Ketamine/Placebo Family History Positive Study

Study Overview
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Brief Summary
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The proposed study is the first to explore the contribution of brain glutamate systems, a major target of ethanol in the brain, to the vulnerability to develop alcoholism. This study may lead to an enhanced understanding of the underlying neurobiological mechanism in high-risk individuals that may lead to the transition from moderate to excessive use of alcohol.

Detailed Description
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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 2 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 Biphasic Alcohol Scale 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.

Official Title
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NMDA Dysregulation in Individuals With a Family Vulnerability to Alcoholism

Conditions
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Alcoholism

Intervention / Treatment
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* Drug: Ketamine and Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female between the ages of 21 and 30 years Medically and neurologically healthy on the basis of history, physical examination, EKG, screening laboratories, absence of current and/or past substance abuse For Family History Positive (FHP) Subjects: Biological father and another first or second-degree biological relative with history of alcoholism Exclusion Criteria: Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (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 History of counseling or psychotherapy; except family therapy centered around another family member Extended unwillingness to remain alcohol-free for three days prior to testing and for the duration of the testing period For women: positive pregnancy test at screening or intention to engage in unprotected sex during the study Alcohol naïve Previous bad experience with ketamine Adoptee and no contact with family members 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)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Family History Positive<br>Subjects with a positive family history of alcoholism | Drug: Ketamine and Placebo<br>* Two test days will involve administration of placebo and Ketamine (0.23 mg/kg, loading dose and infusion rate 0.58 mg/kg/minute) intravenously for 60 minutes<br>* Other names: intravenous;|
| Experimental: Family History Negative<br>Subjects with a negative family history of alcoholism | Drug: Ketamine and Placebo<br>* Two test days will involve administration of placebo and Ketamine (0.23 mg/kg, loading dose and infusion rate 0.58 mg/kg/minute) intravenously for 60 minutes<br>* Other names: intravenous;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedation | Self-reporting rating scale to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | Baseline | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedation | Self-reporting rating scale to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | 15 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedation | Self-reporting rating scale to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | 45 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedation | Self-reporting rating scale to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | 80 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulation | Self-reporting rating scale to measure the stimulation effects (0 not at all stimulated - 70 extremely stimulated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | Baseline | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulation | Self-reporting rating scale to measure the stimulation effects (0 not at all stimulated - 70 extremely stimulated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | 15 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulation | Self-reporting rating scale to measure the stimulation effects (0 not at all stimulated - 70 extremely stimulated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | 45 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulation | Self-reporting rating scale to measure the stimulation effects (0 not at all stimulated - 70 extremely stimulated) of alcohol effects. We used the BAES to measure alcohol-like effects in subjects that received ketamine infusions. | 80 minutes |