Stimulant Oxytocin Study

Study Overview
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Brief Summary
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This study will investigate the effects of intranasal administration of oxytocin, a social neuropeptide, on reducing stimulant use, enhancing therapeutic engagement, and susceptibility to stress-induced relapse in Veterans with stimulant use disorders and enrolled in opioid replacement therapy (ORT) program for co-occurring opioid use disorder (OUD).

Detailed Description
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High rates of substance use disorders (SUDs) in Veterans compared to the general population are heavily influenced by psychosocial factors - such as difficulty reintegrating into civilian life due to avoidance of vital support systems - leading to disproportionately elevated unmet addiction treatment needs. Although the gold standard for treatment for most SUDs involves pharmacological interventions, there are currently no effective pharmacological interventions approved by the Federal Drug Administration for stimulant users, who have the most difficulty adhering to treatment programs and the most susceptibility to stress-induced relapse of any SUD. Administering oxytocin, a mammalian neuropeptide, intranasally to healthy controls facilitates the stress-buffering properties of social support. Oxytocin may also have an independent role in mitigating the symptoms of SUDs. For example, in animal models of addiction, oxytocin administration directly reduces tolerance, withdrawal effects, self-administration, and stress-induced reinstatement of drug seeking for a range of addictive substances. A more integrated understanding of oxytocin's distinct effects on the behavior and psychology of 1) addiction, 2) sociality, and 3) stress reactivity could be the key to defining oxytocin's role in SUD treatment. This study proposes to translate promising preclinical and early proof-of-concept clinical results related to the anti-addiction, pro-social, and stress-tempering properties of oxytocin administration in Veterans with moderate-severe stimulant use disorders enrolled in a opioid replacement therapy (ORT) program for co-occurring opioid use disorder (OUD) at the San Francisco VA Medical Center (SFVAMC). The investigators' primary outcome is Aim 1) reduction in stimulant use, as measured by stimulant positive urine drug screen. Secondarily, the investigators will focus on Aim 2) improving psychosocial treatment engagement (social support) and Aim 3) mitigating social stress-related relapse, targeting two important barriers to stimulant use disorder recovery likely to respond to oxytocin administration.

Official Title
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6-week Trial of Oxytocin for Co-occurring Cocaine and Opioid Use Disorders

Conditions
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Stimulant Use & Co-occuring Opioid Use Disorders

