A Pilot Study of Transcranial Magnetic Stimulation for Treatment of Methamphetamine Use Disorders
Phase: NA
Conditions: Stimulant Dependence, Methamphetamine-dependence, Addiction, Drug
Sponsor: Ryan M. Carnahan

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Study Title:  A Pilot Study of Transcranial Magnetic Stimulation for Treatment of 
Methamphetamine Use Disorder 
 
NCT Number:  NCT04449055 
 
Protocol and Statistical Analysis Plan 
 
Document Date:  May 24, 2023  
 
Author:   
Ryan Carnahan, PharmD, MS 
Professor of Epidemiology 
The University of Iowa College of Public Health 
 
 
 
 

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Document Contents: 
Protocol:  Page 3 
Statistical Analysis Plan:  Page 20 
References: Page 23 
 
 
 

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Study Protocol 
Overview 
This is a pilot study to test the feasibility of a recruitment strategy and study 
protocol to examine the effects of transcranial magnetic stimulation (TMS) using 
intermittent theta burst stimulation targeting the dorsolateral prefrontal cortex 
(DLPFC) and continuous theta burst stimulation targeting the medial prefrontal 
cortex (MPFC) in people with methamphetamine use disorder (MAUD) who are 
engaged in psychosocial treatment. This TMS treatment is approved by the Food 
and Drug Administration for major depressive disorder. We will administer TMS 
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 magnetic resonance imaging (MRI) and 
functional magnetic resonance imaging (fMRI) before and after treatment. We 
expect to observe changes in connectivity between the DLPFC and other regions 
implicated in addiction and impulsivity. Furthermore, we will evaluate if baseline 
differences in functional connectivity can be used to predict TMS response. 
Psychological tests focusing on state impulsivity and risk taking will be 
administered, and we expect to observe reductions in these characteristics after 
treatment. Participants will be randomized to receive stimulation targeting the 
DLPFC first or stimulation targeting the MPFC first, although all participants will 
receive stimulation at both sites at each treatment visit. 
Primary objective 
Evaluate the feasibility of a protocol to examine effects of intermittent theta burst 
stimulation (iTBS) to the dorsolateral prefrontal cortex (DLPFC) and continuous 
theta burst stimulation (cTBS) to the medial prefrontal cortex (dual target TBS) in 
people receiving psychosocial treatment for methamphetamine use disorder 
(MAUD).  
Secondary Objectives 
Estimate the effect size of dual target TBS on functional connectivity and 
impulsivity in patients with MAUD. Evaluate craving, sleep quality, depressive 

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symptoms, anxiety symptoms, and withdrawal symptoms during TBS treatment. 
Evaluate the level of continued use of methamphetamine during TBS treatment. 
 
This pilot study will focus on our ability to engage patients with 
methamphetamine use disorder in TBS treatment and to complete a series of 
assessments over three months. We expect to observe reductions in cravings, 
withdrawal and related symptoms over time, and changes in anterior cingulate 
cortex functional connectivity from baseline to 4 weeks. Differences between 
subjects randomized to receive stimulation at the DLPFC and MPFC will be 
examined.  
Significance 
Methamphetamine (MA) use can cause many serious adverse health 
consequences and is of particular concern in Iowa. In the 2017 Treatment Episode 
Data Set (TEDS), 27.7% of substance use disorder treatment admissions involved 
MA as the primary substance, representing 7,641 admissions, second only to 
alcohol. Overdose deaths in Iowa involving MA roughly doubled to 91 from 2013 
to 2018.(1,2) Treatment for MA use disorder (MAUD) is primarily psychosocial, 
rates of treatment induction and retention are poor, and relapse rates are 
high.(3) There is a pressing need to identify effective interventions that enhance 
psychosocial treatments. rTMS is a non-invasive brain stimulation technique that 
effectively treats major depressive disorder and is considered safe, well-tolerated, 
and potent. rTMS has increasingly been studied to treat addiction.(4-7) The 
dorsolateral prefrontal cortex (DLPFC), a brain region implicated in regulatory 
processes related to emotion, motivation, and craving, is a common target for 
rTMS. DLPFC stimulation using high frequency rTMS has reduced craving in many 
studies of addictive disorders, including cocaine and MA use disorders.(4) Despite 
these encouraging findings, no trials have reported on the efficacy for reducing 
MA use or preventing relapse. iTBS is a type of TMS has been studied in 
depression and shown to have equivalent efficacy to rTMS, and treatments can be 
delivered much more quickly than traditional rTMS.(8) In contrast to high-
frequency rTMS and intermittent theta burst stimulation, which increase neuronal 
excitability, continuous theta burst stimulation (cTBS) decreases excitability. cTBS 
targeting the MPFC during drug cue activation reduced craving and related brain 

