Does cannabis use substitute for opioids? A preliminary exploratory survey in opioid maintenance patients.

Various studies showed that people with substance use disorder use cannabis to reduce withdrawal or dose of their main drug. Using a questionnaire about their cannabis use, 118 participants in an opioid maintenance treatment (OMT) in Germany were examined regarding this strategy. 60% reported to use cannabis. Of those, 72% were using cannabis in the suggested way. Cannabis was used to substitute for, e.g., heroin (44.8%) and benzodiazepines (16.4%). We also asked for an estimation of how good cannabis was able to substitute for several substances (in German school grades (1 till 6)); heroin average grade: 2.6 ± 1.49. Besides that we asked about the idea of cannabis as "self-medication", e.g., to reduce pain (47%) and about negative consequences from cannabis use. Our results suggest to consider the use of cannabis by patients in OMT rather as a harm reduction strategy to reduce the intake of more dangerous drugs.

A History of Childhood Maltreatment Has Substance- and Sex-Specific Effects on Craving During Treatment for Substance Use Disorders.

Rationale: Childhood maltreatment (CM) leads to detrimental mental health outcomes, such as substance use disorders (SUD). This study examined prevalence and severity of all five types of CM with respect to specific substances and sex in treatment-seeking individuals with SUD. The influences of type of CM and symptoms of depressiveness, anxiety, and perceived stress on substance craving at admission as well as craving reduction during SUD treatment were examined. Methods: N = 546 patients in treatment for SUD and N = 109 individuals in opioid maintenance treatment filled out questionnaires regarding CM (Childhood Trauma Questionnaire) and psychopathologies. Substance craving was assessed throughout treatment using the Mannheim Craving Scale. Group differences in CM, type of substance and sex were examined. General linear models were applied to examine influences on substance craving. Results: Higher prevalence and severity of all five subtypes of CM were observed in individuals with SUD compared to the general population. Women were more severely affected by emotional and sexual abuse than men. Patients with cannabis use disorder reported more severe experiences of emotional abuse compared to all other substances. Craving at admission to treatment was influenced by emotional abuse, however, symptoms of depressiveness, anxiety, and perceived stress contributed to craving at admission or craving reduction during treatment. Conclusion: CM relates to SUD and should be incorporated in prevention and treatment of SUD. Underlying mechanisms of the association might relate to impairments in processing and regulation of stress, emotions, and interpersonal relations following a history of CM.

Increased network centrality of the anterior insula in early abstinence from alcohol.

Abnormal resting-state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph-theoretical analyses, enabling improved resolution and fine-grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large-scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region-specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular-supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment.

Exploring Influences on Theory of Mind Impairment in Opioid Dependent Patients.

Theory of mind (ToM) is an aspect of social cognition impaired in different addictive disorders, including opioid addiction. This study aimed at replicating ToM deficits in opioid dependent patients undergoing opioid maintenance treatment (OMT) and exploring the influence of substance use related variables, executive functions and childhood maltreatment on ToM in opioid dependent patients. 66 opioid dependent patients were tested using the Movie for Assessment of Social Cognition (MASC) and compared with the data of healthy controls. Furthermore, the opioid dependent patients underwent testing for executive functions and filled in the Childhood Trauma Questionnaire (CTQ). Performance on the MASC was significantly poorer in the opioid dependence group than in the control group, even when recent additional drug use and psychiatric comorbidities were controlled for. No correlations were found between ToM and substance use related factors. Aspects of ToM performance in opioid dependent patients correlated significantly with different EF domains. ToM correlated significantly with the CTQ scales for physical maltreatment. The results confirm impaired ToM in opioid dependent patients and highlight executive functions and childhood maltreatment as influential factors. The lack of associations between ToM and substance use related variables and the association with childhood maltreatment suggest that ToM impairments might be a risk factor predating substance abuse.

Cortical Glutamate and GABA Changes During Early Abstinence in Alcohol Dependence and Their Associations With Benzodiazepine Medication.

