Association Between Stimulant Treatment and Substance Use Through Adolescence Into Early Adulthood.

Importance: Possible associations between stimulant treatment of attention-deficit/hyperactivity disorder (ADHD) and subsequent substance use remain debated and clinically relevant. Objective: To assess the association of stimulant treatment of ADHD with subsequent substance use using the Multimodal Treatment Study of ADHD (MTA), which provides a unique opportunity to test this association while addressing methodologic complexities (principally, multiple dynamic confounding variables). Design, Setting, and Participants: MTA was a multisite study initiated at 6 sites in the US and 1 in Canada as a 14-month randomized clinical trial of medication and behavior therapy for ADHD but transitioned to a longitudinal observational study. Participants were recruited between 1994 and 1996. Multi-informant assessments included comprehensively assessed demographic, clinical (including substance use), and treatment (including stimulant treatment) variables. Children aged 7 to 9 years with rigorously diagnosed DSM-IV combined-type ADHD were repeatedly assessed until a mean age of 25 years. Analysis took place between April 2018 and February 2023. Exposure: Stimulant treatment of ADHD was measured prospectively from baseline for 16 years (10 assessments) initially using parent report followed by young adult report. Main Outcomes and Measures: Frequency of heavy drinking, marijuana use, daily cigarette smoking, and other substance use were confidentially self-reported with a standardized substance use questionnaire. Results: A total of 579 children (mean [SD] age at baseline, 8.5 [0.8] years; 465 [80%] male) were analyzed. Generalized multilevel linear models showed no evidence that current (B [SE] range, -0.62 [0.55] to 0.34 [0.47]) or prior stimulant treatment (B [SE] range, -0.06 [0.26] to 0.70 [0.37]) or their interaction (B [SE] range, -0.49 [0.70] to 0.86 [0.68]) were associated with substance use after adjusting for developmental trends in substance use and age. Marginal structural models adjusting for dynamic confounding by demographic, clinical, and familial factors revealed no evidence that more years of stimulant treatment (B [SE] range, -0.003 [0.01] to 0.04 [0.02]) or continuous, uninterrupted stimulant treatment (B [SE] range, -0.25 [0.33] to -0.03 [0.10]) were associated with adulthood substance use. Findings were the same for substance use disorder as outcome. Conclusions and Relevance: This study found no evidence that stimulant treatment was associated with increased or decreased risk for later frequent use of alcohol, marijuana, cigarette smoking, or other substances used for adolescents and young adults with childhood ADHD. These findings do not appear to result from other factors that might drive treatment over time and findings held even after considering opposing age-related trends in stimulant treatment and substance use.

Heart rate and gas exchange dynamic responses to multiple brief exercise bouts (MBEB) in early- and late-pubertal boys and girls.

Natural patterns of physical activity in youth are characterized by brief periods of exercise of varying intensity interspersed with rest. To better understand systemic physiologic response mechanisms in children and adolescents, we examined five responses [heart rate (HR), respiratory rate (RR), oxygen uptake (V̇O2 ), carbon dioxide production (V̇CO2 ), and minute ventilation (V̇E), measured breath-by-breath] to multiple brief exercise bouts (MBEB). Two groups of healthy participants (early pubertal: 17 female, 20 male; late-pubertal: 23 female, 21 male) performed five consecutive 2-min bouts of constant work rate cycle-ergometer exercise interspersed with 1-min of rest during separate sessions of low- or high-intensity (~40% or 80% peak work, respectively). For each 2-min on-transient and 1-min off-transient we calculated the average value of each cardiopulmonary exercise testing (CPET) variable (Y̅). There were significant MBEB changes in 67 of 80 on- and off-transients. Y̅ increased bout-to-bout for all CPET variables, and the magnitude of increase was greater in the high-intensity exercise. We measured the metabolic cost of MBEB, scaled to work performed, for the entire 15 min and found significantly higher V̇O2 , V̇CO2 , and V̇E costs in the early-pubertal participants for both low- and high-intensity MBEB. To reduce breath-by-breath variability in estimation of CPET variable kinetics, we time-interpolated (second-by-second), superimposed, and averaged responses. Reasonable estimates of τ (<20% coefficient of variation) were found only for on-transients of HR and V̇O2 . There was a remarkable reduction in τHR following the first exercise bout in all groups. Natural patterns of physical activity shape cardiorespiratory responses in healthy children and adolescents. Protocols that measure the effect of a previous bout on the kinetics of subsequent bouts may aid in the clinical utility of CPET.