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activity in cocaine users in a sham-controlled trial evaluating the effects of a single 
cTBS session.(9,10) Prior work showed that rTMS to the DLPFC reduced MPFC 
activity in controls but not cocaine users. The findings of studies by Hanlon and 
colleagues supported a National Institute on Drug Abuse-funded randomized 
sham-controlled trial of MPFC cTBS for cocaine use disorder.(9) 
Study Sites 
The University of Iowa, the University of Utah, and the University of New Mexico 
are participating in this study. 
Subject Recruitment 
Subjects will be recruited through advertising as well as through colleague referral 
and medical record review. Patients admitted to a crisis stabilization unit, 
inpatient unit, or partial hospitalization or intensive outpatient substance use 
disorder treatment program, or seen in an outpatient addiction medicine clinic, 
with a diagnosis of methamphetamine use disorder will be provided with 
information about the study by clinicians to consider participation. Initial 
discussions will take place in private rooms. Posters and brochures will also be 
located in care locations. 
Inclusion/Exclusion Criteria 
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 
 
Exclusion Criteria: 
-Age less than 18 years 

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-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. 
-Status as a prisoner. 
-Receiving treatment as an alternative to incarceration. 
-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 within the last 12 months. 
-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 

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-Metal in body including bullets, shrapnel, metal slivers 
-Claustrophobia 
-Uncontrolled high blood pressure 
-Atrial fibrillation 
-Significant heart disease 
-Hemodynamic instability 
-Kidney disease 
-Pregnant 
 
Eligibility Screening Questions 
• Are you receiving care for this condition (methamphetamine use disorder), 
or are you interested in receiving care? 
• Are you less than 18 or grater than 60 years of age? 
• Have you been diagnosed with epilepsy, a seizure disorder, or have you 
ever had a seizure? 
• Have you received transcranial magnetic stimulation? 
• --(If yes) Was you last TMS session within the last 3 months? 
• Did have to complete the scan in more than one sitting or did you 
(personally) ask for the scan to stop/ to take a break? 
• Have you received electroconvulsive therapy within the last three months? 
• Do you have any metal implants or implanted medical devices? 
• (If yes) Are they MRI safe? (no-disqualified) 
• Do you have any other metal in your body, such as bullets, shrapnel, or 
metal slivers? 
• Do you have uncontrolled high blood pressure, atrial fibrillation, other 
heart disease? 
• Do you have another medical illness that is difficult to manage or unstable? 
• Do you have kidney disease? 
• Have you been diagnosed with schizophrenia, schizoaffective disorder, 
bipolar disorder, or another psychotic disorder? 

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• Have you been diagnosed with a cognitive disorder, such as mild cognitive 
impairment, Alzheimer's disease, or dementia? 
• Are you currently pregnant or do you plan to become pregnant anytime 
soon? 
• Are you currently taking clozapine or a prescribed stimulant such as 
methylphenidate (e.g. Ritalin) or dextroamphetamine (e.g. Adderall)? 
Stimulants are usually prescribed for attention deficit disorder. 
• Are you legally required to receive treatment as an alternative to criminal 
prosecution or going to jail or prison? 
 
Screening questions that warrant follow up if the participant answers "yes": 
• Have you been diagnosed with a methamphetamine use disorder? (follow 
up- providers to determine if participant should have a methamphetamine 
use diagnosis, if not currently diagnosed) 
• Are you claustrophobic or afraid of small, closed-in spaces? (follow-up- 
participant needs to confirm that they can handle being in an MRI machine 
through additional questions) 
• Do you have a problem with loud noises? (follow-up- participant needs to 
confirm that the noises from the MRI are not too loud through additional 
questions) 
• Have you ever had a neurosurgical procedure? (follow up- type of 
procedure matters) 
• Have you been diagnosed with another neurological disorder?(follow-up- 
type of disorder matters) 
• Are you able to make it to all visits for this study without assistance? 
Additional information: This involves a baseline visit, then visits five days a 
week for two weeks and three days a week for two more weeks. The visits 
need to take place Monday through Friday, but we can start most any day 
depending on what's convenient for you. There will also be follow-up visits 
that can be completed by phone or in person one month and two months 
after the other visits are completed. 
o If not, Please explain any additional services you may need to get to 
and from study appointments, (i.e. transportation) 

