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

NCT05610072 | Completed Early Phase 1 FDA Drug

• 2 other identifiers: 80485R33DA049130
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Cocaine Use Disorder; Opioid Use Disorder; Stimulant Use Disorder

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (3)

• Craving

  After at least seven days of maintenance on n-acetylcysteine or placebo

• Subjective opioid withdrawal

  After at least seven days of maintenance on n-acetylcysteine or placebo

• Clinical opioid withdrawal

  After at least seven days of maintenance on n-acetylcysteine or placebo

Other Outcomes (7)

• Side effects

  Daily during approximately 10 day inpatient admission

• Pupil diameter

  Daily during approximately 10 day inpatient admission

• Heart rate

  Daily during approximately 10 day inpatient admission

Study Arms (2)

n-Acetylcysteine

EXPERIMENTAL

Subjects will receive 0.6 g oral n-acetylcysteine 4 times per day.

Drug: n-acetylcysteine; Drug: Hydromorphone; Drug: Placebo hydromorphone

Placebo

PLACEBO COMPARATOR

Subjects will receive oral placebo 4 times per day.

Drug: Hydromorphone; Drug: Placebo n-acetylcystine; Drug: Placebo hydromorphone

Interventions

Placebo hydromorphone DRUG

Prior to some experimental sessions, subjects will receive placebo hydromorphone

Placebo; n-Acetylcysteine

n-acetylcysteine DRUG

Subjects will be randomized to receive 2.4 oral n-acetylcysteine daily.

n-Acetylcysteine

Hydromorphone DRUG

Subjects will receive up to 192 mg oral hydromorphone daily.

Placebo; n-Acetylcysteine

Placebo n-acetylcystine DRUG

Subjects will be randomized to receive placebo n-acetylcysteine daily.

Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• William Stoops: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (2)

University of Kentucky Laboratory of Human Behavioral Pharmacology

Lexington, Kentucky, 40507, United States

Location

University of Kentucky Department of Behavioral Science

Lexington, Kentucky, 40536-0086, United States

Location

MeSH Terms

Conditions

Opioid-Related Disorders

Interventions

Acetylcysteine; Hydromorphone

Condition Hierarchy (Ancestors)

Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• William W Stoops

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: October 31, 2022
• First Posted: November 9, 2022
• Study Start: December 15, 2022
• Primary Completion: March 27, 2026
• Study Completion: March 27, 2026
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)