Intervention / Treatment
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* Drug: Intranasal oxytocin
* Drug: Intranasal placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years old Enrolled as a patient who at the SFVAMC Opioid Treatment Program or the Oakland Behavioral Health Clinic Opioid Treatment Program Stable dose of opioid replacement therapy for at least 2 consecutive weeks Veteran One documented urine toxicology screen positive for stimulants in the past 12 months. Exclusion Criteria: Severe neuropsychological disorder Suicidal or homicidal ideation within the past 90 days or a suicide attempt in the past 6 months Hemodialysis, unless participant can produce urine samples weekly Sensitivity to methylparaben or propylparaben Positive urine pregnancy test or women of childbearing age not practicing effective means of non-hormonal birth control Chronic nasal obstruction, discharge, or bleeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxytocin<br>Patients in methadone maintenance treatment (MMT) programs are required to come in every day for their methadone. Additionally they are required to come in weekly for psycho- educational/therapy groups, biweekly random urine screenings, and monthly individual therapy sessions. The investigators will piggy-back off this existing structure and randomize Veterans with stimulant use disorders and receiving MMT for co-occurring opioid use disorder (OUD) to receive either oxytocin or placebo, to be administered twice daily for six weeks while in the MMT program. | Drug: Intranasal oxytocin<br>* Each Veteran with a stimulant use disorder, receiving MMT for OUD will receive a oxytocin nasal spray 40 International Units (IU) to be self administered twice daily over 6 weeks while in the MMT program. The veteran will come in for a total of 7 weekly visits. At baseline and during the last visit the veteran will complete at Trier Social Stress Test (TSST), and psychophysiological and biomarkers of stress will be collected. At every weekly visit a urine sample and self-reported drug use will be collected and therapy attendance will be recorded.<br>* Other names: Syntocinon;|
| Placebo Comparator: Placebo<br>Patients in MMT programs are required to come in every day for their methadone. Additionally they are required to come in weekly for psycho- educational/therapy groups, biweekly random urine screenings, and monthly individual therapy sessions. The investigators will piggy-back off this existing structure and randomize Veterans with stimulant use disorders and receiving MMT for co-occurring OUD to receive either oxytocin or placebo, to be administered twice daily for six weeks while in the MMT program. | Drug: Intranasal placebo<br>* Each Veteran with a stimulant use disorder, receiving MMT for OUD will receive a placebo nasal spray 40IU to be self administered twice daily over 6 weeks while in the MMT program. The veteran will come in for a total of 7 weekly visits. At baseline and during the last visit the veteran will complete at Trier Social Stress Test (TSST), and psychophysiological and biomarkers of stress will be collected. At every weekly visit a urine sample and self-reported drug use will be collected and therapy attendance will be recorded.<br>* Other names: Saline placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Stimulant Positive Drug Screen | Aim 1: To evaluate the effectiveness of intranasal oxytocin on reducing stimulant use. | Baseline, Visits 1-7, up to 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Working Alliance Inventory (WAI) | Aim 2: To evaluate the effectiveness of intranasal oxytocin on improving psychosocial treatment engagement (social support) as measured by the Working Alliance Inventory, an inventory of therapeutic alliance. The Working Alliance Inventory is a 36 question inventory. Each item is scored from 1-7, minimum = 1 and maximum = 7. Minimum total score = 36 to maximum total score = 252. Higher scores represent higher satisfaction. | Visits 1 and 7, Up to 7 weeks | 
| Heart Rate in Response to Trier Social Stress Test (TSST). | Aim 3: To evaluate the effectiveness of intranasal oxytocin on reducing stress-related psycho-physiological measures in response to the Trier Social Stress Test (TSST). The Trier Social Stress Test is a series of tasks which predictably induce stress in participants. First, physiological states are measured at baseline. Then participants are told they must prepare a 5 minute speech for a panel of researchers, which they then present. Participants are then asked verbal arithmetic questions. Finally, this is followed by a period of 5 minute rest referred to as the 'cooldown' period. Heart rate was assessed at different time points during the TSST. These time point are as follows: baseline, during speech preparation, during speech presentation, during arithmetic problems, and during the cooldown period. Higher scores indicate higher stress levels. | Visits 1 and 7, up to 7 weeks | 
