Cocaine Dependence
Conditions
Brief summary
Cocaine dependence involves problematic neuroadaptations, such as heightened reactivity to cocaine cues, that may be responsive to pharmacological modulation of glutamatergic circuits. Despite promising preclinical findings with n-methyl-d-aspartate receptor (NMDAr) modulators, studies with human subjects have been unsuccessful to date. The purpose of this investigation is to examine the effects of the NMDAr antagonist ketamine, recently found to have potent therapeutic effects in humans, on cue-induced craving and impaired motivation for quitting cocaine in cocaine dependent participants, 24-hours post-infusion.
Detailed description
In this study, volunteers will undergo a 9 day inpatient trial during which they will receive three counter-balanced infusions (two doses of ketamine and a dose of lorazepam) on three separate days in a within-subject, double-blind, controlled design. Of the various glutamate antagonists available for human use, ketamine will be utilized because its safety profile, pharmacokinetics, and range of tolerable sub-anesthetic dosings have been very well studied. Also, ketamine has shown promise in managing opiate and alcohol use disorders in certain studies, and may therefore be the most likely glutamate antagonist to dampen cue reactivity and increase motivation in cocaine users. If ketamine significantly improves these deficits, this would suggest that the drug should be investigated further for potential utility as a treatment for cocaine dependence.
Interventions
DRUGKetamine 0.41 mg/kg
52 minute iv infusion of ketamine 0.41 mg/kg
DRUGKetamine 0.71 mg/kg
52 minute iv infusion of ketamine 0.71 mg/kg. This dose follows K1 in all 3 orderings.
DRUGLorazepam 2 mg
52 minute infusion of lorazepam 2 mg. This serves as an active control.
Sponsors
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 52 Years
Healthy volunteers
No
Inclusion criteria
1. Active free-base cocaine dependence (at least 4 days of use over the past month, with at least 1 use per week); if the participant uses through another route (IN, IV), then the FB route is dominant (\> 80% of occasions). 2. Physically healthy 3. No adverse reactions to study medications 4. 21-52 years of age 5. Normal body weight 6. Responsive to drug cues 7. Capacity to consent
Exclusion criteria
1. Seeking treatment or abstinence 2. DSM IV criteria for substance dependence (other than methamphetamine, cocaine, cannabis, or nicotine), or DSM IV criteria for abuse of ketamine or lorazepam 3. DSM-IV criteria for other Axis I psychiatric illness that may make participation hazardous such as schizophrenia, schizoaffective disorder, psychosis NOS, MDD, psychosis secondary to substances, or bipolar disorder 4. Delirium, Dementia, Amnesia, Cognitive Disorders, or dissociative disorders 5. Current suicide risk or a history of suicide attempt within the past 2 years 6. Current use of prescribed psychotropic medication 7. Pregnancy, nursing, or had a baby within the past 6 mo. 8. Heart disease as indicated by history, abnormal ECG, previous cardiac surgery. 9. Unstable physical disorders which might make participation hazardous such as end-stage AIDS, hypertension (\>140/90), anemia, active hepatitis or other liver disease, or diabetes 10. Bad reaction/experience with prior exposure to ketamine or lorazepam 11. History of significant violence 12. First degree relative with a psychotic disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cue Reactivity | Baseline and 24 hours after infusion | Serial visual analogue scale (VAS) scores for craving elicited by cocaine cue: units on a scale (0-200), high is worse. Scores are obtained at baseline and at 24 hours after the infusion. |
| Change in Motivation to Quit | Baseline and 24 hours post-infusion | Motivation score obtained from the University of Rhode Island Change Assessment (URICA). Scores are obtained at baseline and at 24 hours after each infusion. The scores are 0-13, with higher scores indicating greater motivation. The analysis is within-subject. Scores included below are means; higher scores represent higher motivation to quit than do lower scores. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited using advertisements and were seen at NYSPI.
Pre-assignment details
Participants were excluded if they could not comply with study procedures or if they were found to be ineligible.
Participants by arm
| Arm | Count |
|---|---|
| K1, LZP, and K2 Ketamine 0.41 (K1) followed by lorazepam (LZP) and then ketamine 0.71. Infusions are separated by 48 hours. This ordering allows for comparison between K1 and LZP, and between the post-K1 additive effects of LZP and K2. | 3 |
| LZP, K1, and K2 LZP followed by K1 and then K2. Infusions are separated by 48 hours. This order allows for comparison between LZP and K1. | 3 |
| K1, K2, and LZP K1 followed by K2 and then LZP. Infusions are separated by 48 hours. This allows for within-subject comparison of the post-K1 additive effects of K2 and LZP. | 2 |
| Total | 8 |
Baseline characteristics
| Characteristic | LZP, K1, and K2 | K1, K2, and LZP | K1, LZP, and K2 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Age, Continuous | 48.2 years STANDARD_DEVIATION 6.1 | 44.2 years STANDARD_DEVIATION 8.2 | 46.8 years STANDARD_DEVIATION 9 | 47.5 years STANDARD_DEVIATION 5.5 |
| Region of Enrollment United States | 3 participants | 2 participants | 3 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Change in Cue Reactivity
Serial visual analogue scale (VAS) scores for craving elicited by cocaine cue: units on a scale (0-200), high is worse. Scores are obtained at baseline and at 24 hours after the infusion.
Time frame: Baseline and 24 hours after infusion
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Ketamine Infusion 0.41 mg/kg Over 52 Minutes (K1) | Change in Cue Reactivity | 126 units on a scale (0-200), high is worse | Standard Error 66 |
| Ketamine Infusion 0.71 mg/kg Over 52 Minutes (K2) | Change in Cue Reactivity | 18 units on a scale (0-200), high is worse | Standard Error 13 |
| Lorazepam Infusion 2 mg/kg Over 52 Minutes (LZP) | Change in Cue Reactivity | 16 units on a scale (0-200), high is worse | Standard Error 12 |
Primary
Change in Motivation to Quit
Motivation score obtained from the University of Rhode Island Change Assessment (URICA). Scores are obtained at baseline and at 24 hours after each infusion. The scores are 0-13, with higher scores indicating greater motivation. The analysis is within-subject. Scores included below are means; higher scores represent higher motivation to quit than do lower scores.
Time frame: Baseline and 24 hours post-infusion
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketamine Infusion 0.41 mg/kg Over 52 Minutes (K1) | Change in Motivation to Quit | 4.35 units on a scale |
| Ketamine Infusion 0.71 mg/kg Over 52 Minutes (K2) | Change in Motivation to Quit | 3.2 units on a scale |
| Lorazepam Infusion 2 mg/kg Over 52 Minutes (LZP) | Change in Motivation to Quit | 4.2 units on a scale |