Joseph T. Sakai

Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado.

BACKGROUND Legal medical marijuana has been commercially available on a widespread basis in Colorado since mid-2009; however, there is a dearth of information about the impact of marijuana commercialization on impaired driving. This study examined if the proportions of drivers in a fatal motor vehicle crash who were marijuana-positive and alcohol-impaired, respectively, have changed in Colorado before and after mid-2009 and then compared changes in Colorado with 34 non-medical marijuana states (NMMS). METHODS Thirty-six 6-month intervals (1994-2011) from the Fatality Analysis Reporting System were used to examine temporal changes in the proportions of drivers in a fatal motor vehicle crash who were alcohol-impaired (≥0.08 g/dl) and marijuana-positive, respectively. The pre-commercial marijuana time period in Colorado was defined as 1994-June 2009 while July 2009-2011 represented the post-commercialization period. RESULTS In Colorado, since mid-2009 when medical marijuana became commercially available and prevalent, the trend became positive in the proportion of drivers in a fatal motor vehicle crash who were marijuana-positive (change in trend, 2.16 (0.45), p<0.0001); in contrast, no significant changes were seen in NMMS. For both Colorado and NMMS, no significant changes were seen in the proportion of drivers in a fatal motor vehicle crash who were alcohol-impaired. CONCLUSIONS Prevention efforts and policy changes in Colorado are needed to address this concerning trend in marijuana-positive drivers. In addition, education on the risks of marijuana-positive driving needs to be implemented.

Case-control and within-family tests for an association between conduct disorder and 5HTTLPR†

Several lines of research have suggested that serotonin dysfunction is associated with aggression, impulsivity, and antisocial behavior. A functional polymorphism in the promoter region (s, short and l, long allele variant) of the serotonin transporter gene (SLC6A4) that results in decreased transcription of the serotonin transporter gene has been linked with such serotonin dysfunction. To test for an association between 5HTTLPR genotype and conduct disorder diagnosis/aggression. Analysis for association between 5HTTLPR and conduct disorder/aggression using a case‐control design and the transmission disequilibrium test. Conduct‐disordered adolescents, who were drawn from admissions to a program that treats adolescents with serious substance and behavior problems, and conduct‐disordered siblings of these patients (n, 297) were compared with non‐conduct‐disordered control adolescents and non‐conduct‐disordered siblings of these controls (n, 93). Second, using patient families where parental DNA was available, transmission disequilibrium tests were conducted for two phenotypes: (1) conduct disorder (74 trios), and (2) conduct disorder with at least one aggressive symptom (57 trios). Case‐control analyses suggested a strong association between the ss genotype and conduct disorder (χ  22  = 14.3; P < 0.01). Within‐family analyses for conduct disorder with at least one aggressive symptom significantly favored greater transmission of the s‐allele to affected offspring (χ  tdt2  = 4.13; P = 0.04); for conduct disorder, without aggressive symptoms, however, results were non‐significant (χ  tdt2  = 1.61; P = 0.20). These data suggest that the s‐allele may confer some risk for aggressive behavior or may be in linkage disequilibrium with such an allele.

Item Response Theory Analysis of DSM-IV Cannabis Abuse and Dependence Criteria in Adolescents.

OBJECTIVE To examine three aspects of adolescent cannabis problems: do DSM-IV cannabis abuse and dependence criteria represent two different levels of severity of substance involvement, to what degree do each of the 11 abuse and dependence criteria assess adolescent cannabis problems, and do the DSM-IV items function similarly across different adolescent populations? METHOD We examined 5,587 adolescents ages 11 to 19, including 615 youths in treatment for substance use disorders, 179 adjudicated youths, and 4,793 youths from the community. All of the subjects were assessed with a structured diagnostic interview. Item response theory was used to analyze symptom endorsement patterns. RESULTS Abuse and dependence criteria were not found to represent different levels of severity of problem cannabis use in any of the samples. Among the 11 abuse and dependence criteria, problems cutting down and legal problems were the least informative for distinguishing problem users. Two dependence criteria and three of the four abuse criteria indicated different severities of cannabis problems across samples. CONCLUSIONS We found little evidence to support the idea that abuse and dependence are separate constructs for adolescent cannabis problems. Furthermore, certain abuse criteria may indicate severe substance problems, whereas specific dependence items may indicate less severe problems. The abuse items in particular need further study. These results have implications for the refinement of the current substance use disorder criteria for DSM-V.

