Oxytocin, Stress, Craving, Opioid Use Disorder (OSCO)

Oxytocin to Reduce Stress-induced Craving in Individuals With Opioid Use Disorder

Although stress has long been linked to substance use, craving and relapse, there are no available medications that target stress-induced substance use disorder (SUD). In particular, with the rise in opioid use, there is still a crucial need for developing effective pharmacological treatments that target and integrate the complexity of this disease. The long term goal of this project is to identify the key neuroendocrine pathways that are responsible for stress-induced craving in individuals with opioid use disorder (OUD) in order to better understand how they can be effectively treated.

Study Overview

• Status: Completed
• Conditions: Opioid Use Disorder
• Intervention / Treatment: Drug: intranasal oxytocin, 40 IU, twice a day for 7 days

Detailed Description

The goal of this research is to evaluate whether oxytocin, a hormone with anti-stress properties, dampens the effects of stress and opioid-associated cues on opioid craving and thus may be an effective adjunctive treatment for OUD.

The central hypothesis of this research is that oxytocin will reduce stress-induced opioid craving in patients with OUD treated with buprenorphine/naloxone as opioid replacement therapy (ORT). This hypothesis is based on the model of addiction (Koob, Neuron 2008) in which chronic substance use and stress lead to neurobehavioral counter-adaptations that dysregulate biobehavioral response.

In this double-blind, cross-over, placebo controlled, randomized trial, individuals with OUD (N=20 who are currently receiving treatment with buprenorphine/naloxone or methadone will be randomized to intranasal oxytocin (40 international units, IU) and oxytocin-matched placebo, administered twice/day for 7 days with a minimum of two days between the opposite condition (oxytocin or placebo). On days 5 and 7, and on days 14 and 16, participants will complete two counter-balanced sessions in which they receive yohimbine (32.4 mg) or yohimbine-matched placebo.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Rhode Island
    • Providence, Rhode Island, United States, 02291
      • Brown University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female (50%), 18 to 70 (inclusive) years of age;
• Currently meets DSM-5 criteria for OUD;
• Currently on a stable dose of buprenorphine/naloxone or methadone for at least 3 months;
• In good health as confirmed by medical history, physical examination and blood work (Liver function within 5x the Upper normal limits (AST/ALT) and renal function within 2x the Lower Normal Limit (bilirubin, creatine clearance).
• Willing to take medication and adhere to the study procedures;- Understand informed consent and questionnaires in English at an 8th grade level;
• Clinical Opiate Withdrawal Scale (COWS) = 0 at study screening and prior laboratory sessions.

Exclusion Criteria:

• Women who are breastfeeding, test positive for pregnancy or are unwilling to use medically-approved birth control;
• Suicide attempts in the last three months;
• Current substance disorder other than marijuana, nicotine and caffeine as assessed by self-report and urine toxicology screen at baseline;
• Current use of medications that may interact with study medications;
• History of hypersensitivity to study medications;
• Clinically significant electrolyte abnormalities, current rhinitis or use of vasoconstricting medications or prostaglandins.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oxytocin first, then placebo; Oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days. After a 2 day washout period, Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days.	Drug: intranasal oxytocin, 40 IU, twice a day for 7 days; Adjunct therapy; Other Names: Pitocin
Placebo Comparator: Matching placebo, then oxytocin; Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days. After a 2 day washout period, oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days.	Drug: intranasal oxytocin, 40 IU, twice a day for 7 days; Adjunct therapy; Other Names: Pitocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid Craving	The primary outcome will test the effect of oxytocin, compared to placebo, on opioid craving during two laboratory stress induction, paired to a cue reactivity paradigm. The dependent measure for the primary aim is the Desire for Drug Questionnaire (DDQ). The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the DDQ will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo. Minimum score=0 no craving at all, maximum score= 91 severe craving (13 questions on a 7-step Likert-scale)	Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Opiate Withdrawal Syndrome	Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: opiate withdrawal syndrome by Clinical Opiate Withdrawal Scale (COWS) pre and post the laboratory procedures. The COWS is an 11-item scale designed to be administered by a clinician. Minimum=0 (no withdrawal); Maximum=36 (sever withdrawal). The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. High score worse outcome. At each visit the COWS will be administered 2 times: before starting any procedure, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo.	Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16.
Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Anxiety	Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor anxiety (HAMA) during lab sessions. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of Minimum=0 (not present), Maximum=56 (sever), where <17 mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. High score worse outcome. At each visit the HAMA will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo.	Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16.
Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Systolic Blood Pressure (SBP)	Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor systolic blood pressure (SBP) during lab sessions. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the SBP will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo.	Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16.
Safety and Tolerability of Oxytocin and Yohimbine in OUD Individuals Receiving Opioid Agonist Therapy: Heart Rate (HR)	Participants will complete a laboratory session that includes a battery of medical/physiological/psychological assessments to monitor adverse events. Safety measures include: monitor Heart rate (HR) during lab sessions. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the HR will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo.	Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stress-related Response in OUD Individuals Receiving Opioid Agonist Therapy: Salivary Cortisol	Cortisol (biomarker for stress level) will be measured at the same 3 time points as other measures. The stress induction will be done using yohimbine or matching placebo (counterbalanced) during the two laboratory sessions. At each visit the cortisol will be administered 3 times: before starting any procedure, after the yohimbine challenge, and after the cue-reactivity. This outcome will be compared between oxytocin and matching-placebo.	Before starting any procedure, after the yohimbine challenge, and after the cue-reactivity at each laboratory session, which occurred between days 5-7 and days 14-16.

Collaborators and Investigators

• Sponsor: Brown University
• Collaborators: National Institute of General Medical Sciences (NIGMS)

Publications and helpful links

General Publications

• Gully BJ, Brown ZE, Hornbacher R, Brown JC, Back SE, McCance-Katz EF, Swift RM, Haass-Koffler CL. Oxytocin Reduces Noradrenergic-Induced Opioid-Like Withdrawal Symptoms in Individuals on Opioid Agonist Therapy. Biol Psychiatry Glob Open Sci. 2024 Sep 18;5(1):100395. doi: 10.1016/j.bpsgos.2024.100395. eCollection 2025 Jan.

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2020
• Primary Completion (Actual): December 22, 2023
• Study Completion (Actual): December 23, 2023

Study Registration Dates

• First Submitted: August 6, 2019
• First Submitted That Met QC Criteria: August 7, 2019
• First Posted (Actual): August 9, 2019

Study Record Updates

• Last Update Posted (Actual): May 25, 2025
• Last Update Submitted That Met QC Criteria: May 6, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Mental Disorders; Chemically-Induced Disorders; Opioid-Related Disorders; Substance-Related Disorders; Physiological Effects of Drugs; Reproductive Control Agents; Oxytocics; Oxytocin
• Other Study ID Numbers: 1904002426; P20GM130414 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No