Title: Prevention of Substance Abuse in Adolescents: Lessons from the Brain Sciences
1Prevention of Substance Abuse in Adolescents
Lessons from the Brain Sciences
- Jeffery N. Wilkins, M.D.
- Lincy / Heyward-Moynihan, Chair
- in Addiction Medicine
- Vice Chair, Dept. of Psychiatry
- Cedars-Sinai Med Center
- Professor, Dept. of Psychiatry
- David Geffen School of Medicine _at_ UCLA
2Conflict of Interest Disclosure
- Jeffery N. Wilkins, M.D.
- Consultant Alkermes Inc., Cephalon, Inc.,
Hythiam, Inc. - Unrestricted Research Grant Hythiam, Inc.
- Honoraria CME LLC
- Member, Board of Directors
- Brent Shapiro Foundation for Drug Awareness
- California Society of Addiction Medicine
- Psychological Trauma Center
3Goals of Presentation
- Describe 3 major public health problems with
substance use in children and adolescents - Describe brain mechanisms that may contribute to
these 3 major public health substance use
problems - Discuss overall risk model for prevention of
alcohol, drugs and cigarette use in children and
adolescents with specific focus on brain
development and genetics
4Learning Objectives
- 1. At the completion of this presentation, the
attendee will be able to describe key age windows
of risk for substance use by children and
adolescents and their relationship to stages of
brain development. - 2. At the completion of this presentation, the
attendee will be able to describe where addiction
is manifested in select areas of the brain
including the prefrontal cortex.
5Learning Objectives
- 3. At the completion of this presentation, the
attendee will be able to describe strategies for
prevention of substance abuse in children and
adolescents based on lessions from the brain
sciences.
6Three Major Public Health Problems
- Development of Dependence (i.e., Addiction)
occurs from changes in the brain that occur
following chronic and regular use of most
substances of abuse. Although amenable to
treatment intervention, these changes in the
brain are semi-permanent or permanent - Substance use in children lt 14 leads to high
rates of substance problems in adulthood - Nicotine and probably other select substances of
abuse induce significant semi-permanent to
permanent changes in the brain with even casual
use
7Public Health Problem 1 Chronic and Regular
Substance Use Leads to Alteration of
Neurobiological Mechanisms that Regulate
Motivated Behavior
8Substances Alter Neurobiological Mechanisms of
Motivated Behavior
- Select brain areas assign a degree of importance
to our behaviors, thereby shaping our behavior. - When addiction is not present, these behaviors
target the obtaining of desired items/life events
and avoidance of undesired items/life events . - When addiction is present, changes to key brain
areas (e.g. prefrontal cortex, nucleus accumbens,
amygdala) are altered and motivated behavior is
diverted to drug use cues and away from normal
life processes. This has been demonstrated in
animal and human studies of cocaine dependence
and normal controls. - Kalivas and Volkow. The neural basis of
addiction a pathology of motivation and choice
(2005), Am J Psych 1621403-1413
9(No Transcript)
10Cellular Site of Action for Naltrexone
11Circuitry Mediating Activation of Goal-Directed
Behavior
Kalivas Volkow, 2005
12GABA and Glutamate Role in Motivation
Dopamine
GABA
Glutamate
Adapted from Kalivas and Nakamura, Curr. Opin.
Neurobiol., 1999.
13Neural Circuitry Mediating Drug Seeking
Kalivas Volkow, 2005
14Addiction and the Brain as Shown by MRI
15Salience List Model Pre-Exposure
16Salience Model Post-Exposure
- FOOD
- FAMILY
- AVOID DANGER
- DRUG CUES
- (Fueled by Stress)
17Salience Model Dependence
- FOOD
- FAMILY
- AVOID DANGER
- DRUG CUES
- (Fueled by Stress)
18Salience Model Treatment
- FOOD
- FAMILY
- AVOID DANGER
- DRUG CUES
- (Fueled by Stress)
Reinstate Natural Reinforcers
Mitigate Cue Stimulation and Diminish Stress
19Public Health Problem 2 Substance use in
children lt 14 leads to high rates of substance
problems in adulthood
20Flexibility Invites Vulnerability
- Our brains are sculpted by our early
experiences. Maltreatment is a chisel that shapes
a brain to contend with strife, but at the cost
ofdeep, enduring wounds. - Teicher, 2000
- Plasticity is a double-edged sword that leads to
both adaptation and vulnerability. - Shonkoff Phillips, 2000
-
21Stress, Early Drinking, Alc. Dependence
- Nationwide survey of 27,000, mean age 43
- Persons who started alcohol use lt14 and reported
gt6 stressors in past year drank average of 6
drinks per day 5x that of similarly stressed
individuals who started drinking at age 18 or
older. - Dawson et al., Alc Clin Exp Res, 2007
22Defining the ProblemNational Surveys
- Monitoring the Future (N50, 000)
- National Survey on Drug Use Health (N68,000)
- Ellickson et al., 2006 (N6,338)
- Dawson et al., Alc Clin Exp Res, 2007 (N27,000)
- Hingson et al., Arch Ped Adol Med, 2006 (N43,
093) - Clark et al., 1998 (N262)
23Monitoring the Future (www.monitoringthefuture.org
)
- Approximately 50,000 8th, 10th and 12th grade
students are surveyed (12th graders since 1975,
and 8th and 10th graders since 1991). - Annual follow-up questionnaires are mailed to a
sample of each graduating class for a number of
years after their initial participation. - Funded by NIDA, conducted at U. of Michigan.
