Impact of Omega 3 in Alcohol Use Disorder

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Alcohol Use Disorder, Severe

Intervention / Treatment
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* Dietary Supplement: Active Comparator: Omega-3
* Dietary Supplement: Placebo Comparator: olive oil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Olive oil<br>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 | Dietary Supplement: Placebo Comparator: olive oil<br>* Refined olive oil is the usual placebo used in studies with n-3 PUFA.<br>|
| Active Comparator: Omega-3<br>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 | Dietary Supplement: Active Comparator: Omega-3<br>* It is a dietary supplement made of fish oil rich in n-3 PUFA.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in depression | Beck Depression Inventory (BDI) (score 0-63) Higher score indicates higher depression level. | On day 2, day 19 and day 90 | 
| Change in anxiety | State-Trait Anxiety Inventory (STAI) (score 20-80) Higher score indicates higher anxiety level. | On day 2, day 19 and day 90 | 
| Change in fatigue | Multidimensional Fatigue Inventory (MFI) (score 20-140) Higher score indicates higher fatigue level. | On day 2, day 19 and day 90 | 
| Change in alcohol craving | Obsessive Compulsive Drinking Scale (OCDS) (score 0-40) Higher score indicates higher craving level. | On day 2, day 19 and day 90 | 
| Change in impulsivity | 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. | On day 19 and day 90 | 
| Change in social anxiety | Liebowitz Scale of Social Anxiety (EASL) (score 0-144) Higher score indicates higher social anxiety level. | On day 19 and day 90 | 
| Change in trauma | Post-traumatic diagnostic scale (PDS-F): calculation of score is complex and described in the related publication | On day 19 | 
| Childhood trauma | Childhood Trauma Questionnaire (CTQ) (28-144) Higher score indicates higher childhood trauma level. | On day 19 | 
| Self-stigma | Self-Stigma in Alcohol Dependence (SSAD) (16-80) Higher score indicates higher self-stigma level. | On day 19 | 
| Change in work memory | Letter Memory Task | On day 2, day 19 and day 90 | 
| Change in inhibition | Stop Signal Task | On day 2, day 19 and day 90 | 
| Change in decision making | Fisher Task | On day 19 and day 90 | 
| Change in facial emotions recognition | Facial Emotions Recognition Task (TREF) | On day 19 and day 90 | 
| Change in visual perspective taking | Visual Perspective Taking Task | On day 19 and day 90 | 
| Sociability | Sociogram | On day 19 | 
| Emotional intelligence | Trait Emotional Intelligence Questionnaire (TEI Que-75) : calculation of score is complex and described in the related publication | Day 19 | 
| Change in social activity | Social Activities Questionnaire (28-196) | On day 2, day 19 and day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in markers of microbial translocation | measurement of sCD14, PGRP in blood sample using ELISA kits (pg/mL) | On day 2, day 19 and day 90 | 
| Change in inflammation | 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 | On day 2, day 19 and day 90 | 
| Change in gut microbiota composition | Analysis of gut microbiota (16S rDNA) by high-throughput sequencing (Illumina) | On day 2, day 19 and day 90 | 
| Intestinal permeability | 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 | On day 19 | 
| Change in omega-3 levels | Omega-3 levels in plasma and red blood cells | On day 2, day 19 and day 90 | 
| Change in diet profile | The dietary anamnesis will consist of a 24-hour recall over 3 days (2 weekdays and 1 weekend day) | On day 2, day 19 and day 90 | 
| Change in brain functioning | Magnetic Resonance Imaging | On day 2, day 19 and day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Omega 3, gut microbiota, metabolomics, Depression, Anxiety, Alcohol craving, Sociability, Cognition, Inflammation, Brain imaging