The main purpose of this study is to learn how stimulating a region in the brain influences craving and opioid use. The brain will be stimulated using TMS. Participants may choose to receive brain imaging (magnetic resonance imaging, MRI) as part of this study. The MRI will be used to identify areas in the brain that to stimulate and to measure brain changes as a result of TMS.

Participants will be asked to attend a total of 12 visits over about 5 months. Each visit will last between 1-2 hours with breaks. The study will involve interviews, questionnaires, computer tasks, TMS, and optional MRIs.

There are minor risks associated with this study. Answering some of the study questionnaires may cause stress or fatigue. The physical risks of TMS are low. Participants may experience mild pain or headache during or after receiving TMS. These symptoms may extend to adjacent areas of the face. The discomfort may be associated with twitching or movement of these areas during stimulation. This is generally transient and can be treated with over-the-counter pain medication. To minimize any risk of hearing loss during TMS, participants wear earplugs for the entire procedure. An evaluation of the participant's medical history will also be completed to ensure that it will be safe for participants to receive TMS. There is no direct benefit to participants from being in this study. However, participation may help others in the future as a result of knowledge gained from the research. The physical risks of the optional MRI are minimal, and a health questionnaire will be filled out before to determine if it is safe for participants to complete the MRI.

Confidentiality:

All efforts, within reason, will be made to keep personal information in participants' research records confidential but total confidentiality cannot be guaranteed. Documents containing identifiable subject information, like this consent form, will be stored in locked filing cabinets located in the Departments of Psychiatry and Radiology at Vanderbilt. Electronic files containing identifiable information will be stored on password protected systems at Vanderbilt. If a Week 10, 12, or 20 study visit is conducted over video-conferencing, links to the video-call will be sent only to the research participant and approved staff. Video-calls will take place in private locations where the risk of someone hearing or seeing the research visit is minimized. Subjects will be assigned a numeric code that will be used to label all research data, including brain imaging scans. Only Dr. Ward and approved research staff will have access to this data. Only de-identified data will be stored on this server.

Disclosures that participants consent to in this document are not protected. This includes putting research data in the medical record or sharing research data for this study or future research. Disclosures that participants make are also not protected.

Privacy:

Any samples and information about participants may be made available to others to use for research. To protect privacy, participant's name's will not be released. Participants will not receive any benefit as a result of the tests done on samples. These tests may help us or other researchers learn more about the causes, risks, treatments, or how to prevent this and other health problems.

Study Results:

Participant's individual study results will not be shared with them. The final results of the study will potentially be published in the scientific literature.

Opioid Use Disorder is a Public Health Crisis with a High Risk of Relapse Worldwide, opioid use disorder (OUD) affects >16 million people annually, and >300 people/day die from overdose. Buprenorphine is an effective medication for OUD that reduces use, relapse, and mortality. However, within 6 months of starting buprenorphine, only 50% continue treatment and 91% will relapse. The 3-month period following buprenorphine initiation is highest risk for treatment discontinuation and relapse. Those who discontinue treatment have high risk of relapse and overdose. Thus, personalized interventions in the period following buprenorphine initiation may improve retention and reduce relapse. The strongest predictor of relapse is craving, defined as a "strong desire for drugs,". Following buprenorphine initiation, craving remains the top predictor of relapse. Relapse occurs when the urge to use (i.e., craving) is outweighed by the ability to resist that urge (i.e. inhibitory control). Higher inhibitory control is associated with less craving and less relapse. After an acute period of abstinence, individuals with OUD continue to struggle with craving, poor inhibitory control, depression, pain, and sleep disturbance, even with buprenorphine treatment. Both patients (The Voice of the Patient: A Series of Reports From the US Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative: Opioid Use Disorder 2018) and experts have called for novel, symptom-specific interventions that enable personalized treatment of these refractory symptoms of OUD. Craving and inhibitory control can be readily measured and quantified using broadly available behavioral tasks (e.g., cue reactivity, go/no-go) and are targets for intervention.