In this report, we present cross-sectional and longitudinal findings from single-voxel MEGA-PRESS MRS of GABA as well as Glu, and Glu + glutamine (Glx) concentrations in the ACC of treatment-seeking alcohol-dependent patients (ADPs) during detoxification (first 2 weeks of abstinence). The focus of this study was to examine whether the amount of benzodiazepine administered to treat withdrawal symptoms was associated with longitudinal changes in Glu, Glx, and GABA. The tNAA levels served as an internal quality reference; in agreement with the vast majority of previous reports, these levels were initially decreased and normalized during the course of abstinence in ADPs. Our results on Glu and Glx support hyperglutamatergic functioning during alcohol withdrawal, by showing higher ACC Glu and Glx levels on the first day of detoxification in ADPs. Withdrawal severity is reflected in cumulative benzodiazepine requirements throughout the withdrawal period. The importance of withdrawal severity for the study of GABA and Glu changes in early abstinence is emphasized by the benzodiazepine-dependent Glu, Glx, and GABA changes observed during the course of abstinence.

Cannabis Use and Car Crashes: A Review.

In this review, state-of-the-art evidence on the relationship between cannabis use, traffic crash risks, and driving safety were analyzed. Systematic reviews, meta-analyses, and other relevant papers published within the last decade were systematically searched and synthesized. Findings show that meta-analyses and culpability studies consistently indicate a slightly but significantly increased risk of crashes after acute cannabis use. These risks vary across included study type, crash severity, and method of substance application and measurement. Some studies show a significant correlation between high THC blood concentrations and car crash risk. Most studies do not support this relationship at lower THC concentrations. However, no scientifically supported clear cut-off concentration can be derived from these results. Further research is needed to determine dose-response effects on driving skills combined with measures of neuropsychological functioning related to driving skills and crash risk.

Nalmefene attenuates neural alcohol cue-reactivity in the ventral striatum and subjective alcohol craving in patients with alcohol use disorder.

RATIONALE: Alcohol use disorder is a common and devastating mental illness for which satisfactory treatments are still lacking. Nalmefene, as an opioid receptor modulator, could pharmacologically support the reduction of drinking by reducing the (anticipated) rewarding effects of alcohol and expanding the range of treatment options. It has been hypothesized that nalmefene acts via an indirect modulation of the mesolimbic reward system. So far, only a few imaging findings on the neuronal response to nalmefene are available. OBJECTIVES: We tested the effect of a single dose of 18 mg nalmefene on neuronal cue-reactivity in the ventral and dorsal striatum and subjective craving. METHODS: Eighteen non-treatment-seeking participants with alcohol use disorder (67% male, M = 50.3 ± 13.9 years) with a current high-risk drinking level (M = 76.9 ± 52 g of pure alcohol per day) were investigated using a cue-reactivity task during functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled, cross-over study/design. In addition, self-reported craving was assessed before and after exposure to alcohol cues. RESULTS: An a priori defined region of interest (ROI) analysis of fMRI data from 15 participants revealed that nalmefene reduced alcohol cue-reactivity in the ventral, but not the dorsal striatum. Additionally, the subjective craving was significantly reduced after the cue-reactivity task under nalmefene compared to placebo. CONCLUSION: In the present study, reduced craving and cue-reactivity to alcohol stimuli in the ventral striatum by nalmefene indicates a potential anti-craving effect of this drug via attenuation of neural alcohol cue-reactivity.

FMRI-based prediction of naltrexone response in alcohol use disorder: a replication study.

