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Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3–3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6–68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites ( n = 3–66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. Trial registration: ClinicalTrials.gov Identifier: NCT04648423

Contains fulltext : 219494.pdf (Publisher’s version ) (Closed access) While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics - the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD) - that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures. 15 p.

While it has been suggested that cocaine use and relapse in women is more strongly related to stress-relief craving, whereas cocaine use in men is more strongly related to reward craving, the neural mechanisms that underlie these differences are poorly understood. The aim of this study was to investigate sex-dependent differences in insular morphometry and associations with craving, in a sample of regular cocaine users (CUs) and non-drug using controls (non-CUs). It was hypothesized that insular volume, thickness and surface area would be lower in CU women, compared with CU men and non-CUs. It was furthermore hypothesized that insular morphometry, particularly insular thickness, would be negatively associated to reward craving in CU men, while being negatively associated with stress-relief craving in CU women. In contrast to the hypothesis, we did not find evidence of sex-specific differences in insular morphometry in CUs. However, sex-specific association between stress-relief craving and insular morphometry were found: Right insular volume was negatively associated with stress-relief craving in CU women, whereas this association was positive in CU men. Additionally, right insular surface area was negatively associated with stress-relief craving in cocaine-using men, whereas this association was positive in cocaine-using women. In conclusion, the current study provides first evidence of sex-specific differences in the association between craving and insular morphometry in a sample of regular cocaine users. Although speculative, these sex-specific alterations in insular morphometry may underlie higher stress-induced craving and relapse in CU women compared with CU men.

Background Depressive disorders and problematic drinking often co-occur, also among young adults. These co-occurring conditions are associated with various negative health outcomes compared to both conditions alone. Early intervention by addressing alcohol use and depressive symptoms simultaneously in the same treatment might improve both conditions. However, evidence on the (cost-) effectiveness of digital combined depression and alcohol interventions for young adults is currently insufficient. We therefore developed an add-on digital alcohol moderation adherence-focussed guided intervention to complement treatment as usual (TAU) for depressive disorders. The digital intervention is a web-app, including 6 modules based on motivational interviewing and cognitive behavioural therapy. This study aims to evaluate the (cost-)effectiveness of a digital alcohol moderation intervention + TAU compared to TAU on alcohol and depression outcomes among young adults with co-occurring depressive disorders and problematic alcohol use. Methods One hundred fifty-six participants, aged 18–35 years, with problematic alcohol use and a diagnosed depressive disorder will participate in a pragmatic multicentre two-arm randomized controlled trial. Problematic alcohol use is operationalised as scoring ≥5 for women and ≥ 8 for men on the Alcohol Use Disorder Identification Test (AUDIT). Participants will be randomized to either the experimental group (digital alcohol intervention + TAU) or control group (TAU only). Participants will be recruited at three Dutch mental health care centres and through social media. Assessments take place at baseline and after 3, 6 and 12 months post-randomization. The primary outcome is treatment response at 6-month follow-up, operationalized as a composite score that combines alcohol use and depression measures and indicates whether treatment has been successful or not. Secondary outcomes are depressive symptoms and alcohol use (i.e. number of weekly standard drinks and AUDIT score). An economic evaluation will be conducted alongside the trial. Discussion This study evaluates the (cost-) effectiveness of an add-on digital alcohol moderation intervention for young adults who are in treatment for depressive disorders. If proven effective, the digital intervention could be implemented in mental health care and improve treatment for people with co-occurring depressive disorders and problematic alcohol use. Trial registration Pre-registered on October 29, 2019 in The Netherlands Trial Register (NL8122).

IntroductionCurrent treatments for cocaine use disorder (CUD) are not very effective and better treatments are needed. This study investigates the effectiveness of a combined intervention that targets the assumed underlying glutamate pathology in cocaine users. To this end, the combined effects of N-acetylcysteine (NAC) and working memory (WM) training on glutamate concentrations in the dorsal and rostral ACC were investigated in a randomized, double-blind placebo-controlled design.MethodsIn this study, 38 regular cocaine-using men were randomized to either 25-days with 2400 mg/day NAC and WM-training or 25 days with placebo with WM-training. Cocaine use, impulsivity, and glutamate concentrations in the dACC and rACC using proton Magnetic Resonance Spectroscopy were assessed at baseline and after treatment.ResultsTwenty-four participants completed the study, of which 9 received NAC and 15 received placebo. There were no baseline correlations of glutamate concentrations in the dACC or rACC with cocaine use measures or impulsivity. Additionally, there were no effects of NAC, WM-training, or the combination thereof on (changes in) glutamate concentrations in the dACC or rACC.DiscussionThis randomized proof of concept study could not confirm our hypotheses. Possible explanations are insufficient power and the possible absence of deviant baseline glutamate concentrations in the included participants. Future studies should consider larger samples and a non-using control group to confirm baseline deviations in glutamate in cocaine users.

Contains fulltext : 229772.pdf (Publisher’s version ) (Closed access) Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence. 9 p.

Objective: Patients with both a substance use disorder and comorbid mental disorder, or dual diagnosis, form a heterogeneous group with complex treatment needs. Dual diagnosis patients have worse treatment outcomes compared to patients with substance use disorders alone. There is a lack of research focusing on predictors of treatment outcome in dual diagnosis patients. The aim of this study was to identify patient characteristics associated with abstinence in dual diagnosis patients. Methods: In a cohort design, we examined associations between baseline demographic and clinical patient characteristics and abstinence at 14-month follow-up in 102 dual diagnosis patients undergoing treatment in an addiction-psychiatry service in Amsterdam. Immigration, employment, housing, age, emotion regulation, psychiatric symptoms, and frequency and nature of substance abuse were examined as possible predictors of abstinence. Patients were considered abstinent if they had refrained from any substance use in the 30 days prior to the follow-up assessment, as measured with the Timeline Follow Back method. Results: In a multiple logistic regression analysis corrected for treatment utilization, being a first- or second-generation immigrant was associated with lower odds of abstinence (OR = 5.13; 95% CI [1.63, 18.18]), as well as higher levels of depressive and anxiety symptoms at baseline (OR = 0.90; 95% CI [0.81, 0.99]). Gender, age, housing, employment, emotion regulation, frequency and nature of substance abuse, and the psychiatric symptoms positive symptoms, negative symptoms, and manic excitement and disorganization did not show a significant relationship with abstinence. Conclusions: The results indicate that being a first- or second-generation immigrant and experiencing more symptoms of depression and anxiety are predictive of non-abstinence. Attention for linguistic and cultural congruence of dual diagnosis treatments may enhance abstinence in immigrants. Additionally, addressing symptoms of depression and anxiety in dual diagnosis treatment may be beneficial for the maintenance of abstinence. More research is needed on factors influencing treatment success in dual diagnosis patients.

Despite apparent sex differences in the development and treatment of alcohol use disorder, relatively little is known about the underlying neural mechanisms. In this study we therefore investigated neural cue-reactivity in a sample of male (n=28) and female (n=27) problem drinkers (matched on age and alcohol use severity) with an average alcohol use disorder identification test score of 12 which is indicative of a likely alcohol use disorder. Neural cue-reactivity data were extracted from four regions of interest: the ventral and dorsal striatum and the ventral and dorsal anterior cingulate cortex, with a significance level set at p

Males and females with alcohol dependence have distinct mental health and cognitive problems. Animal models of addiction postulate that the underlying neurobiological mechanisms are partially distinct, but there is little evidence of sex differences in humans with alcohol dependence as most neuroimaging studies have been conducted in males. We examined hippocampal and amygdala subregions in a large sample of 966 people from the ENIGMA Addiction Working Group. This comprised 643 people with alcohol dependence (225 females), and a comparison group of 323 people without alcohol dependence (98 females). Males with alcohol dependence had smaller volumes of the total amygdala and its basolateral nucleus than male controls, that exacerbated with alcohol dose. Alcohol dependence was also associated with smaller volumes of the hippocampus and its CA1 and subiculum subfield volumes in both males and females. In summary, hippocampal and amygdalar subregions may be sensitive to both shared and distinct mechanisms in alcohol-dependent males and females.

Males and females show different patterns of cannabis use and related psychosocial outcomes. However, the neuroanatomical substrates underlying such differences are poorly understood. The aim of this study was to map sex differences in the neurobiology (as indexed by brain volumes) of dependent and recreational cannabis use. We compared the volume of a priori regions of interest (i.e., amygdala, hippocampus, nucleus accumbens, insula, orbitofrontal cortex (OFC), anterior cingulate cortex and cerebellum) between 129 regular cannabis users (of whom 70 were recreational users and 59 cannabis dependent) and 114 controls recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age, IQ, and alcohol and tobacco use. Dependent cannabis users, particularly females, had (marginally significant) smaller volumes of the lateral OFC and cerebellar white matter than recreational users and controls. In dependent (but not recreational) cannabis users, there was a significant association between female sex and smaller volumes of the cerebellar white matter and OFC. Volume of the OFC was also predicted by monthly standard drinks. No significant effects emerged the other brain regions of interest. Our findings warrant future multimodal studies that examine if sex and cannabis dependence are specific key drivers of neurobiological alterations in cannabis users. This, in turn, could help to identify neural pathways specifically involved in vulnerable cannabis users (e.g., females with cannabis dependence) and inform individually tailored neurobiological targets for treatment.