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Randomization 
The randomization scheme was block randomization stratified by study site, with 
block sizes of 4 and a 1:1 ratio, designed to ensure approximate balance in the 
number of subjects. Subjects are randomized to receive stimulation at the DLPFC 
or MPFC first, although both groups receive stimulation at both sites at each visit. 
The subject is assigned to a group at the first TMS treatment visit. 
Intervention 
The study intervention is open-label dual-target theta burst stimulation delivered 
in sequential fashion to the DLPFC and the MPFC. The order of treatments is 
determined by the randomization scheme, but the treatments are otherwise 
identical. Treatment targeting will occur at the Beam F3 and FP1 scalp regions as 
defined by the 10-20 EEG system. A Magventure MagPro X100 figure-8 coil with 
theta burst capabilities will be used to deliver the stimulus, including intermittent 
theta burst stimulation to the DLPFC (2 seconds of 50-Hz triplets delivered at 5 Hz, 
8 seconds intertrain interval, 600 total pulses) and continuous theta burst to the 
MPFC (continuous 50-Hz stimulation triplets, 600 pulses).  Stimulation will be 
delivered at 110% of the resting motor threshold, as determined by the 
stimulation threshold at which single-pulse TMS stimulation over the motor 
cortex hand knob region can elicit visible finger movement on 3 of 5 trials, with 
stimulation dose adjustment for distance from target to coil as needed.  
Treatment sessions will consist of a single treatment protocol at each stimulation 
site. Sessions will occur 5 times per week for the first 2 weeks, followed by 3 
sessions per week for an additional 2 weeks (16 treatment sessions total).   
 
Study Procedures 
This study lasts for a total of 12-13 weeks, and involves 19 visits. Although visits 
vary from 15 minutes to 5 hours, they average 45-50 minutes. The first week 
involves a baseline visit that will take 3-4 hours. If the subject elects to participate 
in the optional EEG and timing task, this will add about an hour to their first visit. 
Subjects will receive 4 weeks of TMS treatments, and each treatment should take 
about 15 minutes. The first two weeks of treatment involve 5 visits per week 

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where the subject receives TMS. The third and fourth weeks of treatment involve 
3 visits per week where the subject receives TMS. Additional assessments are 
done on the last treatment day of each treatment week. These visits, including 
treatment time, will take about 30 minutes after the first and third weeks of 
treatment, 45-60 minutes after the second week of treatment, and 3-4 hours 
after the fourth week of treatment. If the subject elects to participate in the 
optional EEG and timing task, this will add about an hour to their visit after the 
fourth week of treatment. Follow-up phone calls lasting 45-60 minutes will take 
place 4 weeks and 8 weeks after the end of TMS treatment (week 9 and week 13 
of the study). 
Assessment visit 1 will take place prior to TMS treatment. Information will be 
collected on demographics and a history of substance use and medical conditions. 
Subjects will be screened using the MINI International Neuropsychiatric Interview 
to ensure they do not have mental health conditions that should lead to 
exclusion. This may be conducted remotely by a psychiatrist investigator using a 
HIPAA compliant Zoom meeting if a psychiatrist is not available to perform the 
MINI on-site. The subject will complete all assessment surveys. They will also 
complete several psychological tests, including a Flanker task administered with 
an iPad, and a digitally administered delay discounting task. They will also submit 
a urine drug screen if there is not a recent result on file in their EHR, or one is not 
known to be planned for that day. Then they will complete fMRI imaging. This 
visit should take 3-4 hours. If the subject elects to participate in the optional EEG 
and timing task, this will add about an hour to this visit. If they elect to participate 
in this optional EEG and task, investigators will adhere electroencephalogram 
(EEG) leads to their scalp and then have them perform 2 blocks of the interval 
timing task where they estimate the passage of a specified (3 or 12 second) 
passage of time (~22min - 11 min blocks). The beginning of the trial is indicated by 
the presentation of either a 3 or a 12 on the computer screen which also indicates 
the duration of time the subject should estimate. During performance, we will 
collect electroencephalographic data from patients which will be analyzed offline. 
Within a week of this visit, the subject will begin TMS treatment. TMS treatment 
could start as early as the same day if the subject prefers and the schedule allows. 

