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.

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

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.

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

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.

Experience of social discrimination correlates with neurometabolism: a pilot study in heroin addicts.

Experimental social neuroscience has shown that being socially excluded is processed in the anterior cingulate cortex (ACC). We hypothesize that a chronic form of social exclusion resembling one aspect of social stigmatization is associated with altered neural plasticity reflected by neurometabolic alterations in the ACC. To test this hypothesis, a highly stigmatized patient group of heroin addicts (N = 15) during opiate maintenance therapy rated a questionnaire about being stigmatized, and neurometabolic markers in the ACC were determined using (1)H MR spectroscopy. We found a negative correlation between discrimination experience and N-acetylaspartate (NAA), indicating attenuated neuron functioning in the anterior cingulate cortex in those patients reporting high discrimination experience. Furthermore, perceived stigmatization showed an association with anxiety that was mediated by NAA. Although the correlative analysis cannot give evidence for a causal relationship, the relation of NAA in the ACC and discrimination experience indicates a malfunction of the neural system involved in cognitive control over emotionally relevant social stimuli in discrimination reporting heroin addicts. Further research is needed to elucidate factors associated with chronic stigmatization.

[Pregabalin for the reduction of opiate withdrawal symptoms]. / Pregabalin zur Reduktion von Opiatentzugssymptomen.

Pregabalin is a substance which modulates monoamine release in "hyper-excited" neurons. It binds potently to the α2-δ subunit of calcium channels. Pilotstudies on alcohol- and benzodiazepine dependent patients reported a reduction of withdrawal symptoms through Pregabalin. To our knowledge, no studies have been conducted so far assessing this effect in opiate dependent patients. We report the case of a 43-year-old patient with Pregabalin intake during opiate withdrawal. Multiple inpatient and outpatient detoxifications from maintenance replacement therapy with Buprenorphine in order to reach complete abstinence did not show success because of extended withdrawal symptoms and repeated drug intake. Finally he disrupted his heroine intake with a simultaneously self administration of 300  mg Pregabaline per day and was able to control the withdrawal symptoms. In this time we did control the Pregabalin level in serum and urine in our outpatient clinic. In the course the patient reported that he could treat further relapse with opiate or opioids with Pregabalin successful. This case shows first details for Pregabalin to relief withdrawal symptoms in opiate withdrawal.

Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: a critical review.

Cannabis use and the development of schizophrenic psychoses share a variety of similarities. Both start during late adolescence; go along with neuropsychological deficits, reduced activity, motivation deficits, and hallucinations suggesting impairment of similar brain structures. In cannabis heavy users diminished regional gray and white matter volume was reported. Similar alterations were observed in the large literature addressing structural abnormalities in schizophrenia. Furthermore, in cannabis using schizophrenic patients, these brain alterations were especially pronounced. Close relatives of schizophrenic patients showed greater cannabis-associated brain tissue loss than non-relatives indicating a genetically mediated particular sensitivity to brain tissue loss. Possible mechanisms for the induction of structural brain alterations are here discussed including impairments of neurogenesis, disturbance of endocannabinoids and diminished neuroplasticity. Especially direct THC effects (or via endocannabinoids) may mediate diminished glutamatergic neurotransmission usually driving neuroplasticity. Correspondingly, alterations of the kynurenic acid blocking NMDA receptors may contribute to brain structure alterations. However, different cannabis compounds may exert opposite effects on the neuroanatomical changes underlying psychosis. In particular, cannabidiol (CBD) was shown to prevent THC associated hippocampal volume loss in a small pilot study. This finding is further supported by several animal experiments supporting neuroprotective properties of CBD mainly via anti-oxidative effects, CB2 receptors or adenosine receptors. We will discuss here the mechanisms by which CBD may reduce brain volume loss, including antagonism of THC, interactions with endocannabinoids, and mechanisms that specifically underlie antipsychotic properties of CBD.

