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1.  The Role of Habits and Motivation in Human Drug Addiction: A Reflection 
doi:10.3389/fpsyt.2014.00008
PMCID: PMC3905212  PMID: 24523702
habits; habit formation; motivation; addiction; goal-directed behavior
2.  Cue Reactivity Is Associated with Duration and Severity of Alcohol Dependence: An fMRI Study 
PLoS ONE  2014;9(1):e84560.
Introduction
With the progression of substance dependence, drug cue-related brain activation is thought to shift from motivational towards habit pathways. However, a direct association between cue-induced brain activation and dependence duration has not yet been shown. We therefore examined the relationship between alcohol cue-reactivity in the brain, cue-induced subjective craving and alcohol dependence duration and severity. Since alcohol dependence is highly comorbid with depression/anxiety, which may modulate brain responses to alcohol cues, we also examined the relation between comorbid depression/anxiety and cue-reactivity.
Methods
We compared 30 alcohol dependent patients with 15 healthy controls and 15 depression/anxiety patients during a visual alcohol cue-reactivity task using functional magnetic resonance imaging blood oxygenated level-dependent responses and subjective craving as outcomes. Within the alcohol dependent group we correlated cue-reactivity with alcohol dependence severity and duration, with cue-induced craving and with depression/anxiety levels.
Results
Alcohol dependent patients showed greater cue-reactivity in motivational brain pathways and stronger subjective craving than depression/anxiety patients and healthy controls. Depression/anxiety was not associated with cue-reactivity, but depression severity in alcohol dependent patients was positively associated with craving. Within alcohol dependence, longer duration of alcohol dependence was associated with stronger cue-related activation of the posterior putamen, a structure involved in habits, whereas higher alcohol dependence severity was associated with lower cue-reactivity in the anterior putamen, an area implicated in goal-directed behavior preceding habit formation.
Conclusion
Cue-reactivity in alcohol dependence is not modulated by comorbid depression or anxiety. More importantly, the current data confirm the hypothesis of a ventral to dorsal striatal shift of learning processes with longer dependence duration, which could underlie increasingly habitual substance use with progressing substance dependence.
doi:10.1371/journal.pone.0084560
PMCID: PMC3882248  PMID: 24400099
3.  Reduced Frontal Brain Volume in Non-Treatment-Seeking Cocaine-Dependent Individuals: Exploring the Role of Impulsivity, Depression, and Smoking 
In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume in the right orbitofrontal cortex, the left precentral gyrus, and the right superior frontal gyrus, whereas no effect of smoking severity, depressive symptoms, or duration of cocaine use was observed on regional GM volumes. Our data show an important association between trait impulsivity and frontal GM volumes in cocaine-dependent individuals. In contrast to previous studies with treatment-seeking cocaine-dependent patients, no significant effects of smoking severity, depressive symptoms, or duration of cocaine use on frontal GM volume were observed. Reduced frontal GM volumes in non-treatment-seeking cocaine-dependent subjects are associated with trait impulsivity and are not associated with co-occurring nicotine dependence or depression.
doi:10.3389/fnhum.2014.00007
PMCID: PMC3894477  PMID: 24478673
cocaine dependence; drug abuse; voxel-based morphometry; frontal; depression; nicotine
4.  The Role of Study and Work in Cannabis Use and Dependence Trajectories among Young Adult Frequent Cannabis Users 
Life course theory considers events in study and work as potential turning points in deviance, including illicit drug use. This qualitative study explores the role of occupational life in cannabis use and dependence in young adults. Two and three years after the initial structured interview, 47 at baseline frequent cannabis users were interviewed in-depth about the dynamics underlying changes in their cannabis use and dependence. Overall, cannabis use and dependence declined, including interviewees who quit using cannabis completely, in particular with students, both during their study and after they got employed. Life course theory appeared to be a useful framework to explore how and why occupational life is related to cannabis use and dependence over time. Our study showed that life events in this realm are rather common in young adults and can have a strong impact on cannabis use. While sometimes changes in use are temporary, turning points can evolve from changes in educational and employment situations; an effect that seems to be related to the consequences of these changes in terms of amount of leisure time and agency (i.e., feelings of being in control).
doi:10.3389/fpsyt.2013.00085
PMCID: PMC3739012  PMID: 23950748
frequent cannabis use; cannabis dependence; young adults; qualitative research; life course approach; longitudinal study; education; employment
5.  N-Acetylcysteine Normalizes Glutamate Levels in Cocaine-Dependent Patients: A Randomized Crossover Magnetic Resonance Spectroscopy Study 
Neuropsychopharmacology  2012;37(9):2143-2152.
Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy (1H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine-dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities.
doi:10.1038/npp.2012.66
PMCID: PMC3398721  PMID: 22549117
cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity; cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity
6.  Efficacy of As-Needed Nalmefene in Alcohol-Dependent Patients with at Least a High Drinking Risk Level: Results from a Subgroup Analysis of Two Randomized Controlled 6-Month Studies 
Aims: The aim of the study was to investigate the efficacy and safety of as-needed use of nalmefene 18 mg versus placebo in reducing alcohol consumption in patients who did not reduce their alcohol consumption after an initial assessment, i.e. the pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) at both screening and randomization from the two randomized controlled 6-month studies ESENSE 1 (NCT00811720) and ESENSE 2 (NCT00812461). Methods: Nalmefene 18 mg and placebo were taken on an as-needed basis. All the patients also received a motivational and adherence-enhancing intervention (BRENDA). The co-primary outcomes were number of heavy drinking days (HDDs) and mean total alcohol consumption (g/day) in Month 6 measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study. Results: The pooled population consisted of 667 patients: placebo n = 332; nalmefene n = 335. There was a superior effect of nalmefene compared with placebo in reducing the number of HDDs [treatment difference: −3.2 days (95% CI: −4.8; −1.6); P < 0.0001] and total alcohol consumption [treatment difference: −14.3 g/day (−20.8; −7.8); P < 0.0001] at Month 6. Improvements in clinical status and liver parameters were greater in the nalmefene group compared with the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo. Conclusion: As-needed nalmefene was efficacious in reducing alcohol consumption in patients with at least a high drinking risk level at both screening and randomization, and the effect in this subgroup was larger than in the total population.
doi:10.1093/alcalc/agt061
PMCID: PMC3746807  PMID: 23873853
7.  Investigating the efficacy of integrated cognitive behavioral therapy for adult treatment seeking substance use disorder patients with comorbid ADHD: study protocol of a randomized controlled trial 
BMC Psychiatry  2013;13:132.
Background
Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with substance use disorders (SUD). The combination of ADHD and SUD is associated with a negative prognosis of both SUD and ADHD. Pharmacological treatments of comorbid ADHD in adult patients with SUD have not been very successful. Recent studies show positive effects of cognitive behavioral therapy (CBT) in ADHD patients without SUD, but CBT has not been studied in ADHD patients with comorbid SUD.
Methods/design
This paper presents the protocol of a randomized controlled trial to test the efficacy of an integrated CBT protocol aimed at reducing SUD as well as ADHD symptoms in SUD patients with a comorbid diagnosis of ADHD. The experimental group receives 15 CBT sessions directed at symptom reduction of SUD as well as ADHD. The control group receives treatment as usual, i.e. 10 CBT sessions directed at symptom reduction of SUD only. The primary outcome is the level of self-reported ADHD symptoms. Secondary outcomes include measures of substance use, depression and anxiety, quality of life, health care consumption and neuropsychological functions.
Discussion
This is the first randomized controlled trial to test the efficacy of an integrated CBT protocol for adult SUD patients with a comorbid diagnosis of ADHD. The rationale for the trial, the design, and the strengths and limitations of the study are discussed.
Trial registration
This trial is registered in http://www.clinicaltrials.gov as NCT01431235.
doi:10.1186/1471-244X-13-132
PMCID: PMC3659028  PMID: 23663651
ADHD; SUD; Cognitive behavioral therapy; Adult; Integrated treatment
8.  Cannabinoid-1 receptor antagonist rimonabant (SR141716) increases striatal dopamine D2 receptor availability 
Addiction biology  2011;10.1111/j.1369-1600.2011.00369.x.
