Clinical trial NCT03016598
Conditions: Stimulant Use & Co-occuring Opioid Use Disorders
Keywords: oxytocin substance-related disorders Opioid Replacement Therapy Psychophysiology Stress Biomarkers
Sponsor: VA Office of Research and Development
Start date: 2018-01-26; Completion date: 2020-02-14
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Intranasal oxytocin intervention 2: Intranasal placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
ICF_002.pdf: 
 
 
 
 
 
 
 
Stimulant Oxytocin Study 
NCT03016598 
08/08/2019 


Date of Document
VA 10-1086
  Department of Veterans Affairs
INFORMED CONSENT FORM
Subject Name:
Date:
Title of Study: 6-week trial of oxytocin for co-occurring cocaine and opioid use 
disorders.
Principal Investigator: Christopher Stauffer, MD
 San Francisco VAMC
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
This is a research study designed to examine how the hormone, oxytocin, affects the behavior of patients with 
cocaine use disorder and amphetamine use disorder. The study Principal Investigator, Chris Stauffer, M.D., from 
the San Francisco VA Medical Center (SFVAMC) Research Department and the University of California, San 
Francisco (UCSF) Department of Psychiatry, or one of his research assistants, will explain this study to you.
Research studies include only people who choose to take part. Please take your time to make your decision about 
participating and discuss your decision with your family or friends if you wish. If you have any questions, you may 
ask the researchers.
You are being asked to take part in this study because you have been identified as an individual over age 18 who 
uses cocaine or amphetamines and receives methadone maintenance therapy.
Why is this study being done?
The purpose of this study is to test the effects of oxytocin on thoughts and behavior in individuals who use cocaine 
or amphetamines.
Who is funding this study?
This study is funded by the Department of Veterans Affairs.
What is oxytocin and what is the dosage in this study?
Oxytocin is a hormone found naturally in both men and women and has an effect on social behavior, response to 
stress, and addiction behavior.
Synthetic versions of oxytocin are approved by the U.S. Food and Drug Administration in intravenous form 
(Pitocin) to induce uterine contraction during childbirth and in intranasal form (Syntocinon) to help with 
breastfeeding. It is not currently approved for use in people with substance use disorders; therefore, its use in this 
study is considered experimental.
Intranasal oxytocin has been widely studied and administered at the dose you may receive - 40 International Units 
(IU). It is considered very safe.
How many people will take part in this study?
Approximately 50 people will take part in this study. Half of these participants will receive oxytocin and half will 
receive a placebo. A placebo is an inactive substance.
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What will happen if I take part in this research study?
If you agree, the following procedures will occur:
Before you begin the main part of the study:
Your eligibility for the study will be assessed in a 3-4-hour visit. This will include receiving your written consent 
and determination of eligibility. We will conduct some basic baseline measures including a urine toxicology screen, 
a urine pregnancy test (female participants), surveys/questionnaires, and an interview about your mental health and 
past/current substance use.
During the main part of the study:
The testing portion of the study will include intranasal study drug administration (oxytocin or placebo) twice daily 
for six weeks. On the days that you receive your opioid replacement at OTP, a dispensing nurse, or member of the 
study staff will administer morning oxytocin doses. If you come to OTP to receive your methadone dose, but do 
not receive your study drug, you will lose $1. For individuals who receive more than 3 take home doses, you will 
be trained to video chat via Zoom, a HIPAA compliant video conferencing app, during your screening visit. You 
will contact the study staff on weekdays you do not receive your opioid replacement therapy; during these video 
calls, you will self-administer the study drug in view of the study staff.  If you do not self-administer oxytocin over 
Zoom with the study staff during the days you are scheduled to, you will lose $1 per day. 
You will be given a take-home bottle containing your take-home study drug doses to be self-administered; Evening 
doses should happen 8-12 hours after each morning dose. We ask that you return your self-administration bottle, 
empty or not, each week when you meet with us. There will not be any penalty for forgetting to take an evening 
dose, so return it even if doses have not been administered However, your compensation for the week will be 
reduced if you do not return your bottle. It is important that you take the evening dose as often as possible and that 
you not share the medication with anyone else, which would hinder our ability to determine if this medication 
might be a helpful treatment option.
In addition to twice daily study drug administration, your participation will include seven weekly in-person visits 
with study staff. At each in-person visit, you will provide a urine sample and complete some questionnaires. Each 
visit will be about a half hour, except for the first and final (seventh) visits, which will be two hours. For visits 2-
7, you will be asked to return your self-administration bottles. Below is a detailed list of additional procedures that 
you will be asked to complete throughout the study:

Urine Drug Screen: We will ask you for a urine sample to test for drug use (and pregnancy for female 
participants) at each of the seven visits. Your results will not affect your participation with the exception of a 
positive pregnancy test, which will lead to study termination.

