- Email: [email protected]
Adverse Experience Reports of Seizures in Youth and Young Adult Electronic Nicotine Delivery Systems Users
Journal of Adolescent Health 66 (2020) 15e17
www.jahonline.org Original article
Adverse Experience Reports of Seizures in Youth and Young Adult Electronic Nicotine Delivery Systems Users Lisa M. Faulcon, M.D. *, Susan Rudy, M.S.N., C.R.N.P., Jean Limpert, M.D., Baoguang Wang, M.D., Dr.P.H., and Iilun Murphy, M.D. Center for Tobacco Products, Food and Drug Administration, Beltsville, Maryland
Article history: Received September 4, 2019; Accepted October 2, 2019 Keywords: Seizures; Electronic nicotine delivery systems (ENDS); Nicotine
See Related Editorial and Commentary on pp.1, 10 A B S T R A C T
Purpose: Electronic nicotine delivery systems (ENDS) use poses significant and avoidable health risks to young people. Until recently, seizures were most often associated with cases of liquid nicotine ingestion. Methods: We examined 122 voluntary reports of seizures (n ¼ 114) and neurological symptoms (syncope, n ¼ 7; and tremor, n ¼ 1) in 123 ENDS users (one report contained information on two users) received by the Food and Drug Administration between December 1, 2010, and June 30, 2019. Results: The median age (interquartile range) of users was 20 years (17e27); 67% of reports were in youth and young adults aged 14e24 years. Fifty-one (41%) reported other underlying medical conditions, including previous history of anxiety (n ¼ 11), attention deficit hyperactivity disorder (n ¼ 7), seizure (n ¼ 6), and depression (n ¼ 5). Of the 79 reports with available information, 67 (85%) reported seizure occurred within 24 hours of last use; 49 (62%) reported seizure within 30 minutes. The potential impact of concomitant use of marijuana or cannabidiol oil could not be evaluated from the eight reports that mentioned concomitant use. Conclusions: Findings suggest an association between ENDS use and seizures. Additional information will help to clarify the relationship between ENDS use and seizures and to understand how product attributes such as nicotine content, formulation, quantity, and other ingredients or contaminants may contribute to seizures. It is important that health care providers ask about ENDS use when evaluating neurological symptoms and that users, parents, school personnel, and health care providers report adverse experiences involving tobacco products to Food and Drug Administration via the Safety Reporting Portal (www.safetyreporting.hhs.gov). Ó 2019 Society for Adolescent Health and Medicine. All rights reserved.
Conflicts of interest: The authors have no conflicts of interest to disclose. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Food and Drug Administration. * Address correspondence to: Lisa M. Faulcon, M.D., Center for Tobacco Products, Food and Drug Administration, Calverton Tower, 11785 Beltsville Drive, Beltsville, MD 20705. E-mail address: [email protected] (L.M. Faulcon). 1054-139X/Ó 2019 Society for Adolescent Health and Medicine. All rights reserved. https://doi.org/10.1016/j.jadohealth.2019.10.002
IMPLICATIONS AND CONTRIBUTION
This article provides novel information on the association between seizures and inhaled nicotine toxicity. Such information may inform our understanding of the potential health risks of ENDS, impact the design of future clinical studies, and support future regulation.
