Opioid Use DisorderPhase 2NCT04231708
Effects of Pharmacological Stress and rTMS on Executive Function in Opioid Use Disorder
A Phase 2 study testing Yohimbine + Hydrocortisone and Active rTMS in people with Opioid Use Disorder, run by Wayne State University at 1 site in United States.
Trial summary
This preliminary study is designed to evaluate mechanisms by which excitatory dorsolateral prefrontal cortex (dlPFC) repetitive transcranial magnetic stimulation (rTMS) (vs. sham) and pharmacological stress (vs. placebo) alter behavior in non-treatment seeking individuals with opioid use disorder (OUD). Read more about this study
- Who is it for?
- Ages 21 to 60 years
- Conditions the study is for
- Opioid Use Disorder
- What is being tested?
- Yohimbine + Hydrocortisone and Active rTMS
- Type of treatment
- Pill or oral medicine, Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2026to Dec 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Meet DSM-5 criteria for OUD;
- Age 21-60 yr;
- Right handed;
- Males and non-pregnant/non-lactating females;
- cognitively intact (total IQ score >80 on Shipley Institute of Living Scale);
- Screening cardiovascular indices within ranges for safe use of the pharmacological stressor: resting HR 50-90 bpm, systolic BP 90-140 mmHg, and diastolic BP 50-90 mmHg;
- Use alcohol and/or marijuana <3 times/week; each "time" should consist of <1 marijuana "joint" equivalent and <3 alcoholic drinks.
Who cannot join
- Under influence of any substance during session;
- Past 7-day use of illicit drugs other than opioids (except marijuana, which is legal in Michigan);
- Urinalysis positive for cocaine metabolites, benzodiazepines, barbiturates, amphetamines or pregnancy;
- Medical conditions prohibiting use of rTMS (e.g. seizure history; based on rTMS screening questionnaire);
- Lifetime diagnosis of: psychotic disorder, bipolar disorder, generalized anxiety disorder, or obsessive compulsive disorder; major depression in the past 5 years; or potentially antisocial personality disorder (if the clinical psychologist judges such behaviors to be potentially disruptive or unsafe in our lab);
- Past-year SUD other than OUD;
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- Acute/unstable illness: conditions making it unsafe for participation (e.g. neurological, cardiovascular, pulmonary, or systemic diseases);
- Lactose intolerance (placebo dose);
- Any prohibited medications: medications that lower seizure threshold, psychiatric medications, prescription pain medications, or blood pressure medications;
- Chronic head or neck pain; and
- Past-month participation in a research study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Tolan Park Medical Building
Detroit, Michigan, 48201
About this study
Official title: Effects of Pharmacological Stress and Repetitive Transcranial Magnetic Stimulation Interventions on Executive Function in Opioid Use Disorder
This preliminary study is designed to evaluate mechanisms by which excitatory dorsolateral prefrontal cortex (dlPFC) repetitive transcranial magnetic stimulation (rTMS) (vs. sham) and pharmacological stress (vs. placebo) alter behavior in non-treatment seeking individuals with opioid use disorder (OUD). Specific Aims are to (1) Evaluate how stress impacts domains of behavior including (1a) executive function and (1b) opioid-seeking behavior; and (2) Determine whether rTMS stimulation attenuates (2a) executive dysfunction, (2b) stress-reactivity, and (2c) opioid-seeking in individuals with OUD not receiving treatment.
Read the detailed description
This study will use a double-blind, 10Hz left dlPFC rTMS (vs. sham) and pharmacological stressor ([yohimbine + hydrocortisone] vs. placebo) within-subject, randomized crossover design. Each participant will complete 4 sessions (stressor vs. placebo, crossed with rTMS vs. sham), each separated by at least 1 week. Participants will complete these 4 (2x2 within subject) test conditions in randomized order: sham rTMS/placebo stress, sham rTMS/active stress, active rTMS/ placebo stress, and active rTMS/active stress.
The PI will perform randomization using a Latin Square and will assign participants to conditions and prepare medication (stressor or placebo) for each participant's sessions. The PI will keep others blinded and will not be involved in study assessments.
- Conditions
- Opioid Use Disorder
- Being tested
- Yohimbine + Hydrocortisone, Active rTMS, Placebo, Sham rTMS
- Medical subject headings
- Opioid-Related Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Yohimbine + HydrocortisoneDrug
Yohimbine (54mg bulk powder inside capsule) administered in combination with Hydrocortisone (20mg tablet inside capsule)
Active rTMSDevice
10Hz rTMS over the left dlPFC
PlaceboDrug
lactose (inside capsule)
Sham rTMSDevice
inactive stimulation over the left dlPFC
| Study group | Role | What they receive |
|---|---|---|
| placebo stressor, sham rTMS | Placebo comparator | Placebo stressor (lactose) + sham (inactive) rTMS over the left dlPFC Receives: Drug: Placebo; Device: Sham rTMS |
| placebo stressor, active rTMS | Experimental | Placebo stressor (lactose) + active 10Hz rTMS over the left dlPFC Receives: Device: Active rTMS; Drug: Placebo |
| active stressor, sham rTMS | Experimental | Stressor (yohimbine 54mg + hydrocortisone 20mg) + sham (inactive) rTMS over the left dlPFC Receives: Drug: Yohimbine + Hydrocortisone; Device: Sham rTMS |
| active stressor, active rTMS | Experimental | Stressor (yohimbine 54mg + hydrocortisone 20mg) + active 10Hz rTMS over the left dlPFC Receives: Drug: Yohimbine + Hydrocortisone; Device: Active rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Color-Word Stroop Task
measures cognitive control in response to opioid-related words.
