Ketogenic Diet (KD) in Alcoholism
Phase: NA
Conditions: Alcoholism
Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

17-AA-0152 (5/20/2022)
Protocol Title:  Ketogenic Diet (KD) in Alcoholism
Abbreviated Title: KD in Alcoholism
Protocol Number: 17-AA-0152
Date of This Submission/Version:   20MAY2022 / Version 10 AM 11
Principal Investigator
Name, Degree
Branch/Institute
Bldg/Rm
Phone
E-mail
Gene-Jack Wang, MD
LNI/NIAAA
10/B2L124
301-496-5012
gene-jack.wang@mail.nih.gov
Total requested accrual:  100 subjects with the aim of completing 50 subjects total:
 (50) Patients with Alcohol Use Disorder (AUD)
Project Uses Ionizing Radiation: 
No 
Yes
IND/IDE
No 
Yes 
Durable Power of Attorney 
No 
Yes
Multi-institutional Project
No 
Yes
Data and Safety Monitoring Board 
No 
Yes  
Technology Transfer Agreement 
No 
Yes  
Samples are being stored 
No 
Yes
Flesch-Kincaid reading level of consent form: AUD = 8.0

17-AA-0152 (5/20/2022)
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Précis:
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 [1]. With repeated alcohol exposure both clinical and 
preclinical studies have shown a shift of brain substrate preference towards ketones 
[1, 2, 3, 4]. 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.
Table of Contents 
Précis:.........................................................................................................................................................2
List of Abbreviations (if applicable).................................................................................................3
1. Introduction and Background.......................................................................................................4
2. Study Objectives.................................................................................................................................4
3. Subjects.................................................................................................................................................8
4. Study Design and Methods...........................................................................................................10
5. Management of Data and Samples ............................................................................................20

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6. Additional Considerations ...........................................................................................................22
7. Risks and Discomforts...................................................................................................................22
8. Subject Safety Monitoring ............................................................................................................25
9. Outcome Measures .........................................................................................................................25
10. Statistical Analysis .......................................................................................................................25
11. Human Subjects Protection.......................................................................................................28
12. Anticipated Benefit ......................................................................................................................29
13. Consent Documents and Process ............................................................................................29
14. Data and Safety Monitoring.......................................................................................................30
15. Quality Assurance.........................................................................................................................30
16. Reportable Events                                                                                                                               31
17. Alternatives to Participation....................................................................................................31
18. Privacy..............................................................................................................................................31
19. Confidentiality...............................................................................................................................31
20. Conflict of Interest........................................................................................................................32
21. Technology Transfer ...................................................................................................................32
22. Research and Travel Compensation ......................................................................................33
23. References ......................................................................................................................................36
24. Attachments/ Appendices.........................................................................................................36
25. Consent Forms...............................................................................................................................37
List of Abbreviations
AUD
alcohol use disorder
ADS
alcohol dependence scale
ASI
Addiction Severity Index 
ATP
adenosine triphosphate
BOLD
blood-oxygenation level-dependent
CANTAB
Cambridge Neuropsychological Test Automated Battery 
CBF
cerebral blood flow
CIWA
Clinical Institute Withdrawal Assessment
CMRGlc
cerebral metabolic rate of glucose
DDT
Delayed discounting task
EPI
echo-planar imaging
FTND
Fagerström Test for Nicotine Dependence
KD
Ketogenic Diet

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MPQ
Multidimensional personality questionnaire
MPRAGE
magnetization-prepared rapid gradient-echo
MRI
magnetic resonance imaging
mI
myo-inositol
NADPH
nicotinamide adenine dinucleotide phosphate
NEM
negative emotionality
NP
neuropsychological tests
PEM
positive emotionality 
RFC
resting functional connectivity
RS
resting state
SA
Standard American diet
TLFB
Alcohol Timeline Follow-back
TS 
task state
VAT
visual attention task
VBM
voxel-based morphometry
1. Introduction and Background
Effects of Alcohol on Brain Glucose and Acetate Metabolism
Alcohol is widely consumed; approximately 56% of Americans 18 years or older drink 
alcohol at least once a month [5]. Although the majority of individuals use alcohol in 
moderation, approximately 7.1% are heavy drinkers (5 or more drinks/day on at least 
5 different days in the past 30 days) [6]. Thus, understanding the effects of heavy 
alcohol drinking on the human brain is crucial for developing interventions to 
minimize potential adverse effects.
Brain imaging studies have shown that acute alcohol administration decreases glucose 
metabolism in the human brain, which initially was thought to reflect decreased brain 
activity [7, 8, 9, 10]. However, subsequent studies showed that even low doses of 
alcohol and minimal behavioral effects also decreased baseline brain glucose 
metabolism [11], and that alcohol-induced reductions in brain glucose metabolism 
were significantly larger than those induced by benzodiazepines at doses that induced 
sedation [12]. Moreover in alcoholics the glucose metabolic decrements triggered by 
acute alcohol were significantly larger than those in controls even when the symptoms 
of intoxication where much lower than in controls [12]. This prompted us to 
hypothesize that the reduction in brain glucose metabolism during alcohol intoxication 
reflected the increased utilization by the brain of the alcohol metabolite acetate as an 
energy substrate. Specifically, acetate, which serves as an energy substrate for 
astrocytes [13], is readily taken up into the brain, and though its concentration in blood 
is normally low, it rises significantly during intoxication and this is enhanced in heavy 
alcohol users (see below). 
Indeed using PET and [11C]acetate, we recently showed that during alcohol 
intoxication the brain increased metabolism of acetate while decreasing metabolism 

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of glucose an effect that was more pronounced in heavy drinkers (HD) than in controls 
[1]. Similarly, a recent magnetic resonance spectroscopy (MRS) study also reported 
greater acetate metabolism in the occipital cortex for heavy drinkers studied during 
sobriety than for controls [4], corroborating a shift to acetate metabolism that appears 
to persist beyond the acute intoxication state. Preclinical studies have corroborated 
that repeated exposure to alcohol increases the metabolism of acetate by the brain [2, 
14]. 
Plasma Acetate levels during Alcohol Intoxication
During alcohol intoxication plasma acetate levels increase significantly as alcohol is 
oxidized to acetaldehyde by alcohol dehydrogenases and subsequently oxidized to 
acetate by aldehyde dehydrogenase [15]. Acetate is readily taken up by the brain and 
is metabolized by glia [13].  Under normal physiological conditions plasma acetate 
levels are constitutively low (about 0.2 to 0.3 mM) and glucose levels typically high 
(about 5 mM) so acetate brain metabolism is one order of magnitude lower than 
glucose metabolism [16, 17]. However, during alcohol intoxication the concentration 
of acetate in blood increases (around 1 mM) [18] to levels that could support 10-20% 
of the total brain metabolic rate [19]. The increases in blood acetate concentrations 
after alcohol intoxication are higher for alcoholics than for controls [20], which could 
facilitate their reliance on ketones as an energy substrate. 
Ketogenic Diet for Alcohol Detoxification
The above findings led us and others to question the potential therapeutic benefits of 
a ketogenic diet in managing alcohol withdrawal and detoxification.   The justification 
being that during alcohol detoxification as the acetate levels in plasma decrease, the 
brain may encounter an energy deficit state that might contribute to neurotoxicity and 
the enhanced excitability observed during the acute phase of abstinence [21].
To our knowledge no clinical studies have been reported, yet preclinical studies in 
rodents exposed chronically to alcohol have provided evidence of a beneficial effects 
of a ketogenic diet during alcohol discontinuation. Rodents chronically exposed to 
alcohol have higher levels of ketones (butyrate, lactate and the beta-hydroxybutyrate) 
in blood that can be used as substrates for energy generation though the Krebs cycle 
[22]. Thus, studies in rodents evaluated the effects of ketone on the suppression of 
alcohol withdrawal syndrome in rats exposed chronically to ethanol through 
intragastric administration (doses of 9-15 g/kg per day, over a period of 4 days). These 
studies showed that ketones suppressed the signs of ethanol withdrawal in the rats 
[22].
Evidence of Disrupted Brain Function in Alcoholics
Numerous NP studies have documented cognitive impairment in multiple domains in 
alcoholics including perceptuomotor, visuospatial and executive functions (working 
memory, attention control and response inhibition) [23] with some evidence of 
recovery of cognitive function with abstinence from alcohol [23, 24, 25]. Brain 
imaging technologies have revealed structural and functional changes in the brain of 
alcoholics including cortical atrophy, ventricular enlargement and white matter 
degradation [25, 26, 27, 28] with evidence that some of these changes recover with 

17-AA-0152 (5/20/2022)
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abstinence [29, 30]. 
Functional imaging studies using fMRI have revealed disrupted brain activation 
during task processing, cues exposure or exposure to emotional stimuli [31]. These 
include: deficits in executive function associated with abnormal prefrontal activity 
[23, 32],  deficits in decoding negative emotional facial expressions associated with 
abnormal rostral anterior cingulate activity [33],  enhanced reactivity to cues 
associated with increased activation of reward (NAc, midbrain and ventral PFC) [34], 
and limbic regions (amygdala, hippocampus and insula) [35] and the cue reactivity 
has been associated with craving and clinical severity [36, 37, 38].  Some of these 
changes and has shown improve after detoxification and treatment [37, 39, 40, 41]. 
The delay discounting tasks (DDT) is also disrupted in alcoholics (as well as other 
substance use disorders), and involves a greater discount of delayed reinforcers 
[42][43] that reflect impairments in self-control [44] and associated with deficits in 
prefrontal and cortical limbic regions (insula/orbitofrontal cortex)[45, 46].
More recently studies using resting functional connectivity (RFC), showed disrupted 
connectivity in the default mode network (DMN) [47], and in the saliency network in 
alcoholics [48]. Magnetic Resonance Spectroscopy (MRS) can quantify a variety of 
neurochemicals, including various neurotransmitters and their byproducts (glutamate, 
glutamine and GABA) constituents of metabolic pathways (choline and creatine) as 
well as the glial marker myo-inositol (mI) [49]. In recently detoxified alcoholics, 
higher concentrations of mI in thalamus, anterior cingulum and prefrontal white matter 
[50] have been reported when compared to controls. However, to our knowledge there 
are no studies that have assessed if these changes recover with detoxification. 
These studies providence evidence that chronic alcohol impairs brain structure and 
function and cognitive performance but they also indicate that some of these changes 
recover with detoxification. We hypothesize that some of the cognitive structural and 
functional changes reported in alcoholics reflect the effects of energy substrate 
deprivation that follows withdrawal from alcohol. Here we will test if a ketogenic diet 
can protect the brain from the negative effects of energy deprivation that we 
hypothesize occurs during alcohol detoxification. We hypothesize that this will result 
in a faster recovery of brain function. 
Ketogenic Diet
Ketogenic diets are based on foods high in fat but very low in carbohydrates. 
Ketogenic diets are approved non-pharmacological interventions for the treatment of 
child epilepsy [51, 52], [Metanalyses:53, 54]. In addition to the clinical efficacy of a 
ketogenic diet in epilepsy in decreasing seizures [55, 56], the diet has also been shown 
to improve sleep in children with epilepsy [57], and improved executive functioning 
in elderly healthy volunteers [58]. There is also increased interest on the value of 
ketogenic diets for other conditions, including diseases of substrate insufficiency or of 
insulin resistance, diseases of free radical damage and disorders of hypoxia [59], and 
preliminary evidence suggests a potential therapeutic role of ketogenic diets in brain 
and other cancers, hypoxia or ischemic encephalopathy, stroke, heart failure, 

17-AA-0152 (5/20/2022)
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Alzheimer's, Parkinsonism, amyotrophic lateral sclerosis, diabetes, autism, 
inflammatory disorders, migraine, severe hyperactivity [60, 61, 62].
Despite its clinical importance, studies on the effects of a ketogenic diet on the brain 
are scarce. Using MRS, the detection of cerebral β-hydroxybutyrate, acetone and 
acetoacetate have been reported in children with diabetic ketoacidosis during an 
episode [63], in a child with Ohtahara syndrome treated with a ketogenic diet [64], 
and in children with epilepsy on a ketogenic diet [65]. Further, an MRS study in 
patients with diabetic ketoacidosis showed increased myo-inositol and choline 
metabolism in gray and white matter; yet reduced N-acetyl metabolites in the parietal 
cortex, as compared to controls [66]. These studies suggest MRS to be sensitive for 
measuring ketone bodies in the human brain. 
Ketogenic diets are generally very well tolerated and safe. However, they are not 
recommended in patients that have a history of metabolic disorders and in the presence 
of clinical complications such as kidney stones, dyslipidemia, liver disorders, 
gastroesophageal reflux, constipation, cardiomyopathy and chronic metabolic acidosis 
[67]. Most complications of the ketogenic diet include short-lived gastrointestinal 
disturbances, acidosis, and dyslipidemia [54].
Genetic Testing (genotyping)
We will collect blood samples to test for specific biomarkers associated with responses 
to the ketogenic diet. We will determine if polymorphisms in the alcohol 
dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes predict the 
response to the ketogenic diet in alcoholics.  
Innovation 
This is the first study to evaluate the potential beneficial effects of a ketogenic diet for 
alcohol detoxification in alcoholics. 
Summary and Significance   
If beneficial effects of a ketogenic diet can be documented in the brain of patients with 
AUD, then this could be targeted as a therapeutic intervention to improve brain 
function and enhance success in recovery.
2. Study Objectives 
a. Primary objectives
To assess the effects of a ketogenic diet in alcoholic patients hospitalized for the 
treatment of alcohol detoxification, on: (1) withdrawal symptoms, which will be 
measured using the Clinical Institute Withdrawal Assessment for Alcohol-Revised 
(CIWA-Ar), as well as with the quantification of medications required to control 
withdrawal symptoms (benzodiazepines); (2) brain functions as assessed by fMRI 
(rest and activation), (3) MRS and (4) structural MRI. We will complete studies in 
50 alcoholics (25 given a ketogenic diet and 25 a regular diet). 