Urine pregnancy test (female participants): We will also perform a urine pregnancy test at each visit. If a 
pregnancy test is positive at any point, study participation will end in order to avoid medical risks.

Birth Control (female participants): Women of childbearing potential wishing to participate in this study must 
agree to use an adequate form of non-hormonal birth control throughout the six weeks of study participation. 
A study physician will ask you questions about your current birth control methods. Not of childbearing 
potential is defined as permanent sterilization, postmenopausal, or assigned male at birth.

Alcohol Breath Test: You may be asked to perform an alcohol breath test to ensure that you are not 
intoxicated during study sessions. If you test >0.00 on the breath test, you will not be eligible to complete 
testing and you will not be paid for your time that day.

Randomization: You will be randomized to receive either oxytocin or placebo. You will receive the same 
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study drug throughout the study duration. Randomization means that you are put into a group by chance. A 
computer program will place you into one of the groups. Neither you nor the study staff can choose the 
group you will be in and neither of you will know which study drug you are receiving during the study. You 
will have an equal chance of being placed in either the oxytocin or placebo group.

Oxytocin/Placebo: We will train you how to self-administer the intranasal study drug. The study drug will be 
dosed twice daily for six weeks

Surveys/Questionnaires: Throughout the study, you will be given surveys and questionnaires. These 
questionnaires will ask you about how you feel physically and mentally and ask about past and recent drug 
use and mental health symptoms.

Speech Task: You will be asked to give a 5-minute speech on a topic we have selected for you. The speech 
will be video recorded and it will be adjudicated for quality and delivery.

Arithmetic Task: You will be asked to complete an arithmetic task while being video recorded. The recording 
will be adjudicated for correctness, speed, and cognitive abilities. During the task, a live adjudicator will 
correct any mistakes.

Video recording: You will be video recorded during the speech and arithmetic tasks. We will inform you 
before starting the video recording. The recording will be kept secure, private, and confidential. The 
researchers will use this content to look at your experience of and judge your performance on the speech and 
arithmetic tasks.

Physiologic measurements: You will be asked to wear a harness with sensitive physiology instruments in 
order to measure your psychophysiological responses during various tasks.

Daily Video Calls: If you receive 3 or more take-home opioid replacement therapy (ORT) doses, in order 
to monitor adherence, the study staff will ask you to video chat with them while you take your morning 
dose of the study drug on days you use your take home does of ORT. 
Additional Information:

If at any point in this study you report that you have thoughts of hurting yourself or harming others, you 
will consult with one of the study psychiatrists. If necessary, a staff member will contact emergency 
services for further evaluation.

With your permission, we may contact your primary physician in case of emergency or if we need 
additional information about your current symptoms and medications that you cannot provide.
Study location: All testing will be conducted at the San Francisco Veterans Affairs Medical Center, 4150 Clement 
St, San Francisco, CA 94121
How long will I be in the study?
Participation in the study will include: administering study drug twice daily, an initial 3-4 hour visit to determine 
eligibility, and seven weekly visits. The first and last of the weekly visits will be 2-hours long and the five visits 
between will be a half-hour each. Total participation in the study will be around 10 hours over about six weeks.
Can I stop being in the study?
Yes. You can decide to stop at any time. Just tell the study researcher or staff person right away if you wish to stop 
being in the study.
Also, the study researcher may stop you from taking part in this study at any time if he or she believes it is in your 
best interest, if you do not follow the study rules, or if the study is stopped for unforeseen reasons.
What side effects or risks can I expect from being in the study?

Urine Drug Screen/Alcohol Breath Test: There is a possibility that your test may come back falsely positive. 
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A positive alcohol breath test will make you ineligible to participate in that day’s study session; however, 
you are welcome to participate in the study on another occasion when you do not test positive for alcohol. 
Results from the urine drug screen and alcohol breath test will only be used for the purposes of the study and 
will not be available to any third party.

