StressPhase 2OTC-1NCT04181515
Using rTMS to Explore Neural Mechanisms of Stress-Induced Opioid Use
A Phase 2 study testing Yohimbine + Hydrocortisone and active rTMS in people with Stress and Opioid-use Disorder, run by Wayne State University.
Trial summary
This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative loci differentially influence stress-reactivity and opioid reinforcement in… Read more about this study
- Who is it for?
- Ages 21 to 60 years
- Conditions the study is for
- Stress, Opioid-use Disorder
- What is being tested?
- Yohimbine + Hydrocortisone and active rTMS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 10 Apr 2023to 10 Apr 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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
- Past-month participation in a research study
About this study
Official title: Using Repetitive Transcranial Magnetic Stimulation (rTMS) to Explore Neural Mechanisms of Stress-Induced Opioid Use
This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.
Read the detailed description
The Competing Neurobehavioral Decisions Systems (CNDS) model of addiction suggests that persons with SUDs have hyperactive limbic reward circuitry and hypoactive executive control circuitry. CNDS theory supports targeting the dorsolateral prefrontal cortex (dlPFC, part of executive control circuit) and other cortical targets with repetitive transcranial magnetic stimulation (rTMS). One candidate-the medial prefrontal cortex (mPFC)-is part of limbic reward circuitry and accessible using rTMS. We validated a rigorous pharmacological stress-induction method (yohimbine + hydrocortisone) that emulates endogenous stress-reactivity and have established linkages between stress-exposure, executive dysfunction, and drug seeking. Our lab is developing rTMS as a potential "anti-stress" neuromodulation approach in people with opioid use disorder (OUD).
This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative cortical loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.
- Conditions
- Stress, Opioid-use Disorder
- Being tested
- Placebo oral tablet, Yohimbine + Hydrocortisone, sham rTMS, active 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.
Placebo oral tabletDrug
placebo stressor
Yohimbine + HydrocortisoneDrug
Yohimbine 54mg + Hydrocortisone 20mg
sham rTMSDevice
sham rTMS (inactive coil)
active rTMSDevice
active rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2)
| Study group | Role | What they receive |
|---|---|---|
| placebo stressor, sham rTMS | Placebo comparator | placebo stressor (lactose), sham rTMS (inactive coil) Receives: Drug: Placebo oral tablet; Device: sham rTMS |
| placebo stressor, active rTMS | Active comparator | placebo stressor (lactose), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2) Receives: Drug: Placebo oral tablet; Device: active rTMS |
| stressor, sham rTMS | Active comparator | stressor (yohimbine 54mg + hydrocortisone 20mg), sham rTMS (inactive coil) Receives: Drug: Yohimbine + Hydrocortisone; Device: sham rTMS |
| stressor, active rTMS | Active comparator | stressor (yohimbine 54mg + hydrocortisone 20mg), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2) Receives: Drug: Yohimbine + Hydrocortisone; Device: active rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Addiction Stroop task
reaction time (msec) measure of cognitive interference
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Digit Span Task
number of digits recalled, measure of verbal working memory
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Wisconsin Card Sorting Task
number of correct items, measures ability to shift set and assesses cognitive flexibility
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Monetary Incentive Delay task
number of rewards received, measure of motivation
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Delay Discounting task
rate of monetary discounting
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Drug/Money Choice Task
number of hypothetical choices between a constant amount of preferred opioid (relative to money)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Blood pressure
Systolic/diastolic BP (mm Hg)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Heart rate
Heart rate (beats/min)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva cortisol level
Saliva cortisol level (µg/dL)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva alpha-amylase level
Saliva alpha-amylase level (U/mL)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum prolactin level
Serum prolactin level (pg/dL)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum BDNF level
Serum brain derived neurotrophic factor level (pg/dL)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Positive and Negative Affect Schedule (PANAS) positive affect
10-item sub scale score of positive affect
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Positive and Negative Affect Schedule (PANAS) negative affect
10-item sub scale score of negative affect
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
State Trait Anxiety Inventory
state anxiety scores
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Desire for Drug Questionnaire
opioid craving score
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opiate-32 Questionnaire, Agonist score
total opioid agonist score (16 items)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Opiate-32 Questionnaire, Withdrawal score
total opioid withdrawal symptom score (16 items)
Measured: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Resting-state EEG activation
relative (gamma band ÷ slow band) ratio in electroencephalogram (EEG) power during resting state
Measured: change from pre- and 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 posted29 Nov 2019
- Study start10 Apr 2023
- Primary completion10 Apr 2023
- Study completion10 Apr 2023
Why it stopped: Lack of funding
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for StressStudies 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
- mixed design, with 4 (2x2) within-subject conditions (placebo vs. stressor X sham vs. rTMS), each occurring in two parallel groups (10 Hz dorsolateral prefrontal cortex vs. sham rTMS in group 1, and 1 Hz medial prefrontal cortex vs. sham rTMS in group 2)
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Wayne State University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mark Greenwald, PhD, Wayne State University
- Investigators
- Mark Greenwald, PhD, Principal investigator, Wayne State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04181515
- Sponsor's protocol ID
- OTC-1
- Acronym
- OTC-1
- Status last verified
- Apr 2023
- First submitted
- 24 Nov 2019
- Last updated
- 13 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: After the study is completed, qualified investigators may apply in writing to receive the study protocol. At this time, it has not been determined whether data will be shared and the conditions for access.
