Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder
Phase: NA
Conditions: Cocaine Use Disorder, Cocaine Dependence
Sponsor: National Institute on Drug Abuse (NIDA)

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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Protocol Title: Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use 
Disorder 
Abbreviated Title: TBS in Cocaine Use 
Protocol Number: 17-DA-N002 
Date of This Submission/Version: December 6, 2023 
NCT02927236 
 
NIH Principal Investigator: 
 
 
Yihong Yang, PhD  
Chief, Neuroimaging Research Branch 
NIDA IRP 
Biomedical Research Center 
251 Bayview Blvd., Suite 200  
Baltimore, MD 21224  
(667) 312-5364  phone 
yihongyang@nih.gov  
 
 
 
 
 
 
 
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
Addictions IRB New Protocol Template              April 15, 2014 
 
 
 
 
 
 
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PRÉCIS: 
Objectives: Illicit drug use affects tens of millions of Americans and costs nearly 
$200 billion annually in health care costs and lost productivity. Cocaine dependence 
accounts for 25% of reported lifetime drug dependence though few successfully abstain 
with treatment. For efforts toward positive long-term outcomes, it is imperative to identify 
risk factors of poor outcomes, specialized treatments, neural mechanisms that change 
with treatment, and predictive measures of treatment outcomes. Substance abusers are 
known to have dysregulation in cue reactivity, reward processing, executive control, and 
intrinsic network connectivity. Non-invasive brain stimulation (NIBS) has proven 
effective at reducing drug craving in nicotine, alcohol, and cocaine users. Here, 
intermittent theta-burst stimulation (iTBS), a type of NIBS, delivered to left dorsolateral 
prefrontal cortex (dlPFC) is implemented to modulate substance abuse related circuit 
dysregulations and assess the relationship of iTBS-induced changes in circuitry to 
ongoing cocaine use.  
 
Study population: Recruitment from the Baltimore, Maryland area will take place 
for this protocol. For the Pilot, 20 cocaine dependent (CD) individuals will be recruited. 
(The Pilot was completed in July 2018). For the Expanded Feasibility Study, 45 healthy 
adults (HC) and 90 CD individuals will be recruited. All of the HC group will receive both 
active- and sham-iTBS in a within-subject crossover design. Half (45) of the CD 
group will receive active-iTBS and half (45) will receive sham-iTBS. The Expanded 
Feasibility Study groups will be matched on demographic measures (e.g., age, IQ, sex). 
Design: The Pilot is designed to be a tolerability pilot where iTBS parameters are 
assessed in CD participants. The first half of the Pilot participants will be inpatient (for 
initial close observations) and the second half will be outpatient (closely reflecting the 
Expanded Feasibility Study). Throughout the Pilot, clinical measures will be collected 
and participants closely monitored. The general outline for the Expanded Feasibility 
Study is to characterize the treatment cohort (vs. HC) and assess effectiveness of iTBS 
over the left dlPFC in altering task and resting brain activity. The iTBS intervention 
consists of 30 sessions over a 2-3week (10 treatment days) period as an add-on to a 
treatment-as-usual, contingency management, which will begin as soon as the iTBS 
treatment is completed. Structural and functional magnetic resonance imaging, neural 
measures of cue reactivity, reward processing, executive control, and intrinsic network 
connectivity will be collected to identify differences between CD and HC participants at 
baseline. In CD participants, neural measures along with cocaine use will be tracked 
longitudinally to assess neuroplastic changes, along with safety monitoring. 
Contingency management will begin when iTBS sessions are done and will continue for 
11 weeks. A 3-month follow-up period follows the end of CM. The Expanded Feasibility 
Study includes ~43 visits. 
Outcome parameters: Two main comparisons are of interest. First, baseline 
differences in neural measures between CD and HC participants will be identified. CD 
participants are expected to show dysregulations in these functions, relative to HC 
participants. Second, neural plasticity related to these functions due to iTBS treatment 
and reduction in cocaine use will be measured. The active-iTBS intervention is expected 
to be effective in reducing cocaine use, relative to the sham-iTBS intervention. 
Normalization of circuit dysregulation is hypothesized to be associated with reduction of 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
Addictions IRB New Protocol Template              April 15, 2014 
 
 
 
 
 
 
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cocaine use. Overall, the current protocol is designed to test whether iTBS to left dlPFC 
is efficacious in altering brain circuitry related to chronic cocaine use. 
 
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
Addictions IRB New Protocol Template              April 15, 2014 
 
 
 
 
 
 
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Table of Contents 
Précis ...................................................................................................................................................... ii 
 Background .......................................................................................................................................... 1 
A. The Problem ................................................................................................................................... 1 
B. Dysregulation in Addiction .............................................................................................................. 2 
C. Non-Invasive Brain Stimulation (NIBS) .......................................................................................... 4 
D. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Risk Minimization and Data 
Integrity ...................................................................................................................................................... 6 
 Tolerability Pilot [PILOT COMPLETE – Last Enrollee Was June 2018]............................................. 8 
A. Study Objectives ............................................................................................................................ 8 
B. Primary Goal .................................................................................................................................. 9 
C. Experimental Design ...................................................................................................................... 9 
D. Inclusion and Exclusion Criteria ................................................................................................... 10 
 
Description of the Study Population .................................................................................... 10 
 
Recruitment ......................................................................................................................... 11 
 
Inclusion Criteria.................................................................................................................. 12 
 
Exclusion Criteria ................................................................................................................ 14 
E. Clinical and Laboratory Methods .................................................................................................. 18 
 
Study Procedures ................................................................................................................ 18 
 
Screening ........................................................................................................................ 18 
 
Nursing Assessment ....................................................................................................... 20 
 
Orientation and iTBS Sessions ....................................................................................... 21 
 
Follow-Up ........................................................................................................................ 27 
 
iTBS Administration ............................................................................................................. 27 
 
Apparatus and Tests ....................................................................................................... 27 
 
Localization of Dorsolateral Prefrontal Cortex ................................................................ 27 
 
Motor Threshold Determination ....................................................................................... 28 
 
Stimulation Procedure ..................................................................................................... 29 
 
Discharge Procedures ......................................................................................................... 29 
 
Participant Monitoring ......................................................................................................... 29 
 
Risks .................................................................................................................................... 31 
 Expanded Feasibility Study ............................................................................................................. 31 
A. Study Objectives .......................................................................................................................... 32 
B. Goals ............................................................................................................................................ 32 
C. Aims ............................................................................................................................................. 33 
D. Hypotheses .................................................................................................................................. 33 
E. Experimental Design .................................................................................................................... 34 
F. Inclusion and Exclusion ................................................................................................................ 40 
 
Description of the Study Population .................................................................................... 40 
 
Inclusion Criteria.................................................................................................................. 41 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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Exclusion Criteria ................................................................................................................ 43 
G. Clinical and Laboratory Methods ................................................................................................. 47 
 
Study Procedures ................................................................................................................ 47 
 
Screening ........................................................................................................................ 49 
 
Nursing Assessments and Task Preparation .................................................................. 51 
 
MRI Scan Sessions ......................................................................................................... 56 
 
iTBS Sessions ................................................................................................................. 58 
 
Post-Treatment Follow-Up .............................................................................................. 59 
 
Experimental Measures ...................................................................................................... 61 
 
Imaging Measures ........................................................................................................... 61 
 
MRI Measures ................................................................................................................. 62 
 
fMRI Measures ................................................................................................................ 62 
 
Behavioral Measures ...................................................................................................... 64 
 
iTBS Administration ............................................................................................................. 65 
 
Apparatus and tests ........................................................................................................ 65 
 
Localization of Dorsolateral Prefrontal Cortex ................................................................ 65 
 
Motor Threshold Determination ....................................................................................... 65 
 
Stimulation Procedure ..................................................................................................... 66 
 
Sham Stimulation ............................................................................................................ 67 
 
Risks .................................................................................................................................... 70 
 
Additional Considerations ................................................................................................... 71 
 