Reduced cortical gray matter volume in male adolescents with substance and conduct problems

UNLABELLED Boys with serious conduct and substance problems (Antisocial Substance Dependence (ASD)) repeatedly make impulsive and risky decisions in spite of possible negative consequences. Because prefrontal cortex (PFC) is involved in planning behavior in accord with prior rewards and punishments, structural abnormalities in PFC could contribute to a persons propensity to make risky decisions. METHODS We acquired high-resolution structural images of 25 male ASD patients (ages 14-18 years) and 19 controls of similar ages using a 3T MR system. We conducted whole-brain voxel-based morphometric analysis (p<0.05, corrected for multiple comparisons at whole-brain cluster-level) using Statistical Parametric Mapping version-5 and tested group differences in regional gray matter (GM) volume with analyses of covariance, adjusting for total GM volume, age, and IQ; we further adjusted between-group analyses for ADHD and depression. As secondary analyses, we tested for negative associations between GM volume and impulsivity within groups and separately, GM volume and symptom severity within patients using whole-brain regression analyses. RESULTS ASD boys had significantly lower GM volume than controls in left dorsolateral PFC (DLPFC), right lingual gyrus and bilateral cerebellum, and significantly higher GM volume in right precuneus. Left DLPFC GM volume showed negative association with impulsivity within controls and negative association with substance dependence severity within patients. CONCLUSIONS ASD boys show reduced GM volumes in several regions including DLPFC, a region highly relevant to impulsivity, disinhibition, and decision-making, and cerebellum, a region important for behavioral regulation, while they showed increased GM in precuneus, a region associated with self-referential and self-centered thinking.

Default mode network activity in male adolescents with conduct and substance use disorder

BACKGROUND Adolescents with conduct disorder (CD) and substance use disorders (SUD) experience difficulty evaluating and regulating their behavior in anticipation of future consequences. Given the role of the brains default mode network (DMN) in self-reflection and future thought, this study investigates whether DMN is altered in adolescents with CD and SUD, relative to controls. METHODS Twenty adolescent males with CD and SUD and 20 male controls of similar ages underwent functional magnetic resonance imaging as they completed a risk-taking decision task. We used independent component analysis as a data-driven approach to identify the DMN spatial component in individual subjects. DMN activity was then compared between groups. RESULTS Compared to controls, patients showed reduced activity in superior, medial and middle frontal gyrus (Brodmann area (BA) 10), retrosplenial cortex (BA 30) and lingual gyrus (BA 18), and bilateral middle temporal gryus (BA 21/22) - DMN regions thought to support self-referential evaluation, memory, foresight, and perspective taking. Furthermore, this pattern of reduced activity in patients remained robust after adjusting for the effects of depression and attention-deficit hyperactivity disorder (ADHD). Conversely, when not adjusting for effects of depression and ADHD, patients demonstrated greater DMN activity than controls solely in the cuneus (BA 19). CONCLUSIONS Collectively, these results suggest that comorbid CD and SUD in adolescents is characterized by atypical activity in brain regions thought to play an important role in introspective processing. These functional imbalances in brain networks may provide further insight into the neural underpinnings of conduct and substance use disorders.

