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. Author manuscript; available in PMC: 2024 Mar 1.
Published in final edited form as: Drug Alcohol Depend. 2023 Feb 6;244:109798. doi: 10.1016/j.drugalcdep.2023.109798

ADHD Symptoms and Smoking Outcomes in a Randomized Controlled Trial of Varenicline for Adolescent and Young Adult Tobacco Cessation

ReJoyce Green 1, Nathaniel L Baker 2, Pamela L Ferguson 2, Daniel Hashemi 1, Kevin M Gray 1
PMCID: PMC10010149  NIHMSID: NIHMS1875333  PMID: 36774808

Abstract

Background:

Most adult daily smokers try their first cigarette during adolescence. Attention-Deficit Hyperactivity Disorder (ADHD) in adolescents is associated with increased risk for cigarette smoking. The impact of ADHD symptoms on smoking cessation among adolescents has been less well-studied. The present secondary data analysis from a clinical trial of varenicline examined ADHD symptoms as a moderator of smoking cessation in adolescents and young adults.

Methods:

The double-blind, placebo-controlled trial included treatment-seeking daily cigarette smokers ages 14 – 21 (N = 157) randomized to receive a 12-week course of varenicline or placebo, added to weekly smoking cessation counseling. At pre-treatment assessment, participants were administered a self-report measure of ADHD symptoms, the ADHD – Rating Scale (ADHD-RS). High (≥5) versus low (<5) and continuous ADHD-RS symptom counts in both hyperactive/impulsive (HI) and inattention (IA) domains were examined as predictors of smoking outcomes.

Results:

Participants with high IA symptoms at baseline were less likely to achieve 7-day point prevalence abstinence (PPA) at weekly visits (p = .001) during active treatment and end-of-treatment (p = .002) compared to those with low IA symptoms. In contrast, high HI symptoms did not predict differences in 7-day PPA or end-of-treatment abstinence versus low symptoms (p’s ≥ .07). These findings were not modified by varenicline versus placebo treatment assignment.

Conclusions:

ADHD IA symptoms were associated with poorer cessation outcomes among adolescent smokers. These findings warrant additional investigation into how ADHD symptoms may be accounted for in smoking cessation interventions for adolescents and young adults.

Keywords: nicotine, attention-deficit / hyperactivity disorder, varenicline, treatment planning, inattentive symptoms

1. Introduction

While tobacco use in adults has declined over the last 15 years (Cornelius et al., 2022; USDHHS, 2014), it remains a leading preventable cause of death (USDHHS, 2014). Most adult tobacco users report first trying tobacco when they are adolescents (ages 10 – 19) (USDHHS, 2012). Recent trends suggest a shift with many new cigarette smokers beginning to smoke during young adulthood (ages 18 – 23), providing support for expanding prevention efforts beyond adolescents to young adults (Barrington-Trimis et al., 2020). Results from the 2021 National Youth Tobacco Survey revealed 13.4% of high-school students reported using any tobacco product, and e-cigarettes were the most common (11.3%), followed by cigars (2.1%) and cigarettes (1.9%) (Gentzke et al., 2022). The 2020 National Health Interview Survey (NHIS) found 7.4% of young adults ages 18 – 24 reported using cigarettes (Cornelius et al., 2022). Nicotine use during adolescence confers greater risk for use of nicotine, alcohol, and psychostimulants in adulthood (Ren and Lotfipour, 2019), which necessitate efforts to reduce the use of tobacco during adolescence.

One of the most common neurodevelopmental disorders associated with adolescent and young adult nicotine use is Attention-Deficit Hyperactivity Disorder (ADHD), which involves a persistent pattern of inattention, hyperactivity-impulsivity, or a combination of these clusters of symptoms that interferes with functioning (A.P.A., 2013). A recent report estimated approximately 10% of children ages 6-11, and 13% of children ages 12-17, have received a diagnosis of ADHD (Bitsko et al., 2022). Numerous studies have highlighted how adolescents and adults with ADHD are more likely to engage in cigarette smoking compared to those without ADHD (Gudjonsson et al., 2012; Kollins et al., 2005; Mitchell et al., 2019; Whalen et al., 2002). These findings underscore the pervasive, long-term effects of ADHD-related smoking risk among adolescents and young adults. One explanation underlying the association between ADHD and nicotine dependence is the ‘self-medication’ hypothesis which suggest that nicotine use offsets the attention, cognitive, and impulsivity related deficits among those with ADHD (van Amsterdam et al., 2018). This hypothesis has strong pharmacological support as both ADHD and nicotine may alter the striatal dopaminergic system (van Amsterdam et al., 2018; Volkow et al., 2009). Given the robust association between ADHD and smoking, smoking cessation interventions for adolescents and young adults may benefit from increased attention to how ADHD may alter treatment response.