Randomization risks: You will be assigned to a treatment group by chance, and the treatment you receive may 
prove to be less effective or to have more side effects than the other study treatment(s) or other available 
treatments.

Oxytocin Nasal Spray: The most common side effects of oxytocin nasal spray include a runny, stuffy, or 
irritated nose. Potential, rare, adverse effects of the preservatives in the nasal spray include skin rashes and 
anaphylactoid reactions associated with shortness of breath, low blood pressure, or shock. Side effects that are 
uncommon include irregular heartbeats, nausea and vomiting. Water intoxication is also an uncommon side 
effect which may result from high dose or prolonged use of oxytocin and large water consumption. These 
uncommon side effects are associated with intravenous infusion of oxytocin rather than intranasal 
administration. No studies using intranasal administration of oxytocin have provided evidence for any of these 
side effects and it is widely considered safe. A medically licensed doctor will be available on-site throughout 
study participation.

Psychological distress: The sensitive nature of topics in assessments or self-report questionnaires may lead to 
psychological distress. You may take a break from assessments or questionnaires at any time. Additionally, the 
speech and arithmetic tasks may cause some psychological distress. However, research participation will not be 
any more distressing than situations you may encounter in everyday life. If there are any concerns over your 
immediate safety or the safety of others, we may escort you to emergency services or contact appropriate 
emergency personnel.

Risks of Cue-Induced Craving: Some of the questionnaires and discussion topics may lead to mild emotional 
discomfort or a temporary increase in substance craving. The stimuli are generally no more triggering than 
what is found in your environment.

Video recording: Video recording during study tasks increases the risk that your confidentiality and privacy may 
be compromised given the identifiable nature of video contents. Such recordings will be saved on password-
protected computers that are within the SFVAMC network or on a secure, encrypted, and password- protected 
hard drive. Recordings will only be viewed by researchers involved in the study to examine facial and body 
expressions and evaluate performance in the speech and arithmetic tasks and will be kept indefinitely.

Video Chat (if applicable): Video conferencing during the study increases the risk that your confidentiality and 
privacy may be compromised given the identifiable nature of video contents. Study staff will talk with you via the 
HIPAA compliant video conferencing app, Zoom. Password protected tablets will be used in a private room in the 
SFVAMC to ensure confidentiality. Videos will not be recorded or kept. Only study-approved research staff will 
talk with you over Zoom. 

Physiologic measurements: The physiology instrument that we use is like a harness that goes around your chest 
and shoulder. It is non-invasive and causes no physical pain. Some people experience some mild discomfort 
while wearing the harness, but that quickly goes away after removing it. Should you begin to experience 
discomfort such as redness or itching at any point while wearing the harness, we can remove it.