Reproducibility of Task Paradigms.................................................................................. 71 
 
Relationship to Other Protocols ...................................................................................... 72 
 
Statistical Analysis............................................................................................................... 72 
 Collection and Storage of Human Specimens or Data ................................................................... 77 
A. Genomic Data Sharing (GDS) ...................................................................................................... 77 
B. Human Data Sharing (HDS) ......................................................................................................... 77 
C. Participant Safety Monitoring ....................................................................................................... 78 
 
Primary Saftey Endpoints and Associated Stop Rules ....................................................... 80 
 
Clinical Efficacy Cocaine Use Endpoint .............................................................................. 83 
D. Consent Process .......................................................................................................................... 85 
E. Rational for Participant selection .................................................................................................. 88 
 Evaluation of Risks/Discomforts and Benefits ................................................................................. 91 
A. Anticipated Benefit ....................................................................................................................... 91 
B. Risks and discomforts .................................................................................................................. 91 
 
Experimental Tasks ............................................................................................................. 91 
 
iTBS ..................................................................................................................................... 92 
 
Magnetic stimulation ....................................................................................................... 92 
 
Seizure ............................................................................................................................ 92 
 
Vasovagal Syncope ........................................................................................................ 93 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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Scalp Pain, Headache, and Other Minor Symptoms ...................................................... 94 
 
Acoustic Noise ................................................................................................................. 95 
 
Other Complications ........................................................................................................ 95 
 
MRI scanning ...................................................................................................................... 97 
 
Magnetic Field ................................................................................................................. 97 
 
Acoustic Noise ................................................................................................................. 98 
 
Mock Scanner ..................................................................................................................... 98 
 
Research Involving NIH Employees as Participants ........................................................... 99 
 Protection of Participants’ Privacy and Confidentiality .................................................................... 99 
A. Medical Records ........................................................................................................................... 99 
B. Research Records/Data ............................................................................................................... 99 
C. Stored Samples .......................................................................................................................... 100 
 Study Agents/Interventions .......................................................................................................... 100 
 Plan for Reporting Unanticipated Problems and Adverse Events .............................................. 100 
 Data Safety Monitoring PLan ........................................................................................................ 101 
A. Selection of a Data and Safety Monitoring Mechanism ............................................................. 101 
B. Frequency of the Monitoring ...................................................................................................... 101 
C. Stop or Change Rules ................................................................................................................ 102 
 
Primary Safety Endpoints and Associated Stop Rules ..................................................... 102 
 
Clinical Efficacy Cocaine Use Endpoint ............................................................................ 104 
D. Advanced Plans for Any Interim Analyses and/or Futility Analyses .......................................... 105 
E. Information to be Monitored ....................................................................................................... 105 
F. Communication ........................................................................................................................... 106 
G. Criteria for Study Withdrawal ..................................................................................................... 107 
 Data/Records Management ........................................................................................................... 107 
 Compensation ............................................................................................................................... 108 
 Quality Assurance ........................................................................................................................ 112 
A. Quality Assurance Monitor ......................................................................................................... 112 
B. Quality Assurance Plan .............................................................................................................. 113 
 Alternatives to Participation or Alternative Therapies ................................................................. 113 
 Conflict of Interest ....................................................................................................................... 113 
 Distribution of NIH Guidelines...................................................................................................... 113 
 Role of a Commercial Company or Sponsor .............................................................................. 113 
 Technology Transfer .................................................................................................................. 114 
 References................................................................................................................................ 115 
 
 
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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 BACKGROUND  
A. The Problem 
Addiction is a widespread, complex neurobiological disease1. Reportedly, 25 million 
Americans use illicit drugs costing $193 billion annually in areas such as health care 
and lost productivity2. Nearly 10% of Americans report lifetime drug dependence but 
only 25% have sought treatment3. Many who seek treatment do not successfully 
eliminate drug use behavior. As recidivism remains disturbingly high for those who enter 
treatment, there is substantial and immediate need to thoroughly identify risk factors for 
poor treatment outcomes, potential treatment targets, and more efficacious 
interventions. The longer an individual remains in treatment, the more outcomes 
improve4 highlighting the primary need to establish successful, potentially specialized, 
treatments that retain individuals throughout treatment. Cocaine dependence is the 
most often reported illicit drug dependence with nearly 25% of Americans reporting a 
lifetime drug dependence also reporting cocaine dependence3. Cocaine use in 
Maryland overall is below the national average at 15.4% but use in Baltimore is slightly 
above the national average at 26.5%5. Therefore, studying cocaine users in Baltimore 
could affect change locally with the potential to generalize more broadly.  
Presented here is a brief summary of cognitive and affective dysregulations 
previously identified in individuals with cocaine dependence, providing potential 
functional targets for therapeutic interventions. Ultimately, some of these targets may 
also serve as biomarkers for treatment efficacy. Overall, it is important to delineate the 
relationship between cocaine dependence and abnormalities in neural measures. 
Following this summary, a novel non-invasive brain stimulation (NIBS; intermittent theta-
burst stimulation or iTBS) intervention is proposed. Several NIBS techniques have been 
implemented in an attempt to reduce craving for nicotine, alcohol, and cocaine, with 
repetitive transcranial magnetic stimulation (rTMS) as the most common NIBS applied. 
Implementation of iTBS can be less time consuming and found to be more tolerable by 
participants thus offering the potential for widespread application. This is an initial step 
toward developing a new, efficacious treatment for cocaine dependence. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
Addictions IRB New Protocol Template              April 15, 2014 
 
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A protocol is proposed with a Pilot designed to assess tolerability of iTBS 
parameters to employ in a subsequent Expanded Feasibility Study assessing 
neuroplasticity related to the intervention was completed. The iTBS experimental 
treatment will be an add-on to a contingency management (CM) treatment as usual 
(TAU) that has been implemented successfully to reduce cocaine use (albeit with 
minimal long-term efficacy following CM). Neural risk factors will be monitored during 
and after treatment to identify changes with treatment. Cocaine use will also be tracked 
to inform any neural changes and treatment efficacy. Malleable risk factors identified 
here will be prime targets for future studies and treatment development. 
 
This proposal allows for a comprehensive neural picture of cocaine dependence. 
As discussed below, functional differences within tasks will be acquired with blood 
oxygenation level dependent (BOLD) fMRI and non-task related group differences will 
be identified with measures of structural, diffusion tensor imaging (DTI), functional 
connectivity (e.g., resting state measures), arterial spin labeling (ASL), magnetic 
resonance spectroscopy (MRS). Specific cognitive and affective constructs probed in 
this protocol are discussed in detail below. Changes in neural measures will be 
assessed in relation to reductions in cocaine use. 
 
