Cocaine-Related Disorders
Conditions
Brief summary
To use pregnenolone (PREG; 300; 500mg) daily versus placebo (PLA) as a probe to assess the role of neuroactive steroids in individuals with cocaine use disorder (CUD).
Detailed description
This experimental study aims to examine the effects of PREG on a) repeated cocaine craving, mood and neurobiological reactivity to brief, guided imagery exposure to stress, drug cues and neutral situations in the laboratory and b) daily cocaine intake, craving, cognition and mood in men and women with CUD; and c) sex differences in all of these outcomes. The study's hypothesis is that PREG vs PLA will dose-specifically decrease stress-induced and drug-cue induced cocaine craving, improve mood and cognitive performance, and normalize hypothalamic pituitary adrenal (HPA) axis response to stress and drug-cue imagery, and reduce cocaine intake and craving in daily life in individuals with CUD.
Interventions
DRUGPregnenolone (PREG)
2 doses of PREG (300 or 500 mg/day)
DRUGPlacebos
placebo
Sponsors
National Institute on Drug Abuse (NIDA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
Eligible participants will be randomly assigned to 2 doses of PREG (300/500 mg/day) vs placebo (PLA) treatment (N=20/group) over 8 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male or female individuals, ages 18 to 60. * Subjects must meet current DSM-V criteria for cocaine use disorder; documented positive urine toxicology screen for cocaine at intake or collateral information from family members, significant others, room-mates etc., on recent use. * Subject has voluntarily given informed consent and signed the informed consent document. * Able to read English and complete study evaluations.
Exclusion criteria
* Women who are pregnant, or nursing or are of childbearing potential and not practicing an effective means of birth control. * Meet current criteria for use disorder on another psychoactive substance, such as, heroin, amphetamines, hallucinogens/PCP, excluding alcohol and nicotine. * Any current use of opiates or past history of opiate use disorder. * Current use of any psychoactive drugs, including anxiolytics, antidepressants, naltrexone or antabuse. * Any psychotic disorder or current Axis I psychiatric symptoms requiring specific attention, including need for psychiatric medications for current major depression and anxiety disorders. * Significant underlying medical conditions such as cerebral, renal, thyroid or cardiac pathology which in the opinion of study physician would preclude patient from fully cooperating or be of potential harm during the course of the study. * Abstinent from cocaine for more than two weeks prior to admission. * Hypotensive individuals with sitting blood pressure below 90/50 mmHG.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Craving Change in Stress and Cue Relative to Neutral | Experiment during treatment week 2 | Cocaine craving assessed in a laboratory experiment with exposure to stress, cocaine cue and neutral control condition in those receiving PREG (300mg; 500mg) vs Placebo. Cocaine craving was assessed using the Cocaine Craving Questionnaire (CCQ), a brief 10-item self-report craving scale that ranges in mean score from 1 to 7, where a higher score indicates higher craving. Data presented here is craving change in stress relative to neutral and craving change in cue relative to neutral, where the possible range in mean change score is -6 to +6. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anxiety Change in Stress and Cue Relative to Neutral | Experiment during treatment week 2 | Anxiety assessed in laboratory experiment with exposure to stress, cocaine cue and neutral control condition in participants receiving PREG (300mg; 500mg) vs. Placebo treatment. Anxiety was assessed using a 10-point visual analog scale (VAS) in which 0=not at all and 10=extremely high, with the mean score ranging from 0 to 10, and where higher score means higher anxiety. Data presented here is anxiety change in stress relative to neutral and anxiety change in cue relative to neutral, where the possible range in mean change score is -10 to +10. |
| Cortisol Level Change in Stress and Cue Relative to Neutral | Experiment during treatment week 2 | Plasma was collected at each laboratory session to measure cortisol level and assess change in cortisol response to stress and cocaine cue relative neutral imagery condition exposure. Data presented here are change in cortisol level (mg/dl) in stress relative to neutral condition and cue relative to neutral condition. |
| Pregnenolone Concentration | between weeks 2-3 of treatment | Blood plasma concentration of pregnenolone in two doses of PREG (300mg; 500mg), and matching placebo, assessed over a 24 hour period. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cocaine Dollar Amount During Trial Period | up to 8 weeks | Mean dollar amount of cocaine per use day was assessed by daily self report on the Timeline Followback Substance Use Calendar and corroborated by daily self-reporting on smartphone (measurement unit in dollars). |