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b. Secondary objectives
To assess the effects of a ketogenic diet on cognitive performance, alcohol 
craving, sleep and mood.
3. Subjects
a.
Description of study populations 
Subjects include individuals diagnosed with an alcohol use disorder (AUD) that 
is moderate or severe and who are interested in treatment for their AUD.  The 
accrual number for the total study will be 100, of which the estimated number to 
complete studies are 50 AUD; half of whom are randomized to receive KD food 
and shakes for up to 4 weeks while inpatient.  We expect that 50% of subjects 
that undergo screening will not complete the study or don’t fulfill criteria.
b.
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.
c.
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.

17-AA-0152 (5/20/2022)
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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 
550 lbs.
11.
Milk or soy allergy (self-report).

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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 THC-COOH, 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. 
4. Study Design and Methods
a.
Study overview 
This study includes an inpatient component and outpatient follow-up. 
Patients are admitted to the Clinical Center (CC) for detoxification and treatment 
as usual (TAU) under protocol 14-AA-0181. Under the current protocol, patients 
will be randomized into a meal and shake plan consisting of either a standard 
American (SA) versus a ketogenic diet (KD).  Patients will be given 
benzodiazepines only if withdrawal symptoms emerge while receiving either the 
KD or the SA diet. Subjects may be administered benzodiazepines only if 
withdrawal symptoms emerge.  On day 2-6 after admission, all patients will 
undergo an MRI (brain structure, functional reactivity, functional connectivity 
and MRS) and will have a battery of neuropsychological tests (NP).  Personality 
tests will be obtained during week 1 at the time of NP testing.  The MRI scans 
will be repeated at 1 week intervals (Week 2 and 3).  The Sleep Profiler device 
will be obtained 2X p/week in weeks 1-3.  The ™GENEActiv (actigraphy) will 
be done for an entire week in weeks 1 and 3.  The NP studies will be repeated 
coincident with the last MRI session. We will complete studies on at least 25 
alcoholics with the ketogenic diet and 25 with the regular diet. 
Procedures
Week 
1
Week 
2
Weeks 
3-4
KD/SA Randomization (solid food and shake) 
3 snacks and 3 shakes p/day until stopped – 
up to 4 weeks while inpatient
x
x
x
Neuropsychological test battery (NPT)
x
x
Personality tests
x
MRI Scan session (structure, functional 
reactivity, functional connectivity, MRS) ~ 3 
hrs
x
x
x
Sleep Profiler
2x
2x
2x

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™GENEActive (actigraphy) – full week
x
X
Urine tests for ketones
Daily
Daily
Daily
Finger pricks for ketones
up to 5x
up to 5x
up to 5x
Blood tests for ketones and ghrelin
2x
1x
1x
Blood tests for fatty acids, liver function, 
platelets and coagulation
1x
1x
1x
Time points are targets, and the order can be adjusted for practical considerations 
during the inpatient stay.
Upon discharge from the NIH CC, participants in the study will be followed up 
for 3 months.  For this purpose, we will call the participants by phone at weeks 1, 
2, 4, 8 and 12 to ask questions about relapse and sobriety.  This will take about 5 
minutes or less.  The following questions which are from the Alcohol Timeline 
Follow Back (ATFB) will be asked during the follow up:
i.
In the last 7 days, did you drink any alcohol?;  Y___N___
ii.
If yes we then ask “On what days did you drink”?; and 
iii.
How much did you drink?
b. Recruitment
Participants will be recruited through referrals from the NIH Volunteer Office, 
the Patient Recruitment and Public Liaison (PRPL) Office, the NIAAA 
Intramural Research Program screening protocol 14-AA-0181 and through 
ResearchMatch.org and www.craigslist.com.
Participants (including NIH employees with an AUD) will also be recruited by 
word of mouth and through IRB-approved local advertisements.  There will be 
no direct solicitation of employees by supervisors or coworkers.  These will 
include: (1) Flyers posted on NIH campus, campuses of universities and colleges, 
public places and public transportation services in the greater Washington DC 
area; (2) Advertisements in electronic and printed local media (newsletters, 
websites 
including 
www.niaaa.nih.gov/join-study#, 
researchstudies.drugabuse.gov, newspapers including the Baltimore Beat, 
Baltimore Sun, the Beacon, Washington City Paper, Streetsense, the Express, 
craigslist.org, NIH and other local email distribution lists), following IRB 
approval, (3) through substance abuse treatment programs of clinics (e.g. Caron 
Treatment Facilities).
ClinicalTrials.gov may also represent a source of recruitment.
Participants will also be recruited via the NIAAA clinical program.
c.
Telephone Pre-Screening
Initial contact with potential subjects will be done through use of a telephone pre-
screening questionnaire.  Subjects will be briefly interviewed over the telephone 
to determine that they report meeting inclusion and not meeting exclusion criteria 

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as described above.   Subjects who appear to meet criteria will be scheduled for a 
screening visit.  Subjects who do not meet criteria based on this telephone 
interview will not be scheduled for a screening visit and their telephone screening 
form will be shredded in a cross-cut shredder.
d.
Admission and Initial Screening:  Participant will be admitted to the NIAAA 
inpatient unit (under NIAAA protocol #14-AA-0181) for detoxification where 
they will remain for about 4 weeks.  Participants will be screened under the 
protocol 14-AA-0181 titled “Unit and Clinic Evaluation, Screening, Assessment 
and Management” and the results will be shared with this protocol. All 
inclusion/exclusion tests will be done under 14-AA-0181.  Tests may be repeated 
to assure eligibility.  In addition, any test required to insure ongoing eligibility 
(pregnancy testing prior to MRIs for women of childbearing potential) will be 
done as necessary in subsequent visits under the ketogenic diet protocol.
The first step for our screening is to obtain informed consent for 14-AA-0181 
prior to any procedures being implemented.  Subjects will undergo a 
comprehensive medical history and physical examination by a clinically 
credentialed licensed independent practitioner. The purpose of the medical 
history and examination is to rule out serious medical conditions that may be 
contraindications to protocol participation.  A copy of the medical evaluation will 
be placed in the subjects NIH chart.  Screening procedures will include: 
Demographics; vital signs including height, weight and temperature; standard 
laboratory tests (Chem Screen, CBC, and Urinalysis); STAT urine tests to 
identify drug abuse and NP testing; a urine pregnancy test for females who are 
able to become pregnant; and an EKG.  We will also interview the subject to 
obtain a lifetime drug history (including but not limited to everything from 
caffeine, tobacco, alcohol, and common illicit drugs) and we will administer self-
report questionnaires, which provide descriptive data necessary to our brain 
imaging program.  Some of the self-report assessments will be administered to 
evaluate the inclusion of participants as well as to provide descriptive data in all 
of our subjects.  It is possible that subjects could be excluded from the ketogenic 
diet study based on the information they provide to us. If on the 14-AA-0181 
admission and screening day the subject agrees to participate, they are given the 
informed consent for the ketogenic diet study.
e.
Study procedures
Study Timeline:  After admission and initial 14-AA-0181 screening, AUD 
patients who agree to participate will first sign the consent for this study and then 
begin to undergo detoxification in the 1SE unit under 14-AA-0181.  The current 
protocol will involve being randomized into one of two diets.  One diet consists of 
a ketogenic diet (KD) snacks and shakes 3x p/day (high in fat).  The other liquid 
diet consists of a standard American (SA) diet shakes 3x p/day in the proportions 
of carbohydrates, protein and fat of traditional western diet.  SA will receive the 
same KD solid snacks, in order to keep the diets blind to participants.  Both diets 
will be eucaloric such that a standard equation based on weight, height, sex and 

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age will be used to determine how many calories are provided to each participant.  
While on the KD/SA diet, patients are limited to drink non-caloric drinks (water, 
diet soda, coffee and tea without milk or sugar). In addition to the diets, 
MRI/fMRI/MRS scans, genetic tests, self-report ratings, motor activity, sleeping 
behavior, NP testing and personality measures will be obtained in all participants.
The first MRI session and the first NP testing will be performed within the first 
2-6 days of admission. The MRI sessions will be repeated on a weekly basis 
(second and third week of hospitalization; the later corresponding to the last week 
of their inpatient stay) and the NP testing will be repeated during the third week 
of hospitalization. MRI scanning session and NP tests are described below and are 
for research purpose only. 
During the inpatient period, participants will be periodically monitored for signs 
of withdrawal and evaluated for mood, sleep and alcohol cravings. Compliance 
with diet adherence (KD or SA) will be closely monitored during the hospital stay 
using daily urine tests.  
After the final MRI sessions, the study diets are discontinued and the individual 
blind will be broken on a per subject basis.  If KD is discontinued this will be done 
by slowly increasing the levels of carbohydrates to the diets of the SA group [68]. 
The levels of carbohydrates in the control group remains constant throughout the 
study, but patients are still blind to treatment group. 
Participants will then be released at about 3-4 weeks from the Clinical Center and 
will have a 3 month follow up period under this protocol which is discussed below 
in section 4.d.12 Follow-Up.
1. Ketogenic Diet (KD) / Standard American (SA) Snacks and Shakes:  
Participants will be randomized to a meal plan of either a ketogenic diet (KD) 
or standard American (SA) diet at the time they sign the consent (day 1 or 2 
of admission). For each meal at breakfast, lunch and dinner, the diets will 
consist of SA meal (carbohydrate rich) or KD meal   depending on treatment 
randomization. Compliance tests are done daily with urine tests measuring 
ketone levels by an independent person (BSN RN) [69], results of which are 
retained.  To ensure that the diet is double blind in both the outpatient and 
inpatient phases, solid snacks are always ketogenic and shakes are either KD 
or SA.  
To measure the effectiveness of the ketogenic diet in increasing ketone 
bodies, we will measure ketones in urine daily as recommended for 
monitoring ketogenic diets in the management of epilepsy [70].  Specifically, 
we will measure acetoacetate (AA) in urine, in the early morning starting the 
day after initiation of the KD diet or the control diet and every day thereafter.  
We will use over-the-counter reagent strips (Ketostix, Bayer Vital GmbH, 
Leverkusen, Germany), which determine the presence of AA. Moreover, 