Substance Use Disorder Symptoms are Linked to Brain Circuit Dysfunction The brain correlates of craving and inhibitory control are well-established in frontal-striatal circuitry, and it is well-known that individuals with substance use disorders have dysfunction in these circuits. Craving and impaired inhibitory control have been linked to decreased functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and dorsal striatum. Therefore, modulating connectivity in this circuit may serve as effective interventions to treat substance use disorders.

iTBS is an FDA-Approved Treatment for Depression with Promising Applications for OUD. Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive brain stimulation that uses electromagnetic fields to temporarily change neuronal patterns of connectivity in brain networks. When international safety guidelines are followed, rTMS is a safe and well-tolerated intervention in individuals with and without psychiatric illness. rTMS is also a versatile research tool whose stimulation parameters can be changed. Depending on the parameters, rTMS can increase or decrease brain activity. Specifically, intermittent theta burst stimulation (iTBS) tends to increase brain activity, while continuous theta burst stimulation (cTBS) tends to decrease brain activity.

rTMS is FDA-approved for the treatment of major depressive disorder, obsessive-compulsive disorder, and smoking cessation. rTMS has also shown promising results in research studies as a potential treatment for substance use disorders. Multiple systematic reviews have observed that rTMS reduces substance use and craving across substance use disorders, including OUD.

In studies of rTMS for OUD, the majority of trials have applied high frequency (10-20 Hz) rTMS or iTBS to the L DLPFC and observed significant reductions in craving and opioid use. It is hypothesized that applying high frequency (10-20 Hz) rTMS or iTBS to the L DLPFC will increase DLPFC activation and increase connectivity between the DLPFC and dorsal striatum, thereby improving inhibitory control and reducing craving and opioid use. In preliminary data for this proposal, a single session of iTBS applied to the L DLPFC in individuals with OUD receiving medication for OUD significantly reduced craving (n=30, p<.03).

Therefore, in this protocol, this intervention will be scaled-up to deliver a total of 16 sessions of iTBS to the L DLPFC to rescue impaired L DLPFC activity in OUD to reduce opioid craving and opioid use. This will test this intervention in a population of individuals with OUD who are currently taking buprenorphine, the most commonly used medication for OUD. iTBS applied to the L DLPFC is an FDA-approved treatment for depression. When international safety guidelines are followed, rTMS is a safe and well-tolerated intervention for people with and without substance use disorders.

In most clinical and research protocols, iTBS is applied in daily sessions for 4-6 weeks. In one of the FDA-approved protocols for depression, iTBS is applied 10-times per day for 5 consecutive days, totaling 50 sessions. In this study, 16 sessions of iTBS (2 per day x 8 weeks) will be applied to individuals with OUD using the same FDA-approved parameters approved for depression. It is believed that weekly sessions will enhance feasibility of this intervention for an OUD population, as previous studies have shown that individuals with SUDs have difficulty attending daily TMS sessions.

The central hypothesis is this: Opioid craving and use can be reduced with iTBS when applied to individuals with OUD. This study seeks to provide evidence that L DLFPC-targeted iTBS leads to reduced craving and opioid use in individuals with OUD. If successful, this will have identified a safe, effective, and broadly applicable adjunctive treatment to reduce craving and relapse for people with OUD - a devastating disease with deadly consequences and partially-effective treatments.

This is a randomized, sham-controlled trial testing the effect of an FDA-approved protocol (L DLPFC-targeted iTBS) on craving and opioid use in individuals with OUD who are taking buprenorphine. This is a multisite study where VUMC is both the Coordinating Site and a recruiting site. This study will enroll up to 60 individuals with OUD at VUMC to obtain a completion sample of n=50. Across all sites, there will be a completion sample of n=100.

The principal aim of this investigation is:

Aim 1: Determine the effects of active L DLPFC-targeted iTBS compared to sham on craving and opioid use in people with OUD (n=100).

As an exploratory analysis, it will also determine if L DLPFC functional connectivity change is associated with change in craving (n=50).

