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1.  Default mode network activity in male adolescents with conduct and substance use disorder* 
Drug and alcohol dependence  2013;134:242-250.
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 brain's 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.
doi:10.1016/j.drugalcdep.2013.10.009
PMCID: PMC3895766  PMID: 24210423
Default Mode Network; Conduct Disorder; Substance Use Disorder; Independent Component Analysis; Functional MRI
2.  Prevalence and predictors of injection drug use and risky sexual behaviors among adolescents in substance treatment 
Background and Objectives
The longitudinal risk for human immunodeficiency virus (HIV) infection following adolescent substance treatment is not known. Therefore, it is not known if adolescent substance treatment should include HIV prevention interventions. To address this important research gap, this study evaluates the longitudinal prevalence and predictors of injection drug use (IDU) and sex risk behaviors among adolescents in substance treatment.
Methods
Participants were 260 adolescents (13-18 years) in substance treatment and 201 community control adolescents (11-19 years). Participants were assessed at baseline and follow-up (mean time between assessments=6.9 years for the clinical sample and 5.6 years for the community control sample). Outcomes included self-report lifetime history of IDU, number of lifetime sex partners and frequency of unprotected sexual intercourse.
Results
At baseline, 7.5% of the clinical sample, compared to 1.0% of the community control sample had a lifetime history of IDU (χ12=10.53, p=0.001). At follow-up, 17.4% of the clinical sample compared to 0% of the community control sample had a lifetime history of IDU (χ12=26.61, p=0.0005). The number of baseline substance use disorders and onset age of marijuana use significantly predicted the presence of lifetime IDU at follow-up, after adjusting for baseline age, race, and sex. The clinical sample reported more lifetime sex partners and more frequent unprotected sex than the community control sample at baseline and follow-up.
Conclusions
Many adolescents in substance treatment develop IDU and report persistent risky sex. Effective risk reduction interventions for adolescents in substance treatment are needed that address both IDU and risky sex.
doi:10.1111/j.1521-0391.2013.12064.x
PMCID: PMC3931469  PMID: 24131163
Adolescent; Injection Drug Use; HIV; Substance treatment
3.  SUBJECTIVE EFFECTS FOR ALCOHOL, TOBACCO, AND MARIJUANA ASSOCIATION WITH CROSS-DRUG OUTCOMES 
Drug and alcohol dependence  2012;123(0 1):S52-S58.
METHODS
The cross-drug relationship of subjective experiences between alcohol, tobacco, and marijuana and problem drug use behaviors were examined. Data were drawn from 3853 individuals between the ages of 11 and 30 years of age participating in the Colorado Center on Antisocial Drug Dependence [CADD]. Subjective experiences were assessed using a 13-item questionnaire that included positive and negative responses for alcohol, tobacco, and marijuana. Lifetime abuse and dependence on these three drugs was assessed using the Composite International Diagnostic Interview, Substance Abuse Module [CIDI-SAM].
RESULTS
Positive and negative subjective experience scales were similar for alcohol, tobacco, and marijuana, although the hierarchical ordering of items differed by drug. Subjective experience scales for each of the three drugs examined correlated significantly, with the strongest relationship being for alcohol and marijuana experiences. Significant associations were identified between how a person experienced a drug and abuse and dependence status for the same or different drug.
CONCLUSION
Cross-drug relationships provide evidence for a common liability or sensitivity towards responding in a similar manner to drugs of abuse within and across different pharmacological classes.
doi:10.1016/j.drugalcdep.2012.02.014
PMCID: PMC3729264  PMID: 22445481
Subjective effects; alcohol; tobacco; marijuana
4.  Test of Association Between 10 SNPs in the Oxytocin Receptor Gene and Conduct Disorder 
Psychiatric Genetics  2012;22(2):99-102.
Animal and human studies have implicated oxytocin (OXT) in affiliative and prosocial behaviors. We tested whether genetic variation in the OXT receptor (OXTR) gene is associated with conduct disorder (CD).
