Behavioral Effects of Drugs (Inpatient): 43 (Opioids, Cocaine, n-Acetylcysteine)

Study Overview
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Brief Summary
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The overarching hypotheses of this protocol are that (1) persistent brain glutamate changes induced by chronic opioid use will exacerbate use of cocaine during opioid physical dependence and withdrawal and (2) n-acetylcysteine (NAC) will ameliorate glutamatergic dysregulation, and thus will reduce both opioid and cocaine demand. These hypotheses will be tested with two specific aims. Specific Aim 1. Determine the reinforcing effects of cocaine in individuals with comorbid opioid and cocaine use disorder with physiological dependence on opioids during NAC maintenance. All subjects will be maintained on oral hydromorphone. They will also be randomly assigned to receive placebo or oral NAC (2.4 g/day), stratified by sex. After dose stabilization, experimental sessions will be conducted in which subjects complete hypothetical cocaine purchase tasks during opioid maintenance and opioid withdrawal. The hypotheses are: 1) cocaine purchasing will be greater during opioid withdrawal and 2) NAC maintenance will attenuate cocaine purchasing across opioid maintenance and withdrawal periods. Specific Aim 2. Evaluate glutamate functionality during periods of opioid maintenance and withdrawal in individuals with comorbid opioid and cocaine use disorder and physiological dependence on opioids during NAC maintenance. Subjects will undergo magnetic resonance spectroscopy to evaluate brain glutamate changes as a function of opioid maintenance/withdrawal state and NAC maintenance. The hypotheses are: 1) glutamate levels will be elevated during opioid withdrawal and 2) NAC maintenance will ameliorate elevated glutamate levels.

Official Title
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Glutamatergic Mechanisms in Opioid and Cocaine Co-Use

Conditions
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Cocaine Use Disorder, Opioid Use Disorder

Intervention / Treatment
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* Drug: n-acetylcysteine
* Drug: Hydromorphone
* Drug: Placebo n-acetylcystine
* Drug: Placebo hydromorphone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between the ages of 18 and 55 years, Report recent use of opioids and cocaine and must not be seeking treatment for their drug use, Be physically dependent on short-acting opioids, Meet Diagnostic and Statistical Manual (DSM)-5 diagnostic criteria for current opioid use disorder (OUD) and current or past cocaine use disorder (CUD) and have either a urine sample positive for recent opioid use during each visit or if opioid negative, displaying frank withdrawal during screening Other than the diagnosis for opioid and cocaine use disorder at the time of the screening, subjects must be healthy, Laboratory chemistries (e.g., blood chemistry screen, complete blood count, urinalysis) and electrocardiogram (ECG) results must be normal or within normal range and any abnormal results must be considered as not clinically significant by the study physicians, No contraindications to magnetic resonance imagining (MRI; e.g., metallic objects in their body, BMI > or = 40, claustrophobia) will be considered ineligible, Female subjects must be using an effective form of birth control (e.g., birth control pills, surgical sterilization, intrauterine device, barrier method, condoms with spermicide, cervical cap with a spermicide or abstinence) to participate and must not be pregnant, All study subjects will be judged by the medical staff to be psychiatrically and physically healthy. Exclusion Criteria: Any potential subject with a history of serious physical disease, current physical disease (e.g., impaired cardiovascular functioning, histories of seizure, head trauma, diabetes, asthma, or central nervous system [CNS] tumors) or current or past histories of serious psychiatric disorder (e.g., schizophrenia) that would limit compliance in the study, other than substance use disorder, will be excluded from research participation, Potential subjects that meet diagnostic criteria for moderate - severe substance use disorder for substances other than opioids, stimulants, cannabis, or nicotine at the time of the interview will not be eligible for study participation, Subjects who report a positive first-degree family history of schizophrenia, serious cardiovascular disease, or seizure disorders will also be excluded from research participation. Subjects with contraindications to hydromorphone or n-acetylcysteine will not be eligible.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study will use a double-blind, placebo-controlled design with all subjects receiving all hydromorphone (i.e., hydromorphone dose is a within subject factors). Half of the subjects will receive placebo and half of the subjects will receive 2.4mg/day NAC.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: n-Acetylcysteine<br>Subjects will receive 0.6 g oral n-acetylcysteine 4 times per day. | Drug: n-acetylcysteine<br>* Subjects will be randomized to receive 2.4 oral n-acetylcysteine daily.<br>Drug: Hydromorphone<br>* Subjects will receive up to 144 mg oral hydromorphone daily.<br>Drug: Placebo hydromorphone<br>* Prior to some experimental sessions, subjects will receive placebo hydromorphone<br>|
| Placebo Comparator: Placebo<br>Subjects will receive oral placebo 4 times per day. | Drug: Hydromorphone<br>* Subjects will receive up to 144 mg oral hydromorphone daily.<br>Drug: Placebo n-acetylcystine<br>* Subjects will be randomized to receive placebo n-acetylcysteine daily.<br>Drug: Placebo hydromorphone<br>* Prior to some experimental sessions, subjects will receive placebo hydromorphone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypothetical opioid purchasing | Amount of opioids purchased on a hypothetical purchase task | After at least seven days of maintenance on n-acetylcysteine or placebo | 
| Hypothetical cocaine purchasing | Amount of cocaine purchased on a hypothetical purchase task | After at least seven days of maintenance on n-acetylcysteine or placebo | 
| Glutamate function | Magnetic resonance spectroscopy of brain glutamate levels | After at least seven days of maintenance on n-acetylcysteine or placebo | 
| Gamma Aminobutyric Acid (GABA) function | Magnetic resonance spectroscopy of brain GABA levels | After at least seven days of maintenance on n-acetylcysteine or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Craving | Scores on a locally developed craving scale from 1-10, with higher scores indicating more craving | After at least seven days of maintenance on n-acetylcysteine or placebo | 
| Subjective opioid withdrawal | Self-reported scores on the Subjective Opioid Withdrawal Scale with scores from 0-64, with higher scores indicating more withdrawal | After at least seven days of maintenance on n-acetylcysteine or placebo | 
| Clinical opioid withdrawal | Self-reported scores on the Clinical Opioid Withdrawal Scale with scores from 0-48, with higher scores indicating more withdrawal | After at least seven days of maintenance on n-acetylcysteine or placebo |