Ketamine/Placebo Family History Positive Study

Males and females with a paternal family history of alcoholism have a high risk for
developing alcoholism. These individuals have been shown to decrease dysphoric responses to
alcohol self-administration that may promote the excessive use of alcohol. Ethanol has been
shown to be an antagonist at the N-methyl-D-aspartate (NMDA) glutamate receptor. We have
recently shown that sober alcoholics have decreased dysphoric response to the NMDA
antagonist, ketamine. We propose to test the hypothesis that this characteristic exists as a
vulnerability factor in those individuals susceptible to develop alcoholism. Specifically,
the objective is to determine whether individuals with a family history positive (FHP) for
alcoholism will experience less dysphoric, anxiogenic, and psychotogenic effects to ketamine
infusion when compared to family history negative (FHN) control subjects.

Male and female subjects, FHP (biological father and one other first degree relative)
between the ages of 21-30, and matched controls (FHN) will complete 3 test days in a
randomized balanced order under double-blind conditions. Test days will involve the
60-minute intravenous infusion of placebo and ketamine. Outcome measures include the
Positive and Negative Symptom Scale and the Clinician-Administered Dissociative States Scale
to measure perceptual responses to ketamine, and visual analog scales for mood states.
Secondary measures include visual analog scales for high, similarity to ethanol, the
Sensation Scale (a validated measure of ethanol-like sensations) and aspects of craving for
alcohol.

Inclusion Criteria:

1. Male and female between the ages of 21 and 30 years

2. Medically and neurologically healthy on the basis of history, physical examination,
EKG, screening laboratories, absence of current and/or past substance abuse

3. For Family History Positive (FHP) Subjects: Biological father and another first or
second-degree biological relative with history of alcoholism

Exclusion Criteria:

1. DSM-IV psychiatric and substance abuse diagnosis by history on psychiatric evaluation
that includes a structured diagnostic interview (The Semi-Structured Assessment for
the Genetics of alcoholism: SSAGA) and the Wisconsin Scales of Psychosis Proneness

2. History of counseling or psychotherapy; except family therapy centered around another
family member

3. Extended unwillingness to remain alcohol-free for three days prior to testing and for
the duration of the testing period

4. For women: positive pregnancy test at screening or intention to engage in unprotected
sex during the study

5. Alcohol naïve

6. Previous bad experience with ketamine

7. Adoptee and no contact with family members

8. For Family History Negative (FHN) Subjects: NO family history of alcoholism in any
first or second-degree relatives (subjects must reliably report on three first-degree
relatives)