Pharmacological treatment in alcohol use disorder suffers from modest effect sizes. Efforts have been undertaken to identify patient characteristics that help to select individuals that benefit from pharmacological treatment. Previous studies indicated that neural alcohol cue-reactivity (CR) might provide a marker that identifies patients, which benefit from naltrexone treatment.We investigated the reproducibility of the association between ventral striatum (VS) activation and naltrexone (NTX) treatment response by analyzing data from a recent longitudinal clinical trial in N = 44 abstinent treatment-seeking alcohol-dependent patients. A follow-up was conducted over 3 months. We computed the percentage of significant voxels in VS and tested main effects and interactions with NTX treatment on relapse risk using Cox Regression models.We found a significant interaction effect between pre-treatment cue reactivity in the VS and NTX treatment on time to first heavy relapse (Hazard Ratio = 7.406, 95% CI 1.17-46.56, p = 0.033), such that the patient group with high VS activation (defined by a mean split) showed a significant medication effect (Hazard Ratio = 0.140, 95% CI 0.02-0.75, p = 0.022) with a number needed to treat of 3.4 [95% CI 2.413.5], while there was no significant effect in the group with low VS activation (Hazard Ratio = 0.726, p = 0.454).Thus, using an independent sample we replicated the previously described positive association between VS activation and NTX efficacy. Although our results should be considered cautiously in light of the small sample size, our results support the potential of neural alcohol CR as a tool for precision medicine approaches in alcohol dependence.

Investigation of brain functional connectivity to assess cognitive control over cue-processing in Alcohol Use Disorder.

Alcohol Use Disorder has been associated with impairments of functional connectivity between neural networks underlying reward processing and cognitive control. Evidence for aberrant functional connectivity between the striatum, insula, and frontal cortex in alcohol users exists at rest, but not during cue-exposure. In this study, we investigated functional connectivity changes during a cue-reactivity task across different subgroups of alcohol consumers. Ninety-six participants (ranging from light social to heavy social drinkers and nonabstinent dependent to abstinent dependent drinkers) were examined. A functional magnetic resonance imaging cue-reactivity paradigm was administered, during which alcohol-related and neutral stimuli were presented. Applying psychophysiological interaction analyses, we found: (a) Abstinent alcohol-dependent patients compared with non-abstinent dependent drinkers showed a greater increase of functional connectivity of the ventral striatum and anterior insula with the anterior cingulate cortex and dorsolateral prefrontal cortex during the presentation of alcohol cues compared with neutral cues. (b) Subjective craving correlated positively with functional connectivity change between the posterior insula and the medial orbitofrontal cortex and negatively with functional connectivity change between the ventral striatum and the anterior cingulate cortex, dorsolateral prefrontal cortex, and lateral orbitofrontal cortex. (c) Compulsivity of alcohol use correlated positively with functional connectivity change between the dorsolateral prefrontal cortex and the ventral striatum, anterior insula, and posterior insula. Results suggest increased cognitive control over cue-processing in abstinent alcohol-dependent patients, compensating high levels of cue-provoked craving and compulsive use. Clinical trial registration details: ClinicalTrials.gov ID: NCT00926900.

Impaired working memory performance in opioid-dependent patients is related to reduced insula gray matter volume: a voxel-based morphometric study.

Opioid-dependent patients frequently show deficits in multiple cognitive domains that might impact on their everyday life performance and interfere with therapeutic efforts. To date, the neurobiological underpinnings of those deficits remain to be determined. We investigated working memory performance and gray matter volume (GMV) differences in 17 patients on opioid maintenance treatment (OMT) and 17 healthy individuals using magnetic resonance imaging and voxel-based morphometry. In addition, we explored associations between substance intake, gray matter volume, and working memory task performance. Patients on OMT committed more errors during the working memory task than healthy individuals and showed smaller insula and putamen GMV. The duration of heroin use prior to OMT was associated with working memory performance and insula GMV in patients. Neither the substitution agent (methadone and buprenorphine) nor concurrent abuse of illegal substances during the 3 months prior to the experiment was significantly associated with GMV. Results indicate that impaired working memory performance and structural deficits in the insula of opioid-dependent patients are related to the duration of heroin use. This suggests that early inclusion into OMT or abstinence-oriented therapies that shorten the period of heroin abuse may limit the impairments to GMV and cognitive performance of opioid-dependent individuals.

Incubation of neural alcohol cue reactivity after withdrawal and its blockade by naltrexone.

