abuse: developmental, biological and societal perspectives|journal=Acta Paediatrica|volume=104|issue=2|year=2015|pages=130–137|issn=0803-5253|doi=10.1111/apa.12851|pmid=25377988|s2cid=33575141}}

Nicotine may have a profound impact on sleep. The effects on sleep vary after being intoxicated, during withdrawal, and from long-term use. Nicotine may result in arousal and wakefulness, mainly via incitement in the basal forebrain.{{cite journal|last1=Irish|first1=Leah A.|last2=Kline|first2=Christopher E.|last3=Gunn|first3=Heather E.|last4=Buysse|first4=Daniel J.|last5=Hall|first5=Martica H.|title=The role of sleep hygiene in promoting public health: A review of empirical evidence|journal=Sleep Medicine Reviews|volume=22|year=2015|pages=23–36|issn=1087-0792|doi=10.1016/j.smrv.2014.10.001|pmc=4400203|pmid=25454674}} Nicotine withdrawal, after abstaining from nicotine use in non-smokers, was linked with longer overall length of sleep and REM rebound.{{cite journal|last1=Garcia|first1=Alexandra N.|last2=Salloum|first2=Ihsan M.|title=Polysomnographic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: A focused review|journal=The American Journal on Addictions|volume=24|issue=7|year=2015|pages=590–598|issn=1055-0496|doi=10.1111/ajad.12291|pmid=26346395}} A 2016 review states that "Although smokers say they smoke to control stress, studies show a significant increase in cortisol concentrations in daily smokers compared with occasional smokers or nonsmokers. These findings suggest that, despite the subjective effects, smoking may actually worsen the negative emotional states. The effects of nicotine on the sleep-wake cycle through nicotine receptors may have a functional significance. Nicotine receptor stimulation promotes wake time and reduces both total sleep time and rapid eye movement sleep."{{cite journal|last1=Siqueira|first1=Lorena M.|title=Nicotine and Tobacco as Substances of Abuse in Children and Adolescents|journal=Pediatrics|volume=139|issue=1|year=2016|pages=e20163436|issn=0031-4005|doi=10.1542/peds.2016-3436|pmid=27994114|s2cid=2451568|doi-access=free}}

File:Nicotine3Dan2-12-seconds.gif structure.|alt=Animated nicotine structure.]]

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| caption = The teen years are critical for brain development, which continues into young adulthood. Young people who use nicotine products in any form, including e-cigarettes, are uniquely at risk for long-lasting effects.

| alt = The diagram is titled Possible effects of nicotine on the developing human brain. The text states: The use of products containing nicotine in any form among youth, including the use of e-cigarettes, is unsafe. Brain development: Impairs brain development Reduced impulse control Deficits in attention Deficits in mood disorders Impedes growth of neurons Impedes growth of brain circuits Affects brain architecture Affects brain chemistry Affects brain neurobehavioral activity Cognitive development: Affects neurocognitive growth in children Affects cognitive development Associated with cognitive impairment Addiction: Adolescents can get addicted more easily than adults E-cigarettes can prime the adolescent brain for addiction to other drugs like cocaine. E-cigarettes can make other drugs such as cocaine and methamphetamine more pleasurable to a teen's developing brain. The final words states: The teen years are critical for brain development, which continues into young adulthood. Young people who use nicotine products in any form, including e-cigarettes, are uniquely at risk for long-lasting effects.

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{{Annotation|7|10|

The use of products containing

nicotine in any form among

youth, including the use of

e-cigarettes, is unsafe.{{sfn|SGUS|2016|p=5; Chapter 1}}

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}}

{{Annotation|7|192|

Brain development:

• Impairs brain development
• Reduced impulse control{{sfn|SGUS|2016|p=113; Chapter 3}}
• Deficits in attention{{sfn|SGUS|2016|p=113; Chapter 3}}
• Deficits in mood disorders{{sfn|SGUS|2016|p=113; Chapter 3}}
• Impedes growth of neurons
• Impedes growth of brain circuits
• Affects brain architecture
• Affects brain chemistry
• Affects brain neurobehavioral activity

Cognitive development:

• Affects neurocognitive growth in children
• Affects cognitive development
• Associated with cognitive impairment

Addiction:

• Adolescents can get addicted more easily than adults
• E-cigarettes can prime the adolescent brain for addiction to other drugs like cocaine
• E-cigarettes can make other drugs such as cocaine and methamphetamine more pleasurable to a teen's developing brain

| text-align=left | font-size=14 | color=black

}}

}}

Nicotine, a key ingredient{{cite journal|last1=Kaisar|first1=Mohammad Abul|last2=Prasad|first2=Shikha|last3=Liles|first3=Tylor|last4=Cucullo|first4=Luca|title=A Decade of e-Cigarettes: Limited Research & Unresolved Safety Concerns|journal=Toxicology|volume=365|pages=67–75|year=2016|issn=0300-483X|doi=10.1016/j.tox.2016.07.020|pmid=27477296|pmc=4993660}} in most e-liquids,{{cite journal|last1=Weaver|first1=Michael|last2=Breland|first2=Alison|last3=Spindle|first3=Tory|last4=Eissenberg|first4=Thomas|title=Electronic Cigarettes|journal=Journal of Addiction Medicine|volume=8|issue=4|year=2014|pages=234–240|issn=1932-0620|doi=10.1097/ADM.0000000000000043|pmc=4123220|pmid=25089953}} is well-recognized as one of the most addictive substances, as addictive as heroin and cocaine. Addiction is believed to be a disorder of experience-dependent brain plasticity.{{cite journal|last1=Kenny|first1=PJ|title=Genetics of Substance Use Disorders|journal=Dialogues Clin Neurosci|volume=16|issue=3|date=September 2014|pages=335–344|doi=10.31887/DCNS.2014.16.3/pkenny|pmc=4214176|pmid=25364284}} The reinforcing effects of nicotine play a significant role in the beginning and continuing use of the drug.{{cite journal|last1=D'Souza|first1=Manoranjan S.|title=Glutamatergic transmission in drug reward: implications for drug addiction|journal=Frontiers in Neuroscience|volume=9|page=404|year=2015|issn=1662-453X|doi=10.3389/fnins.2015.00404|pmc=4633516|pmid=26594139|doi-access=free}} First-time nicotine users develop a dependence about 32% of the time.{{cite journal|last1=MacDonald|first1=K|last2=Pappa|first2=K|title=WHY NOT POT?: A Review of the Brain-based Risks of Cannabis|journal=Innov Clin Neurosci|volume=13|issue=3–4|date=April 2016|pages=13–22|pmc=4911936|pmid=27354924}} Chronic nicotine use involves both psychological and physical dependence.{{cite journal|last1=Kishioka|first1=Shiroh|last2=Kiguchi|first2=Norikazu|last3=Kobayashi|first3=Yuka|last4=Saika|first4=Fumihiro|title=Nicotine Effects and the Endogenous Opioid System|journal=Journal of Pharmacological Sciences|volume=125|issue=2|year=2014|pages=117–124|issn=1347-8613|doi=10.1254/jphs.14R03CP|pmid=24882143|doi-access=free}} Nicotine-containing e-cigarette aerosol induces addiction-related neurochemical, physiological and behavioral changes.

Nicotine affects neurological, neuromuscular, cardiovascular, respiratory, immunological and gastrointestinal systems.{{cite journal|last1=Lee|first1=Peter N.|last2=Fariss|first2=Marc W.|title=A systematic review of possible serious adverse health effects of nicotine replacement therapy|journal=Archives of Toxicology|volume=91|issue=4|year=2016|pages=1565–1594|issn=0340-5761|doi=10.1007/s00204-016-1856-y|pmc=5364244|pmid=27699443}} Neuroplasticity within the brain's reward system occurs as a result of long-term nicotine use, leading to nicotine dependence.{{cite journal|vauthors=D'Souza MS, Markou A |title=Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments|journal=Addict Sci Clin Pract|volume=6|issue=1|pages=4–16|year=2011|pmc=3188825|pmid=22003417}} The neurophysiological activities that are the basis of nicotine dependence are intricate. It includes genetic components, age, gender, and the environment.{{cite journal|last1=Jackson|first1=K.J.|last2=Muldoon|first2=P.P.|last3=De Biasi|first3=M.|last4=Damaj|first4=M.I.|title=New mechanisms and perspectives in nicotine withdrawal|journal=Neuropharmacology|volume=96|issue=Pt B|year=2015|pages=223–234|issn=0028-3908|doi=10.1016/j.neuropharm.2014.11.009|pmc=4444410|pmid=25433149}} Pre-existing cognitive and mood disorders may influence the development and maintenance of nicotine dependence.{{cite journal|last1=Besson|first1=Morgane|last2=Forget|first2=Benoît|title=Cognitive Dysfunction, Affective States, and Vulnerability to Nicotine Addiction: A Multifactorial Perspective|journal=Frontiers in Psychiatry|volume=7|page=160|year=2016|issn=1664-0640|doi=10.3389/fpsyt.2016.00160|pmc=5030478|pmid=27708591|doi-access=free}}{{CC-notice|cc=by4|url=http://journal.frontiersin.org/article/10.3389/fpsyt.2016.00160/full|author(s)=Morgane Besson and Benoît Forget}}

Nicotine addiction is a disorder which alters different neural systems such as dopaminergic, glutamatergic, GABAergic, serotoninergic, that take part in reacting to nicotine.{{cite journal|last1=Hadjiconstantinou|first1=Maria|last2=Neff|first2=Norton H.|title=Nicotine and endogenous opioids: Neurochemical and pharmacological evidence|journal=Neuropharmacology|volume=60|issue=7–8|year=2011|pages=1209–1220|issn=0028-3908|doi=10.1016/j.neuropharm.2010.11.010|pmid=21108953|s2cid=45539554}} In 2015 the psychological and behavioral effects of e-cigarettes were studied using whole-body exposure to e-cigarette aerosol, followed by a series of biochemical and behavioral studies. The results showed that nicotine-containing e-cigarette aerosol induces addiction-related neurochemical, physiological and behavioral changes.