Symptoms of obstructive sleep apnea are associated with less frequent exercise and worse subjective cognitive function across adulthood.

STUDY OBJECTIVES: To determine whether subjective measures of exercise and sleep are associated with cognitive complaints and whether exercise effects are mediated by sleep. METHODS: This study analyzed questionnaire data from adults (18-89) enrolled in a recruitment registry. The Cognitive Function Instrument (CFI) assessed cognitive complaints. Medical Outcomes Study Sleep Scale (MOS-SS) subscales and factor scores assessed sleep quality, daytime sleepiness, nighttime disturbance, and insomnia and obstructive sleep apnea (OSA)-like symptoms. Exercise frequency was defined as the weekly number of exercise sessions. Exercise frequency, MOS-SS subscales, and factor scores were examined as predictors of CFI score, adjusting for age, body mass index, education, sex, cancer diagnosis, antidepressant usage, psychiatric conditions, and medical comorbidities. Analyses of covariance examined the relationship between sleep duration groups (short, mid-range, and long) and CFI score, adjusting for covariates. Mediation by sleep in the exercise-CFI score relationship was tested. RESULTS: Data from 2106 adults were analyzed. Exercise and MOS-SS subscales and factor scores were associated with CFI score. Higher Sleep Adequacy scores were associated with fewer cognitive complaints, whereas higher Sleep Somnolence, Sleep Disturbance, Sleep Problems Index I, Sleep Problems Index II, and factor scores were associated with more cognitive complaints. MOS-SS subscales and factor scores, except Sleep Disturbance and the insomnia factor score, mediated the association between exercise and cognitive complaints. CONCLUSIONS: The relationship between exercise frequency and subjective cognitive performance is mediated by sleep. In particular, the mediation effect appears to be driven by symptoms possibly suggestive of OSA which are negatively associated with exercise engagement, sleep quality, daytime sleepiness, and subjective cognitive performance.

Early substance use in the pathway from childhood attention-deficit/hyperactivity disorder (ADHD) to young adult substance use: Evidence of statistical mediation and substance specificity.

This study tested whether early and developmentally atypical substance use mediates risk for adult substance use among children with attention-deficit/hyperactivity disorder (ADHD), and whether that risk is substance-specific. Participants were children with ADHD previously enrolled in a randomized controlled trial (RCT), and a demographically similar non-ADHD group, assessed at 2 through 16 years after the original RCT baseline. Self-reports of heavy drinking, marijuana use, daily smoking, and other illicit drug use were collected at follow-ups to establish atypically early and frequent use. Models estimated statistically mediated effects of childhood ADHD on adult substance use via early substance involvement, with planned comparisons to evaluate substance specificity. Results supported the mediation hypothesis, showing that childhood ADHD was associated with more frequent adult substance use via early substance involvement for marijuana, cigarettes, illicit drugs, and to a lesser extent, alcohol. Mediation was not escalated by comorbid childhood conduct disorder or oppositional defiant disorder except for early use of nonmarijuana illicit drugs. Substance-specificity in the mediational pathway was largely absent except for cigarette use, where ADHD-related early smoking most strongly predicted adult daily smoking. Findings from this study provide new evidence that atypically early substance use associated with childhood ADHD signals important cross-drug vulnerability by early adulthood, but cigarette use at a young age is especially associated with increased risk for habitual (daily) smoking specifically. Efforts to prevent, delay, or reduce substance experimentation should occur early and focus on factors relevant to multiple drugs of abuse in this at-risk population. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Adult substance use as a function of growth in peer use across adolescence and young adulthood in the context of ADHD: Findings from the MTA.

Peer substance use strongly predicts adolescent and young adult substance use, but its role in ADHD-related risk for substance use, especially in adulthood, is unclear. In a sample with (n = 516) and without (n = 249) childhood ADHD from the Multimodal Treatment Study of ADHD, we compared associations between change over time in peer substance use and personal substance use (alcohol, cigarettes, marijuana, illicit drugs) from age 14-26 by ADHD status. Developmentally typical peer substance use trajectories across adolescence and young adulthood coincided with similar changes in personal use - but less so for those with ADHD histories. Concurrent associations between peer and personal use in adolescence and young adulthood were weaker for those with ADHD histories than without for commonly used substances (alcohol, marijuana). Prospectively, escalating peer use during adolescence forecasted adulthood declines for commonly used substances, yet persistently high substance use at age 25, regardless of ADHD history. In the reverse direction, growth in adolescent substance use predicted developmentally normative young adult declines in peer use - but for the ADHD group, adolescent heavy drinking predicted increases in young adult peer use. Findings suggest that individuals with ADHD may have difficulty emulating their peers' developmentally normative declines in substance use, highlighting the importance of social factors when treating young adults affected by ADHD and substance abuse.

