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Decision-making deficits are thought to play an important role in the development and persistence of substance use disorders. Individual differences in decision-making abilities and their underlying neurocircuitry may, therefore, constitute an important predictor for the course of substance use and the development of substance use disorders. Here, we investigate the predictive value of decision making and neural mechanisms underlying decision making for future cannabis use and problem severity in a sample of heavy cannabis users. Brain activity during a monetary decision-making task (Iowa gambling task) was compared between 32 heavy cannabis users and 41 matched non-using controls using functional magnetic resonance imaging. In addition, within the group of heavy cannabis users, associations were examined between task-related brain activations, cannabis use and cannabis use-related problems at baseline, and change in cannabis use and problem severity after a 6-month follow-up. Despite normal task performance, heavy cannabis users compared with controls showed higher activation during wins in core areas associated with decision making. Moreover, within the group of heavy cannabis users, win-related activity and activity anticipating loss outcomes in areas generally involved in executive functions predicted change in cannabis use after 6 months. These findings are consistent with previous studies and point to abnormal processing of motivational information in heavy cannabis users. A new finding is that individuals who are biased toward immediate rewards have a higher probability of increasing drug use, highlighting the importance of the relative balance between motivational processes and regulatory executive processes in the development of substance use disorders.

Cue-reactivity reflects enhanced motivational processing underlying continued substance use and relapse in substance use disorders. Substance use disorders are associated with greater cue-reactivity in orbitofrontal cortex, anterior cingulate cortex, striatum, ventral tegmental area and amygdala. Here we examine whether this also holds for frequent cannabis users. Using functional magnetic resonance imaging (fMRI), neural responses to neutral and cannabis-related cues were compared between frequent cannabis users (n = 31), sporadic cannabis users (n = 20) and cannabis-naive controls (n = 21). In addition, fMRI findings were correlated with the level of cannabis use, problem severity and craving. In frequent users compared with sporadic users and controls, cannabis images engendered higher activation than control images in the ventral tegmental area. Activation of the orbitofrontal cortex, anterior cingulate cortex and striatum was only higher in a subgroup of frequent users with high compared with low-problem severity. Activity in the right putamen and right dorsolateral prefrontal cortex correlated negatively with subjective craving in frequent users. Activity was not correlated with level of cannabis use. These findings indicate that cannabis cues activate areas associated with addiction pathology in frequent cannabis users compared with sporadic users and controls. However, among frequent users, cue-reactivity seems to be primarily associated with problem severity, not with amount of cannabis use. These findings imply neural cue-reactivity as a tool in assessing problem severity of cannabis use.

Aims Repeated drug exposure can lead to an approach-bias, i.e. the relatively automatically triggered tendencies to approachratherthatavoiddrug-relatedstimuli.Ourmainaimwastostudythisapproach-biasinheavycannabisusers with the newly developed cannabis Approach Avoidance Task (cannabis-AAT) and to investigate the predictive relationship between an approach-bias for cannabis-related materials and levels of cannabis use, craving, and the course of cannabis use. Design, settings and participants Cross-sectional assessment and six-month follow-up in 32 heavy cannabis users and 39 non-using controls. Measurements Approach and avoidance action-tendencies towards cannabis and neutral images were assessed with the cannabis AAT. During the AAT, participants pulled or pushed a joystick in response to image orientation. To generate additional sense of approach or avoidance, pulling the joystick increased picture size while pushing decreased it. Craving was measured pre- and post-test with the multi-factorial Marijuana Craving Questionnaire (MCQ). Cannabis use frequencies and levels of dependence were measured at baseline and after a six-month follow-up. Findings Heavy cannabis users demonstrated an approach-bias for cannabis images, as compared to controls. The approach-bias predicted changes in cannabis use at six-month follow-up. The pre-test MCQ emotionality and expectancy factor were associated negatively with the approach-bias. No effects were foundonlevelsof cannabisdependence.Conclusions Heavycannabisuserswithastrongapproach-biasforcannabis aremorelikelytoincreasetheircannabisuse.Thisapproach-biascouldbeusedasapredictorof thecourseof cannabis use to identify individuals at risk from increasing cannabis use.

