Unique, long-term effects of nicotine on adolescent brain.

In the paper

“Use of e-cigarettes was almost as prevalent among 10th graders, and was particularly troubling among 8th graders who showed a 157% increase in 30-day e-cigarette use over the last two years.”

What the sources say

• Partly supported

  The ‘To the Editor’ results report increased nicotine vaping among both 10th- and 8th-graders from 2017 to 2018. They give an 8th-grade increase of 2.6 percentage points over one year, not a 157% increase over two years, and do not establish that use among 10th-graders was almost as prevalent as among 12th-graders. (LLM, conf=0.83)

  cites Miech et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“In absolute numbers, the National Youth Tobacco Survey shows that ~5 million students in grades 6–12 have tried e-cigarettes within the past 30 days, an increase from ~3.6 million in 2018 (Cullen et al., 2019).”

What the sources say

• Partly supported

  The 2018 NYTS table (Discussion) estimates 3.64 million current e-cigarette users among middle and high school students, supporting the comparison figure. It estimates 4.92 million current users of any tobacco product—not e-cigarettes—and the paper covers data only through 2018, so it does not support the claimed increase to about 5 million e-cigarette users. (LLM, conf=0.88)

  cites Cullen et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“According to Monitoring the Future survey data (Miech et al., 2019), 25.4% of 12th graders in 2019 used e-cigarettes within the last thirty days, an increase of 131% from two years previously”

What the sources say

• Partly supported

  The To the Editor section reports Monitoring the Future data showing an increase in nicotine vaping among 12th graders from 2017 to 2018. It does not report 2019 use, a 25.4% prevalence, or a 131% increase over two years; those specifics are not supported by this paper. (LLM, conf=0.88)

  cites Miech et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Although there has been a decline in teen use of cigarettes in recent years, there has been a huge increase in nicotine vaping.”

What the sources say

• Partly supported

  The Abstract (page unavailable) reports decreased menthol-cigarette use and increased flavored e-cigarette use among high school tobacco-product users from 2014 to 2018. It does not establish a decline in cigarette use generally or a huge increase in nicotine vaping among teenagers; the reported high-school flavored e-cigarette measure rose from 65.1% to 67.8%, and the middle-school measure was comparable in 2014 and 2018. (LLM, conf=0.87)

  cites Cullen et al., 2019 sourceExperimental — accuracy not yet measured
• Partly supported

  The To the Editor section reports a sharp increase in nicotine vaping from 2017 to 2018. It also says use of each of six other nicotine products declined in a sample of 12th-graders, but those declines were not statistically significant; it does not establish a broader, multi-year decline in cigarette use among teenagers. (LLM, conf=0.84)

  cites Miech et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Although introduced as recently as 2007 to the US market, e-cigarettes are now the most commonly used tobacco product among teenagers (Miech et al., 2017; Wang et al., 2019).”

What the sources say

• Partly supported

  The Introduction reports rapid growth in e-cigarette use among U.S. students, and the Results say recent vaping was about 50% more prevalent than recent cigarette smoking in the study sample. Neither passage establishes that e-cigarettes were introduced to the U.S. market in 2007 or that they were the most commonly used tobacco product among teenagers overall. (LLM, conf=0.83)

  cites Miech et al., 2017 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract (Results) and Results (Current Tobacco Product Use) identify e-cigarettes as the most commonly used tobacco product among U.S. middle and high school students in 2019. Our copy does not state that e-cigarettes entered the U.S. market in 2007; searches for that date and market introduction found no supporting passage. (LLM, conf=0.87)

  cites Wang et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Whereas the use of tobacco cigarettes has declined in the United States within recent years, the use of electronic cigarettes (e-cigarettes) has increased exponentially (Cullen et al., 2019; Miech et al., 2019).”

What the sources say

• Partly supported

  The Abstract (page unavailable) reports that, among U.S. high school tobacco-product users, menthol cigarette use decreased and flavored e-cigarette use increased during 2014–2018. It does not establish a decline in cigarette use or an exponential increase in e-cigarette use across the United States generally; the reported e-cigarette increase was from 65.1% to 67.8% in that subgroup. (LLM, conf=0.88)

  cites Cullen et al., 2019 sourceExperimental — accuracy not yet measured
• Partly supported

  In “TO THE EDITOR” (page unavailable), the paper reports a sharp rise in nicotine vaping among U.S. adolescents from 2017 to 2018 and says use of six other nicotine products declined, though not significantly. It does not establish exponential growth or a decline in cigarette use across the U.S. population as a whole. (LLM, conf=0.88)

  cites Miech et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“To date there has been insufficient regulation of these potentially dangerous tobacco products and, as a result, they have been readily available to minors in some states (Paradise, 2014).”

