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Background Research has shown involvement of hormones of the hypothalamic pituitary adrenal (HPA) axis and hypothalamic pituitary gonadal (HPG) axis in the regulation of behaviors that contribute to SUD risk and its intergenerational transmission. Neighborhood environment has also been shown to relate to hormones of these two neuroendocrine systems and behaviors associated with SUD liability. Accordingly, it was hypothesized that (1) parental SUD severity and neighborhood quality correlate with activity of the HPG axis (testosterone level) and HPA axis (cortisol stability), and (2) transmissible risk during childhood mediates these hormone variables on development of SUD measured in adulthood. Methods Transmissible risk for SUD measured by the transmissible liability index (TLI; Vanyukov et al., 2009 ) along with saliva cortisol and plasma testosterone were prospectively measured in boys at ages 10–12 and 16. Neighborhood quality was measured using a composite score encompassing indicators of residential instability and economic disadvantage. SUD was assessed at age 22. Results Neither hormone variable cross-sectionally correlated with transmissible risk measured at ages 10–12 and 16. However, the TLI at age 10–12 predicted testosterone level and cortisol stability at age 16. Moreover, testosterone level, correlated with cortisol stability at age 16, predicted SUD at age 22. Conclusion HPA and HPG axes activity do not underlie variation in TLI, however, high transmissible risk in childhood predicts neuroendocrine system activity presaging development of SUD.

Two competing concepts address the development of involvement with psychoactive substances: the "gateway hypothesis" (GH) and common liability to addiction (CLA).The literature on theoretical foundations and empirical findings related to both concepts is reviewed.The data suggest that drug use initiation sequencing, the core GH element, is variable and opportunistic rather than uniform and developmentally deterministic. The association between risks for use of different substances, if any, can be more readily explained by common underpinnings than by specific staging. In contrast, the CLA concept is grounded in genetic theory and supported by data identifying common sources of variation in the risk for specific addictions. This commonality has identifiable neurobiological substrate and plausible evolutionary explanations.Whereas the "gateway" hypothesis does not specify mechanistic connections between "stages", and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, and establishes a theoretical and empirical foundation to research in etiology, quantitative risk and severity measurement, as well as targeted non-drug-specific prevention and early intervention.

Effective response inhibition is a key component of recovery from addiction. Some research suggests that response inhibition can be enhanced through reward contingencies. We examined the effect of monetary incentive on response inhibition among adolescents with and without substance use disorder (SUD) using a fast event-related fMRI antisaccade reward task. The fMRI task permits investigation of how reward (monetary incentive) might modulate inhibitory control during three task phases: cue presentation (reward or neutral trial), response preparation, and response execution. Adolescents with lifetime SUD (n=12; 100% marijuana use disorder) were gender and age-matched to healthy controls (n=12). Monetary incentive facilitated inhibitory control for SUD adolescents; for healthy controls, the difference in error rate for neutral and reward trials was not significant. There were no significant differences in behavioral performance between groups across reward and neutral trials, however, group differences in regional brain activation were identified. During the response preparation phase of reward trials, SUD adolescents, compared to controls, showed increased activation of prefrontal and oculomotor control (e.g., frontal eye field) areas, brain regions that have been associated with effective response inhibition. Results indicate differences in brain activation between SUD and control youth when preparing to inhibit a prepotent response in the context of reward, and support a possible role for incentives in enhancing response inhibition among youth with SUD.

Few studies have focused on the neurobiological correlates of adolescent-onset substance use disorders (SUDs), particularly with respect to white matter development and organization. This study investigated microstructural white matter characteristics associated with SUDs during the adolescent developmental period. Twenty-four case adolescents (ages 14-18) entering treatment for SUDs and 12 sex- and age-matched control adolescents with no psychopathology were compared. Diffusion tensor imaging data were collected and analyzed using the whole brain, tract-based spatial statistics (TBSS) method. In order to comprehensively characterize diffusivity characteristics, we first studied fractional anisotropy (FA), and within regions that differed in FA, other indicators of microstructure, including the axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). A large cluster of significantly lower FA values was found in cases compared to controls in the superior longitudinal fasciculus (SLF). Within this cluster, AD and RD were also significantly different between the groups, while MD was not significantly different. For FA, a significant group by sex interaction was found; females with SUD exhibited lower FA than males with SUD, while control females exhibited higher FA than control males. These results indicated significantly lower white matter integrity in the superior longitudinal fasciculus region of association cortex, and assessed using multiple indicators of diffusion. These findings suggest that the disruption of normal white matter development due to substance exposure may be more severe in females than in males.