Relapse is the rule rather than the exception in smokers aiming to quit smoking. Recently, evidence has emerged that glutamate transmission plays an important role in relapse. N-acetylcysteine (NAC), a cysteine prodrug, restores glutamate homeostasis and appears to be a potential new treatment for substance dependence. In the current pilot study, the effects of NAC on short-term abstinence of smoking were investigated. Subjects were heavy smokers randomized to receive placebo (n = 12) or NAC 3,600 mg/day (n = 10) in a double-blind fashion during 3.5 days. Subjects were asked to stop smoking and report on nicotine craving, nicotine withdrawal symptoms, and cigarette smoking during treatment. At the end of the treatment, subjects were invited to smoke a cigarette and to rate the rewarding effect of this cigarette. There was no significant effect of NAC on craving (p = 0.23, d = 0.52) and only a statistical trend towards fewer withdrawal symptoms in the NAC condition (p = 0.07, d = 0.80). Interestingly, subjects receiving NAC rated the first cigarette after the abstinence period of 3.5 days as significantly less rewarding than subjects on placebo (p = 0.04, d = 0.85). It is concluded that the results of this pilot study are encouraging and suggest that NAC might be a promising new treatment option for relapse prevention in nicotine dependence.

There is preliminary evidence that approach avoid training can shift implicit alcohol associations and improve treatment outcomes. We sought to replicate and extend those findings in US undergraduate social drinkers (Study 1) and at-risk drinkers (Study 2). Three adaptations of the approach avoid task (AAT) were tested. The first adaptation - the approach avoid training - was a replication and targeted implicit alcohol approach associations. The remaining two adaptations - the general identity and personalized identity trainings - targeted implicit drinking identity associations, which are robust predictors of hazardous drinking in US undergraduates. Study 1 included 300 undergraduate social drinkers. They were randomly assigned to real or sham training conditions for one of the three training adaptations, and completed two training sessions, spaced one week apart. Study 2 included 288 undergraduates at risk for alcohol use disorders. The same training procedures were used, but the two training sessions occurred within a single week. Results were not as expected. Across both studies, the approach avoid training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. The general identity training also yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes with one exception; individuals who completed real training demonstrated no changes in drinking refusal self-efficacy whereas individuals who completed sham training had reductions in self-efficacy. Finally, across both studies, the personalized identity training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. Despite having relatively large samples and using a well-validated training task, study results indicated all three training adaptations were ineffective at this dose in US undergraduates. These findings are important because training studies are costly and labor-intensive. Future research may benefit from focusing on more severe populations, pairing training with other interventions, increasing training dose, and increasing gamification of training tasks.

Emotion regulation research has shown successful altering of unwanted aversive emotional reactions. Cognitive strategies can also regulate expectations of reward arising from conditioned stimuli. However, less is known about the efficacy of such strategies with expectations elicited by conditioned appetitive sexual stimuli, and possible sex differences therein. In the present study it was examined whether a cognitive strategy (attentional deployment) could successfully down-regulate sexual arousal elicited by sexual reward-conditioned cues in men and women. A differential conditioning paradigm was applied, with genital vibrostimulation as unconditioned stimulus (US) and sexually relevant pictures as conditional stimuli (CSs). Evidence was found for emotion down-regulation to effect extinction of conditioned sexual responding in men. In women, the emotion down-regulatory strategy resulted in attenuated conditioned approach tendencies towards the CSs. The findings support that top-down modulation may indeed influence conditioned sexual responses. This knowledge may have implications for treating disturbances in sexual appetitive responses.

Background: This pilot study conducted a preliminary examination of whether Cognitive Bias Modification (CBM), a computerized task to retrain cognitive-approach biases towards smoking stimuli (a) changed approach bias for cigarettes, and (b) improved smoking cessation outcomes in adolescent smokers. Methods: Sixty adolescent smokers received four weeks of Cognitive Behavioral Therapy (CBT) for smoking cessation, with CBM (90% avoidance/10% approach for smoking stimuli and 10% avoidance/90% approach for neutral stimuli) or sham (50% avoidance/50% approach for smoking and neutral stimuli) training in the Netherlands (n = 42) and the United States (n = 18). Results: While we did not observe changes in action tendencies related to CBM, adolescents with higher smoking approach biases at baseline had greater decreases in approach biases at follow-up, compared to adolescents with smoking avoidance biases, regardless of treatment condition (p = 0.01). Intent-to-treat (ITT) analyses showed that CBM, when compared with sham trended toward higher end-of-treatment, biochemically-confirmed, seven-day point prevalence abstinence, (17.2% vs. 3.2%, p = 0.071). ITT analysis also showed that regardless of treatment condition, cotinine level (p = 0.045) and average number of cigarette smoked (p ≤ 0.001) significantly decreased over the course of treatment. Conclusions: The findings from this pilot study suggests that re-training approach biases toward cigarettes shows promise for smoking cessation among adolescent smokers. Future research should utilize larger samples and increased distinction between CBM and sham conditions, and examine mechanisms underlying the CBM approach.

Aims: To describe deaths in prison in a cohort of opioiddependent people, and examine associations between receipt of opioid substitution therapy (OST) and risk of death while in prison. Methods: We linked state-wide OST data to incarceration and mortality data. We calculated crude mortality rates (CMR) for allcause and unnatural (suicide, drug-induced, violent and injury) deaths in prison, and used Cox regression to assess adjusted associations between death and receipt of OST. Rates and hazard ratios were calculated for the entirety of time in prison, and for the first four weeks in prison. Results: The cohort comprised 16,715 opioid-dependent people who had been incarcerated. Fifty-one people died in prison. Compared to periods of time in OST, all-cause and unnatural mortality rateswere significantly higherwhile not in OST (all-cause rate ratio (RR): 4.1; 95% confidence interval (CI): 2.1, 8.0; unnatural death RR: 6.7; 95% CI: 2.6, 17.3). Compared to time out of OST, the hazard of all-cause deathwas 74% lowerwhile in OST (adjusted hazard ratio (AHR): 0.26; 95% CI: 0.13, 0.50), and the hazard of unnatural death was 87% lower while in OST (AHR: 0.13; 95% CI: 0.05, 0.35). In the first fourweeks of incarceration, compared to periods in OST, all-cause mortality was 16.6 (95% CI: 2.2, 124.9) times higher, and unnaturalmortalitywas14.0 (95%CI: 1.8, 107.9) timeshigherwhen not in OST. Compared to periods not in OST, the hazard of all-cause death during the first 4weeks of incarcerationwas 94% lowerwhile in OST (AHR: 0.06; 95% CI: 0.01, 0.48), and the hazard of unnatural death was 93% lower while in OST (AHR: 0.07; 95% CI: 0.01, 0.53). Conclusions: Ensuring a high coverage of OST in correctional facilities will help to minimize deaths, particularly unnatural deaths, among opioid-dependent prisoners. Timely access to OST while incarcerated is critical to realizing this benefit. Financial Support:NationalHealthandMedicalResearchCouncil.

Although the general public perceives cannabis as one of the less harmful illicit drugs, the past decades saw a surge in treatment demands for CUDs (UNODC, 2014). Cannabis nowadays is the primary illicit drug of concern in drug treatment services across North America, Oceania and Africa (UNODC, 2014). The low perceived harms of cannabis use are reflected in the small number of studies investigating the neurocognitive processes underlying CUDs [e.g., only 3 published functional Magnetic Resonance Imaging (fMRI) studies in individuals with a diagnosed CUD compared to controls, contrasting more than 1000 studies in individuals with an Alcohol Use Disorder]. Most studies on the mechanisms underlying cannabis abuse, including my own, investigated heterogeneous groups of chronic or heavy cannabis users with various levels of cannabis use related problems, not groups with diagnosed CUDs. Even though a substantial part of regular cannabis users will not experience any clear negative social and health consequences of cannabis, this does not imply that CUDs are less severe than other Substance Use Disorders (SUDs). The mental health issues associated with CUDs are substantial and often include comorbid psychiatric disorders including depression and anxiety (Stinson et al., 2006). Moreover, CUDs are difficult to treat and long-term abstinence is achieved by fewer than 20% (Danovitch and Gorelick, 2012). This urgently calls for a better understanding of CUDs. It is therefore time to reach out to those coping with CUDs by studying the mechanisms underneath. The goal of this opinion article is twofold: First, I want to address the strong need for neurocognitive studies in CUDs. Second, I propose that studying neurocognitive commonalities and differences between CUDs and comorbid disorders like depression and anxiety has great potential to unravel the mechanisms underlying CUDs and to eventually reveal new treatment targets.

