Pilot TMS for Methamphetamine Use Disorder

A Pilot Study of Transcranial Magnetic Stimulation for Treatment of Methamphetamine Use Disorders

This is a pilot study to test the feasibility of a recruitment strategy and study protocol to examine the effects of a dual target transcranial magnetic stimulation treatment in methamphetamine use disorder. The study will test intermittent theta burst stimulation (TBS) targeting the dorsolateral prefrontal cortex (DLPFC) combined with continuous TBS targeting the medial prefrontal cortex (MPFC) in people with methamphetamine use disorder (MAUD) who are engaged in psychosocial treatment. We will randomize the order in which these treatments are delivered at each treatment session, but all subjects will receive both treatments. Intermittent TBS targeting the DLPFC is approved by the Food and Drug Administration for major depressive disorder, and continuous TBS targeting the MPFC has been studied in cocaine use disorder. We will administer this dual target TBS daily for 2 weeks, followed by three times weekly for 2 weeks, and monitor depressive symptoms, anxiety, sleep, craving, quality of life, and methamphetamine use for three months. Changes in functional connectivity of brain circuits will be evaluated with functional magnetic resonance imaging (fMRI) before and after treatment. We expect to observe changes in connectivity between the DLPFC, MPFC, and other regions implicated in addiction and impulsivity. Furthermore, we will evaluate if baseline differences in functional connectivity can be used to predict response. Psychological tests focusing on state impulsivity and risk taking will be administered, and we expect to observe reductions in these characteristics after treatment. We will test this protocol in 20 patients recruited from clinical care settings at University of Iowa Hospitals and Clinics, University of New Mexico Health System, and University of Utah Health to illustrate the feasibility of recruitment and completing the protocol, to support an external funding proposal.

Study Overview

• Status: Completed
• Conditions: Methamphetamine-dependence; Stimulant Dependence; Addiction, Drug
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation--DPFC first, MPFC second; Device: Transcranial Magnetic Stimulation--MPFC first, DPFC second

Detailed Description

Overview: This is a two-arm randomized controlled trial. Participants with MAUD will receive 16 sessions of dual-target theta burst stimulation to the DLPFC and MPFC over 4 weeks. Participants will be randomized to whether they receive stimulation to the DLPFC or MPFC first, but both sites will be stimulated at each treatment. We will follow outcomes for 12 weeks. Outcomes include treatment retention, craving, self-reported MA or stimulant use, urine drug screen results, depressive symptoms, anxiety symptoms, sleep quality, quality of life, response inhibition, and functional connectivity. Magnetic resonance imaging (MRI) to measure functional connectivity and a flanker task to measure response inhibition will be completed at baseline and four weeks. More detail is provided in the outcome measures section. Subjects will also complete the Big Five Inventory at baseline, a measure of personality characteristics, to explore how these relate to outcomes including retention in treatment and the study.

MR Image Acquisition: MRI will be completed at baseline and after the last TMS session. The MRI sessions will be conducted using research dedicated MRI scanners at each site. Anatomical images will include volumetric T1 and T2 weighted images with a 1.0 mm isotropic spatial resolution. Resting state fMRI will be performed to collect 20 minutes worth of data.

Statistical Analysis:

Retention in the Study and Psychosocial Treatment: We will describe the proportion of subjects who complete the 4-week TMS treatment period and complete each subsequent monthly follow-up visit, depending on randomization group. We will use Kaplan-Meier curves to describe retention in the study and in psychosocial treatment, and log-rank tests to compare them. If non-retention is common enough, we will use Cox regression to explore baseline measures as predictors of retention. We anticipate that multivariate analysis will not be feasible with the sample size.

Symptoms and Impulse Control Measures: Primary analyses for other measures will focus on changes over the 4-week TMS treatment period. Changes in symptoms evaluated weekly or biweekly (e.g. craving, depression, affect, anxiety, sleep) will be assessed using generalized linear mixed models with appropriate distributions. We anticipate a Poisson distribution for days of MA or other stimulant use and will use a binomial distribution with a logit link to evaluate changes in positive urine drug screens. Randomization group by time interactions will be the primary variables of interest to assess the differences between slopes of change between groups during treatment. Paired t-tests or Wilcoxon signed-rank tests will be used to evaluate changes in measures completed at baseline and after 4 weeks of treatment. We will compare measures at baseline and 4 weeks to those at 8 weeks and 12 weeks similarly, but in separate analyses since decay in effects may occur after TMS ends.