B. Dysregulation in Addiction 
Several cognitive and affective differences have been identified between generally 
healthy individuals and individuals with substance dependence. Broadly, substance 
users have been identified to have dysregulation in attention, working memory, reward 
processing, executive control (e.g., response inhibition and error-processing) relative to 
healthy individuals6-10. Of specific interest here, are the neural deficiencies related to 
cognitive and affective processes identified in cocaine dependent individuals (CD). 
These systems engage brain regions that have been implicated to be dysregulated by 
the disease including dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex 
(ACC), inferior frontal gyrus (IFG) orbitofrontal cortex (OFC), striatum, hippocampus, 
basolateral amygdala, and insula7-9. Dopaminergic dysfunction is thought to be at the 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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heart of many of these group differences11 specifically dopamine (DA) released from the 
ventral tegmental area (VTA) into the nucleus accumbens (NAcc), prefrontal cortex 
(PFC), and amygdala. This DA system dysfunction has been linked to initiation and 
maintenance of addictive behaviors12. Drug use increases DA release in the 
mesocorticolimbic (MCL)-DA system13-15, which is thought to be an important element in 
learning, goal-directed behavior, and reward processing16, 17. Allocation of attention with 
respect to goal-directed behavior has also been linked to DA release18. Chronic drug 
use is associated with hypodopaminergic states19-21 suggesting treatments targeting the 
MCL-DA system may be essential for treating addiction (although it should be noted that 
dopamine agonist therapy is generally ineffective in cocaine dependence). Explicit 
modulation of the MCL-DA system by eliciting craving, reward processing, and 
executive control will inherently require the activity within dlPFC, ACC, IFG, OFC, 
striatum, hippocampus, basolateral amygdala, and insula; all areas implicated in 
addiction, differentiate CD from HC individuals, and are hypothesized to serve as 
targets for potential modulation. 
Cognitive and affective dysregulation in CD individuals has been shown in cue 
reactivity, reward processing, executive control, and intrinsic network connectivity. Cue-
induced hypoactivations have been related to addiction severity22 suggesting a 
malleable network, at least with increased exposure to cocaine. Alternatively, these cue-
induced hypoactivations could be preexisting and related to addiction severity. 
Identifying the sequential relationship between hypoactivations and addiction severity is 
difficult without longitudinal methods. Nonetheless, several hypo- and hyperactivations 
have been identified in samples of substance users. Hyperactivations from cue 
processing in sensory association cortex, motor cortex, and PCC elicited to cues have 
been associated with relapse to cocaine use23 and ACC activation has predicted 
relapse to nicotine24 and alcohol25. Neural activity related to reward processing within 
the caudate has differentiated CD from HC26, 27 as well as CD and former CD 
participants27. These functional differences may derive from reduced striatal volume in 
CD relative to HC participants28. The amygdala has also been implicated in reward 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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processing in addition to perception of fearful and threatening stimuli29. Response 
inhibition executive control tasks elicit hypoactivation for CD relative to HC participants 
in medial prefrontal regions, supplemental motor area, insula, and ACC30, 31. Findings 
from error-processing executive control tasks are somewhat mixed with hypoactivation 
measured in the ACC31-33, MFG/pre-SMA, left insula, left inferior frontal gyrus31 and 
hyperactivation in the ACC, MFG, inferior parietal lobe, angular gyrus34, and insula35 in 
CD compared to HC participants. Event-related potentials (ERPs) measures of error-
processing thought to originate in the ACC36, 37 also differentiate CD from HC 
participants38-40. Both fMRI41 and ERP40, 42, 43 measures of error-processing have been 
used to predict drug treatment outcomes. Intrinsic network connectivity is often 
measured by analyzing resting-state seed-based network connectivity. Such analyses 
have proven useful in identifying network connectivity differences in CD44-47 as well as 
other substances of abuse48-54. Overall, previously published tasks will be implemented 
to elicit cue reactivity55-57, reward processing58-62, response inhibition63-65, error-
processing63-65, and intrinsic network connectivity. 
 
C. Non-Invasive Brain Stimulation (NIBS) 
NIBS is designed to transiently stimulate localized cortex66-69 and their subcortical 
connections. NIBS is thought to change the baseline electrical steady-state of the 
targeted region by applying alternating magnetic pulses to the scalp to induce current in 
underlying neuronal tissue. With the wide range of research and clinical applications, 
rTMS has become a prominent excitatory stimulation method68, 69. Therapeutic effects of 
rTMS have induced long-term plastic changes with side-effects such as pain near the 
application site and muscle twitching which are experienced by about 36% and 20% of 
participants, respectively70. Serious adverse events, such as seizures, are rare71 and 
considered unlikely during NIBS applications. During a traditional rTMS session, 3000 
pulses at 10 Hz are applied over 37.5 minutes70, 72. The large number of pulses and 
length of protocol can prove difficult to complete for some participants. A viable 
alternative is iTBS71, 73 where only 600 total pulses in 50 Hz bursts of 3 pulses 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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separated by 200 msec for 2 seconds are applied at a frequency of .1 Hz over about 3 
minutes. The post-iTBS shift in electrical baseline has been shown to exceed the 
duration measured for rTMS74-76 while requiring far fewer stimulations and less time to 
implement. Three TBS stimulation paradigms have been described73 each administering 
600 pulses: iTBS wherein 2 seconds of pulses (i.e., train) are administered every 10 s 
for a total of 200 s; intermediate TBS (imTBS) wherein a 5 s train is administered every 
15 s for a total of 120 s; continuous TBS (cTBS) wherein a 40 s train is administered.  
rTMS has most often been applied effectively for treatment-resistant depression77, 78, 
but has also been explored in other disorders79. Stimulation over the left dlPFC is 
common and is now an FDA approved intervention for treatment-resistant depression79 
with substantial evidence for reducing depression symptoms80. Network connectivity 
between the dlPFC and ACC is normalized with this treatment81 suggesting network 
malleability with NIBS stimulation. In fact, broad activity changes81 and increases in DA 
release in the caudate nucleus82, 83 have been found with left dlPFC stimulation. 
Therefore, stimulation of the left dlPFC is a potential intervention tool in disorders of the 
DA system, such as addiction84, 85. Considering DA is related to plasticity necessary for 
learning and memory13, targeting deficiencies in the DA system in substance users with 
NIBS could be specifically useful. Applications of high frequency (thought to be 
excitatory) rTMS over left dlPFC have been successful in reducing craving for cocaine86-
88 and nicotine89. Only a single rTMS session was implemented although there is 
evidence that more sessions affect greater, longer-lasting reductions in cocaine 
craving87, 88. iTBS and cTBS over left and right dlPFC, respectively, were more effective 
at treating depression than rTMS90, 91. Applying iTBS, also thought to be excitatory, over 
left dlPFC has the potential to modulate the neural regions associated with 
dysregulations of addiction.  
The cognitive and affective dysregulations of addiction are associated with neural 
activity in the ACC, insula, or striatum and could be modulated by left dlPFC NIBS81. 
Cocaine craving86-88, 92 has been reduced with NIBS but implementing NIBS targeted at 
long-term reduction of substance use has yet to be explored. Adding iTBS to a TAU has 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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been effective in smoking cessation treatment93 and could be added to TAUs targeting 
other substances of abuse. A new application of the iTBS intervention is proposed here 
and is modeled after the rTMS implementation designed to reduce symptoms of 
depression. For depression, positive effects occur after 26-28 NIBS sessions94, 95. To 
decrease time to positive effects, multiple rTMS sessions have been implemented in a 
single day. As many as 10 daily sessions96, though more modest schedules of 2 
sessions per day for 10 days97 to 4 sessions per day for 5 days98, have also been 
implemented. By implementing multiple treatment sessions in a single day, the 
scheduled duration of treatment is condensed. This condensed schedule could increase 
retention rates compared to longer treatment schedules and be easier to implement in 
clinical settings. A single study has implemented multiple NIBS sessions a day in a 
sample of cocaine users92. In that study, participants received two 120 second trains of 
cTBS with a 60 second break between trains over mPFC. A total of 3,600 cTBS pulses 
were administered over a 5-minute period. This protocol reported no adverse events 
and was effective in reducing cocaine craving while administering 600 more pulses than 
a traditional rTMS session (3,000 pulses) in much less time (5 minutes) than a 
traditional 30 minute rTMS session. The treatment reduced resting activity in the ventral 
striatum while also reducing subjective cocaine craving. Another group administered 3 
iTBS sessions (1,800) pulses with only a 15-minute break between trains of 600 
pulses99, 100. This group identified no benefit to administering subsequent iTBS sessions 
before after-effects had dissipated from a previous administration. To account for after-
effects between iTBS administrations, a break of at least 30 minutes is necessary. 
Based on the above, we propose administering 3 iTBS sessions totaling 1,800 pulses 
per day in a cocaine dependent sample. However, tolerability of multiple daily iTBS 
sessions within CD participants will be first established in a Pilot before initiating the 
Expanded Feasibility Study.  
 
D. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Risk 
Minimization and Data Integrity  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) belongs to the 
coronavirus family, a major cause of upper respiratory infections world-wide that is also 
is known to have neurotropic properties [reviewed in (Li et al. 2020b; Ng Kee Kwong et 
al. 2020; Yashavantha Rao and Jayabaskaran 2020)]. SARS-CoV-2 is the cause of the 
current Coronavirus 2019 disease (COVID-19) which has infected over 19 million 
individuals and claimed the lives of about 750,000 worldwide as of August 10, 2020. 
https://coronavirus.jhu.edu/map.html 
COVID-19 can produce neurologic manifestations ranging from loss of taste and 
smell to dizziness, headache, confusion, mild cognitive impairment, encephalitis, 
autoimmune Guillain Barre Syndrome and acute cerebrovascular disease [reviewed in 
(Ahmed et al. 2020; Leonardi et al. 2020; Li et al. 2020a; Montalvan et al. 2020; Niazkar 
et al. 2020)]. There are several possible mechanisms by which SARS-CoV-2 may 
impact the brain: (1) Direct invasion through the cribriform plate, (2) Retrograde 
transmission through cranial nerve axons in the periphery, (3) Hematogenous spread 
through infecting vascular endothelial cells, (4) Indirect impact through an exaggerated 
inflammatory response, and (5) Indirect impact through severe respiratory infection-
induced hypoxia [reviewed in (Ahmed et al. 2020; Troyer et al. 2020; Zhou et al. 2020)].  
While current published reports of brain involvement in COVID-19 patients come 
from severe hospitalized cases, it is highly likely that the virus also impacts the brain in 
mild or even asymptomatic cases. For instance, loss of smell in mild cases suggests 
that SARS-CoV-2 can affect the brain regardless of the presence of respiratory 
symptoms. Regional alterations in brain structure (voxel-based morphometry and 
diffusion tensor imaging) have already been documented in recovered COVID-19 
patients (Lu et al 2020). Given this wide range of possible CNS effects, it is likely that 
COVID-19-associated changes may also alter BOLD signal which is dependent on both 
neuronal and vascular functioning. Further, substance users may be particularly 
vulnerable to CNS effects given evidence of structural, functional and neurochemical 
differences from non-substance users at least some of which may represent damage 
resulting from chronic exposure to substances of abuse. Vascular changes evident in 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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substance use disorders (ref Weis and Buttner 2017; doi: 10.1016/B978-0-12-802395-
2.00014-6) may also predispose substance users to the vascular effects of COVID-19. 
Given the wide range of potential impact and differential impact of COVID-19 infection 
on both healthy control participants and those with a substance use disorder, 
understanding participants’ COVID-19 status may be important for the integrity of our 
research data. Therefore, we will assess SARS-CoV-2 antibodies in order to assess for 
possible effects. We will use COVID diagnostic testing to exclude participants with 
active infection. We are NOT studying the SARS-CoV-2 virus in this protocol, nor are 
we evaluating the safety or efficacy of a COVID-19 diagnostic test or antibody test. 
As long as the SARS-CoV-2 pandemic continues, it will be important to minimize 
person-to-person contact in order to reduce the risk of transmission. Thus, a number of 
procedural changes, detailed below, will be necessary as long as there is significant risk 
of disease spread.  
 
 
 TOLERABILITY PILOT [PILOT COMPLETE – Last Enrollee Was June 2018] 
A. Study Objectives  
The Pilot is designed to establish tolerability criteria for administering iTBS to 
cocaine users, initially as inpatient followed by an outpatient cohort. The cohort 
recruited for this Pilot will closely mimic the treatment population for the Expanded 
Feasibility Study. This two-step design allows for more complete monitoring of the initial 
participants receiving this novel iTBS intervention. rTMS has been administered as 
many as 10 times a day with as many as 30,000 pulses delivered. One group 
administered 3 iTBS sessions (1,800 pulses) with only a 15-minute break between 
trains of 600 pulses99, 100. In an abundance of caution and in the absence of previously 
published data in CD participants, we propose to limit iTBS to only 3 daily intervention 
sessions with at least a 60-minute interval between sessions. This method is designed 
to increase the cumulative dose of iTBS each day while staying well within tolerability 
thresholds. Considering a previous group has administered 3 iTBS sessions (1,800 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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pulses)99, 100 in a 1 hour window, we expect 3 iTBS sessions (1,800 pulses)92 
administered within a 2 hour window will also be well tolerated. 
 
 
B. Primary Goal 
The primary goal of the Pilot is to establish tolerability of 3 daily iTBS sessions with 
an inter-administration interval of at least 60-minutes in CD participants.  
 
C. Experimental Design 
CD individuals will be recruited from the greater Baltimore community. Twenty 
participants will be recruited to ensure the target number of participants (n = 10) will 
complete the two-week pilot protocol. The first half (n = 5) of these participants will be 
enrolled as inpatients and the second half (n = 5) will be enrolled as outpatients. 
Participants will be consented to the protocol and complete several questionnaires prior 
to starting the iTBS treatments. The consent and questionnaire completion will require 
one or two visits prior to enrolling in the treatment protocol. 
Initially, 5 (who complete) participants will stay in the on-campus inpatient facility 
approved by the NIDA Clinical Director’s office while they participate in this iTBS 
protocol. In general, participants will arrive at the inpatient facility on Sunday afternoon. 
Participants will be escorted by study staff to and from the inpatient unit on treatment 
days, which may include automotive pick-up service (e.g., shuttle, taxi). Three sessions 
of iTBS will be administered each of the 10 weekdays over a 2-week period with a 
duration between iTBS administration of at least 60-minutes. Participants will be allowed 
to go home over the weekend between the first and second week of the pilot. Generally, 
they will be released Friday afternoon and return Sunday afternoon for the second week 
of the pilot. Alternatively, participants may be admitted on Monday afternoons, begin 
treatment on Tuesday for 5 consecutive days, and be discharged on Saturday. They will 
return Monday for the second week of treatment. 
Other than stimulations over the motor cortex to identify resting motor threshold 
(RMT), all iTBS administrations will be over the dlPFC. Cognitive and affective 

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measures (see Study Procedures below) will be monitored throughout the 2-week 
period. Recruitment curves (i.e., ratio of GABA and glutamate) will be measured at 
orientation, on four separate days of iTBS administration, and each of the follow-up 
visits. Recruitment curves are collected with a sequence of single TMS pulses over 
about a 5-minute period. Generally, six single pulses are delivered over the motor 
hotspot at seven different intensities relative to that participant’s identified RMT (90% of 
RMT, 95%, 100%, 105%, 110%, 115%, & 120%). Motor evoked potentials will be 
recorded during the recruitment curve sessions. The sequence of pulses will be 
randomized with a jittered inter-stimulation-interval between about 5 and 10s. In the 
absence of significant and unexpected adverse events, an additional 5 (who complete) 
participants will be recruited to adhere to a similar treatment schedule but as outpatients 
to better model the Expanded Feasibility Study design.  
All participants will be observed for a minimum of 2 hours after iTBS completion 
before being discharged. Before administering iTBS each day, participants will be 
assessed for any lingering or delayed effects from iTBS with the TBS Monitoring 
Questionnaire (Appendix 1). Contact attempts will be made by phone approximately 1-3 
days after completion of their treatment to assess any residual or delayed effects from 
the iTBS. Also, two post-treatment follow-up visits for participants who complete at least 
7 of 10 days of iTBS treatment will be attempted to assess, RMT, recruitment curve, 
drug use, and any behavioral changes post-treatment (may repeat some or all 
characterization measures and assessments of drug use). The first attempted follow-up 
visit will be approximately 1 week post-treatment and the second will be after 
approximately 4-weeks post-treatment. 
 
D. Inclusion and Exclusion Criteria 
 
Description of the Study Population 
We will enroll 20 CD individuals willing to participate in an open-label iTBS feasibility 
and tolerability study who and meet the inclusion and exclusion criteria outlined below. 
Twenty CD participants will be recruited to obtain the necessary number of (n = 10) 

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completers. Screening will be conducted under the NIDA screening protocol 06-DA-
N415 to determine eligibility (Pilot Eligibility Checklist; Appendix 30).  
 
