IMPORTANCE Exposure to nicotine in electronic cigarettes (e-cigarettes) is becoming increasingly common among adolescents who report never having smoked combustible tobacco.OBJECTIVE To evaluate whether e-cigarette use among 14-year-old adolescents who have never tried combustible tobacco is associated with risk of initiating use of 3 combustible tobacco products (ie, cigarettes, cigars, and hookah). DESIGN, SETTING, AND PARTICIPANTSLongitudinal repeated assessment of a school-based cohort at baseline (fall 2013, 9th grade, mean age = 14.1 years) and at a 6-month follow-up (spring 2014, 9th grade) and a 12-month follow-up (fall 2014, 10th grade). Ten public high schools in Los Angeles, California, were recruited through convenience sampling. Participants were students who reported never using combustible tobacco at baseline and completed follow-up assessments at 6 or 12 months (N = 2530). At each time point, students completed self-report surveys during in-classroom data collections. EXPOSURE Student self-report of whether he or she ever used e-cigarettes (yes or no) at baseline. MAIN OUTCOMES AND MEASURESSix-and 12-month follow-up reports on use of any of the following tobacco products within the prior 6 months: (1) any combustible tobacco product (yes or no); (2) combustible cigarettes (yes or no), (3) cigars (yes or no); (4) hookah (yes or no); and (5) number of combustible tobacco products (range: 0-3).RESULTS Past 6-month use of any combustible tobacco product was more frequent in baseline e-cigarette ever users (n = 222) than never users (n = 2308) at the 6-month follow-up (30.7% vs 8.1%, respectively; difference between groups in prevalence rates, 22.7% [95% CI, 16.4%-28.9%]) and at the 12-month follow-up (25.2% vs 9.3%, respectively; difference between groups, 15.9% [95% CI, 10.0%-21.8%]). Baseline e-cigarette use was associated with greater likelihood of use of any combustible tobacco product averaged across the 2 follow-up periods in the unadjusted analyses (odds ratio [OR], 4.27 [95% CI,) and in the analyses adjusted for sociodemographic, environmental, and intrapersonal risk factors for smoking (OR, 2.73 [95% CI, 2.00-3.73]). Product-specific analyses showed that baseline e-cigarette use was positively associated with combustible cigarette (OR, 2.65 [95% CI, 1.73-4.05]), cigar (OR, 4.85 [95% CI,), and hookah (OR, 3.25 [95% CI, 2.29-4.62]) use and with the number of different combustible products used (OR, 4.26 [95% CI,) averaged across the 2 follow-up periods.CONCLUSIONS AND RELEVANCE Among high school students in Los Angeles, those who had ever used e-cigarettes at baseline compared with nonusers were more likely to report initiation of combustible tobacco use over the next year. Further research is needed to understand whether this association may be causal.

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MDMA (±3,4-methylenedioxymethamphetamine, 'ecstasy') is used recreationally, reportedly because it increases feelings of empathy, sociability, and interpersonal closeness. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. MDMA users (N ¼ 65) participated in a 4-session, within-between-subjects study in which they received oral MDMA (0.75, 1.5 mg/kg), intranasal oxytocin (20 or 40 IU), or placebo under double-blind conditions. The primary outcomes included measures of emotion recognition and sociability (desire to be with others). Cardiovascular and subjective effects were also assessed. As expected, MDMA dose-dependently increased heart rate and blood pressure and feelings of euphoria (eg, 'High' and 'Like Drug'). On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose (1.5 mg/kg) increased desire to be with others, compared with placebo. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.

The popularity of electronic (e-) cigarettes has greatly increased recently, particularly in adolescents. However, the extent of psychiatric comorbidity with adolescent e-cigarette use and dual use of conventional (combustible) and e-cigarettes is unknown. This study characterized psychiatric comorbidity in adolescent conventional and e-cigarette use. Ninth grade students attending high schools in Los Angeles, CA (M age=14) completed self-report measures of conventional/e-cigarette use, emotional disorders, substance use/problems, and transdiagnostic psychiatric phenotypes consistent with the NIMH-Research Domain Criteria Initiative. Outcomes were compared by lifetime use of: (1) neither conventional nor e-cigarettes (non-use; N=2557, 77.3%); (2) e-cigarettes only (N=412, 12.4%); (3) conventional cigarettes only (N=152, 4.6%); and (4) conventional and e-cigarettes (dual use; N=189, 5.6%). In comparison to adolescents who used conventional cigarettes only, e-cigarette only users reported lower levels of internalizing syndromes (depression, generalized anxiety, panic, social phobia, and obsessive-compulsive disorder) and transdiagnostic phenotypes (i.e., distress intolerance, anxiety sensitivity, rash action during negative affect). Depression, panic disorder, and anhedonia were higher in e-cigarette only vs. non-users. For several externalizing outcomes (mania, rash action during positive affect, alcohol drug use/abuse) and anhedonia, an ordered pattern was observed, whereby comorbidity was lowest in non-users, moderate in single product users (conventional or e-cigarette), and highest in dual users. These findings: (1) raise question of whether emotionally-healthier (‘lower-risk’) adolescents who are not interested in conventional cigarettes are being attracted to e-cigarettes; (2) indicate that research, intervention, and policy dedicated to adolescent tobacco-psychiatric comorbidity should distinguish conventional cigarette, e-cigarette, and dual use.

