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

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ClinicalTrials.gov Identifier: NCT00635102
Recruitment Status : Completed
First Posted : March 13, 2008
Results First Posted : December 16, 2016
Last Update Posted : December 16, 2016
Sponsor:
Information provided by (Responsible Party):
Yale University

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Alcohol Dependence 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 Not Applicable

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects
Study Start Date : October 1997
Actual Primary Completion Date : February 2008
Actual Study Completion Date : February 2008

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Alcohol dependent
Alcohol dependent patients will receive 4 interventions
 Drug: D-Cycloserine PO and Glycine IV
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:
  • Glycine infusion
  • Cycloserine

Drug: Placebo D-Cycloserine PO and placebo Glycine IV
Placebo
Other Name: placebo

Drug: Placebo D-Cycloserine PO and Glycine IV
Drug: D-Cycloserine PO and placebo Glycine IV
Active Comparator: Healthy subjects
Healthy subjects will receive 4 interventions
 Drug: D-Cycloserine PO and Glycine IV
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:
  • Glycine infusion
  • Cycloserine

Drug: Placebo D-Cycloserine PO and placebo Glycine IV
Placebo
Other Name: placebo

Drug: Placebo D-Cycloserine PO and Glycine IV
Drug: D-Cycloserine PO and placebo Glycine IV


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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)

  11. 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)

  12. 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)

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 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)

  19. 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)

  20. 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)

  21. 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)

  22. 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)

  23. 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)

  24. 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)

  25. 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)

  26. 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)

  27. 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)

  28. 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)

  29. 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)

  30. 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)

  31. 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)

  32. 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)

  33. 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)

  34. 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)

  35. 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)

  36. 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)

  37. 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)

  38. 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)

  39. 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)

  40. 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)


Eligibility Criteria
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Ages Eligible for Study:   21 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00635102


Locations
United States, Connecticut
VA Connecticut Healthcare System
West Haven, Connecticut, United States, 06516
Sponsors and Collaborators
Yale University
Investigators
Principal Investigator: John H Krystal, M.D. Yale University
More Information
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Publications of Results:

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT00635102     History of Changes
Other Study ID Numbers: 12449
VA Merit Grant ( Other Grant/Funding Number: VA Merit Grant )
First Posted: March 13, 2008    Key Record Dates
Results First Posted: December 16, 2016
Last Update Posted: December 16, 2016
Last Verified: December 2016

Keywords provided by Yale University:
Alcohol Dependence, Alcoholism, Glycine, D-Cycloserine

Additional relevant MeSH terms:
Cycloserine
Alcoholism
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Glycine
Anti-Infective Agents, Urinary
Anti-Infective Agents
 Renal Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs