Addiction and the Human Adolescent Brain

C H A P T E R

36 Addiction and the Human Adolescent Brain Alecia Dager*, Lindsay Squeglia$, Norma Castro$, Susan F. Tapert$ *

Olin Neuropsychiatry Research Center, Yale University, Hartford, CT, USA $ University of California, San Diego, CA, USA

O U T L I N E Overview

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Background Definition of Addiction Definition of Adolescence Scope of the Problem Methods for Studying the Adolescent Brain Neuropsychological Testing Neuroimaging Electrophysiological Approaches Adolescent Brain Development Adolescent Vulnerability Behavioral and Psychiatric Risk Factors Family History Conduct Disorder

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OVERVIEW Alcohol and other drug use are widespread, and typically begins during adolescence. Early onset of use is linked to a greater lifetime chance of addiction and other poor outcomes. Some neural features have been associated with a propensity for engaging in substance use and other problem behaviors during adolescence. Neural consequences of adolescent substance use have been suggested and the adolescent brain appears overall more vulnerable to these effects than the adult brain. This entry will provide relevant definitions, review techniques for studying adolescent brain functioning,

Biological Research on Addiction, Volume 2 http://dx.doi.org/10.1016/B978-0-12-398335-0.00036-4

Attention Deficit Hyperactivity Disorder Mood and Anxiety Disorders Gender

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Neural Consequences of Addiction Alcohol Nicotine Marijuana Stimulants Methylenedioxymethamphetamine Opioids Polysubstance Use

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Summary

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describe risk factors for early substance use and related addiction problems, review findings on how substance use appears to affect the brain, and discuss how the adolescent brain appears to be particularly vulnerable to these effects.

BACKGROUND Definition of Addiction The Diagnostic and Statistical Manual of Mental Disorders defines substance use disorders (SUD) as

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“a maladaptive pattern of substance use leading to clinically significant impairment or distress.” Substance abuse is a pattern of hazardous use, such as repeated legal problems, use in hazardous situations, inability to meet obligations, and use despite social or interpersonal conflicts. Substance dependence, or addiction, is characterized by loss of control over use that leads to significant impairment in functioning, and may include tolerance, withdrawal, continued use despite negative consequences, reduction of important activities, using at greater levels than intended, or spending a great deal of time than using. Environmental factors typically drive substance initiation, whereas genetic factors have a greater influence on sustained and escalated use. Accurate diagnosis of SUDs can point to appropriate interventions but can be less accurately applied with adolescents. Teenagers are less likely to experience many of the negative consequences of use, such as failure to meet obligations or reducing activities, physical or psychological problems related to use, or using at greater levels than intended. Therefore, adolescents who use heavily may not necessarily meet diagnostic criteria for SUD. The quantity and frequency with which a teenager uses may be more important for understanding neurobiological consequences. Although many studies described examined teens with SUD, others focused on adolescents who used heavily, regardless of diagnostic status.

Definition of Adolescence Adolescence is a period that is difficult to define objectively, and varied descriptions have been utilized. Historically, it is thought of as the period between the onset of puberty and the age of assuming adult roles and responsibilities: these boundaries vary across time, place, and culture. For instance, in many modern societies, individuals do not gain independence until after college, much later than in previous decades. Yet many researchers refer to college students as “young adults” rather than adolescents. For our purposes, we will consider adolescence to be in ages 12–18 years, as this is the age range of heightened vulnerability to substance use initiation.

most commonly used substance after alcohol, with 42% of high school seniors endorsing use. While tobacco use has decreased in recent decades, 11% of 12th graders continue to smoke cigarettes every day. Alcohol, marijuana, and tobacco are the most commonly used addictive compounds for adolescents, but some youth also have used heroin (1%), opioids other than heroin (13%), amphetamines (10%), inhalants (10%), sedatives (8%), hallucinogens (7%), ecstasy (7%), cocaine (6%), and steroids (2%). In addition to increased substance use during adolescence, past year SUD rates rise dramatically during adolescence, increasing from 7% for ages 12–17 years to 20% by age 20years. Substance use during adolescence has important public health and clinical implications. Substance use is related to damaging social behaviors like interpersonal violence, criminal activities, impaired driving or riding with impaired drivers, school truancy, and engaging in risky or unwanted sexual behavior, and negative health consequences like traumatic injury, alcohol poisoning, and sexually transmitted diseases. Substance use is associated with the three leading causes of death among youth: unintentional injury, homicide, and suicide, and accounts for huge social costs, with underage drinking estimated to cost as much as $62 billion per year considering medical costs, work loss, and lost quality of life. Binge drinking is of particular concern, as it is common (i.e. 90% of all alcohol consumed by 12- to 17-year olds is consumed during binge episodes) and increases the likelihood of dangerous health and behavioral consequences. Importantly, substance use during adolescence may impact neuromaturation and contribute to diminished neurocognitive functioning. As adolescence is a crucial time for continued education and transition into adult roles, the negative influence of substance use could have long-term implications for academic performance and, ultimately, occupational and social achievement. Understanding the neural correlates of substance use in adolescence may contribute to better prevention and intervention programs.