Functional Connectivity Analysis: fMRI functional connectivity analysis will be performed using a standard analysis pipeline. Functional images will undergo pre-processing including brain extraction, motion correction, spatial smoothing (6 mm FWHM), and temporal filtering (.008 Hz < f < 0.08 Hz). Following preprocessing, the fMRI signal will be corrected for potential sources of noise using image-based estimates and motion correction parameters. The resulting corrected time-series will be used for all functional connectivity analyses. Functional connectivity will be measured by extracting time-series data from the pre-processed imaging data for the regions of interest (ROIs). Multiple ROIs will be examined and will be defined as spheres (6mm radius) based on coordinate locations previously published by Yeo and colleagues. Specifically, we will focus on connectivity in the cingulo-opercular network involved in cognitive control and salience (DLPFC - anterior insula; DLPFC - anterior cingulate) and reward processing/motivation circuit (MPFC - ventral striatum). Analyses will be averaged across right and left hemispheres but we will also explore differences between right and left hemispheres. The time series from the ROIs will be cross-correlated with the time-series from the other ROIs to determine the strength of functional connectivity between regions. The resulting Pearson's r will be converted to Fisher's z scores to improve normality for the statistical analysis. We will treat each ROI pair connection (DLPFC - anterior insula, DLPFC - anterior cingulate, MPFC - ventral striatum) as a dependent variable. Primary analyses will use Wilcoxon rank-sum tests to compare changes in connectivity at baseline vs. after TMS treatment between groups. We will explore correlates of connectivity and changes using Pearson or Spearman correlations and linear regression or mixed models.

Exploratory Analysis: Follow-up exploratory voxel-wise analyses will be conducted for functional connectivity, which will provide thousands of individual predictors. This will help confirm findings in large parcel ROI based analysis. We will use the same statistical models as used for the ROI based analysis described above but at the voxel level. Voxel-wise data creates a high-dimensional problem in which the number of predictors far exceeds the number of participants. Machine learning methods, such as random forest will be used to handle the high-dimensional sub-analyses. Random forest requires a minimum of data assumptions, automatically accounts for non-linear and interaction effects, and it has proven useful in identifying useful predictors in high-dimensional contexts.

Comparison with Historical Controls: We will compare retention in psychosocial treatment programs and positive urine drug screens from chart review with between the two randomization groups. Treatment retention will be compared using a log-rank test. Positive urine drug screens in each week of follow-up will be compared using generalized estimating equation models with a logit link, clustered on subject, with participation in the TMS study as the variable of interest.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed with an active methamphetamine use disorder
• Is engaged in psychosocial treatment or articulates a plan to engage in psychosocial treatment for methamphetamine use disorder during the study period
• Age 18 to 60 years
• Able to consent for treatment and research participation
• English-speaking
• Receiving care from UIHC's Addiction Medicine service. This includes patients in the Crisis Stabilization Unit, seen by the inpatient consultation service, enrolling in partial hospitalization or intensive outpatient treatment, or seen in the outpatient Addiction Medicine clinics.

Exclusion Criteria:

• Age less than 18 years
• Patients that are excluded during TMS assessment including: patients with epilepsy or seizure disorder, patients with implanted ferromagnetic equipment in their face or skull near the stimulation target.
• Current medical treatment with clozapine or stimulants.
• Current diagnosis of bipolar disorder, schizoaffective disorder, schizophrenia, that is deemed by research team psychiatrists not to have been drug-induced. Psychotic disorder not associated with drug use per the MINI International Neuropsychiatric Interview. Psychosis NOS, in remission, or drug-induced psychotic episodes are not exclusion criteria since these may be related to methamphetamine misuse.
• Lacks the mental capacity to provide informed consent (i.e. not able to demonstrate understanding of the risks and benefits of participation)
• Has a court appointed guardian.
• Unstable medical illness.
• Current diagnosis of neurological disorder or neurocognitive disorder.
• Prior neurosurgical procedure.
• History of seizure.
• History of ECT treatment within the past three months.
• History of any previous TMS treatment.
• Known inability to complete the protocol, as assessed by asking them if they are able to make it to all visits for this study without assistance.

MRI Exclusion criteria:

• Implanted device including pacemaker, coronary stent, defibrillator, or neurostimulation device that is not MRI-compatible
• Metal in body including bullets, shrapnel, metal slivers
• Claustrophobia
• Uncontrolled high blood pressure
• Atrial fibrillation
• Significant heart disease
• Hemodynamic instability
• Kidney disease
• Pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DPFC first; Participants in this arm will undergo all study procedures including consent; pre-, during, and post-psychological assessments; pre- and post- MRI and fMRI; 16 treatments of dual target TMS over a 4-week period; and substance use-related assessments to include substance use, withdrawal symptoms, and cravings to use. This arm will receive the dorsolateral prefrontal cortex stimulation first.	Device: Transcranial Magnetic Stimulation--DPFC first, MPFC second; Participants will undergo 16 treatments consisting of intermittent theta burst stimulation targeting the dorsolateral prefrontal cortex and continuous theta burst stimulation targeting the medial prefrontal cortex, over a 4-week period that coincides with psychosocial treatment for methamphetamine use disorder. Both treatments will be delivered at each TMS treatment visit. The DPFC first group will receive stimulation to the dorsolateral prefrontal cortex first and medial prefrontal cortex second at each treatment visit.; Other Names: Theta burst stimulation
Experimental: MPFC first; Participants in this arm will undergo all study procedures including consent; pre-, during, and post-psychological assessments; pre- and post- MRI and fMRI; 16 treatments of dual target TMS over a 4-week period; and substance use-related assessments to include substance use, withdrawal symptoms, and cravings to use. This arm will receive the medial prefrontal cortex stimulation first.	Device: Transcranial Magnetic Stimulation--MPFC first, DPFC second; Participants will undergo 16 treatments consisting of intermittent theta burst stimulation targeting the dorsolateral prefrontal cortex and continuous theta burst stimulation targeting the medial prefrontal cortex, over a 4-week period that coincides with psychosocial treatment for methamphetamine use disorder. Both treatments will be delivered at each TMS treatment visit. The MPFC first group will receive stimulation to the medial prefrontal cortex first and DPFC second at each treatment visit.; Other Names: Theta burst stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retention in the Study	Time to study dropout (to assess feasibility and tolerability of the protocol)	Baseline to 12 weeks (continuous)
Retention in Psychosocial Treatment	Time to discontinuation of psychosocial treatment	Baseline to 18 days (continuous--assessed weekly)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Connectivity of the Dorsolateral Prefrontal Cortex and Anterior Insula	Functional connectivity of the dorsolateral prefrontal cortex and anterior insula (mean of left and right side connectivity) measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.	Baseline, 4 weeks
Functional Connectivity Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex	Functional connectivity of the left dorsolateral prefrontal cortex and left dorsal anterior cingulate cortex measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.	Baseline, 4 weeks
Functional Connectivity of the Medial Prefrontal Cortex and Ventral Striatum (Nucleus Accumbens)	Functional connectivity of the left medial prefrontal cortex and ventral striatum (mean of medial prefrontal cortex connectivity to left and right nucleus accumbens) measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.	Baseline, 4 weeks
Flanker Inhibitor Control and Attention Test, Age 12+	Summary score of accuracy and reaction time. Higher scores indicate stronger inhibitory control and attention (better ability to attend to relevant stimuli and block out irrelevant stimuli). The reported scores are age-corrected standard scores, which have a population mean of 100 and standard deviation of 15. Means are estimated from mixed models.	Baseline, 4 weeks
Kirby Delay Discounting Questionnaire, 27 Item	Summary score of discounting rate. Scores range from 0.00016 to 0.5, with smaller values indicating a lack of discounting and preference for delayed rewards, and higher values indicating strong discounting and preference for immediate rewards. Higher scores are associated with addictive behaviors. The log of K is reported due to its skewed nature. Values are estimated from a mixed model.	Baseline, 4 weeks
Number of Days of Stimulant Use in the Past Week (Estimated Change Per Day)	Estimated change per day in number of days of stimulant use in the last week (self-reported) from mixed models. Measured as number of days of methamphetamine use because methamphetamine and other stimulant use were reported separately, and it was not clear if these were on the same or different days. The vast majority of subjects reported using only methamphetamine.	Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks
Urine Drug Screen Positive for Stimulant	Urine dipstick positive or not for stimulants (amphetamine, methamphetamine, cocaine)	Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks
Brief Substance Craving Scale (Estimated Change in Score Per Day)	The Brief Substance Craving Scale Score used was the summary score of intensity, frequency and length of cravings in the last 24 hours. Scores based on stimulant craving responses and range from 0-12 with higher scores indicating more craving. Scores are least squared means from mixed models of actual measures, without last observation carried forward or any imputation. Change in score per day estimated from a mixed model.	12 weeks
Brief Addiction Monitor Use Subscale (Estimated Change in Score Per Day)	Use subscale. Scores range from 0 to 12 with higher scores indicating more use. Outcome measures reported as change per day estimated from mixed models.	Baseline, 4 weeks, 8 weeks, 12 weeks
Brief Addiction Monitor Risk Factors Subscale (Estimated Change in Score Per Day)	Risk factors subscale. Scores range from 0 to 24 with higher scores indicating more risk. Results presented as change in score per day estimated from a mixed model.	Baseline, 4 weeks, 8 weeks, 12 weeks
Brief Addiction Monitor Protective Factors Subscale (Estimated Change in Score Per Day)	Protective factors subscale. Scores range from 0 to 24 with higher scores indicating more protection. Change in score per day estimated from mixed model.	Baseline, 4 weeks, 8 weeks, 12 weeks
Brief Addiction Monitor Satisfaction With Progress Toward Achieving Recovery Goals (Estimated Change Per Day)	Item 17, satisfaction with progress toward achieving recovery goals. Scores range from 0 to 4 with higher scores indicating less satisfaction. Reported as change per day estimated from a mixed model.	Baseline, 4 weeks, 8 weeks, 12 weeks
Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Estimated Change in Score Per Day)	Total score. Scores range from 16 to 80 with higher scores indicating more satisfaction. Scores generally reported as a percent of the maximum possible score, such that scores can be calculated with missing responses as long as less than one-third of responses are missing. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
Patient Health Questionnaire--8 Item Scale (Estimated Change in Score Per Day)	Total score. Scores range from 0 to 24 with higher scores indicating worse depressive symptoms. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
Generalized Anxiety Disorder 7-item Scale (Estimated Change Per Day)	Total score. Scores range from 0 to 21 with higher scores indicating worse anxiety. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
Assessment of Recovery Capital (Estimated Change Per Day)	Total score. Scores range from 0 to 50 with higher scores indicating greater recovery capital. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 4 weeks, 8 weeks, 12 weeks
Positive and Negative Affect Scale Positive Affect Score (Estimated Change Per Day)	Positive affect score. Scores range from 10 to 50 with higher scores indicating higher positive affect. Higher positive affect is a better outcome. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
Positive and Negative Affect Scale Negative Affect Score (Estimated Change Per Day)	Negative affect score. Scores range from 10 to 50 with lower scores indicating lower negative affect. Lower negative affect is a better outcome. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
Pittsburgh Sleep Quality Index (Estimated Change Per Day)	Total score. Scores range from 0 to 21, with lower scores indicating better sleep quality. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
Difficulties in Emotion Regulation Scale--Short Form (Estimated Change Per Day)	Total score. Scores range from 18 to 90 with higher values indicating more difficulty with emotional regulation. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 4 weeks
UPPS-P Impulsive Behavior Scale, 59-item Revised Version (Estimated Change Per Day)	Summary score. Scores range from 59 to 236 with higher scores indicating more impulsive behavior. This outcome measure is reported as change in score per day estimated from mixed models.	Baseline, 4 weeks