Deficient executive functions play an important role in the development of addiction. Working-memory may therefore be a powerful predictor of the course of drug use, but chronic substance use may also impair working-memory. The aim of this 3-year longitudinal neuro-imaging study was to investigate the relationship between substance use (e.g. alcohol, cannabis, nicotine, illegal psychotropic drugs) and working-memory network function over time in heavy cannabis users and controls. Forty-nine participants performed an n-back working-memory task at baseline and at 3-year follow-up. At follow-up, there were 22 current heavy cannabis users, 4 abstinent heavy cannabis users and 23 non-cannabis-using controls. Tensor-independent component analysis (Tensor-ICA) was used to investigate individual differences in working-memory network functionality over time. Within the group of cannabis users, cannabis-related problems remained stable, whereas alcohol-related problems, nicotine dependence and illegal psychotropic substance use increased over time. At both measurements, behavioral performance and network functionality during the n-back task did not differ between heavy cannabis users and controls. Although n-back accuracy improved, working-memory network function remained stable over time. Within the group of cannabis users, working-memory network functionality was not associated with substance use. These results suggest that sustained moderate to heavy levels of cannabis, nicotine, alcohol and illegal psychotropic substance use do not change working-memory network functionality. Moreover, baseline network functionality did not predict cannabis use and related problems three years later, warranting longitudinal studies in more chronic or dependent cannabis users.

Cognitive biases, including implicit memory associations are thought to play an important role in the development of addictive behaviors. The aim of the present study was to investigate implicit affective memory associations in heavy cannabis users. Implicit positive-arousal, sedation, and negative associations towards cannabis were measured with three Single Category Implicit Association Tests (SC-IAT’s) and compared between 59 heavy cannabis users and 89 controls. Moreover, we investigated the relationship between these implicit affective associations and explicit expectancies, subjective craving, cannabis use, and cannabis related problems. Results show that heavy cannabis users had stronger implicit positive-arousal associations but weaker implicit negative associations towards cannabis compared to controls. Moreover, heavy cannabis users had stronger sedation but weaker negative explicit expectancies towards cannabis compared to controls. Within heavy cannabis users, more cannabis use was associated with stronger implicit negative associations whereas more cannabis use related problems was associated with stronger explicit negative expectancies, decreasing the overall difference on negative associations between cannabis users and controls. No other associations were observed between implicit associations, explicit expectancies, measures of cannabis use, cannabis use related problems, or subjective craving. These findings indicate that, in contrast to other substances of abuse like alcohol and tobacco, the relationship between implicit associations and cannabis use appears to be weak in heavy cannabis users.

Decision-making deficits are thought to play an important role in the development and persistence of substance use disorders. Individual differences in decision-making abilities and their underlying neurocircuitry may, therefore, constitute an important predictor for the course of substance use and the development of substance use disorders. Here, we investigate the predictive value of decision making and neural mechanisms underlying decision making for future cannabis use and problem severity in a sample of heavy cannabis users. Brain activity during a monetary decision-making task (Iowa gambling task) was compared between 32 heavy cannabis users and 41 matched non-using controls using functional magnetic resonance imaging. In addition, within the group of heavy cannabis users, associations were examined between task-related brain activations, cannabis use and cannabis use-related problems at baseline, and change in cannabis use and problem severity after a 6-month follow-up. Despite normal task performance, heavy cannabis users compared with controls showed higher activation during wins in core areas associated with decision making. Moreover, within the group of heavy cannabis users, win-related activity and activity anticipating loss outcomes in areas generally involved in executive functions predicted change in cannabis use after 6 months. These findings are consistent with previous studies and point to abnormal processing of motivational information in heavy cannabis users. A new finding is that individuals who are biased toward immediate rewards have a higher probability of increasing drug use, highlighting the importance of the relative balance between motivational processes and regulatory executive processes in the development of substance use disorders.

