Neurobiology of Adolescent Substance Abuse from a ... · 1. Family history -Mom (depression), Mat Uncle PTSD died of cirrhosis, Pat GP and Dad alcoholics.(Cadoret, RJ, etal, Arch

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Neurobiology of Adolescent Substance Abuse from a Developmental Perspective

Deborah R. Simkin, M.D.

Clinical Assistant Professor

Department of Psychiatry

University of Emory School of Medicine

Disclosures

• Pfizer Inc. Research Support

Learning Objectives

• Scope of the problem

• Developmental vulnerability

Narcotics other than Heroin: Trends in Annual Use and Availability Grades 8, 10, and 12 Source. The Monitoring the Future study, the University of Michigan.

Narcotics other than Heroin: Trends in Annual Use and Availability Grades 8, 10, and 12 Source. The Monitoring the Future study, the University of Michigan.

Scope of the Problem

Domains of Factors Associated with Drug Use

(Newcomb, 1997)

I. Cultural/Societal – Laws favorable to drug use

– Social norms favorable to drug use

– Availability of drugs

– Extreme economic deprivations

– Neighborhood disorganization

Protective Factors

– RESILENCE - Good life events and an internal locus of control seem to cushion the development of substance use disorders in sons of alcoholics (Springer, '95)

– stable environment – high degree of motivation – strong parent-child bond consistent parental

supervision & discipline – bonding to pro-social institution – association with peers who hold conventional

attitudes – consistent community wide anti-drug use messages

(Glantz, '98)

Scope of the Problem Newcomb, 1997

Child and Adolescent Psychobehavioral Influences

• Age of first use-higher % of those who start <11 yo met criteria for dependence than those that start 14-15 yo

• Rapid progression of SUD occurred with earlier onset & frequency and not duration of use of substances (DeWitt, ’00, Kandel ’92)

• Earlier onset had shorter time span between 1st exposure to dependence than adult onset groups

(Clark,’98)

Scope of the problem

• ALCOHOL

• Event Age

• First drink- 13

• First drunk -15

• First problem -18

• First dependence -25-40

• Death -60

• (Schukit, 2000)

• Therefore, Addiction is a pediatric disease

Developmental Vulnerability

• family

• history Pre school Kindergarten- 5th grade middle school high school

• MJH &

• drinks q d

• age birth 3-5 5-7 8- 9-10 11-14 15----- 16-17--18__

•

events: -Pare nts separate -Parents

• Pre-natal -Separation -Untreated -Sexual abuse separate -

• exposure anxiety ADHD by neighbor again - raped

nicotine and LD while

• and drunk

• MJH l -Driving while

• -Hypoxia at birth -Po or grades intoxicated

• -Poor nutrition co ntinue - Stops soccer

• -Cigarette use begins -Begins using

• marijuana and alcohol

• and loratab in mom’s

• medicine cabinet

Neurobiological insults that increase risk for substance abuse from developmental perspective as seen in case example above

1. Family history -Mom (depression), Mat Uncle PTSD died of cirrhosis, Pat GP and Dad alcoholics.

(Cadoret, RJ, etal, Arch of Gen Psychiatry 1986. Kendler, KS, Presscott, CA. Amer. J. Psychiatry 1998)

-Lower D2 receptors in NaC, seen in families with alcoholism, decreases ability to inhibit drive to use drugs

2. Prenatal nicotine exposure -increased toddler negativity, -increased externalizing disorders such as, ADHD or ADHD symptoms and/or conduct

disorders -lower IQ and auditory functions (Niaura, J, et al, Amer J of Addic, 2001. Weissman, MM, et al, JAACP, 1999)

3. Prenatal exposure to MJH- -visual working memory deficits -inattention -short term memory deficits (Day, N, et al, ADDICTION, 2006. Goldschmidt, L, et al, JAACP 2008. Smith AM, et al, Neurotoxicol Terato, 2006.)

What causes Adolescents to experiment-role of early development of the Pre Frontal Cortex

• Casey, et al 2008

Neurobiological insults that increase risk for substance abuse from developmental perspective

4. Hypoxia and nutritional deficits=

– increased risk for ADHD and LD (Stein, MB, et al. Neuropsychopharm, 2008. Levenson, JM, Nat Rev Neurosci. 2005.

Koob G & LeMoal M, Annual Rev Psychol, 2008)

Note: for examples # 2, 3 and 4,

– Substance abuse at age 14 or 15 could be predicted by academic and social behavior between the ages of 7 and 9

(Hyman Hops, et al, J Study Alcohol Suppl. 1999)

– Adolescents with attention difficulties not associated with ADHD but with undiagnosed LD’s, predicted substance abuse and dependence eight years later. (Tapert, SF, et al, JAACAP, 2002)


5. 2006-2008 National Survey on Drug Use and Health. (Fiellin, et al, J Adol Health, 2013)

• RESULTS: • Twelve percent of the survey population of 18-25 year olds (n =

6,496) reported current abuse of prescription opioids. • For this population, prevalence of previous substance use was

57% for alcohol, 56% for cigarettes, and 34% for marijuana. • Among both men and women, previous marijuana use was 2.5

times more likely than no previous marijuana to be associated with subsequent abuse of prescription opioids.

