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Completed

NCT Number: NCT00635102

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

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.

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Key information

Conditions

Alcohol Dependence Alcohol-Related Disorders Alcoholism Chemically-Induced Disorders Mental Disorders Substance-Related Disorders

Age range

21 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

VA Connecticut Healthcare System

West Haven, Connecticut, 06516, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

D-Cycloserine PO and Glycine IV

Drug

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

Placebo D-Cycloserine PO and placebo Glycine IV

Drug

Placebo

Other names: placebo

Placebo D-Cycloserine PO and Glycine IV

Drug

D-Cycloserine PO and placebo Glycine IV

Drug

Primary outcomes

  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 outcomes

  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)

Sponsors and collaborators

Lead sponsor

Yale University

Other

Registry information

Important dates

Study start
1997
Primary completion
2008
Study completion
2008
First posted
Mar 13, 2008
Registry last updated
Dec 16, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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