Oxytocin Treatment of Alcohol Dependence

The purpose of this research study is to learn whether oxytocin treatment decreases drinking
in people who have been consuming alcohol heavily for long periods and are unable to stop
drinking on their own. Oxytocin is made naturally and is released in parts of the brain
where it acts like a chemical signal from one cell to another. Oxytocin is approved by the
Food and Drug Administration for stimulating labor in pregnant women but is not approved as
a treatment to decrease alcohol drinking.

People who drink large amounts of alcohol every day or many days per week for weeks or
months undergo chemical changes in their brains. Patients continue to drink frequently and
heavily because, even though patients may know drinking is not good for their health,
patients have unpleasant experiences if they stop or decrease drinking. Those experiences
can include increased anxiety, difficulty sleeping, difficulty tolerating stress, mild to
moderate withdrawal symptoms such as tremors, nausea, feeling sweaty and/or headaches, and
cravings to drink. Studies have shown that giving oxytocin to alcohol-addicted animals
diminished drinking after they had been denied access to alcohol for a while and reduced
symptoms when they were put into alcohol withdrawal. A pilot study conducted at UNC found
that oxytocin treatment decreased withdrawal symptoms in heavy drinkers who were admitted to
a hospital for medical treatment to come off alcohol.

This study will test whether oxytocin treatment for 12 weeks starting shortly after
subjects' discharge from Freedom House or UNC Hospitals or after patients are evaluated
during an outpatient clinic visit will decrease how much patients drink as well as patients
desire to drink and patients anxiety. After study medications are stopped, the amount of
drinking, desire to drink and anxiety will be assessed over an additional 12-week period.

Patients are being asked to participate in this study because they have been drinking large
amounts of alcohol frequently and want help to stop or cut back on their drinking. Patients
may receive oxytocin or placebo in this study as an intranasal spray. The placebo contains
all of the ingredients of the oxytocin spray EXCEPT oxytocin, the active ingredient.
Patients' assignment to oxytocin or placebo treatment will be random (like a flip of a
coin).

Patients must sign this consent form to take part in this study. Patients participation in
the study will last up to 25-26 weeks. If Patients are recruited while they are an inpatient
at Freedom House or UNC Hospitals, the duration of their participation will extend over the
remaining days they are an inpatient, an initial clinic visit shortly after they are
discharged when they will start taking the intranasal test treatment, a 12-week period
during which they will take the intranasal study medication each day at home and attend 8
clinic visits and a final 12-week period after stopping medication during which they will
attend clinic visits at the 4 and 12-week time points. If patients are not an inpatient and
are recruited during an initial outpatient clinic visit, they will attend another clinic
visit to start the intranasal study medication and then take the intranasal test treatment
each day at home and attend 8 additional clinic visits over a 12 week period and then attend
2 additional clinic visits at 4 and 12 weeks after stopping the intranasal medication. Each
clinic visit will last 1-2 hours.

If patients are an inpatient at Freedom House or UNC Hospitals, they will undergo an
evaluation toward the end of their admission to determine if they are eligible to
participate in the study. If patients are not an inpatient, they will undergo an evaluation
during an initial outpatient clinic visit. Patients must have no alcohol in their blood
(Breathalyzer reading of zero) when they read the consent form and when they undergo the
initial evaluation. Patients' Breathalyzer readings must be less than 0.08 at each
subsequent clinic visit for evaluations to be conducted. If patients' Breathalyzer readings
are equal to or greater than 0.08, patients will not drive themselves home and they will
accept assistance from a friend, relative or cab driver in getting back home in a safe
manner. Patients will sign the Breath Alcohol Policy agreeing to abide by these rules when
they are first evaluated as an inpatient or at an initial outpatient clinic visit.

Procedures if patients are evaluated toward the end of an admission to Freedom House or UNC
Hospitals

- Patients will be interviewed about their medical and psychiatric history, whether they
have ever had alcohol withdrawal, especially bad withdrawal (delirium tremens,
seizures, hallucination), as well as about how much patients drank during the 90 days
before they were admitted and their use of other drugs.

- Patients will complete questionnaires about drinking by members of their family, how
much of a problem patients think their drinking has been for patients, and their
understanding of the consequences of their drinking.

Procedures (in addition to those above) if patients are evaluated during an initial
outpatient clinic visit

- Patients will take a Breathalyzer test to determine the concentration of alcohol in
their blood.

- The severity of withdrawal symptoms that patients may be experiencing will be measured
based on their vital signs (blood pressure, heart rate) and ratings of symptoms using
the CIWA scale.

- Patients urine will be tested to see if they take street or illegal drugs. If patients
test positive, investigators will keep this data confidential unless investigators are
required by law to disclose the data.

- Patients will have blood (15 ml or about 1 tablespoon) and urine samples taken for
laboratory tests and, if patients are women, to determine if they are pregnant.