 
Recruitment 
Individuals will be recruited primarily from material developed and distributed via 
NIDA’s approved recruiting techniques such as advertisements circulated by 
newspapers, magazines, flyers, and online. Recruiting will also include radio ads and 
landing pages on the NIDA recruitment website, https://researchstudies.drugabuse.gov/.  
All approved recruiting methods described within this protocol may be applied. With 
these materials, participants may be recruited from the community using the NIDA IRP 
recruitment contractor. 
Material will be developed and distributed via NIDA approved recruiting techniques 
such as advertisements circulated by newspapers, magazines, flyers, and online. All 
approved recruiting methods described within this protocol may be applied. With this 
material, participants may be recruited from the community using the NIDA IRP 
recruitment contractor. We may also use the services provided at the NIH Office of 
Patient Recruitment. We anticipate an average accrual rate of 1-2 participants per 
week.  
Participant Testimonials: 
We will develop videos clips or still ads using real participant testimonials with a 
photo and a quote from participants who are willing to have their photos and quotes 
used as ads. Participant testimonials are currently used at NIH 
(https://www.drugabuse.gov/related-topics/treatment/one-patients-story-nida-clinical-
trials-bring-new-life-to-woman-struggling-opioid-addiction  and 
https://www.nih.gov/health-information/nih-clinical-research-trials-you/personal-stories ). 
We are interested in using high-impact quotes from similar interviews with our current 
and former participants (both treatment seeking and non-treatment) to improve the 
authenticity and relatability of our advertising campaigns. 

PI Name: Yihong Yang, Ph.D. 
 
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We would ask participants if 1) they would like to tell us about their experience in this 
study and have us use their picture and quote used for advertising purposes. If they are 
interested, we may ask them questions such as those listed below, then develop the 
ads, submit to PILB and then to IRB. The ads would look very similar to current ads with 
a quote from the participant.  These ads would be posted as currently approved ads do, 
in print, online, social media, and on the NIDA website. Past subjects may also be 
contacted via phone so that we may ask them if they are interested in doing a 
testimonial ad with NIDA. Participants will be notified that not all quotes will be used and 
that the final ad may not be published. They will also be asked to sign a media release 
form if they would like to have their photo and/or quote used in an ad. 
“What would you say to someone who is thinking about being in this study?” 
“How has being in this study affected your daily life?”  
“When considering personal interactions throughout the duration of the trial, how    
would you describe your experience?” 
 
 
Inclusion Criteria 
Participants must: 
 Be able to give valid informed consent. 
 Be 18 – 60 years of age.  
a. Justification: Many neural processes change with age, and these changes 
could introduce unwanted variability in both behavioral and MRI signals. 
b. Screening tool: Self-report. Government-issued forms of identification (e.g. 
driver’s license, birth certificate). 
 Right-Handed. 
a. Justification: Differences in hemispheric dominance could confound iTBS 
administration and MRI measurements. 
b. Screening tool: Edinburgh Handedness Inventory. 
 Be in good health.  

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a. Justification: Many illnesses may alter neural functioning as well as fMRI 
signals. 
b. Screening tools: Medical Assessment, Medical History and Physical 
Examination. Medical assessments include: Vital Signs, EKG, oral HIV 
test, height/weight measurements, urinalysis, and blood sample. Tests on 
the blood sample include CBC, complete metabolic profile, TSH, ESR, 
syphilis test, and HIV (if needed to confirm a positive salivary test for HIV). 
The following individual laboratory results will independently disqualify 
individuals: Cholesterol >250 mg/dl, Hemoglobin < 10 g/dl, WBC < 
2400/µl, LFTs > 3 X upper normal limit, HCG positive, Casual serum 
glucose > 200 mg/dl, Urine protein > 1+, HIV positive. (Serum glucose 
over 140 mg/dl will be followed up with a fasting serum glucose 
assessment. Those with fasting glucose below 100 mg/dl may be 
considered for the protocol. Others will be rejected and referred for work-
up.). Liver function will be evaluated with aspartate aminotransferase 
(AST) and alanine transaminase (ALT). A greater than 3 x upper normal 
limit for AST or ALT will disqualify individuals. MAI reserves the right to 
exclude at less extreme lab values if clinical judgment warrants exclusion. 
 Absence of a specific learning disability, ADHD or cognitive impairment. 
a. Justification: Participants must be able to perform a cognitively challenging 
task to a high standard. 
b. Screening tool:  Adult ADHD Self-Report Scale with follow up clinical 
interview, Wechsler Abbreviated Scale of Intelligence (WASI), History of 
placement in special education classes for a learning problem. 
 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. 
a. Justification: cocaine use disorder, in regular users, is the focus of this 
protocol. 

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b. Screening tool: Potential diagnoses will be evaluated by a counselor using 
any one or more of the following: Drug Use Survey, SCID Screen Patient 
Questionnaire, Mini International Neuropsychiatric Interview (M.I.N.I), 
Addiction Severity Index, and Brief Cocaine Cessation Motivation 
Assessment. The interviewer will supplement SCID with questions to 
assess for DSM-5 substance use disorders. The MAI may be consulted in 
this determination.  
 
Exclusion Criteria 
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. 
a. Justification: Stroke, vascular lesions or head trauma can lower the 
seizure threshold and are therefore contra-indications for iTBS. Fainting 
episodes or syncope of unknown cause could indicate an undiagnosed 
condition associated with seizures. 
b. Screening tool: TMS safety Screen and Medical History. 
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 buprenorphine containing medication for therapeutic maintenance) 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 a buprenorphine 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 

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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 buprenorphine 
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. Individuals must be receiving their buprenorphine 
maintenance medication as take-home doses from an external (i.e., non-NIDA-
IRP) provider. 
a. Justification: While use of multiple substances is the norm and some use 
will be allowed, the focus of the current protocol is on cocaine. However, 
participants with tolerance or withdrawal symptoms to alcohol or a 
sedative/hypnotic/anxiolytic will be at increased risk of a seizure from iTBS 
and will therefore be excluded. Individuals receiving buprenorphine 
maintenance and struggling with cocaine use are an ecologically valid 
population in the greater Baltimore area and do not increase risk of 
seizure. 
b. Screening tool: Drug Use Survey and SCID Screen Patient Questionnaire 
or M.I.N.I). The interviewer will supplement SCID with questions to assess 
for DSM-5 substance use disorders. Potential diagnoses will be further 
evaluated with a clinical interview with a counselor. 
3. First-degree family history of any neurological disorder with a potentially 
hereditary basis, including migraines, epilepsy, or multiple sclerosis.  
a. Justification: Neurological disorders can lower the seizure threshold, and 
are therefore contra-indications for iTBS. First-degree family history of 
certain neurological disorders with a hereditary component increases the 
risk of the participant having an undiagnosed condition that is associated 
with lowered seizure threshold. 
b. Screening tool: TMS safety screening, Medical History. 

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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. 
a. Justification: Certain metal in the body is a contra-indication for iTBS 
administration, as this method involves exposure to a relatively strong 
static magnetic field that can move magnetic material not securely bound 
and rapidly alternating magnetic fields that can generate heat and current 
in metal contained in the body.  
b. Screening tool: Medical History, TMS safety screen. 
5. Noise-induced hearing loss or tinnitus.  
a. Justification: individuals with noise-induced hearing problems may be 
particularly vulnerable to the acoustic noise generated by iTBS equipment.  
b. Screening tools: TMS safety screening. 
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. 
a. Justification: The use of certain medications or drugs can lower seizure 
threshold during use or withdrawal and is therefore contra-indicated for 
iTBS. Such medications may also alter neural functioning independent of 
the individual’s drug use or the effects of the iTBS and thus add more 
variability to our data. 
b. Screening tools: Medical history, Medical Assessments: Urine toxicology 
analysis for presence of a broad range of prescription and nonprescription 
drugs.  
7. Lifetime history of schizophrenia, bipolar disorder, mania, or hypomania. 