Most adolescent cannabis use occurs in social settings among peers. Solitary cannabis use during adolescence may represent an informative divergence from normative behavior with important implications for understanding risk for cannabis problems. This longitudinal study examined associations of adolescent solitary cannabis use with levels of cannabis use and problems in adolescence and in young adulthood.Cannabis using-adolescents aged 12-18 were recruited from clinical programs (n=354; 43.8% female; 83.3% Caucasian) and community sources (n=93; 52.7% female; 80.6% Caucasian). Participants reported on cannabis use patterns and diagnostic symptoms at baseline and multiple follow-ups into young adulthood.Compared to social-only users, adolescent solitary cannabis users were more likely to be male and reported more frequent cannabis use and more DSM-IV cannabis use disorder (CUD) symptoms. Regression analyses showed that solitary cannabis use in adolescence predicted CUD symptom counts in young adulthood (age 25) after controlling for demographic variables and the frequency of adolescent cannabis use. However, solitary adolescent cannabis use was no longer predictive of age 25 CUD symptoms after additionally controlling for adolescent CUD symptoms.Solitary cannabis use is associated with greater cannabis use and problems during adolescence, but evidence is mixed that it predicts young adult cannabis problems.

Childhood risks for adolescent substance involvement include parental substance use disorders (SUDs), psychological dysregulation and early tobacco and alcohol experimentation. This study was designed to identify childhood risk categories predicting accelerated adolescent substance involvement across drug types and stages. The index subjects were 560 children recruited from high risk (n = 266) or low risk (n = 294) families based on fathers' SUDs. Assessments were conducted at approximately ages 11 (baseline), 13, 16, and 19 years. Childhood predictors included parent SUDs, early tobacco or alcohol use (i.e., substance use), and neurobehavior disinhibition (ND) as determined by indicators of cognitive, affective and behavioral disinhibition. A cluster analysis defined five risk categories based on baseline characteristics as follows: (1) High (n = 31; 100% had both parents with SUDs, 100% had early substance use, and the mean ND score = 58.9); (2) Intermediate-High (n = 76; 45% had one parent with SUD, 100% early substance use and ND = 51.9); (3) Intermediate (n = 76; 100% both parents with SUDs, 0% early substance use and ND = 51.4); (4) Intermediate-Low (n = 161; 100% with one SUD parent; 0% early substance use and ND = 49.9) and; (5) Low (n = 216; no parental SUD, no early substance use and ND = 47.5). Compared with all other groups, children in the High risk group had significantly accelerated substance involvement across all substance types and stages. The ordering of risk categories from low to high was also consistent for all substance involvement outcomes. The findings indicate that these five risk categories constitute general liability classes for adolescent substance involvement, and may identify homogeneous groups of children requiring distinct preventive interventions.

This review provides a synthesis of the literature on the complex sequence of maturational, psychosocial, and neuroadaptive processes that lead to substance use disorders (SUD) in adolescence. A brief overview introduces the concepts of liability to SUD and epigenesis. A theory is presented explaining how affective, cognitive, and behavioral dysregulation in late childhood is exacerbated during early and middle adolescence by family and peer factors, as well as puberty, leading to substance use. Continued exacerbation of the three components of dysregulation by drug and non-drug stressors during late adolescence is posited to result in neuroadaptations that increase the likelihood of developing SUD, particularly in high-risk individuals. Implications for etiologic research as well as clinical and preventive interventions are discussed.

Objective This study compared the acute phase (12-week) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid major depression (MDD) and a cannabis use disorder (CUD) (cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid MDD/CUD. Methods We conducted the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study. Results Fluoxetine was well tolerated in this treatment population. No significant group-by-time interactions were noted for any depression-related or cannabis-use related outcome variable over the 12-week study. Subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in number of DSM diagnostic criteria for a CUD. Large magnitude decreases in depressive symptoms were noted in both treatment groups, and end-of-study levels of depressive symptoms were low in both treatment groups. Conclusions Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample of comorbid adolescents and young adults. The lack of a significant between-group difference in these symptoms may reflect limited medication efficacy, or may result from efficacy of the CBT/MET psychotherapy or from limited sample size.