During the first weeks of abstinence, alcohol craving in patients may increase or "incubate." We hypothesize that Naltrexone (NTX) blocks this incubation effect. Here, we compared NTX effects on neural alcohol cue reactivity (CR) over the first weeks of abstinence and on long-term clinical outcomes to standard treatment. Male alcohol-dependent patients (n = 55) and healthy controls (n = 35) were enrolled. Participants underwent baseline psychometric testing and functional magnetic resonance imaging (fMRI) assessment of mesolimbic alcohol CR. Patients participated in a standard treatment program with the option of adjuvant NTX. They received another scan after 2 weeks of treatment. We found higher CR in several brain regions in patients versus healthy controls. CR significantly increased over 2 weeks in the standard treatment group (n = 13) but not in the NTX group (n = 22). NTX significantly attenuated CR in the left putamen and reduced relapse risk to heavy drinking within 3 months of treatment. Additionally, increased CR in the left putamen and its course over time predicted both NTX response and relapse risk. Carrier status for the functional OPRM1 variant rs1799971:A > G was considered but had no effect on NTX efficacy. In conclusion, NTX was most effective in patients with high CR in the left putamen. While the results from our naturalistic study await further confirmation from prospective randomized trials, they support a potential role of neural CR as a biomarker in the development of precision medicine approaches with NTX.

Reconsolidation impairment of reward memory by stimulating stress response.

Research in memory reconsolidation has raised hope for new treatment options of persistent psychiatric disorders like substance dependence and post-traumatic stress disorder (PTSD). While animal research showed successful memory modification by interfering with reconsolidation, human research requires less invasive techniques. In our pilot study, we aimed to reduce appetitive memory reconsolidation of a newly acquired reward memory by exerting a stressor. Thirty healthy participants were randomly assigned to two groups performing a monetary reward paradigm at a personal computer. Day 1 was considered to allow for memory acquisition; on day 2, the experimental group was exposed to a frightening stimulus in the reconsolidation window; and day 3 again served to determine reward memory effects. Measures of reward memory were reaction times to reward announcing stimuli (ie, showing instrumental behavior), actual reward gained, and electrodermal response as a measure for reward anticipation. We found significantly smaller reaction time improvements to reward stimuli over time in the experimental group, as well as reduced achievements in monetary reward. Electrodermal response to reward announcing stimuli was lower in the experimental group after intervention, whereas it was higher in the untreated group. Thus, we argue in favor of the reconsolidation hypothesis, assuming our intervention had successfully interfered with the reconsolidation process. This points towards future treatment options that interfere with an addiction memory.

Addiction Research Consortium: Losing and regaining control over drug intake (ReCoDe)-From trajectories to mechanisms and interventions.

One of the major risk factors for global death and disability is alcohol, tobacco, and illicit drug use. While there is increasing knowledge with respect to individual factors promoting the initiation and maintenance of substance use disorders (SUDs), disease trajectories involved in losing and regaining control over drug intake (ReCoDe) are still not well described. Our newly formed German Collaborative Research Centre (CRC) on ReCoDe has an interdisciplinary approach funded by the German Research Foundation (DFG) with a 12-year perspective. The main goals of our research consortium are (i) to identify triggers and modifying factors that longitudinally modulate the trajectories of losing and regaining control over drug consumption in real life, (ii) to study underlying behavioral, cognitive, and neurobiological mechanisms, and (iii) to implicate mechanism-based interventions. These goals will be achieved by: (i) using mobile health (m-health) tools to longitudinally monitor the effects of triggers (drug cues, stressors, and priming doses) and modify factors (eg, age, gender, physical activity, and cognitive control) on drug consumption patterns in real-life conditions and in animal models of addiction; (ii) the identification and computational modeling of key mechanisms mediating the effects of such triggers and modifying factors on goal-directed, habitual, and compulsive aspects of behavior from human studies and animal models; and (iii) developing and testing interventions that specifically target the underlying mechanisms for regaining control over drug intake.

Higher Social Rejection Sensitivity in Opioid-Dependent Patients Is Related to Smaller Insula Gray Matter Volume: A Voxel-Based Morphometric Study.