| Respiratory Rate in Response to Trier Social Stress Test (TSST). | Aim 3: To evaluate the effectiveness of intranasal oxytocin on reducing stress-related psycho-physiological measures in response to the Trier Social Stress Test (TSST). The Trier Social Stress Test is a series of tasks which predictably induce stress in participants. First, physiological states are measured at baseline. Then participants are told they must prepare a 5 minute speech for a panel of researchers, which they then present. Participants are then asked verbal arithmetic questions. Finally, this is followed by a period of 5 minute rest referred to as the 'cooldown' period. Respiratory rate was assessed at different time points during the TSST. These time point are as follows: baseline, during speech preparation, during speech presentation, during arithmetic problems, and during the cooldown period. Higher scores indicate higher stress levels. | Visits 1 and 7, up to 7 weeks | 
| Respiratory Sinus Arrythmia (RSA) in Response to Trier Social Stress Test (TSST). | Aim 3: To evaluate the effectiveness of intranasal oxytocin on reducing stress-related psycho-physiological measures in response to the Trier Social Stress Test (TSST). The Trier Social Stress Test is a series of tasks which predictably induce stress in participants. First, physiological states are measured at baseline. Then participants are told they must prepare a 5 minute speech for a panel of researchers, which they then present. Participants are then asked verbal arithmetic questions. Finally, this is followed by a period of 5 minute rest referred to as the 'cooldown' period. Respiratory sinus arrythmia (RSA) was assessed at different time points during the TSST. These time point are as follows: baseline, during speech preparation, during speech presentation, during arithmetic problems, and during the cooldown period. Higher scores indicate higher stress levels. | Visits 1 and 7, up to 7 weeks | 
| Root Mean Square of Successive Differences (RMSSD) of Heart Rate Variability in Response to Trier Social Stress Test (TSST). | Aim 3: To evaluate the effectiveness of intranasal oxytocin on reducing stress-related psycho-physiological measures in response to the Trier Social Stress Test (TSST). The Trier Social Stress Test is a series of tasks which predictably induce stress in participants. First, physiological states are measured at baseline. Then participants are told they must prepare a 5 minute speech for a panel of researchers, which they then present. Participants are then asked verbal arithmetic questions. Finally, this is followed by a period of 5 minute rest referred to as the 'cooldown' period. The root mean square of successive differences (RMSSD) were assessed at different time points during the TSST. These time point are as follows: baseline, during speech preparation, during speech presentation, during arithmetic problems, and during the cooldown period. Higher scores indicate higher stress levels. Calculated by measuring each successive time difference between heartbeats in ms. | Visits 1 and 7, up to 7 weeks | 
| Self-reported Stimulant Craving | Aim 4: To evaluate the effectiveness of intranasal oxytocin on reducing stimulant craving in response the Trier Social Stress Test (TSST). The Cocaine Craving Questionnaire (CCQ) (brief) was modified to include all stimulants and administered. The CCQ is a 10-item questionnaire, with each item ranking on a scale of 1-7. 1 indicates 'Strongly Disagree' and 7 indicates 'Strongly Agree'. Higher scores indicate higher rates of craving. The CCQ was administered at three distinct time points: before the TSST, immediately after the TSST and 20 minutes post-TSST. The Trier Social Stress Test is a series of tasks which predictably induce stress in participants. First, physiological states are measured at baseline. Then participants are told they must prepare a 5 minute speech for a panel of researchers, which they then present. Participants are then asked verbal arithmetic questions. Finally, this is followed by a period of 5 minute rest referred to as the 'cooldown' period. | Visits 1 and 7, Up to 7 weeks | 
| Individual and Group Therapy Attendance Rates | Aim 5: To evaluate the effectiveness of intranasal oxytocin on improving psychosocial treatment engagement (social support) as measured by individual and group therapy attendance rates. | Visits 1-7, Up to 7 weeks | 
| Cortisol Levels in Response to Trier Social Stress Test (TSST). | Aim 6: To evaluate the effectiveness of intranasal oxytocin on reducing stress biomarkers in response to the TSST. | Visits 1 and 7, up to 7 weeks | 
| Dehydroepiandrosterone (DHEA) Levels in Response to Trier Social Stress Test (TSST) | Aim 6: To evaluate the effectiveness of intranasal oxytocin on reducing stress biomarkers in response to the TSST. | Visits 1 and 7, up to 7 weeks | 
| Self-reported Stress/Anxiety | Aim 7: To evaluate the effectiveness of intranasal oxytocin on reducing self-reported stress/anxiety levels in response to the TSST. The scale used to measure anxiety was the State-Trait Anxiety Inventory (STAI-6). This scale consists of 40 questions, all of which are rated on a 4-point likert scale. 1 indicates 'Almost Never' while 4 indicates 'Almost Always'. The minimum score is 0, indicating no anxiety, and maximum score is 63, indicating severe anxiety. | Visits 1 and 7, Up to 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid Replacement Therapy, Psychophysiology, Stress Biomarkers, oxytocin, substance-related disorders