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TMS treatment using theta burst stimulation will be provided 5 days in the first 
week, five days in the second week, and three times per week in weeks 3 and 4. 
The start day will be somewhat flexible. Subjects will participate in 5 treatment 
sessions in each of the first two 7-day periods, and three treatment sessions in 
each of the third and fourth 7-day periods (treatment weeks). Theta burst 
stimulation can be completed in as little as 3 minutes per treatment (two sites), 
so these visits should take roughly 15-20 minutes total when once-weekly 
additional assessments are not being completed. We will measure blood pressure 
and pulse prior to each treatment. If systolic blood pressure exceeds 160 mmHg, 
diastolic blood pressure exceeds 100 mmHg, or pulse exceeds 110 beats per 
minute, then we will confirm this with a second measurement. If it is confirmed 
by a second measurement, then the treatment will be withheld, and a clinician 
contacted to assess the patient. Before each treatment, we will also ask the 
subject when they last used methamphetamine. Treatment may be withheld if it 
is too recent to minimize risk of adverse effects, particularly seizure. Participants 
will be asked to report craving using a single question before and after each 
treatment. Participants will only be asked to report any adverse event 
experiences at these visits. 
On the last day of TMS in each treatment week when TMS is administered, the 
subject will be asked to complete additional assessments. At 1 week, 2 weeks, 
and 3 weeks, these will involve completion of surveys. At weeks 1 and 3 only the 
Brief Substance Craving Scale will be administered, while additional survey 
instruments will be administered after week 2. These visits will also involve 
reporting of the number of days in the last week in which they used 
methamphetamine as well as whether they remain engaged in a psychosocial 
treatment and what treatments (partial hospitalization, intensive outpatient, 
outpatient medical, outpatient psychotherapy, group therapy, other, none). If 
they were engaged in partial hospitalization or intensive outpatient treatment, we 
will ask whether they completed the planned course of treatment or stopped 
early. 
After the last treatment in week 4, the subject will be asked to again complete all 
assessment instruments, provide information on substance use in the last week, 
complete the psychological tests, submit a urine drug screen (if there is not a 
recent result on file in their EHR), and complete fMRI imaging. If the subject elects 

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to participate in the optional EEG and timing task, this will add about an hour to 
this visit. If they elect to participate in this optional EEG and task, we will be 
adhering electroencephalogram (EEG) leads to their scalp and then have them 
perform 2 blocks of the interval timing task where they estimate the passage of a 
specified (3 or 12 second) passage of time (~22min - 11 min blocks). The 
beginning of the trial is indicated by the presentation of either a 3 or a 12 on the 
computer screen which also indicates the duration of time the subject should 
estimate. During performance, we will collect electroencephalographic data from 
patients which will be analyzed offline. 
TMS treatment will end at this time. We will then plan follow-up visits at 8 weeks 
and 12 weeks after the start of treatment, which can be completed by 
phone/online or in person base on the subject's preference. At these visits 
subjects will complete the survey-based assessments. They will also be asked 
about the number of days of methamphetamine use in the last week and their 
current psychosocial treatment modality. 
An example study schedule and full list of assessments I provided below. 
Figure 1: Example Study Schedule 
Study Week 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
1 
First visit:  determine eligibility to continue, questionnaires, psychological testing, urine drug 
screen if needed, MRI, optional EEG  
(3-5 hours) 
 
1 
TMS 
TMS 
TMS 
TMS 
TMS, questionnaires, urine sample if 
needed (about 30 minutes) 
2 
TMS 
TMS 
TMS 
TMS 
TMS, questionnaires, urine sample if 
needed (45-60 minutes) 
3 
TMS 
 
TMS 
 
TMS, questionnaires, urine sample if 
needed (about 30 minutes) 
4 
TMS 
 
TMS 
 
TMS, questionnaires psychological 
testing, urine sample if needed, MRI, 
optional EEG  
(3-5 hours) 
8 
One follow-up visit or phone call to complete questionnaires (45-60 minutes) 
12 
One follow-up visit or phone call to complete questionnaires (45-60 minutes) 
 
Figure 2: Schedule of study assessments by visit 
Measure 
Time to 
complete 
(minutes) 
First 
Visit 
Last 
TMS 
day 
week 1 
Last 
TMS 
day 
week 2 
Last 
TMS 
day 
week 3 
Last 
TMS 
day 
week 4 
Week 8 
Week 12 

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Interview Questions 
 
 
 
 
 
 
 
 
Personal information, 
medical history, 
substance use history 
20 
x 
 
 
 
 
 
 
Report substance use 
and current treatment 
2 
x 
x 
x 
x 
x 
x 
x 
Urine drug screen (if 
needed) 
10 
x 
x 
x 
x 
x 
 
 
Mini International 
Neuropsychiatric 
Interview 
20 
x 
 
 
 
 
 
 
Written 
Questionnaires 
 
 
 
 
 
 
 
 
Brief Substance 
Craving Scale 
5 
x 
x 
x 
x 
x 
x 
x 
Assessment of 
Recovery Capital 
5-10 
x 
 