Highlights • We tested gender differences in brain volumes of alcohol dependent vs control groups. • Group differences in brain volumes emerged as gross and widespread. • Group-by-gender effects emerged in selected brain regions (cerebellum, amygdala) • In dependent users, greater alcohol use predicted smaller amygdala and larger cerebellum GM volume. • Our results highlight the need to account for gender differences in MRI studies of alcohol dependence., Gender-related differences in the susceptibility, progression and clinical outcomes of alcohol dependence are well-known. However, the neurobiological substrates underlying such differences remain unclear. Therefore, this study aimed to investigate gender differences in the neuroanatomy (i.e. regional brain volumes) of alcohol dependence. We examined the volume of a priori regions of interest (i.e., orbitofrontal cortex, hippocampus, amygdala, nucleus accumbens, caudate, putamen, pallidum, thalamus, corpus callosum, cerebellum) and global brain measures (i.e., total grey matter (GM), total white matter (WM) and cerebrospinal fluid). Volumes were compared between 660 people with alcohol dependence (228 women) and 326 controls (99 women) recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age and education years. Compared to controls, individuals with alcohol dependence on average had (3–9%) smaller volumes of the hippocampus (bilateral), putamen (left), pallidum (left), thalamus (right), corpus callosum, total GM and WM, and cerebellar GM (bilateral), the latter more prominently in women (right). Alcohol-dependent men showed smaller amygdala volume than control men, but this effect was unclear among women. In people with alcohol dependence, more monthly standard drinks predicted smaller amygdala and larger cerebellum GM volumes. The neuroanatomical differences associated with alcohol dependence emerged as gross and widespread, while those associated with a specific gender may be confined to selected brain regions. These findings warrant future neuroscience research to account for gender differences in alcohol dependence to further understand the neurobiological effects of alcohol dependence.

BACKGROUND: Patients with substance use disorder (SUD) or Attention Deficit Hyperactivity Disorder (ADHD) have a high risk of drop out from treatment. Few studies have investigated predictors of therapy drop out and outcome in SUD patients with comorbid ADHD. Recently, integrated cognitive behavioral therapy (CBT/Integrated) was shown to be more effective than standard CBT (CBT/SUD) in the treatment of SUD + ADHD.OBJECTIVE: To investigate the association of demographic, clinical and neurocognitive variables with drop-out and treatment outcome, and to examine which of these variables are suitable for patient-treatment matching.METHODS: We performed an RCT in which 119 patients were allocated to CBT/Integrated (n = 60) or CBT/SUD (n = 59). In addition, 55 patients had dropped out before randomization. Demographic variables, clinical characteristics and measures of cognitive functioning (Stroop, Tower of London (ToL) and Balloon Analogue Risk Task (BART)) were included as predictors. Outcome measures were: early treatment drop-out, ADHD symptom severity, and substance use severity at end of treatment and follow up.RESULTS: Primary substance of abuse (drugs as opposed to alcohol only) and lower accuracy scores on the ToL were significant predictors of early treatment drop-out. Having more depression and anxiety symptoms and using ADHD medication at baseline significantly predicted more ADHD symptoms at end of treatment, and higher accuracy scores on the ToL significantly predicted higher substance use at end of treatment. No significant predictor-by-treatment interactions were found.CONCLUSION: The results add to the existing realization that also relatively mild cognitive deficits are a risk factor for treatment drop-out in these patients.

Deficits in instrumental, goal-directed control, combined with the influence of drug-associated Pavlovian-conditioned stimuli, are thought to influence the development and maintenance of addiction. However, direct evidence has mainly come from animal studies. We sought to establish whether alcohol use disorder (AUD) is characterized by behavioral or neurobiological deficits in (i) the integration of Pavlovian and instrumental values and (ii) goal-directed control; and (iii) whether duration or severity of AUD is associated with such deficits. The influence of cues predicting food rewards on instrumental action was assessed in a Pavlovian-to-instrumental transfer (PIT) test, measuring both specific and general PIT, and goal-directed behavior in an outcome-devaluation test. Brain activity was measured using functional MRI in 38 abstinent individuals with AUD and 22 matched healthy control individuals (HCs). We found significant specific and general PIT and outcome-devaluation effects across groups indicating goal-directed control, mediated by distinct corticostriatal signals, but no significant differences between individuals with AUD and healthy controls. Bayesian analyses provided substantial-to-strong evidence for the absence of group differences for these effects, or any relationship with duration or severity of AUD. These results suggest intact ability to integrate action-outcome associations on specific and general PIT and goal-directed learning in AUD during abstinence.

Background: Alcohol use disorder (AUD) is to a high degree heritable, and in clinical practice it is common to assert presence of alcohol abuse family history (FH) in treatment-seeking AUD patients. Patients with AUD also exhibit cognitive deficits, including elevated impulsivity and impairments in executive functions (EF), but less is known regarding the relation between FH and these cognitive domains. The aim of the current study was to investigate if alcohol abuse FH in AUD patients is associated with a specific cognitive profile. Methods: Patients with AUD (n = 197) from Sweden (n = 106) and Belgium (n = 91) were recruited. Self-rated impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). EF assessed were response inhibition (stop signal task), attention (rapid visual processing task), and working memory (digit span). A series of linear regression models were run to explore the effect of FH on cognitive outcomes. Results: A FH of alcohol abuse was associated with elevated score in self-rated impulsivity assessed by the BIS, with the greatest effect on the subscale of nonplanning. There was no statistically significant association between FH and any of the other neuropsychological task outcomes. Conclusion: Presence of alcohol abuse FH within AUD patients could be a marker of higher impulsivity, which may have clinical implications regarding diagnostic evaluation and treatment.

Background and Aims: Patients with co-occurring substance use and other mental disorders are vulnerable to crime victimization, yet no evidence-based preventive interventions exist. Our aim was to test the efficacy of a new intervention, Self-wise, Other-wise, Streetwise training (SOS training), to prevent victimization in these dual-diagnosis patients as an add-on to care as usual. Design: Multi-site single-blind parallel randomized controlled trial. Setting: Three sites within one psychiatric service in Amsterdam, the Netherlands. Participants: Adult in-patients and out-patients with dual diagnosis (n = 250), who were predominantly male (70.4%), aged on average 42.1 years, and diagnosed with 3.7 DSM-IV disorders. Intervention and comparator: Care as usual, consisting of pharmacotherapy combined with individual psychotherapy, group psychotherapy and/or supportive counselling (n = 125) was compared with care as usual plus SOS training: a 6-week, 12-session manualized group training focused on enhancing emotion regulation skills, conflict resolution skills and street skills (n = 125). Measurements: Victimization was assessed with the Safety Monitor, the Dutch equivalent of the International Crime Victims Survey, in a face-to-face assessment. The primary outcome measure was treatment response (yes/no), with ‘yes’ defined as reporting at least a 50% reduction in the number of past-year victimization incidents at the 14-month follow-up compared with baseline. Analyses were performed according to the intention-to-treat principle. Findings: The proportion of participants achieving treatment response for total victimization was 54.0% in the control group and 67.6% in the experimental group, a significant difference [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.02–3.11, P = 0.042]. Treatment response for violent victimization was achieved by 68.7% of the control group and 79.3% of the experimental group (OR = 1.75, 95% CI = 0.91–3.34, P = 0.092). With a Bayes factor of 2.26, this result was inconclusive. Conclusions: Among dual-diagnosis patients, care as usual plus Self-wise, Other-wise, Streetwise training was more effective in preventing victimization than care as usual alone.