The effect of test modality on dynamic exercise biomarkers in children, adolescents, and young adults.

Cardiopulmonary exercise testing (CPET) modalities, treadmill (TM), and cycle ergometer (CE), influence maximal gas exchange and heart rate (HR) responses. Little is known regarding CPET modality effect on submaximal biomarkers during childhood and adolescence. Ninety-four healthy participants (7-34 y.o., 53% female) performed TM and CE CPET to address two major gaps: (1) the effect of modality on submaximal CPET biomarkers, and (2) estimation of work rate in TM CPET. Breath-by-breath gas exchange enabled calculation of linear regression slopes such as V˙ O2 /ΔHR and Δ V˙ E/Δ V˙ CO2 . Lean body mass (LBM) was measured with dual X-ray absorptiometry. We tested a novel TM CPET estimate of work rate based on TM velocity2 , incline, and body mass (VIM). Like the linear relationship between V˙ O2 and work rate in CE CPET, V˙ O2 increased linearly with TM VIM. TM Δ V˙ O2 /ΔHR was highly correlated with CE (r = 0.92), and each increased substantially with LBM (P < 0.0001 for TM and CE). Δ V˙ O2 /ΔHR was to a small (~8.7%) but significant extent larger in TM (1.6 mL/min/beat, P = 0.04). In contrast, TM and CE Δ V˙ E/Δ V˙ CO2 decreased significantly with LBM, supporting earlier observations from CE CPET. For both CE and TM, males had significantly higher Δ V˙ O2 /ΔHR but lower Δ V˙ E/Δ V˙ CO2 than females. Novel TM CPET biomarkers such as ΔVIM/ΔHR and ∆ V˙ O2 /ΔVIM paralleled effects of LBM observed in CE CPET. TM and CE CPET submaximal biomarkers are not interchangeable, but similarly reflect maturation during critical periods. CPET analysis that utilizes data actually measured (rather than estimated) may improve the clinical value of TM and CE CPET.

Discrepancies in the Validity of Self-Reported Cigarette Smoking in Adults With and Without ADHD.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is associated with an increased smoking prevalence and impairments in executive function, which may negatively affect the validity of self-reported smoking rates. This study compares the utility of self-reported smoking with salivary cotinine in adult smokers and nonsmokers with and without ADHD. Methods: Participants (N = 82) were adult smokers and nonsmokers with and without ADHD (n = 35 ADHD and n = 47 controls) from an observational study. Odds ratios (ORs) for accuracy of self-reported smoking compared to salivary cotinine were calculated using diagnosis (ADHD vs. control), gender, age, education, employment, and number of cigarettes per day as predictors. Post-hoc analysis stratified sensitivity, specificity, and accuracy of self-reported smoking in individuals with ADHD and without ADHD. Results: The initial analysis identified education as a significant independent predictor of odds of accuracy, OR = 6.22, p = .013, after adjusting for diagnosis, gender, age, employment, and cigarettes per day. Post-hoc analysis revealed that sensitivity, specificity, and accuracy of self-reported smoking was 100% for individuals with ADHD who had more than high school education compared to those with high school or less, which was 83.3%, 45.5%, and 65.2%, respectively. Self-reported smoking of control participants with greater than a high school education had a sensitivity of 85.7%, a specificity of 91.7%, and an accuracy of 88.5%. Control participants with a high school or lower education had a sensitivity of 54.6%, a specificity of 90%, and an accuracy of 71.4% for their self-reported smoking. Conclusions: Individuals with ADHD and high school or lower education showed the lowest specificity and accuracy in their self-reported smoking, which may affect documented smoking prevalence rates. This is a secondary analysis of data collected as part of a clinical trial registered as NCT00915798 at www.clinicaltrials.gov .

Cigarette Smoking Progression Among Young Adults Diagnosed With ADHD in Childhood: A 16-year Longitudinal Study of Children With and Without ADHD.