Methods for Studying the Adolescent Brain Neuropsychological Testing

Scope of the Problem Substance use is prevalent during adolescence and increases throughout young adulthood. Alcohol is the most commonly used substance, and by the end of high school, 72% of adolescents have at least tried alcohol, 57% have been drunk at least once, and 25% have had five or more drinks in a row (i.e. binge drinking) in the past two weeks. Marijuana is the second

Neuropsychological tests are tasks designed to measure an individual’s level of performance in terms of accuracy, speed, and efficiency in particular cognitive domains (e.g. memory, attention, language, motor, visuospatial, and executive functioning) that are linked to certain brain regions or systems. Visuospatial skills refer to cognitive functions that enable individuals to analyze and understand their surroundings in a twoand three-dimensional way, and perceive object

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locations, navigate oneself through space, judge distances and depth, copy or construct objects, and mental imagery. Visuospatial functions involve the integration of visual data, and usually involve proper functioning of the parietal cortex. Executive functioning refers to the higher-order brain processes that control and regulate other cognitive processes, and comprises a number of cognitive functions including planning, problem solving, inhibition, set-shifting, abstract thinking, concept formation, selective attention, working memory, and verbal fluency. Executive functions are distributed throughout the brain, predominantly centered in the prefrontal cortex and frontal circuits. Neuroimaging Neuroimaging techniques have been used to study brain health across typical development, and for a range of disorders to better understand the principal regions and pathways that underlie neuropsychological deficits or psychiatric symptoms. Magnetic resonance imaging (MRI) is a noninvasive technique that creates highresolution structural pictures of the brain through the use of a magnetic field and radio waves. MRI data can be compared within individuals over time, or compared across groups of people with varying histories or pathologies. White matter comprises fatty myelin-coated axons and is crucial for efficient communication between brain regions. Diffusion tensor imaging (DTI) is an MRI technique that examines the integrity of white matter tracts. Specifically, DTI measures the diffusion of water molecules within a given volume element (i.e. voxel), providing an estimate of the underlying tissue’s overall coherence and organization. Greater white matter integrity has been associated with more efficient connectivity between brain regions and is related to better behavioral performance. Two common variables used in DTI research are fractional anisotropy (FA), which measures water diffusion along a single direction, and mean diffusivity (MD), an index of the overall displacement of water molecules. In general, higher FA and lower MD signify a more organized, healthy, and developed white matter quality, which in turn implies quicker neural processing. Whole fiber tractography DTI is a method that examines thick bundles of white matter fibers responsible for communicating across widespread brain regions, and has been used to investigate white matter pathways in substance-exposed individuals. Functional magnetic resonance imaging (fMRI) is a widely used, noninvasive, safe technique that investigates brain activation by measuring changes in blood oxygen level dependent (BOLD) signal during mental tasks or exposure to a stimulus. BOLD signals are correlated with blood flow, and therefore, higher BOLD

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signal indicates regions of the brain with increased neural activation. fMRI can be used to characterize the neural correlates of cognitive changes in adolescent substance users. Other functional neuroimaging techniques (e.g. positron emission tomography and single photon emission computed tomography) can require radioactive tracers and are generally not considered safe for use in research with normal pediatric populations. Electrophysiological Approaches Electrophysiological indices, such as the eventrelated potential , electroencephalography , and magnetoencephalography , have the ability to measure brain waves during cognitive paradigms. Very accurate timing of neural response to specific stimuli can be inferred, but the spatial resolution and localization of these data are poorer than with fMRI. These techniques are particularly useful for examining neural activation during fast-paced cognitive tasks, such as attentional allocation and novelty response paradigms.

Adolescent Brain Development Adolescence is a critical neurodevelopmental period. The adolescent brain undergoes significant anatomical, functional, neurochemical, and hormonal changes to create a more refined, efficient central nervous system. The brain is composed of gray matter, the outer layer or cortex of the cerebral hemispheres consisting largely of nerve cell bodies, and white matter, the bundles of myelinated nerve cell axons that connect gray matter areas and allow nerve cells to communicate with each other. Both gray and white matter undergo important developmental changes during adolescence. Although overall brain volume remains largely unchanged after puberty, ongoing synaptic refinement and myelination result in reduced gray matter and increased white matter volume by late adolescence. Cortical gray matter loss during late childhood and adolescence is related to the elimination of synapses and begins primarily in dorsal parietal cortices, continuing anteriorly to the frontal cortex, then posteriorly to the parietal, occipital, and finally temporal cortices, with decreases in dorsal prefrontal cortical volume by late adolescence. Gray matter reduction during adolescence is also observed in subcortical structures such as the globus pallidus, caudate, putamen, thalamus, and nucleus accumbens. Co-occurring increases in white matter during adolescence are associated with greater connectivity between brain regions and increased fiber track efficiency between frontal–subcortical brain regions. In particular, significant volume increases in right internal capsule and left arcuate fasciculus have been found,

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suggesting increased connectivity between regions associated with speech, as well as increased white matter volume of the corpus callosum (i.e. the white matter bundle that connects the left and right hemispheres of the brain), suggesting greater interhemispheric communication. These neurobiological developments underlie continued cognitive maturation during adolescence. Late-developing brain regions subserve higher-order cognitive functions, such as executive functioning, visuospatial performance, speeded processing, and declarative memory. These abilities are imperative to optimal academic performance, and compromised function could detrimentally influence future opportunities. It has been suggested that these neural transformations may render the brain more vulnerable to potential neurotoxic effects of substance use.

