Cocaine Abuse
Conditions
Keywords
Aripiprazole, Cocaine abuse
Brief summary
The purpose of this study is to investigate whether aripiprazole will decrease cocaine self-administration, subjective effects and cravings compared to placebo.
Detailed description
Despite the recent increase in data about cocaine's basic neurochemical mechanisms of action, progress towards the development of an effective pharmacological treatment for cocaine abuse has been disappointing. We are proposing to use our laboratory model of repeated dose cocaine self-administration to assess the potential efficacy of the novel antipsychotic, aripiprazole. Aripiprazole is a partial agonist at both the dopamine D2 receptor and at the serotonin 5HT1a receptor, while antagonizing the 5HT2a receptor. By functioning as a partial D2 agonist, aripiprazole is hypothesized to function as a D2 antagonist during hypodopaminergic states, such as during cocaine use, while functioning as a D2 agonist during hypodopaminergic states, such as during cocaine withdrawal. This 42-day, outpatient/inpatient/outpatient/inpatient protocol will evaluate the effects of aripiprazole maintenance (0, 15 mg/day) on cocaine craving, subjective effects, and self-administration using a within-subjects design. Non-treatment seeking cocaine abusers will be maintained outpatient for 16 days of dose maintenance prior to inpatient cocaine self-administration sessions. During the inpatient phases, volunteers will live on a hospital clinical research unit and will participate in laboratory sessions in which they will have the opportunity to choose between repeated doses of smoked cocaine and $5. In addition to measuring their cocaine self-administration, we will measure the cardiovascular and subjective effects of cocaine under each aripiprazole maintenance condition.
Interventions
DRUGAripiprazole + Cocaine
Participants received aripiprazole (15mg/day) in conjunction with a dose-response of cocaine (0, 12, 25, 50 mg).
DRUGPlacebo + Cocaine
Placebo (0 mg/day) in conjunction with a dose-response of cocaine (0, 12, 25, 50 mg).
Sponsors
National Institute on Drug Abuse (NIDA)
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
In order to achieve steady-state concentrations, participants (n=8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose-response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance.
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Meets DSM-IV criteria for current cocaine abuse * Average use of smoked cocaine is at least 2x/week for past 6 mos); currently spends at least $70 per week on cocaine * Has patterns of smoked cocaine use in terms of frequency and amounts which parallel or exceed those administered in the study * Age 21-45 * Able to give informed consent, and comply with study procedures
Exclusion criteria
* Current seizure disorder, heart disease or psychiatric disorders (other than cocaine dependence) * Dependence on substances other than cocaine or nicotine * Request for drug treatment * Judged to be noncompliant with study protocol * Current use of any medication that has the potential to interact with aripiprazole (i.e., seizure medications, anti-fungal medications, cardiac medications, or medication that produces drowsiness) * Clinical laboratory tests outside normal limits that are clinically unacceptable to the study physician (BP \> 140/90; BUN, creatinine, LFTs \> 1.5 ULN; hematocrit \< 34 for women, \< 36 for men; pseudocholinesterase deficiency) * Currently meeting DSM-IV criteria for all major psychiatric/psychotic disorders other than transient psychosis due to drug abuse * Current parole or probation * History of significant violent or suicidal behavior
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cocaine Self-administration | 5 days | Mean number of cocaine choices as a function of cocaine dose and aripiprazole dose (n=8). Participants sampled the dose of cocaine available for the session and then had five choices to respond for money ($5.00) or cocaine using a modified progressive-ratio schedule. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Effects of Cocaine | 5 days | Mean Visual Analog Scale (VAS) ratings (items: Quality, Pay for Dose, Good Drug Effect, and Cocaine Craving) from 0-100mm as a function of cocaine dose and aripiprazole dose 4 min following a single administration of cocaine (the sample dose) at the start of the session. For Quality item, the perceived quality of the drug is rated. The higher the rating, the better quality the drug was perceived to be. For Pay for Dose item, the likelihood that the participant would pay for the drug is indicated. Higher ratings indicate a better likelihood that the person would pay for the dose received. For Good Drug Effect, the likelihood of feeling a good drug effect is indicated. The higher the number, the more of a good drug effect the person reported. For Cocaine Craving, the intensity of craving is reported. Higher scores indicate more craving for cocaine. |
| Plasma Cocaine | 8 minutes | Mean plasma cocaine levels after a single administration of each cocaine dose as a function of aripiprazole and cocaine dose. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole vs. Placebo Aripiprazole + Cocaine: Participants received aripiprazole (15mg/day) or placebo (o mg/day) in conjunction with a dose-response of cocaine (0, 12, 25, 50 mg). | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Arrested | 1 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Protocol Violation | 14 |
Baseline characteristics
| Characteristic | Aripiprazole vs. Placebo |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 41.8 years STANDARD_DEVIATION 3.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Cocaine Self-administration
Mean number of cocaine choices as a function of cocaine dose and aripiprazole dose (n=8). Participants sampled the dose of cocaine available for the session and then had five choices to respond for money ($5.00) or cocaine using a modified progressive-ratio schedule.