Long-term nicotine use affects a broad range of genes associated with neurotransmission, signal transduction, and synaptic architecture. The most well-known hereditary influence related to nicotine dependence is a mutation at rs16969968 in the nicotinic acetylcholine receptor CHRNA5, resulting in an amino acid alteration from aspartic acid to asparagine.{{cite journal|last1=Yu|first1=Cassie|last2=McClellan|first2=Jon|title=Genetics of Substance Use Disorders|journal=Child and Adolescent Psychiatric Clinics of North America|volume=25|issue=3|year=2016|pages=377–385|issn=1056-4993|doi=10.1016/j.chc.2016.02.002|pmid=27338962}} The single-nucleotide polymorphisms (SNPs) rs6474413 and rs10958726 in CHRNB3 are highly correlated with nicotine dependence. Many other known variants within the CHRNB3–CHRNA6 nicotinic acetylcholine receptors are also correlated with nicotine dependence in certain ethnic groups.{{cite journal|last1=Wen|first1=L|last2=Yang|first2=Z|last3=Cui|first3=W|last4=Li|first4=M D|title=Crucial roles of the CHRNB3–CHRNA6 gene cluster on chromosome 8 in nicotine dependence: update and subjects for future research|journal=Translational Psychiatry|volume=6|issue=6|year=2016|pages=e843|issn=2158-3188|doi=10.1038/tp.2016.103|pmid=27327258|pmc=4931601}} There is a relationship between CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptors and complete smoking cessation.

Increasing evidence indicates that the genetic variant CHRNA5 predicts the response to smoking cessation medicine.{{cite journal|last1=Chen|first1=Li-Shiun|last2=Horton|first2=Amy|last3=Bierut|first3=Laura|title=Pathways to precision medicine in smoking cessation treatments|journal=Neuroscience Letters|volume=669|pages=83–92|year=2016|issn=0304-3940|doi=10.1016/j.neulet.2016.05.033|pmid=27208830|pmc=5115988}} The ability to quitting smoking is affected by genetic factors, including genetically based differences in the way nicotine is metabolized.{{cite journal|last1=Chenoweth|first1=Meghan J.|last2=Tyndale|first2=Rachel F.|title=Pharmacogenetic Optimization of Smoking Cessation Treatment|journal=Trends in Pharmacological Sciences|volume=38|issue=1|year=2017|pages=55–66|issn=0165-6147|doi=10.1016/j.tips.2016.09.006|pmc=5195866|pmid=27712845}} In the CYP450 system there are 173 genetic variants, which impacts how quickly nicotine is metabolizes by each individual. The speed of metabolism impacts the regularity and quantity of nicotine used. For instance, in people who metabolize nicotine gradually their central nervous system effects of nicotine lasts longer, increasing their probability of dependence, but also increasing ability with quitting smoking.{{cite journal|last1=Baraona|first1=L. Kim|last2=Lovelace|first2=Dawn|last3=Daniels|first3=Julie L.|last4=McDaniel|first4=Linda|title=Tobacco Harms, Nicotine Pharmacology, and Pharmacologic Tobacco Cessation Interventions for Women|journal=Journal of Midwifery & Women's Health|volume=62|issue=3|year=2017|pages=253–269|issn=1526-9523|doi=10.1111/jmwh.12616|pmid=28556464|s2cid=1267977|url=https://cdr.lib.unc.edu/downloads/kp78gs98b }}

File:Recolored Overview of reward structures in the human brain2.png, such as nicotine, are associated with its ability to excite the mesolimbic and dopaminergic systems.{{cite journal|last1=Di Matteo|first1=Vincenzo|last2=Pierucci|first2=Massimo|last3=Di Giovanni|first3=Giuseppe|last4=Benigno|first4=Arcangelo|last5=Esposito|first5=Ennio|title=The Neurobiological Bases for the Pharmacotherapy of Nicotine Addiction|journal=Current Pharmaceutical Design|volume=13|issue=12|year=2007|pages=1269–1284|issn=1381-6128|doi=10.2174/138161207780618920|pmid=17504235}}
How does the nicotine in e-cigarettes affect the brain? Until about age 25, the brain is still growing. Each time a new memory is created or a new skill is learned, stronger connections – or synapses – are built between brain cells. Young people's brains build synapses faster than adult brains. Because addiction is a form of learning, adolescents can get addicted more easily than adults. The nicotine in e-cigarettes and other tobacco products can also prime the adolescent brain for addiction to other drugs such as cocaine.{{cite web|url=https://e-cigarettes.surgeongeneral.gov/knowtherisks.html#addiction|title=Know The Risks: E-Cigarettes & Young People – Addiction|publisher=Surgeon General of the United States|year=2016}}{{PD-notice}}|alt=An image of the human brain. The reinforcing effects of drugs of abuse, such as nicotine, is associated with its ability to excite the mesolimbic and dopaminergic systems. How does the nicotine in e-cigarettes affect the brain? Until about age 25, the brain is still growing. Each time a new memory is created or a new skill is learned, stronger connections – or synapses – are built between brain cells. Young people's brains build synapses faster than adult brains. Because addiction is a form of learning, adolescents can get addicted more easily than adults. The nicotine in e-cigarettes and other tobacco products can also prime the adolescent brain for addiction to other drugs such as cocaine.]]

Nicotine is a parasympathomimetic stimulant{{cite book|author1=Richard Beebe|author2=Jeff Myers|title=Professional Paramedic, Volume I: Foundations of Paramedic Care|url=https://books.google.com/books?id=bS8KAAAAQBAJ&pg=PA640|date=19 July 2012|publisher=Cengage Learning|isbn=978-1-133-71465-1|pages=640–}} that binds to and activates nicotinic acetylcholine receptors in the brain, which subsequently causes the release of dopamine and other neurotransmitters, such as norepinephrine, acetylcholine, serotonin, gamma-aminobutyric acid, glutamate, endorphins,{{cite journal|title=Republished: Nicotine and health|journal=BMJ|volume=349|issue=nov26 9|year=2014|pages=2014.7.0264rep|issn=1756-1833|doi=10.1136/bmj.2014.7.0264rep|pmid=25428425|s2cid=45426626|last1=Drug Therapeutics |first1=Bulletin }} and several neuropeptides, including proopiomelanocortin-derived α-MSH and adrenocorticotropic hormone.{{cite book|author1=Atta-ur- Rahman|author2=Allen B. Reitz|title=Frontiers in Medicinal Chemistry|url=https://books.google.com/books?id=tCyDoIHToBQC&pg=PA279|date=1 January 2005|publisher=Bentham Science Publishers|isbn=978-1-60805-205-9|pages=279–}} Corticotropin-releasing factor, Neuropeptide Y, orexins, and norepinephrine are involved in nicotine addiction.{{cite journal|last1=Bruijnzeel|first1=Adrie W.|title=Tobacco addiction and the dysregulation of brain stress systems|journal=Neuroscience & Biobehavioral Reviews|volume=36|issue=5|year=2012|pages=1418–1441|issn=0149-7634|doi=10.1016/j.neubiorev.2012.02.015|pmc=3340450|pmid=22405889}}