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion data came from multiple personality inventories; extraversion scores were harmonized across cohorts and included as the phenotype in the GWA meta-analysis. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with gene action different from other complex behavioral traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.

Introduction Product characteristics that impact e-cigarette appeal by altering the sensory experience of vaping need to be identified to formulate evidence-based regulatory policies. While products that contain sweet flavorings and produce a “throat hit” (i.e., desirable airway irritation putatively caused by nicotine) are anecdotally cited as desirable reasons for vaping among young adults, experimental evidence of their impact on user appeal is lacking. This experiment applied a novel laboratory protocol to assess whether: (1) sweet flavorings and nicotine affect e-cigarette appeal; (2) sweet flavorings increase perceived sweetness; (3) nicotine increases throat hit; and (4) perceived sweetness and throat hit are associated with appeal. Methods Young adult vapers (N=20; age 19–34) self-administered 20 standardized doses of aerosolized e-cigarette solutions varied according to a 3 flavor (sweet [e.g., cotton candy] vs. non-sweet [e.g., tobacco-flavored] vs. flavorless) × 2 nicotine (6 mg/mL nicotine vs. 0 mg/mL [placebo]) double-blind, cross-over design. Participants rated appeal (liking, willingness to use again and perceived monetary value), perceived sweetness and throat hit strength after each administration. Results Sweet-flavored (vs. non-sweet and flavorless) solutions produced greater appeal and perceived sweetness ratings. Nicotine produced greater throat hit ratings than placebo, but did not significantly increase appeal nor interact with flavor effects on appeal. Controlling for flavor and nicotine, perceived sweetness was positively associated with appeal ratings; throat hit was not positively associated with appeal. Conclusions Further identification of compounds in e-cigarette solutions that enhance sensory perceptions of sweetness, appeal, and utilization of e-cigarettes are warranted to inform evidence-based regulatory policies.

Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and 'positive' subjective effects, with peaks occurring approximately 5-15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses. INTRODUCTIONAlthough methamphetamine abuse has increased dramatically over the past decade, much of our knowledge about its acute effects in humans is anecdotal. The drug is frequently abused via the intranasal, i.v., and smoked routes (Domier et al, 2000; Community Epidemiology Work Group, 2005), but few studies have evaluated the acute effects of methamphetamine in humans using these routes of administration. The majority of studies conducted with humans have focused primarily on the cardiovascular and subjective effects produced by oral methamphetamine, a route of administration least often associated with abuse presumably due to its slow onset of effects. The onset of peak effects produced by oral methamphetamine does not occur until about 90 min after the administration (Hart et al, 2001a). By comparison, peak effects produced by intranasal, smoked, and i.v. methamphetamine occur within 15 min (Harris et al, 2003;Newton et al, 2005).Given that the rapidity of drug-related effects is a critical determinant of abuse liability (Hatsukami and Fischman, 1996), it is surprising that only a few studies have examined methamphetamine-related effects via routes of administration other than oral (eg Cook et al, 1993;Mendelson et al, 1995;Newton et al, 2006). Although inhalation by s...

IMPORTANCEOpioids are frequently prescribed to children and adolescents after surgery. Prescription opioid misuse is associated with high-risk behavior in youth. Evidence-based guidelines for opioid prescribing practices in children are lacking.OBJECTIVE To assemble a multidisciplinary team of health care experts and leaders in opioid stewardship, review current literature regarding opioid use and risks unique to pediatric populations, and develop a broad framework for evidence-based opioid prescribing guidelines for children who require surgery.EVIDENCE REVIEW Reviews of relevant literature were performed including all English-language articles published from January 1, 1988, to February 28, 2019, found via searches of the PubMed (MEDLINE), CINAHL, Embase, and Cochrane databases. Pediatric was defined as children younger than 18 years. Animal and experimental studies, case reports, review articles, and editorials were excluded. Selected articles were graded using tools from the Oxford Centre for Evidence-based Medicine 2011 levels of evidence. The Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument was applied throughout guideline creation. Consensus was determined using a modified Delphi technique.FINDINGS Overall, 14 574 articles were screened for inclusion, with 217 unique articles included for qualitative synthesis. Twenty guideline statements were generated from a 2-day in-person meeting and subsequently reviewed, edited, and endorsed externally by pediatric surgical specialists, the American Pediatric Surgery Association Board of Governors, the American Academy of Pediatrics Section on Surgery Executive Committee, and the American College of Surgeons Board of Regents. Review of the literature and guideline statements underscored 3 primary themes: (1) health care professionals caring for children who require surgery must recognize the risks of opioid misuse associated with prescription opioids, (2) nonopioid analgesic use should be optimized in the perioperative period, and (3) patient and family education regarding perioperative pain management and safe opioid use practices must occur both before and after surgery.CONCLUSIONS AND RELEVANCE These are the first opioid-prescribing guidelines to address the unique needs of children who require surgery. Health care professionals caring for children and adolescents in the perioperative period should optimize pain management and minimize risks associated with opioid use by engaging patients and families in opioid stewardship efforts.