MR spectroscopy in opiate maintenance therapy: association of glutamate with the number of previous withdrawals in the anterior cingulate cortex.

Pre-clinical research indicates that opioids reduce extracellular glutamate in acute opioid treatment, whereas during withdrawal, glutamatergic neurotransmission is increased and withdrawal symptoms can be blocked by glutamate receptor antagonists. The glutamate hypothesis of addiction suggests that withdrawal-associated hyperglutamatergic states destabilize the glutamatergic system chronically and contribute to relapse. magnetic resonance spectroscopy at three tesla optimized for glutamate assessment (TE 80 ms) was performed in the anterior cingulate gyrus (ACC) and frontal white matter (fWM) of 17 opiate-dependent patients during opiate maintenance therapy and 20 healthy controls. Controlling for age and gray matter content, glutamate in the ACC was positively associated with the number of previous withdrawals. For glutamate + glutamine (Glx), a significant group-age interaction was found. Whereas Glx declines with age in healthy controls, Glx increases with age in opiate-dependent patients. The number of previous withdrawals did not correlate with age. In fWM spectra, increased Cho concentrations were observed in opiate-dependent patients. Both new findings, the positive correlation of glutamate and previous withdrawals and increasing Glx with age in contrast to an age-dependent Glx decrease in controls indicate a destabilization of the glutamate system in opiate-dependent patients and support the glutamate hypothesis of addiction. Increased Cho concentrations in fWM corroborate findings of WM abnormalities in opioid-dependent subjects.

The vicious circle of perceived stigmatization, depressiveness, anxiety, and low quality of life in substituted heroin addicts.

BACKGROUND: Perceived stigmatization of drug addicts may interact with negative mood states and thus may contribute to the maintenance of addictive behavior. METHODS: Opiate maintenance patients (n = 106) and an unselected comparison group (n = 144) rated self-report questionnaires about perceived stigmatization, quality of life (QoL), depressiveness, anxiety, self-esteem, addiction characteristics, and social support. RESULTS: 63% of opiate maintenance patients felt discriminated in contrast to 16% of the comparison group. Perceived stigmatization was rated higher by opiate maintenance patients, and all domains of QoL were rated lower, even when statistically controlling depressiveness, anxiety and social factors. Perceived stigmatization was correlated to depressiveness, anxiety, low self-esteem and low QoL, but not addiction characteristics and social support. Structural equation models revealed anxiety and the pathway depressiveness enhancing feelings of being stigmatized resulting in low self-esteem to explain 74% of variance in mental QoL, whereas anxiety and a pathway stigmatization inducing depressiveness leading to low self-esteem explained 49% of variance in physical QoL. CONCLUSIONS: A vicious circle of stigmatization, negative affective states and low QoL was confirmed. In addition to societal antistigma campaigns, antidepressive and anxiolytic therapy might have the potential to diminish feelings of being stigmatized and to improve QoL.

The effect of pictorial warnings on cigarette packages on attentional bias of smokers.

Given that previous studies demonstrated that smoking-related cues (like cigarette packages) grab the attention of smokers and thereby contribute to craving and tobacco seeking we investigated how pictorial health warnings presented on cigarette packages affect attention allocation towards cigarette packages. The WHO advises the use of pictorial health warnings on cigarette packages. However, at present no experimental studies are available investigating if pictorial warnings modulate incentive properties of cigarette packages. Fifty-nine tobacco smokers and 55 non-smokers performed a visual dot probe task to assess attention allocation towards cigarette packages with and without health warnings. Smokers were divided a priori in a group of light smokers (<20 cigarettes/day; n=39) and heavy smokers (≥20 cigarettes/day; n=20). Psychometric measures on anxiety and nicotine craving were administered. Light smokers showed an attentional bias towards packages without pictorial warnings while no effects were observed in the other groups. In heavy smokers attention allocation towards pictorial health warnings was associated with an increase of craving and anxiety. The results have a potential public health perspective as pictorial health warnings might be an effective strategy to reduce attentional bias towards cigarette packages of light smokers, while counterproductive effects in heavy smokers warrant further investigation.

Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol.

BACKGROUND: Chronic cannabis use has been associated with memory deficits and a volume reduction of the hippocampus, but none of the studies accounted for different effects of tetrahydrocannabinol (THC) and cannabidiol (CBD). METHODS: Using a voxel based morphometry approach optimized for small subcortical structures (DARTEL) gray matter (GM) concentration and volume of the hippocampus were measured in 11 chronic recreational cannabis users and 13 healthy controls, and correlated with THC and CBD from hair analyses. GM volume was calculated by modulating VBM using Jacobian determinants derived from the spatial normalization. RESULTS: Cannabis users showed lower GM volume located in a cluster of the right anterior hippocampus (P(uncorr)=0.002; effect size Cohen's d=1.34). In a regression analysis an inverse correlation of the ratio THC/CBD with the volume of the right hippocampus (P(uncorr) p<0.001, Cohen's d=3.43) was observed. Furthermore Cannabidiol correlated positively with GM concentration (unmodulated VBM data), but not with GM volume (modulated VBM) in the bilateral hippocampus (P=0.03 after correction for hippocampal volume; left hippocampus Cohen's d=4.37 and right hippocampus 4.65). CONCLUSIONS: Lower volume in the right hippocampus in chronic cannabis users was corroborated. Higher THC and lower CBD was associated with this volume reduction indicating neurotoxic effects of THC and neuroprotective effects of CBD. This confirms existing preclinical and clinical results. As a possible mechanism the influence of cannabinoids on hippocampal neurogenesis is suggested.

Urinary ethylglucuronide assessment in patients treated with disulfiram: a tool to improve verification of abstention and safety.

AIM: Disulfiram has been shown to be efficacious and safe in the treatment of alcohol relapse prevention. However, drinking alcohol while taking disulfiram can be harmful because of the resulting alcohol-disulfiram reaction/acetaldehyde reaction. Alcohol consumption of patients receiving a low disulfiram dose or low alcohol consumption in normal disulfiram dose can result in subclinical alcohol-disulfiram reactions. This undermines the learning of alcohol-associated punishment, might increase the risk to raise alcohol consumption, and can result in chronic acetaldehyde exposure, which has carcinogenic, neurotoxic, and cardiotoxic properties. Therefore, the use of an alcohol marker monitoring retrospective alcohol use is tested in this study. METHOD: A total of 51 patients being treated with supervised disulfiram were unheralded measured for ethylglucuronide (EtG) if they attended at least for 2 weeks in the outpatient treatment program. Ethylglucuronide was measured with liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS). Detection limit was 0.1 mg/L. RESULTS: Urinary EtG was found positive in 5.9% (3/51) of the patients. Regularly conducted breathalyzer tests had been continuously negative in these patients. Moreover, vegetative withdrawal symptoms had not been found in these patients. Two of the positive EtG tests could be classified as covered relapses, whereas the third remained unclear but showed a negative EtG in a repetition of the test few days later. CONCLUSIONS: Unheralded urinary EtG monitoring improved verification of abstinence in patients treated with disulfiram, was helpful in detecting covered consumption of alcoholic beverages or hidden alcohol exposition (eg, fruit juice or personal care products), and thereby improved safety by preventing chronic acetaldehyde reaction.

Reduced affective symptoms during tobacco dependence treatment with varenicline.

BACKGROUND: The nicotinic acetylcholine receptor partial agonist varenicline has been shown to be effective in the treatment of tobacco dependence, but has been reported to induce exacerbations of psychiatric symptoms in subjects with pre-existing psychiatric disorders. CASE DESCRIPTION: We report a tobacco-dependent patient who developed depression and suicidal tendencies during several cessation attempts, but was finally able to stay nicotine-abstinent by taking varenicline. CONCLUSION: In this case varenicline did not lead to exacerbation but appeared to improve the affective symptoms.