The cannabinoid 1 (CB1) receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and 3.0 mg/kg/day) dose-dependently increased DRD2 availability in the dorsal striatum (14% and 23%) compared to vehicle. High-dose rimonabant also increased DRD2 availability in the ventral striatum (12%) and reduced weight gain. Thus, upregulation of striatal DRD2 by chronic rimonabant administration may be an underlying mechanism of action and confirms the interactions of the endocannabinoid and dopaminergic systems.
doi:10.1111/j.1369-1600.2011.00369.x
PMCID: PMC3252421  PMID: 21955259
cannabinoid 1 receptor; dopamine D2 receptor; IBZM; nucleus accumbens; rimonabant; striatum
9.  Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study 
PLoS ONE  2012;7(11):e49923.
Background
Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations.
Methods
We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions.
Results
Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition.
Conclusions
During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.
doi:10.1371/journal.pone.0049923
PMCID: PMC3509135  PMID: 23209619
10.  Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study 
PLoS ONE  2012;7(9):e42394.
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.
doi:10.1371/journal.pone.0042394
PMCID: PMC3434213  PMID: 22957019
11.  The association between cingulate cortex glutamate concentration and delay discounting is mediated by resting state functional connectivity 
Brain and Behavior  2012;2(5):553-562.
Humans vary in their ability to delay gratification and impulsive decision making is a common feature in various psychiatric disorders. The level of delay discounting is a relatively stable psychological trait, and therefore neural processes implicated in delay discounting are likely to be based on the overall functional organization of the brain (under task-free conditions) in which state-dependent shifts from baseline levels occur. The current study investigated whether delay discounting can be predicted by intrinsic properties of brain functioning. Fourteen healthy male subjects performed a delay discounting task. In addition, resting state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (¹H MRS) were used to investigate the relationship between individual differences in delay discounting and molecular and regional measures of resting state (baseline) activity of dorsal anterior cingulate cortex (dACC). Results showed that delay discounting was associated with both dACC glutamate concentrations and resting state functional connectivity of the dACC with a midbrain region including ventral tegmental area and substantia nigra. In addition, a neural pathway was established, showing that the effect of glutamate concentrations in the dACC on delay discounting is mediated by functional connectivity of the dACC with the midbrain. The current findings are important to acknowledge because spontaneous intrinsic brain processes have been proposed to be a potential promising biomarker of disease and impulsive decision making is associated with several psychiatric disorders.
doi:10.1002/brb3.74
PMCID: PMC3489808  PMID: 23139901
Anterior cingulate cortex; delay discounting; glutamate; impulsive decision making; magnetic resonance spectroscopy; resting state fMRI
12.  Substrates of neuropsychological functioning in stimulant dependence: a review of functional neuroimaging research 
Brain and Behavior  2012;2(4):499-523.
Stimulant dependence is associated with neuropsychological impairments. Here, we summarize and integrate the existing neuroimaging literature on the neural substrates of neuropsychological (dys)function in stimulant dependence, including cocaine, (meth-)amphetamine, ecstasy and nicotine dependence, and excessive caffeine use, comparing stimulant abusers (SAs) to nondrug using healthy controls (HCs). Despite some inconsistencies, most studies indicated altered brain activation in prefrontal cortex (PFC) and insula in response to reward and punishment, and higher limbic and anterior cingulate cortex (ACC)/PFC activation during craving and attentional bias paradigms in SAs compared with HCs. Impulsivity in SAs was associated with lower ACC and presupplementary motor area activity compared with HCs, and related to both ventral (amygdala, ventrolateral PFC, insula) and dorsal (dorsolateral PFC, dorsal ACC, posterior parietal cortex) systems. Decision making in SAs was associated with low dorsolateral PFC activity and high orbitofrontal activity. Finally, executive function in SAs was associated with lower activation in frontotemporal regions and higher activation in premotor cortex compared with HCs. It is concluded that the lower activations compared with HCs are likely to reflect the neural substrate of impaired neurocognitive functions, whereas higher activations in SAs compared with HCs are likely to reflect compensatory cognitive control mechanisms to keep behavioral task performance to a similar level as in HCs. However, before final conclusions can be drawn, additional research is needed using neuroimaging in SAs and HCs using larger and more homogeneous samples as well as more comparable task paradigms, study designs, and statistical analyses.
doi:10.1002/brb3.65
PMCID: PMC3432971  PMID: 22950052
Addiction; fMRI; functional imaging; magnetic resonance imaging; stimulant dependence; stimulants
13.  The Relationship between Impulsive Choice and Impulsive Action: A Cross-Species Translational Study 
PLoS ONE  2012;7(5):e36781.
Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.
doi:10.1371/journal.pone.0036781
PMCID: PMC3344935  PMID: 22574225
14.  Response Inhibition during Cue Reactivity in Problem Gamblers: An fMRI Study 
PLoS ONE  2012;7(3):e30909.
Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).
Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.
PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.
This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.
doi:10.1371/journal.pone.0030909
PMCID: PMC3316530  PMID: 22479305
15.  Cocaine Addiction Treatments to improve Control and reduce Harm (CATCH): New Pharmacological Treatment Options for Crack-Cocaine Dependence in the Netherlands 
BMC Psychiatry  2011;11:135.
Background
Cocaine, particularly in its base form ('crack'), has become one of the drugs of most concern in the Netherlands, being associated with a wide range of medical, psychiatric and social problems for the individual, and with significant public order consequences for society. Available treatment options for cocaine dependent users are limited, and a substantial part of the cocaine dependent population is not reached by the addiction treatment system. Psychosocial interventions for cocaine dependence generally show modest results, and there are no registered pharmacological treatments to date, despite the wide range of medications tested for this type of dependence.
The present study (Cocaine Addiction Treatments to improve Control and reduce Harm; CATCH) investigates the possibilities and problems associated with new pharmacological treatments for crack dependent patients.
Methods/Design
The CATCH-study consists of three separate randomised controlled, open-label, parallel-group feasibility trials, conducted at three separate addiction treatment institutes in the Netherlands. Patients are either new referrals or patients already in treatment. A total of 216 eligible outpatients are randomised using pre-randomisation double-consent design and receive either 12 weeks treatment with oral topiramate (n = 36; Brijder Addiction Treatment, The Hague), oral modafinil (n = 36; Arkin, Amsterdam), or oral dexamphetamine sustained-release (n = 36; Bouman GGZ, Rotterdam) as an add-on to cognitive behavioural therapy (CBT), or receive a 12-week CBT only (controls: n = 3 × 36).
Primary outcome in these feasibility trials is retention in the underlying psychosocial treatment (CBT). Secondary outcomes are acceptance and compliance with the study medication, safety, changes in cocaine (and other drug) use, physical and mental health, social functioning, and patient satisfaction.
Discussion
To date, the CATCH-study is the first study in the Netherlands that explores new treatment options for crack-cocaine dependence focusing on both abstinence and harm minimisation. It is expected that the study will contribute to the development of new treatments for one of the most problematic substance use disorders.
Trial Registration
The Netherlands National Trial Register NTR2576
The European Union Drug Regulating Authorities Clinical Trials EudraCT2009-010584-16
doi:10.1186/1471-244X-11-135
PMCID: PMC3175153  PMID: 21854580
16.  Brain Imaging Studies in Pathological Gambling 
Current Psychiatry Reports  2010;12(5):418-425.
This article reviews the neuroimaging research on pathological gambling (PG). Because of the similarities between substance dependence and PG, PG research has used paradigms similar to those used in substance use disorder research, focusing on reward and punishment sensitivity, cue reactivity, impulsivity, and decision making. This review shows that PG is consistently associated with blunted mesolimbic-prefrontal cortex activation to nonspecific rewards, whereas these areas show increased activation when exposed to gambling-related stimuli in cue exposure paradigms. Very little is known, and hence more research is needed regarding the neural underpinnings of impulsivity and decision making in PG. This review concludes with a discussion regarding the challenges and new developments in the field of neurobiological gambling research and comments on their implications for the treatment of PG.
doi:10.1007/s11920-010-0141-7
PMCID: PMC2933850  PMID: 20676945
Pathological gambling; Addiction; Neuroimaging; Neuropsychology
17.  Decision making as a predictor of first ecstasy use: a prospective study 
Psychopharmacology  2008;203(3):519-527.
Rationale
Ecstasy (±3,4-methylenedioxymethamphetamine) is a widely used recreational drug that may damage the serotonin system and may entail neuropsychological dysfunctions. Few studies investigated predictors for ecstasy use. Self-reported impulsivity does not predict the initiation of ecstasy use; the question is if neuropsychological indicators of impulsivity can predict first ecstasy use.