Background Cannabis-smoking patients with a psychotic disorder have poorer disease outcomes than non-cannabis-smoking patients with poorest outcomes in patients smoking high-potency cannabis (HPC) containing high Δ9-tetrahydrocannabinol (THC) and low cannabidiol (CBD). Quitting cannabis smoking or substitution of HPC by cannabis variants containing less THC and/or more CBD may benefit these patients. The present study explores whether daily HPC-smoking patients with schizophrenia accept smoking such variants. Methods Twelve male patients were asked to smoke on six different occasions one joint: on two occasions, the cannabis they routinely smoke (HPC; not blind), and blind in random order; on two occasions, cannabis containing low THC and no CBD; and on two occasions, cannabis containing low THC and high CBD. Results Both substitute variants were appreciated, but patients preferred the HPC they usually smoked. The effect of the low THC/high CBD variant was reported by 32% to be too short and by 36% to be not strong enough, whereas this was reported by 5% and 64%, respectively, for the low THC cannabis variant. Conclusions Based on these findings, a larger and longer study on the efficacy of cannabis substitution treatment in HPC-smoking patients with schizophrenia seems feasible and should be considered. Trial registration 2014-005540-17NL. Registered 22 October 2014, 2014-005540-17NL 20141215 CTA.xml

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained great interest in multiple clinical and research fields and is believed to accomplish its effect by influencing neuronal networks. The dorsolateral prefrontal cortex (dlPFC) is frequently chosen as the cortical target for HF-rTMS. However, very little is known about the differential effect of HF-rTMS over the left and right dlPFC on intrinsic functional connectivity networks in patients or in healthy individuals. The current study assessed the differential effects of left or right HF-rTMS (corrected for sham) on intrinsic independent component analysis (ICA)-defined functional connectivity networks in a sample of 45 healthy individuals. All subjects had a first scanning session in which baseline functional connectivity was assessed. During the second session, individuals received one session of left, right, or sham dlPFC HF-rTMS (60 5-sec trains of 10 Hz at 110% motor threshold). The sham condition was used to correct for time and placebo effects. ICAs were performed to assess baseline differences and stimulation effects on within- and between-network functional connectivity. Stimulation of the left dlPFC resulted in decreased functional connectivity in the salience network, whereas right dlPFC stimulation resulted in increased functional connectivity within this network. No differences between left or right dlPFC stimulation were found in between-network connectivity. These results suggest that left and right HF-rTMS may have differential effects, and more research is needed on the clinical consequences.

Depression is a common co-morbid disorder in substance use disorder (SUD) patients. Hence, valid instruments are needed to screen for depression in this subpopulation. In this study, the predictive validity of the Depression, Anxiety and Stress Scale (DASS-21) for the presence of a depressive disorder was investigated in SUD inpatients. Furthermore, differences between DASS-21 scores at intake and those recorded one week after inpatient detoxification were assessed in order to determine the measurement point of the assessment of the DASS-21 leading to the best predictive validity. The DASS-21 was administered to 47 patients at intake and shortly after inpatient detoxification. The results of the DASS-21 were compared to the Mini International Neuropsychiatric Interview (MINI), which served as the gold standard. Levels of sensitivity and specificity of 78–89% and 71–76% were found for the DASS-21 assessed after detoxification, satisfactorily predicting depression as diagnosed with the MINI. Total DASS-21 scores as well as the DASS subscale for depression were significantly reduced at the second measurement, compared to the DASS at intake. We conclude that the DASS-21 may be a suitable instrument to screen for depressive disorders in SUD patients when administered (shortly) after detoxification. Future research is needed to support this conclusion.

Objective: The purpose of this study was to determine the prevalence of victimization in patients with co-occurring mental health and substance use disorders (dual diagnosis) and compare them to the general population. Methods: In this cross-sectional survey study conducted in the Netherlands, 9 different types of victimization (e.g., physical assault) were assessed with the Safety Monitor in patients with dual diagnosis (n = 243) and a sample of the general population (n = 10,865). Chi-square tests were used to compare patients with a weighted sample of the general population. Results: Compared to the general population, patients with dual diagnosis were more likely to have been a victim of violence (60% vs. 11%), property crime (58% vs. 30%), and vandalism (21% vs. 14%) in the year preceding the assessment. Threats, sexual assault, physical assault, robbery, bicycle theft, other theft, and vandalism were more prevalent in patients with dual diagnosis compared to the general population. Car theft was more prevalent in the general population. The risk of burglary did not differ significantly between groups. Conclusions: Patients with dual diagnosis are highly prone to victimization. In patients with severe mental illness, victimization is associated with psychopathology, substance use, homelessness, and engagement in criminal activity. Future research is necessary to explore underlying mechanisms in patients with dual diagnosis and develop interventions to reduce their vulnerability for victimization.

The current study investigated the combined effects of N-acetylcysteine and working memory (WM) training on behavioral and neural mechanisms of cue reactivity and WM in cocaine users in a randomized, double-blind design. Twenty-four of 38 cocaine-using men completed a 25-day treatment with either 2400 mg/day NAC or placebo. Both groups performed WM-training. During pre- and post-test lab-visits, neural mechanisms of cue reactivity and WM, and cue-induced craving and WM performance were assessed. Additionally, exploratory whole brain analyses were performed. Overall, the hypotheses were not confirmed, possibly due to small sample size, low WM-training adherence and/or ongoing substance use.

Item does not contain fulltext Cannabis exerts its psychoactive effect through cannabinoid receptors that are widely distributed across the cortical surface of the human brain. It is suggested that cannabis use may contribute to structural alterations across the cortical surface. In a large, multisite dataset of 120 controls and 141 cannabis users, we examined whether differences in key characteristics of the cortical surface - including cortical thickness, surface area, and gyrification index were related to cannabis use characteristics, including (i) cannabis use vs. non-use, (ii) cannabis dependence vs. non-dependence vs. non-use, and (iii) early adolescent vs. late adolescent onset of cannabis use vs. non-use. Our results revealed that cortical morphology was not associated with cannabis use, dependence, or onset age. The lack of effect of regular cannabis use, including problematic use, on cortical structure in our study is contrary to previous evidence of cortical morphological alterations (particularly in relation to cannabis dependence and cannabis onset age) in cannabis users. Careful reevaluation of the evidence on cannabis-related harm will be necessary to address concerns surrounding the long-term effects of cannabis use and inform policies in a changing cannabis regulation climate.

Many offenders with a substance use disorder (SUD) do not enter addiction treatment. The aim of this study was to examine predictors of addiction treatment entry and to get more insight in the predictive value of treatment motivation. A total of 83 male offenders with a SUD under probation supervision in the Netherlands were assessed at the start of probation supervision and at 12-month follow-up. A total of 38 offenders (45.5%) entered addiction treatment in the follow-up period. Offenders with any mandated treatment ( p = .028) and higher treatment motivation ( p = .005) were more likely to enter treatment. Multiple logistic regression analysis showed that treatment motivation predicts addiction treatment entry in the first year of probation (OR = 2.215, p < .01). This emphasizes the relevance of treatment motivation for addiction treatment entry among offenders with a SUD. Pretreatment motivational interventions are therefore recommended for offenders with low motivation for treatment in probation settings.

Cannabis use is highly prevalent and often considered to be relatively harmless. Nonetheless, a subset of regular cannabis users may develop dependence, experiencing poorer quality of life and greater mental health problems relative to non-dependent users. The neuroanatomy characterizing cannabis use versus dependence is poorly understood. We aimed to delineate the contributing role of cannabis use and dependence on morphology of the hippocampus, one of the most consistently altered brain regions in cannabis users, in a large multi-site dataset aggregated across four research sites. We compared hippocampal volume and vertex-level hippocampal shape differences (1) between 121 non-using controls and 140 cannabis users; (2) between 106 controls, 50 non-dependent users and 70 dependent users; and (3) between a subset of 41 controls, 41 non-dependent users and 41 dependent users, matched on sample characteristics and cannabis use pattern (onset age and dosage). Cannabis users did not differ from controls in hippocampal volume or shape. However, cannabis-dependent users had significantly smaller right and left hippocampi relative to controls and non-dependent users, irrespective of cannabis dosage. Shape analysis indicated localized deflations in the superior-medial body of the hippocampus. Our findings support neuroscientific theories postulating dependence-specific neuroadaptations in cannabis users. Future efforts should uncover the neurobiological risk and liabilities separating dependent and non-dependent use of cannabis.

Background Reconsolidation-based interventions have been suggested to be a promising treatment strategy for substance use disorders. In this study, we aimed to investigate the effectiveness of a working memory intervention to interfere with the reconsolidation of alcohol-related memories in a sample of non-treatment seeking heavy drinkers. Methods Participants were randomized to one of the two conditions that underwent a 3-day intervention: in the experimental condition, a 30-min working memory training was performed immediately after a 15-min memory retrieval session (i.e., within the memory reconsolidation time-window), whereas in the control condition, the working memory training was performed prior to a memory retrieval session. Results In contrast to our original hypothesis, a high working memory load after memory retrieval did not interfere with the reconsolidation of those memories while a high working memory load prior to memory retrieval (the original control condition) strongly reduced retrieval-induced craving and craving for alcohol at follow-up. Conclusion Whereas the neurocognitive mechanism behind this effect needs to be further investigated, the current findings suggest that, if replicated, working memory training prior to addiction-related memory retrieval has the potential to become an effective (adjunctive) intervention in the treatment of substance use disorders. Electronic supplementary material The online version of this article (10.1007/s00213-017-4785-4) contains supplementary material, which is available to authorized users.

