Ketogenic Diet (KD) in Alcoholism

Not Applicable

Completed

Conditions: Alcoholism

Interventions: Other: Standard American (SA) Meals and Shakes
Other: Ketogenic Diet (KD)

Registration Number: NCT03255031

Lead Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Brief Summary: Background:

A ketogenic diet (KD) is high in fat and low in carbohydrates. Research has shown that a KD can lessen tremor in animals withdrawing from alcohol. KD can also help people who have difficulties with thinking, sleep, and mood. Researchers want to see if KD can lessen symptoms of alcohol withdrawal in people with alcohol use disorder.

Objective:

To test the effects of a ketogenic diet on alcohol withdrawal symptoms.

Eligibility:

Adults 18 years or older who are moderate or severe alcohol drinkers and are seeking treatment for alcohol use. They must be in the NIAAA inpatient alcohol treatment program.

Design:

Participants will be screened under another protocol. They will have a medical and psychiatric history, physical exam, and blood and urine tests. Participants will have a breath test for alcohol.

The study will be done in a 3-week stay in the clinic.

Participants will get either a KD or Standard American diet.

Participants will have breathalyzer, blood, and urine tests.

Participants will have magnetic resonance imaging (MRI) scans. The scanner is a cylinder in a magnetic field. They will lie on a table that slides in and out of the cylinder. They will do tasks on a computer during the scan.

Participants will have tests of thinking, memory, and attention.

Participants will have their sleeping and waking measured. They will wear a device like a headband held in place with elastic straps. Several electrodes will be placed on the body.

Participants will have heart tests.

Participants will wear an activity monitor on the wrist.

After the clinic stay, participants will be called by phone about 5 times over 3 months.

Detailed Description: Alcohol intoxication leads to marked reductions in brain glucose metabolism that reflect in part the use of ketones (including acetate) as alternative energy sources by the brain during intoxication. With repeated alcohol exposure both clinical and preclinical studies have shown a shift of brain substrate preference towards ketones. This has led us to question the potential value of a ketogenic diet in alcohol detoxification in order to prevent the ketone deprivation that would follow alcohol detoxification in alcoholics.

Objectives: Here we propose a blinded randomized design to assess the effects of a ketogenic diet on symptoms of alcohol withdrawal and on brain function in alcoholics undergoing inpatient treatment of alcohol detoxification. We hypothesize that a ketogenic diet will increase acetate levels in brain resulting in improved brain function in alcoholics as well as a reduction of alcohol withdrawal symptoms during detoxification.

Study population: Participants diagnosed with alcohol use disorder (AUD) as per Diagnostic and Statistical Manual (DSM) IV or DSM 5. Males and females ages 18 years and older will be included.

Design: This will include an inpatient component and outpatient follow-up. Patients are admitted to the Clinical Center (CC) for detoxification, where they undergo treatment as usual (TAU) and will be randomized into a regular versus a ketogenic diet. Patients will be given benzodiazepines only if withdrawal symptoms emerge while receiving either the ketogenic or the regular diet. Within 2-6 days after admission, all patients will undergo an MRI (brain structure and function, functional connectivity and spectroscopy, i.e. MRS) and a battery of neuropsychological tests (NP). MRI scans will also be obtained in week 2. After 3 weeks of inpatient care the MRI scans and NP studies will be repeated. We will complete all study procedures in n=25 patients with AUD with the ketogenic diet and n=25 with the regular diet.

Outcome parameters: Main outcome: To assess the effects of a ketogenic diet in patients hospitalized for the treatment of alcohol detoxification, on: (1) withdrawal symptoms including the need of medications to control them (benzodiazepines); (2) brain function as assessed by functional magnetic resonance imaging (fMRI) (at rest and during task conditions), (3) MRS, and (4) structural MRI. Secondary Outcomes: To assess the effects of a ketogenic diet on performance of cognitive tests, sleep, mood and craving.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 53

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard American (SA) diet	Standard American (SA) Meals and Shakes	Subjects with alcohol use disorder receive Standard American (SA) diet which consists of ketogenic diet (KD) food, snacks, and shakes three times per day (high in fat) in the proportions of carbohydrates, protein and fat of traditional western diet for up to four weeks while inpatient.
Ketogenic diet (KD)	Ketogenic Diet (KD)	Subjects with alcohol use disorder receive ketogenic diet (KD) which consists of food, snacks, and shakes three times per day (high in fat) for up to four weeks while inpatient.