Adolescent Vulnerability The most common period of first substance use is between ages 12 and 18years, with rates of initiation significantly declining following the teenage years. While only 20% of 8th graders have tried an illicit drug, by 12th grade, 47% have experimented with substances. The highest rates of alcohol and other drug abuse and dependence are among 18- to 20-year olds. This is of concern, as young people initiate and develop problems with substances during a time of continued neuromaturation. Aside from social and psychological influences, several neurobiological processes contribute to the increased probability of substance use during adolescence. Specific neuronal alterations during adolescence correspond to cognitive, emotional, and behavioral changes that increase adolescents’ proclivity to use substances. Importantly, there are discrepant neurodevelopmental trajectories between prefrontal and limbic regions during adolescence. Dopamine activity decreases substantially in the nucleus accumbens during adolescence, potentially increasing adolescents’ propensity to engage in risky and novel behaviors to compensate for this dopamine reduction. However, the prefrontal systems underlying inhibition and cognitive control mature much later, well into late adolescence. Thus, adolescence is a period characterized by increased sensation seeking and emotionality, yet immature inhibitory control. Greater motivational drives for novel experiences, coupled with less mature inhibitory capacity, could further influence an adolescent’s susceptibility to impulsive and risky behaviors like substance use. The adolescent brain is uniquely affected by acute intoxication. For instance, receptor levels change through adolescence. N-methyl-D-aspartic acid (NMDA)

glutamate receptors, with which alcohol interacts, as well as CB1 receptors, which are the primary target of marijuana, reach peak levels in adolescence. Because of these receptor densities, adolescents experience intoxication differently than adults. Adolescents subjectively experience more positive effects and less negative effects from alcohol consumption, showing greater stimulation and less sedation. Adolescents also generally exhibit fewer hangover symptoms than adults. Thus, the overall experience of drinking is more rewarding and less aversive. In sum, adolescents exhibit increased sensation seeking and less inhibitory control that contribute to greater susceptibility to substance initiation. Greater reinforcing effects and fewer negative experiences with intoxication may underlie continued use. Together, these processes contribute to heightened vulnerability to substance use in adolescence.

Behavioral and Psychiatric Risk Factors Family History Family history of SUDs represents one of the strongest risk factors for SUD. Adolescents of alcoholic parents (family history positive, or FHP) exhibit alcohol use disorders (AUD) more than four times as often as their family history negative (FHN) counterparts. Approximately 50% of the risk for alcoholism is accounted for by genetic factors. FHP individuals appear to respond differently to acute intoxication than FHN individuals, typically showing lower levels of subjective and objective indices of alcohol consumption, and generally reporting more stimulatory and less sedating effects. FHP individuals also show more risk taking on monetary incentive delay tasks, and poorer inhibitory processing than FHN individuals. Among adolescents, a family history of alcoholism has been linked to neural abnormalities prior to the onset of personal drinking. FHP nondrinking teens demonstrated spatial deficits compared to FHN youths. fMRI has revealed altered anterior cingulate response during spatial working memory among FHP nonusing teens. FHP youths also show less frontal response during inhibitory processing than FHN youths. Thus, preexisting differences in neural functioning may partially underlie the family-mediated increased risk for substance use. Conduct Disorder Conduct disorder has been found to be a strong predictor of substance use and related disorders in adolescence. Conduct disorder is a pattern of violating the rights of others or transgressing social norms without regard for the consequences of one’s actions.

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This includes clinically significant levels of impulsivity, risk taking, rule-violation, and physical aggression. Conduct disorder is the most common psychiatric diagnosis associated with SUD in adolescents, with approximately half of teens with an SUD also meeting criteria for conduct disorder. Moreover, individuals with conduct disorder are more likely to initiate use and develop substance-related problems at a younger age than those without conduct disorder. Conduct disorder has been associated with neurobiological features that may overlap with the neural decrements associated with substance use. Gray matter volume in bilateral anterior insular cortex and the left amygdala has been shown to be lower in individuals with conduct disorder as compared to healthy control subjects. Attention Deficit Hyperactivity Disorder In the United States, attention deficit hyperactivity disorder (ADHD) is diagnosed in approximately 8% of children in ages 4–17 years, characterized by impulsivity, inattention, and overactivity. Among teens with SUD, 12% exhibit comorbid ADHD, and SUD rates may be up to six times higher among adolescents with ADHD than in the general population. The nature of the relationship between ADHD and SUD has been challenging to discern, due to the high co-occurrence between ADHD and conduct disorder. In the absence of conduct disorder, adolescents with ADHD appear to have only a moderately elevated risk of substance use. Adolescents with ADHD may be more susceptible to the neurobiological influences of substance use. Teens with ADHD report significantly more alcoholrelated problems and greater frequency of drinking, indicating that childhood ADHD may be associated with greater impairment from drinking. However, several neurocognitive alterations have also been associated with ADHD, and may be difficult to disentangle from substance-related changes. Individuals with ADHD show smaller frontal, cerebellar, and subcortical volumes, as well as frontal and cingulate hypoactivation during inhibitory processing than those without ADHD. Notably, these differences parallel many observations among individuals with substance use disorders. Mood and Anxiety Disorders Mood disorders, such as major depression or bipolar disorder, are characterized by dysregulated mood. Anxiety disorders comprise symptoms of anxiety or fear that impair functioning. Both mood and anxiety disorders present additional risk for substance use disorders. Approximately one in three adolescents with SUD also suffer from mood disorders, and one in five with SUD meet criteria from anxiety disorders. Both major depression and bipolar disorder have been