Unknown Risks: The experimental treatments may have side effects that no one knows about yet. The 
researchers will let you know if they learn anything that might make you change your mind about participating in 
the study. For more information about risks and side effects, feel free to ask your study doctor.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor if you feel that you have been injured because of taking part in this 
study. You can tell the doctor in person or call him/her at (415) 221-4810 x2-3673.
Treatment and Compensation for Injury: If you are injured as a result of being in this study, VA will ensure that 
treatment is made available at a VA medical facility. If you are eligible for veteran’s benefits, the costs of such 
treatment will be covered by the Department of Veterans Affairs. If you are not eligible for veteran’s benefits, the 
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costs of treatment may be billed to you or your insurer just like any other medical costs, or covered by the Department 
of Veterans’ Affairs or the University of California, depending on a number of factors. The Department of Veterans 
Affairs and the University do not normally provide any other form of compensation for injury. For further information 
about this, call the VA Regional Counsel at (415) 750-2288 or the office of the UCSF Institutional Review Board at 
(415) 476-1814.
Are there benefits to taking part in the study?
Detailed psychological assessments before and during the participation in the study may assist you in better 
understanding your substance use history and current psychosocial functioning. The treatment interventions may also 
help you with your substance use, although this is certainly not guaranteed. While doctors hope oxytocin will be 
beneficial to you, there is no proof of this yet. We do know that the information from this study will help doctors learn 
more about oxytocin as a treatment for substance use disorders and contribute to our scientific understanding of 
substance use and social engagement. This information could help future patients struggling with substance use 
issues.
What other choices do I have if I do not take part in this study?
You are free to choose not to participate in the study. If you decide not to take part in this study, there will be no 
penalty to you. You will not lose any of your regular benefits, and you may continue receiving other medical and 
psychological treatment as usual without participating in the study. You may enter a treatment program without 
taking part in this study.
Will information about me be kept private?
Participation in research involves some loss of privacy. We will do our best to make sure that information about you 
is kept confidential, but we cannot guarantee total privacy. Some information from your medical records will be 
collected and used for this study. If you do not have a VAMC medical record, one will be created for you.
For studies that involve a medical intervention, a progress note entry should indicate that an individual has been 
enrolled in a research study, any details about study interventions that might affect the subject’s clinical care, and 
the name and contact information for the investigator conducting the study. Subjects’ informed consent forms and 
HIPAA authorization documents are not to be included in the health record. Study tests that are performed by 
research labs, and information gathered directly from you by the researchers will be part of your research records 
but will not be added to your medical record. Your personal information may be given out if required by law. If 
information from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.
In this study, you will be asked about and tested for illegal drug use. The researchers will keep information about 
you as confidential as possible, but complete confidentiality cannot be guaranteed. On rare occasions, research 
records have been subpoenaed by a court. To help us protect your privacy, we have obtained a Certificate of 
Confidentiality from the National Institutes of Health. With this Certificate, the researchers cannot be forced to 
disclose information that may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings.
Exceptions: A Certificate of Confidentiality does not prevent researchers from voluntarily disclosing information 
about you, without your consent. For example, we are obligated under State and Federal law to report information 
about incidents such as child abuse, intent to harm yourself or others. In the case of being a danger to yourself or 
others, if necessary, study staff may contact emergency services for further evaluation. In addition, a Certificate of 
Confidentiality does not prevent you or a member of your family from voluntarily releasing information about 
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yourself or your involvement in this research. If an insurer, employer, or other person obtains your written consent to 
receive research information, then the researchers may not use the Certificate to withhold that information.
Finally, the Certificate may not be used to withhold information from the Federal government needed for auditing or 
evaluating federally funded projects or information needed by the FDA.
Organizations that may look at and/or copy your research records for research, quality assurance, and data analysis 
include:

UCSF’s Institutional Review Board

VA Regulatory Personnel

The U.S. Food and Drug Administration
Participation in research may involve a loss of privacy, but information about you will be handled as confidentially as 
possible.
What are the costs of taking part in this study?
You will not be charged for any of the study treatments or procedures.
Will I be paid for taking part in this study?
You will be compensated for participating in this study to cover your time and travel expenses. You can make up to $350 
for your full participation in the study. After today’s screening visit you will receive $50. For the remaining visits, you 
will receive some of the money you earned for your participation, at the time of your visit, while the remainder will be 
put into a completion bonus pot. The money you earn towards your completion bonus pot will be provided to you after 
your final visit with us.
Visit 1: You will earn $50 after completing the first visit; you will receive $30 immediately after your visit and $20 
will go towards your completion bonus.
Visits 2-6: You can earn up to $40 at each follow-up visit. At the time of the visit, if you remember to return your 
nasal spray bottles, you will receive $30. If you do not return your nasal spray bottle during the visit, $10 will be 
subtracted from your earnings that day and you will only receive $20. After each of these visits, $10 will be added to 
your completion bonus pot whether or not you remember to bring your bottle.  If you have take home ORT doses do 
not complete a study drug self-administration in the view of study staff, you will forfeit $1 from the next week’s 
pay. If you arrive at OTP and do not receive your study drug, you will lose $1 from next week’s pay. 
Visit 7: You will earn $50 after completing the final visit; you will receive $30 ($10 will be subtracted from this if 
you do not bring your bottle back) plus $20 that will go towards the completion pot. Upon completing this visit, you 
will also receive your completion bonus pot earnings, which can be up to $90.
Remember: it does not matter if the bottle you bring is full or empty, just that you return it for adherence 
monitoring.
Examples:

If you attend all visits, your completion bonus will be $90 ($20 for the first and last visits, $10 for visits 2- 6).