 
 
x 
x 
x 
Brief Addiction 
Monitor 
10 
x 
 
 
 
x 
x 
x 
Quality of Life 
Enjoyment and 
Satisfaction 
Questionnaire—Short 
Form 
5 
x 
 
x 
 
x 
x 
x 
Patient Health 
Questionnaire  
3 
x 
 
x 
 
x 
x 
x 
Generalized Anxiety 
Disorder 7-item scale  
2 
x 
 
x 
 
x 
x 
x 
Positive and Negative 
Affect Scale 
5-10 
x 
 
x 
 
x 
x 
x 
Pittsburgh Sleep 
Quality Index 
5-10 
x 
 
x 
 
x 
x 
x 
Big Five Inventory-2 
5-15 
x 
 
 
 
 
 
 
UPPS-P Impulsive 
Behavior Scale 
15 
x 
 
 
 
x 
 
 
Difficulties in 
Emotion Regulation 
Scale-Short-Form 
5 
x 
 
 
 
x 
 
 
Monetary Choice 
Questionnaire 
5 
x 
 
 
 
x 
 
 
Psychological 
Testing 
 
 
 
 
 
 
 
 
Flanker Inhibitory 
Control and Attention  
3-5 
x 
 
 
 
x 
 
 
Imaging 
 
 
 
 
 
 
 
 
MRI 
60-90 
x 
 
 
 
x 
 
 
EEG and Timing 
Task (optional) 
60 
x 
 
 
 
x 
 
 
 
Procedures for contacting subjects lost to follow-up 

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The subject will be called or texted (per their preference) up to 5 times after each 
loss to follow-up with two days between contacts and messages left to contact 
the research assistant if voice messaging is available. If the subject provided a 
secondary contact person that individual will be called up to three times with two 
days between calls and voice messages left if available, starting after the third 
failed attempt to contact the subject. We will inform that person that we are 
trying to reach the study subject about a research study and the subject said they 
might be able to help us find them, without disclosing the details of the study or 
the subject's health conditions. If the secondary contact is reached, they will be 
asked if they know the whereabouts of the person, if they could reach out to 
them, and for new contact information if that has changed. If the secondary 
contact provides information saying that the person cannot be reached for a 
particular reason, then this will be documented in the record. If the subject is said 
to be deceased, then the secondary contact will be asked if they know the 
circumstances of the death. 
Expected Risks of Participation 
TMS Risks 
Transcranial magnetic stimulation is a non-invasive method of brain stimulation 
that relies on electromagnetic induction using an insulated coil placed over the 
left prefrontal cortex. The coil generates brief magnetic pulses, which pass easily 
and painlessly through the skull and into the brain. The pulses generated are of 
the same type and strength as those generated by magnetic resonance imaging 
(MRI) machines. When these pulses are administered in rapid succession, it is 
referred to as "repetitive TMS" or "rTMS", which can produce longer lasting 
changes in brain activity. During the treatment, the patient may experience light-
headedness, tapping, tingling, itching, headaches, or muscle twitching while the 
magnetic coil is turned on. However, TMS has been proven safe in major 
depressive disorder and the treatment team will be using an FDA-approved 
protocol for DLPFC iTBS. We will also be using a cTBS protocol that has been 
previously studied by Hanlon et al, who did not note meaningful differences in 
adverse effects. Because the TMS device produces a loud click with each pulse, 
the subject will wear earplugs during treatment to minimize discomfort. The most 
serious known risk of TMS is the production of a seizure. To minimize this risk, all 

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subjects with a history of epilepsy or epileptogenic intracranial lesions will be 
excluded from the study; any subjects that are deemed inappropriate for TMS 
treatment by the physician who administers TMS will also be excluded from the 
study. 
MRI Risks 
A metal object flying through the air toward the magnet and hitting the subject 
comprises the greatest risk associated with MRI. 
-There is a minimal risk to the subject's hearing. 
-There is a risk that we will discover an abnormality or disease in the subject, 
which would otherwise not be found. This risk can increase the psychologically-
induced stress associated with participating in this study. 
-Although there are no known risks associated with limited exposure to magnetic 
fields, we cannot rule out the possibility that in the future some risks may be 
discovered. 
Emotional Risks 
-When answering questions about emotionally-charged topics such as depressive 
symptoms and substance use, there is a risk of triggering negative thoughts or 
emotions in the participant. Similarly, the subject may experience some stress 
when performing psychological tests. However, there is no evidence to suggest 
that asking these questions could make the specific symptoms or disease state 
worse. 
EEG 
There are no risks, although patients will be required to have gel applied in their 
hair and the surface of their skin may be mildly scratched by the EEG gel 
applicator. These risks will be mitigated by asking for feedback from the patient 
frequently and adjusting procedure as needed to minimize discomfort. 
Other Risks 
Loss of confidentiality is a risk. This has potential legal consequences since the 
study involves questions about illegal drug use and urine drug screens. There is 
also a risk of boredom or cognitive fatigue, particularly from the lengthier visits 