Electronic nicotine delivery systems (ENDS) are typically battery-powered devices that heat e-liquids and deliver aerosolized nicotine, flavorings, humectants, and other chemicals. Eliquids may contain high nicotine levels and are available in several flavors that may appeal to youth. ENDS use may result in exposure to toxic volatile organic compounds, heavy metals, and
16
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nicotine [1]. Since 2011, ENDS use among middle school and high school students has increased significantly; current (past 30 days) ENDS use increased from 1.5% in 2011 to 20.8% in 2018 for high school students and from .6% in 2011 to 4.9% in 2018 for middle school students [2]. The 2018 National Youth Tobacco Survey and the Monitoring the Future survey showed significant increases in ENDS use among middle school and high school students between 2017 and 2018 [2,3]. The adverse health effects of ENDS use are not well characterized. Recently, severe pulmonary illness associated with the use of ENDS has been reported [4,5]. Nicotine is addictive, and its acute toxic effects can include seizures [6]. Reports of Seizures in ENDS Users The Food and Drug Administration (FDA) Center for Tobacco Products has been receiving voluntary adverse experience (AE) reports (i.e., health or product problems) about tobacco products since its inception in 2009. Since 2014, Center for Tobacco Products has collected AE reports via Web-based tobacco questionnaires on the Health and Human Services Safety Reporting Portal. In April 2019, FDA issued a Special Announcement alerting the public of reports received by the FDA and the American Association of Poison Control Centers of seizures in some ENDS users [7]. Between December 1, 2010, and June 30, 2019, FDA received 122 voluntary reports of seizures (n ¼ 114), syncope (n ¼ 8), and tremor (n ¼ 1) in 123 ENDS users (Supplementary Table 1) [8]. One report included information on two ENDS users who experienced seizures. One report was of an unexplained death from seizure in a 25-year-old female ENDS user with a known history of polyglandular autoimmune disease type II. The median age (interquartile range) was 20 years (17e27). Seizures were reported in both new users and experienced users, including eight reports of seizure after first use. Seizures occurred immediately after one puff, all-day use, and with use weeks before the event. Of the 79 reports with available information, 49 (62%) reported seizure within 30 minutes of last use. An additional five reported seizure within 2 hours of last use; overall, 67 (85%) reported seizure within 24 hours. Six users had a prior history of seizure. Fifty-one (41%) reported other underlying medical conditions, including previous history of anxiety (n ¼ 11), attention-deficit/ hyperactivity disorder (n ¼ 7), seizure (n ¼ 6), and depression (n ¼ 5). Fifty-three users reported repeat seizures with continued use of their ENDS product. Details on products, such as brand name, nicotine concentration, and quantity, were not provided in most reports. Review of reports containing product information did not identify product-specific trends; when product information was provided, JUUL, Suorin, SMOK, and Vuse brands were the most commonly named. Most of the reports involved youth and young adults (82/123; 67%) aged 14e24 years who were white (n ¼ 74/82; 88%) and males (n ¼ 54/82; 66%). Seizure (n ¼ 77), syncope (n ¼ 4), and tremor (n ¼ 1) were reported in this age group. Five youth/young adult users had a prior history of seizure. More than half of the youth and young adults (n ¼ 45) reported continued use of their ENDS product after the first seizure or neurological symptom, of which at least 73% (33/45) reported at least one additional seizure or repeat neurological symptom. Psychiatric disorders, such as depression, anxiety, and attention-deficit/hyperactivity
disorder, were the most commonly named comorbidities. In 43% (35/82) of youth and young adults, concurrent use of medications known to cause seizures (such as sertraline [n ¼ 7], escitalopram [n ¼ 6], bupropion [n ¼ 5], and lisdexamfetamine dimesylate [n ¼ 2]), alcohol, and/or marijuana was reported. Cannabidiol oil or marijuana was the most frequently reported additional substances used (8/11 reports with available information). Discussion Until the public's reports of seizures associated with ENDS use, seizures were most often associated with cases of liquid nicotine ingestion [9]. The reports summarized here to provide information on seizures involving intended use of ENDS (i.e., via inhalation). The predominance of seizures reported in youth and young adults may reflect the demographics of ENDS use. Given the proconvulsant effects of nicotine [10], it is possible that high nicotine content in ENDS products may lead to inhaled nicotine toxicity. Certain populations of ENDS users may be more prone to seizures, such as youth. ENDS use poses significant and avoidable health risks to young people [10]. The long-term clinical implications of seizures after ENDS use is unknown. ENDS use in youth is associated with conventional cigarette use [6]; this increases the risks of addiction and adverse health effects in users, given the potential long-term harm of cigarettes on brain development and known respiratory and cardiovascular health effects. Youth have demonstrated misperceptions about the potential adverse health effects of ecigarettes, reinforcing the need to increase awareness and education about the dangers of nicotine and ENDS use in youth [11]. The extent to which product design