Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: A meta-analytic review☆
Research Highlights
► We meta-analyzed the prospective effect of childhood ADHD on substance outcomes. ► Children with ADHD were more likely to use substances than children without ADHD. ► Youth with ADHD were also more likely to have substance use disorders. ► This suggests that adolescent/adult substance problems are associated with early ADHD.
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is characterized by an early onset of persistent and impairing levels of inattention–disorganization and hyperactivity–impulsivity (American Psychiatric Association, 2000). ADHD occurs in 5–10% of school-age children (Scahill & Schwab-Stone, 2000) and represents one of the most common referrals for mental health and pediatric services in the U.S. (Barkley, 1998). ADHD is associated with comorbid mood (e.g., depression, anxiety) and disruptive behavior disorders (oppositional defiant disorder [ODD] and conduct disorder [CD]) (DBD), neuropsychological deficits (e.g., verbal working memory), family problems (e.g., negative parent–child interactions), poor academic achievement, and social dysfunction (e.g., peer rejection). These associations have been reported in boys and girls, including as young as preschool who have been followed prospectively into adolescence and young adulthood (Biederman et al., 2010, Lee et al., 2008, Owens et al., 2009). Thus, ADHD predicts a highly dispersed pattern of impairment across behavioral, academic, social, affective, and family domains (i.e., multifinality).
Substance use disorders (SUD) (i.e., abuse and dependence) also constitute a substantial clinical, public health, and economic concern in the United States and globally (Demyttenaere et al., 2004). In 2000, substance dependence was estimated to account for $67 billion in economic loss due to crime, social problems, foster care, and other health services (McLellan, Lewis, O'Brien, & Kleber, 2000). Among 18–59 year-old individuals participating in the National Comorbidity Survey Replication, a nationally-representative study of English-speaking adults in the United States, lifetime prevalence estimates ranged from 14.0% to 16.3% and 6.0% to 6.4% for alcohol abuse and alcohol dependence disorders, respectively (Kessler et al., 2005). For SUD more broadly (i.e., combining abuse and dependence), the lifetime prevalence in the same age range varied from 15.3% to 18.0% (Kessler, Berglund, et al., 2005). Although the 12-month prevalence of SUD in the same sample was expectedly lower (0.4% for drug dependence to 3.1% for alcohol abuse disorder), the severity of the disorders, based on functional impairment (e.g., suicide attempts, work disability, poor social relationships), was moderate to severe for most individuals (Kessler, Chiu, Demler, & Walters, 2005). In terms of clinical significance, SUD are frequently comorbid with other disorders. Substance abuse and dependence was each uniquely associated with increased comorbidity with mood disorders across six countries, and with externalizing problems (e.g., CD, antisocial behavior [ASB]) in the U.S. and Canada specifically (Merikangas et al., 1998). Finally, in addition to comorbidity, substance problems (e.g., binge drinking) are often associated with violence, accidental injuries, risky behavior (e.g., sexually transmitted disease), and poor health outcomes (e.g., hypertension) (Courtney & Polich, 2009). Thus, SUD are highly prevalent, costly, impairing, and resistant to treatment (Goldstein et al., 2009). To facilitate the development of interventions, there is an urgent need to identify precursors of SUD, particularly early in development. Detection of individuals at risk for SUD may facilitate implementation of early, targeted interventions to prevent the onset of SUD or to minimize their negative sequelae.
There are several reasons that ADHD and substance problems may be related. First, dopamine (DA) neurotransmission is central to current models of ADHD and SUD (Bédard et al., 2010, Ray et al., 2010, Volkow, Fowler, et al., 2009, Volkow, Wang, et al., 2009) and methylphenidate (MPH) is a highly efficacious treatment for the core symptoms of ADHD, although recent evidence suggests that therapeutic response may be time-limited (Molina et al., 2008). Positron emission tomography (PET) suggests that MPH enhances extracellular DA in the basal ganglia and anterior cingulate gyrus (Volkow, Fowler, Wang, Ding, & Gatley, 2002). MPH, by virtue of activating positive attention networks and distilling task-irrelevant stimuli, improves attention, vigilance, and motivation (Swanson, Baler, & Volkow, 2010). Second, a recent review of neuroimaging studies of humans with ADHD and SUD found replicated evidence of blunted striatal DA release and disrupted neural circuitry between the anterior cingulate cortex and striatum with prefrontal cortex (Frodl, 2010). Rodent and non-human primate models suggest the centrality of deficits in response inhibition, including dysfunctional circuitry in ventrolateral frontal, cingulate cortices, and basal ganglia regions, in both ADHD and SUD (Groman, James, & Jentsch, 2009). Third, offspring of adults with SUD are more likely to develop psychopathology, including ADHD (Clark et al., 1997, Schuckit and Smith, 1996). Elevated substance use problems have also been frequently reported in parents of children with ADHD (Chronis et al., 2003, Lahey et al., 1988, Molina et al., 1997). Finally, the prevalence of psychopathology, including SUD, is higher in first-degree relatives of ADHD probands than in healthy controls (Biederman, Faraone, Keenan, & Benjamin, 1992). Therefore, ADHD and SUD may share common etiological influences, including similar genetic factors (Iacono et al., 2008, Young et al., 2009; see Biederman et al., 2009, for an exception).
