Publications by authors named "Derik Hermann"

73 Publications

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

Front Psychiatry 2021 5;12:656468. Epub 2021 Jul 5.

Department of Neuroimaging, Central Institute of Mental Health, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.

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.
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http://dx.doi.org/10.3389/fpsyt.2021.656468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287125PMC
July 2021

Cannabis Use and Car Crashes: A Review.

Front Psychiatry 2021 28;12:643315. Epub 2021 May 28.

Clinic and Polyclinic for Psychiatry and Psychotherapy, Clinic of the Ludwig-Maximilian-University Munich, Munich, Germany.

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.
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http://dx.doi.org/10.3389/fpsyt.2021.643315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195290PMC
May 2021

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

Eur Arch Psychiatry Clin Neurosci 2021 Aug 21;271(5):915-927. Epub 2021 Apr 21.

Department of Addictive Behavior and Addiction Medicine, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Square J5, 68159, Mannheim, Germany.

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.
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http://dx.doi.org/10.1007/s00406-021-01259-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236024PMC
August 2021

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

Psychopharmacology (Berl) 2021 Aug 12;238(8):2179-2189. Epub 2021 Apr 12.

Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.

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.
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http://dx.doi.org/10.1007/s00213-021-05842-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292278PMC
August 2021

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

Addict Biol 2021 01 6;26(1):e12863. Epub 2020 Jan 6.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1111/adb.12863DOI Listing
January 2021

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

Addict Biol 2020 03 20;25(2):e12866. Epub 2019 Dec 20.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

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.
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http://dx.doi.org/10.1111/adb.12866DOI Listing
March 2020

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

Soc Cogn Affect Neurosci 2019 11;14(11):1187-1195

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, 68159 Mannheim, Germany.

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.
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http://dx.doi.org/10.1093/scan/nsz094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057285PMC
November 2019

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

Eur Neuropsychopharmacol 2019 12 15;29(12):1442-1452. Epub 2019 Nov 15.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Square J5, D-68159 Mannheim, Germany; Feuerlein Center on Translational Addiction Medicine (FCTS), University of Heidelberg, Germany.

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.
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http://dx.doi.org/10.1016/j.euroneuro.2019.10.014DOI Listing
December 2019

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

Eur Arch Psychiatry Clin Neurosci 2021 Aug 17;271(5):813-822. Epub 2019 Aug 17.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Square J5, 68159, Mannheim, Germany.

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.
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http://dx.doi.org/10.1007/s00406-019-01052-7DOI Listing
August 2021

[Sexual Abuse of Children by Catholic Priests since 2009: Course and Relative Frequency Compared to the Male General Population].

Psychiatr Prax 2019 Jul 3;46(5):256-262. Epub 2019 Jul 3.

Zentralinstitut für Seelische Gesundheit, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim.

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.
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http://dx.doi.org/10.1055/a-0936-3869DOI Listing
July 2019

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

JAMA Psychiatry 2019 07;76(7):749-758

Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández de Elche, Sant Joan d'Alacant, Alicante, Spain.

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.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.0318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583663PMC
July 2019

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

Addict Biol 2020 01 12;25(1):e12717. Epub 2019 Feb 12.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.

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.
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http://dx.doi.org/10.1111/adb.12717DOI Listing
January 2020

Reconsolidation impairment of reward memory by stimulating stress response.

Addict Biol 2020 01 22;25(1):e12712. Epub 2019 Jan 22.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany.

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.
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http://dx.doi.org/10.1111/adb.12712DOI Listing
January 2020

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

Eur Neuropsychopharmacol 2019 12 27;29(2):291-305. Epub 2018 Nov 27.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Square J5, D-68159 Mannheim, Germany.

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.
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http://dx.doi.org/10.1016/j.euroneuro.2018.11.1109DOI Listing
December 2019

Massive Creatine Kinase Elevation in 2 Patients During Short-Term and Low-Dose Antipsychotic Monotherapy With Quetiapine.

J Clin Psychopharmacol 2018 08;38(4):385-387

Department of Addictive Behaviorand Addiction MedicineCentral Institute of Mental HealthUniversity of HeidelbergMedical Faculty Mannheim, Department of Addictive Behavior and Addiction Medicine Central Institute of Mental Health University of Heidelberg Medical Faculty Mannheim, Germany.