If you attend all but one study visit, you will forfeit your $40 for that visit ($30 the day of and $10 in the 
bonus pot, making your total bonus pot $80).

If you miss two follow-up visits total, you will forfeit the $30 for those visit days and your completion 
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bonus will be $70, and so on.

If you miss the final session, you will not receive your bonus pot or you final $30 payment.

If you forget to video call the study staff three days, you will forfeit $3 from your next visit pay. You will receive 
$27 if you bring back your spray bottle instead of the possible $30.  
This means that in order to receive the full $350, you must attend every single visit ,return all of your nasal spray 
bottles, video chat with the study staff every weekday (if applicable,) and receive the study drug dose during 
every visit to OTP. 
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you 
decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will 
be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical 
care. You can still get your medical care from our institution.
We will tell you about new information or changes in the study that may affect your health or your willingness to 
continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing 
this form.
Who can answer my questions about the study?
You can talk to the researcher(s) about any questions or concerns you have about this study. Contact the 
researchers at (415) 221-4810 x2-3673.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
If you have any questions, comments, or concerns about taking part in this study, first talk to the researchers (above). 
If for any reason you do not wish to do this, or you still have concerns after doing so, you may contact the office of 
the Committee on Human Research, UCSF's Institutional Review Board (a group of people who review the research 
Screening 
Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
TOTAL
Take home on 
visit day
$50
$30
$30
$30
$30
$30
$30
$30
$260
Loss if do not 
bring bottle in
n/a
n/a
-$10
-$10
-$10
-$10
-$10
-$10
(up to -$60)
Loss no 
observed AM 
dose
n/a
n/a
(up to -$5 
each missed 
dose)
(up to -$5 
each missed 
dose)
(up to -$5 
each missed 
dose)
(up to -$5 
each missed 
dose)
(up to -$5 
each missed 
dose)
(up to -$5 
each missed 
dose)
(up to -$30)
Completion 
Bonus
n/a
+$20
+$10
+$10
+$10
+$10
+$10
+$20
+$90
$254-$350
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to protect your rights).
You can reach the IRB office at (415) 476-1814, 8 am to 5 pm, Monday through Friday. Or you may write to: 
Committee on Human Research, Box 0962, University of California, San Francisco (UCSF), San Francisco, CA 
94143.
****************************
Please read each sentence below and think about your choice. After reading each sentence, put your initials in the 
“Yes” or “No” box.
No matter what you decide to do, it will not affect your care.
1)
Someone may contact me in the future to ask me to take part in more research.
2)
I agree to being videotaped and/or audio taped during the study as specified in the consent.
You have been given a copy of this consent form and the Experimental Subject’s Bill of Rights to keep.
You will be asked to sign a separate form (HIPAA form) authorizing access, use, creation, or disclosure of health 
information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to be in this study, or to 
withdraw from it at any point without penalty or loss of benefits to which you are otherwise entitled.
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If you wish to participate in this study, sign below.
Participant’s Name (print)
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
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IRB NUMBER: 16-20738
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IRB EXPIRATION DATE: 08/05/2020

Prot_000.pdf: 
 
 
 
STIMULANT OXYTOCIN STUDY 
NCT03016598 
12/18/2017 
 
 


Study Protocol 
RESEARCH DESIGN 
We conducted a randomized, double-blind, placebo-controlled study to examine the effects of oxytocin 
administration on stimulant use, psychosocial treatment engagement, and stress-reactivity in a sample 
of 40 individuals with stimulant use disorder receiving opioid agonist therapy within an opioid treatment 
program at the San Francisco and Oakland VA. Following successful screening and an initial baseline 
visit, participants were randomized to receive either oxytocin 40 IU or placebo intranasally twice daily 
for six weeks. 
 