Most smoking cessation efforts for adolescents have focused on psychosocial interventions, though an increasing number are examining pharmacological interventions. Among the most efficacious smoking cessation medication for adults is varenicline, an α4β2 nicotinic acetylcholine partial agonist (Burke et al., 2016). Few studies have examined varenicline for adolescent smokers. Gray and colleagues (2020) compared 12-weeks of high-dose (2 mg/day) and low-dose (1 mg/day) varenicline in adolescent smokers aged 12 – 19 and did not find an added benefit of high-dose or low-dose varenicline over placebo on continuous abstinence (Gray et al., 2020). The rates of adverse events were similar to those among adults, providing additional support for the tolerability of varenicline among adolescents (Gray et al., 2019; Gray et al., 2012). As the efficacy of varenicline among adolescents is limited, additional individual difference characteristics may need to be considered to develop tailored treatment strategies for adolescent smokers. A growing body of evidence suggests varenicline may be uniquely positioned to address smoking cessation among those with ADHD. Prior reports have shown reduced lapses in attention, though with no effect on inhibitory control, following 3-weeks of varenicline treatment among adult smokers without ADHD (Rhodes et al., 2012). These findings highlight the potential for varenicline to exert a positive effect on domains, notably attention, that may be impaired in those with ADHD. Bidwell and colleagues (2017) looked not at ADHD diagnosis, but rather numbers of symptoms in adults, and found adult smokers with hyperactivity-impulsivity (HI) symptoms reported fewer cigarettes per day and lower nicotine withdrawal while randomized to varenicline but this pattern was not observed for inattention (IA) symptoms. While these findings exclusively examined number of symptoms as opposed to formal Diagnostic and Statistical Manual – 5 (DSM-5) diagnosis, they extend epidemiological findings often focused on a formal ADHD diagnosis and highlight how the continuum of ADHD symptoms meets the threshold for having an association with smoking cessation. Extending beyond diagnosis to symptomology allows for greater inclusion of individuals who may also be at risk for poor smoking cessation outcomes due to sub-clinical ADHD symptoms and may benefit from tailored treatment options that are attentive to the ADHD symptoms they report.

We conducted a secondary data analysis of a recent clinical trial of varenicline for smoking cessation among adolescents and young adults (Gray et al., 2019). The primary results of this clinical trial indicated that varenicline was well-tolerated but did not improve end-of-treatment abstinence (Gray et al., 2019). The primary aim of the present analysis was to examine how the number and type of ADHD symptoms associate with smoking cessation outcomes (abstinence and cigarettes per day) and nicotine withdrawal in this study. We also sought to examine how varenicline may alter endorsement of ADHD symptoms throughout the study.

2. Materials and Methods

2.1. Participants

The larger parent trial (Gray et al., 2019) enrolled adolescent and young adult cigarette smokers ages 14-21. Inclusion criteria included daily smoking for a minimum of 6-months, failing at least one prior quit attempt, and interest in quitting. Recruitment was conducted between September 2012 and November 2017. If under age 18, parent(s) or guardians(s) provided informed consent and the adolescent provided assent. Individuals ages 18 and over provided informed consent. The university institutional review board approved the study protocol.

2.2. General Procedures

A detailed overview of study procedures can be found elsewhere (Gray et al., 2019). At the baseline visit, participants received adolescent-targeted smoking cessation brochures and were briefly counseled on cessation strategies. Participants were instructed to set a smoking quit date 1-week after medication initiation. Participants received weekly smoking cessation counseling that was similar to psychosocial interventions in adolescent and adult cessation pharmacotherapy studies (Gonzales et al., 2006; Jorenby et al., 2006; Muramoto et al., 2007; Nides et al., 2006). If participants were unsuccessful with the initial quit date, they were advised to select another quit date.

