1. ADHD Subtypes and Subgroups at Risk for Substance Use Disorders Naimah Weinberg, M.D., Discussant Medical Officer National Institute on Drug Abuse, NIH

2. What is SUD?  Substance Use Disorder (abuse or dependence), per DSM  Distinct from substance use: while use appears driven by both biological and environmental factors, progression to abuse & dependence largely influenced by individual-level (genetic, psychiatric) factors  Difficult to apply to adolescents, but no current standardized substitute  Some studies use early onset drug use as proxy for SUD

3. Current research questions  Is ADHD a risk factor for SUD?  Which children with ADHD might be at increased risk? for which substances?  Why might some children with ADHD be at increased risk for SUD?  Does treatment of ADHD alter risk for SUD?  Does stimulant treatment alter risk for SUD?

4.  Is ADHD a risk factor for SUD?  Many clinical studies and reports suggest it is  HOWEVER:  Not population based (referral bias)  Some didn’t take comorbidity into account  Many are retrospective (subject to systematic recall bias)

5. Population-based studies Population-(or community-)based studies are needed to validate clinical studies because:  Clinic samples more likely to include comorbidity  Clinic and community samples may differ in severity, comorbidity patterns, temporal ordering, risk factors, treatment history  Seeming risk factors for disorder may actually be markers of likelihood for referral (e.g. poverty and Medicaid) Armstrong & Costello, 2002

6. Population-based studies of ADHD and SUD  A few so far  Taken together, do not support ADHD as risk factor when CD is taken into account

7. Comorbidity  Is very common in children with ADHD  Often associated with worse outcomes  Numerous studies: factoring in CD -> ADHD drops out as SUD risk factor  However, some recent literature finding a contribution of ADHD in presence of CD  Externalizing-internalizing combination also associated w/increased SUD risk

8.  Is ADHD a risk factor for SUD? II  Many clinical studies and reports suggest it is  HOWEVER:  Not population based (referral bias)  Some didn’t take comorbidity into account  Many are retrospective (subject to recall bias)  So it isn’t yet clear

9.  Which children with ADHD might be at increased risk? Clinically derived; may offer clues to further study  Comorbid psychiatric disorders  Family history of SUD (may contribute to both ADHD and SUD)  Persistent ADHD  Social skills deficits

10.  Which children might be at increased risk? (con’t)  Severity of childhood symptoms?  Inattention (for tobacco)?  Impulsivity or disinhibition (for other drugs)?  Gender differences: findings contradictory so far  Ethnic or racial group differences: inadequately studied so far

11.  Why might some with ADHD be at increased risk for SUD? Biologically: mostly common risk factors, a few mediators Psychosocially/environmentally: mostly mediators between ADHD and (early) substance use And these interact

12.  Why might some be at increased risk for SUD? (con’t) May both be manifestations of behaviorally disinhibited phenotype Executive cognitive dysfunction present in ADHD and predicts SUD (in high risk samples) Temperament: novelty seeking, low constraint – may mediate, maybe affect dysregulation

13.  Why might some be at increased risk for SUD? (con’t) Other biological associations:  Through prenatal exposure to alcohol, smoking, perhaps drugs  Low birth weight  Dopaminergic system: Self-medication? (especially tobacco)  Perhaps an internalizing/inattentive/self-medicating late-onset subtype?  Perhaps sensitization through use of stimulants

14.  Why might some be at increased risk for SUD? (con’t) Psychosocial factors that might impact use/early use:  Weak attachment to & conflict with parents, school secondary to behavior problems  Disordered alcohol or drug expectancies  Association with deviant peers  Attribution (fulfilling expectations)?  Parental modeling, monitoring, coping (ADHD parents or child-induced)

15.  Does treatment of ADHD alter the risk for SUD?  Little data so far  Focus of ongoing and new studies  However, controlled clinical studies lacking  Answers could help us disentangle etiologic role of ADHD in risk for drug abuse