Continuous exposure to nicotine can cause an increase in the number of nicotinic receptors, which is believed to be a result of receptor desensitization and subsequent receptor upregulation. Long-term exposure to nicotine can also result in downregulation of glutamate transporter 1.{{cite journal|last1=Alasmari|first1=Fawaz|last2=Al-Rejaie|first2=Salim S.|last3=AlSharari|first3=Shakir D.|last4=Sari|first4=Youssef|title=Targeting glutamate homeostasis for potential treatment of nicotine dependence|journal=Brain Research Bulletin|volume=121|year=2016|pages=1–8|issn=0361-9230|doi=10.1016/j.brainresbull.2015.11.010|pmc=4783195|pmid=26589642}} Long-term nicotine exposure upregulates cortical nicotinic receptors, but it also lowers the activity of the nicotinic receptors in the cortical vasodilation region. These effects are not easily understood.{{cite journal|last1=Uchida|first1=Sae|last2=Hotta|first2=Harumi|title=Cerebral Cortical Vasodilatation Mediated by Nicotinic Cholinergic Receptors: Effects of Old Age and of Chronic Nicotine Exposure|journal=Biological & Pharmaceutical Bulletin|volume=32|issue=3|year=2009|pages=341–344|issn=0918-6158|doi=10.1248/bpb.32.341|pmid=19252275|doi-access=free}}

With constant use of nicotine, tolerance occurs at least partially as a result of the development of new nicotinic acetylcholine receptors in the brain. After several months of nicotine abstinence, the number of receptors go back to normal. The extent to which alterations in the brain caused by nicotine use are reversible is not fully understood.{{cite journal|last1=Korpi|first1=E. R.|last2=den Hollander|first2=B.|last3=Farooq|first3=U.|last4=Vashchinkina|first4=E.|last5=Rajkumar|first5=R.|last6=Nutt|first6=D. J.|last7=Hyytia|first7=P.|last8=Dawe|first8=G. S.|title=Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse|journal=Pharmacological Reviews|volume=67|issue=4|year=2015|pages=872–1004|issn=1521-0081|doi=10.1124/pr.115.010967|pmid=26403687|s2cid=24802846|doi-access=free}} Nicotine also stimulates nicotinic acetylcholine receptors in the adrenal medulla, resulting in increased levels of epinephrine and beta-endorphin. Its physiological effects stem from the stimulation of nicotinic acetylcholine receptors, which are located throughout the central and peripheral nervous systems.{{sfn|SGUS|2014|p=111}}

The α4β2 nicotinic receptor subtype is the main nicotinic receptor subtype.{{cite journal|last1=Dineley|first1=Kelly T.|last2=Pandya|first2=Anshul A.|last3=Yakel|first3=Jerrel L.|title=Nicotinic ACh receptors as therapeutic targets in CNS disorders|journal=Trends in Pharmacological Sciences|volume=36|issue=2|year=2015|pages=96–108|issn=0165-6147|doi=10.1016/j.tips.2014.12.002|pmc=4324614|pmid=25639674}} Nicotine activates brain receptors which produce sedative as well as pleasurable effects.{{cite journal|last1=Caponnetto|first1=P.|last2=Russo|first2=C.|last3=Bruno|first3=C.M.|last4=Alamo|first4=A.|last5=Amaradio|first5=M.D.|last6=Polosa|first6=R.|title=Electronic cigarette: a possible substitute for cigarette dependence|journal=Monaldi Archives for Chest Disease|volume=79|issue=1|pages=12–19|date=March 2013|issn=1122-0643|doi=10.4081/monaldi.2013.104|pmid=23741941|doi-access=free}} Chronic nicotinic acetylcholine receptor activation from repeated nicotine exposure can induce strong effects on the brain, including changes in the brain's physiology, that result from the stimulation of regions of the brain associated with reward, pleasure, and anxiety.{{cite journal|last1=Rowell|first1=Temperance R|last2=Tarran|first2=Robert|title=Will Chronic E-Cigarette Use Cause Lung Disease?|journal=American Journal of Physiology. Lung Cellular and Molecular Physiology|year=2015|volume=309|issue=12|pages=L1398–409|issn=1040-0605|doi=10.1152/ajplung.00272.2015|pmc=4683316|pmid=26408554}} These complex effects of nicotine on the brain are still not well understood.

Nicotine interferes with the blood–brain barrier function, and as a consequence raises the risk of brain edema and neuroinflammation.{{cite journal|last1=Sajja|first1=Ravi K|last2=Rahman|first2=Shafiqur|last3=Cucullo|first3=Luca|title=Drugs of abuse and blood–brain barrier endothelial dysfunction: A focus on the role of oxidative stress|journal=Journal of Cerebral Blood Flow & Metabolism|year=2016|volume=36|issue=3|pages=539–54|issn=0271-678X|doi=10.1177/0271678X15616978|pmc=4794105|pmid=26661236}} When nicotine enters the brain it stimulates, among other activities, the midbrain dopaminergic neurons situated in the ventral tegmental area and pars compacta. It induces the release of dopamine in different parts of the brain, such as the nucleus accumbens, amygdala, and hippocampus.{{cite journal|last1=Subramaniyan|first1=Manivannan|last2=Dani|first2=John A.|title=Dopaminergic and cholinergic learning mechanisms in nicotine addiction|journal=Annals of the New York Academy of Sciences|volume=1349|issue=1|year=2015|pages=46–63|issn=0077-8923|doi=10.1111/nyas.12871|pmc=4564314|pmid=26301866|bibcode=2015NYASA1349...46S}} Ghrelin-induced dopamine release occurs as a result of the activation of the cholinergic–dopaminergic reward link in the ventral tegmental area, a critical part of the reward areas in the brain related with reinforcement. Ghrelin signaling may affect the reinforcing effects of drug dependence.{{cite journal|last1=Engel|first1=Jörgen A.|last2=Jerlhag|first2=Elisabet|title=Role of Appetite-Regulating Peptides in the Pathophysiology of Addiction: Implications for Pharmacotherapy|journal=CNS Drugs|volume=28|issue=10|year=2014|pages=875–886|issn=1172-7047|doi=10.1007/s40263-014-0178-y|pmc=4181507|pmid=24958205}}

When nicotine intake stops, the upregulated nicotinic acetylcholine receptors induce withdrawal symptoms.{{cite journal|last1=Bullen|first1=Christopher|title=Electronic Cigarettes for Smoking Cessation|journal=Current Cardiology Reports|volume=16|page=538|issue=11|year=2014|issn=1523-3782|doi=10.1007/s11886-014-0538-8|pmid=25303892|s2cid=2550483|url=http://qmro.qmul.ac.uk/xmlui/handle/123456789/16169|url-access=subscription}} These symptoms can include cravings for nicotine, anger, irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger, weight gain, and difficulty concentrating.{{cite encyclopedia |entry-url=https://www.nlm.nih.gov/medlineplus/ency/article/000953.htm|publisher=Medline Plus|entry=Nicotine and Tobacco |encyclopedia=A.D.A.M. Medical Encyclopedia |date=7 June 2016}} When trying to quit smoking with vaping a base containing nicotine, symptoms of withdrawal can include irritability, restlessness, poor concentration, anxiety, depression, and hunger.{{cite journal|last1=Khoudigian|first1=S.|last2=Devji|first2=T.|last3=Lytvyn|first3=L.|last4=Campbell|first4=K.|last5=Hopkins|first5=R.|last6=O'Reilly|first6=D.|title=The efficacy and short-term effects of electronic cigarettes as a method for smoking cessation: a systematic review and a meta-analysis|journal=International Journal of Public Health|volume=61|issue=2|date=29 January 2016|pages=257–267|issn=1661-8556|doi=10.1007/s00038-016-0786-z|pmid=26825455|s2cid=22227035}} The changes in the brain cause a nicotine user to feel abnormal when not using nicotine. In order to feel normal, the user has to keep his or her body supplied with nicotine.{{cite web|url=https://www.drugabuse.gov/publications/brain-power/grades-6-9/legal-doesn%27t-mean-harmless-module-2/background|title=Nicotine|publisher=National Institute on Drug Abuse|date=June 2007|access-date=2019-09-07|archive-date=2019-06-11|archive-url=https://web.archive.org/web/20190611224353/https://www.drugabuse.gov/publications/brain-power/grades-6-9/legal-doesn%27t-mean-harmless-module-2/background|url-status=dead}}{{PD-notice}} E-cigarettes may reduce cigarette craving and withdrawal symptoms.{{cite journal|last1=Shahab|first1=Lion|last2=Brose|first2=Leonie S.|last3=West|first3=Robert|title=Novel Delivery Systems for Nicotine Replacement Therapy as an Aid to Smoking Cessation and for Harm Reduction: Rationale, and Evidence for Advantages over Existing Systems|journal=CNS Drugs|volume=27|issue=12|year=2013|pages=1007–1019|issn=1172-7047|doi=10.1007/s40263-013-0116-4|pmid=24114587|s2cid=207486096}}