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Digit Span Task
measures verbal working memory. Participants are asked to repeat strings of numbers of increasing length, both forward and backward.
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Wisconsin Card Sorting Task
measures ability to shift set and assesses cognitive flexibility.
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Emotion Regulation Task
subjects rate the unpleasantness and arousal of different emotional pictures
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Positive and Negative Affect Schedule
subjects rate their positive and negative affect
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
State-Trait Anxiety Inventory
subjects rate their level state anxiety
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Monetary Incentive Delay Task
Participants respond to a visual target that follows 2 different cues: incentive or non-incentive. No reward or punishment occurs on non-incentive trials. On incentive trials, participants must respond within a fixed amount of time. In the reward condition, responses within that time result in receiving the incentive , else nothing. In the punishment condition, the participant will lose money if they do not respond within the time limit
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Delay Discounting Task
Participants perform a brief (<1min) hypothetical version of the traditional monetary task with a 5-trial adjusting delay previously validated to rapidly assess discount rate
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Drug/Money Choice Task
participants choose hypothetically between a constant amount of their preferred opioid ($10 unit dose) or money ($2)
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Systolic blood pressure
millimeters mercury (mmHg)
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Diastolic blood pressure
millimeters mercury (mmHg)
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Heart rate
beats per minute
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva cortisol level
measure of the activity of the HPA axis
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva alpha-amylase level
indirect measure of adrenergic stimulation
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum prolactin level
indirect measure of dopamine stimulation
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum brain derived neurotrophic factor (BDNF) level
indirect measure of brain derived neurotrophic factor activation
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Relative electroencephalogram (EEG) gamma power
Prefrontal gamma (25-100 Hz) EEG power, relative to slow-wave EEG power, is a stress biomarker
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Secondary outcomes (3)
Opioid craving
Desire for Drug Questionnaire total score; higher scores indicate greater craving
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opioid agonist symptoms
Opiate-32 questionnaire agonist symptom total score; higher scores indicate greater opioid symptom severity
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opioid withdrawal symptoms
Opiate-32 questionnaire withdrawal symptom total score; higher scores indicate greater withdrawal severity
Measured: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jan 2020
- Study startOct 2026 (estimated)
- Primary completionDec 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Opioid Use DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Double-blind, 10Hz left dlPFC rTMS (vs. sham) X pharmacological stressor (vs. placebo) within-subject, randomized crossover design.
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Wayne State University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mark Greenwald, PhD, Wayne State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04231708
- Sponsor's protocol ID
- DL-STR-OUD
- Status last verified
- Dec 2025
- First submitted
- 9 Jan 2020
- Last updated
- 30 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Pharmacological Stress and Repetitive Transcranial Magnetic Stimulation Interventions on Executive Function in Opioid Use Disorder
- ClinicalTrials.gov ID
- NCT04231708
- Acronym / sponsor ID
- DL-STR-OUD
- Conditions
- Opioid Use Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Wayne State UniversityUniversity, hospital or other
- Study start
- Oct 2026 (estimated)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 18 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This preliminary study is designed to evaluate mechanisms by which excitatory dorsolateral prefrontal cortex (dlPFC) repetitive transcranial magnetic stimulation (rTMS) (vs. sham) and pharmacological stress (vs. placebo) alter behavior in non-treatment seeking individuals with opioid use disorder (OUD). Specific Aims are to (1) Evaluate how stress impacts domains of behavior including (1a) executive function and (1b) opioid-seeking behavior; and (2) Determine whether rTMS stimulation attenuates (2a) executive dysfunction, (2b) stress-reactivity, and (2c) opioid-seeking in individuals with OUD not receiving treatment.
Detailed description
This study will use a double-blind, 10Hz left dlPFC rTMS (vs. sham) and pharmacological stressor ([yohimbine + hydrocortisone] vs. placebo) within-subject, randomized crossover design. Each participant will complete 4 sessions (stressor vs. placebo, crossed with rTMS vs. sham), each separated by at least 1 week. Participants will complete these 4 (2x2 within subject) test conditions in randomized order: sham rTMS/placebo stress, sham rTMS/active stress, active rTMS/ placebo stress, and active rTMS/active stress.