INTRODUCTION: Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for smoking cigarettes, but there is little longitudinal research on the array of smoking characteristics known to be prognostic of long-term smoking outcomes into adulthood. These variables were studied into early adulthood in a multisite sample diagnosed with ADHD combined type at ages 7-9.9 and followed prospectively alongside an age- and sex-matched local normative comparison group (LNCG). METHODS: Cigarette smoking quantity, quit attempts, dependence, and other characteristics were assessed in the longitudinal Multimodal Treatment Study of Children with ADHD (MTA) eight times to a mean age of 24.9 years: ADHD n = 469; LNCG n = 240. RESULTS: In adulthood, the ADHD group had higher rates of daily cigarette smoking, one or more quit attempts, shorter time to first cigarette of the day, and more severe withdrawal than the LNCG. The ADHD group did not appear to have better smoking cessation rates despite a higher proportion quitting at least once. Smoking quantity and nicotine dependence did not differ between groups. The ADHD group reported younger daily smoking onset and faster progression from smoking initiation to daily smoking across assessments. Finally, ADHD symptom severity in later adolescence and adulthood was associated with higher risk for daily smoking across assessments in the ADHD sample. CONCLUSIONS: This study shows that ADHD-related smoking risk begins at a young age, progresses rapidly, and becomes resistant to cessation attempts by adulthood. Prevention efforts should acknowledge the speed of uptake; treatments should target the higher relapse risk in this vulnerable population. IMPLICATIONS: Although childhood ADHD predicts later smoking, longitudinal studies of this population have yet to fully characterize smoking behaviors into adulthood that are known to be prognostic of long-term smoking outcome. The current study demonstrates earlier and faster progression to daily smoking among those with a childhood ADHD diagnosis, as well as greater risk for failed quit attempts. Prevention efforts should address speed of smoking uptake, while treatments are needed that address smoking relapse risk. The current study also demonstrates ADHD symptom severity over development increases daily smoking risk, implicating the need for continuous ADHD symptom management.

Substance use through adolescence into early adulthood after childhood-diagnosed ADHD: findings from the MTA longitudinal study.

BACKGROUND: Inconsistent findings exist regarding long-term substance use (SU) risk for children diagnosed with attention-deficit/hyperactivity disorder (ADHD). The observational follow-up of the Multimodal Treatment Study of Children with ADHD (MTA) provides an opportunity to assess long-term outcomes in a large, diverse sample. METHODS: Five hundred forty-seven children, mean age 8.5, diagnosed with DSM-IV combined-type ADHD and 258 classmates without ADHD (local normative comparison group; LNCG) completed the Substance Use Questionnaire up to eight times from mean age 10 to mean age 25. RESULTS: In adulthood, weekly marijuana use (32.8% ADHD vs. 21.3% LNCG) and daily cigarette smoking (35.9% vs. 17.5%) were more prevalent in the ADHD group than the LNCG. The cumulative record also revealed more early substance users in adolescence for ADHD (57.9%) than LNCG (41.9%), including younger first use of alcohol, cigarettes, marijuana, and illicit drugs. Alcohol and nonmarijuana illicit drug use escalated slightly faster in the ADHD group in early adolescence. Early SU predicted quicker SU escalation and more SU in adulthood for both groups. CONCLUSIONS: Frequent SU for young adults with childhood ADHD is accompanied by greater initial exposure at a young age and slightly faster progression. Early SU prevention and screening is critical before escalation to intractable levels.

Assessment of Dosing and Patient Factors on the Efficacy of Warfarin Following Total Joint Replacement.

The purpose of this study was to determine the percentage of patients discharged with a subtherapeutic INR <1.8 using our institutions inpatient warfarin dosing nomogram following total joint arthroplasty (TJA). We examined predisposing risk factors for a subtherapeutic discharge (INR <1.8), including increased body weight, age, gender, end stage renal disease (ESRD), smoking, and peri-operative transfusion. Chart review identified 249 patients for study inclusion. Logistic regression (LR) was used to identify associated risk factors for a subtherapeutic INR (<1.8) on day of discharge. The majority of patients (58.6%, 146 of 249) following TJA surgery were found to have a subtherapeutic INR level (INR<1.8) at discharge (mean length of stay 2.6 days). Multivariate LR analysis found that weight greater than 180 lbs. (OR 2.08, CI 1.09, 3.98, P=0.027) was found to increase the odds of a subtherapeutic INR on day of discharge. Our results were not significant for weight 20% beyond ideal body weight, age (>65y), gender, peri-operative transfusion, smoking, ESRD or autoimmune disease. A patient's body weight influences response to warfarin following TJA. An inpatient warfarin dosing nomogram that takes into account a patient's weight should be used to reduce the risk of subtherapeutic INR levels in obese TJA patients.