Impact of Adolescent Alcohol and Drug Use on Neuropsychological Functioning in Young Adulthood: 10-Year Outcomes.

BACKGROUND: Alcohol and other substance use disorders (AUD/SUD) are common among youth and often continue into adulthood; therefore, the neurocognitive effects of substance use are of great concern. Because neuromaturation continues into young adulthood, youth with AUD/SUD may be at risk for lasting cognitive decrements. This study prospectively examines neuropsychological functioning over 10 years as a function of AUD/SUD history and outcomes. METHODS: The 51 participants consisted of 18 youth with persisting AUD/SUD, 19 youth with remitted AUD/SUD, and 14 community youth with no AUD/SUD history followed over 10 years (ages 16 to 27 on average) with neuropsychological testing and substance use interviews on 8 occasions. Neuropsychological performance from baseline to 10-year follow-up was compared between the three groups. RESULTS: Despite scoring higher than controls at intake, both AUD/SUD groups showed a relative decline in visuospatial construction at 10-year follow-up (p=.001). Regressions showed that alcohol use (ß=-.33, p < .01) and drug withdrawal symptoms (ß=-.31, p<.05) over follow-up were predictive of year 10 visuospatial function. Alcohol use also predicted verbal learning and memory (ß=-.28, p<.05), while stimulant use predicted visual learning and memory function (ß=-.33, p=.01). More recent substance use was associated with poorer executive function (ß=.28, p<.05). DISCUSSION: These findings confirm prior studies suggesting that heavy, chronic alcohol and other substance use persisting from adolescence to young adulthood may produce cognitive disadvantages, primarily in visuospatial and memory abilities. Youth who chronically consume heavy quantities of alcohol and/or experience drug withdrawal symptoms may be particularly at risk for cognitive deterioration by young adulthood.

Abnormal cerebellar morphometry in abstinent adolescent marijuana users.

Functional neuroimaging data from adults have, in general, revealed frontocerebellar dysfunction associated with acute and chronic marijuana (MJ) use. The goal of this study was to characterize cerebellar volume in adolescent chronic MJ users following 1 month of monitored abstinence. Participants were MJ users (n=16) and controls (n=16) aged 16-18 years. Extensive exclusionary criteria included history of psychiatric or neurologic disorders. Drug use history, neuropsychological data, and structural brain scans were collected after 28 days of monitored abstinence. Trained research staff defined cerebellar volumes (including three cerebellar vermis lobes and both cerebellar hemispheres) on high-resolution T1-weighted magnetic resonance images. Adolescent MJ users demonstrated significantly larger inferior posterior (lobules VIII-X) vermis volume than controls, above and beyond effects of lifetime alcohol and other drug use, gender, and intracranial volume. Larger vermis volumes were associated with poorer executive functioning. Following 1 month of abstinence, adolescent MJ users had significantly larger posterior cerebellar vermis volumes than non-using controls. These greater volumes are suggested to be pathological based on linkage to poorer executive functioning. Longitudinal studies are needed to examine typical cerebellar development during adolescence and the influence of marijuana use.

Hippocampal volumes in adolescents with and without a family history of alcoholism.

BACKGROUND AND OBJECTIVES: The hippocampus may be vulnerable to the effects of heavy alcohol use during adolescence, which is a time of continued neurodevelopment. However, differences in hippocampal volume may be due to risk factors such as a family history (FH) of alcoholism. We examined hippocampal volumes in youth with and without a FH of alcoholism prior to the initiation of alcohol use. METHODS: Participants were demographically matched adolescents (aged 12-14) with positive (n = 15; FHP) and negative (n = 15; FHN) FH of alcoholism. Each group consisted of 10 males and 5 females with minimal previous substance use. Manual hippocampal tracings were completed on high-resolution magnetic resonance images by reliable raters, and intracranial volumes were controlled in analyses. RESULTS: FH groups did not differ on memory or hippocampal volumes, but group x gender interactions (p < .05) indicated that FHP males had larger left hippocampi than FHN males. Females showed greater left versus right hippocampal asymmetry, while males showed larger right versus left asymmetry. For all adolescents, larger right hippocampal volumes predicted poorer delayed visual memory (p < .01). CONCLUSION AND SIGNIFICANCE: Alcoholism risk factors, such as family history of alcoholism, may differentially influence adolescent hippocampal development for boys as compared to girls. Results suggest that FH does not account for prior findings of reduced left hippocampal volumes in heavy drinking youth. Findings are preliminary, but suggest that future studies examining the effects of alcohol use on the adolescent brain should consider the influence of FH, especially among boys.

