Work-Package 1

Efficacy of psilocybin in a unique DSM-5 based rat model (WP1leader Spanagel)

 

Background and rationale: Has been provided in detail in section 1&2A.

 

Working hypothesis: We hypothesize that a single administration of psilocybin will have a long-lasting relapse preventing effect in alcohol addicted rats.

 

Major goals: To conduct a preclinical multi-center phase II trial in alcohol addicted rats in order to test the efficacy and possible side effects of psilocybin; i.e., to determine the benefit/risk ratio on the most advanced preclinical Level.

Our first main objective is to study the efficacy and potential side effects (i.e., the benefit risk ratio) of psilocybin on relapse behavior in a preclinical multi-center placebo controlled trial in alcohol addicted rats with a step-wise translation into alcoholic patients. As preclinical and clinical evidences suggest that sex influences disease trajectories and interventions in alcoholics, male and female rats will be studied in direct comparison. Therefore, a further objective of our proposal is to test the long-lasting efficacy of psilocybin in male and female subjects on relapse behavior.

We hypothesize that a single administration of psilocybin will have long-lasting effects on relapse behavior in alcohol addicted rats. We furthermore hypothesize that our preclinical results will be of high predictive value for the clinical situation since we will use a DSM based rat model and will conduct a well-powered phase II trial that will be performed in accordance to the guideline on the development of medicinal products for the treatment of alcohol addiction provided by the European Medicines Agency (EMA).

 

work Plan -

Objectives, hypotheses and evidence

 

Efficacy of psilocybin in msP rats & Effects of psilocybin on behavioral mechanisms of addiction (WP2+3 leader Ciccocioppo)

Background and rationale: In order to increase data generalizability of our preclinical trial in WP1, we will add here an additional yet smaller preclinical phase II trial using another animal model, the Marchigian Sardinian alcohol-preferring (msP) rats. msP rats show enhanced anxiety, stress, and alcohol drinking, and are highly vulnerable to relapse - as such it is also an ideal animal model with which to study the neurobiology of alcohol addiction.

Working hypothesis: We hypothesize that a single administration of psilocybin will have a long-lasting relapse preventing effect in msPs rats. We further assume that psilocybin will be more efficacious in reducing alcohol consumption in a rat model in which drinking is about three times higher than that in non-selected Wistar populations (as used in WP1) and in which drinking is motivated by negative reinforcement mechanisms.

 

Major goals: To conduct a small preclinical multi-center phase II trial in alcohol-preferring msP rats in order to increase data generalizability and to determine if psilocybin may be more useful in individuals that drink to self-medicate a negative affective state.

Work-Package 2&3

Human and translational studies: Effects of psilocybin on brain connectivity in the alcohol addicted brain (WP4 leader Vollenweider)

Background and rationale: Has been provided in detail in section 1&2A.

 

Working hypothesis: We hypothesize that a single administration of psilocybin will lead to restoration of normal network function in the diseased brain.

 

Primary Outcomes: Functional MRI resting-state connectivity in AUD patients at T1-T3; i.e., before, during and after psilocybin. At T1-T3 epigenetic assessments will be also done.

 

Secondary outcomes: Evaluation of symptom severity on T1-T3: Time-Line Follow-Back, Alcohol Abstinence Self-Efficacy Scale, Penn Alcohol Craving Scale.

Work-Package 4

Effects of psilocybin on the epigenetic and transcriptomic landscape (WP5 leader Naassila)

Background and rationale: Has been provided in detail in section 1&2A.

 

Working hypothesis: Here we will test the hypothesis that psilocybin induces long-lasting epigenetic changes in brain cells that contribute to its therapeutic effect.

 

Major goals: Methylation and gene expression patterns will be analyzed longitudinally.

 

Methodology: Blood samples - provided by WP4 - from two groups of patients (n=30 per group) will be analyzed at 3 different time points (T1-T3 see WP4): before, during and after psilocybin/placebo treatment.

Work-Package 5

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