Opioid-dependent patients are highly sensitized to negative social feedback, and increased social rejection sensitivity was linked to adverse treatment outcome, but its neurobiological underpinnings have not been understood yet. The present study investigated gray matter (GM) volume differences between 19 opioid maintenance treatment (OMT) patients and 20 healthy controls using magnetic resonance imaging and voxel-based morphometry. Associations of GM volumes with subjective feelings of exclusion and inclusion during a social ostracism (Cyberball) paradigm, with rejection sensitivity, social interaction anxiety and social phobia were explored. OMT patients displayed smaller GM volume in the bilateral insula and inferior frontal gyri. Psychometric and task data showed that patients reported significantly higher rejection sensitivity, social anxiety and social phobia scores and felt more excluded and less included during the social ostracism paradigm. Smaller GM volume in the insula was associated with higher subjective exclusion, lower subjective inclusion and higher rejection sensitivity, social anxiety and social phobia scores. Findings indicate that structural deficits in emotion- and anxiety-processing brain regions in OMT patients are associated with increased social rejection sensitivity. As social rejection is a potential trigger for relapse, patients might benefit from therapeutic strategies that promote social integration.

The effects of nalmefene on emotion processing in alcohol use disorder - A randomized, controlled fMRI study.

Nalmefene is a µ- and δ-opioid receptor antagonist and a partial κ-opioid receptor agonist. The drug is suggested to reduce the craving for, and the consumption of alcohol effectively, also alleviating anxiety and anhedonia. The present fMRI study is the first to investigate the processing of emotions as a possible mechanism of action of nalmefene in humans. Fifteen non-treatment-seeking participants suffering from alcohol use disorder (AUD) (24-66 years; 5 females) finished this randomized, placebo controlled, double blind study. Following a cross over design, participants received either a single dose nalmefene or a placebo, with an interval of one week between sessions. Using fMRI, we investigated neural reactivity during the presentation of emotional faces picture sets. Additionally, we performed a visual dot-probe task to detect nalmefene's effects on attentional bias. We detected an increase in the response to emotional faces in the supramarginal gyrus, the angular gyrus as well as the putamen in the nalmefene vs. placebo condition. However, contradictory to our initial hypotheses, amygdala activation was not altered significantly in the placebo condition - a limitation, which might be associated with a lack of activation in the placebo condition maybe due to the small sample size. Attentional bias analyses revealed an interaction effect by trend, which was driven by a significant effect in a sub-analysis showing increased attentional shift towards happy compared to fearful facial expressions under nalmefene. Nalmefene increased brain activation in areas responsible for empathy, social cognition and behavior, which might help alleviating the reinforcing properties of alcohol.

[Sexual Abuse of Children by Catholic Priests since 2009: Course and Relative Frequency Compared to the Male General Population]. / Sexueller Missbrauch von Kindern durch katholische Priester seit 2009: Verlauf und relative Häufigkeit im Vergleich zur männlichen Allgemeinbevölkerung.

OBJECTIVE: This paper explores the frequency of sexual abuse allegations against Catholic priests and deacons in the years 2009 to 2015 in relation to the male general population in Germany. METHOD: An annual rate of sexual abuse accusations is calculated from the sexual abuse allegations against Catholic priests identified in the MHG-study for the years 2009 to 2015. This is compared to figures of the male general population from the police crime statistics. RESULTS: The number of suspected men in the general population ranged from 17.6 - 20.0/100.000 between 2009 and 2015. For Catholic priests the rate of accusations ranged from 8.4 to 31.7/100.000. A decrease of the quota was not detectable in either group during the study period. DISCUSSION: The findings suggest that there is a relatively constant rate of people being disposed to child sexual abuse in the group of Catholic priests. These results should be addressed specifically in the prevention work of the Catholic Church.

Microstructural White Matter Alterations in Men With Alcohol Use Disorder and Rats With Excessive Alcohol Consumption During Early Abstinence.