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involving surveys, neurocognitive testing, and imaging at first visit and at the end 
of the treatment course. 
Procedures to Minimize Risks 
Minimizing psychological risks: 
A psychiatrist will be conducting the initial evaluation of the patient to determine 
appropriateness for treatment. Psychiatrists are trained on how to manage 
responses that demonstrate concern for imminent danger to self or others. The 
study will take place in a safe research environment and if the subject reports any 
current suicidal thoughts, a physician will be available to assist the patient and the 
patient will be sent for immediate psychiatric care at the appropriate level of 
medical and psychiatric attention needed based on the physician's clinical 
judgment. Patients will also have access to the 24-hour nurses number for 
emergent psychiatric needs. This number will be called if there is concern for 
imminent suicidality or concern for safety, and the physician overseeing 
treatment will arrange for urgent patient transport to the emergency room for 
psychiatric stabilization. If a subject expresses suicidal ideation or intent to a 
research assistant or other non-psychiatrist during study participation, a 
psychiatrist investigator will be paged to respond. 
Minimizing the risks of TMS: 
TMS will be administered by combining an FDA-approved protocol and a protocol 
that has been previously studied with no notable differences in adverse effects, 
and will be overseen by a psychiatrist in the clinical TMS service in the standard 
fashion. 
We will measure blood pressure and pulse prior to each treatment. If systolic 
blood pressure exceeds 160 mmHg, diastolic blood pressure exceeds 100 mmHg, 
or pulse exceeds 110 beats per minute, then we will confirm this with a second 
measurement. If it is confirmed by a second measurement then the treatment will 
be withheld and a clinician contacted to assess the subject and their potential 
need for acute medical care. We will also ask the person when they last used 
methamphetamine, and withhold treatment if we believe they may still be 
intoxicated with methamphetamine. 
Minimizing the risks of MRI: 

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To reduce the risk of a metal object flying through the air and hitting the subject, 
technologist or nearby person, we require that all people involved with the study 
remove all metal from their clothing, pockets and body prior to entering the scan 
room. No metal objects will be brought into the magnet room while the subject is 
inside the room. In addition, the door to the room remains closed throughout the 
entire study so that no one accidentally takes a ferrous metal object into the scan 
room. We also have a ferromagnetic detector for the research suite. The metal 
detector will work in tandem with our MRI screening sheet to ensure no metal is 
accidentally overlooked and taken into the scan room. 
-Subjects will be given either ear plugs or headphones to reduce the risk of 
hearing damage. 
-In the event that an abnormal finding is suspected, a radiologist trained in 
reading the examination will be consulted. If it is felt that the subject needs to be 
notified in order to seek out further medical advice, a physician will then contact 
the subject to discuss the issue. 
-Exposure to magnetic fields and radiofrequency fields will be kept to a minimum 
by setting a cutoff time of any study of 90 minutes in the magnet. 
-Subjects will be given a squeeze ball while in the MRI scanner to alert the 
investigators to stop the study. 
Minimizing emotional risks: 
During completion of surveys, testing, and other study procedures, participants 
who express distress or discomfort will be given options of continuing, suspending 
trying again at a later time, or withdrawing from the study. If a subject is able to 
complete most but not all assessments, and the assessments are not required to 
confirm eligibility for the study (e.g. the MINI to confirm diagnoses), then subjects 
may be allowed to continue in the study without completing all assessments. 
Investigator discretion will be used to determine if the subject is still contributing 
adequate data to help inform how outcomes change with TMS treatment. 
Minimizing EEG risks: 
The risk of scratching will be mitigated by asking for feedback from the patient 
frequently and adjusting procedure as needed to minimize discomfort. 