Background: High impulsivity and attentional bias are common in cocaine-dependent patients and predict poor treatment outcomes. The pharmacological agent modafinil is studied for its cognitive-enhancing capacities and may therefore improve clinical outcomes in crack-cocaine dependent patients. In this study, we investigated first whether pre-treatment impulsivity and attentional bias predict treatment outcome; next whether the drug modafinil given as an add-on treatment to cognitive behavioural therapy (CBT) improves impulsivity and attentional bias; and last, whether changes in impulsivity and attentional bias are related to improvements in treatment outcome. Methods: Crack-cocaine dependent outpatients ( n = 65) were randomised to 12 weeks CBT plus modafinil (400 mg/day) or only CBT. Self-reported impulsivity was assessed at baseline using the Barratt Impulsiveness Scale. At baseline and Week 12, we assessed inhibitory control as a behavioural measure of impulsivity, in terms of cognitive interference (Stroop task) and response inhibition (‘stop-signal task’), and attentional bias with the addiction Stroop task. Clinical outcomes were CBT-retention and crack-cocaine use. Results: At baseline, self-reported impulsivity predicted better CBT-retention; low self-reported and behavioural impulsivity and attentional bias predicted less crack-cocaine use. Changes in cognitive performance were not modafinil-related, but most likely due to low adherence. Improvements in impulsivity or attentional bias were not associated with CBT-retention nor changes in crack-cocaine use. Conclusions: Baseline impulsivity and attentional bias predicted clinical outcomes in crack-cocaine dependent patients. There were no firm indications that modafinil reduced impulsivity nor attentional bias in this population. Future studies involving cognitive-enhancing medications should include strategies to optimise adherence, to be better able to evaluate their potential.

Alcohol dependence is thought to result from an overactive neural motivation system and a deficient cognitive control system, and rebalancing these systems may mitigate excessive alcohol use. This study examines the differences in functional connectivity of the fronto-parietal cognitive control network (FPn) and the motivational network (striatum and orbitofrontal cortex) between alcohol dependent patients (ADPs) and healthy controls (HCs), and the effect of repetitive transcranial magnetic stimulation (rTMS) on these networks. This randomized controlled trial included 38 ADPs and 37 HCs, matched on age, gender and education. Participants were randomly assigned to sham or right dorsolateral prefrontal cortex (dlPFC) stimulation with rTMS. A 3T resting state functional Magnetic Resonance Imaging (fMRI) scan was acquired before and after active or sham 10Hz rTMS. Group differences of within and between network connectivity and the effect of rTMS on network connectivity was assessed using independent component analysis. Results showed higher connectivity within the left FPn (p=0.012) and the left fronto-striatal motivational network (p=0.03) in ADPs versus HCs, and a further increase in connectivity within the left FPn after active stimulation in ADPs. ADPs also showed higher connectivity between the left and the right FPns (p=0.025), and this higher connectivity was related to fewer alcohol related problems (r=0.30, p=0.06). The results show higher within and between network connectivity in ADPs and a further increase in fronto-parietal connectivity after right dlPFC rTMS in ADPs, suggesting that frontal rTMS may have a beneficial influence on cognitive control and may result in lower relapse rates.

Background Patients with a substance use disorder and co-occurring mental disorder are prone to victimization. There is a lack of research identifying variables related to violent and property victimization in this high risk group. The aim of this study was to identify factors associated with violent and property victimization in male and female dual diagnosis patients in order to identify targets for prevention. Methods In a cross-sectional study, victimization and demographic, clinical and psychological characteristics were assessed in 243 treatment-seeking patients with dual diagnosis. Patients were recruited in an addiction-psychiatry clinic and an allied outpatient care facility in Amsterdam, The Netherlands. Results In a multiple logistic regression analysis, violent victimization was independently associated with younger age, female gender, violent offending and a self-sacrificing and overly accommodating interpersonal style (p < 0.001; χ2 = 108.83, d.f. = 8, R2 = 0.49) in dual diagnosis patients. In male patients, violent victimization was independently associated with younger age, violent offending and a self-sacrificing and overly accommodating interpersonal style (p < 0.001; χ2 = 91.90, d.f. = 7, R2 = 0.56). In female patients, violent victimization was independently positively associated with homelessness, violent offending, a domineering/controlling interpersonal style, and negatively associated with being socially inhibited and cold/distant (p < 0.001; χ2 = 34.08, d.f. = 4, R2 = 0.53). Property victimization was independently associated with theft offending (p < 0.001, χ2 = 26.99, d.f. = 5, R2 = 0.14). Conclusions Given the high prevalence of victimization in dual diagnosis patients and its related problems, preventive interventions should be developed. Interventions should target interpersonal skills to decrease vulnerability to victimization, address the overlap between victimization and offending and incorporate gender-specific elements.

The opioid receptor antagonist naltrexone is successfully used in the treatment of opioid and alcohol dependence. However, questions have been raised about possible anhedonic side effects, because the opioid system is directly involved in hedonic responses to natural rewarding activities, possibly due to its indirect effects on the striatal dopamine transporter (DAT). In order to test this hypothesis, 30 rats were randomized to either a 10-day treatment with 3 mg/kg short-acting naltrexone or vehicle. No significant differences between the groups were found in striatal DAT availability, cumulative food intake (for 48 or 72 h), body weight gain and abdominal fatpad weight. Thus, the results of this study suggest that (sub)chronic treatment with short-acting naltrexone does not induce possible anhedonic effects. However, it cannot be ruled out the anhedonic effect of naltrexone is only short-lived and thus not detected in the current study. Therefore, future studies are needed to study possible acute anhedonic effects at several time points shortly after short-acting naltrexone administration and to directly compare the possible anhedonic effects of long-acting with those of short-acting opioid antagonists.

BackgroundPatients with a severe mental illness (SMI) are more likely to experience victimisation than the general population.AimsTo examine the prevalence of victimisation in people with SMI, and the relationship between symptoms, treatment facility and indices of substance use/misuse and perpetration, in comparison with the general population.MethodVictimisation was assessed among both randomly selected patients with SMI (n = 216) and the general population (n=10 865).ResultsCompared with the general population, a high prevalence of violent victimisation was found among the SMI group (22.7% v. 8.5%). Compared with out-patients and patients in a sheltered housing facility, in-patients were most often victimised (violent crimes: 35.3%; property crimes: 47.1%). Risk factors among the SMI group for violent victimisation included young age and disorganisation, and risk factors for property crimes included being an in-patient, disorganisation and cannabis use. The SMI group were most often assaulted by someone they knew.ConclusionsCaregivers should be aware that patients with SMI are at risk of violent victimisation. Interventions need to be developed to reduce this vulnerability.

High frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained interest as a neuromodulation treatment technique for alcohol dependence. Single sessions of HF-rTMS have consistently shown to decrease craving for substances. However, the results of randomized controlled clinical trials investigating the effect of multiple HF-rTMS sessions in alcohol dependence on abstinence rates and craving are inconsistent. Furthermore, they lack information on the effect of HF-rTMS on cognition and brain functioning. A single center, single blind, randomized controlled trial with 80 abstinent alcohol dependent subjects in treatment randomized (1:1) to either treatment as usual (TAU) plus ten sessions of active HF-rTMS or TAU plus 10 sessions of placebo/ sham HF-rTMS will be performed. The effects of ten HF-rTMS sessions on craving and neurocognitive functions are obtained. In addition a subset of participants will undergo an MR scanning session before the first and after the last HF-rTMS session in order to investigate the effect of ten HF-rTMS sessions on brain functioning. The primary outcome is the continued abstinence rate after the add-on HF-rTMS treatment. This study uses a randomized controlled trial to examine the clinical, neurocognitive and brain functioning effects of ten add-on HF-rTMS sessions in alcohol dependent individuals in treatment. If the add-on treatment is effective, this may add to the evidence needed for approval of this additional treatment method for alcohol dependence by regulatory authorities. The Netherlands National Trial Register (NTR), NTR5291 , 6-July-2015.

Background: Cannabis exposure, particularly heavy cannabis use, has been associated with neuroanatomical alterations in regions rich with cannabinoid receptors such as the hippocampus in some but not in other (mainly cross-sectional) studies. However, it remains unclear whether continued heavy cannabis use alters hippocampal volume, and whether an earlier age of onset and/or a higher dosage exacerbate these changes. Methods: Twenty heavy cannabis users (mean age 21 years, range 18–24 years) and 23 matched non-cannabis using healthy controls were submitted to a comprehensive psychological assessment and magnetic resonance imaging scan at baseline and at follow-up (average of 39 months post-baseline; standard deviation=2.4). Cannabis users started smoking around 16 years and smoked on average five days per week. A novel aspect of the current study is that hippocampal volume estimates were obtained from manual tracing the hippocampus on T1-weighted anatomical magnetic resonance imaging scans, using a previously validated protocol. Results: Compared to controls, cannabis users did not show hippocampal volume alterations at either baseline or follow-up. Hippocampal volumes increased over time in both cannabis users and controls, following similar trajectories of increase. Cannabis dose and age of onset of cannabis use did not affect hippocampal volumes. Conclusions: Continued heavy cannabis use did not affect hippocampal neuroanatomical changes in early adulthood. This contrasts with prior evidence on alterations in this region in samples of older adult cannabis users. In young adults using cannabis at this level, cannabis use may not be heavy enough to affect hippocampal neuroanatomy.

