Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects

Study Overview
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Brief Summary
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Question #1: Will glycine ameliorate cognitive deficits? Hypothesis #1: Based on positive findings conducted with glycine and milacemide, a glycine prodrug, in schizophrenia and dementia, we expect that glycine will ameliorate cognitive deficits. Question #2: Will alcoholic patients show enhanced endocrinal effects to glycine? Hypothesis #2: Based on the dose-related effects of glycine in healthy subjects, we expect that glycine will increase the endocrinal response to glycine in alcoholic patients with, supposedly, dysregulated NMDA receptor function. Question #3: Will D-cycloserine have ethanol-like effects? Hypothesis #3: If inhibition of NMDA receptor function is fundamental to the subjective effects of ethanol, then the NMDA antagonist properties of D-cycloserine should be recognized as ethanol-like (relative to placebo) in recently detoxified alcoholics and healthy subjects. Question #4: Will D-cycloserine reverse cognitive benefits of glycine? Hypothesis 4: Based on the dose related NMDA antagonist activity of D-cycloserine, we expect that D-cycloserine will compete with the agonist activity of glycine and therefore it will reverse the cognitive benefits of glycine. Question #5: Will D-cycloserine inhibit endocrinal effects of glycine? Hypothesis #5: If the agonist activity of glycine is necessary to determine endocrine response, then the dose-related NMDA antagonist properties of D-cycloserine should block these effects.

Detailed Description
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The purpose of this study is to investigate the interaction between glycine and D-cycloserine in alcoholic patients and healthy subjects. Preclinical studies have shown that compounds acting at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, such as glycine, may reverse the effects of ethanol on the NMDA receptor function (Rabe et al., 1990). The amino acid glycine is a co-agonist of the NMDA receptor complex (Kemp et al., 1993). It binds to the strychnine-insensitive site and positively modulates the NMDA receptor (Mc Donald et al., 1990). Physiologically, the glycine site is not saturated, and administration of glycine can potentiate NMDA receptor mediated responses. In contrast, D-cycloserine (Hood et al., 1989) is a partial-agonist at the glycine site of the NMDA receptor, with dose-dependent NMDA antagonist properties. The NMDA antagonist activity of D-cycloserine should produce ethanol like-effects that can be reversed by the agonist glycine. This study is intended to evaluate possible contributions of the glycine site to the reduction of cognitive deficits of alcoholism and complements the current work at VA Connecticut Healthcare System on the NMDA antagonists in alcoholic and healthy subjects.

Official Title
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Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects

Conditions
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Alcohol Dependence

Intervention / Treatment
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* Drug: D-Cycloserine PO and Glycine IV
* Drug: Placebo D-Cycloserine PO and placebo Glycine IV
* Drug: Placebo D-Cycloserine PO and Glycine IV
* Drug: D-Cycloserine PO and placebo Glycine IV