Severe mental illness and mortality of hospitalized ACS patients in the VHA

BackgroundSevere mental illness (SMI) has been associated with more medical co-morbidity and less cardiovascular procedure use for older patients with myocardial infarction. However, it is unknown whether SMI is associated with increased long term mortality risk among patients presenting with acute coronary syndromes (ACS). We tested the hypothesis that SMI is associated with higher one-year mortality following ACS hospitalization.MethodsAll ACS patients (n = 14,194) presenting to Veterans Health Administration (VHA) hospitals between October 2003 and September 2005 were included. Survival analysis evaluated the association between SMI and one-year all-cause mortality, adjusting for demographics, co-morbidities, in-hospital treatment, and discharge medications.ResultsOverall, 18.4 % of ACS patients had SMI. Patients with SMI were more likely female, younger, Caucasian race, have a history of alcohol abuse, liver disease, dementia, hypertension and more likely to be a current smoker; however, prior cardiac history was similar between the 2 groups. There were no significant differences in cardiac procedure use, including coronary angiogram (38.7% vs. 40.3%, p = 0.14) or coronary revascularization (31.0% vs. 32.3%, p = 0.19), and discharge medications between those with and without SMI. One-year mortality was lower for patients with SMI (15.8% vs. 19.1%, p < 0.001). However, in multivariable analysis, there were no significant differences in mortality (HR 0.91; 95% CI 0.81–1.02) between patients with and without SMI.ConclusionAmong ACS patients in the VHA, SMI is prevalent, affecting almost 1 in 5 patients. However, patients with SMI were as likely to undergo coronary revascularization and be prescribed evidence-based medications at hospital discharge, and were not at elevated risk of adverse 1-year outcomes compared to patients without SMI.

Conduct Disorder and Initiation of Substance Use: A Prospective Longitudinal Study

OBJECTIVE To examine the influence of conduct disorder (CD) on substance use initiation. METHOD Community adolescents without CD (n = 1,165, mean baseline age = 14.6 years), with CD (n = 194, mean baseline age = 15.3 years), and youth with CD recruited from treatment (n = 268, mean baseline age = 15.7 years) were prospectively followed and re-interviewed during young adulthood (mean ages at follow-up respectively: 20, 20.8, and 24). Young adult retrospective reports of age of substance initiation for 10 substance classes were analyzed using Cox regression analyses. Hazard ratios of initiation for the CD cohorts (community without CD as the reference) at ages 15, 18, and 21 were calculated, adjusting for baseline age, gender, and race/ethnicity. RESULTS Among community subjects, CD was associated with elevated adjusted hazards for initiation of all substances, with comparatively greater hazard ratios of initiating illicit substances at age 15 years. By age 18, the adjusted hazard ratios remained significant except for alcohol. At age 21, the adjusted hazard ratios were significant only for cocaine, amphetamines, inhalants, and club drugs. A substantial portion of community subjects without CD never initiated illicit substance use. Clinical youth with CD demonstrated similar patterns, with comparatively larger adjusted hazard ratios. CONCLUSIONS CD confers increased risk for substance use initiation across all substance classes at age 15 years, with greater relative risk for illicit substances compared to licit substances. This effect continues until age 18 years, with the weakest effect for alcohol. It further diminishes for other substances by age 21, However, the likelihood of initiating cocaine, amphetamines, inhalants and club drug use among those who have not initiated yet continues to be highly elevated by age 21.

Test of association between GABRA2 (SNP rs279871) and adolescent conduct/alcohol use disorders utilizing a sample of clinic referred youth with serious substance and conduct problems, controls and available first degree relatives.

UNLABELLED Recent findings have linked the GABRA2 gene with antisocial personality disorder and alcohol dependence (AD) in adults and conduct disorder (CD), but not AD symptoms, in children and adolescents. We sought to replicate previous findings and test for an association between a single nucleotide polymorphism (SNP) in the GABRA2 gene (rs279871) and CD among adolescents. METHODS Adolescent patients (n=371), 13-18 years old, were recruited from a university substance abuse treatment program. Patient siblings (n=245), parents of patients (n=355), adolescent controls (n=185), siblings of controls (n=163) and parents of controls (n=263) were included in these analyses (total sample n=1582). Case-control (using only Caucasian and Hispanic probands) and family-based association tests were completed to test for association between rs279871 and several a priori CD and AD phenotypes. RESULTS For case-control association tests, rs279871 was significantly associated with CD (p=0.02) but not AD phenotypes; the result did not survive strict correction for multiple testing. All family-based association tests were non-significant (CD p=0.48; CD symptom count age corrected within sex p=0.91; AD p=0.84; alcohol use disorder p=0.52). CONCLUSIONS Consistent with previous findings, the results do not support the association between GABRA2 SNP rs279871 and AD in adolescents. Our results also do not support an association between rs279871 and CD; the study limitations are reviewed.