Background Patients with substance use disorders and co-occurring mental health disorders are vulnerable to violent victimization. However, no evidence-based interventions are available to reduce patients’ vulnerability. An exploration of the characteristics of physical and sexual violence can provide valuable information to support the development of interventions for these patients. This study aimed to examine gender differences in characteristics of violent victimization in patients with dual diagnosis. Methods In this cross-sectional survey study recent incidents of physical and sexual assault were examined with the Safety Monitor in 243 patients with dual diagnosis. Chi-square tests were used to examine gender differences in the prevalence of physical and sexual victimization. Fisher’s exact tests and Fisher-Freeman-Halton exact tests were used to determine whether there were significant differences between victimized men and women with regard to perpetrators, locations, reporting to the police and speaking about the assault with others. Results There was no significant difference in the prevalence of physical violence in men (35%) and women (47%) with dual diagnosis. There was a significant association between gender of the victim and type of perpetrator (P

Little is known about the incremental effects of medically assisted detoxification on outpatient treatment for alcohol use disorders. The objective of this study was to compare drinking outcomes in a psychosocial treatment program between two groups of heavy drinking patients who had an alcohol use disorder: (a) one group with initial medically assisted detoxification and (b) a second group without initial medically assisted detoxification. Analyses were conducted on 262 patients with a more severe alcohol use disorder who completed both an intake assessment and a 9-month follow-up assessment. The effect of medically assisted detoxification was determined using logistic regression analysis with a propensity score to control for possible baseline differences between the two groups. Of the 262 patients, 82 (31.3%) received medically assisted detoxification. These patients were more likely to abstain from alcohol than those without medically assisted detoxification. Abstinence rates in the month before follow-up were 32.9% and 18.9%, respectively (ORadj = 3.48, p = .01, number needed to treat = 7.1). Medically assisted detoxification may add to the effects of outpatient psychosocial treatment for heavy drinking patients with an alcohol use disorder

Impulsivity is a core characteristic of pathological gambling (PG), even though the underlying structure and disorder specificity is unclear. This study aimed to explore different dimensions of impulsivity in a clinical sample including PG. Furthermore, we aimed to test which alterations of the impulsivity-related dimensions are disorder specific for PG. Participants were individuals diagnosed with PG ( n = 51) and two groups also characterized by various impulsive behaviors: an alcohol dependence (AD; n = 45) and a Gilles de la Tourette syndrome (GTS; n = 49) group. A healthy control (HC; n = 53) group was recruited as comparison group. A comprehensive assessment was used including impulsivity-related and antipodal parameters of the Stop Signal Task, Stroop Task, Tower of London Task, Card Playing Task, Iowa Gambling Task and the Barratt Impulsiveness Scale-11. Principal axis factor analysis revealed four impulsivity-related dimensions that were labeled ‘self-reported impulsivity’, ‘prepotent response impulsivity’, ‘choice impulsivity’ and ‘motor impulsivity’. The PG group scored significantly higher on all four dimensions compared to the HC group. In contrast, the PG group did not differ on any of the dimensions from the AD or the GTS group, except for ‘choice impulsivity’ where the PG group exhibited higher factor scores compared to the GTS group. Altogether, PG is associated with generally heightened impulsivity profiles compared to a HC group, which may be further used for intervention strategies. However, heightened scores in the impulsivity dimensions are not disorder specific for PG. Further research on shared or different underlying mechanisms of these overlapping impulsivity impairments is necessary.

Background Most studies investigating the role of personality as a risk factor for the development of opioid dependence compare dependent opioid users with healthy controls who never used heroin. In order to understand the potential protective role of personality, it is crucial to compare illicit opioid users who never became dependent with dependent opioid users. Aims This study aims to examine the role of personality as a risk factor for opioid use and as a protective factor for the development of opioid dependence. Methods Comparing personality factors between three groups: (1) 161 never-dependent illicit opioid users who have been using illicit opioids but never became opioid dependent; (2) 402 dependent opioid users in methadone maintenance treatment or heroin-assisted treatment; and (3) 135 healthy controls who never used heroin. Personality was assessed with a short version of Cloninger's Temperament and Character Inventory. Results Never-dependent opioid users reported more Novelty Seeking and Harm Avoidance and less Self-Directedness and Cooperativeness than healthy controls and more Reward Dependence and Self-Directedness, and less Harm Avoidance than dependent opioid users. Furthermore, never-dependent opioid users reported more Self-Transcendence than both dependent opioid users and healthy controls. Conclusions Never-dependent opioid users may have started to use opioids partly due to their tendency to seek novel and/or spiritual experiences (high Novelty Seeking, high Self-Transcendence) and their tendency to avoid aversive stimuli (high Harm Avoidance), whereas they may have been protected against the development of dependence by their need for social approval (high Reward Dependence) and their self-efficacy (high Self-Directedness).

The ability to appropriately process reward and punishment is crucial for adaptive behavior in a constantly changing environment. Intact contingency learning abilities can be seen as the basis for reliable long-term decision-making processes in real life: stimulus–response–outcome associations must be identified and learned appropriately to know which behavior will result in the most rewarding and least damaging outcome. At the same time, these processes must be flexible enough to adapt when reward contingencies in the environment change. Reward and punishment processing are compromised in patients with substance use disorders (SUDs) compared to healthy subjects (De Ruiter et al., 2009; for a review, see Diekhof et al., 2008). Specifically, patients show a motivational bias toward the drug of abuse and related stimuli (Goldstein and Volkow, 2002; Wrase et al., 2002), while at the same time being less sensitive to drug-unrelated rewards (Goldstein et al., 2007; Martin-Soelch et al., 2001). Pathological gambling (PG) is classified as an addiction in the DSM-5 and has also been associated with compromised reward processing (Van Holst et al., 2010). Sensitivity to punishment in particular seems to be reduced in pathological gamblers (PGs; De Ruiter et al., 2009; Reuter et al., 2005). These impairments in patients with SUDs and PG also reflect the dysfunctional reward processing of affected individuals in real life ultimately leading to continued substance use or persistent gambling despite serious negative consequences in terms of health and social functioning. This indicates a lack of flexibility to learn or unlearn new reward contingencies (to be distinguished from a more general cognitive flexibility to change problem-solving strategies when needed, as measured for example by the Wisconsin Card Sorting Test; Heaton, 1981) which is essential for adaptive functioning. Contingency learning has discrimination learning at its basis. In discrimination learning, reward values of certain stimuli are learned. After the discrimination learning phase, cognitive flexibility in response to changing contingencies can be indexed by 2 abilities within contingency learning: reversal learning and extinction learning (Itami and Uno, 2002). Discrimination learning, reversal learning, and extinction learning can be studied in simple visual decision-making tasks, in which the reward values of certain stimuli are learned. Respondents hereby learn when to react and when to refrain from reacting to gain reward and avoid punishment, respectively. When the contingency rules have been sufficiently acquired (discrimination learning), there are 2 main ways in which reward contingencies can be altered. The first is to change contingencies such that responses to previously rewarding stimuli are punished and responses to previously punishing stimuli are rewarded (reversal learning). Alternatively, stimuli and responses can abruptly fail to deliver reward altogether, forcing the respondent to refrain from any type of reaction. This last aspect of contingency learning is called extinction learning. Response perseveration in people with SUD and PG has generally been studied with probabilistic discrimination learning tasks (De Ruiter et al., 2009), Go/No-Go tasks with probabilistic cueing (Fillmore and Rush, 2006). or tasks involving gambling elements (Bechara et al., 2001; Goudriaan et al., 2005; Leeman and Potenza, 2012). In all these tasks, information on reward contingencies must be integrated over a period of time to perform successfully. In probabilistic discrimination learning, responses to stimuli are followed by feedback which is correct most, but not all of the time. One trial per stimulus is therefore not sufficient to learn its reward value. Clearly, this process requires more complex cognitive processing, including working memory, processing of immediate and delayed rewards, and weighing risks and benefits. To study pure contingency learning, a simpler, deterministic task is needed. Itami and Uno (2002) developed a task in which responses are followed by accurate feedback throughout, relieving working memory from integrating probabilistic information during the task. This task is used in the current study. Reversal and extinction learning deficits with a deterministic feedback setup have also been associated with deficient orbitofrontal cortex (OFC) functioning (Fellows and Farah, 2003). Importantly, disruptions in discrimination, reversal, or extinction learning can elucidate the neural basis of the conditions under study. The OFC in particular has been frequently implicated in cognitive flexibility in contingency learning (De Ruiter et al., 2009; Rolls, 2004; Tsuchida et al., 2010). A large number of human lesion studies have shown that lesions to the OFC are associated with increased perseverative responding to previously rewarded stimuli following extinction or reversal of reinforcement contingencies (Bechara et al., 2001; Hornak et al., 2004; Rolls et al., 1994). Interestingly, OFC dysfunctions have been implicated in SUDs and PG (Cavedini et al., 2002; London et al., 2000; Van Holst et al., 2012; Volkow and Fowler, 2000). Specifically, drug exposure may cause alterations in neuronal activity in the OFC and lead to impaired performance on orbitofrontal-dependent learning tasks (Schoenbaum and Shaham, 2008). In line with this reasoning, response perseveration to previously rewarding stimuli in reversal and extinction learning and similar tasks has been shown in patients with cocaine dependence (Ersche et al., 2008, 2011), patients with alcohol dependence (AD; Bechara et al., 2001; Goudriaan et al., 2005), as well as people with a family history of alcoholism (Giancola et al., 1993) and prenatal exposure to alcohol (Kodituwakku et al., 2001), and in people with PG (De Ruiter et al., 2009; Goudriaan et al., 2005; for a review, see Leeman and Potenza, 2012). In conclusion, there is a lack of knowledge on contingency learning in AD and PG, specifically with regard to deterministic feedback (Izquierdo and Jentsch, 2012). In the current study, we therefore examine discrimination, reversal, and extinction learning in alcohol-dependent patients (ADs) and PGs in comparison with healthy controls (HCs) while reducing working memory load during the task by implementing a visual discrimination learning task with deterministic feedback. We expected ADs and PGs to show impaired reversal and extinction learning performance as compared to HCs due to OFC dysfunction in these disorders as well as evidence of maladaptive responding to reward and punishment and inflexibility following contingency changes in some of our previous studies (De Ruiter et al., 2009; Goudriaan et al., 2005).