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http://dx.doi.org/10.1097/JCP.0000000000000902DOI Listing
August 2018

Negative Association Between MR-Spectroscopic Glutamate Markers and Gray Matter Volume After Alcohol Withdrawal in the Hippocampus: A Translational Study in Humans and Rats.

Alcohol Clin Exp Res 2017 02 18;41(2):323-333. Epub 2017 Jan 18.

Research Group for Translational Imaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats.

Methods: Alcohol-dependent patients (N = 39) underwent magnetic resonance imaging (MRI) and MR spectroscopy (MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls (N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence.

Results: In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model.

Conclusions: Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity.
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http://dx.doi.org/10.1111/acer.13308DOI Listing
February 2017

Low μ-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis.

Neuropsychopharmacology 2017 02 11;42(3):606-614. Epub 2016 Aug 11.

Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Blockade of the μ-opioid receptor (MOR) by naltrexone reduces relapse risk in a subpopulation of alcohol-dependent patients. Previous positron-emission-tomography (PET) studies using the MOR ligand [C]carfentanil have found increased MOR availability in abstinent alcoholics, which may reflect either increased MOR expression or lower endogenous ligand concentration. To differentiate between both effects, we investigated two cohorts of alcoholic subjects using either post-mortem or clinical PET analysis. Post-mortem brain tissue of alcohol-dependent subjects and controls (N=43/group) was quantitatively analyzed for MOR ([H]DAMGO)-binding sites and OPRM1 mRNA in striatal regions. [C]carfentanil PET was performed in detoxified, medication free alcohol-dependent patients (N=38), followed by a randomized controlled study of naltrexone versus placebo and follow-up for 1 year (clinical trial number: NCT00317031). Because the functional OPRM1 variant rs1799971:A>G affects the ligand binding, allele carrier status was considered in the analyses. MOR-binding sites were reduced by 23-51% in post-mortem striatal tissue of alcoholics. In the PET study, a significant interaction of OPRM1 genotype, binding potential (BP) for [C]carfentanil in the ventral striatum, and relapse risk was found. Particularly in G-allele carriers, lower striatal BP was associated with a higher relapse risk. Interestingly, this effect was more pronounced in the naltrexone treatment group. Reduced MOR is interpreted as a neuroadaptation to an alcohol-induced release of endogenous ligands in patients with severe alcoholism. Low MOR availability may explain the ineffectiveness of naltrexone treatment in this subpopulation. Finally, low MOR-binding sites are proposed as a molecular marker for a negative disease course.
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http://dx.doi.org/10.1038/npp.2016.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240173PMC
February 2017

The Effect of Nicotine on HPA Axis Activity in Females is Modulated by the FKBP5 Genotype.

Ann Hum Genet 2016 May 8;80(3):154-61. Epub 2016 Apr 8.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Tobacco smoking modulates activity in the hypothalamic-pituitary-adrenal (HPA) axis and is used to cope with stress, especially by females. The single nucleotide polymorphism (SNP) rs1360780, linked to FK506-binding protein 51 (FKBP5), has been shown to affect HPA axis functioning, and has thus been suggested as a promising candidate for indicating vulnerability to stress-related disorders. The aim of this study was to investigate the interaction between nicotine consumption and rs1360780 on cortisol plasma levels in females. A total of 296 female smokers (assessed by the Fagerström Test for Nicotine Dependence; FTND) were genotyped for the SNP rs1360780. We measured participants' cortisol plasma concentration in blood plasma collected 3 h after standardized tobacco smoking exposure. In the 36 TT-homozygotes, we found a significant negative correlation between the FTND sum score and cortisol plasma concentrations. Using linear regression analysis, we found that the FTND sum score accounted for 12.4% of the variance of cortisol plasma levels. This association was not detected in C-allele carriers. Our results suggest that nicotine is an important confounder in the modulation of HPA axis activity by FKBP5. In light of these findings, future studies on FKBP5 should seek to include data on nicotine consumption as a covariate.
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http://dx.doi.org/10.1111/ahg.12153DOI Listing
May 2016

Longitudinal Mapping of Gyral and Sulcal Patterns of Cortical Thickness and Brain Volume Regain during Early Alcohol Abstinence.

