Ketogenic Diet (KD) in Alcoholism

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 angiotensinconverting

enzymeace (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 (selfreport, 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. 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 550 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 (except for benzodiazepines during detox, including oxazepam, 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.