After the baseline visit, eligible treatment-seeking adolescent and young adult smokers were randomized, in 1:1 parallel group allocation, to receive a double-blind 12-week course of orally administered varenicline or placebo. Medication stratification was based on the prognostic covariates age (14-17 versus 18-21) and baseline smoking level (<12 versus 12 or more cigarettes per day [CPD]). The medication titration schedule was consistent with recommendations from an adolescent varenicline pharmacokinetic study, as participants >55 kg received varenicline/placebo 0.5 mg once daily for 3 days, titrated to 0.5 mg twice daily for 4 days, titrated to 1 mg twice daily thereafter (Faessel et al., 2009). Participants ≤55 kg received varenicline/placebo 0.5 mg once daily for 7 days, titrated to 0.5 mg twice daily thereafter.

2.3. Measures

2.3.1. Cigarette Smoking

At weekly visits, self-reported smoking was collected via daily diaries and Timeline Follow-Back (TLFB) methods (Sobell et al., 1988). Breath carbon monoxide (CO) was measured at all visits and urine cotinine was measured at the end-of-treatment visit as biomarkers of smoking. Participants also completed a questionnaire assessing smoking history (i.e., history of quit attempts).

2.3.2. ADHD Symptoms

ADHD symptoms were assessed at baseline and study weeks 4, 8, 12 with the ADHD - Rating Scale (ADHD-RS) (DuPaul et al., 1998). This 18-item self-report measure assesses both inattention and hyperactivity-impulsivity symptoms of ADHD on a 4 point scale (0=never or rarely, 1=sometimes, 2=often, 3=very often). The possible range of total scores for this measure are 0-54. The subscales of inattentive symptoms (IA) and hyperactivity-impulsivity (HI) symptoms contain 9 items each. In these analyses, any positive response (i.e., sometimes, often, very often) was counted as symptom endorsement. Sub-clinical ADHD symptoms have been associated with smoking behavior and cessation (Bidwell et al., 2017; Kollins et al., 2005); therefore, we included “sometimes” responses in the present study. The present study examined both subscale scores as continuous predictors (possible range 0-9 for each), as well as stratified as low/high symptomology, defined as <5 versus ≥5 symptoms endorsed (A.P.A., 2013; Bidwell et al., 2017). Group comparisons allow for a test of the contribution of a meaningful collection of symptoms over and above a 1-unit increase in symptom count.

2.3.3. Nicotine Withdrawal

Nicotine withdrawal was assessed at baseline and at the weekly screening visits with the Minnesota Nicotine Withdrawal Scale (MNWS) (Hughes and Hatsukami, 1986). This 8-item self-report measure captures nicotine withdrawal symptoms on a 5-point scale (0=none, 1=slight, 2=mild, 3=moderate, 4=severe) with total scores ranging from 0-32.

2.4. Statistical Analyses

2.4.1. Outcomes

The primary efficacy outcome was urine cotinine-confirmed (≤50 ng/mL) 7-day self-reported abstinence at the week 12 end-of-treatment visit. Secondary efficacy measures included weekly self-reported and breath CO-confirmed (≤8 parts per million) abstinence (since the prior weekly visit) during study treatment (weeks 1-12), and nicotine withdrawal. Further, weekly measures of self-reported cigarettes smoked per day during study treatment were examined to assess changes in behavior when abstinence was not achieved. TLFB methods allowed for reliable collection of smoking data even over periods when study visits were missed.

2.4.2. Baseline Clinical and Demographic Characteristics

Standard clinical and demographic characteristics were tabulated for the study cohort and stratified by low/high ADHD-RS subscales. Differences between groupings were compared using Pearson Chi-Square test for categorical variables and Wilcoxon Rank-Sum test for continuous variables.

2.4.3. Analysis of the ADHD Symptoms on Efficacy Outcomes

The primary hypothesis was that lower baseline ADHD symptom counts would be associated with an increase in the probability of end-of-treatment cotinine-confirmed 7-day abstinence. A logistic regression model with a sandwich variance estimate was used to assess this primary efficacy outcome (Zou, 2004). Secondarily, repeated measures logistic regression models using the methods of generalized estimating equations (Zeger and Liang, 1986) were constructed to assess self-reported and CO-confirmed abstinence at weekly treatment visits (weeks 1-12). Working correlation structures were independently compared and the final model structure was chosen using the quasi-likelihood under the independence model criterion (QIC) (Pan, 2001) and the variance-covariance matrices; specifically autoregressive, compound symmetric and banded structures were compared. First order autoregressive structure provided a better model fit than a compound symmetric or a banded structure. Risk Ratios (RR) and asymptotic 95% confidence intervals (CI) were computed for all abstinence efficacy estimates.