Time frame: 5 days
Population: Eight participants were included in this within-subjects analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + 0mg Cocaine | Cocaine Self-administration | 0 Number of Choices | Standard Error 0 |
| Placebo + 12mg Cocaine | Cocaine Self-administration | 1.5 Number of Choices | Standard Error 0.5 |
| Placebo + 25mg Cocaine | Cocaine Self-administration | 3 Number of Choices | Standard Error 0.5 |
| Placebo + 50mg Cocaine | Cocaine Self-administration | 4 Number of Choices | Standard Error 0.5 |
| Aripiprazole + 0 mg Cocaine | Cocaine Self-administration | 0.2 Number of Choices | Standard Error 0.1 |
| Aripiprazole + 12mg Cocaine | Cocaine Self-administration | 2.8 Number of Choices | Standard Error 0.5 |
| Aripiprazole + 25mg Cocaine | Cocaine Self-administration | 3.9 Number of Choices | Standard Error 0.5 |
| Aripiprazole + 50mg Cocaine | Cocaine Self-administration | 3.7 Number of Choices | Standard Error 0.5 |
Secondary
Plasma Cocaine
Mean plasma cocaine levels after a single administration of each cocaine dose as a function of aripiprazole and cocaine dose.
Time frame: 8 minutes
Population: Eight participants were included in this within-subjects analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + 0mg Cocaine | Plasma Cocaine | 32 ng/mL | Standard Deviation 2 |
| Placebo + 12mg Cocaine | Plasma Cocaine | 60 ng/mL | Standard Deviation 4 |
| Placebo + 25mg Cocaine | Plasma Cocaine | 67 ng/mL | Standard Deviation 4 |
| Placebo + 50mg Cocaine | Plasma Cocaine | 119 ng/mL | Standard Deviation 12 |
| Aripiprazole + 0 mg Cocaine | Plasma Cocaine | 18 ng/mL | Standard Deviation 1 |
| Aripiprazole + 12mg Cocaine | Plasma Cocaine | 36 ng/mL | Standard Deviation 3 |
| Aripiprazole + 25mg Cocaine | Plasma Cocaine | 75 ng/mL | Standard Deviation 5 |
| Aripiprazole + 50mg Cocaine | Plasma Cocaine | 130 ng/mL | Standard Deviation 10 |
Secondary
Subjective Effects of Cocaine
Mean Visual Analog Scale (VAS) ratings (items: Quality, Pay for Dose, Good Drug Effect, and Cocaine Craving) from 0-100mm as a function of cocaine dose and aripiprazole dose 4 min following a single administration of cocaine (the sample dose) at the start of the session. For Quality item, the perceived quality of the drug is rated. The higher the rating, the better quality the drug was perceived to be. For Pay for Dose item, the likelihood that the participant would pay for the drug is indicated. Higher ratings indicate a better likelihood that the person would pay for the dose received. For Good Drug Effect, the likelihood of feeling a good drug effect is indicated. The higher the number, the more of a good drug effect the person reported. For Cocaine Craving, the intensity of craving is reported. Higher scores indicate more craving for cocaine.