| Mean Percent Cocaine Days | up to 8 weeks | The mean percent cocaine days as assessed by self report on daily smartphone monitoring and corroborated by the Timeline Followback Substance Use Calendar over the 8 week period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PREG 300 mg/Day Eligible participants will be randomly assigned to 300 mg/day PREG over 8 weeks with a) an inpatient-outpatient option where they will be admitted to the Clinical Neuroscience Research Unit (CNRU) at the Connecticut Mental Health Center (CMHC) for first two weeks and then outpatient at Yale Stress Center (YSC) for the remaining 6 weeks, or b) an outpatient option where they will participate in the entire study outpatient at YSC. | 20 |
| PREG 500 mg/Day Eligible participants will be randomly assigned to 500 mg/day PREG over 8 weeks with a) an inpatient-outpatient option where they will be admitted to the Clinical Neuroscience Research Unit (CNRU) at the Connecticut Mental Health Center (CMHC) for first two weeks and then outpatient at Yale Stress Center (YSC) for the remaining 6 weeks, or b) an outpatient option where they will participate in the entire study outpatient at YSC. | 17 |
| Patients Receiving Placebo Eligible participants will be randomly assigned to a placebo (PLA) treatment over 8 weeks with a) an inpatient-outpatient option where they will be admitted to the Clinical Neuroscience Research Unit (CNRU) at the Connecticut Mental Health Center (CMHC) for the first two weeks and then transition to outpatient at Yale Stress Center (YSC) for the remaining 6 weeks, or b) an outpatient only option where they will participate in the entire study outpatient at YSC. | 18 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Randomized but did not start | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | PREG 300 mg/Day | PREG 500 mg/Day | Patients Receiving Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 48.05 years STANDARD_DEVIATION 11.31 | 46.47 years STANDARD_DEVIATION 11.06 | 47.17 years STANDARD_DEVIATION 9.44 | 47.27 years STANDARD_DEVIATION 10.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 14 Participants | 16 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of Smokers | 14 Participants | 14 Participants | 16 Participants | 44 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 10 Participants | 9 Participants | 33 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 4 Participants | 6 Participants | 9 Participants | 19 Participants |
| Region of Enrollment United States | 20 participants | 17 participants | 18 participants | 55 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 6 Participants | 16 Participants |
| Sex: Female, Male Male | 15 Participants | 12 Participants | 12 Participants | 39 Participants |
| Years of Education | 12.5 years STANDARD_DEVIATION 1.4 | 12.35 years STANDARD_DEVIATION 1.87 | 12.56 years STANDARD_DEVIATION 1.58 | 12.47 years STANDARD_DEVIATION 1.59 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 12 / 20 | 13 / 17 | 11 / 18 |
| serious Total, serious adverse events | 1 / 20 | 0 / 17 | 0 / 18 |
Outcome results
Primary
Craving Change in Stress and Cue Relative to Neutral
Cocaine craving assessed in a laboratory experiment with exposure to stress, cocaine cue and neutral control condition in those receiving PREG (300mg; 500mg) vs Placebo. Cocaine craving was assessed using the Cocaine Craving Questionnaire (CCQ), a brief 10-item self-report craving scale that ranges in mean score from 1 to 7, where a higher score indicates higher craving. Data presented here is craving change in stress relative to neutral and craving change in cue relative to neutral, where the possible range in mean change score is -6 to +6.
Time frame: Experiment during treatment week 2
Population: A subset of participants from the full study sample completed the experimental component of stress and cocaine cue provocation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PREG 300 mg/Day | Craving Change in Stress and Cue Relative to Neutral | Stress Craving Change | 3.035 score on a scale | Standard Deviation 1.34 |
| PREG 300 mg/Day | Craving Change in Stress and Cue Relative to Neutral | Cue Craving Change | 0.031 score on a scale | Standard Deviation 1.313 |
| PREG 500 mg/Day | Craving Change in Stress and Cue Relative to Neutral | Stress Craving Change | -0.486 score on a scale | Standard Deviation 1.153 |
| PREG 500 mg/Day | Craving Change in Stress and Cue Relative to Neutral | Cue Craving Change | -1.775 score on a scale | Standard Deviation 1.126 |
| Patients Receiving Placebo | Craving Change in Stress and Cue Relative to Neutral | Stress Craving Change | 3.959 score on a scale | Standard Deviation 1.115 |
| Patients Receiving Placebo | Craving Change in Stress and Cue Relative to Neutral | Cue Craving Change | 4.835 score on a scale | Standard Deviation 1.118 |
p-value: <0.001Mixed Models Analysis
Secondary
Anxiety Change in Stress and Cue Relative to Neutral
Anxiety assessed in laboratory experiment with exposure to stress, cocaine cue and neutral control condition in participants receiving PREG (300mg; 500mg) vs. Placebo treatment. Anxiety was assessed using a 10-point visual analog scale (VAS) in which 0=not at all and 10=extremely high, with the mean score ranging from 0 to 10, and where higher score means higher anxiety. Data presented here is anxiety change in stress relative to neutral and anxiety change in cue relative to neutral, where the possible range in mean change score is -10 to +10.
