A Phase 1/2 interventional study of Ketamine + Naltrexone and Ketamine + Placebo in Major Depressive Disorder and Alcohol Use Disorder, sponsored by VA Office of Research and Development. Completed at 1 site in United States. Open to participants aged 21 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-04-10.
Sponsored by VA Office of Research and Development · Phase 1/2, Interventional, and Treatment
The investigators will compare 3 treatment groups (ketamine plus naltrexone vs. ketamine alone vs. placebo) for treating major depressive disorder (MDD) and alcohol use disorder (AUD) in an 8-week randomized, double-blind, placebo-controlled, between-subjects trial. First, prior to the double-blind trial, the investigators will conduct an open-label trial that will include 5 patients with comorbid MDD and AUD to test safety and efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) with a follow-up of 4 weeks. Second, after reviewing the safety and efficacy of repeated ketamine treatment from the open-label trial, the investigators will conduct an 8-week, randomized, double-blind, placebo-controlled trial that will include 60 patients with comorbid MDD and AUD to test safety and efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) plus naltrexone with a follow-up of 4 weeks. The 4-month follow-up session will also occur.
1,606 studies on the registry are indexed under Alcoholism; 329 are open to participants now.
This study's enrollment of 65 is below the median of 87 across 1,371 interventional studies indexed under Alcoholism.
Browse Alcoholism studies →VA Office of Research and Development is the lead sponsor of 1,733 studies on the registry; 396 are open to participants now.
Of its 206 completed or terminated interventional studies of FDA-regulated products, 180 (87%) have results posted.
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Exclusion Criteria:
Subjects in this arm will receive (1) intravenous ketamine treatment once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular naltrexone once a month (a total of 2 injections).
Drug: Ketamine + Naltrexone
Subjects in this arm will receive (1) intravenous ketamine treatment once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular placebo once a month (a total of 2 injections).
Drug: Ketamine + Placebo
Subjects in this arm will receive (1) intravenous placebo treatment (psychoactive placebo midazolam) once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular placebo once a month (a total of 2 injections).
Drug: Placebo (psychoactive placebo midazolam) + Placebo
Subjects in this arm will receive (1) intravenous ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular naltrexone (380 mg) once a month (a total of 2 injections).
Subjects in this arm will receive (1) intravenous ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular placebo once a month (a total of 2 injections).
Subjects in this arm will receive (1) intravenous psychoactive placebo midazolam (0.045 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular placebo once a month (a total of 2 injections).
Number of Participants With 50% or Greater Improvement in MADRS Scores From Baseline
Our primary analysis (severity of depression) was to compare the proportions of subjects with clinical response in symptoms of major depressive disorder (response defined as a 50% or greater improvement from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores) at the end-of-treatment time point (Day 21, after 4th infusion, T+240 minutes).
Time frame: Day 21 (after 4th infusion, 240 minutes)
Rate of Complete Abstinence From Alcohol
Alcohol consumption was measured using the Time Line Follow Back (TLFB) method. The rates of complete abstinence from alcohol across visits 3 (day 0) through visit 7 (day 28) were compared among the three study groups.
Time frame: Day 28
| Milestone | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo |
|---|---|---|---|
| Started | 22 | 21 | 22 |
| Completed | 16 | 10 | 15 |
| Not completed | 6 | 11 | 7 |
Our primary analysis (severity of depression) was to compare the proportions of subjects with clinical response in symptoms of major depressive disorder (response defined as a 50% or greater improvement from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores) at the end-of-treatment time point (Day 21, after 4th infusion, T+240 minutes).
| Participants | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo |
|---|---|---|---|
| Number of Participants With 50% or Greater Improvement in MADRS Scores From Baseline | 15 | 9 | 13 |
Alcohol consumption was measured using the Time Line Follow Back (TLFB) method. The rates of complete abstinence from alcohol across visits 3 (day 0) through visit 7 (day 28) were compared among the three study groups.
| Participants | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo |
|---|---|---|---|
| Rate of Complete Abstinence From Alcohol | 3 | 6 | 2 |
Collected over During the study period (8 weeks). Non-serious events are listed at a 4% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ketamine + Naltrexone | 0/20 (0%) | 0/20 (0%) | 14/20 (70%) |
| Ketamine + Placebo | 0/19 (0%) | 0/19 (0%) | 11/19 (57.9%) |
| Placebo (Psychoactive Placebo Midazolam) + Placebo | 0/19 (0%) | 0/19 (0%) | 14/19 (73.7%) |
| Event | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo |
|---|---|---|---|
| Unusual tiredness or weaknessGeneral disorders | 0/20 | 3/19 | 7/19 |
| CoughGeneral disorders | 3/20 | 2/19 | 6/19 |
| HeadacheGeneral disorders | 4/20 | 1/19 | 6/19 |
| DrowsinessGeneral disorders | 2/20 | 2/19 | 6/19 |
| AnxietyGeneral disorders | 4/20 | 4/19 | 6/19 |
| TirednessGeneral disorders | 4/20 | 2/19 | 6/19 |
| Weight lossGeneral disorders | 4/20 | 1/19 | 1/19 |
| Chest pain, tightness, or discomfortGeneral disorders | 0/20 | 1/19 | 3/19 |
| Dizziness, faintness, lightheadedness upon risingGeneral disorders | 2/20 | 1/19 | 3/19 |
| Loss of appetiteGeneral disorders | 3/20 | 1/19 | 3/19 |
Subjects receiving at least one infusion were analyzed
| Age, Continuous(years) | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo | Total |
|---|---|---|---|---|
| Mean | 44.1 ± 13.7 | 50.0 ± 10.1 | 41.9 ± 13.5 | 45.3 ± 12.8 |
| Sex: Female, Male(Participants) | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo | Total |
|---|---|---|---|---|
| Female | 4 | 4 | 5 | 13 |
| Male | 16 | 15 | 14 | 45 |
| Race/Ethnicity, Customized(Participants) | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo | Total |
|---|---|---|---|---|
| Race/Ethnicity — White | 18 | 14 | 7 | 39 |
| Race/Ethnicity — Black | 0 | 3 | 5 | 8 |
| Race/Ethnicity — Hispanic or Latino | 2 | 1 | 5 | 8 |
| Race/Ethnicity — Other | 0 | 1 | 2 | 3 |
| Montgomery-Åsberg Depression Rating Scale (MADRS) score, mean (SD)(units on a scale) | Ketamine + Naltrexone | Ketamine + Placebo | Placebo (Psychoactive Placebo Midazolam) + Placebo | Total |
|---|---|---|---|---|
| Mean | 27.8 ± 6.0 | 30.3 ± 6.1 | 30.3 ± 7.1 | 29.4 ± 6.4 |
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Plan to share: Yes
Supporting information: Analytic code
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