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associated with structural and functional differences in prefrontal, cingulate, and subcortical regions among adolescents. Adolescent anxiety disorders were associated with frontal and amygdala abnormalities. Thus, comorbid mood disorders or mood symptoms may influence the relationship between substance use and brain structure or functioning. For example, among adolescent marijuana users, those with greater depressive symptoms showed smaller white matter volumes than those who did not show depressive symptoms. Gender Gender is an important factor to consider for substance use risk, as well as susceptibility to detrimental effects. Survey results reveal that rates of SUD rise throughout adolescence for both males and females, with a steeper increase among males. By late adolescence, gender differences are evident, with SUD rates up to twice as high among males as compared to females. Higher rates of mood disorders have been found among girls with SUD, while behavioral disorders (including conduct disorder and ADHD) are more prevalent among boys. Neurocognitive findings suggest that girls may be more vulnerable to the neurobiological consequences of substance use.

NEURAL CONSEQUENCES OF ADDICTION Alcohol Alcohol is the most widely used intoxicant among adolescents, but perhaps one of the most detrimental to neurocognitive function. National surveys reveal that in the past month, nearly half of 12th graders report drinking, and 27% report having gotten drunk. Although the neural consequences of chronic use have been examined among adults for decades, research among adolescents has only recently expanded. Early studies focused primarily on teens with alcohol use disorders or treatment samples with multiple drug use disorders. However, neurocognitive abnormalities have been seen among teens with minimal other substance use experiences and psychiatric comorbidities, and with relatively limited alcohol exposure. Notably, adolescents who “binge” drink by consuming four or more drinks on an occasion for females or five or more drinks on an occasion for males show abnormalities in white matter quality, brain activation patterns, and neuropsychological performances, despite never having met diagnostic criteria for an SUD. Neuropsychological and neuroimaging findings suggest deficient functioning among adolescent heavy alcohol users on a number of cognitive domains,

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including executive functioning, memory, and visuospatial abilities. Moss and colleagues demonstrated subtle deficits in verbal skills among AUD adolescents, and girls with AUD performed worse on a test of perseveration and problem solving than control girls. Other research has found that teens with AUD showed poorer verbal and nonverbal retention than teens without AUD, and recent alcohol withdrawal was related to poorer visuospatial performance. Importantly, those who continued to drink heavily after treatment demonstrated declines in visuospatial functioning four years later, yet those who maintained abstinence performed similarly as controls at follow-up. Repeated alcohol withdrawal experiences were associated with subsequent poorer functioning on visuospatial tasks in adolescence and young adulthood. Alcohol-dependent teens without psychiatric or other substance use comorbidities showed poorer verbal memory, self-monitoring, and psychomotor speed and coordination compared to nondrinkers. Among teens who demonstrated comparable neurocognition prior to substance use initiation, those who transitioned into heavy drinking during early adolescence exhibited a decline in visuospatial memory and attention abilities at follow-up (Fig. 36.1). Given the neurocognitive decrements observed among adolescent heavy drinkers, neuroimaging studies have attempted to characterize structural integrity of regions subserving these functions. For instance, the prefrontal cortex, which is involved in executive functions and other higher-order cognitions, appears to be compromised. Both overall and white matter prefrontal volumes are diminished among adolescents with AUD. DTI has revealed diminished white matter microstructural quality within frontal lobe pathways, as well as a number of other regions. Animal models have suggested that the hippocampus, which is crucial for the formation of new memories, may be particularly vulnerable to the neurotoxic effects of alcohol. Neuroimaging studies have explored this possibility among human adolescents. Within the hippocampus, reduced volume and greater right to left asymmetry has been observed among adolescents with AUD, with greater symptom severity linked to larger hippocampal abnormalities. Poorer white matter microstructural integrity has been noted within hippocampal projections among alcohol-involved youth. Similar patterns have been observed among teens with heavy other substance use and psychiatric comorbidities, high functioning community youths, as well as less severe binge drinkers, providing converging evidence of the deleterious effects specific to alcohol. Functional aberrations have also been revealed among adolescent drinkers, who show evidence of compensatory neural activity and altered cognitive strategies. Teens with AUD demonstrated increased

FIGURE 36.1 Graphs depict the changes in cognitive functioning following initiation of substance use. For girls, greater recent drinking was associated with a decline in visual memory relative to performance prior to the onset of drinking a. For boys, more hangover symptoms were associated with a decline in attention functioning relative to performance prior to the onset of drinking (Based on Squeglia et al., 2009).

fMRI response in parietal cortex during spatial working memory (SWM), despite similar behavioral performance as compared to nondrinkers. These results suggest increased neural effort within visuospatial networks to maintain task performance. Abnormalities were linked to greater withdrawal symptoms and more extensive drinking. Moreover, frontal lobe abnormalities were more pronounced among female drinkers than males. Similarly, gender-specific patterns have been observed among binge drinking youths without AUD throughout bilateral frontal, anterior cingulate, temporal, and cerebellar regions. Female binge drinkers

