AlcoholismNCT03255031
Ketogenic Diet (KD) in Alcoholism
A study testing Ketogenic Diet (KD) and Standard American (SA) Meals and Shakes in people with Alcoholism, run by National Institute on Alcohol Abuse and Alcoholism (NIAAA) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Alcoholism
- What is being tested?
- Ketogenic Diet (KD) and Standard American (SA) Meals and Shakes
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 53 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Oct 2017to 7 Feb 2023
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- Unwilling or unable to refrain from use, within 24 hours of MRI and NPT procedures, psychoactive medications or medication that may affect study results (e.g., analgesics containing narcotics, antibiotics [must finish course at least 24 hours prior to a scheduled procedure], antidiarrheal preparations, anti-inflammatory drugs [systemic corticosteroids are exclusionary], antinauseants, cough/cold preparations) (self-report, medical history). The following medications are allowable for entry on this study: analgesics (non-narcotic); antacids; antiasthma agents that are not systemic corticosteroids; antifungal agents for topical use; antihistamines (non-sedating); H2-Blockers/proton pump inhibitors (PPI); laxatives. The use of antihyperlipidemics and/or diuretics are permitted as long as they have been taken for at least 1 month before procedure visits and dose has been stabilized.
- 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+).
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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.
Read more
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.
Read the 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.
- Conditions
- Alcoholism
- Being tested
- Ketogenic Diet (KD), Standard American (SA) Meals and Shakes
- Keywords
- Ketogenic Diet, Detoxification, Functional MRI, MRI/MRS, Alcoholism
- Medical subject headings
- Alcoholism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
Standard American (SA) Meals and ShakesOther
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: Standard American (SA) Meals and Shakes |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: Weeks 1 and 3
Secondary outcomes (3)
Effect of Ketogenic Diet on Mood
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.
Measured: Weeks 1, 2, and 3
Effect of Ketogenic Diet on Sleep
Participants self-reported their estimated total sleep time for each night. Weekly responses were reported as the average across seven days.
Measured: Weeks 1, 2, and 3
Effect of Ketogenic Diet on Alcohol Craving
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.
Measured: Weeks 1, 2, and 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2017
- Study start24 Oct 2017
- Primary completion12 May 2020
- Study completion7 Feb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for AlcoholismStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Gene-Jack Wang, M.D., Principal investigator, National Institute on Alcohol Abuse and Alcoholism (NIAAA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03255031
- Sponsor's protocol ID
- 170152
- Other IDs
- 17-AA-0152
- Status last verified
- 25 Jan 2024
- First submitted
- 18 Aug 2017
- Last updated
- 17 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: .Data is analyzed by subject group and not on an individual basis.
Publications
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.
PubMed 33837086Li 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.
PubMed 36311277Wiers 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.
PubMed 38410637Zhang 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.
PubMed 35779511Bornebusch 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.
PubMed 33410985
Study at a glance
From the registry record, last updated by the sponsor on 17 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ketogenic Diet (KD) in Alcoholism
- ClinicalTrials.gov ID
- NCT03255031
- Acronym / sponsor ID
- 170152
- Conditions
- Alcoholism
- Keywords
- Ketogenic Diet, Detoxification, Functional MRI, MRI/MRS, Alcoholism
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 53 participants (actual)
- Lead sponsor
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)US National Institutes of Health
- Study start
- 24 Oct 2017 (actual)
- Primary completion
- 12 May 2020 (actual)
- Study completion
- 7 Feb 2023 (actual)
- First posted
- 21 Aug 2017 (actual)
- Results
- Posted 17 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ketogenic diet (KD) | Active comparator | Other: 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. |
| Standard American (SA) diet | Placebo comparator | Other: Standard American (SA) Meals and ShakesSubjects 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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)
Key exclusion criteria (14 listed)
- Unwilling or unable to refrain from use, within 24 hours of MRI and NPT procedures, psychoactive medications or medication that may affect study results (e.g., analgesics containing narcotics, antibiotics [must finish course at least 24 hours prior to a scheduled procedure], antidiarrheal preparations, anti-inflammatory drugs [systemic corticosteroids are exclusionary], antinauseants, cough/cold preparations) (self-report, medical history). The following medications are allowable for entry on this study: analgesics (non-narcotic); antacids; antiasthma agents that are not systemic corticosteroids; antifungal agents for topical use; antihistamines (non-sedating); H2-Blockers/proton pump inhibitors (PPI); laxatives. The use of antihyperlipidemics and/or diuretics are permitted as long as they have been taken for at least 1 month before procedure visits and dose has been stabilized.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketogenic Diet (KD)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. | Other | Ketogenic diet (KD) |
| Standard American (SA) Meals and ShakesFor 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. | Other | Standard American (SA) diet |
Primary outcome
Withdrawal Symptoms Measured Using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar)
Time frame: 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.
Quantification of Medications for Control of Withdrawal Symptoms
Time frame: 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
Time frame: 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.
Brain Functions During Resting State: Association Brain Network
Time frame: 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.
Neurobiological Craving Signature (NCS) for Alcohol > Food Pictorial Cues
Time frame: 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 Concentrations of Glutamate/Creatine
Time frame: 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.
Brain Volume Measured With Brain MRI
Time frame: 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).
3 secondary outcomes
Effect of Ketogenic Diet on Mood
Time frame: Weeks 1, 2, and 3
Effect of Ketogenic Diet on Sleep
Time frame: Weeks 1, 2, and 3
Effect of Ketogenic Diet on Alcohol Craving
Time frame: Weeks 1, 2, and 3
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 33837086Wiers 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.
- Results publication: PubMed 36311277Li 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.
- Results publication: PubMed 38410637Wiers 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.
- Derived from this study: PubMed 35779511Zhang 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.
- Derived from this study: PubMed 33410985Bornebusch 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No. .Data is analyzed by subject group and not on an individual basis.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gene-Jack Wang, M.D. principal investigator
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Ketogenic Diet (KD) and Standard American (SA) Meals and Shakes in people with Alcoholism, run by National Institute on Alcohol Abuse and Alcoholism (NIAAA) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Withdrawal Symptoms Measured Using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) (time frame: Week 1). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03255031, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2024.