- Patients will have a physical examination by a study doctor. If the results of the
evaluation show patients are eligible to participate, patients will be randomly
assigned (like the flip of a coin) to receive either oxytocin or placebo intranasal
spray. Members of the researcher staff will instruct patients in how to self-administer
intranasal spray doses from a spray bottle. If patients are an inpatient at Freedom
House or UNC Hospitals, they will take their first intranasal test dose during a clinic
visit scheduled a few days after they are discharged. If patients are not an inpatient,
patients will take their first intranasal test dose during a clinic visit scheduled
shortly after this screening visit. Patients will then take an intranasal spray bottle
home with them and continue to self-administer intranasal test doses three time each
day (at approximately breakfast, lunch and dinner time) for two days and thereafter
will take intranasal test doses twice each day (at approximately breakfast and dinner
time). Each dose will be 6 sprays into their nose (3 per nostril). Neither patients nor
the research staff or nurses will know whether patients are taking oxytocin or placebo
nasal spray.

During the clinic visit when patients take their first intranasal test dose and at each of
the following clinic visits while taking study medication, patients will have a Medical
Management session (special talk therapy for alcohol dependence) with the study doctor
before patients are discharged.

Follow-up outpatient clinic visits after the visit when patients take their first intranasal
test dose will take place at UNC Hospitals or at the Alcohol and Substance Abuse Program
Clinic at Timberlyne Mall. Patients will come in weekly for the first four weeks, then every
other week for the next eight weeks (8 total visits) while taking study medications.
Patients will also come to an outpatient clinic visit 4 and 8 weeks after stopping the study
medications.

Procedures at outpatient clinic visits (each 1-2 hours long)

- Patients will undergo a Breathalyzer test to measure the concentration of alcohol in
their blood.

- Study staff will interview patients about how much they have been drinking since the
last clinic visit.

- Patients will complete questionnaires about their alcohol cravings, anxiety and
depression.

- Vital signs and CIWA (alcohol withdrawal symptom) scores will be measured.

- At the week 4, 8, and 12 clinic visits while patients are taking intranasal study
medications, patients will give blood (15 ml or about 1 tablespoon) and urine samples
for laboratory tests, pregnancy tests (for women participants), and to see if they are
taking street or illegal drugs.

- At the final clinic visit while taking study medication (week 12), patients will again
complete a questionnaire about their understanding of the consequences of their
drinking.

Other procedures throughout the 12-week test treatment portion of the study During the
12-week test treatment part of the study, patients will take the intranasal study medication
three times per day for the first two days (at approximately breakfast, lunch and dinner
time) and then twice daily (at approximately breakfast and dinner time). Patients will
receive a new bottle of intranasal spray every 2 weeks. Patients must bring the intranasal
spray bottle they have been using to clinic appointments.

Inclusion Criteria:

- Meeting criteria for DSM-IV-TR alcohol dependence.

- At least one prior episode of DSM-IV-TR alcohol withdrawal as assessed by the SCID
Alcohol Dependence Module or scoring >6 on the CIWA scale since admission to the
inpatient unit.

- Consumption of at least 35 standard drinks/week in men or 28 standard drinks/week in
women during the 4 weeks prior to enrollment into the study.

- Women who are able to conceive children and who are sexually active must be on an
effective form of birth control such as oral contraceptives, IUDs or the use of
condoms with spermicide.

- Competency to give valid informed consent as indicated by a) a Breathalyzer reading
at the time the consent form is signed showing an estimated blood alcohol level (BAL)
<.08 gm/dL (the consent process is repeated when the BAL level has dropped to 0.00
gm/dL) and b) ability to understand the written informed consent form demonstrated by
correctly answering questions about the contents of the form after reading the
consent form without help (this will also determine whether prospective subjects can
read and understand the study questionnaires).

- Ability to get to appointments either through personal or public transportation.

- Ages 18-65.

Exclusion Criteria:

- History of alcohol withdrawal-related seizures, delirium tremens or hallucinations.

- Clinically significant medical disease that might interfere with the evaluation of
the study medication or present a safety concern (e.g., renal insufficiency,
cirrhosis, unstable hypertension, unstable diabetes mellitus, seizure disorder).
Clinically significant psychiatric illnesses including any psychotic disorder,
bipolar disorder, eating disorder, severe depression, or suicidal ideation.

- Other substance dependence disorder with the exceptions of nicotine or caffeine.
Substance abuse disorders are not exclusionary.

- Chronic or subchronic (>3 days in the week prior to admission or outpatient
enrollment) treatment with/consumption of benzodiazepines, barbiturates,
anticonvulsants or stimulants.

- Receipt of >6 mg of lorazepam or any dose of a long half-life benzodiazepine between
admission for medical detoxification and beginning participation in the study (i.e.,
receiving the first intranasal dose of test treatment).

- AST or ALT > 5 times ULN, bilirubin > 1.5 X ULN, sodium < 132 or > 150 mMol/L,
potassium < 3.2 or > 5.3 mMol/L.

- Women who are pregnant or breastfeeding.

- Intent to participate in an additional alcohol treatment program after discharge
other than Alcoholics Anonymous

- Court-mandated participation in alcohol treatment or pending incarceration.