Eur Addict Res 2016 8;22(2):80-9. Epub 2015 Sep 8.

Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

We explored brain volume recovery in terms of cortical thickness (CTh; gyral, sulcal pattern) and surface area (SA), as well as subcortical volume recovery in the first 2 weeks of abstinence in 49 alcohol-dependent patients (ADPs). A widespread reduction of CTh in ADPs at day 1 of abstinence compared to healthy controls, with more pronounced differences in sulci relative to gyri was found. After 2 weeks of abstinence, partial recovery to varying degrees of CTh loss in ADPs was observed for several regions. The longitudinal CTh changes were greater in sulci than in gyri of affected regions. No longitudinal change in SAs and subcortical volumes was found. Alterations of CTh contribute to brain volume loss in alcoholism and recovery during early abstinence. Sulci seem to be more vulnerable to excessive alcohol consumption and to drive abstinence-induced volume recovery. During the initial 2 weeks of abstinence no subcortical volume regain was observed. Either the time span was too short or the lower subcortical volume could represent a predisposing trait marker.
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http://dx.doi.org/10.1159/000438456DOI Listing
July 2016

Effects of Cigarette Smoking on Plasma Concentration of the Appetite-Regulating Peptide Ghrelin.

Ann Nutr Metab 2015 18;66(2-3):155-61. Epub 2015 Apr 18.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany.

Background: Weight gain is a common but only a partially understood consequence of smoking cessation. Existing data suggest modulating effects of the orexigenic peptide ghrelin on food intake. The aim of the present study was to investigate the effect of tobacco withdrawal on plasma concentration of acetylated and total ghrelin.

Methods: Fifty four normal-weighted smokers and 30 non-smoking healthy controls were enrolled in our study. Concentrations of acetylated and total ghrelin were measured in blood plasma drawn two hours after a standardized meal and three hours after the smokers smoked their last cigarette. The severity of tobacco addiction was assessed based on cotinine plasma concentration, the Fagerström Test for Nicotine Dependence (FTND) and the number of cigarettes smoked per day.

Results: The plasma concentration of acetylated ghrelin, but not total ghrelin, was significantly higher in smokers than in non-smokers. Moreover, we found significant negative correlations between acetylated ghrelin and all measures of the severity of nicotine dependence.

Conclusions: Early abstinence from tobacco smoking seems to be associated with increased plasma concentration of the orexigenic peptide acetylated ghrelin. This could be one reason for increased food craving during nicotine withdrawal and subsequent weight gain. Smokers might compensate these effects by increasing tobacco intake.
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http://dx.doi.org/10.1159/000381834DOI Listing
January 2016

Optimized protocol for high resolution functional magnetic resonance imaging at 3T using single-shot echo planar imaging.

J Neurosci Methods 2015 Jan 29;239:170-82. Epub 2014 Oct 29.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany.

Background: To translate highly accelerated EPI-fMRI protocols as commonly used at ultra-high field strengths to clinical 3T settings.

New Method: EPI protocols with increasing matrix sizes and parallel imaging (PI) factors were tested in two separate fMRI studies, a simple motor-task and a complex motivation-task experiment with focus on the sensorimotor cortex (SMC) and the nucleus accumbens (NAcc), respectively.

Results: By increasing the matrix size and the PI-factor simultaneously, BOLD-sensitivity in terms of maximal t-values and numbers of activated clusters was uncompromised in single individuals in both fMRI experiments. In the SMC, the multi-subject analysis revealed an increase of 66% of the maximal t-value whereby the number of activated clusters was increased by a factor of 3.3 when the matrix size (PI-factor) was increased from 96×96 (R=2) to 192×192 (R=4). In the NAcc, the number of activated clusters increased from 5 to 7 whereby the maximal t-value remained unaffected when the matrix size (PI-factor) was increased from 96×96 (R=2) to 160×160 (R=3).