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beta-hydroxybutyrate (BHB) will be measured up to 5 times per week with a 
finger prick (Precision xtra, Abbott).
We will also measure beta-hydroxybutyrate and acetoacetate in blood at 
baseline and once each study week and free fatty acids once per week (no 
more than 8mL per week). These measures will be associated with MRS 
measures (e.g., correlate beta-hydroxybutyrate and acetoacetate in blood with 
β-hydroxybutyrate and acetone concentrations in the anterior cingulate and 
frontal white matter), and will provide information on potentially unwanted 
consequences of KD (e.g., potential disturbing effect of KD on free fatty acid 
concentrations). If the Laboratory of Medicine at the Clinical Center cannot 
provide quantitative measures for beta-hydroxybutyrate and acetoacetate, 
assays will be used from Wako Chemicals GmbH, Neuss, Germany).  We will 
also measure plasma ghrelin (up to 6cc) at baseline and on a weekly basis.
Weekly blood draws are scheduled to monitor liver function (2.5 cc), platelet 
counts (2cc) and coagulation (INR, 3cc).
2. Randomization and blinding: The study has a blinded and randomized 
design. A randomization code will be generated prior to recruiting and patient 
randomization will be assigned accordingly. Since we expect a larger dropout 
in the KD group, we pre-set the ratio of KD:SA participants as 3:2 in the 
randomization generation.* Nurses and research staff who do CIWA, craving 
ratings and other study procedures with patients will not have access to the 
randomization key. An independent person (BSN RN) will perform and 
analyze daily ketone testing and blood pricks and will have access to the key. 
The nutrition department also has access to the randomization key to prepare 
the diets, but patients’ diets will be sent out without information on its 
contents.* This ratio will be set for the first 20 participants. After the 
enrollment of 20 participants, the ratio will be evaluated by an dindependent 
person (BSN RN) based on diet compliance during their 3 weeks inpatient 
stay as per questionnaire and urine screen. Results are shared with the PI who 
will modify the ratio if needed to aim for a 50% KD versus 50% SA study 
completion.
3. Diet Compliance: In addition to daily urine tests (described above in section 
4.e.1) and blood pricks, a daily questionnaire on whether additional food was 
consumed and whether the participant was compliant will be assessed by an 
independent person (BSN RN).  On each day, participants will be asked if 
they were compliant to the diet (i.e. the shakes and snacks provided), or if 
additional food was consumed.  If yes, which food items and at what time.  At 
that time, they will also be encouraged to be compliant with the diet.  All 
participants will be motivated on a daily basis to be compliant to their diet by 
nutrition department staff.  If after the first 3 days of diet initiation a 
participant (in either KD or SA) self-reports non-compliance to the diet for 4 

17-AA-0152 (5/20/2022)
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days, the PI will be informed and participant will be withdrawn and excluded 
from further study participation.
Additionally, if after the first 5 days of diet initiation, a participant in the KD 
group has 3 urine tests that are negative for ketone bodies, this participant will 
also be removed from the study.  In this case, the independent person who 
monitors daily urine testing, will inform study staff about the compliance 
breach and the patient will be removed from the study.  
In this way, all participants will remain in the study for at least the first 7 days 
and will be included in the analysis on the effects of KD on withdrawal 
symptoms, benzodiazepine use, MRI and NPT within the first 7 days. After 7 
days participants may be withdrawn from the study based on non-
complicance to the diet.
4. MRI scans:  MRI evaluations of the brain are being performed at 3Tesla 
(3T)  (Siemens Prisma). These MRI scans are performed on FDA-approved 
scanners with approved radiofrequency coils, and their use conforms to the 
corresponding FDA labels. The MR scanner is being used in normal mode 
(not research mode) using the following pulse sequences: magnetization-
prepared 
rapid 
gradient-echo 
(MPRAGE), 
Prospective 
Acquisition 
Correction (3D PACE), diffusion tensor imaging (DTI), echo-planar imaging 
(EPI), arterial spin-labeling (3D ASL), and Magnetic Resonance 
Spectroscopy (MRS).
MR acquisition:  A high resolution T1-weighted magnetization-prepared 
rapid gradient-echo pulse sequence (MP2RAGE) will be used to map brain 
structure with high spatial resolution and excellent gray-white contrast and to 
map T1 relaxation in the brain. DTI, an MRI technique that can quantify 
isotropic and anisotropic water diffusion, will be used to map fractional 
anisotropy and the apparent diffusion coefficient, and to assess the structural 
connectivity of the brain. ASL, an MRI-based method that utilizes blood as 
an endogenous tracer and provides noninvasive quantification of tissue 
perfusion, will be used to map CBF in the resting state. BOLD-weighted 
functional images will be collected to measure brain activation and to map 
functional connectivity.  Brain activation paradigms:  We will use passive 
viewing of neutral, food and drug related pictures [40 pictures per category; 
the neutral, alcohol and food pictures will be selected from freely available 
online and in-house collections) [71, 72]. Pictures will also be rated for 
characteristics such as valence, liking and wanting.  The stimuli are presented 
to the subjects on an MRI-compatible 32-inches LCD screen synchronized 
with the MR acquisition using an MRI trigger pulse. 
We will use the delayed discounting task (DDT) to evaluate effects on self-
regulation.  The DDT task has been used extensively [for review see [73]. It 

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allows measurement of BOLD response to immediate reward responses 
versus responses to delayed rewards. 
Additionally, we will measure the visual attention task (VAT), which is 
obtained to assess the attentional network, which we and other have shown to 
result in reproducible and robust activation patterns and to be sensitive to 
cognitive impairment in substance use disorders [74, 75].
fMRI for Functional Connectivity:  For functional connectivity we will collect 
three 8 min long RFC scans while subjects keep their eyes open (for resting 
scans this allows us to ensure patients don't fall asleep) while the subjects 
watch a fixation cross on a black screen. During the first minute of the RFC 
scans the subject will watch a 1 minute long alcohol or nature movie scenes 
or a black screen.  An eye tracker will be used to measure subjects’ gaze and 
pupil size during the RFC scan. 
Eye blinking:  as part of the fMRI procedures subjects blinking will also be 
monitored using an eye tracker [76]. Specifically, we will use a semi-
automatic model to detect the eyelid contour from high-speed video data from 
an MRI compatible eye tracker. This method provides eye-blink 
measurements with a detection rate better than 90%. 
MRS acquisition: Large voxels (8 cm3) in anterior cingulate cortex and 
prefrontal white matter will be used for maximal SNR and minimal spectral 
linewidth.  MRS data will be acquired using a point-resolved spectroscopy 
sequence (PRESS) with short echo time (TE/TR = 30/2000 ms). First and 
second order shimming will be used to maximize the magnetic field 
homogeneity in the voxel. The chemical shift selective CHESS technique will 
be used for water suppression. Water suppressed spectra will be analyzed 
using the commercial LC model program using a metabolite spectra database. 
An absolute quantification approach with the “brain water” amplitude as a 
concentration reference will be used during spectral fitting in LC model [77]. 
Repeating MRI/MRS scans - Because fMRI and functional connectivity scans 
are sensitive to excessive head movement, participants who generate unusable 
data (or if there is an equipment failure) during their scanning session may be 
asked to repeat the session.  The likelihood of repeating MRI/MRS is small.  
However, if it becomes necessary we will only repeat one session.
5. Ratings for Mood, Sleep, and Alcohol Craving:  Participants rate the 
quality of their sleep on a daily basis (estimated sleep length in hrs, depth: 1-
10, rested 1-10). Patients are also asked questions about their mood on a scale 
of 1-10 (e.g., Alert, Tired, Happy, Energetic). 

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Prior to diet initiation, and then on each MRI day (up to 5 times in total), 
participants fill out the Desire for Alcohol Questionnaire [78] – a 14 item 
alcohol craving scale.
Mood will be assessed since dysphoria is frequently present during alcohol 
withdrawal and contributes to relapse [79]. We will obtain these measures 
since we want to assess if improving brain energetics would decrease 
withdrawal symptoms and improve brain function along with improved 
mood, and sleep and a reduction in alcohol craving.
6. Motor Activity and Sleeping Behavior measured with ™GENEActiv:  To 
assess spontaneous motor activity we will ask participants to wear the 
GENEActiv accelerometer during their inpatient stay during two separate 
weeks. The recording from the GENEActiv will also allow us to determine 
the average number of hours slept per day and the subject’s levels of 
spontaneous motor activity. The GENEActiv measures can be obtained prior 
to or after completion of the PET scans.  The actigraphy will give us a measure 
of hours slept per day, which is of interest since insomnia is a key symptom 
of alcohol withdrawal [80].  
™Sleep Profiler:  Participants will be hooked up to the Sleep Profiler twice 
per week during their inpatient stay.  Sleep Profiler is an ambulatory device 
providing a flexible and relatively easy way to detect sleep/wake stages 
compared to traditional polysomnographic devices.  It is worn on the head, 
where the main part holds onto the forehead with plastic straps with 3 
electroencephalogram (EEG) electrodes placed underneath. It also has two 
extension cables connected to two electrodes placed on the collar bones which 
measures Electrocardiography (ECG).  With the inclusion of head position 
sensors and snore detection via microphone, this FDA approved device 
provides full scale detection of sleep status. The sleep measure is of interest 
since insomnia is a key symptom of alcohol withdrawal [80].  Preclinical 
studies have demonstrated a role of ketone bodies in sleep regulation [81], 
and a ketogenic diet has been found to improve sleep quality in children with 
epilepsy [57]. If KD also improves sleep in alcoholism, this may mediate 
improvement in alcohol withdrawal and brain function.
7. Neuropsychological Tests:  We will obtain a NP battery of tests at baseline 
once it is determined that the subject meets eligibility and after 3-4 weeks of 
detoxification and ketogenic/control diet. This battery takes about 90 minutes. 
We will use the Cambridge Neuropsychological Test Automated Battery 
(CANTAB), which is a computerized battery of tests [82]. The CANTAB has 
normative data and has good reliability [83] and is sensitive to cognitive 
deficits in alcoholism [23, 84]. We will obtain the following CANTAB tests:  

Reaction Time –Multiple choices reaction time test.  

Stop Signal- it's a measure of response inhibition

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
Intra/Extra-Dimensional Set Shift–Attention test, similar to the 
Wisconsin Card Sorting Test.  

Pattern Recognition Memory-Visual pattern recognition memory test.   

Stockings of Cambridge–Visuospatial planning test that is on the 
‘Tower of London’ test.   

Spatial Span–Spatial working memory span test.  

Spatial Working Memory–This is a test of a subject's ability to retain 
and to manipulate spatial information in working memory. 

*Cambridge Gamble Task, test of decision making

Affective Go/No-go – test for emotional bias

Emotion Recognition Task–test to assess social cognition
* We selected the gambling task since it is disrupted in alcoholism and will 
serve as measure of risk taking and impulse control.
http://www.cambridgecognition.com/?gclid=CNH9qq-
96roCFWrNOgodvHsA8Q 
Personality Measures and Questionnaires: Within the first week of 
admission we will obtain the:

Multidimensional personality questionnaire (MPQ), which measures 
three main personality dimensions: Positive Emotionality or PEM (or 
extraversion), Negative emotionality or NEM (or neuroticism) and 
constraint [85]. These measures tap into characteristics associated with 
vulnerability to substance use disorders and correlate with specific 
patterns of brain activity [86].  The MPQ takes about 35-45 minutes to 
complete. 

Morningness-Eveningness Questionnaire (MEQ), which provides a 
self-report circadian typology that is based on the preferred timing for 
activity, sleep/wake preferences, and optimal timing for mental 
alertness [87]. Responses to these items are considered to represent 
underlying circadian function.