The influence of recency of use on fMRI response during spatial working memory in adolescent marijuana users.

Some neurocognitive recovery occurs within a month of abstinence from heavy marijuana use, yet functional magnetic resonance imaging (fMRI) has revealed altered activation among recent and abstinent adult users. We compared fMRI response during a spatial working memory (SWM) task between adolescent marijuana users with brief and sustained durations of abstinence. Participants were 13 recent users (two to seven days abstinent), 13 abstinent users (27 to 60 days abstinent), and 18 nonusing controls, all ages 15 to 18. Groups were similar on demographics, had no psychiatric or medical disorders, and user groups were similar on substance histories. Teens performed a two-back SWM task during fMRI. Recent users showed greater fMRI response in medial and left superior prefrontal cortices, as well as bilateral insula. Abstinent users had increased response in the right precentral gyrus (clusters > or = 1328 microl, p < .05). Results suggest that adolescents who recently used marijuana show increased brain activity in regions associated with working memory updating and inhibition. This study preliminarily suggests that (1) recent marijuana use may disrupt neural connections associated with SWM and result in compensatory brain response, and (2) sustained abstinence from marijuana may be associated with improvements in SWM response among adolescents.

Prefrontal cortex morphometry in abstinent adolescent marijuana users: subtle gender effects.

Adult human studies suggest frontal dysfunction associated with chronic marijuana (MJ) use, but due to continued neuromaturation, adult studies may not generalize to adolescents. This study characterized prefrontal cortex (PFC) morphometry in chronic MJ-using adolescents following 1 month of monitored abstinence. Data were collected from MJ users (n = 16) and controls (n = 16) aged 16-18. Extensive exclusionary criteria included co-morbid psychiatric and neurologic disorders. Substance use and anatomical measures were collected after 28 days of monitored abstinence. PFC volumes were ascertained from manual tracing by reliable raters on high-resolution magnetic resonance images. After controlling for lifetime alcohol use, gender and intracranial volume, MJ users did not differ from controls in PFC volume. However, marginal group-by-gender interactions were observed (P < 0.09): female MJ users demonstrated comparatively larger PFC volumes while male MJ users had smaller volumes compared with same-gender controls. Further, group status and total PFC volume interacted in predicting executive functioning (P < 0.05). Among MJ users, smaller PFC total volume was associated with better executive functioning while the opposite pattern was seen among the controls. These preliminary results indicate that gender may moderate the relationship between MJ use and PFC morphometry. Given the relationship between larger PFC total volumes and poorer executive functioning among MJ users, female MJ users may be at increased risk for neurocognitive consequences. Future research will measure PFC gray and white matter separately and follow boys and girls over adolescence to examine the influence of MJ use on neurodevelopment.

Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender effects.

BACKGROUND: Adolescents with alcohol use disorders (AUD) have shown smaller prefrontal cortex (PFC) volumes compared with healthy controls; however, differences may have been due to comorbid disorders. This study examined PFC volumes in male and female adolescents with AUD who did not meet criteria for comorbid mood or attention disorders. METHODS: Participants were adolescents aged 15 to 17 who met criteria for AUD (n = 14), and demographically similar healthy controls (n = 17). Exclusions included any history of a psychiatric or neurologic disorder other than AUD or conduct disorder. Magnetic resonance imaging scans occurred after at least 5 days of abstinence from alcohol or drugs. Overall PFC volumes and white matter PFC volumes were compared between groups. RESULTS: After controlling for conduct disorder, gender, and intracranial volume, AUD teens demonstrated marginally smaller anterior ventral PFC volumes (p = 0.09) than controls, and significant interactions between group and gender were observed (p < 0.001 to p < 0.03). Compared with same-gender controls, females with AUD demonstrated smaller PFC volumes, while males with AUD had larger PFC volumes. The same pattern was observed for PFC white matter volumes. CONCLUSIONS: Consistent with adult literature, alcohol use during adolescence is associated with prefrontal volume abnormalities, including white matter differences. However, adolescents with AUD demonstrated gender-specific morphometric patterns. Thus, it is possible that gender may moderate the impact of adolescent alcohol use on prefrontal neurodevelopment, and the neurodevelopmental trajectories of heavy drinking boys and girls should be evaluated separately in longitudinal studies.