Time frame: 5 days
Population: Eight participants were included in this within-subjects analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + 0mg Cocaine | Subjective Effects of Cocaine | Quality | 0 Scores on a scale of 0-100mm | Standard Error 0 |
| Placebo + 0mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 0 Scores on a scale of 0-100mm | Standard Error 0 |
| Placebo + 0mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 1 Scores on a scale of 0-100mm | Standard Error 0.1 |
| Placebo + 0mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 20 Scores on a scale of 0-100mm | Standard Error 5 |
| Placebo + 12mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 28 Scores on a scale of 0-100mm | Standard Error 5 |
| Placebo + 12mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 11 Scores on a scale of 0-100mm | Standard Error 2 |
| Placebo + 12mg Cocaine | Subjective Effects of Cocaine | Quality | 8.5 Scores on a scale of 0-100mm | Standard Error 0.5 |
| Placebo + 12mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 1.4 Scores on a scale of 0-100mm | Standard Error 0.5 |
| Placebo + 25mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 29 Scores on a scale of 0-100mm | Standard Error 5 |
| Placebo + 25mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 5 Scores on a scale of 0-100mm | Standard Error 1 |
| Placebo + 25mg Cocaine | Subjective Effects of Cocaine | Quality | 32 Scores on a scale of 0-100mm | Standard Error 5 |
| Placebo + 25mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 30 Scores on a scale of 0-100mm | Standard Error 5 |
| Placebo + 50mg Cocaine | Subjective Effects of Cocaine | Quality | 38.5 Scores on a scale of 0-100mm | Standard Error 6 |
| Placebo + 50mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 5.75 Scores on a scale of 0-100mm | Standard Error 1 |
| Placebo + 50mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 42 Scores on a scale of 0-100mm | Standard Error 5 |
| Placebo + 50mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 38.5 Scores on a scale of 0-100mm | Standard Error 5 |
| Aripiprazole + 0 mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 2 Scores on a scale of 0-100mm | Standard Error 0.1 |
| Aripiprazole + 0 mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 26 Scores on a scale of 0-100mm | Standard Error 6 |
| Aripiprazole + 0 mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 0 Scores on a scale of 0-100mm | Standard Error 0 |
| Aripiprazole + 0 mg Cocaine | Subjective Effects of Cocaine | Quality | 0 Scores on a scale of 0-100mm | Standard Error 0 |
| Aripiprazole + 12mg Cocaine | Subjective Effects of Cocaine | Quality | 10 Scores on a scale of 0-100mm | Standard Error 0.4 |
| Aripiprazole + 12mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 16 Scores on a scale of 0-100mm | Standard Error 3 |
| Aripiprazole + 12mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 1.6 Scores on a scale of 0-100mm | Standard Error 0.2 |
| Aripiprazole + 12mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 30 Scores on a scale of 0-100mm | Standard Error 5 |
| Aripiprazole + 25mg Cocaine | Subjective Effects of Cocaine | Quality | 25 Scores on a scale of 0-100mm | Standard Error 5 |
| Aripiprazole + 25mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 2.9 Scores on a scale of 0-100mm | Standard Error 0.3 |
| Aripiprazole + 25mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 30.5 Scores on a scale of 0-100mm | Standard Error 5 |
| Aripiprazole + 25mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 36 Scores on a scale of 0-100mm | Standard Error 6 |
| Aripiprazole + 50mg Cocaine | Subjective Effects of Cocaine | Pay for Dose | 6 Scores on a scale of 0-100mm | Standard Error 1.5 |
| Aripiprazole + 50mg Cocaine | Subjective Effects of Cocaine | Good Drug Effect | 35 Scores on a scale of 0-100mm | Standard Error 6 |
| Aripiprazole + 50mg Cocaine | Subjective Effects of Cocaine | Cocaine Craving | 33.5 Scores on a scale of 0-100mm | Standard Error 6 |
| Aripiprazole + 50mg Cocaine | Subjective Effects of Cocaine | Quality | 37 Scores on a scale of 0-100mm | Standard Error 6 |