The Beck Depression Inventory Second Edition (BDI-II) is a 21-
question multiple choice self-report inventory for measuring the 
severity of symptoms of depression as listed in the DSM-IV [88].
Personality measures with the MPQ will be collected to determine if they 
are associated with the biochemical measures. Our group has shown that 
MPQ’s Positive Emotionality covaried with baseline glucose metabolism in 
the brain (i.e, orbitofrontal cortex and default mode network) [86] and that 
in alcoholics Negative Emotionality was associated with decreased 
expression of D2R in striatum in alcoholics [89].
8. Genetic Testing (genotyping):  All participants will be asked to give a total 
of 10 ml of blood split into two vials containing 5 ml each (1 teaspoon) for 

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genetic research purposes.  Providing blood for genotyping is optional. The 
genetic material, DNA, will be extracted from one of the samples and 
analyzed in order to identify polymorphisms in the genes related to alcohol 
metabolism.  Specifically, DNA is collected in order to assess if 
polymorphisms in the alcohol dehydrogenase (ADH) and alcohol aldehyde 
dehydrogenase (ALDH) genes predict the response to the ketogenic diet in 
alcoholics.. Genetic testing will not influence diagnoses or treatment in AUD 
participant. Leftover DNA and the other 5 ml sample will be stored for future 
use.
9. Plasma Ghrelin: It was recently found that a KD intervention decreases 
plasma ghrelin levels and subjective appetite ratings in healthy volunteers 
[90]. This finding is relevant to AUD, since ghrelin levels have been 
positively associated with alcohol craving [91, 92, 93] and with alcohol 
consumption [94] in AUD. Therefore, we will also measure plasma ghrelin 
(up to 6cc) at baseline and on a weekly basis, and associate these scores with 
alcohol craving.
10. End of diet questionnaire
At the end of study participation, patients will be asked to fill out an end of 
diet questionnaire: 
- Which diet did you think you were on? Ketogenic diet / Control diet 
- How certain are you about this answer? (0-10; not at all certain – extremely 
certain) 
- What makes you believe you were on the ketogenic or control diet? [..]
- How pleasurable was it to be on the diet? (0; not at all – extremely)
- Do you think your diet improved your health? (0; not at all – extremely)
- Would you continue the diet if you could? Y___N___  Maybe if [..]
11. Saliva THC screen
On days of MRI/NPT, if a urine drug screen is positive for THC-COOH, a 
saliva drug screen will be performed using the Draeger DrugTest 5000 
(Draeger Safety Diagnostics, Lübeck, Germany). The Draeger DrugTest 5000 
has a 5 μg/L THC screening cutoff, and has shown high diagnostic sensitivity 
(90.7%), specificity (75.0%), and efficiency (87.9%) [95, 96]. DrugTest 5000 
test results were positive for a median of 12h after last cannabis (range: 4-
24h) for occasional smokers, and 21h (range: 1-≥30h) for frequent smokers 
[97].  
The DrugTest 5000 test cassette is equipped with a polymeric non-
compressible pad for oral fluid collection. Oral fluid will be collected by 
swiping the test cassette on the tongue and side of the cheeks. The test cassette 
collects 270μL±15% oral fluid, as indicated by the volume adequacy 
indicator. Oral intake (eating, drinking, cigarette smoking) will be prohibited 
10 min before oral fluid collection. The analysis procedure takes about 5 
minutes.

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The saliva drug screens are for qualitative research purposes only and will not 
be stored.
12. Follow-Up:  We assess participants post discharge at weeks 1, 2, 4, 8 and 12 
to ask questions about relapse and sobriety.  This will take about 5 minutes or 
less.  The following questions which are from the Alcohol Timeline Follow 
Back (ATFB) will be used:  
In the last 7 days: 
Did you drink any alcohol?;  Y___N___  
If yes we then ask “On what days did you drink”?; and  
How much did you drink?
f.
End of participation
While all steps are always taken to ensure quality data from all participants, we 
may ask participants who generate unusable data (or if there is an equipment 
failure) on one of their experimental sessions to repeat that session.  This will 
have the effect of maximizing the risk/benefit ratio as it will prevent having to 
discard usable data from one session and will minimize the number of participants 
recruited overall to obtain sufficient data to meet power requirements.  We may 
ask the participant to return at a later date or to repeat study procedures for genetic 
testing (genotyping) and/or MRI scans. Subjects will receive additional 
compensation if any MRI/MRS session scans are repeated.  Compensation for 
repeated imaging scans will be the same as described in Section 23 Research and 
Travel Compensation table. 
5. Management of Data and Samples
a.
Storage
Data will be stored on an NIH data server, under the management of the ORIT, 
NIAAA. The existence and types of information contained in the data 
management system have been publicly reported as required by the FOIA.
Subject data will be stored in one of two locations. Fully identifiable data will be 
stored in the NIH Clinical Center CRIS system, where clinical patient data are 
routinely stored and adequate privacy protections are implemented by design.  
Additional data will be stored in the B2L124 NIAAA/LNI space in Building 10 
on an access controlled NIAAA server located in secured space to prevent 
physical theft of storage media.  We will feed some of the data residing in CRIS 
and on the NIAAA servers to the NIH Biomedical Translational Research 
Information System (BTRIS).  Data on the NIAAA server will be kept in a coded 
form. The code key will be kept separately by the trial leader or designee.
Biological specimens obtained under this protocol will be stored in coded form 
(protocol identifier plus randomization number), in freezers located in Bldg 10 
CRC Room 1528 area of NIAAA.  We will collect 10 ml of venous blood from 

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each participant, which will be divided into 2 parts; one of which will be frozen 
and stored at -80ºC and the other to be used for DNA isolation and subsequent 
genotyping tests. 
We will collect DNA so that in the future when new findings emerge with respect 
to genes implicated in brain diseases so we can assess across integrated data from 
various brain imaging studies if they are associated with changes in brain 
connectivity.  However, DNA collection will be optional and will not exclude 
subjects from participating in this study if they do not want to give blood for 
genotyping.
b.
Data including genomic data and sample sharing plan
Samples and data, including genomic data may be shared with collaborators. 
The following questionnaires/assessments/interviews collected under the 14-
AA-0181 will be shared with this protocol:  Smoking History Questionnaire 
[98]; Fagerström Test for Nicotine Dependence (FTND) [99]; The Timeline 
Follow-Back (TLFB) [100]; Alcohol Use Disorders Identification Test (AUDIT) 
[101]; Barratt’s Impulsivity Scale (BIS-11) [102]; Structured Clinical Interview 
(SCID) for DSM-IV or DSM 5 [103]; Alcohol Dependence Scale (ADS) [104]; 
and Clinical Institute Withdrawal Assessment – Alcohol revised (CIWA-Ar) 
[105].
Data and samples may also be shared with collaborating laboratories at NIH or 
outside of NIH and/or submitted to NIH-designated repositories and databases if 
consent for sharing was obtained.  Repositories receiving data and/or samples 
from this protocol may be open-access or restricted access. 
Samples and data will be stripped of identifiers and may be coded (“de-
identified”) or unlinked from an identifying code (“anonymized”). When coded 
data is shared, the key to the code will not be provided to collaborators, but will 
remain at NIH.  Data and samples may be shared with investigators and 
institutions with an FWA or operating under the Declaration of Helsinki (DoH) 
and reported at the time of continuing review.  Sharing with investigators without 
an FWA or not operating under the DoH will be submitted for prospective IRB 
approval.  Submissions to NIH-sponsored or supported databases and repositories 
will be reported at the time of Continuing Review.  Submission to non-NIH 
sponsored or supported databases and repositories will be submitted for 
prospective IRB approval.
Required approvals from the collaborating institution will be obtained and 
materials will be shipped in accordance with NIH and federal regulations.

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6. Additional Considerations
a. Research with investigational drugs or devices
N/A
7. Risks and Discomforts
Potential risks from this study include the following: 
a. Medical examination and Laboratory testing: Medical examinations are 
associated with minimal risks. We will first explain and familiarize the subjects 
with the laboratory testing to minimize discomfort, if any, during testing. Tests 
may disclose that the potential subject’s health is at risk.  If there are abnormal 
tests uncovered as part of the physical examination, this information will be 
given to the subject and explained by a physician who will encourage them to 
seek medical evaluation with their primary care physician.
b. Ketogenic diet (KD): Ketogenic diets are not recommended in patients with 
urolithiasis, liver disorders, cardiomyopathy and chronic metabolic acidosis 
[67]. Despite been a controversial treatment, the ketogenic diet has been studied 
as a treatment aid for dyslipidemia, obesity diabetes, epilepsy, brain tumors, 
autism, and neuroprotection with positive results. We will exclude participants 
with a history of urolithiasis and liver disorders other that mild alcoholic hepatic 
changes to decrease the risk to the participants.  Liver function will be 
monitored during the study on a weekly basis as it is standard during the detox 
and treatment of alcoholism. The diet will be discontinued if there is a 
progression of liver damage after the detox is completed (3-5 x the upper-bound 
limit). KD may also have potential side effects, including GI discomfort and 
constipation, dyslipidemia, and low platelet counts and coagulation problems. 
Platelet counts and coagulation will be monitored on a weekly basis and the diet 
will be discontinued if platelet count < 100.000 or INR > 1.5. Free fatty acid 
levels in blood will also be monitored on a weekly basis. To facilitate 
compliance and decrease the burden on the participants the diet will consist of 
a primarily liquid diet (house-made by Nutrition Department), in combination 
with ketogenic solid snacks (e.g., eggs, meat, fish, vegetables). The meals will 
be provided after an assessment with the nutritionist. Most of our treatment 
seeking alcohol dependent subjects have chronic problems with malnutrition 
and have a very poor intake of solids while they drink.  Therefore, the liquid 
diet was considered a better option to improve compliance. An additional 
benefit is that it provides a way to make patients unware of whether they are in 
the ketogenic- or control diet group. We will measure ketones on a weekly basis 
for diet compliance.  If a subject is withdrawn from the study for non-
compliance to the diet, he/she will be paid for procedures completed up to the 
point of withdrawal.   
c.
Venous line placements: Subjects may have some discomfort and bruising from 
the needle insertion. Some people feel light-headed or faint.  The risks of an 

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intravenous catheter also include bleeding, infection, or inflammation of the 
skin and vein with pain and swelling. These will be treated if they occur.
d. Blood sampling:  Blood draw volumes will not exceed the limits allowed by the 
NIH Clinical Center (Medical Administrative Policy 95-9: Guidelines for 
Limits of Blood Drawn for Research Purposes in the Clinical Center: 
http://internal.cc.nih.gov/policies/list_policies.asp?index=med_chrono).  Blood sampling 
may lead to the formation of a small subcutaneous hematoma caused by blood 
leaking from a punctured blood vessel. This hematoma causes only minor 
discomfort. It is not dangerous and requires no treatment other than reassuring 
the patient. There is also a small risk of infection at the site of the needle 
puncture, which can be readily treated with antibiotic therapy. Subjects will be 
asked not to donate blood for a period of eight weeks after the participation is 
completed.  The approximate amount of blood drawn in this protocol is as 
follows: Screening labs: 30 cc (obtained under 14-AA-0181); and Genotyping: 
10 cc; plus up to 48 cc for research purpose to measure free fatty acid and ketone 
concentrations, 24 cc for ghrelin, and up to 23 cc for weekly liver function, 
platelet count and coagulation. Total amount over course of study not to exceed 
140 cc. 
e.
MRI Risks:  People are at risk for injury from the MRI magnet if they have 
pacemakers or other implanted electrical devices, brain stimulators, some types 
of dental implants, aneurysm clips (metal clips on the wall of a large artery), 
metallic prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments.  
Welders and metal workers are also at risk for injury because of possible small 
metal fragments in the eye of which they may be unaware.  Subjects will be 
screened for these conditions before having any scan, and if he/she has any, 
he/she will not receive an MRI scan.  If a subject has a question about any metal 
objects being present in his/her body, he/she should inform the staff.  In 
addition, all magnetic objects (for example, watches, coins, jewelry, and credit 
cards) must be removed before entering the MRI scan room.  
It is not known if MRI is completely safe for a developing fetus.  Therefore, all 
women of childbearing potential will have a pregnancy test performed no more 
than 24 hours before each MRI scan.  The scan will not be done if the pregnancy 
test is positive.  
People with fear of confined spaces may become anxious during an MRI.  
Those with back problems may have back pain or discomfort from lying in the 
scanner.  The noise from the scanner is loud enough to damage hearing, 
especially in people who already have hearing loss.  Everyone having a research 
MRI scan will be fitted with hearing protection.  If the hearing protection comes 
loose during the scan, the subject should let a member of the staff know right 
away.  The subject will be asked to notify the investigators if he/she has hearing 
or ear problems.  The subject will be asked to complete an MRI screening form 

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for each MRI scan he/she has.  There are no known long-term risks of MRI 
scans.
f.
Genotyping (genetic tests):  The genetic testing that will be done as part of this 
study is for research purposes only and results will not be placed in the medical 
record.  It will not provide any information about the participant’s health or 
ancestry.  It is our policy to not provide the results of such genetic testing to 
study participants.  Problems, such as with insurance or employment 
discrimination, may occur if a participant discloses information about this 
genetic testing or if he/she agrees to have his/her medical records released.  We 
will not release any information about a participant to any physician, insurance 
company or employer unless he/she signs a document allowing release of the 
information.
g. Blood Banking For Future Genetic Studies:  This will allow us to repeat our 
genetic tests, thus to ensure and validate the genotyping results.  In addition, we 
will be able to conduct analyses of new variations in the brain related genes that 
are yet to be discovered.   Blood samples will be stored in secured freezers on 
the NIH campus. The participants name and identifying information will not be 
on the samples; we will assign them a code.  The key to the code will be kept 
in a separate, secure area.  The samples may be used for other research 
projects.  If participants do not want his/her sample used for other projects, 
he/she should not participate in this study.  If a participant withdraws from this 
research project before it is complete, any remaining samples he/she have 
contributed will be discarded.  Results obtained before he/she withdraws will 
be kept and the participant’s privacy will be protected.
h. NP and personality measures: These tests are not harmful, but may be 
frustrating or stressful. Subjects may refuse to answer any question that makes 
them uncomfortable and may stop a test at any time and for any reason.
i.
™GENEActiv (actigraphy): Actigraphy is a non-invasive method of monitoring 
rest/activity cycles and is used to study sleep/wake patterns. It can be worn on 
a participant’s wrist to continually record movement, therefore measuring gross 
motor activity. The data can later be transferred to a computer for analysis.  
There are no known risks of wearing the ™GENEActiv watch.
j.
Sleep Profiler Risks:  Sleep Profiler is a non-invasive method of monitoring 
sleep/wake cycles.  It is a device that is worn on the head, where the main part 
holds onto the forehead with plastic straps with 3 electroencephalogram (EEG) 
electrodes placed underneath. It also has two extension cables connected to two 
electrodes placed on the collar bones which measures Electrocardiography 
(ECG).  This device is FDA approved for the use indicated in the protocol.  
There is minimal risk associated with this device.  The conductive gel and/or 
adhesive used to attach the electrodes to skin may cause mild irritation.