Anxiety, depression, and behavioral symptoms of executive dysfunction in ecstasy users: contributions of polydrug use.

BACKGROUND: Given ecstasy's (MDMA) potential serotonergic neurotoxicity, it is plausible that regular ecstasy users would have an elevated prevalence of behavioral executive dysfunction or mood symptoms. However, recent studies have found that the relationship between ecstasy use and psychological symptoms was no longer significant after controlling for marijuana use (e.g., Morgan et al., 2002). The goal of the present study was to examine the relationship between ecstasy exposure and self-reported executive functioning and psychological symptoms after controlling for gender, ethnicity, and other drug use. METHODS: Data were collected from 65 men and women with a wide range of ecstasy use (including 17 marijuana-using controls). Participants were administered the Frontal Systems Behavioral Scale, State-Trait Anxiety Inventory for adults, and the Beck Depression Inventory-2nd edition. RESULTS: Although 19-63% of the ecstasy users demonstrated clinically elevated psychological symptoms, frequency of ecstasy use did not predict the psychological symptoms. No gender differences or interactions were observed. CONCLUSIONS: These results revealed that, although ecstasy users demonstrate elevated levels of psychological symptoms and executive dysfunction, these symptoms are not statistically associated with their ecstasy consumption. Instead, other drug use (alcohol, marijuana, opioids, and inhalants) significantly predict psychological symptoms in this sample of polydrug users.

Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry.

BACKGROUND: Converging lines of evidence suggest that the hippocampus may be particularly vulnerable to deleterious effects of alcohol and marijuana use, especially during adolescence. The goal of this study was to examine hippocampal volume and asymmetry in adolescent users of alcohol and marijuana. METHODS: Participants were adolescent (aged 15-18) alcohol (ALC) users (n=16), marijuana and alcohol (MJ+ALC) users (n=26), and demographically similar controls (n=21). Extensive exclusionary criteria included prenatal toxic exposure, left handedness, and psychiatric and neurologic disorders. Substance use, cognitive, and anatomical measures were collected after at least 2 days of abstinence from all substances. RESULTS: Adolescent ALC users demonstrated a significantly different pattern of hippocampal asymmetry (p<.05) and reduced left hippocampal volume (p<.05) compared to MJ+ALC users and non-using controls. Increased alcohol abuse/dependence severity was associated with increased right>left (R>L) asymmetry and smaller left hippocampal volumes while marijuana abuse/dependence was associated with increased L>R asymmetry and larger left hippocampal volumes. Although MJ+ALC users did not differ from controls in asymmetry, functional relationships with verbal learning were found only among controls, among whom greater right than left hippocampal volume was associated with superior performance (p<.05). CONCLUSIONS: Aberrations in hippocampal asymmetry and left hippocampal volumes were found for adolescent heavy drinkers. Further, the functional relationship between hippocampal asymmetry and verbal learning was abnormal among adolescent substance users compared to healthy controls. These findings suggest differential effects of alcohol and combined marijuana and alcohol use on hippocampal morphometry and the relationship between hippocampal asymmetry and verbal learning performance among adolescents.

Age-related changes in prefrontal white matter volume across adolescence.

Past research has suggested that white matter volume increases from childhood to adulthood; however, during adolescence, there is somewhat limited data to support this finding. In the present study, 65 typically developing adolescents underwent structural magnetic resonance imaging. Using magnetic resonance imaging, prefrontal white matter volumes were examined in relation to adolescent age and sex. Surprisingly, results suggested that prefrontal white matter volume decreased during late adolescence, particularly among the female sex. These findings are inconsistent with past research and suggest that perhaps some developmental processes in late adolescence are not yet fully explained. Possible methodological contributions and implications for the current findings are discussed.

Memory functioning in polysubstance dependent women.

BACKGROUND: The vast majority of studies on polysubstance abuse or dependence have utilized male participants; therefore, the specific neuropsychological effects of polysubstance dependence in women are relatively unknown. The goal of the present study is to examine the effects of polysubstance dependence on women's verbal and visual memory ability. METHODS: Data were collected from 109 women (46 controls and 63 polysubstance dependence women who were similar in ethnic identification, education, age, and verbal ability). A series of multiple regressions were run to test whether group membership significantly predicted performance on the Benton Visual Retention Test and the California Verbal Learning Test after controlling for important demographic characteristics. RESULTS: The primary results indicated that the polysubstance dependent women had significantly poorer verbal learning ability (ranging from p<.005 to .05) than the control group, while no differences were found in visual memory ability. Further, significant bivariate relationships were observed between frequency of alcohol and cocaine use and verbal learning, delayed recall, and recognition ability. CONCLUSIONS: The results confirm that polysubstance dependence is associated with deficient encoding of verbal information. In addition, past year frequent use of alcohol and cocaine was associated with more severe deficits in delayed recall and recognition ability among polysubstance dependent women at the bivariate level.