Individuals who between the ages of 18-65 and who have been diagnosed with OUD and in stable psychiatric outpatient treatment with buprenorphine will be enrolled in the present study. An international TMS consensus group determined that there were no additional risks of major adverse events, including seizures, in individuals with psychiatric disorders. Neither opioid use nor buprenorphine are associated with increased seizure risk or alterations in seizure threshold.

Indeed, in the meta-analysis of the safety of rTMS for substance use disorders, the prevalence of rTMS-induced seizure was approximately 1/1000, which was not significantly different from the seizure risk in the general population. There have been no rTMS-induced seizures in anyone with OUD.

rTMS is FDA-approved for treatment depression in adolescents down to age 15. However, there is a lack of data on the use of rTMS for substance use disorders in adolescents. For this reason children and teens under the age of 18 will be excluded. The same rationale applies to the exclusion based on race, gender, or ethnic background. If, as the study progresses, it is found that a representative population is not being entered into the study with respect to gender and race, recruitment methods will be reviewed.

Up to 60 individuals with OUD will be enrolled taking buprenorphine in a randomized, sham-controlled trial of L DLFPC-targeted iTBS. Prospective participants who meet inclusion and exclusion criteria will be entered into the study.

Participants will undergo an initial phone screening session. Following the phone screening, this study consists of 12 study visits. At the first visit (Consent), participants will complete informed consent. After completing consent, participants will undergo additional screening procedures to ensure safety to under rTMS and MRI (if participants elects to complete the Optional MRIs) and will complete questionnaires about substance use and psychiatric symptoms.

Enrolled participants will then undergo 8 weekly sessions of L DLPFC-targeted iTBS. Prior to the first TMS visit, individuals will be randomized to receive active or sham iTBS. For the sham condition, the iTBS coil will be flipped 180 degrees so that the sham iTBS looks and sounds like active iTBS but delivers no actual significant stimulation to the participant. At each TMS visit, participants will complete questionnaires about their substance use and psychiatric symptoms and provide a sample for urine toxicology.

After the 8-week TMS intervention, participants will return for visits at weeks 10, 12, and 20. At each follow-up visit, participants will complete questionnaires about their substance use and psychiatric symptoms and provide a sample for urine toxicology.

If a participant elects to undergo the Optional MRI visits, they will undergo 2 MRI scans 1) before the first TMS visit; and 2) after the week 8 TMS visit. The MRI scan includes structural and resting-state functional magnetic resonance imaging (rsfMRI). During both MRI scans, participants will also perform a cognitive task.

The primary endpoint will be to use a paired t-test comparing changes in craving and opioid use between active and sham iTBS.

After the week 20 visit, participants who were randomized to receive sham stimulation will be offered the opportunity to receive active FDA-approved L DLPFC-targeted iTBS for 8 weeks.

The PI is a board-certified psychiatrist and internationally recognized expert in the use of rTMS for substance use disorders. She has served as PI on multiple clinical trials of rTMS for substance use disorders, including at VUMC, where she is Director of Neuromodulation Research. All rTMS has been well-tolerated, and there have been no severe adverse events related to rTMS, including no seizures, hospitalizations, or medical treatments. The personal experience is consistent with the vast literature on the safety of rTMS in substance use disorders.

rTMS has been studied in thousands of people with substance use disorders (n = 2,865 participants), including OUD, with no evidence of increased risk of psychiatric or medical adverse events. rTMS has been studied extensively in substance use disorder populations with no evidence of increased medical or psychiatric risk. The Safety of TMS Consensus Group recommended, "available data indicate no additional risks of major AEs [adverse events] in specific patient populations [including OUD] so this is not a concern that needs to be taken into account".

In a meta-analysis examining the prevalence of seizure with rTMS for substance use disorders, the prevalence of rTMS-induced seizure was approximately 1/1000, which was not significantly different from the seizure risk in the general population. Moreover, there were no seizures observed in OUD, providing reassuring evidence that there is no increased risk of rTMS-induced seizure in an OUD population.