17-AA-0152 (5/20/2022)
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8. Subject Safety Monitoring
Subjects’ safety will be monitored by the medical advisory investigator (MAI).
If any participant reports an adverse reaction to the experiment or demonstrates 
adverse responses during the post-experimental assessment of adverse events (AE), 
or appears to be in distress at any point during the experiment, the procedures will 
stop and the patient will meet with the medical advisory investigator to assess 
suitability for continuation in the study. Additionally, procedures will be stopped for 
any participant who asks to stop them at any point.  The reasons for participants’ 
discontinuation from the study will be logged and changes to procedures necessary 
to prevent future adverse reactions will be made.
Any individual may withdraw from the study at any time and with no penalty.  This 
option is clearly stated in the consent form and will be emphasized to participants.
NCI Common Terminology Criteria for Adverse Events v. 3.0 will be used for 
grading and reporting adverse events (CTCAE, 2007).
Criteria for individual subject withdrawal

Significant AE, including clinically significant changes in mood or behavior 
such as aggression, agitation, depression or suicidal ideation or suicidal 
behavior.

Pregnancy

At the discretion of the Principal Investigator (PI) and Medical Investigator, 
based on adverse event (AE) severity

Non-compliance with protocol procedures or investigator request(s)

Patient request
9. Outcome Measures
a.
Primary outcome measures:
To assess ketogenic diet on:
1. Withdrawal ratings (CIWA) and Benzodiazepine use during withdrawal in 
the first week of detoxification.
2. Brain function (during rest and activation assessed with fMRI), 
neurochemistry (assessed with MRS) and structure (assessed with MRI).
3. NP performance.
b.
Secondary outcome measures
To determine if ketogenic diet improves: 
1. sleep.
2. mood.  
3. alcohol craving.

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10. Statistical Analysis
a.
Analysis of data/ study outcomes
Withdrawal symptoms:  We will use the CIWA-Ar to measure alcohol 
withdrawal, which will be measured daily [106, 107].  Because there are no 
studies on the KD on withdrawal symptoms we cannot predict the effect size to 
be expected.  We will compare the scores on the CIWA-Ar between participants 
on the KD and participants on the control diet.  Based on effects of medications 
used for treatment of withdrawal symptoms we expect a 30 % reduction in 
CIWA-Ar scores with KD [108]. 
fMRI data will be analyzed using standard software such as statistical parametric 
mapping (SPM) software, AFNI, FSL, and/or in-house routines. For a standard 
fMRI analysis, all image volumes will be pre-processed to correct for inter-scan 
movement, and realigned within and between scans. Each subject’s EPI images 
will be co-registered with the subject’s own T1 anatomical images for individual 
analysis or co-registered to a template, generated by the population under study 
or a standard template. These co-registered images will also be normalized to a 
standard EPI template such as the Montreal Neurological Institute (MNI) 
reference brain for potential group analysis.   Statistical analyses will be 
performed using fixed effects (for individual data), conjunctions analysis 
(between and/or within subjects), and random effects model (for group analysis 
such as gender differences). The fMRI signal change produced by a task will be 
estimated relative to baseline activation, or in comparison with other task. Resting 
state or steady state scans will also be analyzed using standard or in-house 
software and network analysis might be performed. Statistical contrasts of 
activation maps may be analyzed with within-subjects t-statistics. The analysis 
may include single individual cases, a group of participants with similar 
characteristics, or a comparison between males and females. Region of interest or 
whole brain analysis will be based on functional or anatomical landmarks.  Data 
may be combined with other modalities and behavioral results.
MRI data will be processed using adequate software such as SPM8, Freesurfer, 
Tortoise or DTI studio, to obtain, for each subject, images of gray and white 
matter, diffusion or perfusion maps. Images will then be compared using standard 
statistical parametric mapping software such as SPM, FSL, or AFNI, or even 
other more advanced programs as available. The statistical program will generate 
a group-specific adjusted mean value and an associated adjusted error variance 
for each voxel or region of interest that will be derived. Statistical significance 
may be established based on multiple-comparison corrections, permutations or 
simulations, in accordance with the analysis method selected. Data may be 
combined with other modalities and behavioral results. Accounting for multiple 
non-independent comparisons inherent in the analyses, a voxel level corrected P 
value < 0.05 will be used as the final threshold for significance. However, in line 
with functional imaging literature, results will also be reported as significant at a 
statistical threshold of P < 0.001, uncorrected, when a priori hypotheses require. 

17-AA-0152 (5/20/2022)
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MRS data will be processed using specialized software packages such as 
LCModel, jMRUI or in house routines. These will be used to calculate ratios, 
such as GABA/Cr, NAA/Cr and, NAA/Cho. Anatomical images may be used to 
identify the ROI. Data may be combined with other modalities and behavioral 
results.
In case of group differences in severity of addiction or age due to randomization, 
we will add these variables as covariates to the analyses.
Plasma ghrelin 
Weekly plasma ghrelin (total and acyl-ghrelin) will be analyzed using standard 
lab procedures [94]. Ghrelin levels will be compared between KD and SA group, 
and associated with weekly alcohol craving scores in both groups. We expect 
ghrelin to decrease in the KD versus SA group, and to be associated with the 
expected decreases in alcohol craving in KD. 
b.
Power analysis 
Empirical knowledge regarding the necessary sample size for significant effects 
of a ketogenic diet on withdrawal, NP or brain functioning in AUD during 
withdrawal does not exist. Previous behavioral and pharmacological treatment 
studies in AUD with behavioral, fMRI and MRS as outcome measures have 
studied on average 20-25 patients per group [treatment versus control: reviewed 
in 109]. Clinical efficacy of a ketogenic diet in epilepsy was established in 
randomized-controlled trials in 20 [55] or 94 epilepsy patients [56]. In 20 elderly 
participants, an acute dose of ketogenic meal improved executive functioning 1.5-
3 hours after, as compared to a control meal on a different day [58]. Further, 
beneficial effects of KD on sleep was established in a study in 18 children with 
epilepsy [57]. Thus, for within-subject fMRI studies in individuals with AUD 
sample sizes of 25 patients per group have been effective for obtaining 
interpretable data regarding behavioral and neurocognitive effects of treatment, 
suggesting that the sample size of the current protocol is adequate for the 
identification of effects of ketogenic diet in AUD.
Independent sample t-test will be used to test Hypothesis 1, “withdrawal 
symptom severity within the first week of detoxification will be lower for patients 
with KD compared to control diet”.
Paired t-test on BOLD signals will be used to test Hypothesis 2, “limbic 
activation to alcohol cues would be reduced after 3 weeks of treatment”; 
Hypothesis 3, “the functional connectivity of the saliency network will be 
stronger after 3 weeks of treatment”; Hypothesis 4, ‘prefrontal cortex atrophy 
and ventricular enlargement will stronger decrease after 3 weeks of KD treatment 
compared to control diet’. Assuming a threshold probability for rejecting the null 
hypothesis (Type I error rate),  = 0.05, and a probability of failing to reject the 
null hypothesis under the alternative hypothesis (Type II error rate),  = 0.2, the 

17-AA-0152 (5/20/2022)
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proposed sample sizes (25 KD versus 25 ND) will allow us to detect an effect 
size of 0.66. 
To test KD treatment effects, mixed ANOVAs will be used to assess whether KD 
group shows reduced brain activation (Hypothesis 2), higher functional 
connectivity (Hypothesis 3), and prefrontal cortex atrophy and ventricular 
enlargement (Hypothesis 4) compared to the control diet group. Assuming  = 
0.05 and  = 0.2, the proposed sample sizes will allow us to detect an effect size 
of 0.9.
Pearson correlation will be used to test Hypothesis 5, “acetone and β-
hydroxybutyrate concentration in the anterior cingulate and frontal white matter 
will increase linearly as a function of time week #1, #2 and #3”. Assuming  = 
0.05 and  = 0.2, the proposed sample sizes will allow us to detect statistically 
significant correlation coefficients, r > 0.6.
From our past experience with neuroimaging of patients with AUD, it is expected 
that, even with careful screening and preparation, approximately 50% of 
participants will not be able to complete protocols with neuroimaging like the 
current one being proposed. Thus, we are proposing to recruit 100 participants in 
order to complete studies in 50 of them (25 on KD and 25 on SA diet).
* We expect that more than 25 patients per group will finish the first week 
of KD and its assessment of withdrawal symptoms, and will therefore 
include all patients who finished these assessments to test Hypothesis 1.
11. Human Subjects Protection
a.
Subject selection
Adults who fulfill the eligibility criteria will be included, regardless of race, 
ethnicity, sex, or religious affiliation. We predict the racial composition is 
approximately 60% Caucasian, 35% African American, and remaining 5% 
proportion of Asian or other. We predict the Hispanic ethnicity to be 
approximately 25%. On the same basis, the expected breakdown is 70% male 
and 30% female. The age range of 18 years and older will provide a sample 
size that hits our target inclusion criteria of a minimum of 5 year of heavy 
drinking history. 
b.
Justification for exclusion of children
Children are excluded since it is unlikely that they will meet the ten-year criteria 
of heavy drinking required for the study.
c.
Justification for exclusion of other vulnerable subjects 
Vulnerable populations such as those who lack capacity to consent, are also 
excluded due to the likely inability to follow instructions for tasks to be performed 
during diet (KD or SA meal/shake protocol) randomization, MR scans and NP 

17-AA-0152 (5/20/2022)
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testing.  We also exclude individuals with major psychiatric disorders since this 
may affect brain function and structure, and may influence study results.
d.
Justification for sensitive procedures 
N/A
e.
Safeguards for vulnerable populations and sensitive procedures 
Vulnerable populations such as pregnant and/or breastfeeding women will not be 
studied due to the administration of a ketogenic diet, and MRI tests that have 
potential unknown risks to these populations. Urine pregnancy tests will ensure 
that MRIs are not done to women who may be pregnant and we will rely on self-
report for women who are breast feeding and they too will be excluded.  
Protections for employees and staff participating in this study include 1) assuring 
that the participation or refusal to participate will have no effect, either beneficial 
or adverse, on the subject’s employment or position at the NIH, 2) giving 
employees and staff who are interested in participating the “FAQs- Research 
Involving NIH Staff” which is in compliance with Policy 404 Research Involving 
NIH Staff prior to obtaining consent, and 3) assuring that there will be no direct 
solicitation of employees or staff. Co-workers will not consent each other as a 
3rd party monitor must be present when informed consent is obtained. Waivers 
are not permitted.  This study collects sensitive information on drug/alcohol use, 
medical, neurologic and psychiatric histories.  The PI will train study staff 
regarding obtaining and handling potentially sensitive and private information 
about co-workers through staff discussions and written branch/section 
procedures.  
12. Anticipated Benefit
There is no direct benefit to the subjects participating in the study.  The results of the 
study may improve our understanding of the mechanism underlying neurotoxicity in 
alcoholism.
13. Consent Documents and Process
a.
Designation of those obtaining consent
All study investigators obtaining informed consent have completed the NIMH 
HSPU ‘Elements of Successful Informed Consent’ training.
b.
Consent procedures 
Participants will be consented on this protocol after they sign the 14-AA-0181 
(UnCLESam protocol).  They will receive a verbal explanation in terms suited 
to their comprehension of the purposes, procedures and potential risks of the 
study and of their rights as research participants.  Participants will have the 
opportunity to carefully review the written consent form and ask questions 
regarding this study prior to signing.  Either the PI or an AI will conduct the 