Importance: Although the detrimental effects of alcohol on the brain are widely acknowledged, observed structural changes are highly heterogeneous, and diagnostic markers for characterizing alcohol-induced brain damage, especially in early abstinence, are lacking. This heterogeneity, likely contributed to by comorbidity factors in patients with alcohol use disorder (AUD), challenges a direct link of brain alterations to the pathophysiology of alcohol misuse. Translational studies in animal models may help bridge this causal gap. Objective: To compare microstructural properties extracted using advanced diffusion tensor imaging (DTI) in the brains of patients with AUD and a well-controlled rat model of excessive alcohol consumption and monitor the progression of these properties during early abstinence. Design, Setting, and Participants: This prospective observational study included 2 cohorts of hospitalized patients with AUD (n = 91) and Marchigian Sardinian alcohol-preferring (msP) rats (n = 27). In humans cross-sectional comparison were performed with control participants (healthy men [n = 36]) and longitudinal comparisons between different points after alcohol withdrawal. In rats, longitudinal comparisons were performed in alcohol-exposed (n = 27) and alcohol-naive msP rats (n = 9). Human data were collected from March 7, 2013, to August 3, 2016, and analyzed from June 14, 2017, to May 31, 2018; rat data were collected from January 15, 2017, to May 12, 2017, and analyzed from October 11, 2017, to May 28, 2018. Main Outcomes and Measures: Fractional anisotropy and other DTI measures of white matter properties after long-term alcohol exposure and during early abstinence in both species and clinical and demographic variables and time of abstinence after discharge from hospital in patients. Results: The analysis included 91 men with AUD (mean [SD] age, 46.1 [9.6] years) and 27 male rats in the AUD groups and 36 male controls (mean [SD] age, 41.7 [9.3] years) and 9 male control rats. Comparable DTI alterations were found between alcohol and control groups in both species, with a preferential involvement of the corpus callosum (fractional anisotropy Cohen d = -0.84 [P < .01] corrected in humans and Cohen d = -1.17 [P < .001] corrected in rats) and the fornix/fimbria (fractional anisotropy Cohen d = -0.92 [P < .001] corrected in humans and d = -1.24 [P < .001] corrected in rats). Changes in DTI were associated with preadmission consumption patterns in patients and progress in humans and rats during 6 weeks of abstinence. Mathematical modeling shows this process to be compatible with a sustained demyelination and/or a glial reaction. Conclusions and Relevance: Using a translational DTI approach, comparable white matter alterations were found in patients with AUD and rats with long-term alcohol consumption. In humans and rats, a progression of DTI alterations into early abstinence (2-6 weeks) suggests an underlying process that evolves soon after cessation of alcohol use.

Effects of social exclusion and physical pain in chronic opioid maintenance treatment: fMRI correlates.

Opioids interact with systems processing pain and social stimuli. Both systems are crucial for responding to strains of everyday life and both are linked to relapse risk in opioid-dependent patients. The investigation of those systems seems essential to better understand opioid addiction as a whole. 17 patients on opioid maintenance treatment (OMT) and 21 healthy individuals underwent a functional magnetic resonance imaging (fMRI) social ball-tossing (Cyberball) paradigm simulating social inclusion and exclusion. In addition, painful and non-painful temperature stimuli were applied, in order to test pain sensitivity. Patients on OMT showed reduced pain sensitivity. Subjective pain was higher after social exclusion compared to social inclusion trials. In comparison to healthy controls, OMT patients felt less included and more excluded during inclusion and control conditions, and equally excluded during the social exclusion condition. Feelings of exclusion during the inclusion trials were associated with higher scores on the childhood trauma questionnaire. Across all conditions, OMT patients demonstrated decreased fMRI activation in the bilateral superior and middle occipital and bilateral cunei, the lingual gyri, as well as in the left fusiform gyrus (whole brain FWE-corrected). Comparing social exclusion and inclusion conditions, healthy individuals showed significant activation in brain areas related to social feedback and emotion processing, such as the anterior cingulate cortex, the insula and fusiform gyrus, whereas OMT patients showed no difference across conditions. As negative social affect is a potential trigger for relapse, patients might benefit from therapeutic strategies that enhance social integration.