All rTMS will be administered according to an FDA-approved protocol for depression that applies iTBS to the L DLPFC. rTMS is already FDA-approved for treatment of substance use disorder (nicotine). Compared to nicotine use, opioid use does not represent an increased risk for any rTMS-induced side effect, including seizure. Importantly, opioid use or treatment for OUD is NOT a contraindication to FDA-approved iTBS for depression, meaning that individuals with OUD and depression receive FDA-approved iTBS to the L DLPFC for depression in the community.

Moreover, the FDA has repeatedly determined rTMS for substance use disorder is a Non-Significant Risk intervention and therefore does not require an Investigational Device Exemption (IDE), including in multiple FDA submissions by the PI Dr. Ward from VUMC, including: 1) New IDE Application of rTMS for substance use disorder, where the IDE was denied because rTMS was determined to be Non-Significant Risk; and 2) Q-Submission Pre-Submission a Risk Determination of an 8-Week rTMS Intervention for substance use disorder, where the FDA determined rTMS was Non-Significant Risk.

Potential research participants will be asked if they would like to participate in the current study. If they report potential interest, a pre-screening will occur. This screening will occur over the phone or in person using the Telephone Screen. Per the Telephone Screen, research staff will record whether or not they meet criteria in general, are interested in participating, and appropriate contact information for setting up the first study visit. Informed consent will be obtained by study personnel directly involved in the research (i.e. research staff or PI). Personnel have completed IRB training and have considerable experience running studies in clinical populations.

Informed consent Once pre-screening has occurred, informed consent will be obtained during the first study visit. A research staff member will explain the applicable procedures and the possible risks and benefits to the participants. The details of the informed consent procedure are as follows: Participants will be consented on location to assure privacy. Only when the participant declares that they are comfortable with all aspects will the participant be allowed to offer consent. The informed consent form will be signed by the participant and a member of the study staff. The consent form will be signed and, a copy of the signed consent will be provided to the participant.

1. Optional MRI If, after completing the consenting process, the participant elects to undergo an MRI scan, the participant will be scheduled for a separate MRI study visit before starting TMS. MRI scans of the brain will be obtained using the MRI scanners in the Center for Human Studies in the Vanderbilt University Institute for Imaging Science (VUIIS), located in the Vanderbilt Hospital and Medical Center North. Prior to each scan, the participant will complete the MRI Procedure Screening Form. The purpose of this form is to ensure that there are no implanted medical devices or metals that could injure the participant if exposed to a high magnetic field. This form will be filled out in a private room adjacent to the MRI scanner and reviewed by the MRI Technologist and the research assistant.

2. TMS Visits (Weeks 1-8) Participants will receive 8 weekly sessions of FDA-approved L DLPFC-targeted iTBS (Weeks 1-8). Prior to the first TMS visit, individuals will be randomized to receive active or sham iTBS. For the sham condition, the iTBS coil will be flipped 180 degrees so that the sham iTBS looks and sounds like active iTBS but delivers no actual stimulation to the participant.

   At each TMS visit, participants will receive 2 sessions of iTBS separated by 50 minutes, as in the FDA-approved protocol for depression. Participants will complete questionnaires during the 50-minute break, allowing for maximum efficiency. All rTMS will be administered at the Vanderbilt Psychiatric Hospital. The MagPro coil used in this study targeting the L DLPFC is FDA-approved for treatment of depression.

   Participants will have motor threshold determination before the first rTMS of the day. Single pulse and repetitive stimulation will be performed with a MagPro stimulator (MagVenture) equipped with a biphasic figure-of-eight coil. To obtain an active motor threshold, single pulses will be used in the following manner: The TMS coil will be placed on the scalp. TMS pulses are applied over the hand area of the left motor cortex and individually localized for each participant based on the optimal position for eliciting a visible finger twitch. When possible, neuronavigation will be used to record the motor 'hot-spot.' Resting motor threshold (RMT) will be obtained by following recommendations from the International Federation of Clinical Neurophysiology.