24Age12 13Last 30days
25NSDUH (50 states, N68, 000)
- 74 of adults report beginning drinking prior to
reaching the legal drinking age - 5.9 of children ages 12 to 17 meet criteria for
alcohol dependence or abuse - Those reporting alcohol use lt 14 are 5 times more
likely to report alcohol dependence after age 21
(3 v. 16) - Only 5 percent (fewer than1 million persons) of
adults classified as having past year alcohol
dependence or abuse had started using alcohol at
or after age 21 - NSDUH Report 10/2004
26Evaluation at Grade 7, 12 and age 23
- Early drinkers enrolled in middle school and high
school are more likely to report - academic problems
- substance use
- delinquent behavior
- By the time early drinkers reach the age of 23
they are more likely to have - Employment problems
- Other substance use problems
- Legal problems
- Problems with violence (Ellickson et
al., 2006)
27Grade 7 (Age 12 13)
Ellickson et al., 2006
28FromAge 12to Age 17
Ellickson et al., 2006
29FromAge 12 to Age 23
Ellickson et al., 2006
30Survey of 43,093 Adults for Persons with 6 or 7
DSM IV Alcohol Dependence Criteria
- Hingson et al., Arch Ped Adol Med 160739-746,
2006
31Background
- Centers for Disease Control and Preventions 2003
Youth Risk Behavior Survey of HS students - 28 drank alcohol other than a few sips before
age 13 years - By age 17 years they were 7 times more likely to
consume 5 or more drinks 6 or more times per
month than those who waited until they were 17
years or older to begin drinking.
Grunbaum J, Kaun L, Kinchen S, et al. Youth Risk
Behavior SurveillanceU.S., 2003. MMWR Surveill
Summ. 2004531-96
32Start Alcohol lt14 vs gt 21
- lt14
- ? risk for alcohol dependence
- ? likelihood within 10 years of 1st drink (CIs,
1.78 1.51-2.11 and 1.69 1.38-2.07,
respectively) - Odds of 2.62 (95 CI, 1.79- 3.84) for having at
least 1 episode exceeding 1 year and 2.89 (95
CI, 1.97-4.23) for meeting 6 or 7 dependence
diagnostic criteria
Hingson et al., Arch Ped Adol Med 160739-746,
2006
33Kaplan-Meier Survival Curves for Remaining Non
Alcohol Dependent Hingson et al., Arch Ped
Adol Med 160739-746, 2006
34Risk for Alcohol Depend.AnytimeHingson et
al., Arch Ped Adol Med 160739-746, 2006
35Risk for Alcohol Depend. in 10 Years Hingson
et al., Arch Ped Adol Med 160739-746, 2006
3641,482 young men (18 to 20)
- Marine Corps Recruit Depot, San Diego, Calif.
- 6,128 (14.8) were identified as risky drinkers
- 18,693 (45.1) as nonrisky drinkers
- 16,661 (40.2) as nondrinkers
- Risky Drinking
- 5.5 fold odds if drinking onset lt14
- ? Odds with
- tobacco use, rural or small hometown, higher
education, joined military for travel or
adventure or to leave problems at home, numerous
close friends and relatives, household alcohol
abuse or mental illness, and childhood sexual or
emotional abuse - Young et al., Arch Pediatr Adolesc Med.
1601207-14, 2006
37Conclusion
- Public health efforts to decrease alcohol misuse
may be effectively targeted by prevention of
underage alcohol use, tobacco use, and childhood
abuse.