Comparison With Existing Method: Using the proposed high-resolution EPI protocol, spatial blurring was clearly reduced. Further, BOLD sensitivity was clearly improved in multi-subject analyses and remained unaffected in single individuals compared to using the standard protocols.

Conclusions: Conventionally used matrix sizes (PI-factors) might be non-optimal for some applications sacrificing BOLD spatial specificity. We recommend using the proposed high-resolution protocols applicable in detecting robust BOLD activation in fMRI.
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http://dx.doi.org/10.1016/j.jneumeth.2014.10.014DOI Listing
January 2015

Predicting naltrexone response in alcohol-dependent patients: the contribution of functional magnetic resonance imaging.

Alcohol Clin Exp Res 2014 Nov;38(11):2754-62

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany.

Background: Effect sizes of pharmacotherapy in alcoholism are modest. They might improve if subjects could be divided into more homogeneous subgroups and would then be treated targeted to their neurobiological profile. In such an effort, we tested neural cue reactivity as a potential predictor of treatment response to naltrexone. Alcohol-associated cues cause brain activations in mesocorticolimbic networks due to the positive reinforcing properties of alcohol. These activations were reported to be associated with relapse behavior. Naltrexone, an antagonist at the mu-opioid receptor, improves drinking behavior in some but not all patients probably by blocking the positive reinforcement of alcohol. Conversely, acamprosate is proposed to modulate negative reinforcement (withdrawal and cue-induced withdrawal). Identifying subjects with elevated cue reactivity and testing their response to medical treatment could thus improve our understanding of some of the mechanisms underlying pharmacotherapy response.

Methods: A picture-perception task featuring alcohol-related and neutral stimuli was presented to 64 recently detoxified alcohol-dependent patients. Patients came from 1 center of a larger double-blind randomized multicenter clinical trial (the "PREDICT Study"). They were scanned prior to being randomized to either naltrexone or acamprosate. We examined the interaction between medication and functional magnetic resonance imaging (fMRI) cue reactivity, as measured by the percentage of voxels activated, using the time to the first severe relapse as the outcome criterion. Our a priori formulated hypothesis was that naltrexone but not acamprosate should be efficacious in subjects with high cue reactivity.

Results: We observed an interaction effect between pretreatment brain activation induced by alcohol images and medication (acamprosate/naltrexone) on relapse behavior. In line with our hypothesis, this interaction was driven by treatment response to naltrexone in patients with elevated pretreatment cue reactivity in the ventral striatum.

Conclusions: fMRI has the potential for predicting treatment response to naltrexone in a subgroup of alcohol-dependent patients. However, this approach will be limited to researching the mechanisms and principles of treatment response.
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http://dx.doi.org/10.1111/acer.12546DOI Listing
November 2014

Association between alcohol-cue modulated startle reactions and drinking behaviour in alcohol dependent patients - results of the PREDICT study.

Int J Psychophysiol 2014 Dec 28;94(3):263-71. Epub 2014 Sep 28.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, D-68159 Mannheim, Germany. Electronic address:

Previous research on alcohol dependent patients has shown that variations in eyeblink startle response can be used as an indicator of their emotional responses to alcohol-related stimuli. Postulating that reactions on substance associated stimuli are controlled by either a negative or a positive affective processing system, we expect that abstinent alcoholics react differently (within-group) in the emotional evaluation of alcohol cues. Furthermore, we assumed the startle response to covary with medication response to acamprosate and naltrexone. We measured 74 detoxified inpatients' acoustic startle responses while they were being presented with alcohol-related images as well as affectively negative, neutral, and positive pictures before they were randomized to pharmacotherapy. Group-mean startle peak amplitudes were lowest for alcohol-related cues. The relative startle response (alcohol cues set in relation to the other stimulus categories) did not correlate with craving for alcohol (OCDS) or alcohol cue induced self-ratings of arousal, valence and craving. Patients with a lower percentage of abstinent days in the 90 days prior to the last drinking day showed a lower ("more appetitive") startle response to alcohol cues. A survival analysis using the time to first heavy drinking day as the survival criterion revealed a significant interaction between alcohol-cue startle responses and medication type. The results indicate that the psycho-physiological measure of emotional evaluation of alcohol cues includes unconscious processing not reflected by conscious self-ratings. Furthermore, our result of a differential medication effect may encourage further studies to use biological characteristics to stratify patients as a step towards individualized treatment for alcohol dependence.
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http://dx.doi.org/10.1016/j.ijpsycho.2014.09.009DOI Listing
December 2014

Brain activation induced by voluntary alcohol and saccharin drinking in rats assessed with manganese-enhanced magnetic resonance imaging.