• Previous alcohol, cigarette, and marijuana use were each associated with current abuse of prescription opioids in 18-25-year-old men, but only marijuana use was associated with subsequent abuse of prescription opioids in young women.


6. Disturbed brain connectivity in cannabis users may underlie cognitive impairment and vulnerability to psychosis, depression and anxiety disorders (Lim, et al, 2002) and cognitive function (Meier, 2012)

A. White matter alterations have been associated with various functional and clinical outcomes in schizophrenia, including illness, symptomatic and cognitive measures (Walterfang et al, 2011).

B. White matter pathology underlying faulty integration of cortical–cerebellar–thalamic–cortical circuits are thought to play a primary role in the observed cognitive deficits (Wexler et al, 2009)

The right fimbria of the hippocampus, hippocampal commissure and splenium comprised fewer streamlines in cannabis users compared to non-users (P < 0.05, corrected).

2 different oblique views. Red areas denote fewer streamlines Zalesky A et al. Brain 2012;135:2245-2255


C. Similar connectivity disturbances, particularly in the fimbria of the hippocampus and commissural fibres extending to the precuneus have been reported in a study (Zalesky, 2012).

• The hippocampus appears to have the highest density of CB1 receptors.

• This may underlie the memory impairment and other cognitive deficits that are observed in long-term heavy cannabis users.

Fewer streamlines interconnected the right precuneus with the splenium in cannabis users compared to non-users (P < 0.05, corrected).

Zalesky A et al. Brain 2012;135:2245-2255


C. Long term use and effect on IQ (Meier, et al, 2012)

• Association between persistent cannabis use—prospectively assessed over 20 y—and neuropsychological functioning in a birth cohort of 1,037 individuals.

• Study members underwent neuropsychological testing at age 13 y before the onset of cannabis use and again at age 38 y, after some had developed a persistent pattern of cannabis use.

• Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y.

• Findings:


Findings:

1. More persistent cannabis users did show greater IQ decline, with the most persistent users (n = 41) losing an average of 5–6 IQ points from age 13 y to 38 y

2. Persistent cannabis users showed neuropsychological decline across five different areas of mental function (executive functions, memory, processing speed, perceptual reasoning, and verbal comprehension), indicating that decline is global.

• Furthermore, this decline was still apparent after controlling for years of education

• and after ruling out multiple other alternative explanations (for example, the decline was not due to persistent dependence on alcohol or other substances).


3. Adolescent-onset cannabis users who used cannabis persistently up to age 38 y (n = 23) lost an average of 8 IQ points from age 13 y to 38 y.

4. Cessation of cannabis use did not fully restore functioning among adolescent-onset cannabis users.

• Evidence regarding the acute impairments in memory function induced by cannabis is generally robust, particularly for those using cannabis with a lower proportion of CBD and higher proportion of Δ9-THC (Meier, 2012)

• The hippocampus appears to have the highest density of CB1 receptors-Higher THC in todays cannabis may cause more neurotoxic effects on the developing brain.



7. Stressors –effect on epigenetics (environment and genes) trauma=sexual abuse, (Jones, DJ, 2012), pre natal exposure, hypoxia

at birth, poor nutrition, early life experiences (parental conflict & separating, poor academics), separation anxiety and social phobia (Deas-Nesmith, D, et al, 1998, Nelson, 2000, Merikangas, et al, 1998)

*Alter addiction pathology later in life: - changes gene expression through chromatin remodeling with no

changes in DNA sequences. - Ex.= stressors alter expression of genes that dysregulate the

hypothalamic pituitary axis (HPA) - thus, increasing sensitivity to stress and increase the risk for using

substances to relieve this stress. - Using drugs to relieve stress does the same = vicious cycle

(Stein, MB, et al. Neuropsychopharm, 2008. Levenson, JM, Nat Rev Neurosci. 2005. Koob G & LeMoal M, Annual Rev Psychol, 2008)


8. CRAFFT- (Knight, JR, et al. Arch Pediatr Adolesc Med, 2002)

(Car, Relax (untreated anxiety), Alone, Friends (role of oxytocin), Forgot, Trouble)

9. Personality: Babor type B- – early onset of spontaneous alcohol-seeking behavior;

– diagnosis during adolescence; rapid course of onset;

– genetic precursors that put them at risk to develop substance abuse;

– severe symptoms of deviant behavior, including fighting, high novelty seeking, low harm avoidance

(Babor, TF, et al. Arch of General Psychiatry 1992. )

Positive factors 1. Motivation: (Prochaska and DiClemente Psychother

Theory Res Practice 1982)-Motivational Enhancement Therapy (MET) – precontemplation-denial – contemplation-on a fence-ambivalent

– preparation-she was ready to make concrete change

plan for change – action-reduces or quits and works treatment plan – maintenance-avoids relapse

2. Supportive mother and no previous CD sx.

Treatment She Choose:

• Meetings 3-5 times per week,

• vivitrol monthly injection since alcohol was drug of choice,

• weekly random urine drug screens,

• avoided friends who used,

• went back to church youth group,

• Treated for depression,

• individual weekly therapy with CBT and reforming positive identity,

• got tested for learning disorders and re-entered college gradually

Addiction is a Pediatric Disease

• Importance of early intervention.