Theoretical models of addiction suggest that a substance use disorder represents an imbalance between hypersensitive motivational processes and deficient regulatory executive functions. Working‐memory (a central executive function) may be a powerful predictor of the course of drug use and drug‐related problems. Goal of the current functional magnetic resonance imaging study was to assess the predictive power of working‐memory network function for future cannabis use and cannabis‐related problem severity in heavy cannabis users. Tensor independent component analysis was used to investigate differences in working‐memory network function between 32 heavy cannabis users and 41 nonusing controls during an N‐back working‐memory task. In addition, associations were examined between working‐memory network function and cannabis use and problem severity at baseline and at 6‐month follow‐up. Behavioral performance and working‐memory network function did not significantly differ between heavy cannabis users and controls. However, among heavy cannabis users, individual differences in working‐memory network response had an independent effect on change in weekly cannabis use 6 months later (ΔR (2) = 0.11, P = 0.006, f (2) = 0.37) beyond baseline cannabis use (ΔR (2) = 0.41) and a behavioral measure of approach bias (ΔR (2) = 0.18): a stronger network response during the N‐back task was related to an increase in weekly cannabis use. These findings imply that heavy cannabis users requiring greater effort to accurately complete an N‐back working‐memory task have a higher probability of escalating cannabis use. Working‐memory network function may be a biomarker for the prediction of course and treatment outcome in cannabis users. Hum Brain Mapp 35:2470–2482, 2014. © 2013 Wiley Periodicals, Inc.

Cue-reactivity reflects enhanced motivational processing underlying continued substance use and relapse in substance use disorders. Substance use disorders are associated with greater cue-reactivity in orbitofrontal cortex, anterior cingulate cortex, striatum, ventral tegmental area and amygdala. Here we examine whether this also holds for frequent cannabis users. Using functional magnetic resonance imaging (fMRI), neural responses to neutral and cannabis-related cues were compared between frequent cannabis users (n = 31), sporadic cannabis users (n = 20) and cannabis-naive controls (n = 21). In addition, fMRI findings were correlated with the level of cannabis use, problem severity and craving. In frequent users compared with sporadic users and controls, cannabis images engendered higher activation than control images in the ventral tegmental area. Activation of the orbitofrontal cortex, anterior cingulate cortex and striatum was only higher in a subgroup of frequent users with high compared with low-problem severity. Activity in the right putamen and right dorsolateral prefrontal cortex correlated negatively with subjective craving in frequent users. Activity was not correlated with level of cannabis use. These findings indicate that cannabis cues activate areas associated with addiction pathology in frequent cannabis users compared with sporadic users and controls. However, among frequent users, cue-reactivity seems to be primarily associated with problem severity, not with amount of cannabis use. These findings imply neural cue-reactivity as a tool in assessing problem severity of cannabis use.

A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.

Cannabis abuse is related to impairments in a broad range of cognitive functions. However, studies on cannabis abuse in relation to brain structure are sparse and results are inconsistent, probably due to differences in imaging methodology, severity of cannabis abuse, and use of other substances. The goal of the current MRI study was to investigate brain morphology related to current and lifetime severity of cannabis use and dependence in heavy cannabis users without intensive use of other illicit drugs. Voxel-based morphometry was used to assess differences in regional grey and white matter volume between 33 heavy cannabis users and 42 matched controls. Within heavy cannabis users, grey and white matter volume was correlated with measures of cannabis use and dependence. Analyses were focused a priori on the orbitofrontal cortex, anterior cingulate cortex, striatum, amygdala, hippocampus, and cerebellum, regions implicated in substance dependence and/or with high cannabinoid receptor-1 concentrations. Regional grey matter volume in the anterior cerebellum was larger in heavy cannabis users. Within the group of heavy cannabis users, grey matter volume in the amygdala and hippocampus correlated negatively with the amount of cannabis use or dependence. No associations were found between white matter volume and measures of cannabis use or dependence. These findings indicate that associations between heavy cannabis use and altered brain structure are complex. Differential patterns of structural changes for various cannabis use levels imply that alterations in brain structure are associated with specific characteristics of cannabis use and dependence. (C) 2011 Elsevier Inc. All rights reserved