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TECHNICAL REPORT

Nicotine and as Substances of Abuse in Children and Adolescents Lorena M. Siqueira, MD, MSPH, FAAP, FSAHM, COMMITTEE ON SUBSTANCE USE AND PREVENTION

Nicotine is the primary pharmacologic component of tobacco, and users abstract of tobacco products seek out its effects. The highly addictive nature of nicotine is responsible for its widespread use and diffi culty with quitting. This technical report focuses on nicotine and discusses the stages of use in progression to dependence on nicotine-containing products; the physiologic characteristics, neurobiology, metabolism, pharmacogenetics, and health effects of nicotine; and acute nicotine toxicity. Finally, some newer approaches to cessation are noted. This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have fi led confl ict of statements with the American Academy of Pediatrics. Any confl icts have been resolved through a process approved by the Board of Directors. The American Academy of INTRODUCTION Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.

Technical reports from the American Academy of Pediatrics benefi t Tobacco exposure, whether through personal use, second- or thirdhand from expertise and resources of liaisons and internal (AAP) and smoke exposure, or unintentional exposure, is the most important external reviewers. However, technical reports from the American Academy of Pediatrics may not refl ect the views of the liaisons or the preventable cause of illness, disability, and death among adults in the organizations or government agencies that they represent. 1 United States. Worldwide, tobacco use is also the leading cause of The guidance in this report does not indicate an exclusive course of preventable death. 2 Many preventive measures have increased the treatment or serve as a standard of medical care. Variations, taking perceived risk of , which, along with the decreased access to into account individual circumstances, may be appropriate. , has contributed to a gradual decline in use. However, the All technical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffi rmed, rate of decline has begun to slow for the use of cigarettes, and use revised, or retired at or before that time. has increased significantly for nicotine products such as and DOI: 10.1542/peds.2016-3436 electronic nicotine delivery systems as well as for smokeless tobacco. As PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). reported by the Centers for Disease Control and Prevention, 2 e- experimentation and recent use among US middle and high school Copyright © 2017 by the American Academy of Pediatrics students doubled from 2011 to 2012 and has increased significantly FINANCIAL DISCLOSURE: The author has indicated she does not have a fi nancial relationship relevant to this article to disclose. since then. It is now estimated that 1.78 million students have ever used e-cigarettes. Of these, 9% (an estimated 160 000 students) have FUNDING: No external funding. never used conventional cigarettes. The Monitoring the Future Study POTENTIAL CONFLICT OF INTEREST: The author has indicated she has has also found that more teenagers report using electronic nicotine no potential confl icts of interest to disclose. delivery systems in the past 30 days than any other tobacco product. 3 Although these delivery systems may reduce exposure to some of the To cite: Siqueira LM and AAP COMMITTEE ON SUBSTANCE toxic chemicals in cigarettes, there are additional toxins associated with USE AND PREVENTION. Nicotine and Tobacco as Substances electronic nicotine delivery systems, and exposure to nicotine and its of Abuse in Children and Adolescents. Pediatrics. 2017; 139(1):e20163436 high potential remain major concerns.4

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 :e 20163436 FROM THE AMERICAN ACADEMY OF PEDIATRICS It is well known that tobacco 8% to 12% of the total alkaloid attitudes and beliefs about the utility products contain more than 4000 content of tobacco products. of tobacco and may then begin to different chemicals. 5 Their effects, experiment with a few cigarettes. A along with the sensory few will never use again, and some and the conditioning that develops CRITERIA FOR DEPENDENCE will smoke repeatedly but irregularly. with continued use, may contribute Both the World Health Organization, Traditional theoretical models to the addiction process, but nicotine in its International Classification explaining nicotine addiction is the major contributor to the 9 of Diseases, and the American maintain that, beyond the role development of dependence. It is the Psychiatric Association, in its of nicotine as a key component primary pharmacologic component Diagnostic and Statistical Manual of required for the development of of tobacco, and its effects are sought 10 Mental Disorders, Fifth Edition, have addiction, other behavioral, social, after by users. Its highly addictive issued diagnostic criteria to assess environmental, and psychological nature is responsible for the addiction. Currently, “substance use factors are also important for the widespread use and difficulty with disorder” is the preferred term and development and maintenance quitting. includes dependence and withdrawal of addiction. 15 These include the symptoms. Nicotine meets the attitude and behavior of friends established criteria for a that and family members toward HISTORICAL BACKGROUND produces the symptoms of addiction, smoking, an underestimation of the specifically, dependence, withdrawal, addictive potential of nicotine, and Nicotine was originally isolated and . an overestimation of the prevalence from the herbaceous plant Nicotiana First use of tobacco most often occurs of peer smoking. Users also report tabacum, a native of tropical and in young adolescents, and the earlier that smoking alleviates , subtropical America but now one begins, the less likely one is to be , and and that they, commercially cultivated worldwide. able to stop using tobacco products 11 therefore, use it as a stress reliever. The plant was named after the and the more likely use will continue Although some of these effects may diplomat Jean Nicot de Villemain, with greater quantities. 