Limiting tobacco consumption with the use of campaigns that portray cigarette smoking as unacceptable and harmful have been enacted; though, advocating for the use of e-cigarettes jeopardizes this because of the possibility of escalating nicotine addiction.{{cite journal|last1=Vanker|first1=A.|last2=Gie|first2=R.P.|last3=Zar|first3=H.J.|title=The Association Between Environmental Tobacco Smoke Exposure and Childhood Respiratory Disease: A Review.|journal=Expert Review of Respiratory Medicine|volume=11|issue=8|pages=661–673|year=2017|issn=1747-6348|doi=10.1080/17476348.2017.1338949|pmid=28580865|pmc=6176766}} It is not clear whether e-cigarette use will decrease or increase overall nicotine addiction,{{cite journal|title=Electronic cigarettes and vaping: a new challenge in clinical medicine and public health. A literature review|first1=Dominic L.|last1=Palazzolo|journal=Frontiers in Public Health|volume=1|issue=56|page=56|date=November 2013|doi=10.3389/fpubh.2013.00056|pmc=3859972|pmid=24350225|doi-access=free}} but the nicotine content in e-cigarettes is adequate to sustain nicotine dependence.{{cite journal|last1=Schroeder|first1=M. J.|last2=Hoffman|first2=A. C.|title=Electronic cigarettes and nicotine clinical pharmacology|journal=Tobacco Control|volume=23|issue=Supplement 2|year=2014|pages=ii30–ii35|issn=0964-4563|doi=10.1136/tobaccocontrol-2013-051469|pmc=3995273|pmid=24732160}} Chronic nicotine use causes a broad range of neuroplastic adaptations, making quitting hard to accomplish.

A 2015 study found that users vaping non-nicotine e-liquid exhibited signs of dependence.{{cite journal|last1=Bold|first1=Krysten W.|last2=Sussman|first2=Steve|last3=O'Malley|first3=Stephanie S.|last4=Grana|first4=Rachel|last5=Foulds|first5=Jonathan|last6=Fishbein|first6=Howard|last7=Krishnan-Sarin|first7=Suchitra|title=Measuring E-cigarette dependence: Initial guidance|journal=Addictive Behaviors|volume=79|pages=213–218|year=2017|issn=0306-4603|doi=10.1016/j.addbeh.2017.11.015|pmc=5807200|pmid=29174664}} Experienced users tend to take longer puffs which may result in higher nicotine intake.{{cite journal|last1=Breland|first1=Alison B.|last2=Spindle|first2=Tory|last3=Weaver|first3=Michael|last4=Eissenberg|first4=Thomas|title=Science and Electronic Cigarettes|journal=Journal of Addiction Medicine|volume=8|issue=4|year=2014|pages=223–233|issn=1932-0620|doi=10.1097/ADM.0000000000000049|pmc=4122311|pmid=25089952}} It is difficult to assess the impact of nicotine dependence from e-cigarette use because of the wide range of e-cigarette products. The addiction potential of e-cigarettes may have risen because as they have progressed, they delivery nicotine better.{{sfn|McNeill|2018|p=12}} A 2016 review states that "The highly addictive nature of nicotine is responsible for its widespread use and difficulty with quitting."

File:Youth e-cigarette use is rising.jpg

File:Any Volunteers The Risks of E-cigarettes for Young People.ogv advises parents to "Know the Risks," and highlights how e-cigarettes have the potential to cause lasting harm to the health of young users, especially their brain development, which continues until about age 25.{{cite web|url=https://e-cigarettes.surgeongeneral.gov/|title=THE FACTS on e-cigarette use among youth and young adults|publisher=Surgeon General of the United States|year=2016}}{{PD-notice}}|alt=This video from the US Surgeon General advises parents to "Know the Risks," and highlights how e-cigarettes have the potential to cause lasting harm to the health of young users, especially their brain development, which continues until about age 25.]]

E-cigarettes use by children and adolescents may result in nicotine addiction.{{cite journal|last1=Bhatnagar|first1=A.|last2=Whitsel|first2=L. P.|last3=Ribisl|first3=K. M.|last4=Bullen|first4=C.|last5=Chaloupka|first5=F.|last6=Piano|first6=M. R.|last7=Robertson|first7=R. M.|last8=McAuley|first8=T.|last9=Goff|first9=D.|last10=Benowitz|first10=N.|title=Electronic Cigarettes: A Policy Statement From the American Heart Association|journal=Circulation|date=24 August 2014|volume=130|issue=16|pages=1418–1436|doi=10.1161/CIR.0000000000000107|pmid=25156991|pmc=7643636|s2cid=16075813}}{{rp|C}}{{cite journal|last1=Hildick-Smith|first1=Gordon J.|last2=Pesko|first2=Michael F.|last3=Shearer|first3=Lee|last4=Hughes|first4=Jenna M.|last5=Chang|first5=Jane|last6=Loughlin|first6=Gerald M.|last7=Ipp|first7=Lisa S.|title=A Practitioner's Guide to Electronic Cigarettes in the Adolescent Population|journal=Journal of Adolescent Health|volume=57|issue=6|pages=574–9|year=2015|issn=1054-139X|doi=10.1016/j.jadohealth.2015.07.020|pmid=26422289|doi-access=free}}{{rp|A}} Following the possibility of nicotine addiction via e-cigarettes, there is concern that children may start smoking cigarettes.{{sfn|WHO|2014|p=6}} Adolescents are likely to underestimate nicotine's addictiveness.{{sfn|Chapman|2015|p=5}} Vulnerability to the brain-modifying effects of nicotine, along with youthful experimentation with e-cigarettes, could lead to a lifelong addiction. A long-term nicotine addiction from using a vape may result in using other tobacco products.{{cite web|url=http://www.cancer.org/cancer/cancercauses/tobaccocancer/childandteentobaccouse/child-and-teen-tobacco-use-other-types|title=Teens like different forms of tobacco and nicotine|publisher=American Cancer Society|archive-url=https://web.archive.org/web/20150920232939/http://www.cancer.org/cancer/cancercauses/tobaccocancer/childandteentobaccouse/child-and-teen-tobacco-use-other-types|archive-date=20 September 2015}}

The majority of addiction to nicotine starts during youth and young adulthood. Adolescents are more likely to become nicotine dependent than adults.{{cite journal|last1=Chatterjee|first1=Kshitij|last2=Alzghoul|first2=Bashar|last3=Innabi|first3=Ayoub|last4=Meena|first4=Nikhil|title=Is vaping a gateway to smoking: a review of the longitudinal studies|journal=International Journal of Adolescent Medicine and Health|issue=3|year=2016|volume=30|issn=2191-0278|doi=10.1515/ijamh-2016-0033|doi-broken-date=3 December 2024 |pmid=27505084|s2cid=23977146}} The adolescent brain seems to be particularly sensitive to neuroplasticity as a result of nicotine. Minimal exposure could be enough to produce neuroplastic alterations in the very sensitive adolescent brain. Exposure to nicotine during adolescence may increase vulnerability to getting addicted to cocaine and other drugs.{{cite journal|last1=Dinakar|first1=Chitra|last2=Longo|first2=Dan L.|last3=O'Connor|first3=George T.|title=The Health Effects of Electronic Cigarettes|journal=New England Journal of Medicine|volume=375|issue=14|year=2016|pages=1372–1381|issn=0028-4793|doi=10.1056/NEJMra1502466|pmid=27705269}}

The ability of e-cigarettes to deliver comparable or higher amounts of nicotine compared to traditional cigarettes raises concerns about e-cigarette use generating nicotine dependence among young people.{{sfn|SGUS|2016|p=102; Chapter 3}} Youth who believe they are vaping without nicotine could still be inhaling nicotine because there are significant differences between declared and true nicotine content.{{cite journal|last1=Soneji|first1=Samir|last2=Barrington-Trimis|first2=Jessica L.|last3=Wills|first3=Thomas A.|last4=Leventhal|first4=Adam M.|last5=Unger|first5=Jennifer B.|last6=Gibson|first6=Laura A.|last7=Yang|first7=JaeWon|last8=Primack|first8=Brian A.|last9=Andrews|first9=Judy A.|last10=Miech|first10=Richard A.|last11=Spindle|first11=Tory R.|last12=Dick|first12=Danielle M.|last13=Eissenberg|first13=Thomas|last14=Hornik|first14=Robert C.|last15=Dang|first15=Rui|last16=Sargent|first16=James D.|title=Association Between Initial Use of e-Cigarettes and Subsequent Cigarette Smoking Among Adolescents and Young Adults|journal=JAMA Pediatrics|volume=171|issue=8|year=2017|pages=788–797|issn=2168-6203|doi=10.1001/jamapediatrics.2017.1488|pmc=5656237|pmid=28654986}}