In fact, there is a sizable body of research suggesting that ADHD is associated with elevated substance use and related disorders (e.g., Boyle et al., 1993, Clure et al., 1999, Disney et al., 1999, Katusic et al., 2005, Mannuzza et al., 1998, Milberger, Biederman, Faraone, Chen and Jones, 1997, Milberger, Biederman, Faraone, Wilens and Chu, 1997, Whalen et al., 2002). In a large (n = 240) case-control study, children with ADHD were two times more likely to develop substance dependence disorders than matched controls (Biederman et al., 2006). ADHD was also robustly related (odds ratio > 9) to the likelihood of having an SUD in a study of 968 male adolescents in Brazil (Szobot et al., 2007). Thompson, Riggs, Mikulich, and Crowley (1996) assessed 171 adolescents with CD in a residential treatment program and found that ADHD was significantly associated with severe CD and substance problems. Similarly, ADHD was associated with severe substance dependence in a sample of 367 clinic-referred male and female adolescents (Whitmore et al., 1997). However, null associations between ADHD and substance problems have also been reported. In a sample of 1302 12–16 year-old adolescents, ADHD was unrelated to substance use and related problems (Boyle & Offord, 1991). Similarly, in a prospective study of adolescents diagnosed with ADHD when they were 7–11 years old, maltreatment, but not childhood ADHD, independently predicted substance problems (De Sanctis et al., 2008). However, the inconsistent association between ADHD and SUD may also reflect methodological variability across studies including sample characteristics (e.g., sex, population-based vs. clinic-referred) and assessment methods (e.g., structured interviews, self-report, abuse/dependence vs. frequency). For example, in Biederman et al. (2010), girls were originally ascertained when they were 6–16 years old. Thus, developmentally-sensitive assessments of SUD must consider the censored nature of the age of participants at follow-up and the potential that substance patterns may reflect age-related differences in substance exposure and availability rather than diagnostic differences per se.
Overall, the predictive validity of ADHD for SUD is unknown. Although future research on ADHD and substance outcomes must improve the methodological limitations described above, it is crucial to understand what the literature currently suggests. The goal of this meta-analysis was to characterize the most informative studies, which are likely to be prospective follow-up studies of children with and without ADHD into adolescence/adulthood. Prospective longitudinal studies significantly improve the empirical basis for determining direction of effects, evaluating meditational processes, and differentiating correlates, risk factors, and causal risk factors (Kraemer, Stice, Kazdin, Offord, & Kupfer, 2001). Indeed, temporal ordering of predictors and outcome is one of few methodological devices available to disentangle correlated constructs (Kraemer et al., 2001). Second, meta-analysis rigorously evaluates associations from smaller studies, which is often the case for prospective longitudinal designs (Keenan & Shaw, 1997). To test the predictive validity of ADHD and SUD from methodologically diverse samples, a meta-analysis may provide superior traction relative to a single, larger study. Our aim was two-fold: (1) To meta-analyze the prospective contribution of childhood ADHD (vs. control) on dichotomized measures of lifetime substance use and abuse/dependence across nicotine, alcohol, marijuana, and cocaine; and (2) To test theoretically- and methodologically-relevant moderators (i.e., age, sex, race (percent Caucasian, DSM version, sample source) of these putative associations if and when significant heterogeneity in effect size was found.
Section snippets
Study selection criteria
Each study satisfied the following inclusion criteria: (a) diagnostic ascertainment of ADHD with at least one control or non-ADHD group; (b) prospective longitudinal design (i.e., ADHD diagnosis preceded the measurement of SUD); (c) binary lifetime substance use and abuse/dependence measures; (d) available data to calculate proportions of children with and without ADHD with substance use, SUD, or odds ratios provided; (e) publication between 1980 and August 2009 in English; and (f) a
Results
To review, we evaluated the prospective contribution of childhood ADHD on measures of lifetime adolescent/adult substance use and abuse/dependence. We conducted separate meta-analyses across different substance types to examine the specificity of effects of early ADHD. We utilized random-effects models to estimate the mean effect size (and 95% confidence interval), statistical significance of the OR, and the χ2-based Q statistic for heterogeneity. The Q statistic approximates a chi-square
Discussion
Childhood ADHD is a reliable predictor of negative outcomes across academic, social, neuropsychological, and affective domains. Hence, multifinality, where multiple negative outcomes share a common developmental origin, is a defining feature of ADHD (Cicchetti, 2006). However, far less is known about the prospective contribution of childhood ADHD to subsequent substance use and related disorders (abuse/dependence) than these other domains. To quantitatively characterize the association of ADHD
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This work was supported by the Consortium of Neuropsychiatric Phenomics (CNP) (NIH Roadmap for Medical Research grant UL1-DE019580, RL1DA024853) and NIH Grant 1R03AA020186-01 to Steve S. Lee.