Time frame: Experiment during treatment week 2
Population: A subset of participants from the full study sample completed the experimental component of stress and cocaine cue provocation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PREG 300 mg/Day | Anxiety Change in Stress and Cue Relative to Neutral | Stress Anxiety Change | 0.757 score on a scale | Standard Deviation 0.309 |
| PREG 300 mg/Day | Anxiety Change in Stress and Cue Relative to Neutral | Cue Anxiety Change | -0.305 score on a scale | Standard Deviation 0.302 |
| PREG 500 mg/Day | Anxiety Change in Stress and Cue Relative to Neutral | Stress Anxiety Change | 0.118 score on a scale | Standard Deviation 0.269 |
| PREG 500 mg/Day | Anxiety Change in Stress and Cue Relative to Neutral | Cue Anxiety Change | 0.199 score on a scale | Standard Deviation 0.261 |
| Patients Receiving Placebo | Anxiety Change in Stress and Cue Relative to Neutral | Stress Anxiety Change | 1.334 score on a scale | Standard Deviation 0.263 |
| Patients Receiving Placebo | Anxiety Change in Stress and Cue Relative to Neutral | Cue Anxiety Change | 0.959 score on a scale | Standard Deviation 0.265 |
p-value: <0.001Mixed Models Analysis
Secondary
Cortisol Level Change in Stress and Cue Relative to Neutral
Plasma was collected at each laboratory session to measure cortisol level and assess change in cortisol response to stress and cocaine cue relative neutral imagery condition exposure. Data presented here are change in cortisol level (mg/dl) in stress relative to neutral condition and cue relative to neutral condition.
Time frame: Experiment during treatment week 2
Population: A subset of participants from the full study sample completed the experimental component of stress and cocaine cue provocation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PREG 300 mg/Day | Cortisol Level Change in Stress and Cue Relative to Neutral | Stress Cortisol Level Change | -0.3 mg/dl | Standard Deviation 0.55 |
| PREG 300 mg/Day | Cortisol Level Change in Stress and Cue Relative to Neutral | Cue Cortisol Level Change | 0 mg/dl | Standard Deviation 0.45 |
| PREG 500 mg/Day | Cortisol Level Change in Stress and Cue Relative to Neutral | Stress Cortisol Level Change | -0.52 mg/dl | Standard Deviation 0.64 |
| PREG 500 mg/Day | Cortisol Level Change in Stress and Cue Relative to Neutral | Cue Cortisol Level Change | -0.07 mg/dl | Standard Deviation 0.73 |
| Patients Receiving Placebo | Cortisol Level Change in Stress and Cue Relative to Neutral | Stress Cortisol Level Change | 0.71 mg/dl | Standard Deviation 0.9 |
| Patients Receiving Placebo | Cortisol Level Change in Stress and Cue Relative to Neutral | Cue Cortisol Level Change | 0.58 mg/dl | Standard Deviation 0.67 |
p-value: 0.7Mixed Models Analysis
Secondary
Pregnenolone Concentration
Blood plasma concentration of pregnenolone in two doses of PREG (300mg; 500mg), and matching placebo, assessed over a 24 hour period.
Time frame: between weeks 2-3 of treatment
Population: A subset of participants from the full study sample completed the experimental component of stress and alcohol cue provocation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PREG 300 mg/Day | Pregnenolone Concentration | 1.09 ng/mL | Standard Deviation 0.194 |
| PREG 500 mg/Day | Pregnenolone Concentration | 1.54 ng/mL | Standard Deviation 0.147 |
| Patients Receiving Placebo | Pregnenolone Concentration | 0.5 ng/mL | Standard Deviation 0.146 |
p-value: 0.0001ANOVA
Other Pre-specified
Cocaine Dollar Amount During Trial Period
Mean dollar amount of cocaine per use day was assessed by daily self report on the Timeline Followback Substance Use Calendar and corroborated by daily self-reporting on smartphone (measurement unit in dollars).
Time frame: up to 8 weeks
Population: Intent to Treat Sample Included in Analyses n=55
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PREG 300 mg/Day | Cocaine Dollar Amount During Trial Period | 12.3 dollars | Standard Deviation 17.57 |
| PREG 500 mg/Day | Cocaine Dollar Amount During Trial Period | 26.44 dollars | Standard Deviation 20.59 |
| Patients Receiving Placebo | Cocaine Dollar Amount During Trial Period | 28.28 dollars | Standard Deviation 43.99 |
p-value: 0.042. Negative binomial regression models
Other Pre-specified
Mean Percent Cocaine Days
The mean percent cocaine days as assessed by self report on daily smartphone monitoring and corroborated by the Timeline Followback Substance Use Calendar over the 8 week period.
Time frame: up to 8 weeks
Population: Intent to Treat Sample Included in Analyses n=55
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PREG 300 mg/Day | Mean Percent Cocaine Days | 19.9 percent days | Standard Error 20.46 |
| PREG 500 mg/Day | Mean Percent Cocaine Days | 35.12 percent days | Standard Error 20.05 |
| Patients Receiving Placebo | Mean Percent Cocaine Days | 28.61 percent days | Standard Error 26.19 |
p-value: 0.125. Negative binomial regression models