12 It has be related to the pharmacologic who, in 1556, brought tobacco seeds been estimated that two-thirds of response along with the relief of and leaves as a “ drug” to the children who smoke in sixth grade withdrawal symptoms at times of French court from Brazil. 6 Nicotine become regular adult smokers , the belief that is a potent parasympathomimetic and almost half (46%) of smokers they are coping better with stress is a alkaloid and is now known to occur in the 11th grade become regular psychological effect that may lead to in the nightshade family of plants adult smokers. 13 Even infrequent further use to control mood. Frequent (Solanaceae). It is also present experimentation with smoking dosing of nicotine is associated with in minimal quantities in tomato, cigarettes can increase the risk of hand-to-mouth movement that potato, eggplant (aubergine), becoming a regular adult smoker; often becomes a social crutch that is green pepper, and cocoa leaves. 7 regular (defined as smoking at least difficult to do without after quitting. Nicotine is produced in the roots monthly) smoking by an adolescent Other rituals associated with a and accumulates in the leaves of has been found to increase the risk of particular device used may contribute the tobacco plant, with the amount becoming an adult regular smoker by to continued use. Smoking also varying with position: that is, leaves 16 times compared with nonsmoking becomes connected to specific times, harvested from higher stalk positions adolescents. 13 Of tobacco-dependent experiences, and events, referred to contain more nicotine than those adults, 90% started smoking before as cues, and these become reinforcing from lower positions. Flue curing 18 years of age and 99% started of use over time. Light or intermittent of the leaves changes the pH so that smoking before 26 years of age.14 smokers may be more influenced by the smoke of the leaves is better these associated activities, such as inhaled and, as a result, both more A number of researchers have after eating or drinking , than addictive and more toxic. Leaves studied the development of nicotine the need to use tobacco to relieve are usually combined so that, on addiction in adolescents. Even before withdrawal symptoms. 16 average, cigarettes (in any of 15 any experimentation, adolescents’ different cigarette brands) contain exposure to advertising and the More recently, a newer model, the approximately 1.5% nicotine by marketing of the range of tobacco sensitization-homeostasis model, weight. 8 Burning tobacco releases the products available can influence their has been proposed as an alternative nicotine, which is carried proximally attitudes about the risks and benefits model, and a number of studies have on tar droplets and in the vapor when of tobacco use. This initial preparatory supported this model to explain the inhaled. Other alkaloids constitute stage is when individuals develop development of nicotine addiction in

Downloaded from www.aappublications.org/news by guest on September 30, 2021 e2 FROM THE AMERICAN ACADEMY OF PEDIATRICS adolescents. 17 This model suggests not rapidly cross membranes in an characteristics: that is, the depth of that, for adolescents, even infrequent acidic environment when it is in the puff and the frequency. Smokers smoking, such as at monthly an ionized form. The predominant typically take 10 puffs within the intervals, is enough to put the form of tobacco in American span of 5 minutes and absorb 1 to individual at risk of dependence. 18, 19 cigarettes is flue cured. The initial 2 mg of nicotine (range: 0.5–3 mg). 24 With nondaily smoking, even after puffs from these cigarettes have The elimination half-life of nicotine is the first cigarette, early symptoms an acidic pH resulting in almost 2 to 3 hours, meaning that the level of dependence, such as wanting to completely ionized nicotine that of nicotine in the blood decreases smoke or craving a cigarette, can has little if any absorption across by one-half after a smoker stops develop if adolescents go too long the buccal membranes. Air-cured smoking for that length of time. This without a cigarette. 20 One study has tobacco, the predominant form in elimination half-life will decrease shown that monthly smoking can pipes, , and a few European with repeated exposures to nicotine. increase the likelihood of developing cigarettes, is alkaline. The released dependence by 10-fold.21 These nicotine is largely nonionized and researchers also found that there is thus well absorbed through the INCREASING PALATABILITY a reciprocal relationship between mouth. , , and Several additives are used in the diminished autonomy about smoking nicotine polacrilex gum are also of manufacture of cigarettes to reduce and the frequency of smoking. They alkaline pH, facilitating absorption the harshness of the smoke. 25 suggest that the urge to smoke occurs through the oral mucous membranes. Menthol is an additive that is actively early on after initiation and that Nicotine can be absorbed through promoted by the this, in turn, drives the teenager to the skin, and toxicity has been for its perceived sensory benefits. increase the frequency of smoking, documented in tobacco field-workers A large number of young people which increases the risk of further and those with skin contact with and occasional users of cigarettes dependence symptoms, such as pesticides containing nicotine. In use menthol cigarettes because it a need to smoke. With increased the lungs, the large surface area helps reduce harshness. The specific frequency, the adolescent is more provided by the small airways candylike taste of menthol and its likely to experience a more rapid and the alveoli as well as the local cooling, , and progression to addiction and the physiologic (slightly alkaline) pH of properties make it appealing to these need for daily smoking, such as one 7.4 allow for the rapid absorption of smokers.26 The sensory effects of would see in a dose-response effect. nicotine from cigarette smoke, where menthol serve as conditioned stimuli, it reaches the systemic circulation Researchers have also found that increasing the reinforcing effects without first passing through the symptoms of dependence develop of nicotine and thus the addiction liver. It is estimated to reach the in a predictable sequence, beginning potential of menthol cigarettes. As in as little as 7 seconds after with wanting to smoke, followed users become tolerant of this flavor, inhalation. 