Objective
This study tested the hypothesis that a neuropsychological indicator of impulsivity predicts initiation of ecstasy use.
Materials and methods
Decision-making strategy and decision-making reaction times were examined with the Iowa Gambling Task in 149 ecstasy-naive subjects. The performance of 59 subjects who initiated ecstasy use during a mean follow-up period of 18 months (range, 11–26) was compared with the performance of 90 subjects that remained ecstasy-naive.
Results
Significant differences in decision-making strategy between female future ecstasy users and female persistent ecstasy-naive subjects were found. In addition, the gap between decision-making reaction time after advantageous choices and reaction time after disadvantageous choices was smaller in future ecstasy users than in persistent ecstasy-naives.
Conclusion
Decision-making strategy on a gambling task was predictive for future use of ecstasy in female subjects. Differences in decision-making time between future ecstasy users and persistent ecstasy-naives may point to lower punishment sensitivity or higher impulsivity in future ecstasy users. Because differences were small, the clinical relevance is questionable.
doi:10.1007/s00213-008-1398-y
PMCID: PMC2761546  PMID: 19020868
Ecstasy; MDMA; Decision-making; Iowa Gambling Task; Neuropsychology
18.  Using the Autism-Spectrum Quotient to Discriminate Autism Spectrum Disorder from ADHD in Adult Patients With and Without Comorbid Substance Use Disorder 
It is unknown whether the Autism-spectrum quotient (AQ) can discriminate between Autism Spectrum Disorder (ASD) and Attention Deficit and Hyperactivity Disorder (ADHD) with or without comorbid Substance Use Disorder (SUD). ANOVA’s were used to analyse the mean AQ (sub)scores of 129 adults with ASD or ADHD. We applied receiver operating characteristic (ROC) computations to assess discriminant power. All but one of the mean AQ (sub)scores were significantly higher for adults with ASD compared to those with ADHD. The SUD status in general was not significantly associated with AQ (sub)scores. On the Social Skills subscale patients with ASD and comorbid SUD showed less impairment than those without SUD. The cut-off score 26 yielded 73% correct classifications. The clinical use of the AQ in differentiating between ASD and ADHD is limited.
doi:10.1007/s10803-009-0743-2
PMCID: PMC2727364  PMID: 19396535
Autism spectrum disorder; ADHD; Substance use disorder; Autism-spectrum quotient
19.  Heroin-assisted Treatment (HAT) a Decade Later: A Brief Update on Science and Politics 
Since the initial Swiss heroin-assisted treatment (HAT) study conducted in the mid-1990s, several other jurisdictions in Europe and North America have implemented HAT trials. All of these studies embrace the same goal—investigating the utility of medical heroin prescribing for problematic opioid users—yet are distinct in various key details. This paper briefly reviews (initiated or completed) studies and their main parameters, including primary research objectives, design, target populations, outcome measures, current status and—where available—key results. We conclude this overview with some final observations on a decade of intensive HAT research in the jurisdictions examined, including the suggestion that there is a mounting onus on the realm of politics to translate the—largely positive—data from completed HAT science into corresponding policy and programming in order to expand effective treatment options for the high-risk population of illicit opioid users.
doi:10.1007/s11524-007-9198-y
PMCID: PMC2219559  PMID: 17562183
Heroin-assisted treatment; Science; Politics; Opioid dependence; Clinical trials
20.  Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials 
BMJ : British Medical Journal  2005;330(7503):1297.
Objective To determine the cost utility of medical co-prescription of heroin compared with methadone maintenance treatment for chronic, treatment resistant heroin addicts.
Design Cost utility analysis of two pooled open label randomised controlled trials.
Setting Methadone maintenance programmes in six cities in the Netherlands.
Participants 430 heroin addicts.
Interventions Inhalable or injectable heroin prescribed over 12 months. Methadone (maximum 150 mg a day) plus heroin (maximum 1000 mg a day) compared with methadone alone (maximum 150 mg a day). Psychosocial treatment was offered throughout.
Main outcome measures One year costs estimated from a societal perspective. Quality adjusted life years (QALYs) based on responses to the EuroQol EQ-5D at baseline and during the treatment period.