What the sources say

• Supported

  The Abstract describes a lack of FDA regulation and says state and local laws do not provide a uniform national policy. It reports that only some jurisdictions had banned sales to minors and warns that gaps in the laws leave access to e-cigarettes as a significant loophole, supporting the paraphrase about availability to minors in some states. (LLM, conf=0.85)

  cites Paradise, 2014 source

In the paper

“Adult female rats show less aversion to nicotine than do adult males or oviarectomized females, suggesting that ovarian hormones protect against this effect (Torres et al, 2009).”

What the sources say

• Supported

  The Discussion reports that at a high nicotine dose, adult males and ovariectomized females showed aversion while intact females showed reward. It explicitly suggests that gonadal hormones may protect females against nicotine’s aversive effects. (LLM, conf=0.94)

  cites Torres et al, 2009 source

In the paper

“Nicotine mediates its effects via nicotinic cholinergic receptors (nAChRs), pentameric ligand-gated ion channels that are widely distributed throughout the brain (Dani, 2015; Zoli et al., 2015).”

What the sources say

• Supported

  The Introduction describes nAChRs as five-subunit receptors whose channels open in response to nicotine. The Conclusion describes their action across broad brain circuits, supporting the claim that they are widely distributed throughout the brain. Page numbers are unavailable in our copy. (LLM, conf=0.94)

  cites Dani, 2015 source
• Supported

  The Introduction describes nicotine binding to brain nAChRs and calls them ubiquitously expressed pentameric ion channels. Section 2 identifies nAChRs as members of the ligand-gated ion-channel superfamily. Page numbers are unavailable in our copy. (LLM, conf=0.94)

  cites Zoli et al., 2015 source

In the paper

“Although presynaptic dopamine markers are not impacted by this nicotine treatment, there is an increase in the efficacy of striatal D2 dopamine receptors (Mojica et al., 2014; Linker et al., 2020).”

What the sources say

• ?Not checked — no full text of the sourcecites Mojica et al., 2014 source
• Partly supported

  The Results section on D2 receptors states that receptor signaling increases after adolescent nicotine exposure, supporting the D2-efficacy part of the claim. The paper does not establish that presynaptic dopamine markers are unaffected; its Results and Discussion instead report decreases in the presynaptic markers synaptophysin and VGlut2, which are not identified as dopamine markers. (LLM, conf=0.85)

  cites Linker et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“Although nicotine is more rapidly metabolized in rodents during pre-adolescence (P23–25) than in adults, leading to lower blood levels, no pharmacokinetic differences have been seen during the adolescent period starting at P28 (Portugal et al., 2012; Ahsan et al., 2014; Craig et al., 2014; Arany et al., 2017).”

What the sources say

• Partly supported

  Results §3.4 finds no difference in plasma nicotine levels among pre-adolescent, adolescent, and adult mice after acute or chronic treatment; the Discussion likewise reports no age-related difference in nicotine metabolism. This contradicts the claimed faster metabolism and lower blood nicotine levels in pre-adolescents. The absence of a detected difference between adolescents and adults is supported, but Methods §2.1 places the adolescent group at PND 38 at the start of experiments, not P28. (LLM, conf=0.88)

  cites Portugal et al., 2012 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results section on blood nicotine levels reports concentrations after doses that produced place preference or self-administration, but does not compare nicotine metabolism or blood levels across ages. The Methods and Discussion likewise do not address faster metabolism at P23–25 or the absence of pharmacokinetic differences from P28; searches for those terms and age-related blood-level differences found no supporting passage. (LLM, conf=0.76)

  cites Ahsan et al., 2014 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Results report lower plasma nicotine levels and faster nicotine clearance in early-adolescent rats at postnatal day 25 than in adults. The Discussion does not support the more specific claim that faster metabolism caused the lower levels; it points primarily to clearance and distribution and does not find faster conversion to cotinine. The paper compares day-25 rats with adults, so it does not establish that pharmacokinetic differences disappear starting at day 28. Page numbers were unavailable in our copy. (LLM, conf=0.88)

  cites Craig et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“nAChRs are expressed early in brain development and play critical maturational roles at many developmental stages, including adolescence (reviewed by Dwyer et al., 2009).”

