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

Glutamatergic Mechanisms in Opioid and Cocaine Co-Use

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.

Study Overview

• Status: Recruiting
• Conditions: Opioid Use Disorder; Cocaine Use Disorder
• Intervention / Treatment: Drug: n-acetylcysteine; Drug: Placebo hydromorphone; Drug: Placebo n-acetylcystine; Drug: Hydromorphone

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: William W Stoops, PhD; Phone Number: 8592575388; Email: william.stoops@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40507
      • Recruiting
      • University of Kentucky Laboratory of Human Behavioral Pharmacology
      • Principal Investigator: William W Stoops, Ph.D.
      • Contact: William W Stoops, Ph.D.; Phone Number: 859-257-5388; Email: william.stoops@uky.edu
    • Lexington, Kentucky, United States, 40536-0086
      • Recruiting
      • University of Kentucky Department of Behavioral Science
      • Principal Investigator: William W Stoops, Ph.D.
      • Contact: William W Stoops, Ph.D.; Phone Number: 859-257-5388; Email: william.stoops@uky.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Between the ages of 18 and 55 years,
2. Report recent use of opioids and cocaine and must not be seeking treatment for their drug use,
3. Be physically dependent on short-acting opioids,
4. 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
5. Other than the diagnosis for opioid and cocaine use disorder at the time of the screening, subjects must be healthy,
6. 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,
7. No contraindications to magnetic resonance imagining (MRI; e.g., metallic objects in their body, BMI > or = 40, claustrophobia) will be considered ineligible,
8. 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,
9. All study subjects will be judged by the medical staff to be psychiatrically and physically healthy.

Exclusion Criteria:

1. 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,
2. 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,
3. Subjects who report a positive first-degree family history of schizophrenia, serious cardiovascular disease, or seizure disorders will also be excluded from research participation.
4. Subjects with contraindications to hydromorphone or n-acetylcysteine will not be eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Side effects	Scores on the Udvalg Fur Kliniske Undersolgelser (UKU) side effects scale with scores from 0-3, with higher scores indicating greater side effects	Daily during approximately 10 day inpatient admission
Pupil diameter	Measurement of pupil diameter using an automated scanner	Daily during approximately 10 day inpatient admission
Heart rate	Measurement of heart rate using an automated monitor	Daily during approximately 10 day inpatient admission
Respiration rate	Measurement of respiration rate using an automated monitor	Daily during approximately 10 day inpatient admission
Oxygen saturation	Measurement of oxygen saturation using an automated monitor	Daily during approximately 10 day inpatient admission
Diastolic blood pressure	Measurement of diastolic blood pressure using an automated monitor	Daily during approximately 10 day inpatient admission
Systolic blood pressure	Measurement of systolic blood pressure using an automated monitor	Daily during approximately 10 day inpatient admission

Collaborators and Investigators

• Sponsor: William Stoops
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: William W Stoops, University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: October 31, 2022
• First Submitted That Met QC Criteria: November 4, 2022
• First Posted (Actual): November 9, 2022

Study Record Updates

• Last Update Posted (Actual): December 8, 2023
• Last Update Submitted That Met QC Criteria: December 1, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Narcotic-Related Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Protective Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine; Hydromorphone
• Other Study ID Numbers: 80485; R33DA049130 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No