The Role of Neuroactive Steroids in Stress, Drug Craving and Drug Use in Cocaine Use Disorders

Study Overview
=================
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.

Official Title
-----------------
The Role of Neuroactive Steroids in Stress, Drug Craving and Drug Use in Cocaine Use Disorders

Conditions
-----------------
Cocaine-Related Disorders

Intervention / Treatment
-----------------
* Drug: PREG 300/500 mg
* Drug: Placebos


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: patients receiving PREG<br>Eligible participants will be randomly assigned to 2 doses of PREG (300/500 mg/day) 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. | Drug: PREG 300/500 mg<br>* 2 doses of PREG (300/500 mg/day)<br>|
| Placebo Comparator: patients receiving placebo<br>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. | Drug: Placebos<br>* placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Craving reactivity in the laboratory | Cocaine craving assessed in laboratory experiment with exposure to stress, drug cues and neutral control condition in week 2 of PREG (300mg; 500mg) vs. Placebo treatment. Cocaine craving will be assessed using a 10-point visual analog scale (VAS) in which 0=not at all and 10=extremely high. | in week 2 of treatment | 
| Plasma cortisol levels as a measure of stress response in the laboratory | Plasma will be collected at each laboratory session to assess cortisol response to stress, drug cue and neutral imagery exposure. | in week 2 of treatment | 
| Blood pressure responses in the laboratory | A General Electric Dynamap will be used to place a blood pressure cuff on the subject's preferred arm to monitor blood pressure (BP) during the laboratory sessions in week 2 in order to assess change in BP responses to stress, drug cue and neutral provocation. | in week 2 of treatment | 
| Heart rate beats per minutes responses in the laboratory | A General Electric Dynamap will be used to place a blood pressure cuff on the subject's preferred arm to monitor heart rate (HR) beats per minutes during the laboratory sessions in week 2 in order to assess change in HR responses to stress, drug cue and neutral provocation. | in week 2 of treatment | 
| Provoked negative emotion and anxiety | Differential Emotion Scale (DES) will be used to measure subjective emotion. During the laboratory sessions, subjects will be asked to rate their current emotional state for the following subscales: anger, fear, sadness, anxiety, joy, neutral-relaxed feelings. Each subscale includes five adjectives (a total of 30 items) and will be used to describe each affect state and subjects are required to rate on a 5-point scale the extent to which each word describes the way s/he feels at the present time. | in week 2 of treatment | 
| Provoked cognitive flexibility | Stroop Color Word Test during stress, drug cue and neutral provocation | in week 2 of treatment | 
| Area under the curve (Pharmacokinetic Profile ) | To examine the blood plasma levels of two doses of PREG (300mg; 500mg; bid), and matching placebo (PLA) will be assessed over a 24 hour period and area under the curve will be plotted as drug concentration over time. | in week 2 of treatment | 
| Maximum Plasma Concentration (Cmax); Pharmacokinetic Profile | The maximum (peak) plasma concentration achieved after two doses of PREG (300mg;500mg; bid) will be calculated. | in week 2 of treatment | 
| Plasma Half-Life (t1/2) of Pregnenolone | The half-life of two doses of PREG (300mg; 500mg; bid), and matching placebo (PLA) will be calculated as the time it takes for the blood plasma concentration of PREG to halve its steady-state. | in week 2 of treatment | 
| Change from baseline Adverse Events | The Systematic Assessment for Treatment Emergent Effects (SAFTEE) Questionnaire will be used to assess the change from baseline adverse events weekly during the trial. | at week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cocaine use as secondary clinical outcome using urine toxicology. | Percent of positive urine tests during the 8 week trial will be assessed by a weekly urine toxicology screening. | weekly during 8 weeks | 
| Cocaine use amount as secondary clinical outcome using Timeline Followback Substance Use Calendar. | Change compared to baseline in daily reporting of amount of cocaine per use day will be assessed by self report on the Timeline Followback Substance Use Calendar. | weekly during 8 weeks |