What the sources say

• Supported

  The Conclusion states that nAChRs are present from the earliest phases of neural development through adolescence and describes critical developmental roles in the prenatal, early postnatal, and adolescent periods. Section 2 likewise says their expression corresponds to critical developmental events. (LLM, conf=0.95)

  cites Dwyer et al., 2009 source

In the paper

“Adolescent males have been shown to have a strong anxiolytic response to nicotine treatment which diminishes with age, whereas adolescent females have much lower anxiolytic or outright anxiogenic responses depending on the behavioral test (Elliott et al., 2004; Cao et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Elliott et al., 2004 source
• Supported

  The Results section reports that nicotine had a more prolonged anxiolytic effect in P28 males than females, no effect at P38, and a shorter-lived anxiolytic effect in adult males. The Discussion reports that, in a different behavioral test, nicotine was anxiolytic in adolescent males but anxiogenic in females. (LLM, conf=0.90)

  cites Cao et al., 2010 source

In the paper

“Whereas adolescent mice only showed learning enhancement at the highest nicotine dose, adult mice exhibited behavioral effects at lower nicotine doses.”

What the sources say

• Supported

  The Results (section 2.1, page unavailable) report enhanced context pre-exposure facilitation at all three nicotine doses in adult mice, but only at the highest dose (0.36 mg/kg) in adolescent mice. The Discussion (section 3, page unavailable) notes that reduced locomotor activity may partly explain the apparent enhancement at the highest dose in the 15-day experiment. (LLM, conf=0.93)

  cites Kutlu et al., 2016 source

In the paper

“Alternatively, tobacco constituents, which have been shown to enhance reinstatement of nicotine seeking behavior (Costello et al., 2014; Cross et al., 2020), may increase withdrawal signs.”

What the sources say

• ?Not checked — no full text of the sourcecites Costello et al., 2014 source
• Supported

  The Conclusion (page unavailable) reports that including aqueous cigarette-smoke constituents with nicotine enhanced seeking after drug re-exposure without cues. The suggestion that constituents may increase withdrawal signs is the citing authors’ proposed explanation, not a finding attributed to Cross et al. (LLM, conf=0.87)

  cites Cross et al., 2020 source

In the paper

“Although these findings may suggest that adolescent females find nicotine and tobacco more rewarding than males, recent data on middle and high school students suggest few sex differences in rates of tobacco product use, with males showing slightly elevated consumption (Wang et al., 2019).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Wang et al., 2019 source

In the paper

“There is limited research on withdrawal from e-cigarettes, but recent analysis of the US Population Assessment of Tobacco and Health Survey and a clinical trial by the same investgators indicated that withdrawal symptoms were mild in never smokers (Hughes & Callas, 2019; Hughes et al., 2020)”

What the sources say

• ?Not checked — no full text of the sourcecites Hughes & Callas, 2019 source
• Supported

  This source is the clinical trial cited in the sentence, not the PATH analysis. Its Abstract reports that withdrawal severity was small in never-smokers who used e-cigarettes daily, and the Discussion likewise describes the symptoms as less severe than in former smokers. (LLM, conf=0.92)

  cites Hughes et al., 2020 source

In the paper

“Two studies in which an inhalation method for tobacco smoke or nicotine was used did note substantial physical withdrawal in adolescents, although adults were not included for comparison (de la Pena, 2015; Kallupi et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites de la Pena, 2015 source
• Supported

  The Abstract reports moderate to severe spontaneous withdrawal signs after adolescent rats inhaled nicotine vapor. The Discussion states that the study used male adolescent rats only; although the rats were later tested for nicotine self-administration in adulthood, there was no adult-exposure group for withdrawal comparison. This verdict addresses Kallupi et al. only, not the other study cited in the sentence. (LLM, conf=0.93)

  cites Kallupi et al., 2019 source

In the paper

“Adolescent nicotine treatment increases subsequent nicotine reward and decreases aversion in adults”

What the sources say

• Partly supported

  The Results report that nicotine pretreatment during periadolescence increased nicotine self-administration in adult rats, and the Discussion interprets this as greater sensitivity to nicotine’s reinforcing effects. Our copy does not report reduced nicotine aversion; searches for aversion and aversive effects did not find support for that part of the claim. No page numbers were available in the indexed passages. (LLM, conf=0.86)

  cites Adriani et al., 2003 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that adult rats exposed to nicotine during adolescence did not show the aversion seen at the highest dose in naïve adults. But it also says those rats did not show increased nicotine reward: their dose-response curve was relatively flat, and adolescent exposure did not facilitate conditioned place preference in adulthood. (LLM, conf=0.90)