Primary Outcome Measures

Name	Time	Method
Quantification of Medications for Control of Withdrawal Symptoms	Week 1	Participants received oral benzodiazepine treatment for alcohol withdrawal when Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores were 8 or higher within the first week of inpatient admission. The effect of alcohol withdrawal and benzodiazepine use was analyzed with ANOVA as the group × time effect on benzodiazepine use.
Brain Functions During Resting State: Sensorimotor Brain Network	Weeks 1, 2, and 3	Brain network segregation was measured by functional MRI (fMRI) using the Power-264 brain atlas. The 264 spherical is defined as brain regions of interest (ROIs) with a 5-mm radius that belong to 13 large-scale functional brain networks. The fronto-parietal, ventral attention, dorsal attention, cingulo-opercular, and salience networks were grouped into the association network. The sensory hand, sensory mouth, visual, and auditory networks were grouped into the sensorimotor network. The mean time series across voxels was extracted for each regions of interest. Then the Pearson correlation coefficients was calculated between the ROIs and converted to Fisher-Z values for further analysis. Segregation equals the relative strength of within-network connectivity (Zw) when compared with between-network connectivity (Zb): Zw - Zb / Zw. Higher segregation value corelates with better functional specificity and energy efficiency. The final segregation output is a ratio of Z-scores.
Withdrawal Symptoms Measured Using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar)	Week 1	Alcohol withdrawal symptoms were measured using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar). The CIWA-Ar is a 10-item scale scored from 0-7, with the exception of the orientation category, scored from 0-4, used in the assessment and management of alcohol withdrawal. Score ranges from 0 - 67. Mild alcohol withdrawal is defined with a score less than or equal to 10, moderate with scores 11 to 15, and severe with any score equal to or greater than 16. Analysis was performed as ANOVA between-groups.
Brain Functions During Resting State: Association Brain Network	Weeks 1, 2, and 3	Brain network segregation was measured by functional MRI (fMRI) using the Power-264 brain atlas. The 264 spherical is defined as brain regions of interest (ROIs) with a 5-mm radius that belong to 13 large-scale functional brain networks. The fronto-parietal, ventral attention, dorsal attention, cingulo-opercular, and salience networks were grouped into the association network. The sensory hand, sensory mouth, visual, and auditory networks were grouped into the sensorimotor network. The mean time series across voxels was extracted for each regions of interest. Then the Pearson correlation coefficients was calculated between the ROIs and converted to Fisher-z values for further analysis. Segregation equals relative strength of within-network connectivity when compared with between-network connectivity: Zw - Zb / Zw. Higher segregation value corelates with better functional specificity and energy efficiency. The final segregation output is a ratio of Z-scores.
Brain Concentrations of Glutamate/Creatine	Weeks 1, 2, and 3	The brain metabolism was measured with weekly magnetic resonance spectroscopy (MRS) scans in a voxel in the dorsal anterior cingulate cortex. The concentrations of Glutamate/Creatine were analyzed with repeated-measures ANOVAs with time as the within-subject factor and diet as the between-subject factor.
Neurobiological Craving Signature (NCS) for Alcohol > Food Pictorial Cues	Weeks 1, 2, and 3	Participants performed an alcohol cue-reactivity paradigm with functional magnetic resonance imaging in which they viewed alcohol and food pictorial cues. The blood-oxygen-level dependent (BOLD) responses to food and alcohol cues was extracted and quantified the degree to which each set of brain images shared a pattern of activation using the Neurobiological Craving Signature (NCS). The NCS is a whole-brain pattern of responses to cues, with prominent regions including ventromedial prefrontal and cingulate cortices, ventral striatum, temporal/parietal association areas, mediodorsal thalamus and cerebellum. A group-by-time repeated measures ANOVA was used to test for differences in craving signature expression between the dietary groups. Positive values indicate stronger brain BOLD responses to alcohol related cues.
Brain Volume Measured With Brain MRI	Weeks 1 and 3	Whole brain total intracranial volume was measured using T1 structural MRI. Voxel-based morphometry (VBM) was performed using the Computational Anatomy Toolbox (CAT12) in Statistical Parametric Mapping software (SPM12).

Secondary Outcome Measures

Name	Time	Method
Effect of Ketogenic Diet on Sleep	Weeks 1, 2, and 3	Participants self-reported their estimated total sleep time for each night. Weekly responses were reported as the average across seven days.
Effect of Ketogenic Diet on Alcohol Craving	Weeks 1, 2, and 3	Participants rated their alcohol craving on the Desire for Alcohol Questionnaire (DAQ) weekly. DAQ is a 14-item scale that assesses current self-reported levels of alcohol craving. Each item is scored from 0 (fully disagree) to 6 (fully agree), with a total score range of zero (0) to maximum score of 84. Higher score indicates higher level of alcohol craving. Analysis was performed as repeated-measure ANOVA.
Effect of Ketogenic Diet on Mood	Weeks 1, 2, and 3	The effect of ketogenic diet on mood was assessed with the Montgomery-Asberg Depression Rating Scale (MADRS). MADRS is a ten-item diagnostic questionnaire which measures the severity of depressive episodes. Each item is rated on a score of 0 (normal/not present) to 6 (extreme symptom). Total score range is zero (0) to 60. Total score of 7-19 represent mild depression; 20-34 moderate; 35-60 indicate severe depression. Higher MADRS score indicates more severe depression/lower mood. Analysis was performed as mixed ANOVAs with group as between-group factor and time as within-subjects factor.