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showed reductions in fMRI response that were associated with greater alcohol consumption as well as poorer cognitive performance, whereas male binge drinkers demonstrated greater fMRI response that was related to improved performance. These findings are consistent with the adult literature indicating greater abnormalities among females with AUD. Alcohol-dependent young adult women who initiated drinking in adolescence evinced reduced frontal and parietal fMRI response and poorer task performance during SWM compared to young women with no history of AUD. Together, these findings could represent increased neural recruitment early in the course of drinking, followed by reduced compensatory ability and diminished performance after greater exposure (Fig. 36.2). Adolescent alcohol use has been associated with poorer learning and memory, as well as reduced hippocampal volumes. Therefore, recent work has also characterized learning-related functional brain response among adolescent drinkers. During fMRI scanning, adolescent binge drinkers and nondrinkers performed a verbal learning task in which they memorized pairs of highly associated words. Cued recall was tested following scanning. Binge drinkers demonstrated increased fMRI response in frontal and parietal regions, as well as a lack of hippocampal activation and slightly poorer recall. These results suggest greater reliance on working memory systems, and less utilization of hippocampally mediated encoding strategies, among binge drinkers. Cue reactivity paradigms examine brain response to substance-related stimuli, and may uncover neural mechanisms underlying craving and relapse vulnerability. Among adolescents with AUD, images of

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preferred alcohol beverages evoked widespread brain activation compared to pictures of nonalcohol drinks. Activation was most pronounced in reward circuits and visual cortex, indicating that alcohol-related pictures provoked greater reinforcing value and careful visual attention among drinkers. The degree of brain response was also correlated to self-reported craving. In summary, the initiation and continuation of AUD or binge level alcohol use in adolescence are associated with poorer neurocognitive functioning and neuroanatomical differences. Although most studies to date have been cross-sectional and are unable to fully characterize preexisting factors, some longitudinal evidence has emerged suggesting declines in functioning following the initiation of drinking. Together, these findings are particularly striking, as most participants did not have long histories of heavy drinking. However, some longitudinal evidence suggests neurocognitive improvement with sustained abstinence, raising the possibility of recovery among those who discontinue use.

Nicotine Tobacco smoking remains common among youths, with recent surveys showing that 20% of 12th graders have smoked in the most recent month and 11% are current daily smokers. Nicotine, the primary psychoactive component of tobacco smoke, produces a pattern of nicotinic receptor upregulation, and mediates the physiological effects of the neurotransmitter acetylcholine. These upregulations of nicotinic acetylcholine

FIGURE 36.2 Representative images of fMRI brain response during spatial working memory among an adolescent male with alcohol use disorder (right) and a nondrinking adolescent male (left). Images are axial slices, with the left hemisphere depicted on the left of each image. Warm colors indicate areas that were active during the task. In bilateral parietal regions, adolescents with AUD demonstrated greater activation than nonusers, suggesting increased neural recruitment to achieve task demands (based on Tapert et al., 2004).

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receptors during adolescence may have important implications for limbic system functioning. fMRI data illustrate that adolescent daily smokers experience acute impairments of verbal memory and working memory after tobacco cessation, along with chronic decrements in cognitive performance. Abstinence in smoking adolescents is associated with reduction in the efficiency of working memory neurocircuits in left ventrolateral prefrontal and left inferior parietal cortices. During nicotine withdrawal, adolescent smokers with prenatal exposure illustrate increased activation of the left parahippocampal gyrus and the bilateral hippocampus during visuospatial recognition. Thus, smoking is associated with reduced efficiency of multiple brain regions, and may be linked to greater effects when exposure occurs at earlier periods in development.

Marijuana Marijuana is the most widely used illicit substance among teenagers, and approximately half of 12th graders have tried it. Marijuana is also the most frequently used illicit substance in teens, with 5% of adolescents endorsing daily marijuana use compared to 2.5% of adolescents endorsing daily drinking. Importantly, only half of 12th graders perceive harmfulness in using marijuana regularly. Although marijuana has been historically viewed as a relatively benign substance, advances in the adolescent neurocognitive literature have questioned this supposition. The study of marijuana use presents unique methodological considerations. Marijuana metabolites remain detectable for weeks following discontinuation, and may continue to influence neural functioning. Thus, it is important to differentiate between the residual impact of recent use and the possible long-term effects. In addition, as with many adolescent substance users, most heavy marijuana users have substantial experience with alcohol, nicotine, and other drugs, making it difficult to isolate the effects attributable to marijuana. Study designs therefore often include a comparison group with similar other substance use histories as marijuana users. Within a few days of use, higher levels of marijuana use during late adolescence significantly predicted poorer performances in young adulthood on tasks of response perseveration, spatial working memory, and memory. Among youths who were in treatment for SUD in adolescence, heavier marijuana use following treatment significantly predicted poorer functioning on tests of attention eight years after treatment. The existing adult literature indicates possible normalization of neurocognitive functioning within a month of abstinence, even among very heavy users.