Collaborators and Investigators

• Sponsor: Ryan M. Carnahan
• Collaborators: University of Utah; University of New Mexico
• Investigators: Principal Investigator: Ryan Carnahan, PharmD, MS, University of Iowa; Principal Investigator: Alison C Lynch, MD, MS, University of Iowa

Publications and helpful links

General Publications

• Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. Drug Alcohol Depend. 2014 Oct 1;143:11-21. doi: 10.1016/j.drugalcdep.2014.08.003. Epub 2014 Aug 17.
• Ma T, Sun Y, Ku Y. Effects of Non-invasive Brain Stimulation on Stimulant Craving in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-Analysis. Front Neurosci. 2019 Oct 18;13:1095. doi: 10.3389/fnins.2019.01095. eCollection 2019.
• Zhang JJQ, Fong KNK, Ouyang RG, Siu AMH, Kranz GS. Effects of repetitive transcranial magnetic stimulation (rTMS) on craving and substance consumption in patients with substance dependence: a systematic review and meta-analysis. Addiction. 2019 Dec;114(12):2137-2149. doi: 10.1111/add.14753. Epub 2019 Aug 16.
• Makani R, Pradhan B, Shah U, Parikh T. Role of Repetitive Transcranial Magnetic Stimulation (rTMS) in Treatment of Addiction and Related Disorders: A Systematic Review. Curr Drug Abuse Rev. 2017;10(1):31-43. doi: 10.2174/1874473710666171129225914.
• Liang Y, Wang L, Yuan TF. Targeting Withdrawal Symptoms in Men Addicted to Methamphetamine With Transcranial Magnetic Stimulation: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Nov 1;75(11):1199-1201. doi: 10.1001/jamapsychiatry.2018.2383.

Helpful Links

• Iowa Department of Public Health. Substance Abuse Brief, December 2018, Issue 7.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2020
• Primary Completion (Actual): March 31, 2022
• Study Completion (Actual): March 31, 2022

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: June 23, 2020
• First Posted (Actual): June 26, 2020

Study Record Updates

• Last Update Posted (Estimated): January 16, 2026
• Last Update Submitted That Met QC Criteria: December 24, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: methamphetamine; transcranial magnetic stimulation; addiction treatment
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders
• Other Study ID Numbers: 202001387

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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