Item does not contain fulltext BACKGROUND: Recent research findings suggest that heavy alcohol use is associated with alterations of the hypothalamic-pituitary-adrenal axis and autonomic nervous system function and that early abstinence is associated with blunted stress responsiveness. METHODS: This study investigated abstinent alcohol-dependent participants (AADs; n = 31), who had a drinking history of levels about 97 drinks per week (abstinence range: 2 weeks to 24 months), actively drinking problem drinkers (PRDs; n = 23), who reported drinking levels about 47 drinks per week and who were abstinent for at least 24 hours, and healthy control (HC) participants (n = 20). It was investigated how participants responded to a psychosocial stress task. All of them were exposed to a modified Trier Social Stress Test. Salivary cortisol, heart rate, skin conductance levels, and negative affect were assessed as stress indicators. RESULTS: AADs showed stress reactions comparable to HC participants, whereas active PRDs showed increased heart rate and cortisol stress responses. In the AAD group, duration of abstinence was positively related to cortisol stress responses. CONCLUSIONS: Active PRDs showed increased responses to psychosocial stress. Results indicate that duration of abstinence is a key factor when analyzing and interpreting stress responses in alcohol abuse and dependence.

Contains fulltext : 177182.pdf (Publisher’s version ) (Open Access) Glutamate and GABA play an important role in substance dependence. However, it remains unclear whether this holds true for different substance use disorders and how this is related to risk-related traits such as impulsivity. We, therefore, compared Glx (as a proxy measure for glutamate) and GABA concentrations in the dorsal anterior cingulate cortex (dACC) of 48 male cigarette smokers, 61 male smoking polysubstance users, and 90 male healthy controls, and investigated the relationship with self-reported impulsivity and substance use. Glx and GABA concentrations were measured using proton Magnetic Resonance Spectroscopy. Impulsivity, smoking, alcohol and cocaine use severity and cannabis use were measured using self-report instruments. Results indicate a trend towards group differences in Glx. Post-hoc analyses showed a difference between smokers and healthy controls (p=0.04) and a trend towards higher concentrations in smoking polysubstance users and healthy controls (p=0.09), but no differences between smokers and smoking polysubstance users. dACC GABA concentrations were not significantly different between groups. Smoking polysubstance users were more impulsive than smokers, and both groups were more impulsive than controls. No significant associations were observed between dACC neurotransmitter concentrations and impulsivity and level and severity of smoking, alcohol or cocaine use or the presence of cannabis use. The results indicate that differences in dACC Glx are unrelated to type and level of substance use. No final conclusion can be drawn on the lack of GABA differences due to assessment difficulties. The relationship between dACC neurotransmitter concentrations and cognitive impairments other than self-reported impulsivity should be further investigated.

Item does not contain fulltext Orbitofrontal cortex (OFC) sulcogyral patterns are stable morphological variations established early in life. They consist of three distinct pattern types, with Type III in particular being associated with poor regulatory control (e.g., high sensation seeking and negative emotionality, low constraint), which may confer risk for earlier onset of cannabis (CB) use and greater use in later life. The OFC sulcogyral pattern may therefore be a stable trait marker in understanding individual differences in substance-use vulnerability and associated affective disturbances in users. In a large multisite cross-sectional study, we compared OFC pattern type distribution between 128 healthy controls (HC) and 146 CB users. Within users (n=140), we explored the association between OFC pattern type and CB use level, and subsequently if level of CB use informed by OFC pattern type may mediate disturbances in affective tone, as indexed by depressive symptoms. While OFC pattern distribution did not distinguish between HC and CB groups, it informed greater lifetime use within users. Specifically, CB users with pattern Type III in the right OFC tended to use more CB over their lifetime, than did CB users with pattern Type I or II. Greater lifetime CB use was subsequently associated with higher depressive symptoms, such that it mediated an indirect association between right OFC pattern Type III and higher depressive symptoms. The present study provides evidence for neurobiological differences, specifically sulcogyral pattern of the OFC, to modulate level of CB use, which may subsequently influence the expression of depressive symptoms.

Background: Differences in clinical characteristics between early and late onset alcohol dependent patients have been examined intensively, but little is known about the differences in neuropsychological functioning between these patient groups. Clinical characteristics and neuropsychological functions of inpatients with early onset and late onset alcohol dependence are therefore investigated in this study. Methods: Ninety-three abstinent alcohol dependent inpatients meeting a current diagnosis of DSM-IV alcohol dependence were divided into early onset alcohol dependent patients (EOA; ≤25 years; n = 36) and late onset alcohol dependent patients (LOA; >25 years; n = 57). Patients using psychoactive medication and patients dependent on other substances than alcohol (and nicotine) were excluded. A comprehensive neuropsychological test battery was administered. Results: EOA reported higher trait impulsivity, antisocial traits, and attention deficit hyperactivity disorder-related traits and exhibited an impulsive reflection style, especially in a high-risk context, compared with LOA. Against expectations, EOA performed significantly better on measures of planning, cognitive control, visual memory, and delayed recognition memory than LOA, whereas no significant group differences occurred on measures of delay discounting, digit span, and attention. Better Stroop interference, better visual memory, and a more impulsive reflection style was predictive of an early age of onset, and explained a significant and additional amount of variance (18.8%) on top of the clinical characteristics, together explaining 53.4% of the variance. Conclusions: Both clinical characteristics and neuropsychological variables contributed independently to the age of onset of problematic alcohol use. Results indicate that especially an impulsive reflection style, besides higher trait impulsivity, may be the core feature of early onset alcohol dependence. However, the contribution of the neuropsychological variables is complex and more research is needed to clarify the role of psychiatric comorbidity and poly-substance abuse in an unselected sample of alcohol dependent patients. © 2012 by the Research Society on Alcoholism.

Background: Impaired response inhibition is a key feature of patients with alcohol dependence. Improving impulse control is a promising target for the treatment of alcohol dependence. The pharmacologic agent modafinil enhances cognitive control functions in both healthy subjects and in patients with various psychiatric disorders. However, very little is known about the underlying neural correlates of improvements in response inhibition following modafinil. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study using functional magnetic resonance imaging with a stop signal task to examine effects of a single dose of modafinil (200 mg) on response inhibition and underlying neural correlates in abstinent alcohol-dependent patients (AD) (n = 16) and healthy control subjects (n = 16). Results: Within the AD group modafinil administration improved response inhibition (reflected by the stop signal reaction time [SSRT]) in subjects with initial poor response inhibition, whereas response inhibition was diminished in better performing subjects. In AD patients with initial poor response inhibition, modafinil-induced SSRT improvement was accompanied by greater activation in the thalamus and supplementary motor area (SMA) and reduced connectivity between the thalamus and the primary motor cortex. In addition, the relationship between baseline response inhibition and modafinil-induced SSRT improvement was mediated by these changes in thalamus and SMA activation. Conclusions: These findings indicate that modafinil can improve response inhibition in alcohol-dependent patients through its effect on thalamus and SMA function but only in subjects with poor baseline response inhibition. Therefore, baseline levels of response inhibition should be taken into account when considering treatment with modafinil in AD.

