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Clinical research has demonstrated the efficacy of injectable opioid treatment for long-term, treatment-refractory opioid-dependent patients. It has been hypothesized that compulsive drug use is particularly associated with neuroplasticity changes in the networks corresponding to withdrawal/negative affect and preoccupation/anticipation rather than binge/intoxication. However, as yet, no study has investigated the effect of long-term opioid treatment on key regions within these networks. Magnetic resonance imaging (MRI) was used to assess brain volumes changes during long-term (approximately 9 years) injectable opioid agonist treatment with diacetylmorphine (DAM) in 22 patients with opioid use disorder. Voxel-based morphometry was applied to detect volumetric changes within the networks of binge/intoxication (ventral/dorsal striatum, globus pallidus and thalamus), withdrawal/negative affect (amygdala and ventral striatum) and preoccupation/anticipation (hippocampus, orbitofrontal and anterior cingulate cortex). The relationships between significant volume changes and features of opioid use disorder were tested using Pearson correlation. Long-term opioid agonist treatment was associated with the enlargement of the right caudate nucleus, which was related to the duration of opioid use disorder. In contrast, reduced volume in the right amygdala, anterior cingulate cortex and orbitofrontal cortex were found that were related to opioid dose, onset of opioid consumption and state anxiety. These findings suggest that long-term opioid agonist treatment is related to structural changes in key brain regions underlying binge/intoxication, withdrawal/negative affect and preoccupation/anticipation, suggesting sustained interaction between these systems.

The compulsion to seek and use heroin is frequently driven by stress and craving during drug-cue exposure. Although previous neuroimaging studies have indicated that craving is mediated by increased prefrontal cortex activity, it remains unknown how heroin administration modulates the prefrontal cortex response. This study examines the acute effects of heroin on brain function in heroin-maintained patients. Using a crossover, double-blind, placebo-controlled design, 27 heroin-maintained patients performed functional magnetic resonance imaging 20 minutes after the administration of heroin or placebo (saline) while drug-related and neutral stimuli were presented. Images were processed and analysed with statistical parametric mapping. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography. Region of interest analyses showed a drug-related cue-associated blood-oxygen-level-dependent activation in the orbitofrontal cortex (OFC) in heroin-dependent patients during both treatment conditions (heroin and placebo). This activation of the OFC was significantly higher after heroin than after placebo administration. These findings may indicate the importance of OFC activity for impulse control and decision-making after regular heroin administration and may emphasize the benefit of the heroin-assisted treatment in heroin dependence.

Research suggests that alpha-synuclein (SNCA) and NACP-Rep1, a polymorphic complex microsatellite repeat ~10 kb upstream of the SNCA gene translational start, may be involved in substance-use behaviors and craving. This study was the first to examine the effects of diacetylmorphine (DAM) on peripheral SNCA protein expression along with craving in opiate-dependent patients and to compare their NACP-Rep1 allele lengths with those of healthy controls. Using an experimental design, opiate-dependent patients on injectable heroin maintenance were investigated at four time points, twice pre- and post-injection of DAM. SNCA protein levels of 30 DAM-maintained patients were measured using enzyme-linked immunosorbent assay. Participant-rated effects were assessed in 42 patients by Tiffany's Heroin Craving Questionnaire (HCQ), Gossop's Short Opiate Withdrawal Scale and Visual Analogs. NACP-Rep1 alleles of 42 patients and 101 controls were analyzed. One-way repeated-measures ANOVAs provided significant overall effects for SNCA protein content (P = 0.028), craving (P

Heroin dependence (HD) is a chronic relapsing brain disorder characterized by a compulsion to seek and use heroin. Stress is seen as a key factor for heroin use. Methadone maintenance and the prescription of pharmaceutical heroin [diacetylmorphine (DAM)] are established treatments for HD in several countries. The present study examined whether DAM-maintained patients and methadone-maintained patients differ from healthy controls in startle reflex and cortisol levels. Fifty-seven participants, 19 of each group matched for age, sex and smoking status, completed a startle session which included the presentation of 24 bursts of white noise while eye-blink responses to startling noises were recorded. Salivary cortisol was collected three times after awakening, before, during and after the startle session. DAM was administered before the experiment, while methadone was administered afterwards. Both heroin-dependent patient groups exhibited significantly smaller startle responses than healthy controls (P < 0.05). Whereas the cortisol levels after awakening did not differ across the three groups, the experimental cortisol levels were significantly lower in DAM-maintained patients, who received their opioid before the experiment, than in methadone-maintained patients and healthy controls (P < 0.0001). Opioid maintenance treatment for HD is associated with reduced startle responses. Acute DAM administration may suppress cortisol levels, and DAM maintenance treatment may represent an effective alternative to methadone in stress-sensitive, heroin-dependent patients.