Research Participants: 
We enrolled 40 male research participants with active stimulant use disorder and stabilized on opioid 
agonist therapy in an opioid treatment program (OTP). OTP clinics operate under strict state and federal 
guidelines for treatment structure and monitoring. Each patient receiving opioid agonist therapy from 
the OTP who is actively using stimulants is in “Phase 0” within the OTPs at the San Francisco and 
Oakland VA. Phase 0 patients must report to the clinic every day the clinic is open for observed opioid 
agonist dosing (i.e., no take-home doses), must submit urine for random toxicology screening 
approximately once every two weeks, and are required to attend weekly psychoeducation/therapy 
groups within the clinic. All patients in the OTP are assigned an individual counselor who meets with 
them at least monthly to support the lifestyle changes necessary to progress in recovery. Phase 0 
patients typically meet with their counselors more frequently.  
Recruitment: Participants were recruited from the OTP through the use of flyers posted visibly in clinic 
common areas and referrals from clinic counselors who were made familiar with inclusion/exclusion 
criteria through presentations at staff meetings and “Dear Provider” letters.  
Adherence Monitoring: Study staff trained in proper spray application (Guastella, Hickie, et al. 2013) 
intranasally administered participants’ morning study drug doses. Each participant was given a nasal 
spray bottle and trained in proper spray application by study staff. Participants were to administer their 
evening dose 8-10 hours following their morning dose. Each week, participants will be incentivized to 
bring their nasal spray bottle from the previous week, whether full or empty, for adherence monitoring 
via weighing. We successfully used similar contingent management strategies in our previous study of 
Trier Social Stress Test & Working Alliance Inventory 
Urine Drug Screen & Weekly Attendance 
FIGURE 1 


repeated oxytocin administration in patients with co-occurring cocaine and opioid use disorders. Our 
participants brought their nasal spray devices in for weighing 98% of the time (no participant forgot 
more than once) and collectively self-administered >78% of their evening doses. 
Randomization: Participants were randomized 1:1 to receive either oxytocin or placebo. A 
randomization plan was created using www.randomization.com. Randomization was managed by the 
Investigational Drug Pharmacist at the San Francisco VA, who also managed the double blind. 
Inclusion Criteria: Participants must be at least 18 years old, enrolled as a patient at the San Francisco or 
Oakland VA OTP, be on a stable dose of methadone or buprenorphine for at least two consecutive 
weeks, and have at least one documented routine urine toxicology screen positive for cocaine or 
methamphetamine in the past month. 
Exclusion Criteria: Urine toxicology screen positive for heroin in the past month; meeting Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition (DSM-V) criteria for previous or current psychotic 
disorder, severe neuropsychological disorder, premenstrual dysphoric disorder, or current moderate 
severe alcohol use disorder; active suicidal or homicidal ideation; hemodialysis; sensitivity to E 216, E 
218, and chlorbutanol hemihydrate (preservatives used in nasal spray); using hormone 
supplementation; positive urine pregnancy test or women of child-bearing age not practicing an 
effective means of non-hormonal birth control; or nasal obstruction, discharge, or bleeding. 
METHODS 
All measures are listed in detail below. In sum, our primary outcome measure will be (1) Stimulant 
positive urine drug screen collected at baseline and weekly throughout the study. To assess psychosocial 
measures, participants and their clinic assigned counselor will complete (2a) the Working Alliance 
Inventory – Short Revised (WAI-SR) (Hatcher & Gillaspy 2006), client and therapist forms, respectively, at 
baseline and after six weeks as well as (2b) OTP attendance rates. Additionally, in response to a Trier 
Social Stress Test, we will measure, (3a) self-reported stimulant craving by completing the Cocaine 
Craving Questionnaire (CCQ-Brief) modified to include methamphetamine in addition to cocaine, (3b) 
psychophysiological measures, including heart rate and heart rate variability, (3c) stress biomarker 
measurements, including salivary cortisol and DHEA, and (3d) self-reported anxiety. 
See Figure 1 for Study Design Outline. 
 
PROCEDURES 
Screening/Baseline: Potential participants were screened by study staff on site and, if preliminarily 
eligible, signed a brief clinic-specific consent in order for us to confirm eligibility via OTP medical records. 
Eligible participants were invited for a baseline interview, which included: 1) written informed consent, 
2) a medical history and brief physical exam conducted by a study physician, 3) a structured mental 
health interview conducted by an advanced psychology trainee, 4) baseline measurements, and 5) a 
urine pregnancy test (for female participants). 
Daily: We asked participants to report daily on their illicit drug use from the previous 24-hours, including 
specific drug, amount, and route of administration. We also monitored daily OTP clinic attendance. 


