# Presentation: 435445

## ADHD Subtypes and Subgroups at Risk for Substance Use Disorders 

**Naimah Weinberg, M.D., Discussant**
**Medical Officer**
**National Institute on Drug Abuse, NIH**

## 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**

## 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?**

##  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)**

## 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**

## 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**

**Notes:**
Add Lynskey? Costello?

## 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**

##  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**

##  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**

##  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**

**Notes:**
Gender: Biederman et al 2004? – no gender differences in outcome, although 2002 AJP reported lower SUD in girls

Inattentive may be more internalizing
I/H may be more externalizing
Risk for abuse/dependence on particular substances?
Historically non-specific risk
Tobacco per several recent studies
Burke; Todd; ...
May depend on subtype or comorbid disorders
MAYBE TAKE OUT THIS SLIDE
Burke; Todd; Tercyak; Milberger; see sum in Rowland, maybe Molina

## 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**

**Notes:**
Iacono article and app; Young; READ TARTER; look at CODA book prn; Volkow & Fowler!, Young et al 2000!

## 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**

**Notes:**
Iacono article and app; Young; READ TARTER; look at CODA book prn; Volkow & Fowler!, Young et al 2000!

##  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**

**Notes:**
Acute nicotine treatment has been found to reduce symptoms of attention deficit/hyperactivity disorder in adults (E. D. Levin, C. K. Conners, et al., 1996). 
Nicotine: psychostimulant that can induce euphoria, relaxation, short-term memory enhancement, increased attention & problem-solving in some smokers (Tercyak from Woolf, 1997; see also Ernst, Levin ED, Levin FR)

##  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)**

**Notes:**
See Molina et al.

##  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**

##  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**

**Notes:**
CASTELLANOS APP; KALIVAS

##  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)**

**Notes:**
Sensitization: progressive increase in an effect of a drug with repeated administration or a persistent hypersensitivity to an effect of the drug as a consequence of past history and exposure to drug or stress.

##  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**

**Notes:**
Why would greater white matter volume protect?

##  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**

**Notes:**
CASTELLANOS APP; KALIVAS

##  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**

**Notes:**
CASTELLANOS APP; KALIVAS

##  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**

**Notes:**
CASTELLANOS APP; KALIVAS

##  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**

**Notes:**
CASTELLANOS APP; KALIVAS

##  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**

**Notes:**
CASTELLANOS APP; KALIVAS

## 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**

## Sources of divergence

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

## 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 **

## 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**

## 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**