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a. Justification: The population of interest here is a healthy population with 
no psychiatric disorders other than substance use disorders. In 
participants with bipolar disorder, mania or hypomania, there is a small 
chance that iTBS can trigger (hypo)manic symptoms. As some degree of 
depressive symptoms is common in cocaine dependence and may result 
from the drug use, mild unipolar depression will not be exclusionary. 
b. Screening tools: SCID Screen Patient Questionnaire or M.I.N.I. Potential 
diagnoses will be further evaluated by a counselor.  
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.  
a. Justifications: the risk of iTBS for individuals with a heart condition is 
unknown. 
b. Screening tool: physical assessment (EKG), medical history. 
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). 
a. Justification: it is unknown whether iTBS poses a risk to fetuses.  
b. Screening tool: Urine and/or serum pregnancy tests, and clinical interview.   
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.  
a. Justification: in order to avoid possible carry-over effects from previous 
exposure to NIBS prior to participation in the proposed intervention, we 
will not enroll participants who have received any NIBS in the two weeks 
preceding enrollment or treatment with NIBS modality with the last 6 
months preceding enrollment.  
b. Screening tool: TMS safety screen. 
 

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E. Clinical and Laboratory Methods  
 
Study Procedures  
Participants will be scheduled for multiple clinical assessment and data collection 
sessions to complete the protocol. These procedures will take place in the on-campus 
inpatient facility approved by the NIDA Clinical Director’s office or at National Institute 
on Drug Abuse Intramural Research Program (NIDA-IRP) depending on availability of 
staff, facilities, and participants. 
 
 Screening 
Candidate participants will be screened for participation based on the Inclusion and 
Exclusion criteria listed above. Informed consent will be obtained prior to the 
commencement of screening procedures. Initial phone screening will utilize the 
approved phone screen in protocol 06-DA-N415. During in-person screening, potential 
participants will be given some initial information regarding the study (see Appendix 3 & 
4 “Fact Sheets”; Appendix 5 “TBS Information Sheet”) to determine if they are interested 
in possible participation. The following assessments will be administered during 
screening: 
Adult ADHD Self-Report Scale (ASRS v1.1101): This questionnaire is an 18-item 
checklist designed by the World Health Organization (WHO) and Workgroup on Adult 
ADHD to determine whether a participant is suffering from symptoms related to 
attention-deficit/hyperactivity disorder. Completion time: ~ 5 minutes. 
Addiction Severity Index (ASI102):  A semi-structured interview designed to provide 
information in 6 areas related to drug abuse and drug abuse treatment: medical, 
employment/support, alcohol and drug use, legal, family/social and psychiatric. 
Completion time: ~ 45-60 minutes. 
Brief Cocaine Cessation Motivation Assessment (BCCMA)(Appendix 28): a semi-
structured interview to assess the stage of change and motivation level for cocaine 
dependent participants. Completion time: 10-15 minutes.  

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Contact Information Form: This form requests multiple methods of contact for a 
participant, as well as the preferred contact method, preferred contact time, and 
emergency contact information. Completion time: < 5 minutes. 
Drug Use Survey (DUS): An interviewer-administered questionnaire designed to 
collect information regarding lifetime history of substance use. Completion time: < 40 
minutes. 
Edinburgh Handedness Inventory103: This 12-item questionnaire assists in 
determining the dominant hand (or handedness) of a particular participant by inquiring 
which hand the participant uses for various tasks. Completion time: ~ 5 minutes. 
Medical Assessments: Vital Signs, height/weight measurements, urinalysis, EKG, 
oral HIV test, blood draw for CBC, chemistries, thyroid and liver function, hepatitis 
screen, erythrocyte sedimentation rate, urine qualitative drug screen for cocaine, THC, 
benzo, morphine/opiates, MDMA, amphetamine /methamphetamine, methadone, 
buprenorphine, PCP, and oxycodone, urine toxicology which analyzes for presence of a 
broad range of prescription and nonprescription drugs, as well as urine and/or serum 
pregnancy testing for menstruating females. Breathalyzer for alcohol will be taken at this 
time as well. Completion time: 30-40 minutes. 
Medical History and Physical Examination: This is a standard physical and detailed 
medical history and physical examination designed to capture the inclusion and 
exclusion criteria for NIDA-IRP protocols. It is administered by a Physician’s Assistant or 
other credentialed medical staff. The estimated time to complete is variable. Completion 
time: 45 to 90 minutes. 
Mini International Neuropsychiatric Interview (M.I.N.I)104: a brief structured interview 
for the major psychiatric disorders in DSM-5 and ICD-10. Follow up questions may 
ensue. Completion time: ~20 minutes. (Participants will complete either the MINI or the 
SCID). 
Participant Safety – MRI Screening Form: A questionnaire that aids in determining 
appropriateness of MRI scan. Completion time: < 5 minutes. 

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SCID Screen Patient Questionnaire – Extended (SSPQ-X)105 with follow up clinical 
interview: Computer-administered screening version of the Structured Clinical Interview 
for DSM-IV™ (SCID), used in assisting with diagnosis of DSM-IV Axis I disorders. 
Interviewer will supplement with questions to assess for DSM-5 substance use 
disorders. (Participants will complete either the MINI or the SCID). 
TBS Information Sheet (Appendix 5): A general information sheet on TBS 
administration with common questions and answers is given to participants as an 
informational item only. Participants are given time to read the handout and to ask 
questions about it while in the clinic. Completion time: ~ 20 minutes. 
TMS Safety Screen:  A questionnaire that aids in determining appropriateness of 
administering TBS. Completion time: < 5 minutes. 
Toronto Alexithymia Scale (TAS-20)106: A 20-item self-report questionnaire to assess 
emotional awareness. Completion time: ~ 10 minutes. 
Wechsler Abbreviated Scale of Intelligence (WASI107): This is an abbreviated version 
of the Wechsler Adult Intelligence Scales – Third Edition that provides IQ measures of 
suitable reliability for matching subjects. Completion time: ~ 1 hour.  
 
 Nursing Assessment 
After completing the consent interview and prior to study sessions, participants will 
undergo a nursing assessment, which, depending on the session type, may include 
measuring vital signs, a breathalyzer test for expired ethanol, an observed urine test for 
common abused drugs, a TMS safety questionnaire, and if females, a urine pregnancy 
test. Participants will also be asked when they last had NIBS and whether this was at 
NIDA or elsewhere.  In addition, participants will be asked to report changes in medical 
history, recent over-the-counter, prescription, or other substance intake, time of last 
meal, hours slept the previous night, and, if female, last menstrual period and whether 
or not they are currently taking a contraceptive pill. Participants will be asked not to use 
alcohol or drugs for at least 24 hours prior to TMS sessions. Participants with a positive 
breathalyzer will be rescheduled. In the event of a positive drug test, an interview to 

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assess last drug use and a neuromotor assessment to test for acute intoxication will be 
performed. If participants test positive for drugs other than THC, or cocaine for the CD 
group, based on the MAI’s judgment, they may be rescheduled, as will those who fail 
the neuromotor. However, if they test positive on a second occasion they may be 
excluded from the study. Inpatient participants will be searched upon intake (Appendix 
CC) and will have vital signs assessed in accordance with the standards of the inpatient 
unit. Upon intake, participants will complete a breathalyzer and urine drug screen. After 
all TMS sessions, participants will have their heart rate and blood pressure taken. 
Completion time: ~10-45 minutes. 
 
 Orientation and iTBS Sessions 
After participants are consented and prior to treatment, they will complete baseline 
characterization measures and a training session where they will be oriented to iTBS 
and the recruitment curve. Individuals receiving buprenorphine maintenance will be 
required to sign a release of information allowing the MAI (or staff clinician) to monitor 
their medical status while enrolled in the study, both at NIDA and via clinical 
assessments performed by the buprenorphine maintenance provider and consultation 
with the outside provider. 
Participants may be scheduled for an additional visit and the necessary additional 
time to complete these assessments prior to beginning the 10-day iTBS treatment 
session. Characterization measures include: 
Attitudes Towards Risk Questionnaire (Appendix 7): A 34-item self-report with 5-
point Likert scales that assess attitudes towards physical and psychological risk. 
Completion time: < 10 min. 
Addiction Severity Index (ASI, Appendix 44):  A semi-structured interview designed 
to provide information in 6 areas related to drug abuse and drug abuse treatment: 
medical, employment/support, alcohol and drug use, legal, family/social and psychiatric. 
Completion time: 45-60 minutes. 