17-AA-0152 (5/20/2022)
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consent process in accordance with NIH policy.  Only subjects that can give 
informed consent will be included in this study.  The PI and/or AI’s will 
determine that the subjects are able to give informed consent based on their 
clinical assessment of the subject’s ability to understand the nature of the 
study and the risks.   If patient’s BAL is more than 0 and/or if their CIWA is 
more than 8 at the time of consent, or if the subject’s capacity to consent 
remains otherwise questionable, the Ability to Consent Assessment team 
(ACAT) will be consulted. HSPU advocates will monitor the informed 
consent discussion conducted between investigator and subject assessing 
subject capacity to enroll in the study and providing ongoing monitoring over 
the course of research participation. Co-workers will not consent each other if 
possible, but if a coworker does consent another, HSPU will monitor the 
consent process.
c.
Consent documents
The consent form contains all required elements.  The original consent is filed 
with their NIH medical record and a digital copy is uploaded into the CRIS 
system. A copy of the signed consent is also made for the subject's research binder 
for regulatory purposes.
14. Data and Safety Monitoring
a.
Data and safety monitor
Data and safety monitoring will be monitored by the PI, who will review all safety 
data for each participant.  The PI will consult with the Medically Accountable 
Investigator (MAI) should any concerns about safety arise.
b.
Data and safety monitoring plan
This study will be monitored on a yearly basis at the time of continuing review. 
We will look at possible trends in AE’s and UP’s to determine if a change to the 
protocol/consent/study procedures becomes necessary via study amendment.  In 
addition, individual subject case report forms will be monitored on an ongoing 
basis upon completion of study visits.  Frequency of monitoring may increase if 
the PI determines it is necessary.
c.
Criteria for stopping the study or suspending enrollment or procedures
This study will be stopped and enrollment suspended if any serious adverse events 
occur that is determined to potentially be related to one of the study procedures.
15. Quality Assurance (QA)
a.
Quality assurance monitoring
The Principal Investigator, Lead Investigator and the MAI will be monitoring 
data collection and the study yearly or more often.  Quality assurance (QA) will 
be performed by NIDA QA and NIAAA QA staff as indicated in the NIDA and 
NIAAA Quality Assurance Monitoring Plan on a schedule determined by the 

17-AA-0152 (5/20/2022)
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Clinical Director.  In addition to yearly monitoring of data collection, the 
Laboratory of Neuroimaging (LNI) utilizes a multi-layer study monitoring 
program.  As a general practice, LNI lab staff records study procedures using a 
case report form (CRF) checklist on the day of each study.  The study procedure 
checklist is completed on the day of study as well as within a few business days 
after the procedures were performed.  Once a subject has completed all 
procedures per the protocol, a final study CRF monitoring log is completed for 
each participant.  The CRF monitoring log captures that procedures were verified, 
data has been pushed to appropriate databases if necessary, questionnaire data 
entry verified if necessary, and the participant CRF folder monitoring log is 
signed by the LNI lab staff who verified the data.  Following that process, each 
folder is monitored independently by other lab staff (i.e., post bac IRTA, clinical 
protocol coordinator, CRNP) as a final independent check that procedures were 
performed per protocol followed by signoff by the Principal Investigator. 
b.
Quality assurance plan
Quality assurance (QA) will be performed by the PI, as well as by an independent 
QA monitor, which according to established practice is considered sufficient for 
small, single-site trials, like the present project. The QA monitor for this study 
will have considerable expertise in clinical trials in drug dependence, but s/he will 
not work in the same section of the PI. Therefore, his/her role as QA monitoring 
will assure expertise and independence in the same time.
16. Reportable Events
Reportable events will be tracked and submitted to the IRB as outlined in Policy 
801.
17. Alternatives to Participation 
Participants neither receive nor forego treatment in order to participate in this study.  
The alternative, therefore, is not to participate.
18. Privacy
All research activities will be conducted in as private a setting as possible.
19. Confidentiality
a.
For research data and investigator medical records
Medical records will be handled according to standard NIH Clinical Center 
policies, designed to prevent breach of privacy at a level considered sufficient for 
sensitive health care data.  Investigators will be trained to respect the privacy and 
confidentiality of all participants including NIH employees and staff.  Senior staff 
members (i.e., PI, MD, CRNP) will assure that all staff has completed the "Just 
in time" human subject’s protection training course on "Biomedical- Vulnerable 

17-AA-0152 (5/20/2022)
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Subjects-Workers/Employees" prior to engaging in recruitment of NIH 
employees.  Privacy and confidentiality for NIH Employees will be adhered to 
the same as for other subjects.  The certificate of confidentiality (CoC) that will 
be applied for this study will be used to resist demands for subject information as 
allowed by law.  Staff will be reminded when an NIH employee has been 
recruited to use extra precautions so that identifying information will be 
protected.  Confidentiality and information technology standards are in place at 
the NIAAA and NIDA intramural programs to protect electronic repositories of 
patient data as well as other clinical patient related material. It is reasonably 
expected that these safeguards will protect participants' medical and personal 
health information, ensuring their privacy.  
Information obtained in the course of being screened for or participating in this 
protocol will become part of the patient's NIH medical record.  This includes 
potentially sensitive information, such as results of urine tests that are positive for 
illicit drugs.  Access to this information may be requested by third parties. Such 
access will not be granted without the explicit, written consent of the subjects. 
However, failure on the part of the subject to provide access to the information 
may in itself be to the disadvantage of the subject, e.g. in the case of a potential 
employer or insurer requesting the information.  This situation will be made clear 
in the consent.
b.
For stored samples
Samples and data will be stored using codes that we assign.  Data will be kept in 
password protected computers.  Samples will be kept in locked storage.  Only 
study investigators will have access to the samples and data.
c.
Special precautions 
The Investigators are applying for a Certificate of Confidentiality (CoC) issued 
by NIH to further protect subject confidentiality.
20. Conflict of Interest
a.
Distribution of NIH guidelines
NIH guidelines on conflict of interest have been distributed to all investigators.  
b.
Conflict of interest 
There are no conflicts of interest to report.
c.
Role of a commercial company or sponsor 
There is no drug company involved.
21. Technology Transfer
 

17-AA-0152 (5/20/2022)
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This study now has two separate data transfer agreements (DTA’s) in place under 
the following docket numbers:
1. AA DTA 22-11002: This DTA is between UPENN and NIAAA/LNI. We 
will send deidentified (coded) MRI imaging data for further analysis which 
includes: MRS and fMRI time series and associated data as well as craving 
data in response to alcohol cues from the fMRI scan sessions to our 
collaborator at UPENN for analyzation.  UPENN will send back the results 
and we will match it back up to the subjects on our end.
2. AA DTA 22-11006: This DTA is between Zhejiang University, China, and 
NIAAA/LNI. We will send coded MRI imaging data for further analysis 
which includes: fMRI resting state time series and associated data as well as 
craving data in response to alcohol cues from the fMRI scan sessions to 
Zhejiang University China, for analysis. Zhejiang University will send back 
the results and we will match it back up to the subjects on our end.
22. Research and Travel Compensation 
Volunteers will be compensated for time and research-related inconveniences, to 
the extent to which they complete them, as follows:
Procedures
Inconvenience 
Units
$ Payment
Frequency
Total
Week 1 Study Procedures
KD/SA Randomization 
Week 
10
100
1
100
Genetics blood draw
1
10
1
10
Urine Drug Screen prior 
to MRI/NPT
1
10
1
10
Saliva Drug Screen prior 
to MRI/NPT
1
10
1
10
Urine pregnancy if 
female who can become 
pregnant prior to 
MRI/NPT
1
10
1
10
Ketone blood test #1 – 
obtained prior to start of 
KD/SA start
1
10
1
10
Ghrelin blood test #1 – 
obtained prior to start of 
KD/SA start
1
10
1
10
MRI session #1
(structure, functional 
reactivity, functional 
connectivity, MRS)
10
100
1
100
Neuropsychological Test 
Battery and Personality 
tests (NPT) including 
questionnaires Session #1
13
130
1
130

17-AA-0152 (5/20/2022)
page 34 of 43
Sleep Profiler #1
10
100
1
100
Sleep Profiler #2
10
100
1
100
™GENEActiv #1
(entire week of wear)
10
100
1
100
Ratings for Mood, Sleep, 
and Alcohol Craving
7
70
daily
total of 70
Daily urine ketone test 
1
10
daily
total of 70
Ketone finger prick
1
10
Up to 
5x/week
maxl of 50
Ketone blood test  #2
1
10
1
10
Ghrelin blood test #2
1
10
1
10
Liver function, FFA 
platelets/coagulation blood 
test #1
1
10
1
10
Week #1 – Total Compensation up to
$910 
Week 2 Study Procedures
KD/SA Randomization 
Week 2
10
100
1
100
Urine Drug Screen prior 
to MRI
1
10
1
10
Saliva Drug Screen prior 
to MRI
1
10
1
10
Urine pregnancy if 
female who can become 
pregnant prior to MRI
1
10
1
10
MRI session #2
(structure, functional 
reactivity, functional 
connectivity, MRS)
10
100
1
100
Sleep Profiler #3
10
100
1
100
Sleep Profiler #4
10
100
1
100
Ratings for Mood, Sleep, 
and Alcohol Craving
7
70
daily
total of 70
Daily urine ketone test 
1
10
daily
total of 70
Ketone finger prick
1
10
Up to 
5x/week
max of 50
Ketone blood test #3
1
10
1
10
Ghrelin blood test #3
1
10
1
10
Liver function, FFA, 
platelets/coagulation blood 
test #2
1
10
1
10
Week #2 – Total Compensation up to
$650
Week 3 Study Procedures

17-AA-0152 (5/20/2022)
page 35 of 43
KD/SA Randomization 
Week 
10
100
1
100
Urine Drug Screen prior 
to MRI/NPT
1
10
1
10
Saliva Drug Screen prior 
to MRI/NPT
1
10
1
10
Urine pregnancy if 
female who can become 
pregnant prior to 
MRI/NPT
1
10
1
10
MRI session #3
(structure, functional 
reactivity, functional 
connectivity, MRS)
10
100
1
100
NPT including 
questionnaires Session #2 
(Personality Measures will 
not be repeated)
13
130
1
130
Sleep Profiler #5
10
100
1
100
Sleep Profiler #6
10
100
1
100
™GENEActiv #2
(entire week of wear)
10
100
1
100
Ratings for Mood, Sleep, 
and Alcohol Craving
7
70
daily
total of 70
 Daily urine ketone test 
1
10
daily
total of 70
Ketone finger prick
1
10
Up to 
5x/week
max of 50
Ketone blood test #4
1
10
1
10
Ghrelin blood test #4
1
10
1
10
Liver function, FFA, 
platelets/coagulation blood 
test #3
1
10
1
10
Week #3 – Total Compensation up to
$880
Potential Week 4 Study Procedures
♦KD/SA Randomization 
Week 
10
100
1
100
Week #4 – Total Compensation up to
$100
Total Compensation to all subjects up to paid on discharge
$ 2540
Telephone Follow-Ups 
    Week 1 post discharge
1
10
1
10

17-AA-0152 (5/20/2022)
page 36 of 43
    Week 2 post discharge
1
10
1
10
    Week 4 post discharge
1
10
1
10
    Week 8 post discharge
1
10
1
10
    Week 12 post 
discharge
1
10
1
10
Total Compensation for F-Ups
50
Total Compensation to all subjects up to paid on discharge
$ 2590
♦ Note that if KD continues into Week 4, subjects will be compensated.
Compensation will be paid to subjects on day of discharge, and separately for each 
follow-up call.  Compensation will be prorated for parts completed if subjects do 
not complete the study.  If a subject is withdrawn from the study for non-
compliance, he/she will be paid for procedures completed up to the point of 
withdrawal.   If needed, subjects will be provided with a taxi paid for by NIH. *If 
needed, MRI/MRS scans may be repeated due to excessive head motion or 
equipment failure, for which participants will be paid an additional $100 per MRI 
session. The maximum number of scans in the protocol is 5. If patients need to 
repeat other study procedures, they will be reimbursed for this according to the 
same inconvenience units for these procedures; e.g., $100 for 1 night of sleep 
profiler, $100 for GENActiv, $10 per urine ketone test.  
NIH employees or staff who participate during work hours must have permission 
from their supervisor.  NIH employees or staff must either participate outside of 
work hours or take leave in order to receive compensation.
23. References
See end of document.
24. Attachments/ Appendices
a. Eligibility checklists 
Uploaded to iRIS.
b. Recruiting advertisements 
Uploaded to iRIS.
c.
AUD medications list
Uploaded to iRIS for IRB review.
d. Eligibility Exclusion Medications checklist 
Uploaded to iRIS for IRB review.
e.
Study Day Medications checklist 

