Theta-Burst Stimulation as a Treatment for Reducing Cocaine Use

Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder

Objective: The goal of this clinical trial is to assess the tolerability of an accelerated intermittent theta burst stimulation (iTBS), a form of transcranial magnetic stimulation, intervention in participants with cocaine use disorder and then to determine if the intervention changes brain circuits related to cocaine use disorder and whether these changes relate to clinical outcomes.

The main questions it aims to answer are:

• Can individuals with cocaine use disorder tolerate accelerated iTBS (3 treatments per day for 10 days) (Pilot study)?
• Does iTBS (compared to sham iTBS) alter brain circuits related to cocaine use disorder (Expanded feasibility study)?

Researchers will compare individuals with cocaine use disorder to those without cocaine use disorder to identify differences at baseline, compare effects of the first day of iTBS treatment, and see if changes after treatment align brain circuits in those with cocaine use disorder more closely to patterns seen in those without cocaine use disorder.

Participants will:

• Undergo 10 days of iTBS treatment and two follow-up visits (1 week and 4 weeks after treatment) and complete questionnaires throughout to assess tolerability and drug use (Pilot study).
• Participants with cocaine use disorder will complete a characterization phase with questionnaires, two fMRI scans and a trial session of iTBS (sham or active) before the treatment phase (Expanded feasibility study).

Study Overview

• Status: Terminated
• Conditions: Cocaine Use Disorder; Cocaine Dependence
• Intervention / Treatment: Device: Transcranial magnetic stimulation (TMS)

Detailed Description

Background and objective: The goal of this clinical trial is to assess the tolerability of an accelerated intermittent theta burst stimulation (iTBS), a form of transcranial magnetic stimulation, intervention in participants with cocaine use disorder and then to determine if the intervention changes brain circuits related to cocaine use disorder and whether these changes relate to clinical outcomes.

The main questions it aims to answer are:

• Can individuals with cocaine use disorder tolerate accelerated iTBS (3 treatments per day for 10 days) (Pilot study)?
• Does iTBS (compared to sham iTBS) alter brain circuits related to cocaine use disorder (Expanded feasibility study)?

Researchers will compare individuals with cocaine use disorder to those without cocaine use disorder to identify differences at baseline, compare effects of the first day of iTBS treatment, and see if changes after treatment align brain circuits in those with cocaine use disorder more closely to patterns seen in those without cocaine use disorder.

Participants will:

• Undergo 10 days of iTBS treatment and two follow-up visits (1 week and 4 weeks after treatment) and complete questionnaires throughout to assess tolerability and drug use (Pilot study).
• Participants with cocaine use disorder will complete a characterization phase with questionnaires, two fMRI scans and a trial session of iTBS (sham or active) before the treatment phase (Expanded feasibility study).
• Participants with cocaine use disorder will complete a treatment phase with questionnaires, urine drug testing, two fMRI scans before and after the first day of treatment, ten days with three iTBS treatments (sham or active) each day (Expanded feasibility study).
• Participants with cocaine use disorder will complete a follow-up phase with contingency management for 11 weeks, follow-up fMRI scans 2 weeks and three months after the end of iTBS treatment and three monthly follow-up visits with urine drug testing and questionnaires after completion of the contingency management phase.
• Participants without cocaine use disorder will complete the same characterization phase as those with cocaine use disorder but will not receive a full treatment course of iTBS. Instead, they will complete the first treatment day twice, once with active and once with sham iTBS.

Study Population: Participants age 18 - 60 years of age (pilot study) and participants age 22 - 60 (Expanded Feasibility Study)

Study Design:

• Participants with cocaine dependence will receive open label iTBS in the pilot study
• Participants with cocaine dependence will receive active or sham iTBS in double blinded experiment in the Expanded Feasibility Study (EFS)
• Healthy Participants will complete the first treatment day twice and receive both active and sham iTBS treatment over two visits with at least five days between visits in a double blinded experiment

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • National Institute on Drug Abuse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

• INCLUSION CRITERIA - PILOT PHASE: P1:

  1. Be able to give valid informed consent.
  2. Be 18 - 60 years of age.
  3. Right-handed.
  4. Be in good health.
  5. Absence of a specific learning disability, attention deficit hyperactivity disorder (ADHD) or cognitive impairment
  6. Participants will meet DSM-5 criteria for current moderate to severe substance (i.e., cocaine) use disorder, without a period of continuous abstinence lasting a one-month period over the last year, other than in a controlled environment.