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Minimizing other risks: 
Data will be encrypted and protected and deidentified. All research data will be 
stored in a secure REDCap database. 
A member of the research team will give instructions on how to provide a urine 
sample. Participants may take a break at any time. 
Data Collection and Protection of Privacy 
No more data than required will be collected. All research data will be stored in a 
secure REDCap database, with the exception of MRI, EEG, and timing task data 
that will be stored on secure research drives. Only research team members will 
have access to this information. Study procedures will take place in secure private 
settings to prevent disclosure of personal health information. We will use a 
shared REDCap database with collaborating sites, but only investigators at specific 
sites will have access to identifiers for subjects from their site (such as name and 
address). 
All survey instruments and other data collection forms will be collected on an iPad 
through REDCap and stored in a secure REDCap database. For follow-up visits 
completed by phone, the research assistant may use a computer to enter data 
into REDCap. Data from fMRI and neuropsychological tests not completed in 
REDCap will be linked to the study ID and contain no other identifiers. 
Neuropsychological test results will be uploaded to REDCap after completion. EEG 
and timing task data will be stored on a secure research drive and stored with a 
study ID and no other identifiers. A special computer will be used for analysis of 
fMRI data, and all software will be protected with encrypted strong passwords. 
Electronic records will be kept on a secure research drive which will only be 
accessible to the research team by password encryption. All patient-identifying 
information will be stored behind UIHC Firewalls on REDCap. Name, contact 
information, medical record number, secondary contact person information, and 
the linked study identifier will be stored in a separate REDCap database from the 
other data to help prevent accidental disclosure and unnecessary downloads of 
identifiable information. The REDCap database with survey responses and other 
data for analysis will use this linked study ID to identify the subject. The REDCap 
surveys that were submitted as attachments will autopopulate with the study ID 
each time the surveys are deployed. 

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Paper copies of consent forms, and the MINI International Neuropsychiatric 
Interview with only a linked study ID, will be stored in a locked file cabinet in 
private office. 
Subjects will collect urine samples using standard methods and provide them to a 
research team member who will perform a dipstick urine drug screen. The urine 
sample will be discarded appropriately after the testing is complete. 
Potential Benefits to Society 
Treatment for methamphetamine use disorder is primarily psychosocial, and 
outcomes are suboptimal. No other treatments for methamphetamine use 
disorder have been proven safe and effective. If TMS treatment proves feasible in 
this study and we see improvements in symptoms, substance use, and functional 
connectivity then this study will justify a randomized controlled trial to evaluate 
the efficacy and safety of TMS for methamphetamine use disorder. If effective, 
this could prove to be a breakthrough in treatment options for 
methamphetamine use disorder. 
 
 
 

20 
 
Statistical Analysis Plan 
Sample Size Justification 
This is a pilot study without an untreated control group so will not be able to 
establish that the treatment is causal in improving outcomes. The overarching 
goal is to evaluate the ability to recruit and retain subjects, establish safety of the 
intervention in this population, evaluate target engagement of TMS using fMRI, 
and to determine the extent to which patient symptoms and substance use 
appear to improve during participation in treatment. We anticipate approximately 
20 subjects, which should be adequate to statistically detect clinically meaningful 
changes in symptoms and other outcome measures, depending on attrition. We 
will randomize order of treatments to gather preliminary data on any differences, 
but do not anticipate power to detect significant differences in effect by order of 
treatment with this sample size. 
Outcomes 
Primary outcomes:  
1. Retention in the Study:  Measured from Baseline to 12 weeks 
2. Retention in Psychosocial Treatment:  Measured from Baseline to 18 days 
(self-reported) 
Secondary outcomes (used all available data points as specified in figure 2): 
1. Functional Connectivity of the Dorsolateral Prefrontal Cortex and Anterior 
Insula—change from baseline to 4 weeks. Measured by correlation of 
region activity over MRI time series data, averaged for left and right 
hemisphere. 
2. Functional Connectivity Dorsolateral Prefrontal Cortex and Anterior 
Cingulate Cortex—change from baseline to 4 weeks. Measured by 
correlation of region activity over MRI time series data, averaged for left 
and right hemisphere. 
3. Functional Connectivity of the Medial Prefrontal Cortex and Ventral 
Striatum—change from baseline to 4 weeks. Measured by correlation of 
region activity over MRI time series data, averaged for left and right 
hemisphere. 
4. Kirby Delay Discounting Questionnaire, 27 Item 

21 
 
5. Number of Days of Methamphetamine Use in the Past Week 
6. Urine Drug Screen Positive for Stimulant 
7. Brief Substance Craving Scale 
8. Brief Addiction Monitor—Use Subscale 
9. Brief Addiction Monitor—Risk Factors Subscale 
10. Brief Addiction Monitor—Protective Factors Subscale 
11. Brief Addiction Monitor—Satisfaction with Progress Toward Achieving 
Recovery Goals (question 17) 
12. Quality of Life Enjoyment and Satisfaction Questionnaire—Short Form 
13. Patient Health Questionnaire--8 Item Scale 
14. Generalized Anxiety Disorder 7-item Scale 
15. Assessment of Recovery Capital 
16. Positive and Negative Affect Scale—Positive Affect Score 
17. Positive and Negative Affect Scale—Negative Affect Score 
18. Pittsburgh Sleep Quality Index 
19. Difficulties in Emotion Regulation Scale--Short Form 
20. UPPS-P Impulsive Behavior Scale, 59-item Revised Version 
 