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Using Repetitive Transcranial Magnetic Stimulation (rTMS) to Explore Neural Mechanisms of Stress-Induced Opioid Use
- ClinicalTrials.gov ID
- NCT04181515
- Acronym / sponsor ID
- OTC-1 / OTC-1
- Conditions
- Stress, Opioid-use Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Lack of funding
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Wayne State UniversityUniversity, hospital or other
- Study start
- 10 Apr 2023 (actual)
- Primary completion
- 10 Apr 2023 (actual)
- Study completion
- 10 Apr 2023 (actual)
- First posted
- 29 Nov 2019 (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 study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.
Detailed description
The Competing Neurobehavioral Decisions Systems (CNDS) model of addiction suggests that persons with SUDs have hyperactive limbic reward circuitry and hypoactive executive control circuitry. CNDS theory supports targeting the dorsolateral prefrontal cortex (dlPFC, part of executive control circuit) and other cortical targets with repetitive transcranial magnetic stimulation (rTMS). One candidate-the medial prefrontal cortex (mPFC)-is part of limbic reward circuitry and accessible using rTMS. We validated a rigorous pharmacological stress-induction method (yohimbine + hydrocortisone) that emulates endogenous stress-reactivity and have established linkages between stress-exposure, executive dysfunction, and drug seeking. Our lab is developing rTMS as a potential "anti-stress" neuromodulation approach in people with opioid use disorder (OUD).
This study will use a stress (vs. placebo) exposure model, paired with single-session sham vs. active rTMS at two distinct cortical locations (dlPFC vs. mPFC in parallel groups) to assess whether rTMS neuromodulation at these alternative cortical loci differentially influence stress-reactivity and opioid reinforcement in non-treatment seeking participants with OUD. Stress-reactivity will be measured using cognitive, affective, behavioral and biological phenotypes.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- mixed design, with 4 (2x2) within-subject conditions (placebo vs. stressor X sham vs. rTMS), each occurring in two parallel groups (10 Hz dorsolateral prefrontal cortex vs. sham rTMS in group 1, and 1 Hz medial prefrontal cortex vs. sham rTMS in group 2)
| Arm | Type | Receives |
|---|---|---|
| placebo stressor, sham rTMS | Placebo comparator | Drug: Placebo oral tablet, Device: sham rTMSplacebo stressor (lactose), sham rTMS (inactive coil) |
| placebo stressor, active rTMS | Active comparator | Drug: Placebo oral tablet, Device: active rTMSplacebo stressor (lactose), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2) |
| stressor, sham rTMS | Active comparator | Drug: Yohimbine + Hydrocortisone, Device: sham rTMSstressor (yohimbine 54mg + hydrocortisone 20mg), sham rTMS (inactive coil) |
| stressor, active rTMS | Active comparator | Drug: Yohimbine + Hydrocortisone, Device: active rTMSstressor (yohimbine 54mg + hydrocortisone 20mg), active rTMS (10 Hz dlPFC in group 1; 1 Hz mPFC in group 2) |
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 |
|---|---|---|
| Placebo oral tabletplacebo stressor | Drug | placebo stressor, active rTMS, placebo stressor, sham rTMS |
| Yohimbine + HydrocortisoneYohimbine 54mg + Hydrocortisone 20mg | Drug | stressor, active rTMS, stressor, sham rTMS |
| sham rTMSsham rTMS (inactive coil) | Device | placebo stressor, sham rTMS, stressor, sham rTMS |
| active rTMSactive rTMS (10 Hz dlPFC stimulation in group 1; 1 Hz mPFC stimulation in group 2) | Device | placebo stressor, active rTMS, stressor, active rTMS |
Primary outcome
Addiction Stroop task
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
reaction time (msec) measure of cognitive interference
Digit Span Task
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
number of digits recalled, measure of verbal working memory
Wisconsin Card Sorting Task
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
number of correct items, measures ability to shift set and assesses cognitive flexibility
Monetary Incentive Delay task
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
number of rewards received, measure of motivation
Delay Discounting task
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
rate of monetary discounting
Drug/Money Choice Task
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
number of hypothetical choices between a constant amount of preferred opioid (relative to money)
Blood pressure
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Systolic/diastolic BP (mm Hg)
Heart rate
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Heart rate (beats/min)
Saliva cortisol level
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva cortisol level (µg/dL)
Saliva alpha-amylase level
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Saliva alpha-amylase level (U/mL)
Serum prolactin level
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum prolactin level (pg/dL)
Serum BDNF level
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
Serum brain derived neurotrophic factor level (pg/dL)
Positive and Negative Affect Schedule (PANAS) positive affect
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
10-item sub scale score of positive affect
Positive and Negative Affect Schedule (PANAS) negative affect
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
10-item sub scale score of negative affect
State Trait Anxiety Inventory
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
state anxiety scores
Desire for Drug Questionnaire
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
opioid craving score
Opiate-32 Questionnaire, Agonist score
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
total opioid agonist score (16 items)
Opiate-32 Questionnaire, Withdrawal score
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
total opioid withdrawal symptom score (16 items)
Resting-state EEG activation
Time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)
relative (gamma band ÷ slow band) ratio in electroencephalogram (EEG) power during resting state
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2023.
- Individual participant dataSharing planned: Yes. After the study is completed, qualified investigators may apply in writing to receive the study protocol. At this time, it has not been determined whether data will be shared and the conditions for access.
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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. This study is not recruiting at the moment.
Mark Greenwald, PhD principal investigator
Wayne State University
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Yohimbine + Hydrocortisone and active rTMS in people with Stress and Opioid-use Disorder, run by Wayne State University.
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: withdrawn, as of the sponsor's last update on 13 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
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?
The study was withdrawn before enrolling participants, so there are no results.
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?
Addiction Stroop task (time frame: change from pre- and post-intervention in each of 4 sessions (through study completion, about 1 month total)). The study lists 19 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 13 Apr 2023; AzTrials last refreshed its copy on 6 Nov 2026.