17-AA-0152 (5/20/2022)
page 37 of 43
Uploaded to iRIS for IRB review
25. Consent Forms 

AUD consent uploaded to iRIS
References
1 
Volkow, N.D., et al., Acute alcohol intoxication decreases glucose metabolism but 
increases acetate uptake in the human brain. Neuroimage, 2013. 64: p. 277-83.
2 
Wang, J., et al., Oxidation of ethanol in the rat brain and effects associated with 
chronic ethanol exposure. Proc Natl Acad Sci U S A, 2013. 110(35): p. 14444-9
3 
Pawlosky, R.J., et al., Alterations in brain glucose utilization accompanying 
elevations in blood ethanol and acetate concentrations in the rat. Alcohol Clin Exp 
Res, 2010. 34(2): p. 375-81.
4 
Jiang, L., et al., Increased brain uptake and oxidation of acetate in heavy drinkers. J 
Clin Invest, 2013. 123(4): p. 1605-14.
5 
SAMHSA. Substance Abuse and Mental Health Services Administration (SAMHSA). 
2012 National Survey on Drug Use and Health (NSDUH). Available at: 
http://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/DetTabs/NSD
UH-DetTabsSect2peTabs43to84-2012.htm - Tab2.71B. 2012  [cited 2014.
6 
SAMHSA, Substance Abuse and Mental Health Services Administration (SAMHSA). 
2012 National Survey on Drug Use and Health (NSDUH). Available at: 
http://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/DetTabs/NSD
UH-DetTabsSect2peTabs43to84-2012.htm - Tab2.46B. 2012.
7 
de Wit, H., et al., Behavioral and subjective effects of ethanol: relationship to 
cerebral metabolism using PET. Alcohol Clin Exp Res, 1990. 14(3): p. 482-9.
8 
Volkow, N.D., et al., Acute effects of ethanol on regional brain glucose metabolism 
and transport. Psychiatry Res, 1990. 35(1): p. 39-48.
9 
Wang, G.J., et al., Regional brain metabolism during alcohol intoxication. Alcohol 
Clin Exp Res, 2000. 24(6): p. 822-9.
10 
Schreckenberger, M., et al., Acute alcohol effects on neuronal and attentional 
processing: striatal reward system and inhibitory sensory interactions under acute 
ethanol challenge. Neuropsychopharmacology, 2004. 29(8): p. 1527-37.
11 
Volkow, N.D., et al., Low doses of alcohol substantially decrease glucose metabolism 
in the human brain. Neuroimage, 2006. 29(1): p. 295-301.
12 
Volkow, N.D., et al., Decreased cerebral response to inhibitory neurotransmission 
in alcoholics. Am J Psychiatry, 1993. 150(3): p. 417-22.
13 
Cruz, N.F., et al., Activation of astrocytes in brain of conscious rats during acoustic 
stimulation: acetate utilization in working brain. J Neurochem, 2005. 92(4): p. 934-
47.

17-AA-0152 (5/20/2022)
page 38 of 43
14 
Wang, J., et al., Metabolic products of [2-(13) C]ethanol in the rat brain after chronic 
ethanol exposure. J Neurochem, 2013. 127(3): p. 353-64.
15 
Korri, U.M., H. Nuutinen, and M. Salaspuro, Increased blood acetate: a new 
laboratory marker of alcoholism and heavy drinking. Alcohol Clin Exp Res, 1985. 
9(5): p. 468-71.
16 
Dienel, G.A., et al., Preferential labeling of glial and meningial brain tumors with 
[2-(14)C]acetate. J Nucl Med, 2001. 42(8): p. 1243-50.
17 
Kammula, R.G. and B.C. Fong, Metabolism of glucose and acetate by the ovine brain 
in vivo. Am J Physiol, 1973. 225(1): p. 110-3.
18 
Orrego, H., F.J. Carmichael, and Y. Israel, New insights on the mechanism of the 
alcohol-induced increase in portal blood flow. Can J Physiol Pharmacol, 1988. 66(1): 
p. 1-9.
19 
Waniewski, R.A. and D.L. Martin, Preferential utilization of acetate by astrocytes is 
attributable to transport. J Neurosci, 1998. 18(14): p. 5225-33.
20 
Nuutinen, H., et al., Elevated blood acetate as indicator of fast ethanol elimination 
in chronic alcoholics. Alcohol, 1985. 2(4): p. 623-6.
21 
Derr, R.F., K. Draves, and M. Derr, Abatement by acetate of an ethanol withdrawal 
syndrome. Life Sci, 1981. 29(17): p. 1787-90.
22 
Derr, R.F., The ethanol withdrawal syndrome: a consequence of lack of substrate for 
a cerebral Krebs-cycle. J Theor Biol, 1984. 106(3): p. 375-81.
23 
Kopera, M., et al., Cognitive functions in abstinent alcohol-dependent patients. 
Alcohol, 2012. 46(7): p. 665-71.
24 
Fein, G. and S. McGillivray, Cognitive performance in long-term abstinent elderly 
alcoholics. Alcohol Clin Exp Res, 2007. 31(11): p. 1788-99.
25 
Fein, G., et al., Cognitive performance in long-term abstinent alcoholic individuals. 
Alcohol Clin Exp Res, 2006. 30(9): p. 1538-44.
26 
Pfefferbaum, A., et al., A controlled study of cortical gray matter and ventricular 
changes in alcoholic men over a 5-year interval. Arch Gen Psychiatry, 1998. 55(10): 
p. 905-12.
27 
Pfefferbaum, A., et al., Degradation of association and projection white matter 
systems in alcoholism detected with quantitative fiber tracking. Biol Psychiatry, 
2009. 65(8): p. 680-90.
28 
Harris, G.J., et al., Frontal white matter and cingulum diffusion tensor imaging 
deficits in alcoholism. Alcohol Clin Exp Res, 2008. 32(6): p. 1001-13.
29 
Muuronen, A., et al., Influence of improved drinking habits on brain atrophy and 
cognitive performance in alcoholic patients: a 5-year follow-up study. Alcohol Clin 
Exp Res, 1989. 13(1): p. 137-41.
30 
Kuhn, S., et al., Plasticity of hippocampal subfield volume cornu ammonis 2+3 over 
the course of withdrawal in patients with alcohol dependence. JAMA Psychiatry, 
2014. 71(7): p. 806-11.
31 
Oscar-Berman, M. and K. Marinkovic, Alcohol: effects on neurobehavioral functions 
and the brain. Neuropsychol Rev, 2007. 17(3): p. 239-57.

17-AA-0152 (5/20/2022)
page 39 of 43
32 
Goldstein, R.Z. and N.D. Volkow, Dysfunction of the prefrontal cortex in addiction: 
neuroimaging findings and clinical implications. Nat Rev Neurosci, 2011. 12(11): p. 
652-69.
33 
Salloum, J.B., et al., Blunted rostral anterior cingulate response during a simplified 
decoding task of negative emotional facial expressions in alcoholic patients. Alcohol 
Clin Exp Res, 2007. 31(9): p. 1490-504.
34 
Goudriaan, A.E., et al., Neurophysiological effects of modafinil on cue-exposure in 
cocaine dependence: a randomized placebo-controlled cross-over study using 
pharmacological fMRI. Addict Behav, 2013. 38(2): p. 1509-17.
35 
Jasinska, A.J., et al., Factors modulating neural reactivity to drug cues in addiction: 
a survey of human neuroimaging studies. Neurosci Biobehav Rev, 2014. 38: p. 1-16.
36 
Grusser, S.M., et al., Cue-induced activation of the striatum and medial prefrontal 
cortex 
is 
associated 
with 
subsequent 
relapse 
in 
abstinent 
alcoholics. 
Psychopharmacology (Berl), 2004. 175(3): p. 296-302.
37 
Wiers, C.E., et al., Effects of cognitive bias modification training on neural alcohol 
cue reactivity in alcohol dependence. Am J Psychiatry, 2015. 172(4): p. 335-43.
38 
Beck, A., et al., Effect of brain structure, brain function, and brain connectivity on 
relapse in alcohol-dependent patients. Arch Gen Psychiatry, 2012. 69(8): p. 842-52.
39 
Vollstadt-Klein, S., et al., Effects of cue-exposure treatment on neural cue reactivity 
in alcohol dependence: a randomized trial. Biol Psychiatry, 2011. 69(11): p. 1060-6.
40 
Myrick, H., et al., The effect of aripiprazole on cue-induced brain activation and 
drinking parameters in alcoholics. J Clin Psychopharmacol, 2010. 30(4): p. 365-72.
41 
Myrick, H., et al., Effect of Naltrexone and Ondansetron on Alcohol Cue–Induced 
Activation of the Ventral Striatum in Alcohol-Dependent People. Archives General 
Psychiatry, 2008. 65(4): p. 466-475.
42 
Amlung, M., et al., Steep delay discounting and addictive behavior: a meta-analysis 
of continuous associations. Addiction, 2017. 112(1): p. 51-62.
43 
Rachlin, H. and L. Green, Commitment, choice and self-control. J Exp Anal Behav, 
1972. 17(1): p. 15-22.
44 
Bickel, W.K. and L.A. Marsch, Toward a behavioral economic understanding of 
drug dependence: delay discounting processes. Addiction, 2001. 96(1): p. 73-86.
45 
Amlung, M., et al., Dissociable brain signatures of choice conflict and immediate 
reward preferences in alcohol use disorders. Addict Biol, 2014. 19(4): p. 743-53.
46 
Claus, E.D., K.A. Kiehl, and K.E. Hutchison, Neural and behavioral mechanisms of 
impulsive choice in alcohol use disorder. Alcohol Clin Exp Res, 2011. 35(7): p. 1209-
19.
47 
Chanraud, S., et al., Disruption of functional connectivity of the default-mode network 
in alcoholism. Cereb Cortex, 2011. 21(10): p. 2272-81.
48 
Sullivan, E.V., et al., A selective insular perfusion deficit contributes to compromised 
salience network connectivity in recovering alcoholic men. Biol Psychiatry, 2013. 
74(7): p. 547-55.
49 
Chang, L., et al., Magnetic resonance spectroscopy to assess neuroinflammation and 
neuropathic pain. J Neuroimmune Pharmacol, 2013. 8(3): p. 576-93.

