Opioid Use DisorderTOTSNCT04920864
rTMS, Stress and Opioid Use Disorder
A study testing rTMS in people with Opioid Use Disorder, run by Wayne State University at 1 site in United States.
Trial summary
Opioid agonist treatments are the gold standard for treating opioid use disorder (OUD). Yet, even effective treatments average only 50% six-month retention. Despite extensive research into treatment options, it remains important to improve understanding of factors that contribute to relapse and identify interventions… Read more about this study
- Who is it for?
- Ages 21 to 70 years
- Conditions the study is for
- Opioid Use Disorder
- What is being tested?
- rTMS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 32 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Apr 2022to Dec 2026
- Phase
- Interventional
- 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 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Meet DSM-5 criteria for OUD;
- In methadone or buprenorphine treatment
- Age 21-70 yr;
- Right handed;
- Males and non-pregnant/non-lactating females;
- Cognitively intact (total IQ score >80);
- Use alcohol and/or marijuana <4 times per week; each "time" should consist of <2 marijuana "joint" equivalent and <4 alcoholic drinks.
Who cannot join
- Acutely under the influence of any substance (except methadone or buprenorphine) during session;
- Current, regular (>2 times/week) use of illicit drugs other than opioids (except cannabis);
- Any past 24 hour use of drugs other than opioids or nicotine;
- Urinalysis positive for pregnancy;
- Medical conditions prohibiting use of rTMS;
- Lifetime psychotic, bipolar, or potentially antisocial personality disorder;
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- Untreated or uncontrolled past-year diagnosis of major depression, generalized anxiety disorder, obsessive compulsive disorder, or post traumatic stress disorder;
- Past-month SUD other than OUD or tobacco use disorder;
- Acute/unstable illness making it unsafe for participation;
- Any prohibited medications including: medications that lower seizure threshold, certain psychiatric medications, or prescription pain medications;
- Chronic head or neck pain;
- Past-month participation in a research study.
Trial locations and contacts
1 site in 1 country.
United States1 site
Tolan Park Medical Building
Detroit, Michigan, 48201
About this study
Official title: Using Neuromodulation to Investigate Treatment Pathways Associated With Stress and Substance Use in Opioid Use Disorder
Opioid agonist treatments are the gold standard for treating opioid use disorder (OUD). Yet, even effective treatments average only 50% six-month retention. Despite extensive research into treatment options, it remains important to improve understanding of factors that contribute to relapse and identify interventions to mitigate these risks.
Stress-exposure is problematic for people trying to recover from substance use disorders (SUDs) because it weakens inhibition of automatic behaviors and increases drug craving and likelihood of relapse. However, paths through which stress affects behavior are incompletely understood and current SUD treatments do not target effects of stress on drug use.
This project will explore whether repetitive transcranial magnetic stimulation (rTMS) might improve treatment outcomes for people with OUD entering methadone treatment. The investigators will examine the impact of rTMS treatment over one of two theoretically-driven neural targets on substance use and cognitive outcomes associated with treatment success (executive function and emotional arousal).
Read the detailed description
The Competing Neurobehavioral Decisions Systems (CNDS) model of addiction suggests that people with SUDs have altered function and connectivity in fronto-cortical executive control regions (e.g. dorsolateral prefrontal cortex [dlPFC]) and fronto-cortical limbic control regions (e.g. medial prefrontal cortex [mPFC]). Namely, elevated activity in limbic circuitry results in hypersensitivity to drug cues and stress, and decreased executive control impairs the ability to resist drug urges. The CNDS theoretical framework can guide selection and testing of rTMS targets that could improve understanding of the mechanisms of SUDs and stress-induced drug use. Results from previous research suggest that therapeutic effects of rTMS for SUD could occur via excitation of dlPFC or inhibition of mPFC.