Methods
Utilizing a family-based sample of adolescent probands recruited from an adolescent substance abuse treatment program, control probands and their families (total sample n=1,750), we conducted three tests of association with CD and 10 SNPs (single nucleotide polymorphisms) in the OXTR gene: (1) family-based comparison utilizing the entire sample; (2) within-Whites, case-control comparison of adolescent patients with CD and controls without CD; and (3) within-Whites case-control comparison of parents of patients and parents of controls.
Results
Family-based association tests failed to show significant results (no results p<0.05). While strictly correcting for the number of tests (α=0.002), adolescent patients with CD did not differ significantly from adolescent controls in genotype frequency for the OXTR SNPs tested; similarly, comparison of OXTR genotype frequencies for parents failed to differentiate patient and control family type, except a trend association for rs237889 (p=0.004).
Conclusions
In this sample, 10 SNPs in the OXTR gene were not significantly associated with CD.
doi:10.1097/YPG.0b013e32834c0cb2
PMCID: PMC3337143  PMID: 21934640
antisocial; delinquency; callousness; genetics
5.  Reduced Cortical Gray Matter Volume In Male Adolescents With Substance And Conduct Problems 
Drug and alcohol dependence  2011;118(2-3):295-305.
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 person's 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.
doi:10.1016/j.drugalcdep.2011.04.006
PMCID: PMC3170449  PMID: 21592680
Antisocial; DLPFC; Inhibition; Dependence; Precuneus; Self-referential
6.  A Behavioral Test of Accepting Benefits that Cost Others: Associations with Conduct Problems and Callous-Unemotionality 
PLoS ONE  2012;7(4):e36158.
Background
Youth with conduct problems (CP) often make decisions which value self-interest over the interests of others. Self-benefiting behavior despite loss to others is especially common among youth with CP and callous-unemotional traits (CU). Such behavioral tendencies are generally measured using self- or observer-report. We are unaware of attempts to measure this tendency with a behavioral paradigm.
Methods/Principal Findings
In our AlAn's (altruism-antisocial) game a computer program presents subjects with a series of offers in which they will receive money but a planned actual charity donation will be reduced; subjects decide to accept or reject each offer. We tested (1) whether adolescent patients with CP (n = 20) compared with adolescent controls (n = 19) differed on AlAn's game outcomes, (2) whether youths with CP and CU differed significantly from controls without CP or CU, and (3) whether AlAn's game outcomes correlated significantly with CP and separately, CU severity. Patients with CP and CU compared with controls without these problems took significantly more money for themselves and left significantly less money in the charity donation; AlAn's game outcomes were significantly correlated with CU, but not CP.
Conclusions/Significance
In the AlAn's game adolescents with conduct problems and CU traits, compared with controls without CP/CU, are disposed to benefit themselves while costing others even in a novel situation, devoid of peer influences, where anonymity is assured, reciprocity or retribution are impossible, intoxication is absent and when the “other” to be harmed is considered beneficent. AlAn's game outcomes are associated with measures of CU. Results suggest that the AlAn's game provides an objective means of capturing information about CU traits. The AlAn's game, which was designed for future use in the MRI environment, may be used in studies attempting to identify the neural correlates of self-benefiting decision-making.
doi:10.1371/journal.pone.0036158
PMCID: PMC3338604  PMID: 22558367
7.  Ethnicity, Body Mass, and Genome-Wide Data 
Biodemography and social biology  2010;56(2):123-136.
This article combines social and genetic epidemiology to examine the influence of self-reported ethnicity on body mass index (BMI) among a sample of adolescents and young adults. We use genetic information from more than 5,000 single nucleotide polymorphisms in combination with principal components analysis to characterize population ancestry of individuals in this study. We show that non-Hispanic white and Mexican-American respondents differ significantly with respect to BMI and differ on the first principal component from the genetic data. This first component is positively associated with BMI and accounts for roughly 3% of the genetic variance in our sample. However, after controlling for this genetic measure, the observed ethnic differences in BMI remain large and statistically significant. This study demonstrates a parsimonious method to adjust for genetic differences among individual respondents that may contribute to observed differences in outcomes. In this case, adjusting for genetic background has no bearing on the influence of self-identified ethnicity.
doi:10.1080/19485565.2010.524589
PMCID: PMC3155265  PMID: 21387985
8.  SUBJECTIVE EFFECTS TO MARIJUANA ASSOCIATED WITH MARIJUANA USE IN COMMUNITY AND CLINICAL SUBJECTS 
Drug and alcohol dependence  2010;109(1-3):161-166.