38Risk of Early Use May Be Linked to Brain
Development
39Risk of Early Use May Be Linked to Brain
Development
- Brain development is not complete until age 24,
with key developmental milestones achieved while
attending elementary and middle school (i.e., the
same time as the high risk for establishing
sustained use of alcohol, cigarette and drug
use). - Support to children provided by their
parents/families and other social systems can
mitigate less fortunate genetic inheritance that
regulate brain function.
40Genetics
41Social supports and serotonin transporter gene
moderate depression in maltreated children
- Joan Kaufman , Bao-Zhu Yang , Heather Dougla
Palumber, Shadi Houshyar , Deborah Lipschit, John
H. Krystal , and Joel Gelernter - PNAS December 7, 2004 vol. 101 no. 49
42Summary
- In maltreated children, quality and availability
of social supports s/s 5-HTTLPR allele moderate
risk for depression - Maltreated children with the s/s genotype and no
positive supports had 2 fold levels of depression
compared to non-maltreated - Presence of positive supports reduced risk
associated with maltreatment and the s/s
genotype, such that maltreated children with this
profile had only minimal increases in their
depression scores. - Suggests that negative sequelae associated with
early stress are not inevitable, esp. in context
of supplied social support.
435-HTT gene affects the serotonin transporter
- Two alleles (short and long) in 3 configurations
s/s, s/l, l/l) - s/s conveys ? 5-HTT transcription, ? transporter
levels and ? serotonin uptake - Shyness, behavioral inhibition
- Anxiety, ? Negative emotions (e.g. fear),
Depressed mood - ? susceptibility to stressful life events
psychopathology
Kaufman et al., 2004
44Kaufman et al., 2004
45Serotonin Transporter Genetics and Social Support
vs. Maltreatment
Kaufman et al., 2004
46Dopamine, Dominance Model
- High Dopamine less interest in substance abuse
- Low Dopamine high interest
47DA2 Receptor Perception of Methylphenidate Dose
Volkow et al., 1999 Am J Psych 1999 156144043
48Adolescent Brain Development and Drug Abuse
- Ken C. Winters, Ph.D. Professor, Department of
Psychiatry, University of Minnesota - A Special Report Commissioned by the Treatment
Research Institute Philadelphia, P A., A Thomas
McLellan, Executive Director
49Clinical Questions Based on Brain Development
- Do neurodevelopmental factors predispose
adolescents to seek out and abuse alcohol and
drugs? - Are there any deleterious effects on brain
development as result of drug use in adolescence?
50Adolescents Predisposed to seek out and abuse
alcohol and drugs?
- Immature prefrontal cortex increases the
propensity of teenagers to act impulsively and to
ignore the negative consequences of such
behavior. - Immature nucleus accumbens increases the
adolescent's tendency to seek out activities that
are exciting but require little effort. - Adolescents subjectively report greater feelings
of social disinhibition when drinking alcohol
compared to adults (Spear, 2002).
51Adolescents Predisposed to seek out and abuse
alcohol and drugs?
- Poor impulse control
- Predisposed to favor low-effort yet thrilling
experiences - Heightened sensitivity to the social benefits of
intoxication
52Brain Development
- The brain continues through different phases of
development across the life span. - Different brain areas develop at a varying rate.
- Brain development is different between women and
men and even different between identical twins. - Higher-order association cortices mature only
after lower-order somatosensory and visual
cortices, the functions of which they integrate,
are developed. - Phylogenetically older brain areas mature earlier.
Lenroot and Giedd, 2006
53Lenroot and Giedd, 2006
54Brain Development Motor Skills
- The Basal Ganglia loses up to 50 of Betz cells
(involved in fine motor skills) between the ages
7 and 11 - This is evidence of long standing belief that
practicing skills in the early development stages
is essential to mastering technique (sports,
music, etc.)
Giedd, 2003
55Gender and Brain Development
- Males
- On average, the male brain is 10 larger than the
female brain - Amygdala volume increases with age significantly
only in males (high number of androgen receptors) - Females
- Hippocampal volume increases significantly with
age only in females (High number of estrogen
receptors) - Caudate, and possibly globus pallidus and
hippocampus, are disproportionately larger in
female brains, whereas the amygdala is
disproportionately smaller when compared to the
brains of males. - (Giedd et al., 1996b)
Durston et al., 2006
56Brain Development in Twins
- Gyral and sulcal features of monozygotic twins
are surprisingly dissimilar - May occur from differences in intrauterine events
experienced by each of the twins - Supports model that brain development reflects
both genetic and environmental factors Eckert et
al., 2002
57Brain Development Gender
- By the age of 6, brain volume reaches
approximately 95 of its peak volume - The brain volume of men peaks at 14.5 years
- The brain volume of women peaks at 11.5 years
Giedd et al., 1999b
58Cortical Development and Intelligence
- Cortical thickness itself, is most closely
related to level of intelligence. - - correlation between intelligence and cortical
thickness in early childhood - correlation in late childhood and beyond
- More intelligent children demonstrate a
particularly plastic cortex, with an initial
accelerated and prolonged phase of cortical
increase, which yields to equally vigorous
cortical thinning by early adolescence.
