alcohol use disorder

A Double-Blind Randomized Controlled Trial of Daridorexant for Alcohol Use Disorder

Project Summary/Abstract This R01 application proposes integrating a randomized, double-blinded, placebo-controlled clinical trial into a real-world treatment setting to test whether the dual orexin receptor antagonist (DORA) daridorexant reduces alcohol craving and use and improves total sleep time among patients with alcohol use disorder (AUD) and co-occurring sleep disturbance. DORAs have shown promise in modulating reward and reducing alcohol self- administration in preclinical models. Further, DORAs are FDA-approved for insomnia, are highly efficacious for treatment of sleep disturbance, have a favorable safety profile, and demonstrate low abuse liability. Thus, DORAs are a highly promising treatment for AUD, particularly among persons that have co-occurring sleep disturbance. To this end, the proposed study will recruit individuals from a residential treatment facility, following completion of medically managed withdrawal and stabilization. Eligible participants will be randomized to daridorexant to placebo, and will complete measures of alcohol craving, total sleep time (assessed through both wireless electroencephalography and biometric data collection), and adverse events. Following discharge from residential treatment, participants will continue taking the study medication for two weeks while submitting daily reports of alcohol use, alcohol craving, sleep diaries, and biometric sleep data. Participants will also be prompted to submit three-times weekly random breath alcohol level using a portable BACtrack S80 breathalyzer, and will attend weekly check-in visits to assess adverse events and to confirm daily alcohol reports. A one-month follow-up assessment will be conducted to collect long-term data on alcohol use, AUD symptoms, and sleep. Ultimately, this study has the potential to identify a novel treatment for co- occurring AUD and sleep disturbance, and will address the following specific aims: (1) Test whether daridorexant reduces alcohol craving and post-treatment alcohol use relative to placebo. (2) Test whether daridorexant improves objectively measured total sleep time relative to placebo. (3) Examine the frequency of adverse events in persons assigned to daridorexant relative to placebo. If these aims are supported, then we will also explore whether effects are moderated by insomnia severity. We will also examine if the effects replicate across residential environments (with structured sleep/wake times and close monitoring of medication adherence) and outpatient environments (with self-imposed sleep/wake times and self-dosing). Currently, there are no FDA approved medications indicated for both AUD and insomnia. This innovative strategy aims to address a critical gap by investigating the effectiveness of daridorexant in modulating alcohol craving and alcohol use. This study will contribute to a growing literature on the role of the orexin system in reward and alcohol use.

Role of the gut microbiota in the development of alcohol use disorder

The gut microbiota is composed of a very large number of bacteria, viruses, fungi and yeasts that play an important role in the body, through the production of a series of metabolites (including neurotransmitters), and through an essential role in the barrier function of the gut and the regulation of immunity and stress response. In this lecture I will present, based mainly on human studies but also on preclinical studies, the evidence for a role of the gut microbiota in the development of alcohol use disorder. I will show the first results of trials to test the effects of nutritional approaches to address these deficits.

Promising Neuroimmune Targets for Alcohol Use Disorder Pathology

Alcohol Use Disorder Severity is Linked to Altered Functional Connectivity in Default Mode, Salience and Executive Control Networks

Axonal pathology in alcohol use disorders

Neurophysiological correlates of sub-dimensions of alcohol use disorder in rodents

Ventral pallido-subthalamic adaptations underlying pathological decision making in alcohol use disorders

Combined treatment with the glycine transporter-1-inhibitor Org24598, varenicline, and bupropion as a new pharmacological treatment concept for alcohol use disorder

FENS Forum 2024

Examination of adolescent cannabinoid vapour exposure effects on behavioural predictors of addiction and alcohol use disorder features in adult male and female rats

FENS Forum 2024

Microglial activation in the anterior cingulate cortex: A biological marker of early adverse events and future vulnerability to develop alcohol use disorder

FENS Forum 2024

Selective inhibition of phosphodiesterase 7 enzymes reduces alcohol drinking and seeking in animal models of alcohol use disorders

FENS Forum 2024