Introduction
Marijuana is the most commonly used illicit drug among adolescents. Marijuana use induces both psychological and physiological responses, which can be interpreted by an individual in a variety of ways (i.e. subjective effects). We have examined subjective effects in adolescent, young adult community, and clinical populations to determine how patterns of use may be predicted by an individual’s subjective experi bences with the drug.
Method
Participants were community and clinical sample subjects drawn from the Colorado Center of Antisocial Drug Dependence (CADD) and a sample of adjudicated youth from the Denver metropolitan area (aged 11–30). They were evaluated with the Composite International Diagnostic Interview - Substance Abuse Module (CIDI-SAM) and the Lyons battery for subjective effects. Scales for subjective effects were created using Mokken scale analysis. Multivariate linear and logistic regression was used to examine associations between the subjective scales and marijuana outcomes.
Results
Mokken scaling revealed two subjective effects scales, positive and negative. Both scales were significantly positively associated with marijuana abuse or dependence in both the community and clinical sample and regular use in the community sample. The negative scale was negatively associated with past six-month use in the community sample (p<0.05) and clinical sample, after controlling for age and gender effects.
Conclusions
These findings suggest that diverse subjective experiences with marijuana can be ordered hierarchically and that the resulting short scales can be used in either clinical or community settings. Further, they suggest that the potential for marijuana use problems is related to the type of subjective experience from marijuana exposure.
doi:10.1016/j.drugalcdep.2009.12.026
PMCID: PMC3000695  PMID: 20149559
cannabis; subjective effects; etiology; youth; mokken scaling
9.  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 
Drug and alcohol dependence  2009;106(2-3):199-203.
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=1,582). 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.
doi:10.1016/j.drugalcdep.2009.08.015
PMCID: PMC2841007  PMID: 19783384
Externalizing Disorders; Disruptive Behavior; Antisocial
10.  Risky Decisions and Their Consequences: Neural Processing by Boys with Antisocial Substance Disorder 
PLoS ONE  2010;5(9):e12835.
Background
Adolescents with conduct and substance problems (“Antisocial Substance Disorder” (ASD)) repeatedly engage in risky antisocial and drug-using behaviors. We hypothesized that, during processing of risky decisions and resulting rewards and punishments, brain activation would differ between abstinent ASD boys and comparison boys.
Methodology/Principal Findings
We compared 20 abstinent adolescent male patients in treatment for ASD with 20 community controls, examining rapid event-related blood-oxygen-level-dependent (BOLD) responses during functional magnetic resonance imaging. In 90 decision trials participants chose to make either a cautious response that earned one cent, or a risky response that would either gain 5 cents or lose 10 cents; odds of losing increased as the game progressed. We also examined those times when subjects experienced wins, or separately losses, from their risky choices. We contrasted decision trials against very similar comparison trials requiring no decisions, using whole-brain BOLD-response analyses of group differences, corrected for multiple comparisons. During decision-making ASD boys showed hypoactivation in numerous brain regions robustly activated by controls, including orbitofrontal and dorsolateral prefrontal cortices, anterior cingulate, basal ganglia, insula, amygdala, hippocampus, and cerebellum. While experiencing wins, ASD boys had significantly less activity than controls in anterior cingulate, temporal regions, and cerebellum, with more activity nowhere. During losses ASD boys had significantly more activity than controls in orbitofrontal cortex, dorsolateral prefrontal cortex, brain stem, and cerebellum, with less activity nowhere.
Conclusions/Significance
Adolescent boys with ASD had extensive neural hypoactivity during risky decision-making, coupled with decreased activity during reward and increased activity during loss. These neural patterns may underlie the dangerous, excessive, sustained risk-taking of such boys. The findings suggest that the dysphoria, reward insensitivity, and suppressed neural activity observed among older addicted persons also characterize youths early in the development of substance use disorders.
doi:10.1371/journal.pone.0012835
PMCID: PMC2943904  PMID: 20877644
11.  The Association between Cannabinoid Receptor 1 Gene (CNR1) and Cannabis Dependence Symptoms in Adolescents and Young Adults 
Drug and alcohol dependence  2009;104(1-2):11-16.