Safety outcomes 
Adverse events are reported at each TMS treatment visit, or if otherwise 
volunteered by subject. 
Populations to be analyzed 
Intention to treat:  Subjects will be analyzed in the groups they were randomized 
to. However, only complete data will be used, and subjects were discontinued 
from the study if they missed more than 4 TMS treatments.  
Analyses 
Descriptive statistics will be examined for demographic and other variables, 
overall and by intervention group.  
For other analyses, a fixed time will be assigned for each study visit, which 
approximates the time at which the visit would have occurred on a typical study 
schedule.  

22 
 
Primary outcomes 
The primary analysis will compare intervention groups (DLPFC first or MPFC first) 
on time to discontinuation in the study and time to discontinuation of 
psychosocial treatment. The latter is defined as a participant indicating they are 
no longer in or seeking treatment. All subjects were in treatment or planning 
treatment at baseline, as an inclusion criterion. Time retained in the study or 
treatment will be described using Kaplan-Meier curves, and intervention groups 
will be compared using log-rank tests. 
Secondary outcomes 
Most secondary outcomes will be examined using linear mixed models. These 
allow for estimation of within group change over time as well as between group 
differences in change over time. Group by continuous time interaction terms will 
be the primary test of hypotheses for differences between groups. For outcomes 
measured at only two time points (baseline and week 4), if sample size is not 
adequate or mixed models do not converge, changes from baseline to the second 
measure will be calculated. Wilcoxon-rank sum tests or t-tests comparing 
differences in changes from baseline to week 4 will be used to compare groups, as 
appropriate based on the data distribution. A generalized estimating equations 
model clustered on subject with a logit link, with empirical standard error 
estimates, will be used to analyze the outcome of positive urine drug screens for 
stimulants, as this is binary, and this approach does not assume a correlation 
structure. The primary analysis of this outcome will still use a group by continuous 
time interaction to examine whether the odds of a positive urine drug screen 
decreases over time in each group, and whether any reduction over time differs 
between groups.  
Missing data 
As this is a pilot study with a small sample size, and dropout is expected, analyses 
will use all available data as feasible for randomized subjects who received at 
least one treatment, irrespective of the number of data points collected. For 
changes in functional connectivity as measured by MRI, only subjects with both 
baseline and 4-week assessments will be included. No imputation of data will be 
performed.  

23 
 
References 
1. Governor's Office of Drug Control Policy. News Release - Iowa Drug Control 
Report: Life-Changing Progress Amid Evolving Threats. 
https://odcp.iowa.gov/news-release-iowa-drug-control-report-life-changing-
progress-amid-evolving-threats. Published 2019. Updated November 13, 2019. 
Accessed December 13, 2019, 2019. 
2. Iowa Department of Public Health. Substance Abuse Brief, December 2018, 
Issue 7. 
https://idph.iowa.gov/Portals/1/userfiles/133/IASubAbuseBriefNewsletterDec201
8_Final.pdf. Published 2018. Accessed December 13, 2019, 2019. 
3. Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, 
pharmacology, clinical phenomenology, and treatment literature. Drug and 
alcohol dependence. 2014;143:11-21. 
4. 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;13:1095. 
5. 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;114(12):2137-2149. 
6. 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. 
7. 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;75(11):1199-1201. 
8. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst 
versus high-frequency repetitive transcranial magnetic stimulation in patients 
with depression (THREE-D): a randomised non-inferiority trial. Lancet. 
2018;391(10131):1683-1692. 

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9. Hanlon CA, Kearney-Ramos T, Dowdle LT, et al. Developing Repetitive 
Transcranial Magnetic Stimulation (rTMS) as a Treatment Tool for Cocaine Use 
Disorder: a Series of Six Translational Studies. Curr Behav Neurosci Rep. 
2017;4(4):341-352. 
10. Kearney-Ramos TE, Dowdle LT, Mithoefer OJ, Devries W, George MS, Hanlon 
CA. State-Dependent Effects of Ventromedial Prefrontal Cortex Continuous 
Thetaburst Stimulation on Cocaine Cue Reactivity in Chronic Cocaine Users. Front 
Psychiatry. 2019;10:317.