Computer-Assisted Self-Administration of Ethanol

Objective: The goal of this project is to characterize the computer-assisted
self-administration of ethanol (CASE) paradigm by assessing intravenous (IV) alcohol
self-administration behavior and the resulting breath alcohol concentration (BrAC) exposure
and pharmacologic responses in healthy non-dependent participants. The study will also
evaluate the test-retest reliability of alcohol self-administration and examine the influence
of sex and recent drinking history, as well as the effect of acute stress cues on alcohol
self-administration.

Study population: Participants will be 21-60 year-old male and female social drinkers and
binge drinkers in good health, as determined by medical history, physical exam, ECG and lab
tests. Participants with Axis-I psychiatric illness including alcohol or substance dependence
will be excluded.

Design: The CASE system utilizes a model-based algorithm based on previously published
methods to achieve and maintain pre-determined BrACs using IV alcohol infusions. The CASE
system provides flexibility to participants in choosing when to push a button to receive
alcohol, as well as flexibility to investigators in controlling the subsequent BrAC exposure.
The CASE system allows the investigator to specify and assure the same BrAC increment across
all participants, and is set up to prevent the BrAC from exceeding any pre-set upper limit
(e.g., 100 mg%).

Following screening, participants will undergo IV ethanol self-administration sessions.
Participants will be enrolled in four groups: Group 1 will consist of the first 10
participants who will participate in 3 self-administration sessions (a training session
followed by 2 test sessions) to assess the test-retest reliability of alcohol
self-administration behavior. Group 2 will consist of 50 participants, who will each
participate in 2 self-administration sessions (a training session followed by a test
session). During each session, participants will first undergo a directed priming period,
lasting 25 min, where they will be prompted to push a button to receive small standardized
alcohol infusions. This will be followed by an ad-lib period, lasting up to 2 hrs, where they
will have free access to standardized IV alcohol infusions. During the session, BrAC will be
measured, heart-rate and skin blood flow will be continuously recorded, and subjective
perceptions of alcohol effects and urges will be assessed. Group 3 will consist of 15
participants, who will undergo two identical progressive work self-administration sessions
for evaluation of test-retest reliability. During each progressive ratio (PR) schedule
session, participants will be required to push the button progressively higher number of
times for each subsequent alcohol infusion over a 2.5 hr period. Group 4 will consist of 100
participants, who will each participate in 2 sessions: one ad lib self-administration session
and one PR schedule self-administration session. Group 5 will consist of 40 participants, who
will undergo a baseline self-administration session followed by an interview session for
construction of guided imagery scripts. Following this, participants will undergo three
alcohol self-administration sessions, following exposure to personalized stress-, alcohol- or
neutral-condition associated scripts, presented in randomized order on separate days.

Outcome measures: The primary endpoint is the BrAC exposure (highest BrAC, average BrAC,
area-under-the-BrAC-time-curve) achieved during the self-administration session.
Additionally, changes in subjective perceptions of alcohol effects, as well as changes in
heart rate will be evaluated. The influence of sex and recent drinking history as well as
genetic polymorphisms on the self-administration of alcohol will also be examined.
Furthermore, individual-specific cellular responses to alcohol exposure will be examined
using induced pluripotent stem cells (iPSCs) from participants selected based on genotypic
and phenotypic variation in self-administration measures. Outcome measures for group 5 will
include stress and alcohol cue-induced craving and self-administration.

The CASE paradigm can be a valuable tool for evaluating determinants that may underlie
self-administration behavior in humans. The effect of pharmacological agents on alcohol
self-administration can be evaluated as a marker of the clinical effectiveness of these
agents in the treatment of alcohol-dependence.

- GROUPS 1-5:

All participants will be between the ages of 21 and 45 years, social drinkers in good
health. Young females will have normal menstrual cycles and will be tested during the
follicular phase of their cycle (within 10 days of offset of menses) and must have a
negative urine pregnancy (hCG) test at the start of the study session.

INCLUSION CRITERIA:

1. Male and female participants between 21-45 years of age.

2. Good health as determined by normal or non-clinically-significant findings on medical
history, physical exam, ECG and lab tests.

3. Female participants will be tested during the follicular phase of their cycle (within
10 days of offset of menses) and must have a negative urine pregnancy (hCG) test at
the start of each study session. For Group 5, due to the number of study visits,
female subjects will be tested outside the menses phase of their cycle.

4. Group 5 will include 20 subjects who report at least 2 binge drinking episodes in the
month prior to the study (a binge episode is defined as consuming at least 4 drinks
for females and at least 5 drinks for males during the drinking episode) and 20
subjects

who report no binge drinking episodes in the past month.

EXCLUSION CRITERIA:

1. Current or prior history of serious medical illness, including CNS, cardiovascular,
respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders.

2. Positive hepatitis or HIV test at screening.

3. Current history of Axis-I psychiatric illness.

4. Current or lifetime diagnosis of alcohol or substance dependence.

5. Currently seeking treatment for alcohol use disorders.

6. History of significant withdrawal symptoms or presence of clinically significant
withdrawal symptoms (Clinical Institute Withdrawal Assessment (CIWA) score > 8) at
screening.

7. Non-drinkers (alcohol-na(SqrRoot) ve individuals or current abstainers) or individuals
with no experience drinking 5 or more drinks on one occasion in their lifetime.

8. Regular tobacco users will be excluded from the study in order to avoid nicotine
withdrawal symptoms. Occasional use of tobacco products (up to 20 cigarettes/week) is
acceptable. For Groups 3, 4 and 5, participants must be current non-smokers (past
smokers who have quit for over 1 year can be included).

9. Positive result on urine drug screen or positive breathalyzer during screening visit
or at the start of any study visit.