Objective:
This study examined the genetic association between variation in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence symptoms.
Method:
Adolescent and young adult subjects were recruited from three settings: a treatment program for youth with substance use disorders, the criminal justice system, and the community. A case-control sample consisted of 224 cases who endorsed at least one dependence symptom and 108 controls who tried cannabis but endorsed no symptoms. A family-based sample of 219 families was also analyzed.
Results:
Case-control analysis identified a nominal association between SNP rs1049353 and having one or more cannabis dependence symptoms (p = .029), but the association did not hold up in a combined sample. Family-based analysis found a trend for the same SNP (p = .07). We did not replicate a previous report that SNP rs806380 was associated with the development of cannabis dependence.
Conclusion:
These results provide inconclusive evidence of association between rs1049353/rs806380 and the development of cannabis dependence, and underscore the importance of replicating results of genetic association studies. Additional family-based studies are needed to clarify the role of the CNR1 gene, and its various SNPs, in the development of cannabis use disorders.
doi:10.1016/j.drugalcdep.2009.01.022
PMCID: PMC2769509  PMID: 19443135
cannabis dependence; CNR1; genetic association; cannabinoids
12.  Brain activation during the Stroop task in adolescents with severe substance and conduct problems: A pilot study 
Drug and alcohol dependence  2007;90(2-3):175-182.
Background
Although many neuroimaging studies have examined changes in brain function in adults with substance use disorders, far fewer have examined adolescents. This study investigated patterns of brain activation in adolescents with severe substance and conduct problems (SCP) compared to controls.
Methods
Functional magnetic resonance imaging (fMRI) at 1.5 Tesla assessed brain activation in 12 adolescent males with SCP, ranging in age from 14 to 18, and 12 controls similar in age, gender, and neighborhood while performing the attentionally-demanding Stroop task.
Results
Even though the adolescents with SCP performed as well as the controls, they activated a more extensive set of brain structures for incongruent (e.g., “red” in blue ink) versus congruent (e.g. “red” in red ink) trials. These regions included parahippocampal regions bilaterally, posterior regions involved in language-related processing, right-sided medial prefrontal areas, and subcortical regions including the the thalamus and caudate.
Conclusion
These preliminary results suggest that the neural mechanisms of attentional control in youth with SCP differ from youth without such problems. This difficulty may prevent SCP youth from ignoring salient but distracting information in the environment, such as drug-related information.
doi:10.1016/j.drugalcdep.2007.03.009
PMCID: PMC2828145  PMID: 17499456
13.  DSM-IV Conduct disorder criteria as predictors of antisocial personality disorder 
Comprehensive psychiatry  2007;48(6):529-538.
Conduct disorder (CD) is a disorder of childhood and adolescence defined by rule breaking, aggressive and destructive behaviors. For some individuals, CD signals the beginning of a lifelong persistent pattern of antisocial behavior (antisocial personality disorder (ASPD)), while for other people these behaviors either desist or persist at a sub-clinical level. It has generally been accepted that about 40% of individuals with CD persist. This study examined the rate of persistence of DSM-IV CD into ASPD and the utility of individual DSM-IV CD symptom criteria for predicting this progression. We used the nationally representative sample from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Approximately 75% of those with CD also met criteria for ASPD. Individual CD criteria differentially predicted severity and persistence of antisocial behavior with victim-oriented, aggressive behaviors generally being more predictive of persistence. Contrary to previous estimates, progression from CD to ASPD was the norm and not the exception in this sample. Relationships between individual DSM-IV CD symptom criteria and persistent antisocial outcomes are discussed. These findings may be relevant to the development of DSM-V.