23 The rapid onset of by craving, and eventually needing some actively seek even stronger action with inhaled nicotine leads to smoke to avoid withdrawal or sensory attributes in a cigarette, to a greater “high” and reinforces abstinence symptoms, suggesting that and beginning with a menthol- use, which leads to neuroadaptation, the adolescent has neurophysiologic containing product may facilitate and continued use is related not dependence.22 Neurophysiologic an adolescent’s progression to daily only to the need to obtain may lead to tolerance, smoking. Smokers who prefer and but also to conditioning. Nicotine is with a diminished effect experienced choose menthol-containing products poorly absorbed from the stomach with continued use, resulting in tend to be disproportionately black because of the acidic pH but well an increased amount of nicotine and male. 25 The perceived reduction absorbed from the small intestine. needed to maintain equilibrium. This in harshness may result in the intake Reabsorption from the intestine neuroadaptation within the brain may of more cigarettes, and therefore may be a potential source for explain why teenagers report the need more toxic and dependence-causing enterohepatic circulation. for nicotine to function normally. substances, increasing the difficulty in quitting cigarette use. 27 The The dose of nicotine delivered perceived reduced harshness also PHYSIOLOGIC CHARACTERISTICS: cannot be determined solely by contributes to the perception that FORMULATIONS, PREPARATIONS, AND the nicotine content of the product cigarettes are less harmful than they ABSORPTION because of these complexities. In actually are. Nicotine is a weak base, and its addition, when smoking cigarettes, absorption across biological the actual amount of any alkaloid Similarly, other products have membranes is pH dependent. It does delivered depends on the puffing additives that increase their

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 e3 palatability. The tobacco used in subunits is helping researchers of nicotine may result from the hookahs (shisha, maassel, tumbak, develop antismoking . interactions of these various or jurak) is moist and shredded. It In the brain, the most widely . Nicotine is mixed with sweeteners such as expressed nAChR is the α4, β2 receptors in the CNS are located honey, molasses, or fruit, and many subunit, which has a central function mainly in presynaptic membrane, have candy or fruit flavoring added. in the mediation of the physiologic and in that way, they regulate the Bidis, hand-rolled, thin, filterless effects of nicotine. With repeated release of several neurotransmitters. cigarettes, are sold unflavored or exposure, there is an increase in the Nicotine increases concentrations flavored (eg, with vanilla, strawberry, number of nAChRs. This upregulation of , a or mango). Kreteks, clove-flavored is believed to be the response to essential for boosting , cigarettes, have a particularly nicotine-mediated desensitization reward-seeking behaviors, and the pungent smell. Kreteks, used in of the receptors and may a role risk of various , from Indonesia, contain eugenol, which in the development of dependence. gambling to drug use. 30 Dopamine has an anesthetic effect, allowing for Overnight, when these receptors is released in the mesolimbic deeper inhalation. Chewing tobacco become unoccupied, it has been system, the corpus , and is used all over the world; and in suggested that they recover to a frontal cortex and is critical for 1 form used in India, referred to responsive state, which creates the the drug-induced reward effect. as pan masala, areca nuts, slaked craving and withdrawal symptoms Nicotine receptors in the striatum, lime, and other flavoring agents and experienced by many in the morning. where movements are planned and sweeteners are added. Electronic controlled, are located near the Functional imaging studies of the nicotine delivery systems also have terminals that regulate and emit brain have detected differences in >7760 unique flavors, including fruit, dopamine. In animal studies, even brain structure between smokers candy, and dessert flavors, raising a small dose of nicotine stimulates and nonsmokers. Smokers have concerns about the strong appeal of the release of dopamine in the been found to have differences in all these products to children. 28 striatum, stopping movements that the microstructural order in white otherwise would go uncontrolled. matter areas of the brain, specifically This finding has led to research the anterior cingulate bundle. 29 MECHANISM OF ACTION: examining the role of nicotine in the Studies also have found that smokers NEUROBIOLOGY prevention and treatment of a variety reporting more subjective symptoms Nicotine acts on nicotinic of neurologic disorders, including of dependence, by using standardized receptors (nAChRs) Parkinson disease, mild cognitive measures, had a decreased density of in the peripheral nervous system impairment, Tourette syndrome, neural connections, or streamlines, (autonomic ganglia and adrenal schizophrenia, and attention-deficit/ between the anterior cingulate medulla; neuromuscular junction) hyperactivity disorder. The available bundle and the precuneus and and the central nervous system research suggests that youth with increased connections between the (CNS). The nAChRs are ligand-gated mental illness are at increased risk anterior cingulate bundle and the ion channels made up of 5 subunits of tobacco use. 31 The direction of superior-frontal cortex. These areas that assemble around an ion pore. causation remains unclear. of the brain and specific circuits When nicotine or acetylcholine binds, are those correlated with