A Phase 1 interventional study of intranasal oxytocin, 40 IU, twice a day for 7 days in Opioid Use Disorder, sponsored by Brown University. Completed at 1 site in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2025-05-25.
Sponsored by Brown University · Phase 1, Interventional, and Treatment
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.
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.
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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
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
Also known as: Pitocin
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)
Time frame: 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: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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.
Time frame: 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.
| Milestone | Oxytocin First, Then Placebo | Matching Placebo First, Then Oxytocin |
|---|---|---|
| Started | 10 | 10 |
| Received yohimbine and matched placebo during lab sessions 3 and 4. | 8 | 8 |
| Completed | 10 | 10 |
| Not completed | 0 | 0 |
| Milestone | Oxytocin First, Then Placebo | Matching Placebo First, Then Oxytocin |
|---|---|---|
| Started | 10 | 10 |
| Received yohimbine and matched placebo during lab sessions 5 and 6. | 5 | 5 |
| Completed | 7 | 6 |
| Not completed | 3 | 4 |
| Withdrew: Lost to follow-up | 1 | 2 |
| Withdrew: Completed the study prior to initiation cross-over design | 2 | 2 |
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)
| score on a scale | Oxytocin | Matching Placebo |
|---|---|---|
| baseline (yohimbine condition) | 21.6 ± 7.55 | 22.4 ± 6.26 |
| after stress (yohimbine condition) | 23.3 ± 7.66 | 23.4 ± 7.53 |
| cue exposure (yohimbine condition) | 22.9 ± 8.09 | 23.0 ± 7.92 |
| baseline (yohimbine-placebo condition) | 22.7 ± 7.85 | 19.5 ± 6.16 |
| after stress (yohimbine-placebo condition) | 23.1 ± 6.95 | 21.7 ± 7.18 |
| cue exposure (yohimbine-placebo condition) | 22.6 ± 6.74 | 20.9 ± 7.88 |
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.
| score on a scale | Oxytocin | Matching Placebo |
|---|---|---|
| Baseline (Yohimbine Condition) | 1.2 ± 1.17 | 0.8 ± .75 |
| Post (Yohimbine Condition) | 1.8 ± 2.23 | 3.0 ± 3.30 |
| Baseline (Yohimbine-placebo Condition) | 1.0 ± 1.45 | 1.3 ± 1.38 |
| Post (Yohimbine-placebo Condition) | 0.7 ± 0.84 | 0.6 ± 1.10 |
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.
| score on a scale | Oxytocin | Matching Placebo |
|---|---|---|
| Baseline (Yohimbine condition) | 1.8 ± 2.10 | 2.5 ± 2.39 |
| after stress (Yohimbine condition) | 2.0 ± 2.98 | 2.7 ± 3.65 |
| after cue exposure (Yohimbine condition) | 1.9 ± 1.85 | 2.7 ± 2.53 |
| Baseline (Yohimbine-placebo condition) | 1.3 ± 1.69 | 2.2 ± 2.35 |
| after stress (Yohimbine-placebo condition) | 0.9 ± 1.3 | 1.2 ± 1.50 |
| after cue exposure (Yohimbine-placebo condition) | 0.9 ± 1.7 | 1.0 ± 2.14 |
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.
| mmHg | Oxytocin | Matching Placebo |
|---|---|---|
| baseline (yohimbine condition) | 127.9 ± 19.97 | 124.2 ± 19.80 |
| after stress (yohimbine condition) | 134.2 ± 21.90 | 137.2 ± 18.30 |
| after cue exposure (yohimbine condition) | 133.4 ± 28.80 | 147.2 ± 25.40 |
| baseline (yohimbine-placebo condition) | 129.2 ± 16.30 | 126.9 ± 20.50 |
| after stress (yohimbine-placebo condition) | 120.8 ± 10.90 | 121.3 ± 16.60 |
| after cue exposure (yohimbine-placebo condition) | 123.9 ± 16.50 | 123.0 ± 13.40 |
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.
| beat/min | Oxytocin | Matching Placebo |
|---|---|---|
| baseline (yohimbine condition) | 83.0 ± 16.7 | 80.0 ± 13.9 |
| after stress (yohimbine condition) | 75.5 ± 14.6 | 83.1 ± 11.2 |
| after cue exposure (yohimbine condition) | 74.6 ± 18.2 | 77.5 ± 13.1 |
| baseline (yohimbine-placebo condition) | 77.9 ± 16.1 | 80.0 ± 13.1 |
| after stress (yohimbine-placebo condition) | 69.4 ± 14.7 | 81.0 ± 12.9 |
| after cue exposure (yohimbine-placebo condition) | 66.3 ± 12.4 | 82.0 ± 17.9 |
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.
| ug/dL | Oxytocin | Matching Placebo |
|---|---|---|
| baseline (yohimbine condition) | 0.33 ± 0.15 | 0.24 ± 0.14 |
| after stress (yohimbine condition) | 0.29 ± 0.11 | 0.27 ± 0.16 |
| after cue exposure (yohimbine condition) | 0.32 ± 0.25 | 0.80 ± 0.70 |
| baseline (yohimbine-placebo condition) | 0.28 ± 0.21 | 0.31 ± 0.31 |
| after stress (yohimbine-placebo condition) | 0.23 ± 0.13 | 0.24 ± 0.21 |
| after cue exposure (yohimbine-placebo condition) | 0.20 ± 0.11 | 0.17 ± 0.13 |
Collected over Safety and tolerability were measured retrospectively during the one-week outpatient setting. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Oxytocin | 0/16 (0%) | 0/16 (0%) | 8/16 (50%) |
| Matching Placebo | 0/17 (0%) | 0/17 (0%) | 8/17 (47.1%) |
| Event | Oxytocin | Matching Placebo |
|---|---|---|
| Depression or other mood disturbancePsychiatric disorders | 8/16 | 8/17 |
| Nervousness or anxietyPsychiatric disorders | 7/16 | 8/17 |
| Difficulty with concentration or attentionNervous system disorders | 6/16 | 3/17 |
| Difficulty sleepingNervous system disorders | 5/16 | 6/17 |
| HeadacheNervous system disorders | 3/16 | 6/17 |
| Muscle achesMusculoskeletal and connective tissue disorders | 1/16 | 5/17 |
| IrritabilityNervous system disorders | 4/16 | 3/17 |
| Slowness, sleepiness, or fatigueNervous system disorders | 3/16 | 4/17 |
| Tingling in fingers or toesMusculoskeletal and connective tissue disorders | 2/16 | 4/17 |
| TremorMusculoskeletal and connective tissue disorders | 1/16 | 4/17 |
| Age, Categorical(Participants) | All Study Participants |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 19 |
| >=65 years | 1 |
| Age, Continuous(years) | All Study Participants |
|---|---|
| Mean | 49.6 ± 11.65 |
| Sex: Female, Male(Participants) | All Study Participants |
|---|---|
| Female | 6 |
| Male | 14 |
| Race/Ethnicity, Customized(Participants) | All Study Participants |
|---|---|
| Race — Black or multiracial | 4 |
| Race — Caucasian | 16 |
| Region of Enrollment(Participants) | All Study Participants |
|---|---|
| United States | 20 |
| Clinical Opiate Withdrawal Scale (COWS)(score on an 11-item scale) | All Study Participants |
|---|---|
| Mean | .9 ± 1.4 |
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