doi:10.1016/j.comppsych.2007.04.009
PMCID: PMC2764329  PMID: 17954138
15.  Cannabis Receptor Haplotype Associated With Fewer Cannabis Dependence Symptoms In Adolescents 
Cannabis is a major substance of abuse, and the gene encoding for the central cannabinoid receptor (CNR1) is a logical candidate gene for vulnerability toward developing symptoms of cannabis dependence. We studied four single-nucleotide polymorphisms (SNPs) in the CNR1 gene for association with having one or more symptoms of cannabis dependence in 541 adolescent subjects who had all tried cannabis five or more times. Cases (327) were defined as those who had tried marijuana and developed one or more symptoms, and controls (214) as those who had tried marijuana but developed no dependence symptoms. Cannabis dependence symptoms were assessed in these youth when they were 17 or older with the Composite International Diagnostic Interview- Substance Abuse Module. Univariate (single-marker) association tests demonstrated that SNP rs806380, located in intron 2 of the CNR1 gene, was significantly associated with developing one or more cannabis dependence symptoms, with the G allele having a protective effect (p < 0.02). This was consistent with the results of the global haplotype test (p < 0.01). One of the common haplotypes examined (present in 21% of the subjects) was significantly associated with a lower rate of having one or more cannabis dependence symptoms. Our findings provide evidence suggesting that a common CNR1 haplotype is associated with developing fewer cannabis dependence symptoms among adolescents who have experimented with cannabis.
doi:10.1002/ajmg.b.30378
PMCID: PMC2564870  PMID: 16917946
Cannabis; Adolescence; Genetics; CNR1
16.  An Item Response Theory Analysis of DSM-IV Cannabis Abuse and Dependence Criteria in Adolescents 
Objective
To examine three aspects of adolescent cannabis problems: 1) do DSM-IV cannabis abuse and dependence criteria represent two different levels of severity of substance involvement, 2) to what degree do each of the 11 abuse and dependence criteria assess adolescent cannabis problems, and 3) do the DSM-IV items function similarly across different adolescent populations?
Method
We examined 5587 adolescents aged 11–19, including 615 youth in treatment for substance use disorders, 179 adjudicated youth, and 4793 youth from the community. All subjects were assessed with a structured diagnostic interview. Item response theory was utilized 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 while 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.
doi:10.1097/chi.0b013e31815cd9f2
PMCID: PMC2443687  PMID: 18176333
Item Response Theory; cannabis abuse; cannabis dependence; DSM-IV; DSM-V
17.  A Genome-Wide Scan for Loci Influencing Adolescent Cannabis Dependence Symptoms: Evidence for Linkage on Chromosomes 3 and 9 
Drug and alcohol dependence  2006;89(1):34-41.
Objective:
Cannabis is the most frequently abused illicit substance among adolescents and young adults. Genetic risk factors account for part of the variation in the development of Cannabis Dependence symptoms; however, no linkage studies have been performed for Cannabis Dependence symptoms. This study aimed to identify such loci.
Method:
324 sibling pairs from 192 families were assessed for Cannabis Dependence symptoms. Probands (13-19 years of age) were recruited from consecutive admissions to substance abuse treatment facilities. The siblings of the probands ranged in age from 12-25 years. A community-based sample of 4843 adolescents and young adults was utilized to define an age- and sex-corrected index of Cannabis Dependence vulnerability. DSM-IV Cannabis Dependence symptoms were assessed in youth and their family members with the Composite International Diagnostic Instrument -Substance Abuse Module. Siblings and parents were genotyped for 374 microsatellite markers distributed across the 22 autosomes (average inter-marker distance = 9.2 cM). Cannabis Dependence symptoms were analyzed using Merlin-regress, a regression-based method that is robust to sample selection.
Results:
Evidence for suggestive linkage was found on chromosome 3q21 near marker D3S1267 (LOD = 2.61), and on chromosome 9q34 near marker D9S1826 (LOD = 2.57).
Conclusions:
This is the first reported linkage study of cannabis dependence symptoms. Other reports of linkage regions for illicit substance dependence have been reported near 3q21, suggesting that this region may contain a quantitative trait loci influencing cannabis dependence and other substance use disorders.
doi:10.1016/j.drugalcdep.2006.11.015
PMCID: PMC1892279  PMID: 17169504
genetics; Cannabis; antisocial behavior; adolescence; linkage study

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