EXCLUSION CRITERIA - PILOT PHASE: P1:

1. History of any neurological disorder that would increase seizure risk from iTBS such as stroke, brain lesions, previous neurosurgery, any history of seizure or fainting episode of unknown cause, or head trauma resulting in loss of consciousness, lasting over 30 minutes or with sequela lasting longer than one month.
2. Current DSM-5 moderate-severe substance use disorder on a substance other than cocaine, nicotine, marijuana, or opiates (provided they are currently stable on Suboxone) or meeting withdrawal criteria for alcohol or a sedative/hypnotic/anxiolytic, or tolerance criteria in an individual using 3 or more days/week, regardless of diagnosis. Individuals will be considered stable on Suboxone if they have been on a stable dose for at least 2-weeks prior to consenting to 17-DA-N002 and have provided at least 3 urine specimens negative for illicit opioids over the same 2-week period (10 business days) with at least one test collected within two business days of the start of the period, one collected within three business days of the end of the period and one collected at least two days from either of the other two specimens. Urine results may be gathered at National Institute on Drug Abuse (NIDA) as part of screening or be provided by the Suboxone prescriber. Communication between the Suboxone provider and the MAI (or covering Staff Clinician) will be ongoing to establish continued illicit opioid abstinence between participant clearance and consent to 17-DA-N002. Individuals must be receiving their Suboxone as take-home doses from an external (i.e., non-NIDA-IRP) provider.
3. First-degree family history of any neurological disorder with a potentially hereditary basis, including migraines, epilepsy, or multiple sclerosis.
4. Cardiac pacemakers, neural stimulators, implantable defibrillator, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, with intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object in the body that precludes iTBS administration.
5. Noise-induced hearing loss or tinnitus.
6. Current use (any use in the past 4 weeks, daily use for more than a week within past 6 months) of any investigational drug or of any medications with psychotropic (e.g., benzodiazepines), anti or pro-convulsive action, or anti-coagulants. This will be determined at the discretion of the MAI.
7. Lifetime history of schizophrenia, bipolar disorder, mania, or hypomania.
8. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, mitral valve prolapse, or any heart condition currently under medical care.
9. Pregnant or lactating women or women with reproductive potential who engage in heterosexual sex that may lead to pregnancy and not using a medically acceptable form of contraception (such as birth control pills, condoms, or a diaphragm with spermicide).
10. Participation in any NIBS session (excluding the current protocol) less than two weeks ago. No NIBS exposure for treatment purposes in the last 6 months.

INCLUSION CRITERIA - EXPANDED FEASIBILITY PHASE (EFS):

1. Be able to give valid informed consent.
2. Agree to also participate in study 10-DA-N457, where characterization information is gathered and shared with this protocol.
3. Be 22 - 60 years of age.
4. Right-handed.
5. Be in good health.
6. Absence of a specific learning disability, ADHD or cognitive impairment
7. Cocaine dependent (CD) participants, and not healthy control (HC) participants, will meet Diagnostic and Statistical Manual (DSM)-5 criteria for current moderate to severe substance (i.e., cocaine) use disorder, without a period of continuous abstinence lasting a one-month period over the last year, other than in a controlled environment and currently seeking treatment. They will be using at least once a week in the month prior to enrollment.
8. Treatment seeking CD participants
9. MRI compatible

