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

Yale University

Status: Completed

Conditions: Alcohol Dependence

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

Study type: Interventional

Funder types: Other

Identifiers

NCT00635102

VA Merit Grant

12449

Details and patient eligibility

About

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.

Full 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.

Enrollment: 57 patients

Sex: All

Ages: 21 to 70 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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57 participants in 2 patient groups

Alcohol dependent

Active Comparator group

Description:

Alcohol dependent patients will receive 4 interventions

Treatment:

Drug: D-Cycloserine PO and placebo Glycine IV

Drug: Placebo D-Cycloserine PO and placebo Glycine IV

Drug: D-Cycloserine PO and Glycine IV

Drug: Placebo D-Cycloserine PO and Glycine IV

Healthy subjects

Active Comparator group

Description:

Healthy subjects will receive 4 interventions

Treatment:

Drug: D-Cycloserine PO and placebo Glycine IV

Drug: Placebo D-Cycloserine PO and placebo Glycine IV

Drug: D-Cycloserine PO and Glycine IV

Drug: Placebo D-Cycloserine PO and Glycine IV