memory, a change occurs in their conformation Epidemiologic studies have motivation, executive function, that renders the ion pore permeable contributed to the development of and mood. These studies support to cations, which, in turn, excite the gateway drug model that suggest the connection between subjective the cell. There are 12 isoforms, 9 that previous use of the legal symptoms of nicotine dependence α-subunits labeled from α2 to α10 tobacco and alcohol increases the and white matter structure and and 3 β-subunits labeled from β2 vulnerability to the subsequent use suggest that nicotine dependence to β4. The mix of these subunits in of illicit drugs. Studies indicate that over time can result in neuroplastic each receptor gives the receptor its ethanol potentiates the response changes in a number of brain distinct pharmacologic properties of high-affinity nAChRs to both systems. and its response to nicotine acetylcholine and nicotine. 32 Even stimulation. The activation of some In addition, various small amounts of alcohol are receptors promotes the reinforcing neurotransmitters are involved, known to boost nicotine effects, effects, whereas the activation of including acetylcholine, dopamine, inducing subjects to smoke more. others limits and noradrenaline, , glutamate, A recent study in a mouse model possibly mediates the aversive , and γ-aminobutyric acid; examining the effects of nicotine effects. An understanding of these and the overall physiologic effect on abuse has provided a

Downloaded from www.aappublications.org/news by guest on September 30, 2021 e4 FROM THE AMERICAN ACADEMY OF PEDIATRICS biological mechanism to support utility of nicotine and cotinine testing Drug Receptor Genotypes the gateway theory by showing that is important for employers. Although Each of the nAChRs is encoded nicotine increases the expression not commonly tested for, cotinine for by a single CHRN gene. Large of the FosB gene (which has been can also be used for screening genomewide association study related to addiction) and increases adolescents who use these products meta-analyses have brought to light the vulnerability to cocaine or those who are exposed to SHS. the variations in the nAChR subunit 33 dependence. This finding suggests Cotinine can be measured in serum, genes that make the strongest that the prevention and cessation of urine, saliva, and hair. Nonsmokers genetic contribution to smoking- nicotine use may decrease the future exposed to typical levels of SHS have related habits. 40 The gene locus risk of addiction to illicit drugs. serum cotinine concentrations less on chromosome 15q25.1 contains than 1 ng/mL. People with heavy a dense set of highly correlated exposure to SHS have serum cotinine single nucleotide polymorphisms, NICOTINE METABOLISM concentrations in the range of 1 to in the CHRNA5-CHRNA3-CHRNB4 10 ng/mL, whereas active smokers Nicotine is mainly metabolized gene cluster. 41 These may influence almost always have serum cotinine by the liver (85%–90%), and the the age of initiation, the amount concentrations higher than metabolites are then excreted smoked, the development of nicotine 10 ng/mL and occasionally higher through the kidneys. Only 10% of dependence, and adverse effects than 500 ng/mL. 36 nicotine is excreted unchanged. such as lung cancer and chronic Nicotine metabolism involves a obstructive pulmonary disease. 2-step process mediated by the PHARMACOGENETICS OF NICOTINE These associations appear to be more important in early-onset smokers, cytochrome P450 system, mainly by The variation in nicotine response suggesting an age-associated the hepatic enzymes CYP2A6 and can be understood to be the result relationship. In addition to smoking CYP2B6. The first step produces of the interaction between drug quantity and nicotine dependence, the metabolite cotinine, which metabolism and drug receptor variants in nAChR genes have also is then converted to multiple genotypes. 37 This variation in been associated with alcohol and products, the most abundant being response is still an area of active ′ other substance dependencies as 3 -hydroxycotinine. The ratio of investigation, and new data are ′ well as with a predisposition to 3 -hydroxycotinine to cotinine adding to our understanding. is a reflection of in vivo nicotine schizophrenia.41, 42 clearance and is referred to as the Drug Metabolism nicotine metabolic rate. Some data Genetic variation in the CYP2A6 NICOTINE METABOLISM AND RACE, from patients with chronic kidney gene can increase or decrease SEX, AND AGE disease indicate that the excretion of this enzyme’s activity through The rate of nicotine metabolism cotinine is minimally affected. 34 altering the protein’s expression has been found to vary by sex Cotinine has a long half-life (18–20 level or its structure and function and race, which may influence hours), and on average, it takes and thus nicotine metabolism. susceptibility to addiction and ability approximately 72 hours to eliminate Multiple alleles of the CYP2A6 to quit. Differences in the CYP2A6 90% of the cotinine. 35 Although enzyme have been identified allele frequencies may underlie this long half-life makes it difficult (www. cypalleles. ki. se/ cyp2a6. this variability across sexes and to assess the most recent cigarette htm), including single nucleotide ethnic groups. Up to 90% of white intake/smoking pattern, cotinine’s polymorphisms, duplications, smokers are fast metabolizers. Latino concentration in the urine correlates deletions, and conversions, which smokers have rates of metabolism well with blood concentration. The have allowed for grouping people similar to white smokers. African- measurement of urinary cotinine into slow, intermediate, and American smokers are more likely concentration is a useful method normal metabolizers. 38 People to be slow metabolizers, and Asian to distinguish smokers from who carry reduced or null activity smokers have the slowest nicotine nonsmokers and is a marker for CYP2A6 alleles are more likely to metabolic rates. 36 On average, long-term nicotine intake, although be nonsmokers or smoke fewer slow metabolizers smoke fewer an increased urinary cotinine cigarettes per day, are less likely to cigarettes than fast metabolizers concentration can be observed in progress to nicotine dependence, and have higher quit rates, and people exposed to secondhand smoke and may have an easier time quitting the slower nicotine metabolism (SHS). Because employer-based smoking and have a lower risk of may account for their lower risk insurance is now affected by the use lung cancer. 39 The opposite is the of nicotine addiction in studies of tobacco, an understanding of the case for fast metabolizers. in African-American smokers. 43