features, product constituents, and behavioral patterns of use play a role in the development of seizures in ENDS users is unclear. It is plausible that a rapid increase in plasma concentrations of nicotine resulting from inhalation of aerosol from nicotine-containing eliquids may play a role in seizures. Little is known about the inhalation toxicity of many e-liquid ingredients; chemical constituents other than nicotine may play a role in the development of seizures in ENDS users. Although some e-liquid flavorings may be “generally recognized as safe” for use in foods, this designation is not relevant to inhalation. Furthermore, ENDS devices may be used to deliver other substances, such as marijuana and Cannabidiol oils, which have been implicated in the development of pulmonary disease in ENDS users [5]. Research may inform the impact of nicotine formulations and other toxicants on the development of more severe nicotine toxicity symptoms, including seizures. Additional information will help in evaluating the association between seizures and ENDS use. Limitations of event reporting to date have precluded a determination of a causal relationship between the ENDS use and seizures or other neurological symptoms. Given the significant increase in ENDS use among youth and the emerging health concerns associated with ENDS use, it is important that health care providers ask about ENDS use [12], especially when evaluating neurological symptoms for which the etiology is unclear. Stakeholders, including users, parents, school personnel, and health care providers, are encouraged to report AEs involving tobacco products to FDA via the Safety Reporting Portal (www.safetyreporting.hhs.gov). To
L.M. Faulcon et al. / Journal of Adolescent Health 66 (2020) 15e17
assist in appropriate regulatory oversight and understanding of the potential impact of various tobacco products, health care providers are encouraged to thoroughly assess those presenting with seizures and are encouraged to submit reports to FDA when ENDS are involved. When reporting to FDA, it is critical to include the name of the ENDS manufacturer, the brand name, model, and serial number of the device or e-liquid, if applicable; whether the device or e-liquid was modified in any way or if a device malfunction occurred; whether other tobacco products, medications, or substances were used; details about product use patterns preceding the event (duration, amount, and intensity of ENDS use; time between last use and the event); and details about health effects, including specific areas of the body affected, how symptoms progressed, and how long they lasted. Acknowledgments The authors thank Deborah Neveleff for technical editorial assistance and Dr. Anna Sophie Weidner for her assistance with the acquisition of data for this work. Supplementary Data
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
Supplementary data related to this article can be found at http://doi.org/10.1016/j.jadohealth.2019.10.002. References [1] King BA, Gammon DG, Marynak KL, Rogers T. Electronic cigarettes sales in the United States, 2013-2017. JAMA 2018;320:1379e80. [2] Cullen KA, Ambrose BK, Gentzke AS, et al. Notes from the field: Use of electronic cigarettes and any tobacco product among middle and high
[11] [12]
17
school students - United States, 2011-2018. MMWR Morb Mortal Wkly Rep 2018;67:1276e7. Miech RA, Schulenberg JE, Johnston LD, et al. National Adolescent Drug Trends in 2018. Ann Arbor, MI: Monitoring the Future; 2018. Available at: http://www.monitoringthefuture.org. Accessed February 10, 2019. Schier JG, Meiman JG, Layden J, et al. Severe pulmonary disease associated with electronic-cigaretteeproduct use d Interim Guidance. MMWR Morb Mortal Wkly Rep 2019;68:787e90. Layden JE, Ghinai I, Pray I, et al. Pulmonary illness related to e-cigarette use in Illinois and Wisconsin - Preliminary report. N Engl J Med 2019. https:// doi.org/10.1056/NEJMoa1911614. National Academies of Sciences, Engineering, and Medicine. Public health consequences of E-cigarettes. Washington, DC: The National Academies Press; 2018. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Tobacco Products. Some e-cigarette users are having seizures, most reports involving youth and young adults. Available at: https://www. fda.gov/tobacco-products/ctp-newsroom/some-e-cigarette-users-are-having -seizures-most-reports-involving-youth-and-young-adults. Accessed June 28, 2019. U.S. Department of Health and Human Services, Food and Drug Administration. Center for tobacco products. Seizure cases in ENDS users reported to CTP, 2010- 6/30/2019. Available at: https://www.fda.gov/tobaccoproducts/tobacco-science-research/tobacco-product-problem-reports#end s-reports. Accessed July 15, 2019. Maessen GC, Wijnhoven AM, Neijzen RL, et al. Nicotine intoxication by e-cigarette liquids: A study of case reports and pathophysiology. Clin Toxicol (Phila) 2019;9:1e8. U.S. Department of Health and Human Services. E-Cigarette use among youth and young adults: A report of the surgeon general. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2016. Available at: https:// e-cigarettes.surgeongeneral.gov/documents/2016_SGR_Full_Report_non508.pdf. Accessed July 19, 2019. Bernat D, Gasquet N, Wilson KO, et al. Electronic cigarette harm and benefit perceptions and use among youth. Am J Prev Med 2018;55:361e7. Office of the Surgeon General. Surgeon general's advisory on e-cigarette use among youth. Available at: https://e-cigarettes.surgeongeneral.gov/ documents/surgeon-generals-advisory-on-e-cigarette-use-among-youth-2 018.pdf. Accessed July 31, 2019.