However, research among adolescents has characterized subtle decrements that persist for up to 6 weeks following use, particularly in the domains of visual and verbal learning and memory, processing speed, working memory, attention, and planning ability. These findings have been observed both cross-sectionally and prospectively, with abstinence durations between 2 and 6 weeks. Further, a series of studies investigated neurocognition while controlling for premorbid functioning. Adolescents received comprehensive neuropsychological testing at the age of 9–12 years, before the onset of substance use, and again at the age of 17–21 years. Participants included heavy current users, current light users who used less than five times a week, former heavy users who had been abstinent at least three months, and nonusing controls. Despite comparable baseline functioning, current heavy users demonstrated a decline in overall IQ, processing speed, and memory at follow-up testing. Current light users and former heavy users performed similarly as nonusers. Thus, neurocognitive abnormalities related to recent heavy marijuana use may dissipate following three months of abstinence. Structural MRI studies have revealed the neuroanatomical correlates of these cognitive differences. After a month of abstinence, marijuana users show executive dysfunction associated with increased cerebellar and prefrontal volumes. Adolescent users of both alcohol and marijuana demonstrate normal hippocampal volumes and asymmetry as compared to controls, but aberrant relationships between verbal learning and hippocampal volume asymmetry. DTI studies have characterized white matter fiber integrity associated with adolescent marijuana use. Adolescent binge drinking marijuana users demonstrated poorer white matter quality compared to nonusers in major cortical pathways, including the corona radiata and superior longitudinal fasciculus. Abnormal white matter quality among marijuana users was associated with poorer performance on tests of attention, working memory, speeded processing, and verbal memory. Young adults who initiated heavy marijuana use in adolescence show decreased frontal lobe gyrification. fMRI studies of adolescent marijuana users have characterized increased prefrontal activation among users during spatial working memory, inhibitory processing, and executive attention indicative of compensatory neural recruitment of executive networks. Parietal hyperactivation has also been observed during spatial working memory and response inhibition tasks. Marijuana users demonstrate different relationships between brain response and task performance, suggesting the utilization of alternative strategies. During verbal working memory, adolescent nicotine and marijuana users failed to deactivate the hippocampus, but demonstrated increased frontal, parietal, and hippocampal

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activation with greater task difficulty during nicotine withdrawal. The neural sequelae of marijuana use on hippocampally mediated declarative learning may be subtler. In one study of adolescent boys, no differences in hippocampal functioning were observed during picture learning. Yet others have determined that after a month of abstinence, adolescents who used marijuana alone or in combination with binge drinking exhibited altered patterns of brain response during verbal learning both in prefrontal and hippocampal systems. Users of both substances evinced prefrontal hyperactivation, whereas users of marijuana alone failed to significantly activate the hippocampus. Preliminary functional imaging data also support the possibility of normalization with extended abstinence. Compared to those who had been abstinent for a month, adolescents who used within 1 week demonstrated increased prefrontal and insula response during spatial working memory. Evidence has recently emerged suggesting heightened vulnerability to marijuana use among adolescents. Marijuana exerts its psychoactive effects through interaction with the cannabinoid system. Receptors are widely distributed in brain regions involved in higher cognitive functioning, such as frontal cortex, basal ganglia, hippocampus, and cerebellum. Receptor levels peak in adolescence, which may leave the developing brain at greater risk for marijuana-related neurotoxicity. Initial investigations have supported this hypothesis. Neuropsychological investigations have suggested that cognitive abnormalities associated with marijuana use dissipate within a month of abstinence among adults who initiated use after age 17; however, those who began regular use before age 17 demonstrated persisting difficulties on tests of verbal abilities. Others have identified abnormalities in electrophysiological response during visual attention among adolescents who initiated use before age 16, but not in those who started later. Similarly, abnormal electrophysiological response during auditory selective attention has also been observed among early adolescent onset users. Compared to late onset users, early onset users demonstrated increased parietal fMRI response during verbal working memory. Taken together, these studies indicate that earlier initiation of use may be associated with greater neurocognitive abnormalities. However, it is difficult to determine whether these results are due to vulnerability of the adolescent brain, greater lifetime exposure among those who started earlier, or other factors. Animal models have supported the hypothesis of increased susceptibility in adolescents by directly comparing the cognitive impact of administration during adolescence or adulthood.

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Overall, these studies suggest executive, attention, and memory dysfunction that last up to 6 weeks after discontinuation, but may normalize within three months. Continued heavy use into young adulthood is associated with a decline in functioning. Further, adolescents appear to be more vulnerable to the deleterious effects of marijuana use than adults.

Stimulants Few studies have specifically examined the effects of adolescent stimulant (e.g. amphetamine, methamphetamine, and cocaine) use on brain functioning. Longitudinal work has shown that more frequent stimulant use (primarily methamphetamine) during adolescence was associated with worsened attention, speeded psychomotor processing, and working memory functioning in a group of substance dependent individuals when compared to controls over an 8-year follow-up. While the adult literature has shown that cocaine and methamphetamine use is associated with anatomical and neurochemical changes in heavy users when compared to controls, research pertaining specifically to youth is lacking.

Methylenedioxymethamphetamine Methylenedioxymethamphetamine (MDMA, known as “ecstasy”) is a synthetic psychoactive selective serotonin neurotoxin with stimulant and mild hallucinogenic properties that produces sensations of euphoria and distorted time perception and tactile experiences. Few studies have assessed the influence of MDMA on adolescent neurodevelopment; however, ecstasy use during adolescence has been associated with delayed reaction times during tests of selective and divided attention, and altered inhibition in the hippocampus during tasks of high verbal working memory load. The animal literature has found alterations in hippocampal neurogenesis associated with MDMA use in adolescent rats, suggesting hippocampal damage is related to the observed verbal memory deficits in human adolescents. The majority of ecstasy studies have been with young adults, since the prevalence rates of MDMA use are much lower in adolescent populations. In young adults, greater MDMA use has been linked to increased volume of certain brain structures and neurochemical changes. There is also support that MDMA use may be more detrimental to females’ serotonergic systems. Deficits in verbal learning and memory are the most commonly found cognitive abnormalities in MDMA-users, often with dose-related