EXCLUSION -EFS

1. History of any neurological disorder that would increase seizure risk from iTBS such as stroke, brain lesions, previous neurosurgery, any history of seizure or fainting episode of unknown cause, or head trauma resulting in loss of consciousness, lasting over 30 minutes or with sequela lasting longer than one month.
2. Current DSM-5 moderate-severe substance use disorder on a substance other than cocaine, nicotine, marijuana, or opiates (provided they are currently stable on a medication assisted treatment) or meeting withdrawal criteria for a sedative/hypnotic/anxiolytic, or tolerance criteria in an individual using 3 or more days/week, regardless of diagnosis. Individuals will be considered stable on a maintenance medication if they have been on a stable dose for at least 2-weeks prior to consenting to 17-DA-N002 and have provided at least 3 urine specimens negative for illicit opioids over the same 2-week period (10 business days) with at least one test collected within two business days of the start of the period, one collected within three business days of the end of the period and one collected at least two days from either of the other two specimens. Urine results may be gathered at NIDA as part of screening or be provided by the buprenorphine maintenance prescriber. Communication between the maintenance provider and the MAI (or covering Staff Clinician) will be ongoing to establish continued illicit opioid abstinence between participant clearance and consent to 17-DA-N002.
3. HC participants will not currently meet DSM-5 criteria for moderate to severe substance use disorder (excluding nicotine), and in the past, will not meet DSM-5 criteria for moderate to severe substance use disorder for cannabis or alcohol in the past 5 years or ever for other illicit substances. HC will not meet current withdrawal criteria for alcohol or sedative/hypnotics/anxiolytics, or tolerance criteria in an individual using 3 or more days/week. Urine toxicology positive for any illicit substance inconsistent with history given will also be exclusionary.
4. First-degree family history of any form of epilepsy with a potentially hereditary basis .
5. Cardiac pacemakers, neural stimulators, implantable defibrillator, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, with intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object in the body that precludes iTBS administration.
6. Noise-induced hearing loss or tinnitus.
7. Current use (any use in the past 4 weeks, daily use for more than a week within past 6 months) of any investigational drug or of any medications with psychotropic (e.g., benzodiazepines), anti or pro-convulsive action, or anti-coagulants. This will be determined at the discretion of the MAI.
8. Lifetime history of schizophrenia, bipolar disorder, mania, or hypomania.
9. Pregnant women or women with reproductive potential who engage in heterosexual sex that may lead to pregnancy and not using a medically acceptable form of contraception (such as birth control pills, condoms, or a diaphragm with spermicide).
10. Participation in any NIBS session less than two weeks prior to admission. No NIBS exposure for treatment purposes in the last 6 months.
11. Non-English speaking.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pilot Group; Participants with cocaine dependence receive open label three daily intermittent Theta-Burst Stimulation (iTBS) sessions with an inter-administration interval of at least 60-minutes between sessions for up to 10 days.	Device: Transcranial magnetic stimulation (TMS); Theta burst stimulation is a type of TMS.To administer the iTBS treatment, a MagVenture MagPro 100 with MagOption (MagVenture Inc, Alpharetta, GA) machine equipped with a figure-8 active/sham coil will be used.
Experimental: Expanded Feasibility Study (EFS): Cocaine - Active Group; Participants with cocaine dependence receive three active daily intermittent Theta-Burst Stimulation (iTBS) sessions with an inter-administration interval of at least 60-minutes between sessions in a double-blind experiment for up to 10 days and fMRI brain scans.	Device: Transcranial magnetic stimulation (TMS); Theta burst stimulation is a type of TMS.To administer the iTBS treatment, a MagVenture MagPro 100 with MagOption (MagVenture Inc, Alpharetta, GA) machine equipped with a figure-8 active/sham coil will be used.
Sham Comparator: Expanded Feasibility Study (EFS): Cocaine - Sham Group; Participants with cocaine dependence receive three sham daily intermittent Theta-Burst Stimulation (iTBS) sessions with an inter-administration interval of at least 60-minutes between sessions in a double-blind experiment for up to 10 days and fMRI brain scans.	Device: Transcranial magnetic stimulation (TMS); Theta burst stimulation is a type of TMS.To administer the iTBS treatment, a MagVenture MagPro 100 with MagOption (MagVenture Inc, Alpharetta, GA) machine equipped with a figure-8 active/sham coil will be used.
Other: Expanded Feasibility Study (EFS): Healthy Control; Healthy participants without cocaine dependence receive three active daily intermittent Theta-Burst Stimulation (iTBS) sessions with an inter-administration interval of at least 60-minutes between sessions in a double-blind experiment in one day and three sham daily iTBS sessions with an inter-administration interval of at least 60-minutes between sessions in a double-blind experiment in one day with at least five days between the active and sham treatment.	Device: Transcranial magnetic stimulation (TMS); Theta burst stimulation is a type of TMS.To administer the iTBS treatment, a MagVenture MagPro 100 with MagOption (MagVenture Inc, Alpharetta, GA) machine equipped with a figure-8 active/sham coil will be used.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Cocaine Dependent Participants Who Tolerated Intermittent Theta-Burst Stimulation Sessions	Number of cocaine dependent participants who tolerated the intermittent Theta-Burst Stimulation (iTBS) treatment. Participants in the pilot group had a maximum of 2 weeks and participants in the EFS group had a maximum of three weeks to complete the 10 days of treatment.	Up to 10 days of treatment
Change in Brain Global Efficiency After Day One of Intermittent Theta-Burst Stimulation Treatment (Acute Effect)	Participants received resting brain fMRI scan followed by three iTBS sessions then a second brain fMRI scan. Analysis was done to determine if iTBS alters brain networks and calculated as the difference between global efficiency (GE) before and after the first day of iTBS (pre-post). Global efficiency is a graph-theory measure that indicates how well information can be transferred across the entire brain network. A high global efficiency indicates that information can be rapidly transmitted across different brain regions due to short average path lengths between them, suggesting a well-connected and integrated brain network. It is calculated by defining N nodes and calculating the shortest pathway between each pair of nodes. The final value is 1/N(N-1) * sum 1/shortest pathway between each pair of the N nodes. It ranges between 0 and 1 with higher values indicating greater efficiency.	pre/post treatment day 1.
Change in Brain Global Efficiency After Intermittent Theta-Burst Stimulation Treatment (iTBS) Course (Chronic Effect)	Participants received baseline resting brain fMRI scan on day one and had a repeat brain fMRI two weeks after iTBS treatment course. Analysis was done to determine change in brain network with chronic treatment in cocaine dependent participants and calculated as the difference between global efficiency (GE) from baseline to post treatment (2 weeks after end of treatment). Global efficiency is a graph-theory measure that indicates how well information can be transferred across the entire brain network. A high global efficiency indicates that information can be rapidly transmitted across different brain regions due to short average path lengths between them, suggesting a well-connected and integrated brain network. It is calculated by defining N nodes and calculating the shortest pathway between each pair of nodes. The final value is 1/N(N-1) * sum 1/shortest pathway between each pair of the N nodes. It ranges between 0 and 1 with higher values indicating greater efficiency.	Baseline (pre-treatment) minus two weeks post treatment
Brain Global Efficiency Before Intermittent Theta-Burst Stimulation Treatment (iTBS)	The brain global efficiency for cocaine dependent participants and healthy control participants at baseline (pre-treatment), prior to intermittent Theta-Burst Stimulation Treatment (iTBS). Global efficiency is a graph-theory measure that indicates how well information can be transferred across the entire brain network. A high global efficiency indicates that information can be rapidly transmitted across different brain regions due to short average path lengths between them, suggesting a well-connected and integrated brain network. It is calculated by defining N nodes and calculating the shortest pathway between each pair of nodes. The final value is 1/N(N-1) * sum 1/shortest pathway between each pair of the N nodes. It ranges between 0 and 1 with higher values indicating greater efficiency.	Baseline (pre-treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To monitor safety of iTBS applied in cocaine dependent individuals.	monitor ppt and AEs, if any	each visit