www.jahonline.org Original article
Adverse Experience Reports of Seizures in Youth and Young Adult Electronic Nicotine Delivery Systems Users Lisa M. Faulcon, M.D. *, Susan Rudy, M.S.N., C.R.N.P., Jean Limpert, M.D., Baoguang Wang, M.D., Dr.P.H., and Iilun Murphy, M.D. Center for Tobacco Products, Food and Drug Administration, Beltsville, Maryland
Article history: Received September 4, 2019; Accepted October 2, 2019 Keywords: Seizures; Electronic nicotine delivery systems (ENDS); Nicotine
See Related Editorial and Commentary on pp.1, 10 A B S T R A C T
Purpose: Electronic nicotine delivery systems (ENDS) use poses significant and avoidable health risks to young people. Until recently, seizures were most often associated with cases of liquid nicotine ingestion. Methods: We examined 122 voluntary reports of seizures (n ¼ 114) and neurological symptoms (syncope, n ¼ 7; and tremor, n ¼ 1) in 123 ENDS users (one report contained information on two users) received by the Food and Drug Administration between December 1, 2010, and June 30, 2019. Results: The median age (interquartile range) of users was 20 years (17e27); 67% of reports were in youth and young adults aged 14e24 years. Fifty-one (41%) reported other underlying medical conditions, including previous history of anxiety (n ¼ 11), attention deficit hyperactivity disorder (n ¼ 7), seizure (n ¼ 6), and depression (n ¼ 5). Of the 79 reports with available information, 67 (85%) reported seizure occurred within 24 hours of last use; 49 (62%) reported seizure within 30 minutes. The potential impact of concomitant use of marijuana or cannabidiol oil could not be evaluated from the eight reports that mentioned concomitant use. Conclusions: Findings suggest an association between ENDS use and seizures. Additional information will help to clarify the relationship between ENDS use and seizures and to understand how product attributes such as nicotine content, formulation, quantity, and other ingredients or contaminants may contribute to seizures. It is important that health care providers ask about ENDS use when evaluating neurological symptoms and that users, parents, school personnel, and health care providers report adverse experiences involving tobacco products to Food and Drug Administration via the Safety Reporting Portal (www.safetyreporting.hhs.gov). Ó 2019 Society for Adolescent Health and Medicine. All rights reserved.
Conflicts of interest: The authors have no conflicts of interest to disclose. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Food and Drug Administration. * Address correspondence to: Lisa M. Faulcon, M.D., Center for Tobacco Products, Food and Drug Administration, Calverton Tower, 11785 Beltsville Drive, Beltsville, MD 20705. E-mail address: [email protected] (L.M. Faulcon). 1054-139X/Ó 2019 Society for Adolescent Health and Medicine. All rights reserved. https://doi.org/10.1016/j.jadohealth.2019.10.002
IMPLICATIONS AND CONTRIBUTION
This article provides novel information on the association between seizures and inhaled nicotine toxicity. Such information may inform our understanding of the potential health risks of ENDS, impact the design of future clinical studies, and support future regulation.
