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

December 14, 2016 updated by: Yale University

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.

Study Overview

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

57

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Connecticut
      • West Haven, Connecticut, United States, 06516
        • VA Connecticut Healthcare System

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Alcohol dependent
Alcohol dependent patients will receive 4 interventions
Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.
Other Names:
  • Cycloserine
  • Glycine infusion
Placebo
Other Names:
  • placebo
Active Comparator: Healthy subjects
Healthy subjects will receive 4 interventions
Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.
Other Names:
  • Cycloserine
  • Glycine infusion
Placebo
Other Names:
  • placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Visual Analog Scales of Similarity to Alcohol - Baseline
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Principal Investigator: John H Krystal, M.D., Yale University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 1997

Primary Completion (Actual)

February 1, 2008

Study Completion (Actual)

February 1, 2008

Study Registration Dates

First Submitted

March 6, 2008

First Submitted That Met QC Criteria

March 12, 2008

First Posted (Estimate)

March 13, 2008

Study Record Updates

Last Update Posted (Estimate)

December 16, 2016

Last Update Submitted That Met QC Criteria

December 14, 2016

Last Verified

December 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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