10. Pregnancy or intention to become pregnant for women. Female participants will undergo
a urine beta-hCG test to ensure they are not pregnant.

11. Use of prescription or OTC medications known to interact with alcohol within 2 weeks
of the study. These include, but may not be limited to: isosorbide, nitroglycerine,
benzodiazepines, warfarin, anti-depressants such as amitriptyline, clomipramine and
nefazodone, anti-diabetes medications such as glyburide, metformin and tolbutamide,
H2-antagonists for heartburn such as cimetidine and

ranitidine, muscle relaxants, anti-epileptics including phenytoin and phenobarbital
codeine, and narcotics including propoxyphene, oxycodone and hydrocodone. Drugs known
to inhibit or induce enzymes that metabolize alcohol should not be used for 4 weeks
prior to the study. These include chlorzoxazone, isoniazid, metronidazole and
disulfiram. Cough-and-cold preparations which contain anti-histamines, pain medicines
and anti-inflammatories such as aspirin, ibuprofen, acetaminophen, celecoxib and
naproxen, should be withheld for at least 72 hours prior to each study session.

12. Current or prior history of alcohol-induced flushing reactions.

13. Female participants who have abnormal menstrual cycles in the absence of
irregularities caused by hormonal contraception, as defined by irregularities in
menstrual cycle length (cycles of >36 days or < 8 cycles per year), clinically
significant menstrual periods that are heavier or lighter than usual, and/or
accompanied by significant pain, cramping or nausea and vomiting that requires
intervention.

GROUP 6

Group 6 will include heavy drinkers between the ages of 21 and 60 years, in good health.
Unfortunately, heavy drinking does not have a universally agreed upon definition and the
criteria used to define heavy drinking vary from study to study. There is evidence that

incorporating both amount of alcohol consumed per occasion and amount of alcohol consumed
per week is relevant to account for risk related to pattern of drinking and total
consumption. Therefore in our study we will select heavy drinkers using a definition that
takes into account both pattern of drinking and total consumption. For pattern of drinking,
we will require our subjects to have on average at least one binge drinking day per week,
using the NIAAA definition of 5 or more drinks for men and 4 or more drinks for women
(NIAAA website). For total consumption, we will use an average of 8 or more drinks per week
for women and 15 or more drinks per week for men as this level of drinking has been shown
to confer increased risk of mortality.

INCLUSION CRITERIA:

1. Male and female participants between 21-60 years of age.

2. Male participants must have consumed an average of 15 or more standard drinks per week
and females must have consumed an average of 8 or more standard drinks per week during
the past 90 days. Average number of drinks per week will be calculated based on total
number of drinks as measured by the timeline followback (TLFB) (e.g., for 90 days
worth of data, total drinks divided by 90 and then multiplied by 7 will be the average
number of drinks per week).

3. Participants must have on average at least 1 binge drinking day per week during the
last 90 days, defined as a day in which 4 or more standard drinks were consumed for
females and 5 or more standard drinks were consumed for males. Average number of binge
drinking days will be calculated based on total number of binge drinking days from the
TLFB (e.g. for 90 days worth of data, participants with a total of 13 or more binge
drinking days will be eligible).

4. Participants must be able and willing to refrain from consuming alcohol 24 hours prior
to each alcohol self-administration session.

EXCLUSION CRITERIA:

1. Current or prior history of serious medical illness, including CNS, cardiovascular,
respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders.

2. Positive hepatitis or HIV test at screening.

3. Abnormal findings on ECG, unless cleared for participation by cardiologist or Licensed
Independent Practitioner (LIP).

4. Current history of depressive disorder, bipolar disorder, psychotic disorder,
obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), eating
disorder, or any other Axis-I psychiatric disorders requiring intervention.

5. An aspartate transaminase (AST) or alanine transaminase (ALT) level more than 3 times
the upper limit of normal.

6. Current (past 12 months) diagnosis of substance use disorder other than alcohol use
disorder, unless in early remission (no criteria met for at least 3 months).

7. Positive result on urine drug screen or breathalyzer test during initial or update
visit under the screening protocol (14-AA-0181) most proximal to enrollment. Positive
urine drug screen during more than 1 study visit or breathalyzer reading during more
than 1 self-administration study visit will result in participant withdrawal from the
study.

8. Currently seeking treatment for alcohol use disorder or having undergone inpatient or
outpatient detoxification or treatment for alcohol problems in the past 6 months.

9. History of significant withdrawal symptoms or presence of clinically significant
withdrawal symptoms (Clinical Institute Withdrawal Assessment (CIWA) score > 8) at
screening.

10. Smokers with Fagerstr(SqrRoot)(Delta)m Test for Nicotine Dependence (FTND) score > 4

11. Pregnancy, intention to become pregnant, or breastfeeding. Female participants will
undergo a urine beta-hCG test to ensure that they are not pregnant.

12. Medication exclusion criteria:

1. . Daily or regular use of prescription or OTC medications known to interact with
alcohol in the 2-week period prior to assessment. These include, but may not be
limited to: isosorbide, nitroglycerine, benzodiazepines, warfarin,
anti-depressants such as amitriptyline, clomipramine and nefazodone,
anti-diabetes medications such as glyburide, metformin and tolbutamide,
H2-antagonists for heartburn such as cimetidine and ranitidine, muscle relaxants,
anti-epileptics including phenytoin and phenobarbital codeine, and narcotics
including propoxyphene, oxycodone and hydrocodone.

2. Daily or regular use of drugs known to inhibit or induce enzymes that metabolize
alcohol in the 4-week period prior to assessment. These include chlorzoxazone,
isoniazid, metronidazole and disulfiram. Note that any discontinuation of
medications will only be done at the recommendation of a physician.

13. Current or prior history of alcohol-induced flushing reactions.