PI Name: Yihong Yang, Ph.D. 
 
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Brief Externalizing Inventory108 (Appendix 9): A 159-item self-report adapted from 
the full Externalizing inventory109 used to assess a range of behavioral and personality 
characteristics that have been attributed to a broad psychological construct termed 
externalizing. These characteristics include: physical/relational destructive-aggression, 
boredom proneness, irresponsibility, problematic impulsivity, drug and alcohol use or 
problems, theft, fraud, rebelliousness, alienation, and blame externalizing. Completion 
time: ~ 15 min. 
The Revised Social Anhedonia Scale (Appendix 42): A 40-item true-false self-report 
questionnaire intended to measure decreased pleasure derived from interpersonal 
sources.  Completion time: ~10 minutes. 
The Physical Anhedonia Scale (Appendix 43): A 61-item true-false self-report that 
taps a range of presumably pleasurable experiences involving eating, touching, feeling, 
sex, movement, smell, and sound. Completion time: ~15 minutes.  
Cocaine Craving Questionnaire (CCQ110; Appendix 11): This measure includes 45 
items that measure current craving for cocaine. Completion time: ~ 10 minutes. 
Cocaine Craving Scale (CCS111; Appendix 12): Five questions on intensity and 
frequency of craving, both currently and in the preceding 24 hours that have been 
shown to possess short-term predictive validity of cocaine use. Completion time: < 5 
minutes. 
Cocaine use, Pattern, and Withdrawal Questionnaire (Appendix 13): This is an 
interview-guided questionnaire, designed by Dr. B. J. Salmeron, and has been 
successfully employed in previous studies. Completion time: ~ 10 minutes. 
Montgomery-Asberg Depression Rating Scale (MADRS112; Appendix 14): A clinical 
assessment to identify symptoms of depression. This assessment is especially useful in 
identifying changes in depression symptoms over time. If a participant reports suicidal 
thoughts, the CDW Critical Item Alert System will be initiated following the NIDA SOP to 
address such responses. Completion time: < 10 minutes. 
Modified Positive and Negative Affect Scale (Modified version of the PANAS; 
Appendix 15): Participants are asked to fill in a questionnaire about possible side-effects 

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since the last iTBS session (the TBS monitoring questionnaire), and a questionnaire 
about their affect (a modified version of the PANAS). The sole purpose for the modified 
version of the PANAS is to assess the answer to one single question (“Right now I feel 
… detached: rate from “not at all” to “extremely”). This is not in the original, validated 
PANAS-SF. Instead, the modified questionnaire is used as a device to ask this one 
single question, without calling unwanted attention to it by asking it as a single item. A 
self-report scale to assess state-level affect. Completion time: < 5 Minutes. 
Profile of Mood States (POMS; Appendix 16): A questionnaire designed to measure 
present mood state by a list of adjectives on a 5-point Likert scale and measures six 
dimensions of affect, including tension-anxiety, depression-dejection, anger-hostility, 
vigor-activity, fatigue-inertia, and confusion-bewilderment. The measure has been 
shown to produce reliable and valid profiles of mood state113, 114. Completion time: ~ 5 
minutes. 
Scale for the Assessment of Positive Symptoms for Cocaine-Induced Psychosis 
(SAPS-CIP115, Appendix 32): The SAPS-CIP is a modification of the Scale for 
Assessment of Positive Symptoms designed to focus on psychotic symptoms related to 
cocaine use. We will use the hallucinations and delusions sections which have been 
shown to be particularly useful in assessing cocaine-induced psychosis. If endorsed, the 
MAI (or staff clinician) will assess current psychosis and need for further evaluation 
and/or treatment. Completion time: < 30 minutes. 
Cocaine-Induced Psychosis: Screener (CIP: Screener, Appendix 33): The CIP: 
Screener is designed for efficient assessment of cocaine-induced psychosis and will be 
used to assess changes, relative to baseline, throughout the protocol. Any worsening 
from baseline in cocaine-induced psychosis measured throughout the protocol will be 
evaluated by the MAI (or staff clinician). Completion time: < 5 minutes. 
Sensation Seeking Scale V (SSS-V, 116; Appendix 17): A 40-item self-report 
questionnaire that assesses individual differences in sensation seeking. The scale 
consists of four subscales (Boredom Susceptibility [BS], Thrill and adventure seeking 

PI Name: Yihong Yang, Ph.D. 
 