3. Weeks 10, 12, and 20 Visits

Approximately two weeks after completing the Week 8 TMS Visit, participants will return for a Week 10 follow-up visit. At this visit, the following procedures will be completed: The same study procedures will occur for the Weeks 12 and 20 visits, which will occur approximately 1 month and 3 months after completing the Week 8 TMS visit.

If the participant is unable to attend an in-person visit, these visits may be conducted by telephone or HIPAA-compliant video conferencing.

3a. Optional MRI #2 If the participant has elected to undergo MRI scanning, the participant will be scheduled for a separate MRI study visit after completing TMS. As in Optional MRI #1, the MRI will take place at the Vanderbilt University Institute for Imaging Science (VUIIS). Study procedures will be identical to those in the Optional MRI #1. This MRI will collect structural and resting-state functional data, cognitive assessments, and physiological measures (pulse and breathing). Outside of the scanner, participants will perform cognitive tasks, as in visit #1. Participants will also provide a sample for urine toxicology.

4. Optional Open-Label L DLFPC-Targeted iTBS for Sham Participants After participants complete the week 20 visit, each participant will be informed if they received active or sham iTBS. Individuals who received sham iTBS will be offered the opportunity to receive 8 weekly sessions of open-label active iTBS and complete the same questionnaires.

5. MRI Safety Screen: This questionnaire, developed by the VUIIS, assesses the safety of MRI.

6. Test Measures Descriptions TMS Safety Screen: This questionnaire was developed based on expert recommendations to assess the safety of rTMS administration for a given individual. Specifically, it assesses a history of seizures and risk factors for seizure (e.g. head trauma). Individuals with risk factors for seizure will be excluded.

SCID: The Structured Clinical Interview for the DSM is a clinician-administered interview used to determine diagnosis of a psychiatric disorder. Module E will be used to assess for a diagnosis of OUD. Other modules will be used as necessary to evaluate for psychosis or bipolar disorder.

DSM-5-TR Self-Rated Cross-Cutting Symptom Measure: The DSM-5 Screener is a 23-item self-report questionnaire developed by the American Psychiatric Association to screen for a broad range of psychiatric disorders. It will be used by the clinician to determine need to further assess for a psychotic disorder or bipolar disorder.

MINI Bipolar Module: The MINI Bipolar Disorder Module is a clinical interview that assesses lifetime history of mania and (if positive) obtains additional information about current and past episodes. If a participant reports a history of bipolar disorder or screens positive in the DSM-5 Screener, then the MINI Bipolar Module will be completed.

Opioid Use History: This questionnaire asks participants about their current and lifetime opioid use.

Stages of Change: This 19-item self-report questionnaire assesses stages of change readiness and treatment eagerness.

Timeline Followback (TLFB): The TLFB is a self-report measure of tobacco use over the past several weeks that is used to assess smoking behavior and abstinence.

Brief Addiction Monitor (BAM): The BAM is a self-report measure of substance use over the past 30 days that is used to assess addiction severity.

Recent Substance Use: This questionnaire asks participants about all forms of opioids and other substance use in the past 24 hours. Individuals who report illicit use of substances that increase seizure risk (benzodiazepines, cocaine, amphetamine, methamphetamine) on this questionnaire will not be permitted to receive rTMS that day.

Readiness to Change Questionnaire: This self-report questionnaire assesses an individual's readiness to change their opioid use.

Time to Relapse Questionnaire (TRQ): The TRQ is a 33-item (or 20- or 9-item) self-report questionnaire that assesses the time from the initial thought of drug use to actual use.

Opioid Craving Scale (OCS): The OCS is a self-reported 3-item instrument craving for opioids.

Subjective Opiate Withdrawal Scale (SOWS): The SOWS is a 16-item self-report questionnaire that assesses severity of opioid withdrawal symptoms (Handelsman et al. 1987).

Beck Depression Inventory (BDI): The BDI is a 21-item self-report questionnaire that assesses depressive symptoms over the past few days.

