Psilocybin-assisted psychotherapy in alcohol use disorder – PAPAUD

Current available treatments for alcohol use disorder (AUD) show modest effectiveness, with a 50% rate of relapse during the first month following alcohol cessation. Psychedelic therapies hold good promises for AUD, but their effectiveness has not yet been attested in only few studies and the involved brain mechanisms are still poorly understood. Our project’s main objectives are threefold: (i) attest the effectiveness of psilocybin for AUD; (ii) to evaluate the relevance and efficacy of repeated versus single dosing; (iii) to evaluate the efficacy of psilocybin on craving as well as on psychological flexibility; (iv) to explore the brain mechanisms involved. Forty-five patients with AUD will be randomized into three groups: "repeated dose" (25mg psilocybin per month for 4 months), "placebo" (1mg psilocybin for 4 months) and "single dose" (25mg psilocybin for the first month, then 1mg psilocybin for the following 3 months). The primary endpoint will be the number of days of use as assessed by the TLFB. The main secondary endpoints will be the number of heavy drinking days, the number of drinks consumed per occasion, the assessment of craving, the realization of biological markers and an assessment of psychological flexibility. These evaluations will be performed after each session, and then at 6 and 12 months. A similar protocol will be carried out with an animal model of the AUD whose consumption will be evaluated at 1 day, 1 week and 3 weeks. The preclinical study will be articulated around 4 main objectives. The first one will be, as for the clinical part, the evaluation of the efficiency of one or several psilocybin intakes on the relapse as well as on the behavioral flexibility. The second will be the study of the effectiveness of psilocybin on the phenomenon of craving incubation. The last two objectives will be to study the mechanism of action of psilocybin on synaptic plasticity and functional connectivity. Changes in brain functional connectivity using pharmaco-fMRI and in the expression levels of the dopamine D2, 5-HT2A, mGlu2 receptors and the HDAC2, will also be assessed in the main brain structures involved in AUD. This translational project would be the first to explore the efficacy as well as the neurobiological and psychological mechanisms involved in the therapeutic effects of psilocybin in patients with AUD.