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 e5 Women metabolize nicotine faster of the adverse health consequences The cardiovascular effects of than men, which may explain why of tobacco use are the result of nicotine are mainly the result of women have more difficulty in damage caused by tar, carbon stimulation of the sympathetic quitting. 44 It is important to use monoxide, oxidizing chemicals, and nervous system. In , nicotine caution in the clinical application other constituents in the product has a biphasic physiologic response. of these data to individual patients rather than nicotine. 14 Although In low concentrations, it acts as a because of heterogeneity and thus smoking affects almost every system by increasing adrenal limitations of how racial categories in the body, only some effects have catecholamines, but high doses of are defined in the literature and the been found to be directly related to nicotine have the opposite effect, unique diversity of use and addiction nicotine use. with hypotension and slowing of the trajectories of each patient. It is heart rate. 52 nAChRs are found not The data are insufficient to conclude anticipated that further research will only in neuronal and muscle cells but that nicotine causes cancer, but make individual-level assessments also in endothelial and immune cells. there is evidence that it may increase available in the future. Another factor Nicotine induces proliferation of the risk of oral, esophageal, and affecting nicotine metabolism is vascular smooth muscle cells and the pancreatic cancer. In women, the the use of hormonal contraception. migration of cells into blood vessels. intensity of current smoking has Studies indicate that these Nicotine also increases lipolysis, been noted to be an independent medications may accelerate cotinine resulting in the release of free fatty risk factor for high-grade cervical metabolism in women, probably by acids; over time, these effects cause intraepithelial neoplasia, after an estrogen induction of CYP2A6 an acceleration of coronary and controlling for cervical human that is independent of ethnicity and peripheral vascular disease as well as papillomavirus infection. 49 cigarette consumption. 45 an increase in the risk of strokes. In the adolescent years, recent As noted previously, nicotine studies have confirmed differences stimulates the release of various A relationship has been found in metabolic rate by race but not neurotransmitters in the CNS. between nicotine and inflammatory by sex. 46 However, the use of oral Nicotine users endorse a reduction bowel disease. Although smoking contraceptive pills, as in women, has in pain, anxiety, and other negative has a deleterious effect on those been found to accelerate nicotine emotional symptoms along with with Crohn disease, it protects those 53,54 metabolism in adolescent tobacco- positive of a mild , with ulcerative colitis. The risk dependent smokers. 47 Another study alertness, increased memory, and of developing ulcerative colitis is by the same authors assessed the rate learning. Nicotine also has many lower in smokers (odds ratio: 0.41; 50 of nicotine metabolism in adolescents neuroendocrine responses. 95% interval:, 0.34–0.48). by using the nicotine metabolic rate Although smokers say they smoke People who stop smoking and then as a reflection of the rate of clearance to control stress, studies show resume smoking experience clinical 54 of nicotine. Slow metabolizers, a significant increase in cortisol improvement. Many possible because they have nicotine present concentrations in daily smokers explanations have been proposed; for a longer time, are expected to compared with occasional smokers these include the effects of smoking 51 smoke less. However, the findings or nonsmokers. These findings on cellular and humoral immunity, were the opposite among slower suggest that, despite the subjective cytokines, eicosanoid-mediated metabolizers. They smoked more effects, smoking may actually worsen inflammation, antioxidant and cigarettes per day and had higher the negative emotional states. The free radicals, endogenous addiction scores. These authors effects of nicotine on the sleep-wake , colonic mucus, hypothesized that the of these cycle through nicotine receptors mucosal blood , thrombosis, gut 55 slower metabolizers are exposed may have a functional significance. permeability, and motility. Recent to greater amounts of nicotine for a Nicotine receptor stimulation research on microbiota changes with longer period of time, and therefore, promotes wake time and reduces smoking may also help explain the slower metabolizers may be more both total sleep time and rapid influence of smoking on inflammatory likely to develop addiction in early eye movement sleep. Dopamine bowel disease. Additional research on stages of smoking. 48 release in the CNS inhibits prolactin whether other chemicals in cigarettes secretion from the anterior pituitary. may also be involved in this process However, decreased concentrations is underway. However, no advantages HEALTH CONSEQUENCES OF EXPOSURE are only seen with long-term use, over standard therapy have been TO NICOTINE possibly because of desensitization advanced, and adverse effects of Although there are adverse health of the nAChRs. Acute nicotine use nicotine preclude a therapeutic effects attributable to nicotine, most increases prolactin secretion. recommendation.