Cigarettes smoked per day were collected via TLFB and weekly average CPD tabulated throughout treatment. As there was an effect of ADHD symptoms on study abstinence, CPD are analyzed only during non-abstinent visits (weeks) to assess if number of ADHD symptoms affects cigarettes per day in those that fail to achieve abstinence. Linear mixed effects models were utilized to assess group level differences in CPD.

Following analysis of baseline ADHD symptoms on study outcomes, models assessing the relationship between co-occurring, longitudinal ADHD symptoms (measured at study weeks 4, 8, 12) and smoking outcomes were assessed utilizing time dependent ADHD variables. Linear mixed effects models were developed to examine the time varying effects of ADHD symptoms during study treatment with smoking outcomes.

Lastly, linear mixed effects models were similarly developed to examine the relationship between baseline and longitudinal ADHD symptoms and nicotine withdrawal severity utilizing the MNWS across participants regardless of abstinence status. All models included study treatment assignment, study visit (where appropriate), baseline smoking rate and baseline measures of study outcomes (e.g., MNWS, ADHD symptoms). Further, all models assessed the interaction of study treatment with ADHD symptoms and are retained in models when statistically significant (p<0.05). Model based means and standard errors were calculated for group level comparisons. Significance is noted with a two-sided alpha of 0.05. All analysis were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

3. RESULTS

3.1. Participant Characteristics

Participant demographics and baseline characteristics are presented in Table 1. Of 206 screened individuals, 157 were randomized to one of two double-blind treatments: 77 to receive varenicline and 80 to receive placebo. The end-of-treatment visit was attended by 90 (57%) participants (45 varenicline, 45 placebo). Randomized participants averaged 19.1 years of age (range 14-21) and were predominantly male (59.9%; n=94) and white (76.4%, n=120). At study entry, randomized participants averaged 11.5 cigarettes per day and had been smoking regularly for more than 4 years. At baseline, participants reported an ADHD symptom count that was in the sub-clinical range (total symptom count: mean=9.0, SD=5.0; IA symptom count: mean=5.0, SD=2.8; HI symptom count: mean=4.0, SD =2.7). As reported in the parent trial (Gray et al., 2019), medication adherence, captured by daily medication diaries and weekly pill count, was 98% in the varenicline group and 96% in the placebo group.

Table 1.

Participant Characteristics Overall and Stratified by Baseline Low/High ADHD-RS Subscale Scores

Characteristic Overall
n=157		 IA HI
Low (n=67) High (n=89) Low (n=93) High (n=63)
Sex n (%)
Female 63 (40%) 30 (45%) 33 (37%) 37 (40%) 26 (41%)
Male 94 (60%) 37 (55%) 56 (63%) 56 (60%) 37 (59%)
Race n (%)
Caucasian 120 (76%) 49 (73%) 70 (79%) 71 (76%) 48 (76%)
Other 37 (24%) 18 (27%) 19 (21%) 22 (24%) 15 (24%)
Age (years) 19.1 (1.5) 19.2 (1.5) 19.0 (1.5) 19.2 (1.39) 19.0 (1.55)
Active Treatment n (%) 77 (49%) 38 (57%) 38 (43%) 48 (52%) 28 (44%)
Cotinine (ng/ml) 1011 (652.0) 937 (678.2) 1062 (633.7) 949 (659.5) 1096 (640.4)
Carbon monoxide 15.2 (10.42) 14.2 (11.22) 15.7 (9.72) 14.0 (10.22) 16.7 (10.49) *
Cigarettes per day 11.5 (6.80) 12.0 (8.11) 11.1 (5.68) 11.2 (6.26) 11.8 (7.61)
Days smoked (30 days) 29.2 (2.72) 28.8 (3.45) 29.4 (2.02) 29.1 (2.78) 29.3 (2.68)
Age began smoking 14.7 (2.42) 14.6 (2.23) 14.8 (2.57) 14.8 (2.27) 14.5 (2.65)
Age began smoking regularly 16.3 (1.90) 16.2 (2.01) 16.4 (1.82) 16.4 (1.92) 16.1 (1.87)
# of quitting attempts 2.5 (2.26) 2.4 (1.54) 2.5 (2.71) 2.3 (2.42) 2.7 (2.04)
MNWS 6.1 (4.6) 4.6 (3.8) 7.3 (4.8) * 4.6 (3.7) 8.4 (5.0) *
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*

p<0.05 as compared to low HI/IA group

IA=Inattention domain; HI=hyperactive/impulsive domain; MNWS=Minnesota Nicotine Withdrawal Scale

1 participant is missing hyperactivity and inattention values.