The PI will perform randomization using a Latin Square and will assign participants to conditions and prepare medication (stressor or placebo) for each participant's sessions. The PI will keep others blinded and will not be involved in study assessments.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 4
- Model description
- Double-blind, 10Hz left dlPFC rTMS (vs. sham) X pharmacological stressor (vs. placebo) within-subject, randomized crossover design.
| Arm | Type | Receives |
|---|---|---|
| placebo stressor, sham rTMS | Placebo comparator | Drug: Placebo, Device: Sham rTMSPlacebo stressor (lactose) + sham (inactive) rTMS over the left dlPFC |
| placebo stressor, active rTMS | Experimental | Device: Active rTMS, Drug: PlaceboPlacebo stressor (lactose) + active 10Hz rTMS over the left dlPFC |
| active stressor, sham rTMS | Experimental | Drug: Yohimbine + Hydrocortisone, Device: Sham rTMSStressor (yohimbine 54mg + hydrocortisone 20mg) + sham (inactive) rTMS over the left dlPFC |
| active stressor, active rTMS | Experimental | Drug: Yohimbine + Hydrocortisone, Device: Active rTMSStressor (yohimbine 54mg + hydrocortisone 20mg) + active 10Hz rTMS over the left dlPFC |
Who may qualify
- Ages
- 21 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Meet DSM-5 criteria for OUD;
- Age 21-60 yr;
- Right handed;
- Males and non-pregnant/non-lactating females;
- cognitively intact (total IQ score >80 on Shipley Institute of Living Scale);
Key exclusion criteria (11 listed)
- Under influence of any substance during session;
- Past 7-day use of illicit drugs other than opioids (except marijuana, which is legal in Michigan);
- Urinalysis positive for cocaine metabolites, benzodiazepines, barbiturates, amphetamines or pregnancy;
- Medical conditions prohibiting use of rTMS (e.g. seizure history; based on rTMS screening questionnaire);
- Lifetime diagnosis of: psychotic disorder, bipolar disorder, generalized anxiety disorder, or obsessive compulsive disorder; major depression in the past 5 years; or potentially antisocial personality disorder (if the clinical psychologist judges such behaviors to be potentially disruptive or unsafe in our lab);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Yohimbine + HydrocortisoneYohimbine (54mg bulk powder inside capsule) administered in combination with Hydrocortisone (20mg tablet inside capsule) | Drug | active stressor, active rTMS, active stressor, sham rTMS |
| Active rTMS10Hz rTMS over the left dlPFC | Device | active stressor, active rTMS, placebo stressor, active rTMS |
| Placebolactose (inside capsule) | Drug | placebo stressor, active rTMS, placebo stressor, sham rTMS |
| Sham rTMSinactive stimulation over the left dlPFC | Device | active stressor, sham rTMS, placebo stressor, sham rTMS |
Primary outcome
Color-Word Stroop Task
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
measures cognitive control in response to opioid-related words.
Digit Span Task
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
measures verbal working memory. Participants are asked to repeat strings of numbers of increasing length, both forward and backward.
Wisconsin Card Sorting Task
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
measures ability to shift set and assesses cognitive flexibility.
Emotion Regulation Task
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
subjects rate the unpleasantness and arousal of different emotional pictures
Positive and Negative Affect Schedule
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
subjects rate their positive and negative affect
State-Trait Anxiety Inventory
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
subjects rate their level state anxiety
Monetary Incentive Delay Task
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Participants respond to a visual target that follows 2 different cues: incentive or non-incentive. No reward or punishment occurs on non-incentive trials. On incentive trials, participants must respond within a fixed amount of time. In the reward condition, responses within that time result in receiving the incentive , else nothing. In the punishment condition, the participant will lose money if they do not respond within the time limit
Delay Discounting Task
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Participants perform a brief (<1min) hypothetical version of the traditional monetary task with a 5-trial adjusting delay previously validated to rapidly assess discount rate
Drug/Money Choice Task
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
participants choose hypothetically between a constant amount of their preferred opioid ($10 unit dose) or money ($2)
Systolic blood pressure
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
millimeters mercury (mmHg)
Diastolic blood pressure
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
millimeters mercury (mmHg)
Heart rate
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
beats per minute
Saliva cortisol level
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
measure of the activity of the HPA axis
Saliva alpha-amylase level
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
indirect measure of adrenergic stimulation
Serum prolactin level
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
indirect measure of dopamine stimulation
Serum brain derived neurotrophic factor (BDNF) level
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
indirect measure of brain derived neurotrophic factor activation
Relative electroencephalogram (EEG) gamma power
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Prefrontal gamma (25-100 Hz) EEG power, relative to slow-wave EEG power, is a stress biomarker
3 secondary outcomes
Opioid craving
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opioid agonist symptoms
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opioid withdrawal symptoms
Time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Dec 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Yohimbine + Hydrocortisone and Active rTMS in people with Opioid Use Disorder, run by Wayne State University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 30 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Color-Word Stroop Task (time frame: change from pre- to post-intervention in each of 4 sessions (through study completion, about 1 month total)). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Dec 2025.