A 2016 US Surgeon General report concluded that e-cigarette use among young adults and youths is of public health concern.{{cite journal|last1=Cullen|first1=Karen A.|last2=Ambrose|first2=Bridget K.|last3=Gentzke|first3=Andrea S.|last4=Apelberg|first4=Benjamin J.|last5=Jamal|first5=Ahmed|last6=King|first6=Brian A.|title=Notes from the Field: Use of Electronic Cigarettes and Any Tobacco Product Among Middle and High School Students — United States, 2011–2018|journal=MMWR. Morbidity and Mortality Weekly Report|volume=67|issue=45|year=2018|pages=1276–1277|issn=0149-2195|doi=10.15585/mmwr.mm6745a5|pmc=6290807|pmid=30439875}}{{PD-notice}} Various organizations,{{cite journal|last1=Kamat|first1=Aarti D.|last2=Van Dyke|first2=Alison L.|s2cid=20909216|title=Use of Electronic Nicotine Delivery Systems Among Adolescents: Status of the Evidence and Public Health Recommendations|journal=Pediatric Annals|volume=46|issue=2|year=2017|pages=e69–e77|issn=1938-2359|doi=10.3928/19382359-20170111-01|pmid=28192582}} including the International Union Against Tuberculosis and Lung Disease, the American Academy of Pediatrics, the American Cancer Society, the Centers for Disease Control and Prevention, and the US Food and Drug Administration (US FDA), have expressed concern that e-cigarette use could increase the prevalence of nicotine addiction in youth.{{cite web|url=http://www.theunion.org/what-we-do/publications/official/body/E-cigarette_statement_FULL.pdf|title=Position Statement on Electronic Cigarettes [ECs] or Electronic Nicotine Delivery Systems [ENDS]|date=October 2013|publisher=The International Union against Tuberculosis and Lung Disease|access-date=2019-09-07|archive-date=2016-03-05|archive-url=https://web.archive.org/web/20160305045407/http://www.theunion.org/what-we-do/publications/official/body/E-cigarette_statement_FULL.pdf|url-status=dead}}{{rp|IUATLD}}{{cite journal|last1=Korioth|first1=Trisha|title=E-cigarettes easy to buy, can hook kids on nicotine|journal=AAP News|date=4 October 2013|pages=E131004-4|doi=10.1542/aapnews.20133411-24d|url=https://publications.aap.org/aapnews/article/34/11/24/10361/E-cigarettes-easy-to-buy-can-hook-kids-on-nicotine|doi-broken-date=1 November 2024}}{{rp|AAP}}{{cite web|url=http://www.cancer.org/cancer/news/news/e-cigarette-use-triples-among-middle-and-high-school-students|title=E-Cigarette Use Triples Among Middle and High School Students|author=Stacy Simon|publisher=American Cancer Society|date=17 April 2015}}{{rp|ACS}}{{cite journal|last1=Singh|first1=Tushar|last2=Arrazola|first2=René A.|last3=Corey|first3=Catherine G.|last4=Husten|first4=Corinne G.|last5=Neff|first5=Linda J.|last6=Homa|first6=David M.|last7=King|first7=Brian A.|title=Tobacco Use Among Middle and High School Students — United States, 2011–2015|journal=MMWR. Morbidity and Mortality Weekly Report|volume=65|issue=14|year=2016|pages=361–367|issn=0149-2195|doi=10.15585/mmwr.mm6514a1|pmid=27077789|doi-access=free}}{{rp|CDC}}{{cite web|url=https://www.fda.gov/forconsumers/consumerupdates/ucm173401.htm|archive-url=https://web.archive.org/web/20090727041917/http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm173401.htm|url-status=dead|archive-date=July 27, 2009|title=FDA Warns of Health Risks Posed by E-Cigarettes|website=United States Food and Drug Administration|date=17 September 2013}} Reviewed 17 September 2013{{rp|US FDA}}

Flavored tobacco is especially enticing to youth, and certain flavored tobacco products increase addiction. There is concern that flavored e-cigarettes could have a similar impact on youth. The extent to which teens are using e-cigarettes may lead to addiction or substance dependence in youth, is unknown.{{cite journal|last1=Durmowicz|first1=E. L.|title=The impact of electronic cigarettes on the paediatric population|journal=Tobacco Control|volume=23|issue=Supplement 2|year=2014|pages=ii41–ii46|issn=0964-4563|doi=10.1136/tobaccocontrol-2013-051468|pmc=3995262|pmid=24732163}} A 2017 review noted that "adolescents experience symptoms of dependence at lower levels of nicotine exposure than adults. Consequently, it is harder to reverse addiction originating in this stage compared with later in life."

Adolescents are particularly susceptible to nicotine addiction: the majority (90%) of smokers start before the age of 18, a fact that has been utilized by tobacco companies for decades in their teen-targeted advertising, marketing and even product design. E-cigarette marketing tactics have the possibility to glamorize smoking and enticing children and never smokers, even when such outcomes are unintended.{{sfn|WHO|2014|p=9}} Adolescents may show signs of dependence with even infrequent nicotine use; sustained nicotine exposure leads to upregulation of the receptors in the prefrontal cortex, pathways which are involved in cognitive control, and which are not fully matured until the mid-twenties. Such disruption of neural circuit development may lead to long-term cognitive and behavioral impairment and has been associated with depression and anxiety.

The nicotine content in e-cigarettes varies widely by product and by use. Refill solutions may contain anywhere from 1.8% nicotine (18 mg/mL) to over 5% (59 mg/mL). Nicotine delivery may be affected by the device itself, for example, by increasing the voltage which changes the aerosol delivered, or by "dripping"—a process of inhaling liquid poured directly onto coils. The latest generation of e-cigarettes, "pod products," such as Juul, have the highest nicotine content (59 mg/mL), in protonated salt, rather than the free-base nicotine form found in earlier generations, which makes it easier for less experienced users to inhale. Despite the clear presence of nicotine in e-cigarettes, adolescents often do not recognize this fact, potentially fueling misperceptions about the health risks and addictive potential of e-cigarettes.

In the US, the unprecedented increase in current (past-month) users from 11.7% of high school students in 2017 to 20.8% in 2018 would imply dependence, if not addiction, given what we know about nicotine and its effects on the adolescent brain. Two recent studies in 2018 utilized validated measures to identify nicotine dependence in e-cigarette using adolescents. Exposure to nicotine from certain types of e-cigarettes may be higher than that from traditional cigarettes. For example, in a study in 2018 of adolescent pod users, their urinary cotinine (a breakdown product used to measure nicotine exposure) levels were higher than levels seen in adolescent cigarette smokers.{{cite journal|last1=Jenssen|first1=Brian P.|last2=Boykan|first2=Rachel|title=Electronic Cigarettes and Youth in the United States: A Call to Action (at the Local, National and Global Levels)|journal=Children|volume=6|issue=2|year=2019|page=30|issn=2227-9067|doi=10.3390/children6020030|pmc=6406299|pmid=30791645|doi-access=free}}{{CC-notice|cc=by4|url=https://www.mdpi.com/2227-9067/6/2/30/htm|author(s)=Brian P. Jenssen and Rachel Boykan}}

File:Use of Two or More Tobacco Products.png's report entitled Use of Two or More Tobacco Products.{{cite web|url=https://e-cigarettes.surgeongeneral.gov/knowtherisks.html#dual-use|title=Know The Risks: E-Cigarettes & Young People – Use of Two or More Tobacco Products|publisher=Surgeon General of the United States|year=2019}}{{PD-notice}}|alt=Graphic from the 2019 US Surgeon General's report entitled Use of Two or More Tobacco Products. The accompanied text states, "Some people have suggested that use of e-cigarettes by young people might "protect" them from using cigarettes. There is no evidence to support this claim. Some studies show that non-smoking youth who use e-cigarettes are more likely to try conventional cigarettes in the future than non-smoking youth who do not use e-cigarettes. And among high school students and young adults who use two or more tobacco products, a majority use both e-cigarettes and burned tobacco products. Burned tobacco products like cigarettes are responsible for the overwhelming majority of tobacco-related deaths and disease in the United States."]]