Electronic nicotine delivery systems (ENDS) are typically battery-powered devices that heat e-liquids and deliver aerosolized nicotine, flavorings, humectants, and other chemicals. Eliquids may contain high nicotine levels and are available in several flavors that may appeal to youth. ENDS use may result in exposure to toxic volatile organic compounds, heavy metals, and
16
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nicotine [1]. Since 2011, ENDS use among middle school and high school students has increased significantly; current (past 30 days) ENDS use increased from 1.5% in 2011 to 20.8% in 2018 for high school students and from .6% in 2011 to 4.9% in 2018 for middle school students [2]. The 2018 National Youth Tobacco Survey and the Monitoring the Future survey showed significant increases in ENDS use among middle school and high school students between 2017 and 2018 [2,3]. The adverse health effects of ENDS use are not well characterized. Recently, severe pulmonary illness associated with the use of ENDS has been reported [4,5]. Nicotine is addictive, and its acute toxic effects can include seizures [6]. Reports of Seizures in ENDS Users The Food and Drug Administration (FDA) Center for Tobacco Products has been receiving voluntary adverse experience (AE) reports (i.e., health or product problems) about tobacco products since its inception in 2009. Since 2014, Center for Tobacco Products has collected AE reports via Web-based tobacco questionnaires on the Health and Human Services Safety Reporting Portal. In April 2019, FDA issued a Special Announcement alerting the public of reports received by the FDA and the American Association of Poison Control Centers of seizures in some ENDS users [7]. Between December 1, 2010, and June 30, 2019, FDA received 122 voluntary reports of seizures (n ¼ 114), syncope (n ¼ 8), and tremor (n ¼ 1) in 123 ENDS users (Supplementary Table 1) [8]. One report included information on two ENDS users who experienced seizures. One report was of an unexplained death from seizure in a 25-year-old female ENDS user with a known history of polyglandular autoimmune disease type II. The median age (interquartile range) was 20 years (17e27). Seizures were reported in both new users and experienced users, including eight reports of seizure after first use. Seizures occurred immediately after one puff, all-day use, and with use weeks before the event. Of the 79 reports with available information, 49 (62%) reported seizure within 30 minutes of last use. An additional five reported seizure within 2 hours of last use; overall, 67 (85%) reported seizure within 24 hours. Six users had a prior history of seizure. Fifty-one (41%) reported other underlying medical conditions, including previous history of anxiety (n ¼ 11), attention-deficit/ hyperactivity disorder (n ¼ 7), seizure (n ¼ 6), and depression (n ¼ 5). Fifty-three users reported repeat seizures with continued use of their ENDS product. Details on products, such as brand name, nicotine concentration, and quantity, were not provided in most reports. Review of reports containing product information did not identify product-specific trends; when product information was provided, JUUL, Suorin, SMOK, and Vuse brands were the most commonly named. Most of the reports involved youth and young adults (82/123; 67%) aged 14e24 years who were white (n ¼ 74/82; 88%) and males (n ¼ 54/82; 66%). Seizure (n ¼ 77), syncope (n ¼ 4), and tremor (n ¼ 1) were reported in this age group. Five youth/young adult users had a prior history of seizure. More than half of the youth and young adults (n ¼ 45) reported continued use of their ENDS product after the first seizure or neurological symptom, of which at least 73% (33/45) reported at least one additional seizure or repeat neurological symptom. Psychiatric disorders, such as depression, anxiety, and attention-deficit/hyperactivity
disorder, were the most commonly named comorbidities. In 43% (35/82) of youth and young adults, concurrent use of medications known to cause seizures (such as sertraline [n ¼ 7], escitalopram [n ¼ 6], bupropion [n ¼ 5], and lisdexamfetamine dimesylate [n ¼ 2]), alcohol, and/or marijuana was reported. Cannabidiol oil or marijuana was the most frequently reported additional substances used (8/11 reports with available information). Discussion Until the public's reports of seizures associated with ENDS use, seizures were most often associated with cases of liquid nicotine ingestion [9]. The reports summarized here to provide information on seizures involving intended use of ENDS (i.e., via inhalation). The predominance of seizures reported in youth and young adults may reflect the demographics of ENDS use. Given the proconvulsant effects of nicotine [10], it is possible that high nicotine content in ENDS products may lead to inhaled nicotine toxicity. Certain populations of ENDS users may be more prone to seizures, such as youth. ENDS use poses significant and avoidable health risks to young people [10]. The long-term clinical implications of seizures after ENDS use is unknown. ENDS use in youth is associated with conventional cigarette use [6]; this increases the risks of addiction and adverse health effects in users, given the potential long-term harm of cigarettes on brain development and known respiratory and cardiovascular health effects. Youth have demonstrated misperceptions about the potential adverse health effects of ecigarettes, reinforcing the need to increase awareness and education about the dangers of nicotine and ENDS use in youth [11]. The extent to which product design