Collaborators and Investigators

• Sponsor: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Yihong Yang, Ph.D., National Institute on Drug Abuse (NIDA)

Publications and helpful links

General Publications

• Steele VR, Maxwell AM, Ross TJ, Moussawi K, Abulseoud OO, Stein EA, Salmeron BJ. Report of transient events in a cocaine-dependent volunteer who received iTBS. Brain Stimul. 2018 May-Jun;11(3):631-633. doi: 10.1016/j.brs.2018.01.004. Epub 2018 Jan 31. No abstract available.
• Steele VR, Rotenberg A, Philip NS, Hallett M, Stein EA, Salmeron BJ. Case report: Tremor in the placebo condition of a blinded clinical trial of intermittent theta-burst stimulation for cocaine use disorder. Front Psychiatry. 2024 Jul 9;15:1391771. doi: 10.3389/fpsyt.2024.1391771. eCollection 2024.
• Steele VR, Maxwell AM, Ross TJ, Stein EA, Salmeron BJ. Accelerated Intermittent Theta-Burst Stimulation as a Treatment for Cocaine Use Disorder: A Proof-of-Concept Study. Front Neurosci. 2019 Oct 30;13:1147. doi: 10.3389/fnins.2019.01147. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2017
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): October 30, 2023

Study Registration Dates

• First Submitted: October 6, 2016
• First Submitted That Met QC Criteria: October 6, 2016
• First Posted (Estimated): October 7, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Non-Invasive Brain Stimulation; Functional Magnetic Resonance Imaging (fMRI); transcranial magnetic stimulation (TMS); intermittent theta burst stimulation (iTBS)
• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Cocaine-Related Disorders
• Other Study ID Numbers: 999917002; 17-DA-N002 (Other Identifier: NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: .We plan to share IPD for this protocol; however, plans have not yet been finalized. We have not yet finalized decisions on types of supporting information that will be shared, IPD Sharing Time Frame, or IPD Sharing Access Criteria. As stated in the protocol, data will be stripped of identifiers prior to release for sharing. De-identified data may be shared with properly administered databases and/or with collaborators with whom proper data sharing agreements are in place (we will set-up proper data sharing agreements once a plan is determined).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No