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effects. Poorer performance on tests of spatial working memory, verbal fluency, impulsivity, mental processing speed, and sustained attention has also been found. Prospective imaging studies, which characterized individuals at risk for using MDMA prior to initiating ecstasy use, have shown that individuals who initiated low-quantity MDMA use (1–80 tablets; mean ¼ 6) exhibit decreased regional relative cerebral blood flow in the globus pallidus and the putamen, an area associated with learning, and poorer white matter integrity in the thalamus and frontoparietal regions compared to individuals who did not initiate MDMA use. In contrast to previous findings, no changes in serotonin transporter densities and brain metabolites were found. Prospective neuropsychological studies of MDMA use found that immediate and delayed verbal recall and verbal recognition were significantly lower in MDMA-users, compared to nonusers despite baseline equivalence on these tasks. Taken together, these findings suggest that even small doses of MDMA may adversely influence neuromaturation and cognitive functioning.

Opioids Recent surveys have revealed a rise in the misuse of prescription opioids, such as oxycodone. Among 12th graders, reported lifetime use of narcotics other than heroin more than doubled from 6% in 1992 to 14% in 2002, and remained at this higher level for the rest of the decade. The potential neurobiological implications of opioid abuse have not been studied in teenagers. Animal models have suggested that adolescents may be more susceptible to the dopamine-altering effects of opioid drugs. Additional research among humans will help clarify these relationships.

Polysubstance Use Few studies have examined neurocognitive sequelae associated with other psychoactive drugs and polysubstance use during adolescence. In a series of studies, neuropsychological functioning was examined among youths who were in treatment for dependence on alcohol and at least one other drug as teenagers. At the time of treatment, teens with polysubstance dependence (i.e. substance dependence in which no single substance predominates) exhibited diminished language skills compared to nonusing controls. Those who continued using following treatment demonstrated poorer attention functioning four years later. Eight years after treatment, greater cumulative substance exposure since treatment was associated with poorer verbal learning and memory. Cognitive functioning was also examined in female adolescents with SUD, many of whom were dependent

on multiple substances. Individuals with SUD demonstrated reduced executive functioning, language skills, sustained attention, and visuospatial skills than nonusers. Young adults who were using four or more different drugs (i.e. “polydrug users”) had the greatest neuropsychological deficits, particularly when using prescription drugs in addition to heavy alcohol use.

SUMMARY The majority of adolescents in Western society have at least experimented with addictive compounds during this phase in life, approximately a quarter engage in risky levels of use, and 5% meet diagnostic criteria for addiction to one of more of these compounds. At the same time, the brain is continuing to develop, with gray matter refinements, white matter enhancements, and neurotransmission alterations. Thus, adolescence is a period when brain size and often physical stature have reached full maturity. Mature limbic structures support greater emotional responsivity and motivational functioning than in childhood. However, inhibitory brain systems are not yet fully developed. Together, the discrepancy between these two systems leads to heightened motivational drives and excitement-seeking, but immature decision-making and inhibitory abilities, making adolescents susceptible to engaging in risky behaviors such as substance use. The vast majority of substance use begins during adolescence, and the highest lifetime rates of abuse and dependence are in young adulthood. The lifetime risk of AUD is over five times higher among individuals who had their first alcohol beverage in early adolescence (age 14 or younger) as compared to those who did not drink until after age 21. These findings raise the possibility that prevention efforts aimed at delaying the onset of drinking may result in reduced rates of addiction overall. It is important to note that not all adolescents engage in risky behaviors, but the constellation of neuromaturational processes at this stage result in a particularly vulnerable time for acting on impulses and engaging in risky behaviors, such as harmful levels of substance use, that may have lifelong consequences. Key risk factors add to the likelihood that an individual will use substances to excess during adolescence. These include familial substance use disorders, externalizing disorders (conduct disorder and attention deficit hyperactivity disorder), and mood and anxiety disorders. These risk factors can convey neural abnormalities, which may make ascertaining the consequences of adolescent substance use challenging. Cross-sectional studies have reported a range of brain functioning features that differ between adolescent substance users and nonusers. Adolescent binge

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FURTHER READING

drinking and AUDs have been associated with poorer performances on tests of memory, visuospatial functioning, executive functioning, attention, and language. Imaging has revealed differences in hippocampus and prefrontal cortex size, lower indicators of white matter integrity, and abnormal activation patterns, raising the possibility of reorganized fronto-occipital circuitry. On the whole, these abnormalities have been more pronounced in female drinkers than in male drinkers, and youth with histories of hangover or alcohol withdrawal. A few longitudinal findings have suggested that the onset of adolescent heavy drinking is followed temporally by reductions in visuospatial and attention performance, and that the persistence of very heavy drinking into young adulthood is followed by further compromise in visuospatial skills. Adolescent tobacco use has been linked to poorer working memory, attention, and cognitive efficiency, and abnormalities in activation of neural substrates of these functions are most notable during nicotine withdrawal. In recent years, adolescent marijuana use has shown some increase and the perception of its harm has decreased, yet evidence suggests that early marijuana use presents risks to the adolescent brain. Marijuanausing adolescents have shown poorer performance than nonusers on tests of learning, working memory, attention, executive functioning, and inhibition. The effects of other substances of abuse during adolescence on brain functioning have not been studied as rigorously, but research suggests that other substance use may be associated with aberrant learning and memory, attention, impulsivity, and executive functioning. Substance use typically onsets during adolescence, and most substances are used commonly during adolescence and young adulthood. Multiple cross-sectional and a few longitudinal studies in humans, as well as animal models, have suggested that the adolescent brain is particularly vulnerable to deleterious effects of alcohol and other drugs. However, very few longitudinal studies have been conducted to ascertain the magnitude of such effects in humans. Future studies tracking youth before the onset of substance use and into the lifetime period of peak use in young adulthood will elucidate the extent to which these substances of abuse alter typical neurodevelopmental trajectories, as well as the potential for recovery following discontinuation. As the field of neuroimaging in adolescent substance users is relatively new and some results have varied, additional work is needed to replicate and extend key findings.