Insula and Orbitofrontal Cortical Morphology in Substance Dependence Is Modulated by Sex

BACKGROUND AND PURPOSE: Frontolimbic circuits are involved in learning and decision-making processes thought to be affected in substance-dependent individuals. We investigated frontolimbic cortical morphometry in substance-dependent men and women and determined whether morphometric measurements correlated with decision-making performance. MATERIALS AND METHODS: Twenty-eight abstinent SDI (17 men/11 women) were compared with 28 controls (13 men/15 women). Cortical thicknesses and volumes were computed by using FreeSurfer. After controlling for age and intracranial volume, group and sex effects were analyzed in 3 a priori regions of interest: the insula, orbitofrontal cortex, and anterior cingulate cortex by using analysis of covariance. A secondary whole-brain analysis was conducted to verify region-of-interest results and to explore potential differences in other brain regions. RESULTS: Region-of-interest analyses revealed a main effect of group on the left insula cortex, which was thinner in SDI compared with controls (P = .02). There was a group by sex interaction on bilateral insula volume (left, P = .02; right, P = .001) and right insula cortical thickness (P = .007). Compared with same-sex controls, female SDI had smaller insulae, whereas male SDI had larger insulae. Neither ACC nor OFC significantly differed across group. Performance on a decision-making task was better in controls than SDI and correlated with OFC measurements in the controls. CONCLUSIONS: SDI and controls differed in insula morphology, and those differences were modulated by sex. No group differences in OFC were observed, but OFC measurements correlated with negative-reinforcement learning in controls. These preliminary results are consistent with a hypothesis that frontolimbic pathways may be involved in behaviors related to substance dependence.

Impaired Decision-Making, Higher Impulsivity, and Drug Severity in Substance Dependence and Pathological Gambling.

Objectives:Substance use disorder is characterized by impaired decision making, impulsivity, and risk taking. Pathological gambling shares many of these characteristics, and having both diagnoses may be associated with greater problems than either diagnosis alone. We investigated whether among substance-dependent individuals, comorbid pathological gambling would be associated with worse decision making, greater impulsivity, risk taking, and drug severity. Methods:Ninety-six substance-dependent individuals were recruited from a residential treatment program and divided into 1 of the 2 groups depending on whether they met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for pathological gambling (SDPG, n = 26) or not (SD, n = 70). Ninety-two controls were recruited from the community. Participants completed a decision-making task (modified Iowa Gambling Task), measures of impulsivity (Barratt Impulsivity Scale and Delay Discounting), and risk taking (Balloon Analog Risk Task). Decision making was analyzed using a computational model. We tested for group differences using analysis of covariance or Kruskal-Wallis and appropriate post-hoc tests. Results:The groups differed in decision-making parameters (P < 0.001) and self-reported impulsivity (P < 0.001). All post-hoc comparisons were significant on these measures, and indicated stepwise changes in controls, followed by SD, followed by SDPG, with SDPG performing worse on decision making and being more impulsive. Compared with SD, SDPG had greater drug severity (P < 0.001). No group differences were observed in delay discounting or risk taking. Conclusions:Compared with individuals with substance dependence without pathological gambling, those with both disorders demonstrated worse decision making and significantly more drug-related symptoms. When evaluating patients with substance dependence, clinicians should consider diagnostic assessments for gambling, as the co-occurrence of both disorders may impact clinical characteristics.