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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This preliminary study is designed to evaluate mechanisms by which excitatory dorsolateral prefrontal cortex (dlPFC) repetitive transcranial magnetic stimulation (rTMS) (vs. sham) and pharmacological stress (vs. placebo) alter behavior in non-treatment seeking individuals with opioid use disorder (OUD). Specific Aims are to (1) Evaluate how stress impacts domains of behavior including (1a) executive function and (1b) opioid-seeking behavior; and (2) Determine whether rTMS stimulation attenuates (2a) executive dysfunction, (2b) stress-reactivity, and (2c) opioid-seeking in individuals with OUD not receiving treatment.

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.

What data supports the effectiveness of this treatment for opioid use disorder?

Repetitive transcranial magnetic stimulation (rTMS) has shown potential in reducing cravings and improving symptoms like depression and impulse control in individuals with opioid use disorder, although its impact on actual drug use is less clear. Additionally, rTMS has been effective in treating other substance dependencies, suggesting it may help with opioid use disorder as well. ^{1 2 3 4 5}

Is rTMS safe for treating opioid use disorder?

Repetitive transcranial magnetic stimulation (rTMS) has been used safely in studies for opioid use disorder and other conditions, with no significant adverse events reported. It is a non-invasive procedure that uses magnetic fields to stimulate specific areas of the brain. ^{2 4 5 6 7}

How does the treatment of Stress Pharmacotherapy + rTMS for Opioid Use Disorder differ from other treatments?

This treatment is unique because it combines stress pharmacotherapy with repetitive transcranial magnetic stimulation (rTMS), a non-invasive method that uses magnetic fields to stimulate specific brain areas. Unlike traditional drug treatments, rTMS targets neural circuits involved in addiction, potentially improving mood, impulse control, and attention without the use of medication. ^{2 3 4 8 9}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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) 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]

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) 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Modulating Neural Circuits with Transcranial Magnetic Stimulation: Implications for Addiction Treatment Development. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Default mode network mechanisms of repeated transcranial magnetic stimulation in heroin addiction. [2023]

3. England 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. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Add-on repetitive transcranial magnetic stimulation in patients with opioid use disorder undergoing methadone maintenance therapy. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Treating cocaine and opioid use disorder with transcranial magnetic stimulation: A path forward. [2023]

6. Ireland 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. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: A pilot study. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Transcranial Magnetic Stimulation as a Tool to Promote Smoking Cessation and Decrease Drug and Alcohol Use. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Chronic repetitive transcranial magnetic stimulation (rTMS) on sleeping quality and mood status in drug dependent male inpatients during abstinence. [2020]