The investigators will administer excitatory (10Hz) dlPFC rTMS and inhibitory (1Hz) mPFC rTMS (through an electromagnetic coil placed against the scalp) coupled with tasks of executive function and emotional arousal during stress and neutral conditions (guided imagery task using personalized scripts) in adults with OUD early in methadone treatment. The investigators will examine and compare how strengthening dlPFC activity or reducing mPFC activity may reverse stress-induced executive and emotional dysfunction, respectively, and improve treatment outcomes in persons with OUD seeking to abstain from opioid use.
A mixed design study will be used to examine the effects of active rTMS vs. sham (within subject) over one of two locations: 10 Hz dlPFC rTMS (group 1) or 1 Hz mPFC rTMS (group 2) in subjects receiving methadone treatment for OUD. The general rTMS treatment protocol will be the same for both groups and will consist of 2 stimulation sessions per day, separated by ~30min, for 5 days (10 total stimulation sessions per treatment protocol). The sham protocol will be the same except the sham rTMS coil will be used. Participants will be randomly assigned to groups and complete the 2 conditions (active vs. sham rTMS) in random order. Immediately prior to and after each 5-day rTMS treatment protocol, participants will attend an assessment visit when they will complete multiple tasks during both stress (guided imagery stressor) and neutral conditions. These tasks are designed to measure executive function, emotional arousal, and drug-seeking behavior.
- Conditions
- Opioid Use Disorder
- Being tested
- 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.
rTMSDevice
Repetitive transcranial magnetic stimulation
| Study group | Role | What they receive |
|---|---|---|
| Active 10 Hz dlPFC rTMS | Experimental | 10 Hz dorsolateral prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) Receives: Device: rTMS |
| Sham dlPFC rTMS | Sham comparator | inactive dorsolateral prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) Receives: Device: rTMS |
| Active 1 Hz mPFC rTMS | Experimental | 1 Hz medial prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) Receives: Device: rTMS |
| Sham mPFC | Sham comparator | inactive medial prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) Receives: Device: rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Wisconsin Card Sorting Task perseverance score
Wisconsin Card Sorting Task perseverance measures cognitive flexibility as an index of executive function. Higher scores reflect better outcome.
Measured: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Emotional Arousal task rating
Average unpleasantness and arousal ratings in response to aversive pictures from the International Affective Picture System (IAPS). Lower unpleasantness and arousal scores reflect better outcome.
Measured: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Opioid progressive ratio breakpoint
Opioid ($10 unit dose) vs. money ($2) hypothetical 10-trial choice task progressive ratio breakpoint is the highest response requirement completed for the drug on an exponentially increasing schedule of reinforcement, where the subject has to click the mouse an increasing number of times to earn drug or money. Lower breakpoint scores reflect better outcome.
Measured: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Treatment success
Number of days of opioid use (based on timeline followback interview) during the 7 days following each 5-day rTMS (active and sham) period. Fewer days of opioid use reflect better outcome.
Measured: change from sham to active condition (randomized to occur on days 6-12 and 18-24, respectively)
Secondary outcomes (4)
Digit Span total score
Digit Span (forward and backward) measures the extent of verbal working memory as an index of executive function. Higher scores reflect better outcome.
Measured: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Monetary delay discounting
Brief version of delay discounting task measures the immediate vs. delayed value of money. Higher area-under-the-curve scores (preference for delayed money) reflect better outcome.
Measured: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
State-Trait Anxiety Inventory state anxiety total score
State anxiety subscale score of the State-Trait Anxiety Inventory. Lower scores reflect better outcome.
Measured: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Positive and Negative Affect Scale total score
Positive and Negative Affect Scale measures both positive and negative affect. Lower total negative affect scores reflect better outcome.
