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Projekte: Translationale Psychopharmakologie

Meinhardt M. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg : Einrichtung eines 3R-Zentrums im Rhein-Neckar Raum . 12/2020-11/2025.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01KC2004A: AhEAD Preclinical Phase II Assessment of Exosomes in Alcohol Addiction. 11/2020-10/2023.

Worldwide two billion people drink alcohol regularly. A major health consequence is alcohol addiction that is characterized by chronic relapses. Preventing relapse is the main treatment goal. Current pharmacological treatments have limited efficacy, thus better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. One major hypothesis in alcohol research is that chronic alcohol intake leads to neuroinflammation that in turn triggers addictive behaviour. It has been shown that intranasal delivery of mesenchymal stem cell-derived exosomes reduces relapse behaviour in rats. Here we propose a multi-center placebo-controlled trial in rats as a preclinical confirmatory proof. We aim to confirm the hypothesis that treatment with exosomes will have long-lasting positive effects on relapse behaviour in animal models of alcohol addiction. The preclinical trial design will follow the guidelines on the development of medicinal products for the treatment of alcohol addiction provided by the European Medicines Agency (EMA), will adhere to the standards proposed for confirmatory biomedical research (Dirnagl, 2016) for nonclinical laboratory studies, and publication of the results will follow the ARRIVE guidelines. An independent third-party company focusing on the evaluation of data quality and practice in biomedical research will ensure adequate quality management and monitoring of our preclinical trial at the best possible level.

Meinhardt M. DFG - Deutsche Forschungsgemeinschaft ME 5279/3-1: Scrutinizing an epigenetic driven dysregulation of prefrontal mGluR2 function in alcohol dependence . 10/2020-09/2023.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB/Transregio 265 : Teilprojekt A05: Intensive behavioral monitoring and dynamical state transitions in animal models of addiction. 07/2019-06/2023.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB/Transregio 265: Teilprojekt B08: Aversion discounting in animal models and human addiction. 07/2019-06/2023.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 031L0190A : Target-OXY - Towards Targeted Oxytocin Treatment in Alcohol Addiction. 06/2019-05/2022.

Worldwide two billion people drink regularly alcohol. A major health consequence is alcohol addiction that is characterized by chronic relapses. Preventing relapse is the main Treatment goal. Current pharmacological treatments have limited effectiveness and there is a large heterogeneity in the treatment response. Better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. In our e:Med funded SysMedAlcoholism consortium we have identified early warning signs and drinking profiles that predict future relapse behavior and treatment response of clinically used anti-relapse medications. We have also identified in a multi-omics approach alterations in the oxytocin (OXY) system in alcoholic patients suggesting OXY as a candidate medication to reduce relapse. Here our Goals are (i) to demonstrate the clinical applicability of OXY and (ii) to computationally predict elapse and identify treatment responsive individuals. For the demonstration of the clinical applicability of OXY, we propose a new module in the drug development process, namely a preclinical multicenter placebo controlled trial in rats with a step-wise translation into a naturalistic pilot trial with ambulatory assessment in alcoholic patients. As a comparator, we will use datasets from previous trials where we tested placebo vs acamprosate – which is a clinically effective medication. These data will be contrasted with a 3-arm design in male and female alcohol addicted rats where two doses of intranasally applied OXY will be tested against placebo in a well-validated rat model for alcohol addiction. From this preclinical trial we will obtain intensive longitudinal data (ILD) sets on drinking and activity. Using new in silico approaches we will then be able to identify early warnings signs and drinking clusters for relapse and OXY treatment responsive individuals. This preclinical work will guide our naturalistic Trial with ambulatory assessment in alcoholic patients.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01EW1908: PsiAlc - Preclinical Phase II Testing of Psilocybin in Alcohol Addiction and Epigenetic and Neuroimaging Studies on the Mode of Action. 05/2019-04/2022.

Alcohol use disorders create the largest health burden globally. Alcohol addiction in particular is a chronic disease characterized by dysfunctional behavior and impairment in quality of life, and thus represents a tremendous burden for the patient, health care services, and the general society. Current pharmacological treatment approaches have limited effectiveness. Due to the need for more efficacious treatments and encouraging safety and feasibility data, scientific interest in the potential clinical benefits of serotonergic hallucinogens such as psilocybin has recently returned, and here we wish to study the effects of psilocybin on alcohol relapse behavior and its underlying neurobiological mechanisms. Prior to time-intensive discussions with regulatory bodies, dose determination and finally cost-intensive phase II clinical testing for psilocybin in alcoholics, we propose for the first time with respect to mental disorders a preclinical multi-center placebo controlled trial in rats with a step-wise translation into alcoholic patients. Our preliminary experiment indicates that psilocybin reduces relapse behavior in rats and we hypothesize that a single administration of psilocybin will have long-lasting effects on relapse behavior. We will use a 4-arm design: placebo vs. acamprosate - a clinically effective medication used as a reference compound - vs. two doses of psilocybin will be tested in our DSM5-based rat model for alcohol addiction. The entire preclinical trial design will follow the guidelines on the development of medicinal products for the treatment of alcohol addiction provided by the European Medicines Agency (EMA) and will adhere to Good Laboratory Practice (GLP) for nonclinical laboratory studies. As preclinical and clinical evidence suggests that sex and gender influence disease trajectories and interventions in alcoholics, male and female rats will be studied in direct comparison in our 4-arm design. Therefore, the first aim of our proposal is to test the long-lasting efficacy of psilocybin in male and female subjects on relapse behavior. Many studies on psilocybin in humans describe very long-lasting positive effects on disease trajectories and quality of life. How can such long-lasting effects be explained and what is the mode of action of psilocybin? Epigenetic effects occur as one possible candidate mechanism, and at a higher systems level, restoration of normal network function in the diseased brain is another candidate. Here we propose to study genome-wide alterations in methylation and transcription in a longitudinal fashion in alcohol addicted rats and humans following a single application of psilocybin. We will also examine resting state activity longitudinally (using rs-fMRI) and subsequent alterations in reward processing in alcohol addicted rats and humans following a single application of psilocybin. Therefore, the second aim of our proposal is to provide translational information on the epigenetic, transcriptional, functional brain network, and behavioral levels to understand the neurobiological underpinnings and mode of action of psilocybin in the alcohol addicted brain.


Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de