1 participant is missing # of quitting attempts.

Cotinine values >2000 entered as 2000, and <50 entered as 49. 2 participants are missing cotinine values.

3.2. Effect of Baseline ADHD Symptoms on Smoking Outcomes

3.2.1. Baseline Inattention

The effect of baseline ADHD IA symptom count on abstinence from cigarettes during study treatment is shown in Table 2. Participants with low ADHD-RS IA item endorsement had nearly three times the probability of end of treatment abstinence as compared with participants with high IA item endorsement [Low IA: 48.6% vs. High IA: 16.7%; RR=2.9 (95% CI=1.5,5.7); p=0.002]. Similarly, increases in continuous ADHD-RS IA scores measured at baseline were associated with decreases in the probability of end of treatment abstinence [RR=0.9 (95% CI=0.9,1.0); p=0.032]. When considering all weekly 7-day point prevalence abstinence measures during treatment (12 weeks), participants with low baseline ADHD-RS IA item endorsement had greater than twice the probability of weekly abstinence than those with high baseline ADHD-RS IA item endorsement [Figure 1a; Low IA: 23.8% vs. High IA: 10.7%; RR=2.4 (95% CI=1.5,3.9); p=0.001], ADHD IA symptom count group at study baseline did not significantly modify end of treatment or during treatment varenicline efficacy (count group × treatment group interaction: ps>0.2). During study weeks in which abstinence was not achieved, those with high IA symptom item endorsement at baseline reported smoking more cigarettes per day as compared to those with low item endorsement [High IA: 4.9 (SE=0.3) CPD vs. Low IA: 3.6 (SE=0.4); p=0.009; Table 3 and Figure 2a] and an increase in overall continuous IA score was associated with a moderate increase in CPD [β=0.104 (SE=0.047); p=0.027].

Table 2.

Association Between Baseline ADHD Symptoms and Self-Reported Point Prevalence Abstinence

During treatment (12 weekly treatment visits) Percent Abstinent Estimates RR (95% CI) χ21, P Value
ADHD-RS IA
Low Score 23.8% (119/500) --- 2.38 (1.46,3.88) χ21=12.6, p=0.001
High Score 10.7% (82/769) ---
Continuous --- β=−0.059 (0.031) 0.94 (0.89,1.00) χ21=3.7, p=0.053
ADHD-RS HI
Low Score 17.2% (128/746) --- 1.42 (0.82, 2.43) χ21=1.7, p=0.21
High Score 14.0% (73/523) ---
Continuous --- β=−0.008 (0.027) 0.99 (0.94,1.05) χ21=0.1, p=0.77
End of Study treatment (Week 12) Percent Abstinent Estimates RR (95% CI) χ21, P Value
ADHD-RS IA
Low Score 48.6% (17/36) --- 2.88 (1.46, 5.69) χ21=9.3, p=0.002
High Score 16.7% (9/54) ---
Continuous --- β=−0.09 (0.04) 0.92 (0.85, 0.99) χ21=4.6, p=0.032
ADHD-RS HI
Low Score 37.7% (20/53) --- 2.10 (0.94, 4.70) χ21=3.3, p=0.070
High Score 16.8% (6/36) ---
Continuous --- β=−0.12 (0.05) 0.89 (0.81, 0.98) χ21=5.6, p=0.018
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IA=Inattention domain; HI=hyperactive/impulsive domain; RR=risk ratio; CI=confidence interval

Models adjusted for study treatment assignment, study visit (where appropriate) and baseline average cigarettes per day.

Figure 1.

Figure 1.

Figure 1.

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Proportion of weekly 7-day point prevalence abstinence stratified by (a) high/low IA ADHD and (b) high/low HI ADHD.

IA=Inattention domain; HI=hyperactive/impulsive domain; PPA = 7-day point prevalence abstinence

Table 3.