Cognitive functioning and length of abstinence in polysubstance dependent men.

To date, there are few large-scale studies that have examined the relationship between duration of abstinence and cognitive functioning in polysubstance-dependent individuals. Existing large-scale studies of polysubstance abusers have reported only minimal recovery of cognitive functioning with abstinence [Arch. Gen. Psychiatry 35 (1978) 1063]. The goal of this study is to test whether length of abstinence (1 day and 14 months) is related to cognitive ability in a large cross-sectional sample of men recovering from dependence on at least two drugs (N = 207). A series of Poisson and linear regressions were run to test whether length of abstinence is associated with neuropsychological performance while controlling for demographic variables, raw Vocabulary score, drug use, and dependency. The primary finding is that increasing length of abstinence was not statistically associated with superior neuropsychological ability. This suggests that the abuse of multiple substances potentially produces long-lasting neuropsychological impairment with minimal recovery of functioning over a 1-year period.

Self-administration of alcohol before and after a public speaking challenge by individuals with social phobia.

K. Abrams, M. Kushner, K. Medina, and A. Voight (2001) showed that alcohol attenuates social anxiety symptoms in socially phobic individuals. This article examines whether social anxiety symptoms can lead to increased alcohol use in this same population. Forty-four individuals with social phobia attended 2 laboratory sessions, spaced 1 week apart, in groups of approximately 10. Participants underwent a social anxiety challenge during 1 session and a control task during the other. Half of the sample self-administered alcohol immediately before, and half immediately after, these 2 activities. As predicted, participants consumed more alcohol following the anxiety challenge than following the control task; however, the opposite pattern was evidenced for drinking preceding [corrected] the 2 activities. These findings add to an understanding of why social phobia and alcohol problems tend to co-occur.

Gender effects on amygdala morphometry in adolescent marijuana users.

Adolescent developments in limbic structures and the endogenous cannabinoid system suggest that teenagers may be more vulnerable to the negative consequences of marijuana use. This study examined the relationships between amygdala volume and internalizing symptoms in teenaged chronic marijuana users. Participants were 35 marijuana users and 47 controls ages 16-19 years. Exclusions included psychiatric (e.g., mood and anxiety) or neurologic disorders. Substance use, internalizing (anxiety/depression) symptoms and brain scans were collected after 28 days of monitored abstinence. Reliable raters manually traced amygdala and intracranial volumes on high-resolution magnetic resonance images. Female marijuana users had larger right amygdala volumes and more internalizing symptoms than female controls, after covarying head size, alcohol, nicotine and other substance use (p<0.05), while male users had similar volumes as male controls. For female controls and males, worse mood/anxiety was linked to smaller right amygdala volume (p<0.05), whereas more internalizing problems was associated with bigger right amygdala in female marijuana users. Gender interactions may reflect marijuana-related interruptions to sex-specific neuromaturational processes and staging. Subtle amygdala development abnormalities may underlie particular vulnerabilities to sub-diagnostic depression and anxiety in teenage female marijuana users.

Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence.

BACKGROUND: Cognitive deficits that persist up to a month have been detected among adult marijuana users, but decrements and their pattern of recovery are less known in adolescent users. Previously, we reported cognitive deficits among adolescent marijuana users after one month of abstinence (Medina, Hanson, Schweinsburg, Cohen-Zion, Nagel, & Tapert, 2007). In this longitudinal study, we characterized neurocognitive changes among marijuana-using adolescents across the first three weeks of abstinence. METHOD: Participants were adolescent marijuana users with limited alcohol and other drug use (n=19) and demographically similar non-using controls (n=21) ages 15-19. Participants completed a brief neuropsychological battery on three occasions, after 3days, 2weeks, and 3weeks of stopping substance use. Abstinence was ascertained by decreasing tetrahydrocannabinol metabolite values on serial urine drug screens. Verbal learning, verbal working memory, attention and vigilance, and time estimation were evaluated. RESULTS: Marijuana users demonstrated poorer verbal learning (p<.01), verbal working memory (p<.05), and attention accuracy (p<.01) compared to controls. Improvements in users were seen on word list learning after 2weeks of abstinence and on verbal working memory after 3weeks. While attention processing speed was similar between groups, attention accuracy remained deficient in users throughout the 3-week abstinence period. CONCLUSIONS: This preliminary study detected poorer verbal learning and verbal working memory among adolescent marijuana users that improved during three weeks of abstinence, while attention deficits persisted. These results implicate possible hippocampal, subcortical, and prefrontal cortex abnormalities.

