Ketogenic Diet (KD) in Alcoholism

NCT03255031 | Completed Results

• 2 other identifiers: 17015217-AA-0152
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

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.

Conditions

Alcoholism

Keywords

Ketogenic Diet; Detoxification; Functional MRI; MRI/MRS; Alcoholism

Outcome Measures

Primary Outcomes (7)

• Withdrawal Symptoms Measured Using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar)

  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.

  Week 1

• Quantification of Medications for Control of Withdrawal Symptoms

  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.

  Week 1

• Brain Functions During Resting State: Sensorimotor Brain Network

  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.

  Weeks 1, 2, and 3

• Brain Functions During Resting State: Association Brain Network

  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.

  Weeks 1, 2, and 3

• Neurobiological Craving Signature (NCS) for Alcohol > Food Pictorial Cues

  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.

  Weeks 1, 2, and 3

• Brain Concentrations of Glutamate/Creatine

  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.

  Weeks 1, 2, and 3

• Brain Volume Measured With Brain MRI

  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).

  Weeks 1 and 3

Secondary Outcomes (3)

• Effect of Ketogenic Diet on Mood

  Weeks 1, 2, and 3

• Effect of Ketogenic Diet on Sleep

  Weeks 1, 2, and 3

• Effect of Ketogenic Diet on Alcohol Craving

  Weeks 1, 2, and 3

Study Arms (2)

Ketogenic diet (KD)

ACTIVE COMPARATOR

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.

Other: Ketogenic Diet (KD)

Standard American (SA) diet

PLACEBO COMPARATOR

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.

Other: Standard American (SA) Meals and Shakes

Interventions

Ketogenic Diet (KD) OTHER

For each meal at breakfast, lunch and dinner, the diets will consist of ketogenic diet (KD) meal. Compliance tests are done twice a week with a blood test measuring ketone levels.

Ketogenic diet (KD)

Standard American (SA) Meals and Shakes OTHER

For each meal at breakfast, lunch and dinner, the diets will consist of SA meal (carbohydrate rich) KD meal. Compliance tests are done twice a week with a blood test measuring ketone levels.

Standard American (SA) diet

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with AUD
• Age 18 years and older.
• Ability to provide written informed consent as determined by clinical examination and verbal communication. Capacity to consent will be determined by those giving the informed consent.
• DSM-IV diagnosis of alcohol dependence or alcohol abuse or DSM 5 diagnosis of moderate or severe AUD (established through history and clinical exam).
• Participants seeking treatment for their AUD (self-report)
• Minimum 5-year history of heavy drinking (SAMSHA s criteria for heavy drinking: for men 5 or more drinks/day on at least 5 different days per month; and for women 4 or more drinks/day on at least 5 different days per month \[self-report\]).
• Alcohol specified as the preferred drug (self-report).
• NIH employees with an AUD may participate in this study.

You may not qualify if:

• Current DSM-IV or DSM 5 diagnosis of a major psychiatric disorder (other than alcohol and nicotine use disorders, or substance use disorders that are mild/moderate) that required hospitalization, or that required daily medications for over 4 weeks in the past year (i.e., antidepressants; anticholinergics; antipsychotics; anxiolytics; lithium; psychotropic drugs not otherwise specified (nos) including herbal products (no drugs with psychomotor effects or with anxiolytics, stimulant, antipsychotic, or sedative properties); sedatives/hypnotics). Chronic benzodiazepine use prior to alcohol detox will also be excluded. Note that nicotine and/or caffeine use will not exclude participation.
• Chronic use of the following medications: analgesics containing narcotics; anorexics (sibutramine); antianginal agents; antiarrhythmics; antiasthma agents that are systemic corticosteroids; antibiotics; anticoagulants; anticonvulsants; antidiarrheal preparations; antifungal agents (systemic); antihistamines (sedating); antihypertensives (except angiotensin - converting
• enzyme (ACE) inhibitors such as Lisinopril, or Angiotensin receptor blockers (ARB) such as Losartan); anti-inflammatory drugs (systemic); antineoplastics; antiobesity; antivirals (except for treatment of HSV with agents without CNS activity, e.g. acyclovir, ganciclovir, famciclovir, valacyclovir); cough/cold preparations (dextromethorphan preparations, pseudoephedrine); hormones (exceptions: thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy); insulin; and muscle relaxants.
• Major medical problems that can impact brain function or the use of a ketogenic diet (e.g., epilepsy, diabetes, liver disease, kidney disease, kidney stones (current and/or in the past), chronic metabolic acidosis or a cardiomyopathy) as determined by EKG, history and clinical exam.
• Clinically significant laboratory findings that could affect brain function (e.g. HIV+).
• Head trauma with loss of consciousness for more than 30 minutes (self-report, medical history).
• Pregnant or breast-feeding: Females of childbearing potential, or with tubal ligation, or are post-menopausal and are age 60 or less will undergo a urine pregnancy test and it must be negative to continue participation. Urine pregnancy tests will be repeated on subsequent days of study. (i.e., within 24 hours before study procedures). Females must not be currently breastfeeding.
• Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head, fear of enclosed spaces, or other standard contraindication to MRI (self-report checklist).
• Cannot lie comfortably flat on his/her back for up to 2 hours in the MRI scanner (self-report).
• Body weight \> 550 lbs. The MR scanner bed is tested to a weight limit of 0 lbs.
• Milk or soy allergy (self-report).
• Note that subjects will not be excluded on initial screening from enrollment onto this study if their breath alcohol test is positive; or if their urine test is positive for drugs. The following guideline will be followed for positive alcohol/drug screens on study procedure days:
• If an AUD subject s breath alcohol and/or urine drug screen test is/are positive on study days (i.e., within 24 hours before study procedures except for benzodiazepines during detox, including oxazepam \[Serax\], the procedures will be postponed and rescheduled to another day. If the urine drug screen is positive for THCCOOH, a saliva drug screen will be performed and subject may proceed with MRI/NPT procedures if saliva results for Delta-9-Tetrahydrocannabinol (THC) are negative. We will not place a limit on rescheduling study days.