Association Between Baseline ADHD Symptoms and Self-Reported Cigarettes per Day During Non-Abstinent Weeks

During treatment (12 weekly treatment visits) Mean (SD) Estimates ES (SEM) F (df), P Value
ADHD-RS IA
Low Score 3.6 (0.4) --- 1.28 (0.49) 6.9 (1,139), p=0.009
High Score 4.9 (0.3) ---
Continuous --- β=0.104 (0.047) --- 5.0 (1,139), p=0.027
ADHD-RS HI
Low Score 4.1 (0.3) --- 0.79 (0.48) 2.7 (1,139), p=0.10
High Score 4.8 (0.4) ---
Continuous --- β=0.073 (0.055) --- 1.7 (1,139), p=0.19
End of Study treatment (Week 12) Mean (SD) Estimates ES (SEM) F (df), P Value
ADHD-RS IA
Low Score 2.9 (0.8) --- 0.30 (0.99) 0.1 (1,59), p=0.76
High Score 3.2 (0.5) ---
Continuous --- β=0.079 (0.083) --- 1.0 (1,59), p=0.35
ADHD-RS HI
Low Score 2.6 (0.6) --- 1.00 (0.9) 1.3 (1,59), p=0.27
High Score 3.6 (0.6) ---
Continuous --- β=0.058 (0.098) 0.4 (1,59), p=0.56
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IA=Inattention domain; HI=hyperactive/impulsive domain; SD = standard deviation, ES=effect size; SEM=standard error of the mean

Models adjusted for study treatment assignment, study visit (where appropriate) and baseline average cigarettes per day.

Figure 2.

Figure 2.

Figure 2.

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Average Cigarettes Smoked per Day (CPD) Measured at Each Study Visit Stratified by (a) high/low IA ADHD and (b) high/low HI ADHD.

IA=Inattention domain; HI=hyperactive/impulsive domain; CPD = cigarettes per day

3.2.1. Baseline Hyperactivity-Impulsivity

The effect of baseline ADHD HI severity on abstinence from cigarettes is shown in Table 2. Consistent with ADHD-RS IA scores, increases in continuous ADHD-RS HI score was associated with decreases in the probability of end of treatment abstinence [RR=0.9 (95% CI=0.8,1.0); p=0.018]. Although failing to meet statistical significance, participants with low ADHD HI item endorsement had twice the probability of end of treatment abstinence as compared to those with low HI item endorsement [Low HI: 37.7% vs. High HI: 16.8%; RR=2.1 (95% CI=0.9,4.7); p=0.07]. When considering all weekly 7-day point prevalence abstinence measures, there were no significant effects of ADHD HI scores on abstinence (Figure 1b). ADHD HI symptom endorsement at study baseline did not significantly modify end of treatment or during treatment varenicline efficacy (ps>0.19). The effect of ADHD HI symptoms on mean CPD are shown in Figure 2b. Although in the same direction as the grouping of IA symptoms, the relationship between ADHD HI and weekly CPD in those who were not abstinent failed to reach statistical significance (Table 3).

3.3. Effect of Longitudinal ADHD Symptoms on Smoking Outcomes

Throughout treatment, ADHD IA and HI scores and count groupings were not different between participants in the varenicline or placebo treatment groups (all p’s> 0.6; data not shown). Additionally, the time varying effects of ADHD item scores on cigarette use outcomes was examined. Model results show that participants who have low ADHD-RS IA item endorsement during study treatment (weeks 4, 8 and/or 12) were more likely to report 7-day point prevalence abstinence at the corresponding visit than those with high ADHD-RS IA item endorsement [Low IA: 26.4% vs. High IA: 14.3%; RR=1.8 (95% CI=1.1,3.2); p=0.03]; Similarly, in those that did not endorse abstinence, participants with low ADHD IA item endorsement reported fewer CPD in the week prior as compared to those with high ADHD IA item endorsement [High IA: 4.2 (SE=0.4) CPD vs. Low IA: 3.0 (SE=0.4); p=0.012]. ADHD HI severity during treatment was not significantly associated with 7-day PPA or average CPD (ps>0.15).

