Stress Pharmacotherapy + rTMS for Opioid Use Disorder

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Wayne State University

Must not be taking: Psychiatric, Pain, Blood pressure, others

Disqualifiers: Psychotic disorder, Bipolar, Anxiety, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for helping individuals with opioid use disorder (OUD). It examines the effects of stress and brain stimulation on decision-making and the urge to use opioids. Participants will receive either brain stimulation, known as repetitive Transcranial Magnetic Stimulation (rTMS), or a sham treatment, along with either a stress-inducing drug (Yohimbine + Hydrocortisone) or a placebo. The trial is suitable for those with OUD who are not currently seeking treatment and meet specific health criteria, such as having normal blood pressure and heart rate and not using other drugs. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant advancements in OUD treatment.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications, including those that lower seizure threshold, psychiatric medications, prescription pain medications, or blood pressure medications, as they are prohibited in this trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies have tested repetitive transcranial magnetic stimulation (rTMS) on individuals with opioid use disorder. These studies show that rTMS is generally well-tolerated. Most participants did not experience serious side effects, though some reported mild headaches or discomfort at the treatment site.

Research on the combined use of yohimbine and hydrocortisone shows a different safety profile. Yohimbine can cause stress-like reactions and may increase opioid cravings in some individuals. It has triggered withdrawal symptoms or anxiety in those taking methadone, a treatment for opioid addiction. This combination requires caution, as it might not suit everyone.

Overall, while rTMS appears quite safe, yohimbine and hydrocortisone have a higher likelihood of causing uncomfortable side effects. Participants should consider these factors when deciding whether to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for opioid use disorder because they combine stress pharmacotherapy with repetitive transcranial magnetic stimulation (rTMS), offering a novel approach compared to traditional methods like medication-assisted treatment (MAT) with methadone or buprenorphine. Unlike these standard options, rTMS uses magnetic fields to stimulate specific brain regions, potentially reducing cravings and withdrawal symptoms without the need for drugs. Additionally, the use of yohimbine and hydrocortisone as stressors is intended to enhance the brain's response to rTMS, offering a unique way to target stress-related relapse triggers. This combination has the potential to provide a non-invasive, drug-free alternative to existing treatments, which is why researchers are eager to see how effective it can be.

What evidence suggests that this trial's treatments could be effective for opioid use disorder?

Research has shown that repetitive transcranial magnetic stimulation (rTMS) can help reduce cravings in people with opioid use disorder (OUD). Studies have found that targeting the left dorsolateral prefrontal cortex (dlPFC) with rTMS can decrease the desire to use opioids and reduce overall substance use. In this trial, some participants will receive active rTMS, while others will receive sham rTMS as part of different treatment arms.

Conversely, the combination of yohimbine and hydrocortisone is known to increase stress and opioid cravings. Researchers use this combination to understand how stress influences the urge to seek opioids, often worsening withdrawal symptoms. In this trial, some participants will receive the active stressor (yohimbine and hydrocortisone) to help researchers learn about the role of stress in addiction, while others will receive a placebo stressor. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

This trial is for right-handed individuals aged 21-60 with opioid use disorder who are not seeking treatment. They must have a stable heart rate and blood pressure, consume alcohol or marijuana minimally, and be cognitively intact. Exclusions include pregnancy, certain drug use, seizure history, unstable illnesses, lactose intolerance, recent participation in other studies, and specific mental health diagnoses.

Inclusion Criteria

Right handed

You have been diagnosed with opioid use disorder according to the DSM-5 guidelines.

I am between 21 and 60 years old.

Exclusion Criteria

You are not allowed to be under the influence of any drugs or alcohol during the session.

Past-month participation in a research study.

Urinalysis positive for cocaine metabolites, benzodiazepines, barbiturates, amphetamines or pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 4 sessions of rTMS and pharmacological stress interventions in a randomized crossover design

4 weeks

4 sessions (in-person), each separated by at least 1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Active rTMS
• Placebo
• Sham rTMS
• Yohimbine + Hydrocortisone

Trial Overview The study tests how rTMS (a non-invasive brain stimulation) versus sham (fake treatment) combined with pharmacological stress (using Yohimbine + Hydrocortisone vs placebo) affects executive function and opioid-seeking behavior in people with OUD. It aims to see if rTMS can reduce the negative effects of stress on behavior.

How Is the Trial Designed?

Group I: placebo stressor, active rTMS Experimental Treatment 2 Interventions

Placebo stressor (lactose) + active 10Hz rTMS over the left dlPFC

Group II: active stressor, sham rTMS Experimental Treatment 2 Interventions

Stressor (yohimbine 54mg + hydrocortisone 20mg) + sham (inactive) rTMS over the left dlPFC

Group III: active stressor, active rTMS Experimental Treatment 2 Interventions

Stressor (yohimbine 54mg + hydrocortisone 20mg) + active 10Hz rTMS over the left dlPFC

Group IV: placebo stressor, sham rTMS Placebo Group 2 Interventions

Placebo stressor (lactose) + sham (inactive) rTMS over the left dlPFC

Who Is Running the Clinical Trial?

Wayne State University

Lead Sponsor

Trials

318

Recruited

111,000+

Published Research Related to This Trial

In a study of 30 heroin-dependent individuals receiving 10 sessions of rTMS over one week, treatment significantly reduced cravings and withdrawal symptoms, indicating its efficacy in managing addiction.