Weekly: Participants provides a weekly urine sample, which was analyzed for various drugs of abuse.  
MEASURES 
Screening Measures: 
1) Structured Clinical Interview for DSM-5 Disorders – Clinical Trials Version (SCID-5-CT): a 
structured psychiatric interview based on current diagnostic standards, customized to the 
inclusion and exclusion criteria of our clinical trial. 
Outcome Measures: 
1) Stimulant positive urine drug screen: (Jufer, Wstadik et al. 2000, Preston, Epstein et al. 2002) 
was measured from baseline and weekly urine samples. Urine samples were screened for a 
variety of drugs of abuse. 
2) a. Working Alliance Inventory – Short Revised (WAI-SR): (Hatcher & Gillaspy, 2006): is a well-
validated 12-item measure of therapeutic alliance. Participants completed individual “client 
forms” for their clinic-assigned individual counselor at baseline and after six weeks. Likewise, the 
counselor completed the “therapist form” for each participant at baseline and after six weeks of 
study participation. Time required for administration per form: <5 minutes. 
b. Attendance in OTP clinic: Daily attendance at OTP clinic was tracked for each participant. 
 
FIGURE 2 
Psychophysiology measurementsBaselineCCQ-Brief, salivary biomarkers, Likert scalesFigure 6: Social Stress-Induced Cocaine Craving Paradigm. TSST = Trier Social Stress 
Test, CCQ-Brief –Cocaine Craving Questionnaire-Brief, salivary biomarkers = cortisol and dehydroepiandrosterone, Likert scales = subjective stress and anxiety. 
3) Trier Social Stress Test (TSST) (see Figure 2): in order to evaluate response to social stress, 
participants engaged in the TSST paradigm at study baseline and after six weeks of intranasal 
oxytocin or placebo. The TSST is a standardized and well-validated psychological stress challenge 
which has shown utility for evoking a strong cardiovascular and HPA axis stress response 
(including salivary cortisol) in a laboratory setting (Dickerson & Kemeny 2004). After a 5-minute 
preparation period, participants are instructed to give a speech and perform serial subtractions, 
for five minutes each, in front of a panel of stone-faced adjudicators. 
a. Cocaine Craving Questionnaire-Brief (CCQ-Brief): (Sussner, Smelson et al. 2006) is a 
valid and reliable 10-item self-report instrument, with each item scored on a scale 1-7, 
used to measure the respondent’s general cocaine craving. We amended this to also 
include methamphetamine and asked for participants’ stimulant of choice. Participants 
TSST 
(15 minutes) 
Psychophysiology measurements 
Baseline 
CCQ-Brief, salivary biomarkers, STAI-6 


completed the amended CCQ-Brief at baseline, immediately after the TSST, and 20 
minutes after the TSST. 
b. Psychophysiological Stress Measures: consisted of two main outcome variables: 
heart rate and heart rate variability. We recorded continuous physiology during the 
TSST, we will include the 5-min averages for: baseline, speech prep, speech, mental 
arithmetic, and 15-20 mins post-TSST. 
c. Salivary cortisol and dehydroepiandrosterone (DHEA): are biological markers of HPA-
axis stress reactivity. We will collect salivary cortisol and DHEA at baseline, immediately 
after the TSST, and 20 minutes after the TSST. 
d. State-Trait Anxiety Inventory, 6-item version (STAI-6): participants will rate their 
levels subjective anxiety using the STAI-6 at baseline, immediately after the TSST, and 20 
minutes after the TSST. 

SAP_001.pdf: 
 
 
 
Stimulant Oxytocin Study 
NCT03016598 
03/02/2016 
 


Data Analysis: 
Aim 1: We will employ linear mixed effects models to examine within- and betweengroup variability in 
positive stimulant urine drug screens across 6 weeks. 
Aim 2: We will employ linear mixed effects models to examine within- and betweengroup differences in 
(H2) client and therapist WAI ratings and (H5) attendance rates. 
Aim 3: We will use linear mixed effects models to assess within- and between-group 
differences in the following stress measures related to the Trier Social Stress Test 
(conducted at baseline and post-6 weeks): (H3) Psychophysiological measures (HR, 
HRV), (H4) self-reported stimulant craving, (H6) salivary stress biomarkers (cortisol and 
DHEA), and (H7) self-reported anxiety (STAI-6).