3.4. Effect of ADHD Symptoms on Nicotine Withdrawal

At study baseline, participants with increased ADHD IA and HI item endorsement reported significantly higher nicotine withdrawal symptoms [Table 1 MNWS; IA Severity high 7.3 (4.8) vs. Low 4.6 (3.8); p<0.001 and HI Severity high 8.4 (5.0) vs. Low 4.6 (3.7); p<0.001]. Withdrawal differences between ADHD symptom count groups persisted throughout study treatment [Figure 3a IA count high F1,140=9.3; p=0.003 and Figure 3b HI count high F1,140=15.0; p<0.001]. Further, examination of time varying association of ADHD-RS item endorsement and withdrawal scores during study treatment was examined. Withdrawal scores were significantly associated with concurrently measured AHDH IA [β=0.181 (SE=0.046); t177=3.9, p<0.001] and ADHD HI symptoms [β=0.209 (SE=0.054); t177=3.9, p<0.001]. This relationship was modified by treatment with varenicline [withdrawal score x treatment group interaction: ADHD IA: t176=2.0, p=0.045; ADHD HI: t176=2.5, p=0.012]. The relationship between withdrawal and ADHD symptoms during treatment is significant in those under the placebo condition [AHDH IA: β=0.344 (SE=0.077); t87=4.5, p<0.001; AHDH HI: β=0.308 (SE=0.070); t87=4.4, p<0.001] but not in those treated with varenicline [AHDH IA: β=0.101 (SE=0.073); t87=1.4, p=0.17; AHDH HI: β=0.074 (SE=0.061); t87=1.2, p=0.23]. Randomized treatment assignment was not independently associated with withdrawal scores during treatment [β=0.65 (SE=0.42); F1,141=2.5; p=0.12] nor was 7-day point prevalence abstinence in the week prior to withdrawal measurement [β=0.25 (SE=0.33); F1,51=0.6; p=0.44]. Although not directly affecting withdrawal, varenicline may modify the relationship between ADHD and withdrawal during study treatment.

Figure 3.

Figure 3.

Figure 3.

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Caption: Mean MNWS Score Measured at Weekly Study Visits Stratified by (a) high/low IA ADHD and (b) high/low HI ADHD.

IA=Inattention domain; HI=hyperactive/impulsive domain; MNWS = Minnesota Nicotine Withdrawal Scale

4. Discussion

While numerous studies have highlighted how adolescents and adults with ADHD are more likely to engage in cigarette smoking (Gudjonsson et al., 2012; Mitchell et al., 2019), fewer studies have examined how the number and type of ADHD symptoms impact smoking cessation treatment outcomes. The primary aims of the present study were to examine how ADHD symptomology may alter smoking cessation in a sample of adolescents and young adults in a clinical trial of varenicline for smoking cessation.

4.1. Effect of Baseline ADHD Symptoms on Smoking Outcomes

We found a consistent pattern such that those with greater IA symptoms at baseline were less likely to be abstinent during treatment and at the end of treatment. This pattern was not seen for HI symptoms. We did observe a significant association when HI symptoms were examined continuously, with lower odds of abstinence among those reporting greater HI scores. When abstinence was not achieved, we observed similar results for cigarettes per day as greater IA symptoms predicted greater cigarettes per day, and there was no association between HI symptoms and smoking. Medication condition did not moderate the effect of either subtype on abstinence of cigarettes per day. It is unlikely this was due to lack of medication adherence as both groups exhibited high rates of adherence (>95%).

Our findings differ from Bidwell and colleagues (2017) which suggested baseline HI symptoms were a more consistent predictor of smoking cessation. At younger age ranges, IA symptoms may exert a stronger impact on smoking cessation. Our sample was on average approximately 15 years younger than the sample from Bidwell and colleagues (2017). Aligned with the ‘self-medication’ hypothesis (van Amsterdam et al., 2018), adolescent and young adult smokers may be more likely to smoke to alleviate lapses in attention. While prior studies have noted the difficulties in understanding the functional impairments of ADHD across the lifespan (Caye et al., 2016), adults with ADHD may have developed alternative strategies to cope with IA symptoms and may be less likely to rely on smoking as maladaptive coping. Compared to those with greater HI symptoms, impairments in sustained attention that are often more strongly associated with greater IA symptoms may render individuals with predominant IA symptoms more susceptible to smoking lapse. Furthermore, within the domain of impulsivity there may be specific facets that are differentially related to cigarette use. Prior studies in adult smokers without ADHD have found sensation seeking is associated with increased cigarette craving while urgency and lack of perseverance is associated with greater negative mood following a smoking cue-exposure paradigm (Doran et al., 2009). Therefore, the umbrella ADHD symptom subtype of HI may conceal these various facets that could differentially impact objective smoking behavior, resulting in the largely null findings in our sample.