16.  Does stimulant treatment alter the risk for SUD? Prescription stimulants:  Methylphenidate (Ritalin)  Amphetamines (Dexedrine, Adderall)  Pemoline (Cylert) Prescription estimates:  3% - >6% of American schoolchildren How they act: release and/or block reuptake of dopamine into presynaptic neuron

17.  Does stimulant treatment alter the risk for SUD? II Why might stimulant medication increase risk for SUD?  Psychologically: engender drug-taking attitudes, use of drug to solve problems; reliance on medication reduces efforts to develop other coping mechanisms or pursue other treatments  Biologically: sensitization, i.e. persistent hypersensitivity to drug effects as result of prior exposure (both stimulants and drugs of abuse act through increased dopamine transmission)

18.  Does stimulant treatment alter the risk for SUD? III Why might stimulant medication reduce risk for SUD?  Psychologically: through improved self-esteem, academic achievement, relationships, parent monitoring  Biologically: reduce “self-medication”; may alter reinforcing properties of drugs; hypothesized that early stimulant treatment normalizes white matter volume, in turn enhancing executive function and reducing later SUD risk

19.  Does stimulant treatment alter the risk for SUD? IV Human follow up studies: findings  Most show no effect or a protective effect  Meta-analysis of 5 studies -> 2.3-fold reduced risk for SUD associated with stimulant treatment in youth (Wilens et al, 2003)  However, some have found increased rates of SUD outcomes  “Protection” may depend on age at prescription, and may dissipate by adulthood

20.  Does stimulant treatment alter the risk for SUD? V Human follow up studies: weaknesses NOT RANDOMIZED!  Self-selection effects and biases: which children receive medication may be function of factors that alter risk  Possible cohort effects on prescription patterns  Need to take into account age at prescription, age at assessment, length of follow up

21.  Does stimulant treatment alter the risk for SUD? VI Animal studies: findings  Recent refinements studying pre- and peri-adolescent rats, using therapeutic-range dosages of methylphenidate  Show long-lasting behavioral and neurobiological adaptations, and altered responses to reinforcing properties of cocaine in adulthood  Results inconsistent: some show enhanced reinforcement by cocaine, some reduced  Response appears to be sensitive to age at administration: younger reduces reinforcement

22.  Does stimulant treatment alter the risk for SUD? VII Animal studies: weaknesses  Rats don’t have ADHD  Rats lack human prefrontal cortex  Medication not administered orally  Outcome measures open to interpretation Volkow & Insel, 2003; Hyman, 2003

23.  Does stimulant treatment alter the risk for SUD? VIII Perhaps no single answer: impact on risk may depend on subtype, interaction with other risk and protective factors, age at medication administration, medication response, choice of stimulant Or, no impact

24. Summary of the science  Lack population-based data supporting ADHD itself as a risk factor for drug abuse  Subgroups appear to be at increased risk: comorbid disorders esp. conduct, family history of drug abuse, perhaps more severe or impairing ADHD  Understanding impact of pharmacologic and behavioral treatments is important, controversial, and not yet clear

25. Sources of divergence  Methodologic: measures, samples (self- selection), constructs, covariates, timing, length of follow up  Individual factors: stimulant exposure, family history, comorbidity

26. State of research  Several NIDA-funded studies underway (many population-based) to address these questions  Data from studies funded by NIMH, NICHD, NIAAA might also be mined to address  For clinical (treatment) questions, data from controlled clinical trials are lacking; MTA may be opportunity

27. Public health implications  Major public health issues, given prevalence of ADHD, SUD, stimulant use, individual and social costs of these disorders  More work needed on all these questions  Ultimate goal: reduction and prevention of SUD and associated adverse outcomes

28. Public health implications II For etiologic questions: require sophisticated transdisciplinary approaches, that nest imaging, neurocognitive tests, behavioral pharmacology, genetics research in studies of population-based samples For treatment issues: need randomized studies (within ethical limits; MTA), prospective studies, creative methodologic approaches, developmental sensitivity, and to take family history of SUD into account Etiologic and prevention research can and must be used to inform each other