• Ongoing CONTROVERSY:

• New DSM V diagnostic criteria is developed for adults and does not take into account developmental issues.

Table I. Proposed alcohol use disorder criteria from the DSM-V (American Psychiatric Association)

Alcohol use disorder is defined as a maladaptive pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least 2 of the following 11 characteristics, occurring within a 12-month period:

• (1) recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school or home;

• (2) recurrent alcohol use in situations in which it is physically hazardous;

• (3) continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance;

• (4) tolerance as defined by either (a) a need for markedly increased amounts of alcohol to achieve intoxication or desired effect or

• (b) markedly diminished effect with continued use of the same amount of alcohol;

• (5) withdrawal, as manifested by either (a) the characteristic withdrawal syndrome for alcohol or (b) alcohol or a closely related substance is taken to relieve or avoid withdrawal symptoms ;

• (6) alcohol is often taken in larger amounts or over a longer period than was intended;

• (7) there is a persistent desire of unsuccessful efforts to cut down or control alcohol use;

• (8) a great deal of time is spent in activities necessary to obtain alcohol, use alcohol or recover from its effects;

• (9) important social, occupational or recreational activities are given up or reduced because of alcohol use;

• (10) alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol;

• (11) craving or a strong desire or urge to use alcohol

DSM V Controversy Beyond the fact that items in bold may not apply to adolescents, another way to distinquish adolescents who may meet DSM V criteria for substance use disorder: Suggestion: • Excluding the Hazardous Use criterion (Can Nicotine fit into this criteria), • Clarifying the operational definitions of Tolerance (since many teens

increase use periodically but not frequently), • Withdrawal and Craving-only 2 sub criteria needed of 8-could be

confused with hangover • Unsuccessful attempts to cut down may have been due to coersion and

not due to motivation and • Critically evaluating the diagnostic threshold for SUDs in adolescents. • Would recognize that using only 2 criteria to diagnose the disorder may

pick up mild cases in adolescents.(Winters, KC, et al. Addiction, 2011)

What constitutes whether an adolescent may progress?

Adolescent-onset adults, compared with other adult-onset groups:

• had higher lifetime rates of cannabis and hallucinogen use disorders,

• shorter times from first exposure to dependence,

• shorter times between the development of their first and second dependence diagnoses and

• higher rates of disruptive behavior disorders and major depression.

• Early onset and frequency, not duration

• (Clark, DB, et al. Drug Alcohol Dep 1998, DeWitt, 2000, Kandel, 1992)

Addiction is a Pediatric Disease Recognition of and Early intervention on risk factors essential to prevention

• Gateway to use may not just be categorized as substances of abuse used, but risk factors that lead to drug use

• Alcohol seems to be most influential as gateway

• (Kirby B & Barry, AE, J Sch Health, 2012)

• So if an adolescent does end up with severe, frequent, chronic and debilitating use, what can be done?

1-3 learned behavior

2

3 VTA

Ventral pallidum

Medial Dorsal

thalmus

PFC (Ant.cing.&

OFC)

Basolateral amygdala

Extended amygdala= Central amygdala nucleus, bed

Nucleus of stria terminalis and

Nucleus Accumbens shell

NAc Core

Dopamine Glutamate GABA GABA/Neuropeptide

1

Neural Circuitry Mediating Drug Seeking

Final Common

Pathway

Cue

Stress

Ventral Pallidum

Nucleus Accumbens

core PFC

VTA Basolateral Amygdala

Extended Amygdala- Central amygdala nucleus, Bednucleus of the stria terminalis, nucleus accumbens shell

• Substance Abuse is a pediatric disease-Early intervention for risk factors (Bio-Psych-Social) is crucial.

• Adolescents is a time of experimentation due to an undeveloped PFC and the effects of substances of abuse on the developing brain are still being explored.

• Interventions that most often lead to relapse have to be explored more extensively in adolescents and converted to positive risk factors

• Access and availability to opioids is on the rise

Documents

Neurobiology of Adolescent Substance Abuse from a ... · 1. Family history -Mom (depression), Mat Uncle PTSD died of cirrhosis, Pat GP and Dad alcoholics.(Cadoret, RJ, etal, Arch