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 e6 FROM THE AMERICAN ACADEMY OF PEDIATRICS Recent studies indicate that the are complex and not completely diabetes, respiratory dysfunction, parasympathetic nervous system understood. The acute response neurobehavioral effects, and controls innate immune responses is suppression of appetite and an impaired fertility. 64 through the modulation of the increase in the metabolic rate, but Two key studies have documented production of multiple inflammatory chronic administration activates the developmental effects on cytokines. Acetylcholine, as the systems that increase appetite and offspring of women who smoked principal neurotransmitter for decrease metabolic rate. 60 Many cigarettes prenatally and support the parasympathetic nervous chronic smokers are overweight concerns that tobacco or nicotine system, has been shown to have and have the metabolic syndrome can have significant effects on early antiinflammatory effects mediated with increased visceral adiposity. neurodevelopment in humans.65, 66 through the nicotinic receptors However, the reduction in appetite These studies have found that infants on macrophages, inhibiting the and the weight control are important born to mothers who smoked during proinflammatory cytokines from effects that are more likely to appeal their pregnancies had reduced weight, these macrophages. 56 The finding of to younger females than males. 61 length, and head circumference but distinct nAChR subtypes expressed The increased appetite and weight also showed significant impairments on immune cells now suggests that gain that occur after stopping in cognitive functioning, impulsivity, this regulation is based on receptor smoking can serve as a deterrent hyperactivity, and increased risk of affinity; evidence has been found to smoking cessation for women. 62 developing an addiction disorder. for a crucial role for an α7 nAChR Women who stop are also at greater These effects were seen throughout subtype in this process. risk of relapse to avoid the weight early childhood and persisted gain. Adequate pharmacotherapy of Clinical and experimental evidence through adolescence and into young tobacco dependence may decrease or indicates that nicotine is at adulthood. least partly responsible for the eliminate the weight gain associated progression of chronic kidney disease with stopping. One study found that The neurobiological systems that are in cigarette smokers. 57 Nicotine also soon after abstinence from tobacco related to these behavioral problems exacerbates acute kidney injury by smoking, an increase in the plasma are found in the dopamine, various mechanisms. 58 concentration of the appetite- , and stimulating peptide acetylated systems in the amygdala and striatal The bone marrow is innervated ghrelin occurs. 63 This finding could regions of the brain and are important by cholinergic nerve fibers and explain the increased food craving for the regulation of processes macrophages, and other cytokine- during and relevant to the behaviors noted α producing cells express the 7 subsequent weight gain. previously.67 Numerous studies that receptor and are functionally used animal models have identified responsive to nicotine, which Nicotine has a negative dose-related the effects of both cigarette smoke or indicates a probable mechanism for impact on both male and female nicotine on brain development during control of inflammation. Similarly, fertility. In men, nicotine affects both fetal development, such as altered microglial cells represent the largest gametogenesis and steroidogenesis. expression of nicotinic acetylcholine class of phagocytes in the CNS and Nicotine also impairs nitric oxide receptors in critical brainstem areas are regulated by acetylcholine. The synthesis, leading to erectile involved in autonomic function and activation of these microglia can be dysfunction. Although cigarette altered excitability of neurons in neurotoxic or neuroprotective and smoking has been associated with brainstem areas involved in sensory thus are important in CNS pathology. decreased fertility rates, adverse integration. 68, 69 Functional correlates Several nicotinic specifically pregnancy outcomes, and higher of nicotine exposure include α targeting the 7 nAChR have been risk of in vitro fertilization failure, hypoventilation and apnea, as well as developed and are being studied the precise role of nicotine is still blunted chemoreflexes in response to for the treatment of neurologic, being evaluated both for the woman hypoxia. 70– 72 inflammatory, and infectious and for the fetus. The short-term diseases. Long-term exposure safety of nicotine replacement Studies in human fetal subjects who to nicotine increases the risk of therapy during pregnancy has been have been exposed to nicotine have osteoporosis and bone fractures evaluated in a limited number of provided a better understanding by creating an imbalance in bone studies, but long-term effects on of the molecular mechanisms remodeling through nicotine’s effects the fetus warrant further studies. underlying the developmental 59 on osteoclasts and osteoblasts. Animal studies suggest that there behaviors seen with prenatal nicotine Nicotine also has an effect on body may be an increased incidence exposure. For example, researchers weight through mechanisms that of obesity, hypertension, type 2 have found that prenatal cigarette