Measured: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jun 2021
- Study start1 Apr 2022
- Primary completion8 Aug 2024
- Study completionDec 2026 (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 N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- A mixed design study will be used to examine the effects of active rTMS vs. sham (within subject) over one of two locations: 10 Hz dlPFC rTMS (group 1) or 1 Hz mPFC rTMS (group 2) in subjects receiving methadone treatment for OUD. The general rTMS treatment protocol will be the same for both groups and will consist of 2 stimulation sessions per day, separated by \~30min, for 5 days (10 total stimulation sessions per treatment protocol). The sham protocol will be the same except the sham rTMS coil will be used. Participants will be randomly assigned to groups and complete the 2 conditions (active vs. sham rTMS) in random order.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 32 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
- Investigators
- Mark K Greenwald, PhD, Study director, Wayne State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04920864
- Sponsor's protocol ID
- IRB-21-01-3111
- Acronym
- TOTS
- Status last verified
- Dec 2025
- First submitted
- 30 May 2021
- Last updated
- 30 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- 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
- Using Neuromodulation to Investigate Treatment Pathways Associated With Stress and Substance Use in Opioid Use Disorder
- ClinicalTrials.gov ID
- NCT04920864
- Acronym / sponsor ID
- TOTS / IRB-21-01-3111
- Conditions
- Opioid Use Disorder
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 32 participants (estimated)
- Lead sponsor
- Wayne State UniversityUniversity, hospital or other
- Study start
- 1 Apr 2022 (actual)
- Primary completion
- 8 Aug 2024 (actual)
- Study completion
- Dec 2026 (estimated)
- First posted
- 10 Jun 2021 (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.
Opioid agonist treatments are the gold standard for treating opioid use disorder (OUD). Yet, even effective treatments average only 50% six-month retention. Despite extensive research into treatment options, it remains important to improve understanding of factors that contribute to relapse and identify interventions to mitigate these risks.
Stress-exposure is problematic for people trying to recover from substance use disorders (SUDs) because it weakens inhibition of automatic behaviors and increases drug craving and likelihood of relapse. However, paths through which stress affects behavior are incompletely understood and current SUD treatments do not target effects of stress on drug use.
This project will explore whether repetitive transcranial magnetic stimulation (rTMS) might improve treatment outcomes for people with OUD entering methadone treatment. The investigators will examine the impact of rTMS treatment over one of two theoretically-driven neural targets on substance use and cognitive outcomes associated with treatment success (executive function and emotional arousal).
Detailed description
The Competing Neurobehavioral Decisions Systems (CNDS) model of addiction suggests that people with SUDs have altered function and connectivity in fronto-cortical executive control regions (e.g. dorsolateral prefrontal cortex [dlPFC]) and fronto-cortical limbic control regions (e.g. medial prefrontal cortex [mPFC]). Namely, elevated activity in limbic circuitry results in hypersensitivity to drug cues and stress, and decreased executive control impairs the ability to resist drug urges. The CNDS theoretical framework can guide selection and testing of rTMS targets that could improve understanding of the mechanisms of SUDs and stress-induced drug use. Results from previous research suggest that therapeutic effects of rTMS for SUD could occur via excitation of dlPFC or inhibition of mPFC.
The investigators will administer excitatory (10Hz) dlPFC rTMS and inhibitory (1Hz) mPFC rTMS (through an electromagnetic coil placed against the scalp) coupled with tasks of executive function and emotional arousal during stress and neutral conditions (guided imagery task using personalized scripts) in adults with OUD early in methadone treatment. The investigators will examine and compare how strengthening dlPFC activity or reducing mPFC activity may reverse stress-induced executive and emotional dysfunction, respectively, and improve treatment outcomes in persons with OUD seeking to abstain from opioid use.
