Ketogenic Diet (KD) in Alcoholism
Ketogenic Diet (KD) in Alcoholism
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:<TAB>

 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.

 ...
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 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 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.
-  INCLUSION CRITERIA:

 Patients with AUD

 1. Age 18 years and older.

 2. 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.

 3. DSM-IV diagnosis of alcohol dependence or alcohol abuse or DSM 5 diagnosis of moderate
 or severe AUD (established through history and clinical exam).

 4. Participants seeking treatment for their AUD (self-report)

 5. 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]).

 6. Alcohol specified as the preferred drug (self-report).

 7. NIH employees with an AUD may participate in this study.

 EXCLUSION CRITERIA:

 1. 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/PPI (proton pump inhibitors); 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.

 2. 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.

 3. Chronic use of the following medications: analgesics containing narcotics; anorexics
 (sibuteramine); 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.

 4. 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.

 5. Clinically significant laboratory findings that could affect brain function (e.g.
 HIV+).

 6. Head trauma with loss of consciousness for more than 30 minutes (self-report, medical
 history).

 7. 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.

 8. 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).

 9. Cannot lie comfortably flat on his/her back for up to 2 hours in the MRI scanner
 (self-report).

 10. Body weight > 550 lbs. The MR scanner bed is tested to a weight limit of 0 lbs.

 11. 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 THC are
 negative. We will not place a limit on rescheduling study days.