Sponsors & Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Wiers CE, Vendruscolo LF, van der Veen JW, Manza P, Shokri-Kojori E, Kroll DS, Feldman DE, McPherson KL, Biesecker CL, Zhang R, Herman K, Elvig SK, Vendruscolo JCM, Turner SA, Yang S, Schwandt M, Tomasi D, Cervenka MC, Fink-Jensen A, Benveniste H, Diazgranados N, Wang GJ, Koob GF, Volkow ND. Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents. Sci Adv. 2021 Apr 9;7(15):eabf6780. doi: 10.1126/sciadv.abf6780. Print 2021 Apr.

  PMID: 33837086 RESULT

• Li X, Shi Z, Byanyima J, Morgan PT, van der Veen JW, Zhang R, Deneke E, Wang GJ, Volkow ND, Wiers CE. Brain glutamate and sleep efficiency associations following a ketogenic diet intervention in individuals with Alcohol Use Disorder. Drug Alcohol Depend Rep. 2022 Dec;5:100092. doi: 10.1016/j.dadr.2022.100092. Epub 2022 Sep 8.

  PMID: 36311277 RESULT

• Wiers CE, Manza P, Wang GJ, Volkow ND. Ketogenic diet reduces a neurobiological craving signature in inpatients with alcohol use disorder. Front Nutr. 2024 Feb 12;11:1254341. doi: 10.3389/fnut.2024.1254341. eCollection 2024.

  PMID: 38410637 RESULT

• Zhang R, Tomasi D, Shokri-Kojori E, Manza P, Feldman DE, Kroll DS, Biesecker CL, McPherson KL, Schwandt M, Wang GJ, Wiers CE, Volkow ND. Effect of detoxification on N3 sleep correlates with brain functional but not structural changes in alcohol use disorder. Drug Alcohol Depend. 2022 Sep 1;238:109545. doi: 10.1016/j.drugalcdep.2022.109545. Epub 2022 Jun 26.

  PMID: 35779511 DERIVED

• Bornebusch AB, Mason GF, Tonetto S, Damsgaard J, Gjedde A, Fink-Jensen A, Thomsen M. Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice. Psychopharmacology (Berl). 2021 Mar;238(3):833-844. doi: 10.1007/s00213-020-05735-1. Epub 2021 Jan 7.

  PMID: 33410985 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Alcoholism

Interventions

Diet, Ketogenic; Meals

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Diet, Carbohydrate-Restricted; Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena; Food; Food and Beverages

Results Point of Contact

• Title: Dr. Gene-Jack Wang
• Organization: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

gene-jack.wang@nih.gov

301-496-5012

Study Officials

• Gene-Jack Wang, M.D.

  National Institute on Alcohol Abuse and Alcoholism (NIAAA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2017
• First Posted: August 21, 2017
• Study Start: October 24, 2017
• Primary Completion: May 12, 2020
• Study Completion: February 7, 2023
• Last Updated: July 17, 2024
• Results First Posted: July 17, 2024

Record last verified: 2024-01-25

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)