Phosphatidylethanol (PEth) is a direct ethanol metabolite, and has recently attracted attention as biomarker of ethanol intake. The aims of the current study are: (1) to characterize the normalization time of PEth in larger samples than previously conducted; (2) to elucidate potential gender differences; and (3) to report the correlation of PEth with other biomarkers and self-reported alcohol consumption. Fifty-seven alcohol-dependent patients (ICD 10 F 10.25; 9 females, 48 males) entering medical detoxification at three study sites were enrolled. The study sample was comprised of 48 males and 9 females, with mean age 43.5. Mean gamma glutamyl transpeptidase (GGT) was 209.61 U/l, average mean corpuscular volume (MCV) was 97.35 fl, mean carbohydrate deficient transferrin (%CDT) was 8.68, and mean total ethanol intake in the last 7 days was 1653 g. PEth was measured in heparinized whole blood with a high-pressure liquid chromatography method, while GGT, MCV and %CDT were measured using routine methods. PEth levels at day 1 of detoxification ranged between 0.63 and 26.95 micromol/l (6.22 mean, 4.70 median, SD 4.97). There were no false negatives at day 1. Sensitivities for the other biomarkers were 40.4% for MCV, 73.1% for GGT and 69.2% for %CDT, respectively. No gender differences were found for PEth levels at any time point. Our data suggest that PEth is (1) a suitable intermediate term marker of ethanol intake in both sexes; and (2) sensitivity is extraordinary high in alcohol dependent patients. The results add further evidence to the data that suggest that PEth has potential as a candidate for a sensitive and specific biomarker, which reflects longer-lasting intake of higher amounts of alcohol and seemingly has the above mentioned certain advantages over traditional biomarkers.

As, for ethical reasons, it is difficult to investigate by an experiment the effect of acute intoxication on leptin levels in alcoholics, we tested the hypothesis of lowered levels as an effect of acute ethanol intake inhealthy volunteers. The subjects comprised (1) 17 healthy male participants, recruited via newspaper advertisements [age 29 + 3.75 years, body mass index (BMI) 24.3 + 3.5, leptin at baseline 3.3 + 3.1 ng/ml]; (2) for comparison, leptin levels of 16 male alcoholic patients at day I of withdrawal were used. They were characterized as follows: (mean, median, standard deviation and range) age in years (41.1, 40.5, 10.2, 24, 57), BMI (23.3, 21.7, 5.4, 16.6, 37.5), 1032g of ethanol (median) consumed within the last 7 days, leptin levels 2.3mglml. A placebo-controlled double-blind trial teas performed. Leptin levels of blood samples were taken at baseline (t 1 ), before ethanol intake (t 2 ), when blood alcohol had reached its maximum (t 3 ) and the morning after (t 4 ). The oral dose of ethanol administered was 0.6 g/kg ethanol. (1) Volunteers: (a) the ethanol and placebo group exhibited leptin levels corresponding closely with levels measured at baseline (t 1 ) (rs = 0.85, p < 0.0001) and follow-up (t 4 ) (r s = 0.768, p < 0.0001). (b) Leptin levels for the placebo and the alcohol-consuming (verum) group did not differ significantly at baseline, after ethanol intake or on the morning after [Mann - Whitney U-test (p = 0.669, p = 1.0 and p = 0.887, respectively)]. (2) Leptin levels in relation to BMI did not significantly differ at any measurement time in either group. (3) Leptin levels/BMI of the healthy volunteers at t 1 and t 4 were not significantly different from those of 16 alcoholics. The data do not support the hypothesis of a significant effect of acute moderate alcohol intake on leptin levels in healthy volunteers.

The compulsion to seek and use heroin is frequently driven by stress and craving during drug-cue exposure. Although previous neuroimaging studies have indicated that craving is mediated by increased prefrontal cortex activity, it remains unknown how heroin administration modulates the prefrontal cortex response. This study examines the acute effects of heroin on brain function in heroin-maintained patients. Using a crossover, double-blind, placebo-controlled design, 27 heroin-maintained patients performed functional magnetic resonance imaging 20 minutes after the administration of heroin or placebo (saline) while drug-related and neutral stimuli were presented. Images were processed and analysed with statistical parametric mapping. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography. Region of interest analyses showed a drug-related cue-associated blood-oxygen-level-dependent activation in the orbitofrontal cortex (OFC) in heroin-dependent patients during both treatment conditions (heroin and placebo). This activation of the OFC was significantly higher after heroin than after placebo administration. These findings may indicate the importance of OFC activity for impulse control and decision-making after regular heroin administration and may emphasize the benefit of the heroin-assisted treatment in heroin dependence.