  cites Torres et al., 2008 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports that high-dose adolescent nicotine-vapor exposure facilitated nicotine self-administration in adult rats. It suggests increased positive reinforcement as one possible explanation, but also offers withdrawal-related reinforcement; it does not establish increased nicotine reward or decreased nicotine aversion. (LLM, conf=0.88)

  cites Kallupi et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“we have used a paradigm in which Sprague Dawley rats are treated once daily for four days with a low dose of nicotine (0.06 mg/kg, i.v.), intended to mimic the early phase of teen smoking, and have shown this enhances subsequent reinforcing effects of cocaine, methamphetamine and alcohol”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites McQown et al., 2007
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Dao et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“Microglial activation then selectively prunes glutamate synapses in the nucleus accumbens and basolateral amygdala, and results in increased cocaine self-administration.”

What the sources say

• Partly supported

  The Results section on synaptophysin reports a microglia-dependent decrease in a presynaptic marker in the nucleus accumbens after adolescent nicotine exposure; VGlut2 decreased while VGlut1 did not. The Results section on cocaine self-administration reports that suppressing or eliminating microglia blocked nicotine-induced increases in cocaine reinforcement. The paper does not show selective pruning of glutamate synapses in both the nucleus accumbens and basolateral amygdala: its synaptic-marker findings concern the nucleus accumbens, and decreased marker levels are not direct evidence of pruning. (LLM, conf=0.88)

  cites Linker et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“Adolescents who use flavorants are also frequently unaware of their nicotine exposure, with 40% of subjects with significant urinary cotinine in a recent study reporting that they used only nicotine-free products (Boykan et al., 2019b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Boykan et al., 2019b

In the paper

“Furthermore, adolescents who used e-cigarettes with non-traditional flavors are more likely to continue vaping and take more puffs per session six months later (Leventhal et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Leventhal et al., 2019 source

In the paper

“Whereas Adriani and colleagues found no sex differences in this effect, most other studies have not compared sex and age differences within the same study to allow a direct comparison of males and females.”

In the paper

“Using an intravenous self-administration paradigm, we have shown that nicotine combined with alcohol is self-administered at much higher rates in male adolescents than adults, and with much greater alcohol intake in adolescents than that of alcohol alone (Figure 2A).”

In the paper

“Although these withdrawal signs are routinely seen in adult rodents, this is not the case for adolescents.”

In the paper

“Flavorants can lead to different patterns of nicotine delivery and a decreased perception of risk (Voos et al., 2019; Jensenn and Boykan, 2019; Boccio et al., 2020).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Voos et al., 2019
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Jensenn and Boykan, 2019
• ?Not checked — no full text of the sourcecites Boccio et al., 2020 source

In the paper

“Adolescents of both sexes are more sensitive than adults to the rewarding effects of nicotine, as shown in conditioned place preference tests (Vastola et al., 2002; Shram et al., 2006; Kota et al., 2007; Torres et al., 2008; Ahsan et al., 2014; Lenoir et al., 2015), with some studies demonstrating reward after a single pairing of drug and context (Belluzzi et al., 2004; Brielmaier et al., 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Vastola et al., 2002 source
• ?Not checked — no full text of the sourcecites Shram et al., 2006 source
• ?Not checked — no full text of the sourcecites Kota et al., 2007 source

In the paper

“However, as has been particularly highlighted in pre-clinical studies, described below, nicotine is a neurotoxicant that can produce unique and long-lasting negative behavioral effects in adolescents.”

In the paper

“However, in one recent study in which reward was measured by reduction in brain reward thresholds, there was no sex difference in the rewarding effects of nicotine in adults, whereas adolescent females (P40–59) were significantly more sensitive to the rewarding effect of nicotine than their male counterparts (Xue et al., 2020).”

What the sources say

• ?Not checked — no full text of the sourcecites Xue et al., 2020 source

In the paper

“Nicotine-stimulated dopamine release from ventral striatal slices shows complex age- and sex-dependence, being highest in male rats during early adolescence (postnatal day (P)30), with females showing no significant age differences (Azam et al., 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Azam et al., 2007 source

In the paper

“Whereas nicotine inhibits locomotor activity in late adolescence and adulthood, it either has no effect (Lopez et al., 2003; Belluzzi et al., 2004; Miller et al., 2019) or stimulates motor activity in early adolescence (Adriani et al., 2002; Cao et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Lopez et al., 2003 source
• ?Not checked — no full text of the sourcecites Belluzzi et al., 2004 source
• ?Not checked — no full text of the sourcecites Miller et al., 2019 source

In the paper

“The perceptions of low health risk, combined with the appeal of flavors and minimal market regulations, have created a climate for the wide use of e-cigarettes among adolescents.”