Results Co-prescription of heroin was associated with 0.058 more QALYs per patient per year (95% confidence interval 0.016 to 0.099) and a mean saving of €12 793 (£8793, $16 122) (€1083 to €25 229) per patient per year. The higher programme costs (€16 222; lower 95% confidence limit €15 084) were compensated for by lower costs of law enforcement (- €4129; upper 95% confidence limit - €486) and damage to victims of crime (- €25 374; upper 95% confidence limit - €16 625). The results were robust for the use of national EQ-5D tariffs and for the exclusion of the initial implementation costs of heroin treatment. Completion of treatment is essential; having participated in any abstinence treatment in the past is not.
Conclusions Co-prescription of heroin is cost effective compared with treatment with methadone alone for chronic, treatment resistant heroin addicts.
PMCID: PMC558200  PMID: 15933353
22.  Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials 
BMJ : British Medical Journal  2003;327(7410):310.
Objective To determine whether supervised medical prescription of heroin can successfully treat addicts who do not sufficiently benefit from methadone maintenance treatment.
Design Two open label randomised controlled trials.
Setting Methadone maintenance programmes in six cities in the Netherlands.
Participants 549 heroin addicts.
Interventions Inhalable heroin (n = 375) or injectable heroin (n = 174) prescribed over 12 months. Heroin (maximum 1000 mg per day) plus methadone (maximum 150 mg per day) compared with methadone alone (maximum 150 mg per day). Psychosocial treatment was offered throughout.
Main outcome measures Dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning.
Results Adherence was excellent with 12 month outcome data available for 94% of the randomised participants. With intention to treat analysis, 12 month treatment with heroin plus methadone was significantly more effective than treatment with methadone alone in the trial of inhalable heroin (response rate 49.7% v 26.9%; difference 22.8%, 95% confidence interval 11.0% to 34.6%) and in the trial of injectable heroin (55.5% v 31.2%; difference 24.3%, 9.6% to 39.0%). Discontinuation of the coprescribed heroin resulted in a rapid deterioration in 82% (94/115) of those who responded to the coprescribed heroin. The incidence of serious adverse events was similar across treatment conditions.
Conclusions Supervised coprescription of heroin is feasible, more effective, and probably as safe as methadone alone in reducing the many physical, mental, and social problems of treatment resistant heroin addicts.
PMCID: PMC169643  PMID: 12907482
23.  Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study 
Addiction Biology  2010;15(4):491-503.
Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event-related cue reactivity paradigm, consisting of gambling, smoking-related and neutral pictures, was employed in 17 treatment-seeking non-smoking PRG, 18 non-gambling HSM, and 17 non-gambling and non-smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerström Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking-related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non-smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking-related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto-limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores.
doi:10.1111/j.1369-1600.2010.00242.x
PMCID: PMC3014110  PMID: 20840335
Addiction; cue reactivity; fMRI; impulse control disorder; nicotine dependence; pathological gambling
24.  The Dutch Cannabis Dependence (CanDep) study on the course of frequent cannabis use and dependence: objectives, methods and sample characteristics 
This paper presents an overview of the prospective cohort design of the Dutch Cannabis Dependence (CanDep) study, which investigates (i) the three-year natural course of frequent cannabis use (≥ three days per week in the past 12 months) and cannabis dependence; and (ii) the factors involved in the transition from frequent non-dependent cannabis use to cannabis dependence, and remission from dependence. Besides its scientific relevance, this knowledge may contribute to improve selective and indicated prevention, early detection, treatment and cannabis policies. The secondary objectives are the identification of factors related to treatment seeking and the validation of self report measures of cannabis use.
Between September 2008 and April 2009, baseline data were collected from 600 frequent cannabis users with an average age of 22.1 years, predominantly male (79.3%) and an average cannabis use history of 7.1 years; 42.0% fulfilled a (12-month DSM-IV) diagnosis of cannabis dependence. The response rate was 83.7% after the first follow up at 18 months. The second and last follow-up is planned at 36 months. Computer assisted personal interviews (CAPI) were conducted which covered: cannabis use (including detailed assessments of exposure, motives for use and potency preference); use of other substances; DSM-IV internalizing and externalizing mental disorders; treatment seeking; personality; life events; social support and social functioning. Copyright © 2011 John Wiley & Sons, Ltd.
doi:10.1002/mpr.345
PMCID: PMC3467998  PMID: 21815231
design; frequent cannabis use; cannabis dependence; longitudinal

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