Despite the critical importance of adolescent smoking, the assessment of nicotine dependence during this developmental period has been the subject of relatively little research. In this study, 301 adolescents (ages 12 through 18 years) reporting daily smoking were recruited for a project on alcohol use disorders (AUDs). The sample included 140 females and 161 males, 251 subjects from clinical and 50 from community sources, and 176 subjects with AUDs at the baseline assessment. Subjects were evaluated with the Nicotine Dependence Syndrome Scale (NDSS), the Fagerstrom Test for Nicotine Dependence (FTND) and a determination of average number of cigarettes per day (cigarettes/day). A varimax factor analysis of 27 NDSS items revealed four factors: (1) Drive/Tolerance (13 items; Cronbach alpha = 0.91); (2) Continuity (five items; Cronbach alpha = 0.67); (3) Priority (three items; Cronbach alpha = 0.64); (4) Stereotypy (five items; Cronbach alpha = 0.66). The NDSS total score, refined by the removal of four items, was also examined (23 items; Cronbach alpha = 0.90). Predicting cigarettes/day at follow-up, initial smoking rate was the best predictor, with the FTND and NDSS Total score showing significant and similar predictive validity. The NDSS Total showed incremental validity in the prediction of smoking progression in a model including demographic characteristics, initial smoking rate and FTND. The findings suggest that the NDSS has acceptable psychometric properties when applied to adolescents, complementing smoking rate and FTND in a multidimensional smoking assessment.

OBJECTIVE: To determine the effects of psychiatric disorders on attempted suicide among adolescents with substance use disorders (SUD). METHODS: Age of onset for psychiatric disorders, age of first suicide attempt, and the relationship of psychiatric disorder with attempted suicide were investigated in a sample of 503 adolescents with DSM-IV defined SUD (age range: 12.2-19.0 years). RESULTS: Males who attempted suicide had a significantly earlier onset of alcohol use disorders (AUD) and significantly more mood, AUD, and disruptive behavior disorder symptoms compared to non-attempting males. Females who attempted suicide had a significantly earlier onset and higher counts of mood disorders and SUD symptoms compared to non-attempting females. Hazard analysis revealed that mood disorders represent the highest psychiatric risk for attempted suicide in both the genders. Attention deficit-hyperactivity disorder (ADHD) increased the risk for attempted suicide among males. The interaction of mood disorder and AUD increased the risk for attempted suicide among females. CONCLUSIONS: Clinicians should closely monitor SUD adolescents for suicide risk and be aware of gender differences for suicidal behavior based on course and severity of psychiatric disorder in this population. Language: en

Adolescents with alcohol use disorders (AUDs) often have major depressive disorder (MDD). While physical abuse and sexual abuse (PS Abuse) have been observed to be common in adolescents with AUDs, the influence of PS Abuse on comorbid MDD and AUD has not been determined. The effect of pre-existing PS Abuse on the young adulthood outcomes of adolescents with AUDs has also not been adequately explored. This study examined the relationships among PS Abuse, MDD, and AUD in adolescence, as well as related young adult outcomes. Adolescents (mean age: 16.4 years; range: 14-18 years) were recruited from clinical and community sources and classified into four groups: (1) AUD+PS Abuse (n=154), (2) AUD only (n=255), (3) PS Abuse only (n=74), and (4) Controls (n=268). Subjects were longitudinally assessed through young adulthood (age 19 years or older). Measures included interview assessments of DSM-IV AUD and MDD, classified as "primary" or "secondary", and questionnaire measures of alcohol consumption and depression. Primary MDD preceded AUD whereas secondary MDD had a later onset than AUD. PS Abuse accelerated the onsets of primary MDD, secondary MDD and AUD. While affected adolescents had typically improved in both alcohol consumption and depression at the young adult assessment, the majority of those with adolescent AUD had AUDs in young adulthood, and MDD remained common in those with a history of PS Abuse. These results indicate that MDD among adolescents with AUD may be partly attributable to PS Abuse.

This study examines the influence of adolescent age of onset on the development of substance use disorders (SUD) by comparing adult males (n = 181) with SUD categorized into adolescent-onset, early-adult onset and late-adult onset groups on patterns of substance use and related disorders, time course of the development of substance dependence and rates of comorbid mental disorders. A sample of male adolescents (n = 81) with SUD was also included as a comparison group. The subjects were recruited from intervention programs in the community and participated in semistructured interviews with diagnoses determined by the best estimate method. Adolescent-onset adults, compared with other adult-onset groups, had higher lifetime rates of cannabis and hallucinogen use disorders, shorter times from first exposure to dependence, shorter times between the development of their first and second dependence diagnoses and higher rates of disruptive behavior disorders and major depression. Adolescents were similar to adolescent-onset adults. While the findings must be interpreted in light of methodological limitations, these results suggest that adolescent-onset SUD is a distinct subtype involving different substances and more rapid development than adult-onset SUD.