4.2. Effect of Longitudinal ADHD Symptoms on Smoking Outcomes

Throughout treatment greater IA symptoms were associated with lower odds of abstinence and greater cigarettes per day at the subsequent visit, but this pattern was not present for HI symptoms. Unlike Bidwell and colleagues (2017) that only assessed for ADHD symptoms at baseline, we measured ADHD symptoms throughout the clinical trial (measured at study weeks 4, 8, 12). Our results aligned with the effects of baseline ADHD symptoms demonstrating how IA symptoms are a more consistent predictor of cessation outcomes compared to HI symptoms. While previous studies have noted an effect of varenicline on related constructs such as reduced lapses in attention in adult smokers (Rhodes et al., 2012), we did not observe an effect of medication on longitudinal ADHD symptom count for either subtype. Finally, the lack of a moderating effect of varenicline in our sample suggests that, for adolescents and young adults, the effect of varenicline on smoking cessation does not vary by ADHD symptom subtype or count. More severe ADHD symptoms, as seen in a sample with an established ADHD diagnosis, may be needed to observe an effect of treatment over and above the relationship between ADHD symptom subtype and smoking cessation outcomes.

4.3. Effect of ADHD Symptoms on Nicotine Withdrawal

Across both ADHD symptom subtypes, we found participants in the high group reported more severe nicotine withdrawal symptoms at baseline and throughout the study. During study treatment, we found a concurrent association between both IA and HI symptom groups that was modified by treatment. The findings were in the opposite direction than we expected, as nicotine withdrawal was associated with both ADHD symptom subtypes when participants were randomized to placebo, but not varenicline. Greater levels of nicotine withdrawal may be needed to observe a moderating effect of varenicline on ADHD symptom count. Unlike our abstinence and cigarettes per day outcomes where we primarily observed an association with IA symptom endorsement, the association between both ADHD symptom subtypes and nicotine withdrawal further highlights the complex relationship between ADHD symptomology and indicators of smoking behavior. Future studies are needed to further understand the associations between ADHD symptom subtypes and severity, and peripheral indicators of smoking behavior including nicotine withdrawal and subjective craving for cigarettes.

The present study must be interpreted in light of strengths and weaknesses. Strengths of the study include relatively equal group sizes and baseline smoking characteristics between ADHD symptom subtype and count (high/low), examining ADHD symptom count as both a continuous and binary outcome, and combination of smoking outcomes including cotinine-confirmed abstinence and continued smoking during non-abstinent weeks throughout trial and at end-of-treatment. Limitations include the use of only self-report for ADHD symptoms without consideration of frequency, as this may have resulted in underreporting of symptoms particularly of HI subtype that may be more difficult to self-identify. There was also a relatively limited range of severity for nicotine withdrawal. An additional limitation is that our study was not focused on a sample of participants who met diagnostic criteria for ADHD; rather, we examined ADHD symptomology regardless of ADHD diagnostic status.

5. Conclusion

The present study demonstrates a relationship between ADHD symptom endorsement and smoking cessation outcomes among adolescents and young adults. Our results suggest that smokers with higher IA symptom endorsement are at greater risk for continued smoking, and that regardless of ADHD symptom subtype, varenicline does not modify treatment response. Across both ADHD symptom subtypes, greater number of symptoms is associated with increased nicotine withdrawal. Collectively, our findings highlight the need to attend to ADHD symptomology in smoking cessation treatment for youth. As ADHD is a risk factor for smoking initiation, examining how ADHD symptoms impact smoking cessation in younger age ranges is critical for tailoring treatment options to prevent continued cigarette use into adulthood.

Highlights.

  • Few studies have examined the impact of ADHD symptoms count on smoking outcomes

  • Greater inattentive symptoms predicted less abstinence and more cigarettes per day

  • Hyperactive-impulsive symptoms did not consistently predict smoking outcomes

  • Varenicline did not moderate the effect of ADHD symptoms on smoking cessation

Role of Funding Source

This study was supported by grants U01 DA031779 (KMG) from the National Institute of Health (NIH). RG was supported by training grant T32AA007474-35 from National Institute on Alcohol Abuse and Alcoholism (NIAAA). Varenicline and placebo tablets were supplied at no cost by Pfizer Inc.

Conflict of Interest

NLB reported receiving grant support from the NIH. KG reported consulting for Pfizer, Inc, and receiving grant support from the NIH. All other authors have no conflicts of interest to disclose.

Footnotes

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