Impact of Omega 3 in Alcohol Use Disorder (W3-AUD)

Impact of Omega-3 Polyunsaturated Fatty Acids on Emotional, Cognitive and Biological Alterations in Alcohol Use Disorder

The goal of this clinical trial is to investigate the biological pathways underlying the beneficial effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on mental health in patients with alcohol use disorder. The main questions this study aims to answer are: Can n-3 PUFA improve mood disorders (depression, anxiety), craving for alcohol, cognitive impairments and sociability disorders ? Are the beneficial effects of n-3 PUFAs due to a modification of the gut microbiota and/or the inflammatory status? Participants will : take a supplementation of omega-3 or placebo during 3 months do a brain MRI be interviewed for a dietary anamnesis provide blood, stool and saliva samples perform psychological tests and neuropsychological tasks Researchers will compare active comparator (omega-3) with placebo comparator (olive oil) to see if omega-3 can have a beneficial effect on AUD patients.

Alcohol use disorder (AUD) is the most widespread addiction in Belgium and Europe and constitutes a major public health problem with important physical, psychological and economic consequences for the consumer and his family, friends, co-workers. For several years, the intestinal microbiota has been increasingly studied because it seems to play an indispensable role in the proper functioning of the body. Indeed, it is involved in the regulation of the immune system, metabolic reactions and the nervous system and therefore influences behaviour. The composition of the microbiota is specific to everyone and is influenced by many factors, such as diet, medication and lifestyle. In the case of AUD, numerous studies have shown that alcohol and its metabolites alter the intestinal microbiota, leading to an increase in inflammation and changes in behaviour. Nutritional intervention is an encouraging and innovative approach to alcohol addiction therapy. The main aim of this research is to see how a nutritional intervention could improve mood, cognition and social behaviour in AUD patients. The interest will therefore focus on Omega-3. These polyunsaturated fatty acids are found in the diet, mainly in fish oils, and are constituents of the body's cell membranes and perform many physiological functions. They also play an important role in the regulation of inflammation. Studies have shown that Omega-3 supplementation can reduce symptoms of depression and have beneficial effects in autism spectrum disorders, schizophrenia, bipolar disorders and neurodegenerative diseases. They have therefore been widely studied, but their role in social interactions, which is an important factor in many mental illnesses including AUD, has not yet been studied. The investigators will conduct a randomised, placebo-controlled, double-blind study, testing the impact of Omega-3 supplementation on AUD patients undergoing a detoxification program at the Saint-Luc University Hospital, Brussels, Belgium. 100 patients will be enrolled and the Omega 3/placebo supplementation will last for 3 months. The patients will be tested 3 times: T1 (2nd day of withdrawal), T2 (18th-19th day of withdrawal) and T3 (after 3 months of supplementation). The investigators hope to see a beneficial effect of omega-3 on social, emotional and cognitive deficits as well as brain functioning (fMRI). They will investigate the mechanisms involved, namely, changes in the composition of the gut microbiota, reduction of systemic inflammation, and production of bacterial metabolites with immune or neuroactive properties.

gut microbiota, Omega 3, metabolomics, Depression, Anxiety, Alcohol craving, Sociability, Cognition, Inflammation, Brain imaging

Dosage form : capsule Dosage : 1000 mg oleic acid (olive oil) + 3.6 mg D-α-tocopherol (vitamin E) Frequency : 4 capsules per day Duration : 3 months

Dosage form : capsule Dosage : 330 mg EPA, 220 mg DHA, 100 mg other n-3 PUFA + 3.6 mg D-α-tocopherol (vitamin E) Frequency : 4 capsules per day Duration : 3 months

Urgency Premeditation Perseverance Sensation seeking impulsive behavior scale (UPPS) : score of different subscales are calculated : "ugency" (0-48), "lack of premeditation" (0-44), "lack of perseverance" (0-40), "sensation seeking) (0-48). Higher score in the different subscales indicates higher impulsivity level.

Liebowitz Scale of Social Anxiety (EASL) (score 0-144) Higher score indicates higher social anxiety level.

Post-traumatic diagnostic scale (PDS-F): calculation of score is complex and described in the related publication

Trait Emotional Intelligence Questionnaire (TEI Que-75) : calculation of score is complex and described in the related publication

Circulating pro- and anti-inflammatory cytokines (TNFa, IL-6, IL-1b, IL-8, IL-10) levels in blood sample Isolation of PBMC to study intracellular inflammatory pathways by RT-qPCR

a duodenal biopsy will be collected and the expression of the tight junctions regulation the intestinal permeability will be analyzed by sectional immunofluorescence and quantitative polymerase chain reaction

Inclusion Criteria: Diagnosis of alcohol use disorder (≥ 4 DSM-5 criteria) Patient at the hospital for a 3 week alcohol withdrawal program Gender : male and female Age : between 18 and 70 years old Language : french Alcohol consumption less than 48 jours before admission Exclusion Criteria: Presence of another addiction, except for smoking and cannabis use Presence of a psychiatric comorbidity (axis 1 DSM-5) Current or recent use (< 2 months) of antibiotics, probiotics, fibre supplements Current or recent (< 2 months) use of omega-3 supplements Current or recent (< 2 months) use of oral anti-coagulants drugs Current or recent (< 2 months) double anti-platelet therapy Coagulation disorders Current or recent (< 1 month) use of non-steroidal anti-inflammatory drugs and glucocorticoids Morbid obesity : body mass index > 35 kg.m-2 Bariatric surgery Type I diabetes and type II diabetes not stabilised (i.e. glycated haemoglobin > 7.2 and unstable drug treatments) Chronic inflammatory diseases Cancer (less than 5 years before admission) Presence of cirrhosis (Fibroscan® = F4 and echodoppler performed as part of clinical routine on patient admission) Known allergy to fish and seafood Any other comorbidity that would be a contraindication to the study in the judgement of the principal investigator

Hearn, M, Ceschi, G., Brillon, P, Fürst, G., & Van der Linden, M. (2012). A French adaptation of the Post-traumatic Diagnostic scale. Canadian Journal of Behavioural Science, 44, 16-28

Petrides KV (2009) Psychometric properties of the trait emotional intelligence questionnaire. In: Stough C, Saklofske DH, Parker JD (eds) Advances in the assessment of emotional intelligence. Springer, New York. 10.1007/978-0-387-88370-0_5