features, product constituents, and behavioral patterns of use play a role in the development of seizures in ENDS users is unclear. It is plausible that a rapid increase in plasma concentrations of nicotine resulting from inhalation of aerosol from nicotine-containing eliquids may play a role in seizures. Little is known about the inhalation toxicity of many e-liquid ingredients; chemical constituents other than nicotine may play a role in the development of seizures in ENDS users. Although some e-liquid flavorings may be “generally recognized as safe” for use in foods, this designation is not relevant to inhalation. Furthermore, ENDS devices may be used to deliver other substances, such as marijuana and Cannabidiol oils, which have been implicated in the development of pulmonary disease in ENDS users [5]. Research may inform the impact of nicotine formulations and other toxicants on the development of more severe nicotine toxicity symptoms, including seizures. Additional information will help in evaluating the association between seizures and ENDS use. Limitations of event reporting to date have precluded a determination of a causal relationship between the ENDS use and seizures or other neurological symptoms. Given the significant increase in ENDS use among youth and the emerging health concerns associated with ENDS use, it is important that health care providers ask about ENDS use [12], especially when evaluating neurological symptoms for which the etiology is unclear. Stakeholders, including users, parents, school personnel, and health care providers, are encouraged to report AEs involving tobacco products to FDA via the Safety Reporting Portal (www.safetyreporting.hhs.gov). To
L.M. Faulcon et al. / Journal of Adolescent Health 66 (2020) 15e17
assist in appropriate regulatory oversight and understanding of the potential impact of various tobacco products, health care providers are encouraged to thoroughly assess those presenting with seizures and are encouraged to submit reports to FDA when ENDS are involved. When reporting to FDA, it is critical to include the name of the ENDS manufacturer, the brand name, model, and serial number of the device or e-liquid, if applicable; whether the device or e-liquid was modified in any way or if a device malfunction occurred; whether other tobacco products, medications, or substances were used; details about product use patterns preceding the event (duration, amount, and intensity of ENDS use; time between last use and the event); and details about health effects, including specific areas of the body affected, how symptoms progressed, and how long they lasted. Acknowledgments The authors thank Deborah Neveleff for technical editorial assistance and Dr. Anna Sophie Weidner for her assistance with the acquisition of data for this work. Supplementary Data
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
Supplementary data related to this article can be found at http://doi.org/10.1016/j.jadohealth.2019.10.002. References [1] King BA, Gammon DG, Marynak KL, Rogers T. Electronic cigarettes sales in the United States, 2013-2017. JAMA 2018;320:1379e80. [2] Cullen KA, Ambrose BK, Gentzke AS, et al. Notes from the field: Use of electronic cigarettes and any tobacco product among middle and high
[11] [12]
17
school students - United States, 2011-2018. MMWR Morb Mortal Wkly Rep 2018;67:1276e7. Miech RA, Schulenberg JE, Johnston LD, et al. National Adolescent Drug Trends in 2018. Ann Arbor, MI: Monitoring the Future; 2018. Available at: http://www.monitoringthefuture.org. Accessed February 10, 2019. Schier JG, Meiman JG, Layden J, et al. Severe pulmonary disease associated with electronic-cigaretteeproduct use d Interim Guidance. MMWR Morb Mortal Wkly Rep 2019;68:787e90. Layden JE, Ghinai I, Pray I, et al. Pulmonary illness related to e-cigarette use in Illinois and Wisconsin - Preliminary report. N Engl J Med 2019. https:// doi.org/10.1056/NEJMoa1911614. National Academies of Sciences, Engineering, and Medicine. Public health consequences of E-cigarettes. Washington, DC: The National Academies Press; 2018. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Tobacco Products. Some e-cigarette users are having seizures, most reports involving youth and young adults. Available at: https://www. fda.gov/tobacco-products/ctp-newsroom/some-e-cigarette-users-are-having -seizures-most-reports-involving-youth-and-young-adults. Accessed June 28, 2019. U.S. Department of Health and Human Services, Food and Drug Administration. Center for tobacco products. Seizure cases in ENDS users reported to CTP, 2010- 6/30/2019. Available at: https://www.fda.gov/tobaccoproducts/tobacco-science-research/tobacco-product-problem-reports#end s-reports. Accessed July 15, 2019. Maessen GC, Wijnhoven AM, Neijzen RL, et al. Nicotine intoxication by e-cigarette liquids: A study of case reports and pathophysiology. Clin Toxicol (Phila) 2019;9:1e8. U.S. Department of Health and Human Services. E-Cigarette use among youth and young adults: A report of the surgeon general. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2016. Available at: https:// e-cigarettes.surgeongeneral.gov/documents/2016_SGR_Full_Report_non508.pdf. Accessed July 19, 2019. Bernat D, Gasquet N, Wilson KO, et al. Electronic cigarette harm and benefit perceptions and use among youth. Am J Prev Med 2018;55:361e7. Office of the Surgeon General. Surgeon general's advisory on e-cigarette use among youth. Available at: https://e-cigarettes.surgeongeneral.gov/ documents/surgeon-generals-advisory-on-e-cigarette-use-among-youth-2 018.pdf. Accessed July 31, 2019.