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 e7 exposure is associated with a tobacco, pipe tobacco, has been estimated to be lethal for decrease in the expression of the and patches, and some insecticides. 50% of adults is between 0.8 and genes related to the endogenous Most such incidents occur in children 13.0 mg/kg. 83 It has been estimated opioid system in areas of the younger than 6 years, and the that 1 teaspoon (5 mL) of a 1.8% brain, the , that frequency and severity of outcomes nicotine solution could be lethal to have been implicated in behavior are generally benign because of the a 90-kg person. 84 The ingestion of a 73 79,80 motivation and mood regulation. ensuing emesis. Recently, the few drops of concentrated solution Prenatal tobacco exposure also newer electronic nicotine delivery is enough to cause severe symptoms alters both nicotinic and muscarinic systems with refillable cartridges that in young children. 85 For example, receptors of the cholinergic systems contain liquid nicotine have become the ingestion of 1 to 2 drops of a in the brainstem and cerebellar a source of accidental exposure to 3.6% solution (1.8–3.6 mg) will put regions.67 Nicotinic acetylcholine a concentrated nicotine solution. most children younger than 5 years receptors are strongly associated The Centers for Disease Control and in this category. With the use of a with serotonergic (5-HT receptors) Prevention has reported a marked midrange of this lethal dose (6 mg/ in the brainstem during fetal increase in e-cigarette liquid-related kg), the ingestion of 0.5 teaspoon development, and abnormalities of calls to poison control centers, from 1 (or 2 mL) of a concentrated nicotine serotonergic neurotransmission in per month (September 2010) to 215 the brainstem have been consistent per month (February 2014). More solution could even be lethal to an 4 with neuropathologic findings in than half (51.1%) of calls involved average 12-kg, 20-month-old child. cases of sudden unexpected and children younger than 5 years. 81 Thus, children who have ingested ≥ unexplained death in infancy. 74, 75 A death of a child who ingested the 0.2 mg/kg of nicotine would be In first-trimester human fetuses, concentrated nicotine solution used expected to be symptomatic and abnormal nicotinic receptor subunit with electronic nicotine delivery will need medical assessment. The levels have also been detected in the systems was reported recently. 82 refill liquids also contain unknown brainstem regions associated with concentrations of oil of wintergreen Early symptoms of nicotine ingestion sudden infant death syndrome.76 (methyl salicylate), glycerin, and include a burning sensation in the Dysfunction of these brainstem propylene glycol, which could mouth and throat, nausea, vomiting, regions, which can be associated also cause multiple toxidromes, , dizziness, weakness, and with sudden infant death syndrome, including salicylism and cholinergic drooling from increased salivation. is strongly associated with maternal 86 The risk posed by nicotine Signs include tachycardia, tachypnea, crisis. cigarette use during pregnancy, hypertension, and agitation followed liquid to children is an important and the alterations that are seen by bradycardia, hypotension, and anticipatory guidance topic to with gene expression in these respiratory depression. Severe discuss with parents and caregivers. cholinergic receptor subunits may poisoning leads to arrhythmias, Preventive measures to reduce toxic be a contributing factor to the coma, convulsions, and cardiac arrest. ingestions include public education brainstem abnormalities seen in Skin or eye contact with concentrated and legislation to improve the safety these infants. 77 These molecular liquid may cause irritation followed profile of electronic nicotine delivery alterations in gene expression as a by variable absorption. Systemic system containers through limited result of prenatal nicotine exposure signs or symptoms may follow. The volumes in available containers and may be explained by epigenetic lethal dose of nicotine has been child-proof packaging. mechanisms, which is currently an estimated to be as little as 50 to area of active research. 67 The reader 60 mg in adults, although this is referred to the American Academy of Pediatrics’ technical report “SIDS number is disputed. The lethal CESSATION dose in children is probably much and Other Sleep-Related Infant Although nearly half of adult Deaths: Evidence Base for 2016 lower, between 1 and 13 mg/kg, and smokers attempt to stop each Updated Recommendations for a severe toxic reactions have been year, <5% succeed because of Safe Infant Sleeping Environment” reported in children with doses as nicotine’s highly addictive nature. 14 for a comprehensive review on this low as 2 mg. Nicotine liquid refills Youth also attempt to quit, and subject. 78 are available in various strengths those with greater evidence of ranging from 6 (0.6%) to 36 (3.6%) dependence are more likely to mg/mL. Assuming there are 20 drops have difficulty stopping. They make ACUTE TOXICITY in 1 mL of solution, 1 drop of 3.6% more quit attempts before being Children can ingest nicotine from nicotine liquid will contain 1.8 mg successful compared with adults. the tobacco in cigarettes, chewing nicotine. The dose of nicotine that Approximately 4% of adolescent

Downloaded from www.aappublications.org/news by guest on September 30, 2021 e8 FROM THE AMERICAN ACADEMY OF PEDIATRICS smokers 12 to 19 years of age Further research is needed to factors also contribute to this successfully quit smoking each evaluate the use of these medications process. Most of the research on year. 87 Starting smoking at a younger in youth at various stages of use to tobacco-dependence treatment age is associated with more severe better define the risks, benefits, and of adolescents has focused on addiction and decreased rates of optimal treatment strategies and to behaviorally based interventions. stopping smoking. 88 inform optimal patient selection for These interventions are most Tobacco-dependence the various pharmacotherapies. effective for those with mild pharmacotherapy has been clearly E-cigarettes have been aggressively degrees of nicotine dependence shown to be safe and effective for promoted as smoking cessation aids, and least effective (although adults and improves cessation rates. but research studies have not been still of some benefit) for those 97 Current US Service able to document their effectiveness with severe dependence. Data guidelines recommend that all in adults. Recent research suggests are limited to support any 1 adults who smoke should be offered that the use of e-cigarettes may clinical approach to adolescent pharmacotherapy for tobacco- encourage, rather than discourage, cessation of nicotine use. Effective dependence treatment. 89 The current the use of conventional cigarettes behaviorally based strategies have US Food and Drug Administration– among US adolescents. 