Depressive symptoms in adolescents: associations with white matter volume and marijuana use.

BACKGROUND: Depressed mood has been associated with decreased white matter and reduced hippocampal volumes. However, the relationship between brain structure and mood may be unique among adolescents who use marijuana heavily. The goal of this study was to examine the relationship between white matter and hippocampal volumes and depressive symptoms among adolescent marijuana users and controls. METHODS: Data were collected from marijuana users (n = 16) and demographically similar controls (n = 16) aged 16-18. Extensive exclusionary criteria included psychiatric and neurologic disorders, including major depression. Substance use, mood, and anatomical measures were collected after 28 days of monitored abstinence. RESULTS: Marijuana (MJ) users demonstrated more depressive symptoms than controls (p < .05). MJ use (beta = .42, p < .005) and smaller white matter volume (beta = -.34, p < .03) each predicted higher levels of depressive symptoms on the Hamilton Depression Rating Scale. MJ use interacted with white matter volume (beta = -.55, p < .03) in predicting depression scores on the Beck Depression Inventory: among MJ users, but not controls, white matter volume was negatively associated with depressive symptoms. CONCLUSIONS: Marijuana use and white matter volume were additive and interactive in predicting depressive symptoms among adolescents. Subtle neurodevelopmental white matter abnormalities may disrupt the connections between areas involved in mood regulation.

Neuropsychological functioning in adolescent marijuana users: subtle deficits detectable after a month of abstinence.

In adults, studies examining the long-lasting cognitive effects of marijuana use demonstrate subtle deficits in attention, executive function, and memory. Because neuromaturation continues through adolescence, these results cannot necessarily generalize to adolescent marijuana users. The goal of this study was to examine neuropsychological functioning in abstinent marijuana using and demographically similar control adolescents. Data were collected from 65 adolescent marijuana users (n=31, 26% females) and controls (n=34, 26% females) 16-18 years of age. Extensive exclusionary criteria included independent psychiatric, medical, and neurologic disorders. Neuropsychological assessments were conducted after>23 days of monitored abstinence. After controlling for lifetime alcohol use and depressive symptoms, adolescent marijuana users demonstrated slower psychomotor speed (p<.05), and poorer complex attention (p<.04), story memory (p<.04), and planning and sequencing ability (p<.001) compared with controls. Post hoc analysis revealed that the number of lifetime marijuana use episodes was associated with poorer cognitive function, even after controlling for lifetime alcohol use. The general pattern of results suggested that, even after a month of monitored abstinence, adolescent marijuana users demonstrate subtle neuropsychological deficits compared with nonusers. It is possible that frequent marijuana use during adolescence may negatively influence neuromaturation and cognitive development.

Ecstasy (MDMA) exposure and neuropsychological functioning: a polydrug perspective.

Ecstasy (MDMA) is a popular drug that can act as a selective serotonin neurotoxin in several species. The goal of the present study was to examine the relationship between ecstasy exposure and cognitive functioning after controlling for other drug use and demographic variables. Furthermore, we assessed whether gender was a moderator of the relationship between cognitive functioning and ecstasy use. Data were collected from 31 men and 34 women with a wide range of ecstasy use (17 marijuana users with no ecstasy use and 48 ecstasy users ranging from low to heavy use). Participants were interviewed and administered a battery of neuropsychological tests. The primary finding was that ecstasy exposure was significantly related to poorer verbal learning and memory ability in a dose-dependent manner, while no such relationship was observed between ecstasy exposure and executive functioning or attentional ability. Gender was found to significantly moderate the relationship between ecstasy consumption and design fluency. These results suggest primary memory dysfunction among abstinent recreational ecstasy users. This finding is consistent with reports of hippocampal vulnerability, particularly among heavy users.