Both preadolescence and adolescence are developmental periods associated with increased vulnerability to nicotine addiction, and exposure to nicotine during these periods may lead to long-lasting changes in behavioral and neuronal plasticity.{{sfn|SGUS|2016|p=107; Chapter 3}} Nicotine has more significant and durable damaging effects on adolescent brains compared to adult brains, the former suffering more harmful effects.{{sfn|SGUS|2016|p=105; Chapter 3}} Preclinical animal studies have shown that in rodent models, nicotinic acetylcholine receptor signaling is still actively changing during adolescence, with higher expression and functional activity of nicotinic acetylcholine receptors in the forebrain of adolescent rodents compared to their adult counterparts.{{sfn|SGUS|2016|p=105; Chapter 3}}

In rodent models, nicotine actually enhances neuronal activity in several reward-related regions and does so more robustly in adolescents than in adults.{{sfn|SGUS|2016|p=105; Chapter 3}} This increased sensitivity to nicotine in the reward pathways of adolescent rats is associated with enhanced behavioral responses, such as strengthening the stimulus response reward for administration of nicotine.{{sfn|SGUS|2016|p=105; Chapter 3}} In conditioned place-preference tests—where reward is measured by the amount of time animals spend in an environment where they receive nicotine compared to an environment where nicotine is not administered—adolescent rodents have shown an increased sensitivity to the rewarding effects of nicotine at very low doses (0.03 mg/kg) and exhibited a unique vulnerability to oral self-administration during the early-adolescent period.{{sfn|SGUS|2016|p=105; Chapter 3}}

Adolescent rodents also have shown higher levels of nicotine self-administration than adults, decreased sensitivity to the aversive effects of nicotine, and less prominent withdrawal symptoms following chronic nicotine exposure.{{sfn|SGUS|2016|p=105; Chapter 3}} This characteristic in rodent models of increased positive and decreased negative short-term effects of nicotine during adolescence (versus adulthood) highlights the possibility that human adolescents might be particularly vulnerable to developing dependency to and continuing to use e-cigarettes.{{sfn|SGUS|2016|p=105; Chapter 3}}

The teen years are critical for brain development, which continues into young adulthood. Young people who use nicotine products in any form, including e-cigarettes, are uniquely at risk for long-lasting effects. Because nicotine affects the development of the brain's reward system, continued e-cigarette use can not only lead to nicotine addiction, but it also can make other drugs such as cocaine and methamphetamine more pleasurable to a teen's developing brain. Concerns exist in respect to adolescence vaping due to studies indicating nicotine may potentially have harmful effects on the brain.{{cite journal|last1=Greenhill|first1=Richard|last2=Dawkins|first2=Lynne|last3=Notley|first3=Caitlin|last4=Finn|first4=Mark D.|last5=Turner|first5=John J.D.|title=Adolescent Awareness and Use of Electronic Cigarettes: A Review of Emerging Trends and Findings|journal=Journal of Adolescent Health|volume=59|issue=6|pages=612–619|year=2016|issn=1054-139X|doi=10.1016/j.jadohealth.2016.08.005|pmid=27693128|doi-access=free}} Nicotine exposure during adolescence adversely affects cognitive development.

Children are more sensitive to nicotine than adults.{{cite journal|vauthors=Schraufnagel DE|title=Electronic Cigarettes: Vulnerability of Youth|journal=Pediatr Allergy Immunol Pulmonol|volume=28|issue=1|pages=2–6|year=2015|doi=10.1089/ped.2015.0490|pmc=4359356|pmid=25830075}} The use of products containing nicotine in any form among youth, including in e-cigarettes, is unsafe.{{sfn|SGUS|2016|p=5; Chapter 1}} Animal research indicates strong evidence that the limbic system, which modulates drug reward, cognition, and emotion, is growing during adolescence and is particularly vulnerable to the long lasting effects of nicotine. In youth, nicotine is associated with cognitive impairment as well as the chance of getting addicted for life.{{cite web|url=https://www.vitalstrategies.org/press/who-right-to-call-for-e-cigarette-regulation/|archive-url=https://web.archive.org/web/20180330075957/https://www.vitalstrategies.org/press/who-right-to-call-for-e-cigarette-regulation/|url-status=usurped|archive-date=March 30, 2018|title=WHO Right to Call for E-Cigarette Regulation|publisher=World Lung Federation|date=26 August 2014}}

The adolescent's developing brain is especially sensitive to the harmful effects of nicotine.{{sfn|Chapman|2015|p=6}} A short period of regular or occasional nicotine exposure in adolescence exerts long-term neurobehavioral damage.{{sfn|Chapman|2015|p=6}} Risks of exposing the developing brain to nicotine include mood disorders and permanent lowering of impulse control.{{cite web|url=https://e-cigarettes.surgeongeneral.gov/knowtherisks.html|title=Know the Risks|publisher=Surgeon General of the United States|year=2016}}{{PD-notice}} The rise in vaping is of great concern because the parts encompassing in greater cognitive activities including the prefrontal cortex of the brain continues to develop into the 20s. Nicotine exposure during brain development may hamper growth of neurons and brain circuits, effecting brain architecture, chemistry, and neurobehavioral activity.{{cite journal|last1=England|first1=Lucinda J.|last2=Bunnell|first2=Rebecca E.|last3=Pechacek|first3=Terry F.|last4=Tong|first4=Van T.|last5=McAfee|first5=Tim A.|title=Nicotine and the Developing Human|journal=American Journal of Preventive Medicine|year=2015|volume=49|issue=2|pages=286–93|issn=0749-3797|doi=10.1016/j.amepre.2015.01.015|pmc=4594223|pmid=25794473}}

Nicotine changes the way synapses are formed, which can harm the parts of the brain that control attention and learning. Preclinical studies indicate that teens being exposed to nicotine interferes with the structural development of the brain, inducing lasting alterations in the brain's neural circuits. Nicotine affects the development of brain circuits that control attention and learning. Other risks include mood disorders and permanent problems with impulse control—failure to fight an urge or impulse that may harm oneself or others. Each e-cigarette brand differs in the exact amount of ingredients and nicotine in each product. Therefore, little is known regarding the health consequences of each brand to the growing brains of youth.{{cite journal|last1=Modesto-Lowe|first1=Vania|last2=Alvarado|first2=Camille|title=E-cigs . . . Are They Cool? Talking to Teens About E-Cigarettes|journal=Clinical Pediatrics|volume=56|issue=10|year=2017|pages=947–952|issn=0009-9228|doi=10.1177/0009922817705188|pmid=28443340|s2cid=44423931}}

E-cigarettes are a source of potential developmental toxicants.{{cite journal|last1=Wolff|first1=Mary S.|last2=Buckley|first2=Jessie P.|last3=Engel|first3=Stephanie M.|last4=McConnell|first4=Rob S.|last5=Barr|first5=Dana B.|title=Emerging exposures of developmental toxicants|journal=Current Opinion in Pediatrics|volume=29|issue=2|year=2017|pages=218–224|issn=1040-8703|doi=10.1097/MOP.0000000000000455|pmc=5473289|pmid=28059904}} E-cigarette aerosol, e-liquids, flavoring, and the metallic coil can cause oxidative stress, and the growing brain is uniquely susceptible to the detrimental effects of oxidative stress.{{cite journal|last1=Tobore|first1=Tobore Onojighofia|title=On the potential harmful effects of E-Cigarettes (EC) on the developing brain: The relationship between vaping-induced oxidative stress and adolescent/young adults social maladjustment.|journal=Journal of Adolescence|volume=76|year=2019|pages=202–209|issn=0140-1971|doi=10.1016/j.adolescence.2019.09.004|pmid=31574388|s2cid=203640780}} As indicated in the limited research from animal studies, there is the potential for induced changes in neurocognitive growth among children who have been subjected to e-cigarette aerosols consisting of nicotine.{{cite journal|last1=Collaco|first1=Joseph M.|last2=McGrath-Morrow|first2=Sharon A.|title=Electronic Cigarettes: Exposure and Use Among Pediatric Populations|journal=Journal of Aerosol Medicine and Pulmonary Drug Delivery|volume=31|issue=2|year=2018|pages=71–77|issn=1941-2711|doi=10.1089/jamp.2017.1418|pmid=29068754|pmc=5915214}} The US FDA stated in 2019 that some people who use e-cigarettes have experienced seizures, with most reports involving youth or young adult users.{{cite web|url=https://www.fda.gov/TobaccoProducts/NewsEvents/ucm635133.htm|archive-url=https://web.archive.org/web/20190403235054/https://www.fda.gov/TobaccoProducts/NewsEvents/ucm635133.htm|url-status=dead|archive-date=April 3, 2019|title=Some E-cigarette Users Are Having Seizures, Most Reports Involving Youth and Young Adults|publisher=United States Food and Drug Administration|date=3 April 2019}}{{PD-notice}} Inhaling lead from e-cigarette aerosol can induce serious neurologic injury, notably to the growing brains of children.{{cite journal|last1=Smith|first1=L|last2=Brar|first2=K|last3=Srinivasan|first3=K|last4=Enja|first4=M|last5=Lippmann|first5=S|title=E-cigarettes: How "safe" are they?|url=http://www.mdedge.com/jfponline/article/109243/addiction-medicine/e-cigarettes-how-safe-are-they|journal=J Fam Pract|date=June 2016|volume=65|issue=6|pages=380–5|pmid=27474819}}