In the paper

“Whereas adults of both sexes experience aversive effects of high doses of nicotine, adolescents tolerate the drug well (Adriani et al., 2002; Shram et al., 2006; Torres et al., 2008, 2009; Lenoir et al., 2015).”

What the sources say

• ?Not checked — no full text of the sourcecites Adriani et al., 2002 source
• ?Not checked — no full text of the sourcecites Shram et al., 2006 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Torres et al., 2008, 2009

In the paper

“Whereas most studies have shown age differences in the acute in vivo effects of nicotine, there is no consistent pattern to these findings.”

In the paper

“Strain differences were observed in which early-adolescent mice of the DBA/2J strain were insensitive to nicotine-induced hypothermia, whereas C57BL/ 6J were sensitive at this age. However, both strains showed increased sensitivity to nicotine as development progressed.”

What the sources say

• ?Not checked — no full text of the sourcecites Miller et al. (2019) source

In the paper

“Although animals in late adolescence exhibit the same inhibitory locomotor response to acute nicotine as adults, they show greater locomotor sensitization to repeated nicotine treatment (Belluzzi et al., 2004).”

What the sources say

• ?Not checked — no full text of the sourcecites Belluzzi et al., 2004 source

In the paper

“Although one group has argued against a biological vulnerability of adolescents to nicotine (Shram et al., 2008), the majority of studies have shown that adolescent rats readily acquire intravenous nicotine self-administration and have higher drug intake than adults (Chen et al., 2007; Levin et al. 2003, 2007; Natividad et al., 2013: Ahsan et al., 2014; Gellner et al., 2016).”

What the sources say

• ?Not checked — no full text of the sourcecites Shram et al., 2008 source
• ?Not checked — no full text of the sourcecites Chen et al., 2007 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Levin et al. 2003, 2007

In the paper

“Strain differences have also been noted in adolescent physical withdrawal signs (Hamilton et al., 2010); whereas Sprague Dawley rats of both sexes were found to show significant withdrawal signs for two days after nicotine removal, Long Evans rats exhibit shortened (males) or non-existent (females) withdrawal.”

What the sources say

• ?Not checked — no full text of the sourcecites Hamilton et al., 2010 source

In the paper

“Whereas both sexes found the drug combination to be highly rewarding during early adolescence (P27), this initial reinforcing effect had significantly diminished in males at later ages (P34 and adult), whereas it remained high in females.”

What the sources say

• ?Not checked — no full text of the sourcecites Park et al., 2007 source

In the paper

“Adolescent, but not adult, nicotine downregulated the chloride channel, KCC2, causing a depolarizing shift in EGABA and resulting inhibition of ethanol-stimulated dopamine release.”

What the sources say

• ?Not checked — no full text of the sourcecites Thomas et al., 2018 source

In the paper

“Smoking and drinking are two of the earliest drug use behaviors in human teens, and many reports indicate a positive interaction of smoking and drinking in this age group (Dani & Harris, 2005; Kristjansson et al., 2015).”

What the sources say

• ?Not checked — no full text of the sourcecites Dani & Harris, 2005 source
• ?Not checked — no full text of the sourcecites Kristjansson et al., 2015 source

In the paper

“Adult dependent smokers are also much more likely to be alcoholics than non-smokers, and the great majority of alcoholics smoke”

What the sources say

• ?Not checked — no full text of the sourcecites DiFranza & Guerrera, 1990 source
• ?Not checked — no full text of the sourcecites Falk et al., 2006

In the paper

“A recent study has reported that teen e-cigarette users are more likely to report dependence signs and be daily users if they use high nicotine content pods, such as Juul (Boykan et al., 2019a).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Boykan et al., 2019a

In the paper

“Nicotine treatment of male adolescent rats resulted in increased impulsive behavior and decreased attention in adulthood, but had no effect on animals that are treated as adults”

What the sources say

• ?Not checked — no full text of the sourcecites Counotte et al., 2011 source

In the paper

“only Lewis rats show enhancement of cocaine conditioned place preference and a concomitant potentiation of dopamine response in the nucleus accumbens shell following adolescent nicotine treatment”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Cadoni et al., 2019

In the paper

“The enhancement of cocaine intake is seen immediately following nicotine pretreatment and persists through adulthood, but is not seen for sucrose.”

In the paper

“adolescent, but not adult nicotine, induces long-term social withdrawal and deficits in social cognition”

What the sources say

• ?Not checked — no full text of the sourcecites Jobson et al., 2019 source