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.

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.

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.

The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults.

BACKGROUND: Both Attention Deficit Hyperactivity Disorder (ADHD) and chronic cannabis (CAN) use have been associated with brain structural abnormalities, although little is known about the effects of both in young adults. METHODS: Participants included: those with a childhood diagnosis of ADHD who were CAN users (ADHD_CAN; n=37) and non-users (NU) (ADHD_NU; n=44) and a local normative comparison group (LNCG) who did (LNCG_CAN; n=18) and did not (LNCG_NU; n=21) use CAN regularly. Multiple regressions and MANCOVAs were used to examine the independent and interactive effects of a childhood ADHD diagnosis and CAN group status and age of onset (CUO) on subcortical volumes and cortical thickness. RESULTS: After controlling for age, gender, total brain volume, nicotine use, and past-year binge drinking, childhood ADHD diagnosis did not predict brain structure; however, persistence of ADHD was associated with smaller left precentral/postcentral cortical thickness. Compared to all non-users, CAN users had decreased cortical thickness in right hemisphere superior frontal sulcus, anterior cingulate, and isthmus of cingulate gyrus regions and left hemisphere superior frontal sulcus and precentral gyrus regions. Early cannabis use age of onset (CUO) in those with ADHD predicted greater right hemisphere superior frontal and postcentral cortical thickness. DISCUSSION: Young adults with persistent ADHD demonstrated brain structure abnormalities in regions underlying motor control, working memory and inhibitory control. Further, CAN use was linked with abnormal brain structure in regions with high concentrations of cannabinoid receptors. Additional large-scale longitudinal studies are needed to clarify how substance use impacts neurodevelopment in youth with and without ADHD.

ADHD and cannabis use in young adults examined using fMRI of a Go/NoGo task.

Children diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for substance abuse. Response inhibition is a hallmark of ADHD, yet the combined effects of ADHD and regular substance use on neural networks associated with response inhibition are unknown. Task-based functional Magnetic Resonance Imaging (fMRI) data from young adults with childhood ADHD with (n = 25) and without (n = 25) cannabis use ≥ monthly in the past year were compared with a local normative comparison group (LNCG) with (n = 11) and without (n = 12) cannabis use. Go/NoGo behavioral and fMRI data were evaluated for main and interaction effects of ADHD diagnosis and cannabis use. ADHD participants made significantly more commission errors on NoGo trials than controls. ADHD participants also had less frontoparietal and frontostriatal activity, independent of cannabis use. No main effects of cannabis use on response inhibition or functional brain activation were observed. An interaction of ADHD diagnosis and cannabis use was found in the right hippocampus and cerebellar vermis, with increased recruitment of these regions in cannabis-using controls during correct response inhibition. ADHD participants had impaired response inhibition combined with less fronto-parietal/striatal activity, regardless of cannabis use history. Cannabis use did not impact behavioral response inhibition. Cannabis use was associated with hippocampal and cerebellar activation, areas rich in cannabinoid receptors, in LNCG but not ADHD participants. This may reflect recruitment of compensatory circuitry in cannabis using controls but not ADHD participants. Future studies targeting hippocampal and cerebellar-dependent function in these groups may provide further insight into how this circuitry is altered by ADHD and cannabis use.

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior.

Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (quicker and higher peak concentrations). We evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic clinical drug delivery. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60mg/kg/day; as well as dual-dosages of 4 and 10mg/kg/day, 20 and 30mg/kg/day, or 30 and 60mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30ng/mL), while the 4/10mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8ng/mL). Treatment with the higher dual-dosage (HD: 30/60mg/kg) resulted in hyperactivity, while the lower (LD: 4/10mg/kg) had no effect. Chronic effects of these dual-dosages were assessed throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle, decreased exploratory behavior, and increased anxiolytic behavior. Findings suggest that these dual-dosage-drinking-paradigms can be used to examine the effects of clinically relevant pharmacokinetic doses of MP and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes.

Impact of ADHD and cannabis use on executive functioning in young adults.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and cannabis use are each associated with specific cognitive deficits. Few studies have investigated the neurocognitive profile of individuals with both an ADHD history and regular cannabis use. The greatest cognitive impairment is expected among ADHD Cannabis Users compared to those with ADHD-only, Cannabis use-only, or neither. METHODS: Young adults (24.2 ± 1.2 years) with a childhood ADHD diagnosis who did (n=42) and did not (n=45) report past year ≥ monthly cannabis use were compared on neuropsychological measures to a local normative comparison group (LNCG) who did (n=20) and did not (n=21) report past year regular cannabis use. Age, gender, IQ, socioeconomic status, and past year alcohol and smoking were statistical covariates. RESULTS: The ADHD group performed worse than LNCG on verbal memory, processing speed, cognitive interference, decision-making, working memory, and response inhibition. No significant effects for cannabis use emerged. Interactions between ADHD and cannabis were non-significant. Exploratory analyses revealed that individuals who began using cannabis regularly before age 16 (n=27) may have poorer executive functioning (i.e., decision-making, working memory, and response inhibition), than users who began later (n=32); replication is warranted with a larger sample. CONCLUSIONS: A childhood diagnosis of ADHD, but not cannabis use in adulthood, was associated with executive dysfunction. Earlier initiation of cannabis use may be linked to poor cognitive outcomes and a significantly greater proportion of the ADHD group began using cannabis before age 16. Regular cannabis use starting after age 16 may not be sufficient to aggravate longstanding cognitive deficits characteristic of ADHD.

Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases.

Chronic exposure to methylphenidate impairs appendicular bone quality in young rats.

Methylphenidate (MP) is a psychostimulant widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD). Although generally well tolerated, growth deficits have been reported in children and adolescents undergoing MP treatment. This study was designed to elucidate the skeletal effects of chronic MP administration in adolescent rats. Male, 4-week-old rats received one of two doses of MP (MP-Low or MP-High) delivered for 8 h a day via drinking water, or were untreated (water only). After 13 weeks, half were sacrificed (N=12/group) and the remaining rats were left to recover, untreated for 5 additional weeks. Femora, tibiae, and L5 vertebra were analyzed using calipers, DXA, and mechanical testing. Immediately following treatment, MP decreased femoral anterior-posterior diameter (5% and 9% for MP-Low and MP-High, respectively), femoral and tibial bone mineral density (BMD) (6% and 5% for MP-High femora and tibiae, respectively), and bone mineral content (BMC) (9% for MP-High femora and tibiae). In addition, femora from MP treated rats had reduced ultimate force (20% for MP-High) and energy to failure (20% and 33% for MP-Low and MP-High, respectively). However, after recovery, there were no statistically significant differences for any measured parameters. Despite these effects on the appendicular skeleton, no differences were identified between vertebral samples at either time-point. In summary, MP treatment resulted in smaller, less mineralized, and weaker bones at appendicular sites, but did not affect the axial site. Although these effects were ameliorated within 5 weeks, these data suggest that adolescents undergoing MP treatment may be at an increased risk for long bone fractures.

Dissociation between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats in baseline performance and methylphenidate response on measures of attention, impulsivity and hyperactivity in a Visual Stimulus Position Discrimination Task.

The spontaneously hypertensive rat (SHR) is a widely accepted rodent model of Attention Deficit/Hyperactivity Disorder (ADHD), and methylphenidate (MP) is a central nervous system stimulant that has been shown to have a dose-related positive effect on attention task performance in humans with ADHD. The current study was undertaken to compare SHR to its typical control strain, Wistar-Kyoto (WKY) rats, on the performance of a Visual Stimulus Position Discrimination Task (VSPDT) as well as of the responsiveness of the two rat strains to MP treatment. The rats were initially trained on the VSPDT, in which a light cue was presented randomly at three different cue-light intervals (1s, 300ms and 100ms) over one of two levers, and presses on the lever corresponding to the light cue were reinforced with a food pellet. Once rats reached stable performance, the treatment phase of the study began, during which they received daily intraperitoneal (IP) injections of saline, 2mg/kg, 5mg/kg, and 10mg/kg of MP in a randomized order immediately prior to being tested on the VSPDT. Baseline performance accuracy on the VSPDT did not differ between the groups. Furthermore, a striking strain dissociation was evident in the response of the two strains to treatment; VSPDT performance was substantially disrupted by the 5 and 10mg/kg dose in the WKY rats but only mildly in the SHR rats. Response omissions were also increased only in WKY rats. Finally, both strains had increased locomotor activity in the operant chamber following MP treatment. These findings point to an important difference in response tendency to MP in the two strains that supports a view that a critical difference between these strains may suggest neurochemical and neuroadaptive differences associated with the behavioral impairments of ADHD.

Developmental origins of health and disease: environmental exposures.

The developmental origins of health and disease (DOHaD) approach has evolved over the past 20 years, and the current hypothesis proposes that fetal adaptations to intrauterine and maternal conditions during development shape structure and function of organs. Here we present a review of some environmental exposures that may trigger fetal maladaptations in these processes, including three examples: exposures to tobacco smoke, antidepressant medication, and folic acid deficits in the food supply. We provide a selected review of current research on the effects of each of these exposures on fetal development and birth outcomes, and use the DOHaD approach to suggest how these exposures may alter long-term outcomes. In the interpretation of this literature, we review the evidence of gene-environment interactions based on evaluation of biological pathways and evidence that some exposures to the fetus may be moderated by maternal and fetal genotypes. Finally, we use the design of the National Children's Study (now in progress) to propose how the DOHaD approach could be used to address questions that have emerged in this area that are relevant to reproductive medicine and subsequent health outcomes.

Parent and teacher SNAP-IV ratings of attention deficit hyperactivity disorder symptoms: psychometric properties and normative ratings from a school district sample.

To examine Swanson, Nolan, and Pelham-IV (SNAP-IV) psychometric properties, parent (N = 1,613) and teacher (N = 1,205) data were collected from a random elementary school student sample in a longitudinal attention deficit hyperactivity disorder (ADHD) detection study. SNAP-IV reliability was acceptable. Factor structure indicated two ADHD factors and an oppositional defiant disorder (ODD) factor. Parent and teacher scores varied by gender and poverty status (d = .49-.56) but not age; only teacher scores varied by race (d = .25-.55). Screening and diagnostic utility was evaluated with likelihood ratios (LRs) and posttest probabilities. Parent SNAP-IV scores above 1.2 increased probability of concern (LR > 10) and above 1.8, of ADHD diagnosis (LR > 3). Teacher hyperactivity/impulsivity scores above 1.2 and inattention scores above 1.8 increased probabilities of concern only (LR = 4.2 and >5, respectively). Higher teacher scores for African American children and race differences in measurement models require future study.