A mixed design study will be used to examine the effects of active rTMS vs. sham (within subject) over one of two locations: 10 Hz dlPFC rTMS (group 1) or 1 Hz mPFC rTMS (group 2) in subjects receiving methadone treatment for OUD. The general rTMS treatment protocol will be the same for both groups and will consist of 2 stimulation sessions per day, separated by ~30min, for 5 days (10 total stimulation sessions per treatment protocol). The sham protocol will be the same except the sham rTMS coil will be used. Participants will be randomly assigned to groups and complete the 2 conditions (active vs. sham rTMS) in random order. Immediately prior to and after each 5-day rTMS treatment protocol, participants will attend an assessment visit when they will complete multiple tasks during both stress (guided imagery stressor) and neutral conditions. These tasks are designed to measure executive function, emotional arousal, and drug-seeking behavior.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- A mixed design study will be used to examine the effects of active rTMS vs. sham (within subject) over one of two locations: 10 Hz dlPFC rTMS (group 1) or 1 Hz mPFC rTMS (group 2) in subjects receiving methadone treatment for OUD. The general rTMS treatment protocol will be the same for both groups and will consist of 2 stimulation sessions per day, separated by ~30min, for 5 days (10 total stimulation sessions per treatment protocol). The sham protocol will be the same except the sham rTMS coil will be used. Participants will be randomly assigned to groups and complete the 2 conditions (active vs. sham rTMS) in random order.
| Arm | Type | Receives |
|---|---|---|
| Active 10 Hz dlPFC rTMS | Experimental | Device: rTMS10 Hz dorsolateral prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) |
| Sham dlPFC rTMS | Sham comparator | Device: rTMSinactive dorsolateral prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) |
| Active 1 Hz mPFC rTMS | Experimental | Device: rTMS1 Hz medial prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) |
| Sham mPFC | Sham comparator | Device: rTMSinactive medial prefrontal cortex stimulation for 10 sessions (2 sessions/day X 5 days) |
Who may qualify
- Ages
- 21 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Meet DSM-5 criteria for OUD;
- In methadone or buprenorphine treatment
- Age 21-70 yr;
- Right handed;
- Males and non-pregnant/non-lactating females;
Key exclusion criteria (12 listed)
- Acutely under the influence of any substance (except methadone or buprenorphine) during session;
- Current, regular (>2 times/week) use of illicit drugs other than opioids (except cannabis);
- Any past 24 hour use of drugs other than opioids or nicotine;
- Urinalysis positive for pregnancy;
- Medical conditions prohibiting use of rTMS;
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 |
|---|---|---|
| rTMSRepetitive transcranial magnetic stimulation | Device | Active 1 Hz mPFC rTMS, Active 10 Hz dlPFC rTMS, Sham dlPFC rTMS, Sham mPFC |
Primary outcome
Wisconsin Card Sorting Task perseverance score
Time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Wisconsin Card Sorting Task perseverance measures cognitive flexibility as an index of executive function. Higher scores reflect better outcome.
Emotional Arousal task rating
Time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Average unpleasantness and arousal ratings in response to aversive pictures from the International Affective Picture System (IAPS). Lower unpleasantness and arousal scores reflect better outcome.
Opioid progressive ratio breakpoint
Time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Opioid ($10 unit dose) vs. money ($2) hypothetical 10-trial choice task progressive ratio breakpoint is the highest response requirement completed for the drug on an exponentially increasing schedule of reinforcement, where the subject has to click the mouse an increasing number of times to earn drug or money. Lower breakpoint scores reflect better outcome.
Treatment success
Time frame: change from sham to active condition (randomized to occur on days 6-12 and 18-24, respectively)
Number of days of opioid use (based on timeline followback interview) during the 7 days following each 5-day rTMS (active and sham) period. Fewer days of opioid use reflect better outcome.
4 secondary outcomes
Digit Span total score
Time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Monetary delay discounting
Time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
State-Trait Anxiety Inventory state anxiety total score
Time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
Positive and Negative Affect Scale total score
Time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions
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. This study is not recruiting at the moment.
Mark K Greenwald, PhD study director
Wayne State University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing 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 12 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: under way, not looking for participants, 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.
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?
Wisconsin Card Sorting Task perseverance score (time frame: change from pre-intervention (day 0) to post-intervention (day 5) in the sham and active conditions). The study lists 4 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.