Background Chronic alcohol abuse is associated with deficits in cognitive control functions. Cognitive control is likely to be mediated through the interaction between intrinsic large-scale brain networks involved in externally oriented executive functioning and internally focused thought processing. Improving the interaction between these functional brain networks could be an important target for treatment. Therefore, the current study aimed to investigate the effects of the cognitive enhancer modafinil on within-network and between-network resting-state functional connectivity and cognitive control functions in alcohol-dependent patients. Methods In a double-blind, placebo-controlled cross-over design, resting-state functional magnetic resonance imaging and a Stroop task were employed in alcohol-dependent patients ( n = 15) and healthy control subjects ( n = 16). Within-network and between-network functional connectivity was calculated using a combination of independent component analysis and functional network connectivity analysis. Results Modafinil significantly increased the negative coupling between executive networks and the default mode network, which was associated with modafinil-induced improvement in cognitive control in alcohol-dependent patients. Conclusions These findings demonstrate that modafinil at least partly exerts its effects by targeting intrinsic functional relationships between large-scale brain systems underlying cognitive control. The current study therefore provides a neurobiological rationale for implementing modafinil as an adjunct in the treatment of alcohol dependence, although clinical studies are needed to substantiate this promise.

Pathological gambling (PG) is a behavioral addiction characterized by an inability to stop gambling despite the negative consequences, which may be mediated by cognitive flexibility deficits. Indeed, impaired cognitive flexibility has previously been linked to PG and also to reduced integrity of white matter connections between the basal ganglia and the prefrontal cortex. It remains unclear, however, how white matter integrity problems relate to cognitive inflexibility seen in PG. We used a cognitive switch paradigm during functional magnetic resonance imaging in pathological gamblers (PGs; n = 26) and healthy controls (HCs; n = 26). Cognitive flexibility performance was measured behaviorally by accuracy and reaction time on the switch task, while brain activity was measured in terms of blood oxygen level-dependent responses. We also used diffusion tensor imaging on a subset of data (PGs = 21; HCs = 21) in combination with tract-based spatial statistics and probabilistic fiber tracking to assess white matter integrity between the basal ganglia and the dorsolateral prefrontal cortex. Although there were no significant group differences in either task performance, related neural activity or tract-based spatial statistics, PGs did show decreased white matter integrity between the left basal ganglia and prefrontal cortex. Our results complement and expand similar findings from a previous study in alcohol-dependent patients. Although we found no association between white matter integrity and task performance here, decreased white matter connections may contribute to a diminished ability to recruit prefrontal networks needed for regulating behavior in PG. Hence, our findings could resonate an underlying risk factor for PG, and we speculate that these findings may extend to addiction in general.

Background: Behavioral addictions like pathological gambling share many clinical characteristics with substance dependence. In addition, both types of disorders are associated with impairments in inhibitory control. Studies in patients with substance use disorders point to hyporesponsiveness of the dorsomedial prefrontal cortex. However, no such data exist on behavioral addictions. Methods: Using functional magnetic resonance imaging, we investigated the neural circuitry associated with impaired response inhibition in a group of male problem gamblers (n = 17) using a stop signal task. We included control conditions tailored to specifically isolate neural correlates of inhibitory control. To investigate the specificity of effects, a group of heavy smokers (n = 18) and a group of healthy controls (n = 17) were also included. Results: Groups did not differ in behavioral performance on the stop signal task. However, both problem gamblers and heavy smokers showed hyporesponsiveness of the dorsomedial prefrontal cortex compared to healthy controls, during successful as well as failed response inhibition. These effects were robust against adjustments for depression and adult attention deficit scores. Conclusions: These findings suggest that hypoactivation of the inhibition circuit is a shared neural mechanism in substance use disorders and behavioral addictions. As such, they support the reclassification of pathological gambling as a behavioral addiction in DSM-V. (c) 2011 Elsevier Ireland Ltd. All rights reserved

Aims To investigate which clusters of gambling activities exist within a longitudinal study of college health, how membership in gambling clusters change over time and whether particular clusters of gambling are associated with unhealthy risk behaviour. Design Four-year longitudinal study (2002–2006). Setting Large, public university. Participants Undergraduate college students. Measurements Ten common gambling activities were measured during 4 consecutive college years (years 1–4). Clusters of gambling activities were examined using latent class analyses. Relations between gambling clusters and gender, Greek membership, alcohol use, drug use, personality indicators of behavioural undercontrol and psychological distress were examined. Findings Four latent gambling classes were identified: (1) a low-gambling class, (2) a card gambling class, (3) a casino/slots gambling class and (4) an extensive gambling class. Over the first college years a high probability of transitioning from the low-gambling class and the card gambling class into the casino/slots gambling class was present. Membership in the card, casino/slots and extensive gambling classes were associated with higher scores on alcohol/drug use, novelty seeking and self-identified gambling problems compared to the low-gambling class. The extensive gambling class scored higher than the other gambling classes on risk factors. Conclusions Extensive gamblers and card gamblers are at higher risk for problem gambling and other risky health behaviours. Prospective examinations of class membership suggested that being in the extensive and the low gambling classes was highly stable across the 4 years of college.

Pathological gambling (PG) is associated with maladaptive perseverative behavior, but the underlying mechanism and neural circuitry is not completely clear. Here, the hypothesis was tested that PG is characterized by response perseveration and abnormalities in reward and/or punishment sensitivity in the ventral frontostriatal circuit. Executive functioning was assessed to verify if these effects are independent of the dorsal frontostriatal circuit. A group of smokers was also included to examine whether impairments in PG generalize to substance use disorders. Response perseveration and reward/punishment sensitivity were measured with a probabilistic reversal-learning task, in which subjects could win and lose money. Executive functioning was measured with a planning task, the Tower of London. Performance and fMRI data were acquired in 19 problem gamblers, 19 smokers, and 19 healthy controls. Problem gamblers showed severe response perseveration, associated with reduced activation of right ventrolateral prefrontal cortex in response to both monetary gain and loss. Results did not fully generalize to smokers. Planning performance and related activation of the dorsal frontostriatal circuit were intact in both problem gamblers and smokers. PG is related to response perseveration and diminished reward and punishment sensitivity as indicated by hypoactivation of the ventrolateral prefrontal cortex when money is gained and lost. Moreover, intact planning abilities and normal dorsal frontostriatal responsiveness indicate that this deficit is not due to impaired executive functioning. Response perseveration and ventral prefrontal hyporesponsiveness to monetary loss may be markers for maladaptive behavior seen in chemical and nonchemical addictions.Neuropsychopharmacology advance online publication, 1 October 2008; doi:10.1038/npp.2008.175

INTRODUCTION: In the general population, alcohol use disorder and depression more often occur together than any other combination of a mental illness with a substance use disorder. It is important to have a cost-effective intervention that is able to reach at-risk individuals in the early stages of developing alcohol use disorders and depression disorders.METHODS AND ANALYSIS: This paper presents the protocol for a 3-arm multicentre randomised controlled trial (RCT) to test the efficacy and cost-effectiveness of the combined internet-based self-help intervention Take Care of You (TCOY) to reduce alcohol misuse and depression symptoms in comparison with a waiting list control group and a comparable intervention focusing on problematic alcohol use only. The active interventions consist of modules designed to reduce alcohol use, based on the principles of motivational interviewing and methods of cognitive behavioural therapy, together with additional modules in the combined study arm to reduce symptoms of depression. Data will be collected at baseline, as well as at 3 and 6 months postrandomisation. The primary outcome is the quantity of alcohol used in the past 7 days. A number of secondary outcome measures will be studied. These include the Centre of Epidemiologic Studies of Depression Scale (CES-D) and a combined measure with the criteria of values below the cut-off for severe alcohol use disorder and for CES-D. Data analysis will follow the intention-to-treat principle using (generalised) linear mixed models. In order to investigate the interventions' cost-utility and cost-effectiveness, a full economic evaluation will be performed.ETHICS AND DISSEMINATION: This RCT will be executed in compliance with the Helsinki Declaration and has been approved by 2 local Ethics Committees. Results will be reported at conferences and in peer-reviewed publications. Participant-friendly summaries of trial findings will be published on the TCOY websites.TRIAL REGISTRATION NUMBER: ISRCTN10323951.