Research suggests that alpha-synuclein (SNCA) and NACP-Rep1, a polymorphic complex microsatellite repeat ~10 kb upstream of the SNCA gene translational start, may be involved in substance-use behaviors and craving. This study was the first to examine the effects of diacetylmorphine (DAM) on peripheral SNCA protein expression along with craving in opiate-dependent patients and to compare their NACP-Rep1 allele lengths with those of healthy controls. Using an experimental design, opiate-dependent patients on injectable heroin maintenance were investigated at four time points, twice pre- and post-injection of DAM. SNCA protein levels of 30 DAM-maintained patients were measured using enzyme-linked immunosorbent assay. Participant-rated effects were assessed in 42 patients by Tiffany's Heroin Craving Questionnaire (HCQ), Gossop's Short Opiate Withdrawal Scale and Visual Analogs. NACP-Rep1 alleles of 42 patients and 101 controls were analyzed. One-way repeated-measures ANOVAs provided significant overall effects for SNCA protein content (P = 0.028), craving (P0.001), withdrawal symptomatology (P0.001) and mood (P0.001), indicating that DAM injections may not only reduce craving but also SNCA protein expression. However, there was no association between protein expression and craving. Relative to controls, patients had significantly longer NACP-Rep1 alleles (P0.001). NACP-Rep1 allele lengths correlated positively with HCQ total scores averaged across all time points (r = 0.420; P = 0.006) as well as with post-DAM HCQ total scores in the morning (r = 0.488, P = 0.001) and afternoon (r = 0.423, P = 0.005). The findings provide evidence of a contributory role of SNCA and NACP-Rep1 for opiate dependence.

Heroin dependence (HD) is a chronic relapsing brain disorder characterized by a compulsion to seek and use heroin. Stress is seen as a key factor for heroin use. Methadone maintenance and the prescription of pharmaceutical heroin [diacetylmorphine (DAM)] are established treatments for HD in several countries. The present study examined whether DAM-maintained patients and methadone-maintained patients differ from healthy controls in startle reflex and cortisol levels. Fifty-seven participants, 19 of each group matched for age, sex and smoking status, completed a startle session which included the presentation of 24 bursts of white noise while eye-blink responses to startling noises were recorded. Salivary cortisol was collected three times after awakening, before, during and after the startle session. DAM was administered before the experiment, while methadone was administered afterwards. Both heroin-dependent patient groups exhibited significantly smaller startle responses than healthy controls (P0.05). Whereas the cortisol levels after awakening did not differ across the three groups, the experimental cortisol levels were significantly lower in DAM-maintained patients, who received their opioid before the experiment, than in methadone-maintained patients and healthy controls (P0.0001). Opioid maintenance treatment for HD is associated with reduced startle responses. Acute DAM administration may suppress cortisol levels, and DAM maintenance treatment may represent an effective alternative to methadone in stress-sensitive, heroin-dependent patients.

This study was conducted to identify the alcohol consumption among hepatitis C-positive people receiving opioid maintenance therapy using self-report and biomarkers. A total of 49 people (28 male, 21 female) were hepatitis C virus (HCV) positive and were included. The alcohol use disorder identification test (AUDIT) and self-reported ethanol intake in the last 28 days were assessed. In addition to gamma-glutamyl-transferase (GGT) and mean corpuscular volume (MCV), ethyl glucuronide (EtG) and ethyl sulphate (EtS) were determined in serum and urine (UEtG, UEtS, SEtG) using liquid chromatography/tandem mass-spectroscopy (LC/MS-MS) with deuterated internal standards. Abstinence from alcohol was reported for the last 28 days by 13 participants and for the last 7 days by 22. AUDIT was8 in 27 cases. The maximum values were 34.8 mg/l for UEtG, 5.3 mg/l for UEtS and 0.15 for SEtG. Among the 19 UEtG positives, 8 had not reported any ethanol intake in the 7 days prior to the study. Six participants reported intake of up to 320 g of ethanol in the last 7 days, but were negative for SEtG, UEtG and UEtS. Self-reported ethanol intake in the last 28 days correlated with AUDIT score (r = 0.733, P0.001), with the direct ethanol metabolites and MCV. In this population, abstinence and episodic heavy drinking are more common than in the general population. Episodic heavy drinking is a significant cause of acute risk in this population. Results from biomarker testing could indicate cases of under- as well as over-reporting of alcohol consumption. Further research on the diagnostic accuracy of direct ethanol metabolites, including the use of phosphatidylethanol (PEth), in this setting is needed.