The study found that rTMS altered the coupling between brain regions in the default mode network, particularly the left inferior parietal lobe, which correlated with reduced cravings, suggesting a potential mechanism for its anti-craving effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Default mode network mechanisms of repeated transcranial magnetic stimulation in heroin addiction. Jin, L., Yuan, M., Zhang, W., et al.[2023]

In a study involving 10 methamphetamine-dependent users and 8 healthy controls, low-frequency rTMS (1 Hz) of the left DLPFC significantly increased self-reported craving for methamphetamine in users compared to sham stimulation, indicating a potential mechanism for craving modulation.

The rTMS procedure was found to be safe and tolerable for all participants, suggesting that while it may enhance craving in certain individuals, it does not pose immediate safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex transiently increases cue-induced craving for methamphetamine: a preliminary study. Li, X., Malcolm, RJ., Huebner, K., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) shows promise as a noninvasive treatment for substance use disorders (SUDs) like cocaine and opioid use disorders by inducing neuroplastic changes in the brain, which can help reduce cravings and drug use.

The field faces several 'known unknowns' that need to be addressed to optimize rTMS for SUDs, including selecting the right cortical targets, understanding subcortical circuit engagement, and determining the best treatment sequences, highlighting the need for collaborative research efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating cocaine and opioid use disorder with transcranial magnetic stimulation: A path forward. Steele, VR., Maxwell, AM.[2023]

Excitatory repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral pre-frontal cortex significantly reduces craving for substances in patients with dependence, with a strong effect size (Hedges' g = -0.62) based on a meta-analysis of 26 randomized controlled trials involving 748 participants.

In addition to reducing cravings, rTMS also effectively decreases substance consumption, particularly when using excitatory stimulation protocols, indicating its potential as a therapeutic intervention for substance dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of repetitive transcranial magnetic stimulation (rTMS) on craving and substance consumption in patients with substance dependence: a systematic review and meta-analysis. Zhang, JJQ., Fong, KNK., Ouyang, RG., et al.[2020]

Transcranial magnetic stimulation (TMS) is emerging as a promising noninvasive treatment for substance dependence, potentially filling a gap in addiction therapies, as it is already FDA-approved for depression.

Repetitive TMS (rTMS) has shown potential in altering behavior and brain activity related to addiction, and future studies may benefit from combining rTMS with medications and cognitive behavioral therapies to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulating Neural Circuits with Transcranial Magnetic Stimulation: Implications for Addiction Treatment Development. Hanlon, CA., Dowdle, LT., Henderson, JS.[2019]

In a pilot trial involving 22 participants with opioid use disorder undergoing methadone maintenance therapy, repetitive transcranial magnetic stimulation (rTMS) did not significantly reduce cravings or heroin use compared to a sham treatment.

However, rTMS was associated with significant improvements in depressive symptoms, impulse control, and attention, suggesting potential benefits for mental health aspects in individuals with opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Add-on repetitive transcranial magnetic stimulation in patients with opioid use disorder undergoing methadone maintenance therapy. Tsai, TY., Wang, TY., Liu, YC., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive treatment recently approved for smoking cessation, showing promise in reducing cravings and consumption in various substance use disorders (SUDs).

The therapeutic efficacy of rTMS is thought to involve modulation of neural circuits related to executive control and salience, particularly targeting areas like the dorsolateral prefrontal cortex (DLPFC) and insula, although further research is needed to explore its potential direct effects on dopamine pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial Magnetic Stimulation as a Tool to Promote Smoking Cessation and Decrease Drug and Alcohol Use. Harmelech, T., Hanlon, CA., Tendler, A.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12178270/

Deep Transcranial Magnetic Stimulation in Patients With ... This randomized controlled trial evaluated the efficacy of accelerated wide‐volume deep TMS using a double‐cone coil in patients with opioid use disorder.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2352396420301845

The effects of repetitive transcranial magnetic stimulation ... Early evidence suggests that repetitive transcranial magnetic stimulation is effective in reducing cue induced craving for patients with opioid use disorder ( ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06689072?term=rtms&viewType=Table&rank=1

Role of High Frequency RTMS in Management of Opioid ... This study aims to evaluate the role of repetitive Transcranial Magnetic Stimulation ( rTMS ) applied to the left dorsolateral prefrontal cortex (DLPFC) in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7037539/

A Case Report Illustrating the Effects of Repetitive ... The one published study on the use of repetitive TMS (rTMS) for OUD found that a single session of rTMS to the left DLPFC reduced cue-induced craving in long- ...

5. nature.com nature.com/articles/s41386-023-01776-0

A systematic review and meta-analysis of neuromodulation ... We found that rTMS reduced substance use and craving, as indicated by medium to large effect sizes (Hedge's g > 0.5). Results were most ...

6. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20240403

Assessment and Management of Concurrent Substance ... Limited data are available to inform clinicians on how to manage concurrent substance use in the context of repetitive transcranial magnetic ...

7. medrxiv.org medrxiv.org/content/10.1101/2025.10.02.25337151v1.full.pdf

Repetitive Transcranial Magnetic Stimulation in Substance ... Numerous randomized controlled trials have investigated the efficacy of TMS in tobacco, alcohol, stimulant, opioid, and cannabis use disorders.