ADHD Subtypes and Subgroups at Risk ADHD Subtypes and Subgroups at Risk
for Substance Use Disordersfor Substance Use Disorders
ADHD Subtypes and Subgroups at Risk ADHD Subtypes and Subgroups at Risk
for Substance Use Disordersfor Substance Use Disorders
Naimah Weinberg, M.D., Discussant
Medical Officer
National Institute on Drug Abuse, NIH
What is SUD?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 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?
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 studiesPopulation-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
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
ComorbidityComorbidity
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
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?
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)
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
Why might some with ADHD be at increased risk for
SUD?
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
Why might some be at increased risk for SUD? (con’t)
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
Why might some be at increased risk for SUD? (con’t)
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
Why might some be at increased risk for SUD? (con’t)
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)
Does treatment of ADHD alter the risk for SUD?
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?
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
Does stimulant treatment alter the risk for SUD? II
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)
Does stimulant treatment alter the risk for SUD? III
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
Does stimulant treatment alter the risk for SUD? IV
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
Does stimulant treatment alter the risk for SUD? V
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
Does stimulant treatment alter the risk for SUD? VI
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
Does stimulant treatment alter the risk for SUD? VII
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
Does stimulant treatment alter the risk for SUD? VIII
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
Summary of the scienceSummary 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 divergenceSources of divergence
Methodologic: measures, samples (self-
selection), constructs, covariates, timing,
length of follow up
Individual factors: stimulant exposure, family
history, comorbidity
State of researchState 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 implicationsPublic 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 IIPublic 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
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