Phosphatidylethanol (PEth), a direct ethanol metabolite, is detectable in blood for more than 2 weeks after sustained ethanol intake. Our aim was to assess the usefulness of PEth [comparing sensitivity, specificity and the area under the curve (AUC)] as compared with carbohydrate-deficient transferrin (CDT), gamma-glutamyl transpeptidase (GGT) and mean corpuscular volume (MCV), calculating the results from sober patients against those from alcohol-dependent patients during withdrawal. Fifty-six alcohol-dependent patients (ICD-10 F 10.25) in detoxification, age 43 years, GGT 81 U/l, MCV 96.4 fl, %CDT 4.2, 1400 g ethanol intake in the last 7 days (median), were included in the study. Over the time of 1 year, 52 samples from 35 sober forensic psychiatric addicted in-patients [age 34 years, GGT 16 U/l, MCV 91 fl, CDT 0.5 (median)] in a closed ward were drawn and used for comparison . PEth was measured in heparinized whole blood with a high-performance liquid chromatography method. GGT, MCV and %CDT were measured using routine methods. A receiver operating characteristic curve analysis was carried out, with 'current drinking status' (sober/drinking) as the state variable and PEth, MCV, GGT and CDT as test variables. The resulting AUC was 0.974 (P < 0.0001, confidence interval 0.932-1.016) for PEth. At a cut-off of 0.36 micromol/l, the sensitivity was 94.5% and specificity 100%. The AUC for CDT, GGT and MCV were 0.931, 0.894 and 0.883, respectively. A significant Spearman's rank correlation was found between PEth and GGT (r = 0.739), CDT (r = 0.643), MVC (r = 0.639) and grams of ethanol consumed in the last 7 days (r = 0.802). Our data suggest that PEth has potential to be a sensitive and specific biomarker, having been found in previous studies to indicate longer lasting intake of higher amounts of alcohol.

Alcohol-dependent patients face a substantial risk of relapse after detoxification. A major risk factor for relapse is stress which is reflected biologically by various physiological changes that include an activation of the hypothalamic-pituitary-adrenal (HPA) axis and release of glucocorticoids. The prospective study examined cortisol concentrations and stress-coping styles in relation to abstinence 1 year following discharge from treatment. Cortisol concentrations were measured in the plasma of 46 alcohol-dependent patients (12 women) on initial presentation for treatment (day 1), and again in plasma and in cerebrospinal fluid (CSF) after 6 weeks of abstinence (day 40). These results were compared with those of 26 age- and sex-matched, healthy control subjects. After withdrawal, the patients completed a comprehensive baseline assessment including a stress-coping questionnaire (Stressverarbeitungsfragebogen SVF120) and were monitored for 1 year after discharge. Negative stress-coping styles (e.g. flight, resignation) positively correlated with higher cortisol concentration in plasma and in CSF after withdrawal (day 40). Compared with relapsers after 1 year, abstainers had significantly lower levels for cortisol in CSF, whereas the stress-coping styles did not differ between abstainers and relapsers in this sample. These findings suggest that relatively stable personality traits like stress-coping styles have no measurable influence on abstinence. The lower cortisol concentration in CSF as an indicator for HPA axis functioning is associated with long-term abstinence in detoxified alcoholics.

This study sought to examine dopamine receptor sensitivity among alcoholics in vivo and to explore whether this sensitivity might be associated with functional variations of dopamine D2(DRD2) and D3(URD3) receptor genes along with a genetic predisposition for alcoholism as reflected by an alcohol-dependent first-degree relative. We analyzed the -141C Ins/Del polymorphism in the promoter region of the DRD2 gene and the Ser 9 Gly (BolI) (polymorphism in exon 1 of the DRD3 gene in 74 alcohol-dependent Caucasian men with or without genetic predisposition for alcoholism. In vivo dopamine receptor sensitivity was assessed by measuring apomorphine-induced growth hormone release. A three-way analysis of variance revealed no significant effects of DRD2, DRD3 genotypes and genetic predisposition on dopamine receptor sensitivity. Given the explorative and preliminary character of this investigation, we cannot provide evidence that in alcohol-dependent Caucasian men a genetic predisposition for alcoholism along with functional variants of the DRD2 and DRD3 genes are associated with differences in dopamine receptor sensitivity.