Participation Criteria
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Eligibility Criteria
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Inclusion / Exclusion Criteria Alcoholic subjects: Male or female (post-menopausal, surgically sterile, or negative pregnancy test at screening and agreement to utilize an established birth control during the testing period) between the age of 21 and 70 yrs. Meet Diagnostic and Statistical Manual (DSM) IV criteria for alcohol dependence by structured clinical interview Meet von Knorring criteria for early onset (type II) alcoholism Without other DSM IV Axis I diagnoses by Structured Clinical Interview (SCID). Without lifetime history of other substance abuse diagnosis by SCID (excluding tobacco) and urine toxicology screen negative for drug of abuse. Medically and neurologically healthy on the basis of history, physical examination, sequential multiple analysis-computer (SMAC-20), complete blood count (CBC) w/diff. and EKG. In light of the proximity to alcohol dependence, liver function test (LFT) elevations of twice normal will be accepted into the study. Patients with stable medical problems may be included in the study if their medications have not been adjusted in the month prior to participation and if these medications lack prominent central nervous system (CNS) effects. Absence of alcohol within the past 15 days. Patients must be free of medications utilized to facilitate detoxification (lorazepam, oxazepam) for at least 3 days prior to initiating testing. Patients must have no history of alcoholic hallucinosis. Patients must not be in acute alcohol withdrawal as evidence by a score no more than 2 for each item of the Clinical Institute Withdrawal Assessment Scale Patients taking ethionamide or isoniazid will be not be allowed to participate in the study. Inclusion / Exclusion Criteria Healthy subjects: Male or female (post-menopausal, surgically sterile, or negative pregnancy test at screening and agreement to utilize an established birth control during the testing period) between the age of 21 and 70 yrs. Absence of a lifetime substance abuse diagnosis by the non-patient version of the SCID. Medically and neurologically healthy on the basis of history, physical examination, SMAC-20, CBC w/diff. and EKG. In light of the proximity to alcohol dependence, LFT elevations of twice normal will be accepted into the study. Absence of alcohol within the past 14 days Healthy subjects will be matched to the patient group for age, sex and educational level.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Alcohol dependent<br>Alcohol dependent patients will receive 4 interventions | Drug: D-Cycloserine PO and Glycine IV<br>* Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.<br>* Other names: Cycloserine;Drug: Placebo D-Cycloserine PO and placebo Glycine IV<br>* Placebo<br>* Other names: placebo;Drug: Placebo D-Cycloserine PO and Glycine IV<br> <br> Drug: D-Cycloserine PO and placebo Glycine IV<br> <br> |
| Active Comparator: Healthy subjects<br>Healthy subjects will receive 4 interventions | Drug: D-Cycloserine PO and Glycine IV<br>* Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.<br>* Other names: Cycloserine;Drug: Placebo D-Cycloserine PO and placebo Glycine IV<br>* Placebo<br>* Other names: placebo;Drug: Placebo D-Cycloserine PO and Glycine IV<br> <br> Drug: D-Cycloserine PO and placebo Glycine IV<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scales of Similarity to Alcohol - Baseline | Visual Analog Scales 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 Scales of Similarity to Alcohol 60 Minutes Prior to Glycine Infusion | Visual Analog Scales 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 prior to Glycine infusion | 
| Visual Analog Scales of Similarity to Alcohol 30 Minutes | Visual Analog Scales 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 Scales of Similarity to Alcohol 60 Minutes | Visual Analog Scales 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 Scales of Similarity to Alcohol 120 Minutes | Visual Analog Scales 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 | 120 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Drinks Felt Consumed at 60 Minutes Prior to Glycine Infusion | The Number of Drinks Scale asks subjects to report on the number of alcoholic drinks they felt they had consumed. | 60 minutes prior to Glycine infusion | 
| 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 60 Minutes | The Number of Drinks Scale asks subjects to report on the number of alcoholic drinks they felt they had consumed. | 60 minutes | 
| Number of Drinks Felt Consumed at 120 Minutes | The Number of Drinks Scale asks subjects to report on the number of alcoholic drinks they felt they had consumed. | 120 minutes | 
| Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - Baseline | Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol | Baseline | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedation 60 Minutes Prior to Glycine Infusion | Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol | 60 minutes prior to Glycine infusion | 
| Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 30 Minutes | Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol | 30 minutes | 
| Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 60 Minutes | Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol | 60 minutes | 
| Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 120 Minutes | Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol | 120 minutes | 
| Visual Analog Scales (VAS) - Baseline | Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely) | Baseline | 
| Visual Analog Scales (VAS) - 60 Minutes Prior to Glycine Infusion | Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely) | 60 minutes prior to Glycine infusion | 
| Visual Analog Scales (VAS) - 30 Minutes | Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely) | 30 minutes | 
| Visual Analog Scales (VAS) - 60 Minutes | Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely) | 60 minutes | 
| Visual Analog Scales (VAS) - 120 Minutes | Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely) | 120 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Desire to Drink- Baseline | Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol) | Baseline | 
| Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 60 Minutes Prior to Glycine Infusion | Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol) | 60 minutes prior to Glycine infusion | 
| Alcohol Craving Scale (ACS) Subscale: Desire to Drink: - 30 Minutes | Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol) | 30 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 60 Minutes | Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol) | 60 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 120 Minutes | Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol) | 120 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Mood Improvement - Baseline | Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely) | Baseline | 
| Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 60 Minutes Prior to Glycine Infusion | Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely) | 60 minutes prior to Glycine infusion | 
| Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 30 Minutes | Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely) | 30 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 60 Minutes | Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely) | 60 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 120 Minutes | Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely) | 120 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Discomfort - Baseline | Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely) | Baseline | 
| Alcohol Craving Scale (ACS) Subscale: Discomfort - 60 Minutes Prior to Glycine Infusion | Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely) | 60 minutes prior to Glycine infusion | 
| Alcohol Craving Scale (ACS) Subscale: Discomfort - 30 Minutes | Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely) | 30 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Discomfort - 60 Minutes | Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely) | 60 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Discomfort - 120 Minutes | Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely) | 120 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - Baseline | Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely) | Baseline | 
| Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 60 Minutes Prior to Glycine Infusion | Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely) | 60 minutes prior to Glycine infusion | 
| Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 30 Minutes | Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely) | 30 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 60 Minutes | Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely) | 60 minutes | 
| Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 120 Minutes | Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely) | 120 minutes | 
| Continuous Performance Task (CPT) - Distractibility A-Prime - 30 Minutes | gordon diagnostic system is a continuous performance task (CPT) to measure distractibility - (A-Prime score range 0 minimum - 1 maximum - the higher number the better the performance) | 30 minutes | 
| Continuous Performance Task (CPT) - Vigilance - A-Prime Score 30 Minutes | gordon diagnostic system is a continuous performance task (CPT) to measure Vigilance - (A-Prime score range 0 minimum - 1 maximum - The higher number the better the performance) | 30 minutes | 
| Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - 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) | 60 minutes - Trial 1 | 
| Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - 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) | 60 minutes - Trial 2 | 
| Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - 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) | 60 minutes - Trial 3 | 
| Hopkins Verbal Learning Task - Delay Recall - 90 Minutes | 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) | 90 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol Dependence, Alcoholism, Glycine, D-Cycloserine