State-Trait Anxiety Inventory (STAI): The STAI is a 40-item self-report to assess state and trait anxiety using a Likert Scale. Only use the 20-item state anxiety form will be used, which takes 5 minutes to complete.

Brief Pain Inventory (BPI): The BPI is a 9-item self-report questionnaire that assesses lifetime history of pain and pain in the last 24 hours.

PTSD Checklist for DSM-5 (PCL-5): The PCL-5 is a 20-item self-report questionnaire that assess trauma symptoms over the past month.

TMS Acute Side Effects Questionnaire: This questionnaire assesses participants for both common as well as rarer side effects of TMS including change in mood.

The following Assessments will only occur at Optional MRI #1 and Optional MRI #2:

Cue-Reactivity Task. The cue-reactivity task is commonly used to measure drug-cue induced craving responses. In this task, participants will be presented with a series of images, including heroin/fentanyl-specific, prescription opioid-specific, and neutral images using a stimulus presentation software program while in the MRI scanner. Participants will be briefly presented with each image and then will complete ratings of opioid craving.

Drug Word Stroop Task. Outside of the scanner, inhibitory control and attentional bias to drug-related stimuli with the Drug Word Stroop task will be measured. Participants are presented with a list of drug-related words (e.g. pill) and neutral words (e.g. field) displayed in different colors. Attentional bias to drug stimuli is measured by comparing response time to drug-related words compared to neutral words. This task will be performed in the MRI.

Signal Detection Task: A signal detection task, designed to measure shift in responding toward a differentially (more) rewarded stimulus will be administered. In this task, participants will respond to earn hypothetical earnings and are instructed to try to win as much as possible. For each trial, participants will be asked to choose which of two stimuli (short or long mouth) was presented on a previously mouthless cartoon face by making a corresponding response on a keyboard. Critically, the difference between mouth sizes (11.5 mm vs 13 mm) and the stimulus exposure time (100 ms) is small, making the participants' choice difficult and thus allowing the development of a response bias. An asymmetric reinforce ratio will be used to elicit a response bias. Correct identification of one stimulus will be rewarded (Correct!!) three times more frequently ("rich stimulus") compared with correct identification of the other stimulus ("lean stimulus"). They will be specifically instructed that not all correct responses would receive reward feedback, that lack of feedback did not indicate inaccuracy, and that they would receive no feedback for errors. They will not be informed about the differential reward schedule. Prior studies with this paradigm have shown that unequal frequency of reward to correct to the more frequently (rich) versus less frequently rewarded (lean) stimulus procedures produces a systematic preference for the response paired with the more frequent reward. Performance will be analyzed in terms of response bias, an index of the tendency to choose the more rewarded stimulus and an objective assessment of reward responsiveness. Control analyses will be performed for accuracy, discriminability of the stimuli, and reaction time, which provide information about overall task performance. Overall, this procedure will be similar to the work presented by Bogdan and Pizzagalli.

The questionnaires and tasks employed as part of the proposed protocol may cause some participants to feel frustrated, bored or upset. It might also cause them to feel dysphoric as it may remind them of their clinical symptoms. Similarly, if patients feel they performed poorly on the tasks this has the potential to adversely affect their mood.

The staff has expertise with this type of testing in a range of patient populations and ample experience with discussing processes and results of these sorts of tests with patients. Testing sessions will be appropriately set up and monitored to prevent distress and staff will be available to speak with any patients who experience distress.

Social risks to participants in this experiment are extremely unlikely. The identity of participants will be protected and any personal information relating to the participants will be safely guarded. The probability of social harm to the participants resulting from participation in this experiment is extremely low.

Data will be collected on hard copies and electronic media. Electronic databases (Redcap) will be stored on password protected systems. Hard copies of research data will be stored in a locked filing cabinet located within the Psychiatric Neuroimaging Program offices or Neuromodulation Lab located at the Vanderbilt Psychiatric Hospital and offices of the department of Radiology (copies of MRI screening and consent forms). Information will be maintained indefinitely. Only the PI and member of her research staff will have access to the information.