SEE ALSO

Consequences of Addiction, Binge Drinking and Withdrawal: Neural Mechanisms in Humans, Alcohol Neuroimaging in Humans, The Impact of Regular Cannabis Use on the Human Brain: A Review of Structural Neuroimaging Studies

Glossary Diffusion tensor imaging (DTI) an MRI technique that examines the integrity of white matter tracts and provides an estimate of the underlying tissue’s overall coherence and organization. Executive functioning the higher-order brain processes that control and regulate other cognitive processes, including planning, problem solving, inhibition, set-shifting, abstract thinking, concept formation, selective attention, working memory, and verbal fluency. Functional magnetic resonance imaging (fMRI) a noninvasive technique that investigates brain activation by measuring changes in blood oxygen level dependent (BOLD) signal during mental tasks or exposure to a stimulus. Gray matter brain tissue comprised mostly of neuron cell bodies and synapses. Magnetic resonance imaging (MRI) a noninvasive technique that creates high-resolution structural pictures of the brain through the use of a magnetic field and radio waves. Substance abuse defined by the DSM-IV as a pattern of hazardous use, such as repeated legal problems, use in hazardous situations, inability to meet obligations, and use despite social or interpersonal conflicts. Substance dependence defined by the DSM-IV as a pattern of loss of control over use that leads to significant impairment in functioning, and may include tolerance, withdrawal, continued use despite negative consequences, reduction of important activities, using at greater levels than intended, or spending a great deal of time using. Also referred to as addiction. Substance use disorders (SUD) a maladaptive pattern of substance use leading to clinically significant impairment or distress; includes both substance abuse and substance dependence. Visuospatial skills cognitive functions that enable individuals to analyze and understand their surroundings in a two- and threedimensional way, and perceive object locations, navigate oneself through space, judge distances and depth, copy or construct objects, and mental imagery. White matter brain tissue comprised mostly of fatty myelin-coated axons. White matter is crucial for efficient communication between brain regions.

List of Abbreviations AUD ADHD BOLD FA FHN FHP MD MDMA SWM

alcohol use disorder attention deficit hyperactivity disorder blood oxygen level dependent fractional anisotropy family history negative family history positive mean diffusivity methylenedioxymethamphetamine; spatial working memory.

Further Reading

Neurobiological Mechanisms of Drug Addiction: An Introduction, Neuropsychological Precursors and

Casey, B.J., Jones, R.M., Levita, L., Libby, V., Pattwell, S.S., Ruberry, E.J., Soliman, F., Somerville, L.H., 2010. The storm and

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stress of adolescence: insights from human imaging and mouse genetics. Developmental Psychobiology 52, 225–235. Nixon, K., McClain, J.A., 2010. Adolescence as a critical window for developing alcohol use disorder: current findings in neuroscience. Current Opinions in Psychiatry. Schweinsburg, A.D., Brown, S.A., Tapert, S.F., 2008. The influence of marijuana use on neurocognitive functioning in adolescents. Current Drug Abuse Reviews 1, 99–111. Squeglia, L.M., Jacobus, J., Tapert, S.F., 2009a. The influence of substance use on adolescent brain development. Clinical EEG and Neuroscience 40, 31–38. Squeglia, L.M., Spadoni, A.D., Infante, M.A., Myers, M.G., Tapert, S.F., 2009b. Initiating moderate to heavy alcohol use predicts changes in neuropsychological functioning for adolescent girls and boys. Psychology of Addictive Behaviors 23, 715–722. Tapert, S.F., Granholm, E., Leedy, N.G., Brown, S.A., 2002. Substance use and withdrawal: neuropsychological functioning over 8 years in youth. Journal of the International Neuropsychological Society 8, 873–883.

Tapert, S.F., Schweinsburg, A.D., Barlett, V.C., Brown, S.A., Frank, L.R., Brown, G.G., Meloy, M.J., 2004. Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders. Alcoholism, Clinical and Experimental Research 28, 1577–1586.

Relevant Websites http://www.cdc.gov/healthyyouth/alcoholdrug/index.htm – Info from the CDC. http://www.drugabuse.gov/infofacts/infofactsindex.html, http:// teens.drugabuse.gov/ – Info from the National Institute of Drug Abuse. http://pubs.niaaa.nih.gov/publications/arh284/205-212.htm – National Institute on Alcohol Abuse and Alcoholism. http://www.sciencedaily.com/news/mind_brain/addiction/ – Science Daily.

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