Intravenous Alcohol Administration Using BrAc Method in Healthy Subjects With and Without a Family History of Alcoholism

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 have decreased 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 alcohol 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 administration of placebo or one of two ethanol doses (target BrAc=40mg%, or target BrAc=100mg%) intravenously for 20 minutes, until the target BrAc is achieved. Once BrAc is achieved (40mg% or 100mg%) it will be maintained using a clamp procedure for over 60 minutes. Outcome measures include the Positive and Negative Symptom Scale, visual analog scales of mood state, (i.e. anxiety) and the Clinician-Administered Dissociative States Scale (CADSS) to measure perceptual responses to alcohol. Secondary measures include visual analog scales for high, similarity to ethanol, Mini Mental Status Examination (MMSE), Placement of electrodes, Biphasic Alcohol Effects Scale, Hopkins Verbal Learning, and number of drinks scale, aspects of craving for alcohol and tests of cognitive impairment.

Official Title
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Intravenous Alcohol Administration Using BrAc Method in Healthy Subjects With and Without a Family History of Alcoholism

Conditions
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Alcoholism

Intervention / Treatment
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* Drug: Ethanol High Dose, Ethanol Low Dose, 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 on the basis of history and urine toxicology and breath alcohol levels at screening and on each test day. For Family History Positive (FHP) Subjects: 1) Biological father and another first or second-degree biological relative with history of alcoholism by Family History Assessment Module (FHAM) developed by COGA. Exclusion Criteria: DSM-IV psychiatric and substance abuse (excluding alcohol abuse) diagnosis by history on psychiatric evaluation that includes a structured diagnostic interview (Structured Clinical Interview for Diagnostic and Statistical Manual (DSM)-IV Axis I Disorders (SCID)) Subjects who meet criteria for alcohol abuse and express an interest in stopping alcohol use and/or express an interest in treatment or are currently enrolled in treatment for alcoholism, or have sought treatment in the last 6 months. history of counseling or psychotherapy; except family therapy centered around another family member extended unwillingness to remain alcohol-free for 48 hours prior to test days; for women: positive pregnancy test at screening or intention to engage in unprotected sex during the study alcohol naïve Adoptee and no contact with family members.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Family HIstory Positive<br>Subjects with a positive family history of alcoholism. | Drug: Ethanol High Dose, Ethanol Low Dose, and Placebo<br>* Three test days will involve administration of placebo, ethanol high dose (BrAc=100mg%) or ethanol low dose (BrAc=40mg%)intravenously for approximately 20 minutes, until the target BrAc is achieved. Once BrAc is achieved (40mg% or 100mg%) it will be maintained using a clamp procedure for 60 minutes.<br>* Other names: intravenous;|
| Active Comparator: Family History Negative<br>Subjects with a negative family history of alcoholism. | Drug: Ethanol High Dose, Ethanol Low Dose, and Placebo<br>* Three test days will involve administration of placebo, ethanol high dose (BrAc=100mg%) or ethanol low dose (BrAc=40mg%)intravenously for approximately 20 minutes, until the target BrAc is achieved. Once BrAc is achieved (40mg% or 100mg%) it will be maintained using a clamp procedure 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 |
| --- | --- | --- |
| Number of Drinks Felt Consumed at Baseline | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | Baseline | 
| Number of Drinks Felt Consumed at 10 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 10 minutes | 
| Number of Drinks Felt Consumed at 30 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 30 minutes | 
| Number of Drinks Felt Consumed at 110 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 110 minutes | 
| Number of Drinks Felt Consumed at 140 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 140 minutes | 
| Number of Drinks Felt Consumed at 170 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 170 minutes | 
| Number of Drinks Felt Consumed at 230 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 230 minutes | 
| Visual Analog Scale of Similarity to Alcohol - Baseline | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | Baseline | 
| Visual Analog Scale of Similarity to Alcohol -10 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 10 minutes | 
| Visual Analog Scale of Similarity to Alcohol - 30 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 30 minutes | 
| Visual Analog Scale of Similarity to Alcohol - 60 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 60 minutes | 
| Visual Analog Scale of Similarity to Alcohol - 110 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 110 minutes | 
| Visual Analog Scale of Similarity to Alcohol - 140 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 140 minutes | 
| Visual Analog Scale of Similarity to Alcohol - 170 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 170 minutes | 
| Visual Analog Scale of Similarity to Alcohol - 230 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 230 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative Baseline | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | Baseline | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 10 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 10 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 30 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 30 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 60 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 60 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 110 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 110 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 140 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 140 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 170 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 170 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 230 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 230 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - Baseline | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | Baseline | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 10 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 10 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 30 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 30 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 60 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 60 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 110 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 110 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 140 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 140 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 170 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 170 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 240 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 240 minutes | 
| Visual Analog Scale (VAS) HIGH - Baseline | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | Baseline | 
| Visual Analog Scale (VAS) HIGH - 10 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 10 minutes | 
| Visual Analog Scale (VAS) HIGH - 30 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 30 minutes | 
| Visual Analog Scale (VAS) HIGH - 60 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 60 minutes | 
| Visual Analog Scale (VAS) HIGH - 110 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 110 minutes | 
| Visual Analog Scale (VAS) HIGH - 140 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 140 minutes | 
| Visual Analog Scale (VAS) HIGH - 170 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 170 minutes | 
| Visual Analog Scale (VAS) HIGH - 240 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 240 minutes | 
| Visual Analog Scale (VAS) Drowsy - Baseline | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | Baseline | 
| Visual Analog Scale (VAS) Drowsy - 10 Minutes | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | 10 minutes | 
| Visual Analog Scale (VAS) Drowsy - 30 Minutes | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | 30 minutes | 
| Visual Analog Scale (VAS) Drowsy - 60 Minutes | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | 60 minutes | 
| Visual Analog Scale (VAS) Drowsy - 110 Minutes | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | 110 minutes | 
| Visual Analog Scale (VAS) Drowsy - 140 Minutes | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | 140 minutes | 
| Visual Analog Scale (VAS) Drowsy - 170 Minutes | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | 170 minutes | 
| Visual Analog Scale (VAS) Drowsy - 230 Minutes | visual analog scale (VAS): self-report scale used to measure Drowsy (0 not at all drowsy - 7 extremely drowsy) | 230 minutes | 
| Hopkins Verbal Learning Task - Immediate Recall - Trial 1 | Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (Three immediate recall trials) (0 no words recalled - 12 all words recalled) | 30 minutes - Trial 1 | 
| Hopkins Verbal Learning Task - Immediate Recall - Trial 2 | Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (Three immediate recall trials) (0 no words recalled - 12 all words recalled) | 30 minutes - Trial 2 | 
| Hopkins Verbal Learning Task - Immediate Recall - Trial 3 | Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (Three immediate recall trials) (0 no words recalled - 12 all words recalled) | 30 minutes - Trial 3 | 
| Hopkins Verbal Learning Task - Delay Recall | Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (Delay Recall: 30 minutes after Trials 1-3 were given) (0 no words recalled - 12 all words recalled) | 60 minutes | 
| Pegboard Task - Baseline (Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds | Baseline | 
| Pegboard Task - 30 Minutes (Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds. | 30 minutes | 
| Pegboard Task - Baseline (Non-Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds. | Baseline | 
| Pegboard Task - 30 Minuites (Non-Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds. | 30 minutes |