BACKGROUND: Individuals with Substance Use Disorders (SUDs) have disruptions in the brain's dopaminergic (DA) system and the functioning of its target neural substrates (striatum and prefrontal cortex). These substrates are important for the normal processing of reward, inhibitory control and motivation. Cognitive deficits in attention, impulsivity and working memory have been found in individuals with SUDs and are predictors of poor SUD treatment outcomes and relapse in alcohol and cocaine dependence specifically. Furthermore, the DA system and accompanying neural substrates play a key role in the timing of motor acts (motor timing). Motor timing deficits have been found in DA system related disorders and more recently also in individuals with SUDs. Motor timing is found to correlate with attention, impulsivity and working memory deficits. To our knowledge motor timing, with regards to treatment outcome and relapse, has not been investigated in populations with SUDs. METHODS/DESIGN: This study aims to investigate motor timing and its relation to treatment response (at 8 weeks) and relapse (at 12 months) in cocaine and/or alcohol dependent individuals. The tested sensitivity values of motor timing parameters will be compared to a battery of neurocognitive tests, owing to the novelty of the motor task battery, the confounding effects of attention and working memory on motor timing paradigms, and high impulsivity levels found in individuals with SUDs. DISCUSSION: This research will contribute to current knowledge of neuropsychological deficits associated with treatment response in SUDs and possibly provide an opportunity to individualize and modify currently available treatments through the possible prognostic value of motor task performance in cocaine and/or alcohol dependent individuals. 16

Alcohol dependent individuals perform worse than controls on tests of neurocognitive functions. For example, persons with a history of alcohol dependence display disadvantageous decision making compared with persons without substance dependence (Bechara et al., 2001). Also, diminished executive functions, that is, self-regulatory functions necessary for goal-directed behavior, have been found in persons with alcohol dependence (for a review, see Giancola and Moss, 1998). Heavy social drinkers (i.e., 21 drinks or more per week) have also been found to display mild deficits on a variety of neurocognitive functions, such as attention, memory, and visuospatial abilities (for a review, see Parsons and Nixon, 1998). Notably, recent neurobehavioral addiction theories have highlighted relations between substance dependence and neural dysfunction, particularly in the ventromedial prefrontal cortex, striatum, and basal ganglia (Goldstein and Volkow, 2002). These brain areas are important in neurocognitive functions involving the evaluation and appraisal of positive and negative consequences, functions which play a role in decision making (Krawczyk, 2002). To date, however, no studies have examined the relation between different longitudinal patterns of alcohol use and decision making or other affective neurocognitive functions. Decision-making skills may be especially important during late adolescence and young adulthood, as this is often a time of change, identity development, and educational and career development. In addition, young adulthood is often a period of heavy alcohol use. For example, a recent study reported that 23% of college students were frequent binge drinkers, and 44% engaged in binge drinking in the past 2 weeks (Wechsler et al., 2000). Some studies suggest that the adolescent brain may be particularly vulnerable to the harmful effects of alcohol. Recent studies indicate that binge drinking has a more detrimental effect on brain structure and functioning in adolescent, compared with adult rats (Crews et al., 2000; Monti et al., 2005). Notably, in humans, the pre-frontal lobes mature throughout adolescence, and into early adulthood (Casey et al., 2000). Therefore, decision-making skills, which rely on prefrontal lobe functioning, may be especially vulnerable to the effects of heavy alcohol use during adolescence. Recent research has highlighted considerable variability in drinking patterns (Cho et al., 2001; Mundt et al., 1995; Searles et al., 2000), and it is unclear whether different drinking trajectories are differentially related to neurocognitive functioning. Therefore, in this study, 200 participants were selected from a large longitudinal study, based on their drinking course over a recent 2.5-year period. Four groups of college students were included, differing in onset and amount of binge drinking. Thus, we were able to investigate what patterns of heavy (binge) drinking were related to diminished decision making. In the alcohol and drug-use literature, an abundance of studies indicate that different developmental trajectories exist for binge drinking. These studies consistently find the existence of stable-low, increasing, and stable-high subgroups (Chassin et al., 2002; Hill et al., 2000; Tucker et al., 2003), with increasing and stable-high subgroups having a higher prevalence in college student samples (Schulenberg and Maggs, 2002). When different drinking trajectories are associated with differences in decision making, this could have consequences for the way in which prevention and intervention strategies target binge drinking, such as targeting groups with a specific binge drinking trajectory (Jackson et al., 2004). Another possibility in explaining differences in decision-making abilities and drinking patterns, may be differences in age of onset of drinking. Differences in age of onset of drinking may indicate being in a more advanced phase of a progression of drinking behavior, or a more severe binge-drinking pattern. Therefore, the effect of age of onset of drinking was examined as well. Recently, controversy surrounds the definition of binge drinking, as the traditional definitions of binge drinking (5/4 drinks per occasion) may be too low for patterns of binge drinking in college students (White et al., 2006). We sampled students on the traditional measure of 5 drinks within 1 sitting, and thus, this measure of binge drinking may underestimate heavy binge drinking. However, binge drinking and a measure of quantity/frequency of alcohol use in this college student sample are highly correlated. We therefore refer to heavy (binge) drinking, or to alcohol use trajectories, and not solely to binge drinking. The current study thus examined relationships between several longitudinal patterns of heavy (binge) drinking, and decision-making skills in a sample of young adults. Decision making was studied using the Iowa Gambling Task (IGT; Bechara et al., 1999). In the IGT, participants play a computerized card game in which they attempt to develop a winning strategy by selecting cards from advantageous, as opposed to disadvantageous decks. Participants have to learn, over the course of the task, which decks are advantageous and which are disadvantageous. Disadvantageous choice patterns on the IGT have been found in a substantial number of studies of people with ventromedial prefrontal lobe damage (Bechara et al., 1994, 2001; but see Manes et al., 2002), and populations with a variety of disinhibited behaviors (Goudriaan et al., 2005; Grant et al., 2000; Rotherham-Fuller et al., 2004; van Honk et al., 2002; Whitlow et al., 2004). Other factors have also been found to affect IGT performance. In particular, attention deficit hyperactivity disorder (ADHD) is negatively related to performance on decision-making tasks (Ernst et al., 2003a, 2003b; Murphy et al., 2001; Raghunathan and Pham, 1999) and is also associated with alcohol dependence (Farrell et al., 2001; Kessler et al., 1997). Higher impulsivity has been related to both poor IGT performance (Crone et al., 2003) and heavy alcohol use (Waldeck and Miller, 1997). A secondary aim of this study therefore was to investigate the influence of both externalizing psychopathological symptoms and impulsivity, on IGT performance. We were also interested in the relation between gender and decision making. The literature on gender and IGT performance is mixed. Two studies of IGT performance have found that women perform less well than men (Bolla et al., 2004; Reavis and Overman, 2001), but other studies have not found gender differences in performance levels (Crone et al., 2003; Fein et al., 2004, 2006; Hooper et al., 2004). One of these studies did indicate a difference in frequency of punishment preference between girls and boys, with both girls and boys preferring lower frequency punishments of a higher amount, but girls having a stronger preference for this response option (Hooper et al., 2004). A brain imaging study reports that men and women also activated different orbitofrontal brain areas during IGT performance (Bolla et al., 2004). Our study consisted of a comparatively large young adult sample with equal gender distribution, and was thus especially suitable for studying the effects of gender on IGT performance and contingency preferences. In summary, the current study is the first to examine relations between decision making and longitudinal heavy (binge) drinking patterns in a large, mixed-gender sample of young adults. In addition, this study examined the degree to which externalizing psychopathology, impulsivity and gender affected the IGT/binge-drinking relation. We aimed to determine whether low-binge drinkers differed from (a) students who engaged in moderate-binge drinking, (b) students who increased their binge drinking when entering college, (c) students who engaged in high-binge drinking both before entering college, and throughout the first 2 college years. We hypothesized that consistent high levels of binge drinking and heavy alcohol use would have a detrimental effect on decision making, as measured by the IGT.

In this review, findings of biobehavioral research into pathological gambling (PG) are discussed, focusing on neuropsychological, psychophysiological, neuroimaging, neurochemical and genetic studies. Neuropsychological studies indicate deficiencies in certain executive functions. Psychophysiological studies indicate that arousal in PG is of importance when reward is present. Neuroimaging studies point to abnormalities in brain functioning. Recent research into the neurochemistry of PG indicates that abnormalities exist in different neurotransmitter systems. Finally, genetic studies indicate the existence of abnormal dopamine receptor genes in PG. Methodological and theoretical factors that may explain discrepancies between studies include differences in screening and assessment, heterogeneity of gambling problems and different underlying cognitive or motivational mechanisms. Results from the PG studies fit in with recent theoretical models of addiction and PG, which stress the involvement of brain reward pathways, neurotransmitter abnormalities, the frontal cortex and the psychophysiological stress system. A framework for future studies is suggested, indicating the need for studies that integrate knowledge from different research areas, and that employ stricter diagnostic screening methods and inclusion of clinical control groups. (C) 2004 Elsevier Ltd. All rights reserved