Addict Biol 2015 Nov 22;20(6):1012-21. Epub 2014 Aug 22.

Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.

The neuroanatomical and neurochemical basis of alcohol reward has been studied extensively, but global alterations of neural activity in reward circuits during chronic alcohol use remain poorly described. Here, we measured brain activity changes produced by long-term voluntary alcohol drinking in the alcohol-preferring AA (Alko alcohol) rats using manganese-enhanced magnetic resonance imaging (MEMRI). MEMRI is based on the ability of paramagnetic manganese ions to accumulate in excitable neurons and thereby enhance the T1-weighted signal in activated brain areas. Following 6 weeks of voluntary alcohol drinking, AA rats were allowed to drink alcohol for an additional week, during which they were administered manganese chloride (MnCl2 ) with subcutaneous osmotic minipumps before MEMRI. A second group with an identical alcohol drinking history received MnCl2 during the abstinence week following alcohol drinking. For comparing alcohol with a natural reinforcer, MEMRI was also performed in saccharin-drinking rats. A water-drinking group receiving MnCl2 served as a control. We found that alcohol drinking increased brain activity extensively in cortical and subcortical areas, including the mesocorticolimbic and nigrostriatal dopamine pathways and their afferents. Remarkably similar activation maps were seen after saccharin ingestion. Particularly in the prelimbic cortex, ventral hippocampus and subthalamic nucleus, activation persisted into early abstinence. These data show that voluntary alcohol recruits an extensive network that includes the ascending dopamine systems and their afferent connections, and that this network is largely shared with saccharin reward. The regions displaying persistent alterations after alcohol drinking could participate in brain networks underlying alcohol seeking and relapse.
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http://dx.doi.org/10.1111/adb.12179DOI Listing
November 2015

Genetic variation in the atrial natriuretic peptide transcription factor GATA4 modulates amygdala responsiveness in alcohol dependence.

Biol Psychiatry 2014 May 4;75(10):790-7. Epub 2013 Nov 4.

Department of Addictive Behavior and Addiction Medicine (AJ, PB, KB, SV-K, MK, DH, KM, FK).

Background: Two genome-wide association studies recently showed alcohol dependence to be associated with a single-nucleotide polymorphism (rs13273672) located on a gene (GATA4) that encodes a transcription factor of atrial natriuretic peptide (ANP). A growing body of evidence suggests that ANP might be involved in the symptomology of alcohol dependence. This study examined whether reactivity to alcohol cues in the ANP target region amygdala, a key area implicated in addictive behavior, differs depending on the GATA4 genotype of a patient. We also investigated potential associations between these differences in amygdala activation and relapse behavior.

Methods: Eighty-one abstinent, alcohol-dependent patients completed a functional magnetic resonance imaging cue-reactivity task in a 3-Tesla scanner and provided blood samples for DNA extraction.

Results: The results showed significantly lower alcohol-cue-induced activations in G-allele carriers as compared with AA-homozygotes in the bilateral amygdala. A survival analysis revealed that a stronger alcohol-specific amygdala response predicted a lowered risk for relapse to heavy drinking in the AA-homozygotes, whereas this effect could not be observed in G-allele carriers.

Conclusions: These results illuminate potential underlying mechanisms of the involvement of the GATA4 gene in the etiology of alcohol dependence via its influence on ANP and amygdala processing.
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http://dx.doi.org/10.1016/j.biopsych.2013.10.020DOI Listing
May 2014

Damaging alcohol consumption: evidence based prevention on the WHO model can help.

Dtsch Arztebl Int 2013 Oct;110(42):701-2

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim and Clinic for Addiction Medicine and Addictive Behaviour, Klinikum Stuttgart.