Shaw et al., 2006
59Gogtay et al., 2004
Right lateral and top views of the dynamic
sequence of GM maturation over the cortical
surface. The side bar shows a color
representation in units of GM volume. Giedd, 1999
60Attention Deficit Disorder
- Boys and girls with ADD show smaller overall
brain size - There are also abnormalities of the caudate
nucleus evidenced by - A lack of normal asymmetry (decreased right-sided
caudate volume) - Lesions on the caudate seems to lead to the
emergence of secondary symptoms of ADHD
Castellano et al., 2006
61ADD / ADHD Twin studies have confirmed
differential brain development
Castellano et al., 2006
62Caudate NucleusVolume in ADHDCastellano et
al., 2006
63Public Health Problem 3 Nicotine and probably
other select substances of abuse induce
significant semi-permanent to permanent changes
in the brain with even casual use.
64Nicotine Dependence
65a4ß2 nAChR
66UpRegulation of Nicotine ReceptorValejo et
al., J. Neurosci., 25556372, 2005
67Time Course of Nicotine Use StagesGervais et
al., CMAJ 175255-61, 2006
68Time Course of Nicotine Use Stages
- Inhalation 1.5 months (1.52.5)
- Mental Addiction 2.5 months (1.52.5)
- Smoking a whole cigarette 2.5 (1.03.0)
- Cravings 4.5 (2.58.8)
- Physical Addiction 5.4 (3.89.7)
- Monthly Smoking 8.8 (7.011.9)
- Withdrawal Symptoms 11.0 (6.416.8)
- Tolerance 13.0 (10.320.5)
- Weekly Smoking 19.4 (14.531.7)
- Lifetime 100 cigarettes 19.5 (14.023.9)
- Daily Smoking 23.1 (19.737.6)
- Tobacco Dependence 40.6 (35.156.0)
69Smoking and the Insula
- There is evidence that lesions to the Insula can
result in a disruption in smoking addictions as
measured by - Reporting quitting smoking less than 1 day after
lesion onset - Reporting that they did not start smoking again
after they quit - Rating the difficulty of quitting as less than
three on a scale of one to seven - Reporting feeling no urges to smoke since
quitting
Naqvi, et al., 2007
70Patients with Brain Lesions in Insula Lost All
Desire to Smoke
Naqvi, et al., 2007
71Smoking and the Insula
- This study found that people with a lesion on the
Insula reported less urges to smoke after the
lesion and fewer smoked cigarettes after the
initial abstention - It has also been shown that a high amount of
activity in the right insula during a simple
decision-making task is associated with relapse
to drug use - These results imply that therapies that modulate
the function of the insula will be useful in
helping smokers quit.
Naqvi, et al., 2007
72Brain Risk Model for Prevention of Alcohol, Drugs
and Cigarette Use in Children and Adolescents
73Risk-Based Prevention Model
74Other Use Patterns
75Resilience Links
- Trauma History
- Stress Reduction System
- Social Support
- Genetics
- Parent/Fam. Supervision
- Family/Peers Use
- Availability of Alc/Drugs/Cigs
- Links to stress reduction
- Links to brain develop.
- Links to stress reduction
- Long allele 5HT transporter
- Usually across-the-board availability though
affluence increases availability
76Goals of Presentation
- Describe 3 major public health problems with
substance use in children and adolescents - Describe brain mechanisms that may contribute to
these 3 major public health substance use
problems - Discuss overall risk model for prevention of
alcohol, drugs and cigarette use in children and
adolescents with specific focus on brain
development and genetics
77Learning Objectives
- 1. At the completion of this presentation, the
attendee will be able to describe key age windows
of risk for substance use by children and
adolescents and their relationship to stages of
brain development. - 2. At the completion of this presentation, the
attendee will be able to describe where addiction
is manifested in select areas of the brain
including the prefrontal cortex.
78Learning Objectives
- 3. At the completion of this presentation, the
attendee will be able to describe strategies for
prevention of substance abuse in children and
adolescents based on lessions from the brain
sciences.