Data obtained from neuropsychological/computerized testing and mood assessments/structured interviews is acquired on a one-on-one basis. All paper data acquired (i.e. completed test forms) will be stored in a locked cabinet located in the Neuromodulation Lab or Psychiatric Neuroimaging Program offices. Only study personnel, including the PI, will have access to paper data. Electronic data, including data entered into a spreadsheet, computerized testing, brain imaging data, will be stored on the PI's data analysis system located at the Vanderbilt Psychiatric Hospital. Each participant will be given a study-specific participant ID which will be used to identify records instead of their name. Access to this system is password protected. Only approved research personnel and the PI will have access to electronic data.

This is a multi-site study, where other sites have obtained separate IRB approval. VUMC will serve as the coordinating site responsible for data analysis and publication. As such, all sites will enter data into a shared, secure REDCap database hosted and managed by VUMC.

All paper information obtained in this study will be kept in a research office under lock and key at VUMC. Research participants will be identified with a 3-digit code. All databases related to the study will be stored on a password protected computer network accessible only from a laboratory kept under lock and key. Only study staff will have access to this information. Identifying data will not be shared with researchers outside of VUMC.

A secure Database will be implemented in REDCap for behavioral data, and in XNAT for MRI data. Data will be database freed of all personal identifiers. A unique code number will be assigned to each participant allowing linking between REDCap and XNAT databases. VUIIS and ACCRE will be instrumental in establishing and maintaining a secure database and repository of all the data collected.

The duration of this study is 4 years. The PI will maintain study information indefinitely according to the procedures described in Section 9.0. This includes electronic (RedCap) and paper storage in locked cabinets in the Vanderbilt Psychiatric Hospital.

Inclusion Criteria:

• Age between 18-65 years
• Diagnosis of OUD according to DSM-5 criteria and confirmed by SCID
• Started taking buprenorphine for OUD in the past 12 months and had return to use of opioids in the past 12 months
• Must be able to read, speak and understand English
• Must be judged by study staff to be capable of completing the study procedures
• Participants will be in stable outpatient psychiatric treatment and psychiatrically stable.

Exclusion Criteria:

• DSM-5 intellectual disability
• Substance use disorder (other than opioid, nicotine, or cannabis) within the past three months
• Current, active suicidal ideation with intent or plan
• Positive urine drug screen for illicit substance use that can increase seizure risk (cocaine, benzodiazepines, amphetamine, methamphetamine)
• History of psychosis in the past 3 months or diagnosis of a primary psychotic disorder
• Any history of a progressive or genetic neurologic disorder (e.g. Parkinson's disease, multiple sclerosis, tuberous sclerosis, Alzheimer's Disease) or acquired neurological disease (e.g. stroke, traumatic brain injury, tumor), including intracranial lesions
• History of head trauma resulting in any loss of consciousness (>15 minutes) or neurological sequelae
• Current history of poorly controlled headaches including chronic medication for migraine prevention
• History of fainting spells of unknown or undetermined etiology that might constitute seizures
• History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy with the exception of a single seizure of benign etiology (e.g. febrile seizures) in the judgment of a board-certified neurologist
• Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
• Any metal in the brain or skull (excluding dental fillings) or elsewhere in the body unless cleared by the responsible covering MD (e.g. MRI compatible joint replacement)
• Any devices such as pacemaker, medication pump, nerve stimulator, TENS unit, ventriculo-peritoneal shunt unless cleared by the responsible covering MD
• All female participants of child-bearing age will be required to have a pregnancy test; any participant who is pregnant or planning to become pregnant will not be enrolled in the study
• Medications will be reviewed by the responsible covering physician and a decision about inclusion will be made based on the participant's past medical history, drug dose, history of recent medication changes or duration of treatment, and use of CNS active drugs. The published TMS guidelines review of medications to be considered with rTMS will be taken into consideration given their described effects on cortical excitability measures.
• Participants who, in the investigator's opinion, might not be suitable for the study or would be unable to tolerate the study visit

Reasonable requests for data will be considered.