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http://dx.doi.org/10.3238/arztebl.2013.0701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820991PMC
October 2013

The impact of atrial natriuretic peptide on anxiety, stress and craving in patients with alcohol dependence.

Alcohol Alcohol 2014 May-Jun;49(3):282-6. Epub 2013 Oct 27.

Corresponding author: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, J5, D-68159 Mannheim, Germany.

Aims: Atrial natriuretic peptide (ANP) is well known to modulate fluid and electrolyte homeostasis but also to counter-regulate hypothalamic-pituitary-adrenal (HPA) axis activity. Correspondingly, recent studies suggest an important role of ANP in the neurobiology of anxiety. Preclinical and clinical data now provide evidence for an involvement of ANP in the pathophysiology of addictive behavior. The present study aims to elucidate the effects of ANP on alcohol-dependent patients' anxiety, perceived stress and craving during alcohol withdrawal.

Methods: A sample of 59 alcohol-dependent inpatients was included in the analysis. A blood sample was taken at day 14 of detoxification in order to assess the concentrations of ANP and cortisol in plasma. In parallel, we assessed patients' alcohol craving, using the Obsessive Compulsive Drinking Scale, as well as anxiety (State-Trait Anxiety Inventory). Patients' stress levels were assessed using the Perceived Stress Scale.

Results: We found a significant negative association between patients' ANP plasma concentrations and anxiety, craving for alcohol and perceived stress. Regression analyses suggest that ANP is a significant predictor both for patients' perceived stress and for the severity of anxiety during early abstinence. The association of patients' ANP plasma levels and craving is suggested to be mediated by perceived stress.

Conclusion: Our results suggest that the association of patients' ANP plasma levels and craving is mediated by their perceived stress. For this reason, intranasal application of ANP may prove to be a new avenue for the treatment of alcohol dependence in patients exhibiting high levels of perceived stress.
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http://dx.doi.org/10.1093/alcalc/agt160DOI Listing
December 2014

Pregabalin abuse among opiate addicted patients.

Eur J Clin Pharmacol 2013 Dec 30;69(12):2021-5. Epub 2013 Aug 30.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, J5/68159, Mannheim, Germany,

Purpose: Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction. Thus, we hypothesized that pregabalin might be abused by patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds.

Methods: Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis.

Results: We found 12.1 % of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7 % of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety.

Conclusions: Our data suggest that pregabalin is liable to be abused among individuals with opiate dependency syndrome Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin.
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http://dx.doi.org/10.1007/s00228-013-1578-5DOI Listing
December 2013

Loss of control of alcohol use and severity of alcohol dependence in non-treatment-seeking heavy drinkers are related to lower glutamate in frontal white matter.

Alcohol Clin Exp Res 2013 Oct 25;37(10):1643-9. Epub 2013 Jun 25.

Department Neuroimaging , Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Background: The development and maintenance of alcohol use disorders (AUD) have been hypothesized to be associated with an imbalance of glutamate (GLU) homeostasis. White matter (WM) loss, especially in anterior brain regions, has been reported in alcohol dependence, which may involve disturbances in both myelin and axonal integrity. Frontal lobe dysfunction plays an important role in addiction, because it is suggested to be associated with the loss of control over substance use. This study investigated magnetic resonance spectroscopy (MRS)-detectable Glu levels in frontal WM of non-treatment-seeking heavy drinkers and its associations with AUD symptoms.

Methods: Single-voxel MR spectra optimized for Glu assessment (TE 80 ms) were acquired at 3T from a frontal WM voxel in a group of heavy drinking, non-treatment-seeking subjects in comparison with a group of subjects with only light alcohol consumption.

Results: The results corroborate previous findings of increased total choline in heavy drinking subjects. A negative association of Glu levels with severity of alcohol dependence and especially loss of control over time and amount of alcohol intake was observed.

Conclusions: In contrast to the rather unspecific rise in choline-containing compounds, low Glu in frontal WM may be specific for the shift from nondependent heavy drinking to dependence and does not reflect a simple effect of the amount of alcohol consumption alone.
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http://dx.doi.org/10.1111/acer.12149DOI Listing
October 2013
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