17-AA-0152 (5/20/2022)
page 40 of 43
50 
Schweinsburg, B.C., et al., Elevated myo-inositol in gray matter of recently detoxified 
but not long-term abstinent alcoholics: a preliminary MR spectroscopy study. 
Alcohol Clin Exp Res, 2000. 24(5): p. 699-705.
51 
Kossoff, E.H., et al., Prospective study of the modified atkins diet in combination 
with a ketogenic liquid supplement during the initial month. J Child Neurol, 2011. 
26(2): p. 147-51.
52 
Carroll, J. and D. Koenigsberger, The ketogenic diet: a practical guide for caregivers. 
J Am Diet Assoc, 1998. 98(3): p. 316-21.
53 
Levy, R.G., P.N. Cooper, and P. Giri, Ketogenic diet and other dietary treatments for 
epilepsy. Cochrane Database Syst Rev, 2012(3): p. CD001903.
54 
Martin, K., et al., Ketogenic diet and other dietary treatments for epilepsy. Cochrane 
Database Syst Rev, 2016. 2: p. CD001903.
55 
Freeman, J.M., et al., A blinded, crossover study of the efficacy of the ketogenic diet. 
Epilepsia, 2009. 50(2): p. 322-5.
56 
Neal, E.G., et al., The ketogenic diet for the treatment of childhood epilepsy: a 
randomised controlled trial. Lancet Neurol, 2008. 7(6): p. 500-6.
57 
Hallbook, T., J. Lundgren, and I. Rosen, Ketogenic diet improves sleep quality in 
children with therapy-resistant epilepsy. Epilepsia, 2007. 48(1): p. 59-65.
58 
Ota, M., et al., Effect of a ketogenic meal on cognitive function in elderly adults: 
potential for cognitive enhancement. Psychopharmacology (Berl), 2016. 233(21-22): 
p. 3797-3802.
59 
Veech, R.L., The therapeutic implications of ketone bodies: the effects of ketone 
bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin 
resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty 
Acids, 2004. 70(3): p. 309-19.
60 
Veech, R.L., Ketone ester effects on metabolism and transcription. J Lipid Res, 2014. 
55(10): p. 2004-6.
61 
Kashiwaya, Y., et al., A ketone ester diet exhibits anxiolytic and cognition-sparing 
properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's 
disease. Neurobiol Aging, 2013. 34(6): p. 1530-9.
62 
Verrotti, A., et al., Ketogenic diet and childhood neurological disorders other than 
epilepsy: an overview. Expert Rev Neurother, 2016: p. 1-13.
63 
Wootton-Gorges, S.L., et al., Detection of cerebral {beta}-hydroxy butyrate, 
acetoacetate, and lactate on proton MR spectroscopy in children with diabetic 
ketoacidosis. AJNR Am J Neuroradiol, 2005. 26(5): p. 1286-91.
64 
Cecil, K.M., et al., Brain ketones detected by proton magnetic resonance 
spectroscopy in an infant with Ohtahara syndrome treated with ketogenic diet. 
Pediatr Radiol, 2015. 45(1): p. 133-7.
65 
Seymour, K.J., et al., Identification of cerebral acetone by 1H-MRS in patients with 
epilepsy controlled by ketogenic diet. MAGMA, 1999. 8(1): p. 33-42.
66 
Kreis, R. and B.D. Ross, Cerebral metabolic disturbances in patients with subacute 
and chronic diabetes mellitus: detection with proton MR spectroscopy. Radiology, 
1992. 184(1): p. 123-30.

17-AA-0152 (5/20/2022)
page 41 of 43
67 
Kossoff, E.H., International consensus statement on clinical implementation of the 
ketogenic diet: agreement, flexibility, and controversy. Epilepsia, 2008. 49 Suppl 8: 
p. 11-3.
68 
Worden, L.T., et al., Is there an ideal way to discontinue the ketogenic diet? Epilepsy 
Res, 2011. 95(3): p. 232-6.
69 
Umpierrez, G.E., et al., Differences in metabolic and hormonal milieu in diabetic- 
and alcohol-induced ketoacidosis. J Crit Care, 2000. 15(2): p. 52-9.
70 
Urbain P1, Bertz H1.Monitoring for compliance with a ketogenic diet: what is the 
best time of day to test for urinary ketosis? Nutr Metab (Lond). 2016 Nov 4;13:77. 
eCollection 2016.
71 
Moeller, S.J., et al., Enhanced choice for viewing cocaine pictures in cocaine 
addiction. Biol Psychiatry, 2009. 66(2): p. 169-76.
72 
Wiers, C.E., et al., Neural Correlates of Alcohol-Approach Bias in Alcohol 
Addiction: the Spirit is Willing but the Flesh is Weak for Spirits. 
Neuropsychopharmacology, 2014. 39(3): p. 688-97.
73 
McClure, S.M., et al., Separate neural systems value immediate and delayed 
monetary rewards. Science, 2004. 306(5695): p. 503-7.
74 
Tomasi, D., et al., Methylphenidate enhances brain activation and deactivation 
responses to visual attention and working memory tasks in healthy controls. 
Neuroimage, 2011. 54(4): p. 3101-10.
75 
Tomasi, D., G.J. Wang, and N.D. Volkow, Association between striatal dopamine 
D2/D3 receptors and brain activation during visual attention: effects of sleep 
deprivation. Transl Psychiatry, 2016. 6(5): p. e828.
76 
Bernard, F., et al., Eyelid contour detection and tracking for startle research related 
eye-blink measurements from high-speed video records. Comput Methods Programs 
Biomed, 2013. 112(1): p. 22-37.
77 
Provencher, S.W., Estimation of metabolite concentrations from localized in vivo 
proton NMR spectra. Magn Reson Med, 1993. 30(6): p. 672-9.
78 
Love, A., D. James, and P. Willner, A comparison of two alcohol craving 
questionnaires. Addiction, 1998. 93(7): p. 1091-102.
79 
Koob GF, Volkow ND.  Neurobiology of addiction: a neurocircuitry analysis.  
Lancet Psychiatry. 2016 Aug;3(8):760-73. doi: 10.1016/S2215-0366(16)00104-8. 
Review.
80 
Muncie HL Jr1, Yasinian Y2, Oge' L1. Outpatient management of alcohol 
withdrawal syndrome.  Am Fam Physician. 2013 Nov 1;88(9):589-95.
81 
Chikahisa S1, Shimizu N1, Shiuchi T1, Séi H2. Ketone body metabolism and sleep 
homeostasis 
in 
mice. 
Neuropharmacology. 
2014 
Apr;79:399-404. 
doi: 
10.1016/j.neuropharm.2013.12.009. Epub 2013 Dec 17.
82 
Robbins, T.W., et al., Cambridge Neuropsychological Test Automated Battery 
(CANTAB): a factor analytic study of a large sample of normal elderly volunteers. 
Dementia, 1994. 5(5): p. 266-81.
83 
Robbins, T.W., et al., A study of performance on tests from the CANTAB battery 
sensitive to frontal lobe dysfunction in a large sample of normal volunteers: 
implications for theories of executive functioning and cognitive aging. Cambridge 

17-AA-0152 (5/20/2022)
page 42 of 43
Neuropsychological Test Automated Battery. J Int Neuropsychol Soc, 1998. 4(5): p. 
474-90.
84 
Choi, S.W., et al., Similarities and differences among Internet gaming disorder, 
gambling disorder and alcohol use disorder: a focus on impulsivity and compulsivity. 
J Behav Addict, 2014. 3(4): p. 246-53.
85 
Patrick, C.J., J.J. Curtin, and A. Tellegen, Development and validation of a brief form 
of the Multidimensional Personality Questionnaire. Psychol Assess, 2002. 14(2): p. 
150-63.
86 
Volkow, N.D., et al., Positive emotionality is associated with baseline metabolism in 
orbitofrontal cortex and in regions of the default network. Mol Psychiatry, 2011. 
16(8): p. 818-25.
87 
Horne, J.A. and O. Ostberg, A self-assessment questionnaire to determine 
morningness-eveningness in human circadian rhythms. Int J Chronobiol, 1976. 4(2): 
p. 97-110.
88 
Beck, A.T., R.A. Steer, and M.G. Garbin, Psychometric Properties of the Beck 
Depression Inventory - 25 Years of Evaluation. Clinical Psychology Review, 1988. 
8(1): p. 77-100.
89 
Volkow ND, Wang GJ, Begleiter H, Porjesz B, Fowler JS, Telang F, Wong C, Ma 
Y, Logan J, Goldstein R, Alexoff D, Thanos PK. High levels of dopamine D2 
receptors in unaffected members of alcoholic families: possible protective factors. 
Arch Gen Psychiatry. 2006 Sep;63(9):999-1008.
90 
Stubbs BJ, Cox PJ, Evans RD, Cyranka M, Clarke K, de Wet H. A Ketone Ester 
Drink Lowers Human Ghrelin and Appetite. Obesity 2018; 26(2): 269-273.
91 
de Timary P, Cani PD, Duchemin J, Neyrinck AM, Gihousse D, Laterre PF et al. The 
loss of metabolic control on alcohol drinking in heavy drinking alcohol-dependent 
subjects. PloS one 2012; 7(7): e38682.
92 
Addolorato G, Capristo E, Leggio L, Ferrulli A, Abenavoli L, Malandrino N et al. 
Relationship between ghrelin levels, alcohol craving, and nutritional status in current 
alcoholic patients. Alcoholism, clinical and experimental research 2006; 30(11): 
1933-1937.
93 
Koopmann A, von der Goltz C, Grosshans M, Dinter C, Vitale M, Wiedemann K et 
al. The association of the appetitive peptide acetylated ghrelin with alcohol craving 
in early abstinent alcohol dependent individuals. Psychoneuroendocrinology 2012; 
37(7): 980-986.
94 
Farokhnia M, Grodin EN, Lee MR, Oot EN, Blackburn AN, Stangl BL et al. 
Exogenous ghrelin administration increases alcohol self-administration and 
modulates brain functional activity in heavydrinking alcohol-dependent individuals. 
Molecular psychiatry 2017.
95 
Desrosiers NA1, Lee D, Schwope DM, Milman G, Barnes AJ, Gorelick DA, 
Huestis MA. On-site test for cannabinoids in oral fluid. Clin Chem. 2012 
Oct;58(10):1418-25. Epub 2012 Aug 21.
96 
Wille SM1, Samyn N, Ramírez-Fernández Mdel M, De Boeck G. Evaluation of on-
site oral fluid screening using Drugwipe-5(+), RapidSTAT and Drug Test 5000 for 

17-AA-0152 (5/20/2022)
page 43 of 43
the detection of drugs of abuse in drivers. Forensic Sci Int. 2010 May 20;198(1-
3):2-6. doi: 10.1016/j.forsciint.2009.10.012. Epub 2009 Nov 12.
97 
Desrosiers NA1, Milman G, Mendu DR, Lee D, Barnes AJ, Gorelick DA, Huestis 
MA. Cannabinoids in oral fluid by on-site immunoassay and by GC-MS using two 
different oral fluid collection devices. Anal Bioanal Chem. 2014 Jul;406(17):4117-
28. doi: 10.1007/s00216-014-7813-9. Epub 2014 May 15.
98 
Brar, R. and J. Venitz, Smoking History Questionnaire. 2006.
99 
Heatherton, T.F., et al., The Fagerstrom Test for Nicotine Dependence: a revision of 
the Fagerstrom Tolerance Questionnaire. Br J Addict, 1991. 86(9): p. 1119-27.
100 Sobell, L.C. and M.B. Sobell, Timeline Followback: User’s Guide - A calendar 
method for assessing alcohol and drug use. 1996, Addiction Research Foundation: 
Toronto.
101 Babor, T.F., H.R. Kranzler, and R.J. Lauerman, Early detection of harmful alcohol 
consumption: comparison of clinical, laboratory, and self-report screening 
procedures. Addict Behav, 1989. 14(2): p. 139-57.
102 Patton, J.H., M.S. Stanford, and E.S. Barratt, Factor structure of the Barratt 
impulsiveness scale. J Clin Psychol, 1995. 51(6): p. 768-74.
103 First, M.B., et al., Structured Clinical Interview for DSM-IV-TR Axis I Disorders, 
Research Version, Patient Edition. (SCID-I/P). 2002, New York: Biometrics 
Research.
104 Skinner, H.A. and B.A. Allen, Alcohol dependence syndrome: measurement and 
validation. J Abnorm Psychol, 1982. 91(3): p. 199-209.
105 Sullivan, J.T., et al., Assessment of alcohol withdrawal: the revised clinical institute 
withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict, 1989. 84(11): p. 
1353-7.
106 Pittman B1, Gueorguieva R, Krupitsky E, Rudenko AA, Flannery BA, Krystal JH. 
Multidimensionality of the Alcohol Withdrawal Symptom Checklist: a factor analysis 
of the Alcohol Withdrawal Symptom Checklist and CIWA-Ar. Alcohol Clin Exp Res. 
2007 Apr;31(4):612-8.
107 Bakhla AK1, Khess CR2, Verma V3, Hembram M4, Praharaj SK5, Soren S4. Factor 
Structure of CIWA-Ar in Alcohol Withdrawal. J Addict. 2014;2014:745839. doi: 
10.1155/2014/745839. Epub 2014 Apr 6.
108 Myrick H1, Malcolm R, Randall PK, Boyle E, Anton RF, Becker HC, Randall CL. A 
double-blind trial of gabapentin versus lorazepam in the treatment of alcohol 
withdrawal. Alcohol Clin Exp Res. 2009 Sep;33(9):1582-8. doi: 10.1111/j.1530-
0277.2009.00986.x. Epub 2009 May 26.
109 Cabrera, E.A., et al., Neuroimaging the Effectiveness of Substance Use Disorder 
Treatments. J Neuroimmune Pharmacol, 2016. 11(3): p. 408-33.