92, 93 focused on problem-solving skills approved tobacco-dependence and on providing support and A new approach to aid in encouragement. 89 The US Public treatment medications include the tobacco cessation is the use of an shorter-acting nicotine polacrilex Health Service recommends the antiaddiction that will 98 gum (over the counter [OTC]), following counseling modalities : induce antibodies that block the cognitive-behavioral strategies (OTC), nicotine nasal 94 pharmacologic effects of nicotine. (self-monitoring and coping skills), spray (by prescription), and nicotine Nicotine is nonimmunogenic and oral inhaler (by prescription). motivational strategies (techniques must be conjugated as a hapten to to clarify for change and These shorter-acting medications a protein carrier. The premise is can be considered as “relievers,” reduce toward change), that the antibody will attach to the and social influence strategies although their onset of action is nicotine molecule and prevent it from much longer than that of cigarettes. (addressing social influences that diffusing through the capillaries. It is serve to promote or maintain Long-acting medications include then less likely to enter the brain and the (OTC), smoking). Dependence treatment bind to the nAChRs. Although this is not the focus of this technical (by prescription), and approach has shown considerable (by prescription). These can be report, and the reader is referred promise in animal models, the to the previously mentioned 2015 considered as controller medications. research on its efficacy in humans Current approaches to tobacco- policy statement from the American thus far is limited. The serum Academy of Pediatrics. 91 dependence pharmacotherapy nicotine-specific antibody titers initiate medications on the basis of induced by the vaccine vary greatly. 95 severity of addiction and, on follow– This variability means that a CONCLUSIONS up, adjusts medications depending on substantial number of nonresponders 90 Nicotine is the chemical in of nicotine withdrawal. have low antibody titers that are not products that has a major role in the likely to be effective. Currently, the As discussed in the 2015 policy development of dependence. The evidence does not show success with statement from the American rapidly developing brains of children long-term smoking cessation with Academy of Pediatrics, “Clinical and adolescents are particularly currently available . 96 Newer Practice Policy to Protect Children susceptible to nicotine addiction. vaccines are now being designed From Tobacco, Nicotine, and Tobacco Given the difficulty adolescents have to enhance the mean antibody Smoke,” 91 pharmacotherapy can with stopping tobacco use, the need titer and to reduce the number be considered to help moderately for the prevention of tobacco use of nonresponders. There are no to severely tobacco-dependent initiation is high. adolescents who want to stop, vaccines currently licensed for use in any country. despite challenges with adherence LEAD AUTHOR and the resulting high relapse rates. As noted previously, whereas Lorena M. Siqueira, MD, MSPH, FAAP A possible concern for nicotine- nicotine is the key component of replacement therapy use during tobacco products required for the COMMITTEE ON SUBSTANCE USE AND adolescence, when smoking often development and maintenance PREVENTION, 2015–2016 begins, is that nicotine can change of addiction, behavioral, social, Sheryl A. Ryan, MD, FAAP, Chairperson the neurodevelopmental trajectory. environmental, and psychological Pamela K. Gonzalez, MD, FAAP

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 e9 Stephen W. Patrick, MD, MPH, MS, FAAP Washington, DC: US Department of National Center for Chronic Disease Joanna Quigley MD, FAAP Health and Human Services, Public Prevention and Health Promotion, Leslie R. Walker, MD, FAAP Health Service, Offi ce of Smoking Offi ce on Smoking and Health; 2014 and Health; 1983. DHHS Publication FORMER COMMITTEE MEMBERS 15. Tyas SL, Pederson LL. Psychosocial PHS-84-50204 factors related to adolescent smoking: Sharon Levy, MD, MPH, FAAP 6. Bristow LR. Tobacco, history, and the a critical review of the literature. Tob Lorena Siqueira, MD, MSPH, FAAP Control. 1998;7(4):409–420 Vincent C. Smith, MD, MPH, FAAP AMA. Lancet. 1995;346(8976):704–705 7. Siegmund B, Leitner E, Pfannhauser 16. Shiffman S, Paty J. Smoking patterns LIAISONS W. Determination of the nicotine and dependence: contrasting chippers Vivian B. Faden, PhD – National Institute of Alcohol content of various edible nightshades and heavy smokers. J Abnorm Psychol. Abuse and (Solanaceae) and their products and 2006;115(3):509–523 Gregory Tau, MD, PhD – American Academy of estimation of the associated dietary 17. DiFranza JR, Wellman RJ. A Child and Adolescent nicotine intake. J Agric Food Chem. sensitization-homeostasis model of 1999;47(8):3113–3120 STAFF nicotine craving, withdrawal, and 8. Benowitz NL, Hall SM, Herning RI, tolerance: integrating the clinical and Renee Jarrett, MPH Jacob P III, Jones RT, Osman AL. basic science literature. Nicotine Tob Smokers of low-yield cigarettes do not Res. 2005;7(1):9–26 ABBREVIATIONS consume less nicotine. N Engl J Med. 18. DiFranza JR, Savageau JA, Rigotti NA, 1983;309(3):139–142 CNS: central nervous system et al. Development of symptoms of tobacco dependence in youths: 30 nAChR: nicotinic acetylcholine 9. World Health Organization. International Classifi cation of Diseases. 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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2016/12/15/peds.2 016-3436 References This article cites 82 articles, 13 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2016/12/15/peds.2 016-3436#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Substance Use http://www.aappublications.org/cgi/collection/substance_abuse_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Nicotine and Tobacco as Substances of Abuse in Children and Adolescents Lorena M. Siqueira and COMMITTEE ON SUBSTANCE USE AND PREVENTION Pediatrics originally published online December 19, 2016;

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