A 2017 review states that "Because the brain does not reach full maturity until the mid-20s, restricting sales of electronic cigarettes and all tobacco products to individuals aged at least 21 years and older could have positive health benefits for adolescents and young adults." Adverse effects to the health of children is mostly not known. Children subjected to e-cigarettes had a higher likelihood of having more than one adverse effect and effects were more significant, than with children subjected to traditional cigarettes. Significant harmful effects were cyanosis, nausea, and coma, among others.{{cite journal|last1=Lødrup Carlsen|first1=Karin C.|last2=Skjerven|first2=Håvard O.|last3=Carlsen|first3=Kai-Håkon|title=The toxicity of E-cigarettes and children's respiratory health|journal=Paediatric Respiratory Reviews|volume=28|pages=63–67|year=2018|issn=1526-0542|doi=10.1016/j.prrv.2018.01.002|pmid=29580719|s2cid=4368058}}

File:Nicotine brain.jpg

{{Annotated image 4

| image = Blausen 0747 Pregnancy-bg.png

| align = center

| width = 600

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| image-width = 600

| header = Possible effects of nicotine on the developing human fetal brain

| caption = Nicotine exposure during pregnancy can harm fetal brain development.

| alt = The diagram is titled Possible effects of nicotine on the developing fetal brain. The text states: Vaping during pregnancy is not safe for the growing fetal brain. Nicotine binds to nicotinic acetylcholine receptors Dysregulation of catecholaminergic neurotransmitter system Dysregulation of serotonergic neurotransmitter system Dysregulation of other neurotransmitter systems Changes to the corpus callosum Changes in brain metabolism Changes in neurotransmitter systems Changes in normal brain development Stillbirth Sudden infant death syndrome Auditory processing complications Developmental disturbances Behavioral abnormalities in adults and children Lower birth weights compared to other infants Reduction in brain weight The caption states: Nicotine exposure during pregnancy can harm fetal brain development.

| link =

| annot-font-size = 100%

| icon = none

| annotations =

{{Annotation|7|10|

Vaping during pregnancy

is not safe for the

growing fetal brain.

| text-align=left | font-size=15 | color=black

}}

{{Annotation|7|148|

Fetal brain development:

• Nicotine binds to
  nicotinic acetylcholine receptors
• Dysregulation of catecholaminergic
  neurotransmitter system{{sfn|SGUS|2016|p=108; Chapter 3}}
• Dysregulation of serotonergic
  neurotransmitter system{{sfn|SGUS|2016|p=108; Chapter 3}}
• Dysregulation of other
  neurotransmitter systems{{sfn|SGUS|2016|p=108; Chapter 3}}
• Modifies the corpus callosum
• Changes in brain metabolism
• Changes in normal
  brain development
• Stillbirth{{sfn|Chapman|2015|p=5}}
• Sudden infant death syndrome
• Auditory processing challenges
• Developmental disturbances
• Behavioral abnormalities in
  adults and children
• Lower birth weights compared
  to other infants
• Reduction in brain weight

| text-align=left | font-size=14 | color=black

}}

}}

There is accumulating research concerning the negative effects of nicotine on prenatal brain development.{{#tag:ref|Fetal exposure to nicotine during pregnancy can result in multiple adverse consequences, including sudden infant death syndrome, altered corpus callosum, auditory processing deficits, effects on behaviors and obesity, and deficits in attention and cognition.{{sfn|SGUS|2016|p=vii; Preface}}|group=notes}}{{cite journal|last1=Drummond|first1=MB|last2=Upson|first2=D|title=Electronic cigarettes. Potential harms and benefits.|journal=Annals of the American Thoracic Society|date=February 2014|volume=11|issue=2|pages=236–42|doi=10.1513/annalsats.201311-391fr|pmc=5469426|pmid=24575993}} Vaping during pregnancy can be harmful to the fetus.{{cite web|url=http://www.health.govt.nz/our-work/preventative-health-wellness/tobacco-control/electronic-nicotine-delivery-systems-ends-including-e-cigarettes|title=Electronic Nicotine Delivery Systems (ENDS), including E-cigarettes|publisher=New Zealand Ministry of Health|archive-url=https://web.archive.org/web/20150511103648/http://www.health.govt.nz/our-work/preventative-health-wellness/tobacco-control/electronic-nicotine-delivery-systems-ends-including-e-cigarettes|archive-date=2015-05-11|year=2014}} There is no supporting evidence demonstrating that vaping is safe for use in pregnant women. Nicotine accumulates in the fetus because it goes through the placenta.{{cite web|title=Electronic Cigarettes – An Overview|url=http://www.dkfz.de/en/presse/download/RS-Vol19-E-Cigarettes-EN.pdf|year=2013|publisher=German Cancer Research Center}} Nicotine has been found in placental tissue as early as seven weeks of embryonic gestation, and nicotine concentrations are higher in fetal fluids than in maternal fluids.{{sfn|SGUS|2016|p=108; Chapter 3}} Nicotine can lead to vasoconstriction of uteroplacental vessels, reducing the delivery of both nutrients and oxygen to the fetus.

As a result, nutrition is re-distributed to prioritize vital organs, such as the heart and the brain, at the cost of less vital organs, such as the liver, kidneys, adrenal glands, and pancreas, leading to underdevelopment and functional disorders later in life.{{cite journal|last1=Li|first1=Gerard|last2=Saad|first2=Sonia|last3=Oliver|first3=Brian|last4=Chen|first4=Hui|title=Heat or Burn? Impacts of Intrauterine Tobacco Smoke and E-Cigarette Vapor Exposure on the Offspring's Health Outcome|journal=Toxics|volume=6|issue=3|year=2018|page=43|issn=2305-6304|doi=10.3390/toxics6030043|pmc=6160993|pmid=30071638|doi-access=free}}{{CC-notice|cc=by4|url=https://www.mdpi.com/2305-6304/6/3/43/htm|author(s)=Gerard Li, Sonia Saad, Brian G. Oliver, and Hui Chen}} Nicotine attaches to nicotinic acetylcholine receptors in the fetus brain. The stage when the human brain is developing is possibly the most sensitive time period to the effects of nicotine. When the brain is being developed, activating or desensitizing nicotinic acetylcholine receptors by being exposed to nicotine can result in long-term developmental disturbances.{{cite journal|last1=England|first1=Lucinda J.|last2=Aagaard|first2=Kjersti|last3=Bloch|first3=Michele|last4=Conway|first4=Kevin|last5=Cosgrove|first5=Kelly|last6=Grana|first6=Rachel|last7=Gould|first7=Thomas J.|last8=Hatsukami|first8=Dorothy|last9=Jensen|first9=Frances|last10=Kandel|first10=Denise|last11=Lanphear|first11=Bruce|last12=Leslie|first12=Frances|last13=Pauly|first13=James R.|last14=Neiderhiser|first14=Jenae|last15=Rubinstein|first15=Mark|last16=Slotkin|first16=Theodore A.|last17=Spindel|first17=Eliot|last18=Stroud|first18=Laura|last19=Wakschlag|first19=Lauren|title=Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products|journal=Neuroscience & Biobehavioral Reviews|volume=72|year=2017|pages=176–189|issn=0149-7634|doi=10.1016/j.neubiorev.2016.11.013|pmc=5965681|pmid=27890689}}

Prenatal nicotine exposure has been associated with dysregulation of catecholaminergic, serotonergic, and other neurotransmitter systems.{{sfn|SGUS|2016|p=108; Chapter 3}} Prenatal nicotine exposure is associated with preterm birth,{{sfn|Chapman|2015|p=5}} stillbirth,{{sfn|Chapman|2015|p=5}} sudden infant death syndrome, auditory processing complications, changes to the corpus callosum,{{cite journal|last1=Makadia|first1=Luv D.|last2=Roper|first2=P. Jervey|last3=Andrews|first3=Jeannette O.|last4=Tingen|first4=Martha S.|title=Tobacco Use and Smoke Exposure in Children: New Trends, Harm, and Strategies to Improve Health Outcomes|journal=Current Allergy and Asthma Reports|volume=17|issue=8|page=55|year=2017|issn=1529-7322|doi=10.1007/s11882-017-0723-0|pmid=28741144|s2cid=22360961}} changes in brain metabolism, changes in neurological systems, changes in neurotransmitter systems,{{cite journal|last1=Behnke|first1=M.|last2=Smith|first2=V. C.|title=Prenatal Substance Abuse: Short- and Long-term Effects on the Exposed Fetus|journal=Pediatrics|volume=131|issue=3|year=2013|pages=e1009–e1024|issn=0031-4005|doi=10.1542/peds.2012-3931|pmid=23439891|pmc=8194464|s2cid=135162|doi-access=free}} changes in normal brain development, lower birth weights compared to other infants,{{cite journal|last1=Holbrook|first1=Bradley D.|title=The effects of nicotine on human fetal development|journal=Birth Defects Research Part C: Embryo Today: Reviews|volume=108|issue=2|year=2016|pages=181–192|issn=1542-975X|doi=10.1002/bdrc.21128|pmid=27297020}} and a reduction in brain weight.{{cite journal|last1=Alkam|first1=Tursun|last2=Nabeshima|first2=Toshitaka|title=Molecular mechanisms for nicotine intoxication|journal=Neurochemistry International|volume=125|year=2019|pages=117–126|issn=0197-0186|doi=10.1016/j.neuint.2019.02.006|pmid=30779928|s2cid=72334402}}

A 2017 review states, "because nicotine targets the fetal brain, damage can be present, even when birth weight is normal." A 2014 US Surgeon General report found "that nicotine adversely affects maternal and fetal health during pregnancy, and that exposure to nicotine during fetal development has lasting adverse consequences for brain development."{{cite journal|last1=Brandon|first1=T. H.|last2=Goniewicz|first2=M. L.|last3=Hanna|first3=N. H.|last4=Hatsukami|first4=D. K.|last5=Herbst|first5=R. S.|last6=Hobin|first6=J. A.|last7=Ostroff|first7=J. S.|last8=Shields|first8=P. G.|last9=Toll|first9=B. A.|last10=Tyne|first10=C. A.|last11=Viswanath|first11=K.|last12=Warren|first12=G. W.|title=Electronic Nicotine Delivery Systems: A Policy Statement from the American Association for Cancer Research and the American Society of Clinical Oncology|journal=Clinical Cancer Research|url=http://clincancerres.aacrjournals.org/content/early/2015/01/08/1078-0432.CCR-14-2544.full.pdf+html|year=2015|issn=1078-0432|volume=21|issue=3|pages=514–525|doi=10.1158/1078-0432.CCR-14-2544|pmid=25573384|s2cid=34471339|doi-access=free|url-access=subscription}} Nicotine prenatal exposure is associated with behavioral abnormalities in adults and children.{{cite journal|last1=Kohlmeier|first1=K. A.|title=Nicotine during pregnancy: changes induced in neurotransmission, which could heighten proclivity to addict and induce maladaptive control of attention|journal=Journal of Developmental Origins of Health and Disease|volume=6|issue=3|year=2015|pages=169–181|issn=2040-1744|doi=10.1017/S2040174414000531|pmid=25385318|s2cid=29298949}} Prenatal nicotine exposure may result in persisting, multigenerational changes in the epigenome.{{cite journal|last1=Yuan|first1=Menglu|last2=Cross|first2=Sarah J.|last3=Loughlin|first3=Sandra E.|last4=Leslie|first4=Frances M.|title=Nicotine and the adolescent brain|journal=The Journal of Physiology|volume=593|issue=16|year=2015|pages=3397–3412|issn=0022-3751|doi=10.1113/JP270492|pmc=4560573|pmid=26018031}}

File:Electronic Cigarettes, What is the bottom line CDC (nicotine effects no numeral).svg|date=22 February 2018}}|alt=Health effects of using e-cigarettes.]]

E-liquid exposure whether intentional or unintentional from ingestion, eye contact, or skin contact can cause adverse effects such as seizures and anoxic brain trauma.{{sfn|Stratton|2018|p=Summary, Conclusion 14-2.; 9}} The nicotine in e-liquids readily absorbs into the bloodstream when a person uses an e-cigarette. Upon entering the blood, nicotine stimulates the adrenal glands to release the hormone epinephrine. Epinephrine stimulates the central nervous system and increases blood pressure, breathing, and heart rate.

As with most addictive substances, nicotine increases levels of a chemical messenger in the brain called dopamine, which affects parts of the brain that control reward (pleasure from natural behaviors such as eating). These feelings motivate some people to use nicotine again and again, despite possible risks to their health and well-being.{{cite web|url=https://www.drugabuse.gov/publications/drugfacts/electronic-cigarettes-e-cigarettes|title=Electronic Cigarettes (E-cigarettes)|publisher=National Institute on Drug Abuse|date=March 2018}}{{PD-notice}}

A 2015 study on the offspring of the pregnant mice, which were exposed to nicotine-containing e-liquid, showed significant behavioral alterations. This indicated that exposure to e-cigarette components in a susceptible time period of brain development could induce persistent behavioral changes.{{cite journal|last1=Hiemstra|first1=Pieter S.|last2=Bals|first2=Robert|title=Basic science of electronic cigarettes: assessment in cell culture and in vivo models|journal=Respiratory Research|volume=17|issue=1|page=127|year=2016|issn=1465-993X|doi=10.1186/s12931-016-0447-z|pmid=27717371|pmc=5055681 |doi-access=free }}{{CC-notice|cc=by4|url=https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-016-0447-z|author(s)=Pieter S. Hiemstra and Robert Bals}} E-cigarette aerosols without containing nicotine could harm the growing conceptus. This indicates that the ingredients in the e-liquid, such as the flavors, could be developmental toxicants.{{cite journal|last1=Greene|first1=Robert M.|last2=Pisano|first2=M. Michele|title=Developmental toxicity of e-cigarette aerosols|journal=Birth Defects Research|volume=111|issue=17|pages=1294–1301|year=2019|issn=2472-1727|doi=10.1002/bdr2.1571|pmid=31400084|s2cid=199518879}}

File:Robbing the Future.webm|alt=Robbing the Future explores the various ways the tobacco industry targets young people, the growing popularity of emerging products, such as e-cigarettes, and the dangers associated with those products.|Robbing the Future - Advertising Aimed at Children.

File:2017 Beyond the Data - E-cigarettes- An Emerging Public Health Challenge.webm|alt=E-cigarettes - An Emerging Public Health Challenge.|E-cigarettes - An Emerging Public Health Challenge.

File:Tobacco Use By Youth Is Rising – February 2019 – Vital Signs.webm|alt=2019 Centers for Disease Control and Prevention video titled: Tobacco Use By Youth Is Rising – February 2019 – Vital Signs.|Tobacco Use By Youth Is Rising – February 2019 – Vital Signs.

File:Nicotine & Vaping - Don't Get Hacked - The Real Cost.webm|alt=Nicotine & Vaping - Don't Get Hacked - The Real Cost.|Nicotine & Vaping - Don't Get Hacked - The Real Cost.

File:Girl Reacts to Julius Dein Doing Magic on A Vape - The Real Cost.webm|alt=Julius Dein Doing A Magic Trick on A Vape - The Real Cost.|Julius Dein Doing A Magic Trick on A Vape - The Real Cost.

{{reflist|group=notes}}

• {{cite web|last1=McNeill|first1=A|last2=Brose|first2=LS|last3=Calder|first3=R|last4=Bauld|first4=L|last5=Robson|first5=D|url=https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/684963/Evidence_review_of_e-cigarettes_and_heated_tobacco_products_2018.pdf|title=Evidence review of e-cigarettes and heated tobacco products 2018|location=UK|publisher=Public Health England|pages=1–243|date=February 2018|ref={{harvid|McNeill|2018}}}}
• {{cite book|last1=Stratton|first1=Kathleen|last2=Kwan|first2=Leslie Y.|last3=Eaton|first3=David L.|editor-first1=Kathleen |editor-first2=Leslie Y. |editor-first3=David L. |editor-last1=Stratton |editor-last2=Kwan |editor-last3=Eaton |url=https://www.nap.edu/resource/24952/012318ecigaretteHighlights.pdf|title=Public Health Consequences of E-Cigarettes|publisher=National Academies of Sciences, Engineering, and Medicine (National Academies Press)|pages=1–774|date=January 2018|doi=10.17226/24952|pmid=29894118|ref={{harvid|Stratton|2018}}|isbn=978-0-309-46834-3}}
• {{cite web|url=https://e-cigarettes.surgeongeneral.gov/documents/2016_SGR_Full_Report_non-508.pdf|title=E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General|publisher=United States Department of Health and Human Services|agency=Surgeon General of the United States|pages=1–298|year=2016|ref={{harvid|SGUS|2016}}}}{{PD-notice}}
• {{cite web|url=https://www.cdph.ca.gov/Programs/CCDPHP/DCDIC/CTCB/CDPH%20Document%20Library/Policy/ElectronicSmokingDevices/StateHealthEcigReport.pdf|title=State Health Officer's Report on E-Cigarettes: A Community Health Threat|publisher=California Tobacco Control Program|agency=California Department of Public Health|pages=1–21|date=January 2015|ref={{harvid|Chapman|2015}}}}{{PD-notice}}
• {{cite web|url=http://apps.who.int/gb/fctc/PDF/cop6/FCTC_COP6_10-en.pdf|title=Electronic nicotine delivery systems|publisher=World Health Organization|pages=1–13|date=21 July 2014|ref={{harvid|WHO|2014}}}}
• {{cite book|url=https://stacks.cdc.gov/view/cdc/21569/Share|title=The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General|publisher=Surgeon General of the United States|pmid=24455788|author1=National Center for Chronic Disease Prevention Health Promotion (US) Office on Smoking Health|pages=1–943|year=2014|ref={{harvid|SGUS|2014}}}}

{{reflist}}

{{Electronic cigarettes}}

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