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[TAS], Experience seeking [ES], and Disinhibition [Dis]) composed of 10-items each. 
Completion time: < 10 minutes. 
Snaith-Hamilton Pleasure Scale (SHAPS, 117; Appendix 18): A 14-item self-report 
scale designed to measure hedonic-tone/anhedonia. Completion time: ~ 5 minutes. 
Temperament and Character Inventory118 (Appendix 19): A widely used test that 
assesses dimensions of personality (e.g., harm avoidance, novelty seeking, reward 
dependence, and persistence) that are considered to be related to monoaminergic 
function. Completion time: ~ 25 minutes. 
The Multidimensional Social Contact Circle119 (Appendix 20): A self-report scale 
designed to measure social ties between the participants and their friend, family, co-
workers, etc. Completion time: ~ 15 minutes. 
Time-line follow back (TLFB; Appendix 21). The TLFB will be used to assess 
substance use behavior. This assessment will be either self-administered or 
administered by one of the investigators. Participants will read the instructions and/or 
will be guided by the therapist or investigator in filling out the calendar. A lifetime TLFB 
will be administered at the start of the protocol then on each visit to assess substance 
use between administrations. Completion time: 15 minutes to 2 hours. 
Prior to the commencement of iTBS treatment sessions, participants will complete a 
training session where they will be oriented to iTBS and recruitment curve. Participant-
specific approximation of the left dlPFC, identified using the BeamF3 heuristic120, will be 
recorded as well as resting motor threshold (RMT). Orientation may take up to 1 hour 
and will precede the first iTBS treatment. RMT will be identified each iTBS treatment 
day and each day, after the first, will use measurements from the previous day as a 
guide.  
The nurse assessment will take place every treatment day for both inpatient and 
outpatient participants. If inpatient participants are on any medications, the inpatient 
facility will provide them while they are on the unit, except for birth control pills which the 
participant should bring. Prior to iTBS, cognitive function will be assessed using a Trail 
Making Task (TMT; Appendix 22). Also, measures of mania (Young Mania Rating Scale 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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[YMRS]; Appendix 23), and suicidality (Columbia-Suicide Severity Rating Scale: 
Baseline [C-SSRS]; Appendix 24) will be collected prior to iTBS. 
Other than stimulations over the motor cortex to identify RMT, all iTBS 
administrations will be over the dlPFC. During iTBS, participants will view cocaine cues 
(i.e., pictures; Appendix 25) with the instruction to try to inhibit any craving elicited by 
the cues in an attempt to elicit activation in networks specifically related to controlling 
responses and cocaine use/substance abuse in general121. During some of these 
sessions we may monitor hand muscle movement. Before and after each day of iTBS, 
participants will complete the TBS monitoring questionnaire and a questionnaire about 
affect (the modified version of the PANAS; see Appendix 1 & 15). A debriefing period for 
discussion of questions and issues related to the day’s activities and 
scheduling/reminder of subsequent visits will conclude the session. A similar schedule 
of events will occur for each day of the 10-day treatment. Urine samples will be 
collected daily during the pilot phase. The TLFB will be collected the first treatment day 
during the inpatient phase and daily during the outpatient phase. The SAPS-CIP will be 
collected by the MAI (or staff clinician) at baseline and the 4-week follow-up visits. 
Recruitment curves (i.e., the ratio of GABA and glutamate) will be measured during 
orientation, on four days of iTBS administration, and each of the follow-up visits. Several 
characterization measures will be collected multiple times throughout the protocol. The 
following measures may be collected daily: TBS monitoring questionnaire, modified 
version of the PANAS, CCQ, CCS, TLFB, & CIP: Screener. The TLFB will cover time 
between the previously collected TLFB and the day of each collection. The CIP: 
Screener will be collected at baseline and any visit where the TLFB is administered and 
the participant reports cocaine use. Post-doctoral or MD level investigators can be 
trained by the MAI to administer the CIP: Screener. Any worsening from baseline in 
cocaine-induced psychosis measured throughout the protocol will trigger a follow-up 
evaluation by the MAI (or staff clinician). All but the TLFB and CIP: Screener, will be 
collected at the beginning and end of each day that includes MRI or iTBS. The POMS 
and MADRS will be collected at baseline, prior to first iTBS session, post final iTBS 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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session, and the first follow-up. The cocaine craving questionnaires will be used to 
assess post-cue-reactivity craving with the possibility of counselor intervention in the 
event of clinically significant craving. A response of 6 or 7 on the CCQ Likert scale for 
questions 3, 4, 16, 33, or 34 or a response of 1 or 2 question 28 would constitute 
clinically significant craving. Similarly, a response of 9 or 10 on the CCS Likert scale for 
question 1 would constitute clinically significant craving. The MAI or other NRB clinical 
personnel will intervene to mitigate craving before discharge if the participant’s self-
report of craving level arouses concern (in the participant or staff) in the context of 
conversation. After completing the two-week course of iTBS treatment, the TMT, YMRS, 
and C-SSRS (since last visit version) will be administered a second time. 
Columbia-Suicide Severity Rating Scale (C-SSRS; Appendix 24): An interview-
based questionnaire designed to assess acute suicidality. Two versions will be 
implemented. A baseline measure (with lifetime and past month symptom assessments) 
will be collected prior to the iTBS intervention and the ‘since last visit’ version will be 
collected post iTBS intervention. A researcher trained in administering these scales 
(e.g., the MAI, LAI, or AI) and approved by the MAI do so, will administer them. The MAI 
will oversee the training of this scale. If a participant reports any positive answer related 
to current suicidal tendencies (questions 1-5 for past month at baseline and since last 
visit assessments), the NIDA-IRP Critical Item Alert System in place in CDW will be 
initiated to address such responses (http://irp.drugabuse.gov/PolicyIndex.php). 
Completion time: < 15 minutes. 
TBS Monitoring Questionnaire (Appendix 1):  An interview-based questionnaire 
designed to assess symptoms related to iTBS administration. Completion time: < 5 
minutes. 
Trail Making Task (TMT; Appendix 22): The TMT is a cognitive test where 
participants are instructed to connect dots in numerical sequence or to alternate 
between numerical and alphabetical sequences. This task is designed to quickly assess 
working memory, visual attention, and task switching. Completion time: < 10 minutes. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Young Mania Rating Scale (YMRS; Appendix 23)122.  An interview-based 
questionnaire designed to assess symptoms of mania. Completion time: < 15 minutes. 
 
 Follow-Up 
Contact attempts will be made by phone 1-3 days after the last iTBS session to 
assess any acute behavioral or health related changes from treatment (Appendix 1). 
Additional contact attempts may include such methods as text, e-mail, and US mail if 
phone contact is not successful and if prior approval from the subject is obtained. Also, 
an attempt to schedule two post-treatment follow-up visits for participants who complete 
at least 7 of 10 days of iTBS treatment will be made to assess, RMT, recruitment curve, 
drug use, and behavioral changes post-treatment. Participants will be asked to repeat 
several of the characterization measures and assessments of drug use at these visits. 
The first visit will be scheduled approximately 1 week post-treatment and the second will 
be scheduled for approximately 4 weeks post-treatment. The nursing assessment for 
these visits will be similar to nursing assessments on other study days.  
 
 
iTBS Administration 
 Apparatus and Tests 
To administer the iTBS treatment, a MagVenture MagPro 100 with MagOption 
(MagVenture Inc, Alpharetta, GA) machine equipped with a figure-8 coil will be used. 
RMT of muscles that move the contralateral hand will be determined at the beginning of 
each treatment day. 
 
 Localization of Dorsolateral Prefrontal Cortex 
The BeamF3 heuristic120 will be implemented to localize left dlPFC for each 
individual. This heuristic has been shown to have a reasonable approximation of MRI-
guided localization of the left dlPFC without the need for an MRI scan (Note: an MRI-
guided localization of the left dlPFC will be used in the Expanded Feasibility Study).  
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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 Motor Threshold Determination   
In determining motor threshold, first the scalp position closest to the motor 
representation (the “motor hot spot”) is sought. Then the RMT at this location is 
determined. The hotspot is located during the initial session and verified at subsequent 
sessions, whereas the RMT will be measured every treatment day. In accordance with 
the manufacturer’s instructions and accepted standards, hand motor cortex will be 
stimulated to obtain RMT123, 124. 
Participants will be seated in a recliner in a comfortable resting position and fitted 
with earplugs. The TMS figure-8 coil will be placed over the hand-associated primary 
motor cortex. The coil will be held tangentially on the head with the handle pointing 
backward and 45° laterally from the midline. Using repeated single pulse, 
suprathreshold stimuli, the coil will be moved to determine the optimal scalp position for 
producing visible contralateral hand twitches. Pulses over this motor cortex location will 
be administered to identify the resting motor threshold using PEST125 software. 
Responses will be either visually detectible motor twitches or motor evoked potentials of 
the muscles that move the contralateral hand. Recruitment curves will be measured as 
a proxy for the ratio between gamma amino butyric acid (GABA) and glutamate126-128. 
The recruitment curve will be monitored at orientation and at three time points relative to 
iTBS administration: 1) prior to iTBS administration; 2) immediately following iTBS 
administration; 3) at least 60 minutes following iTBS administration. This will be done for 
each administration of days 1, 5, 6 and 10 (note: ‘at least 60 minutes following’ will also 
serve as ‘prior to’ for the second and third administrations). 
This entire procedure (hotspot and threshold determination) can take 30-90 minutes. 
If no motor hotspot can be determined within 1 hour or if the motor threshold exceeds 
83% of maximal stimulator output, the participant may be discontinued from the study at 
the discretion of the LAI and/or MAI. Because the initial RMT determination will be 
catalogued, subsequent determinations on treatment days are expected to take very 
little time. 
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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 Stimulation Procedure 
A pre-selected protocol is programmed into the iTBS stimulator73. Three pulses will 
be given at 50 Hz repeated every 200 ms for a 2 second duration followed by 8 seconds 
of no stimulation. This sequence repeats for a total of 190 seconds and 600 pulses. 
Magnetic field intensity will be set at a medium intensity and gradually increased, 
depending on participant tolerability, to the goal of 100% of that participant’s observed 
daily RMT  
 
 
Discharge Procedures  
If a participant experiences somatic or psychological symptoms that interfere with 
his/her ability to participate then he/she will be discharged from the study. The most 
frequent symptom is pain over the area of stimulation which could interfere with 
participation in the study. DLPFC stimulation has rarely been associated with mania. 
The investigators will monitor participants for changes in mood and may discharge a 
participant at any time if they believe that it is in the best interest of the participant. 
 
 
 
Participant Monitoring 
The iTBS monitoring questionnaire, the modified version of the PANAS (see 
Appendix 1 & 15), and staff observation and interactions with participants will be 
assessed daily. A NIDA-IRP physician or physician’s assistant knowledgeable about 
iTBS will be immediately available in the building whenever iTBS is administered and 
will be available by telephone or pager 24 hours a day for consultation or in the event of 
a medical emergency. If immediate medical intervention is required, the participant will 
be referred to an appropriate medical facility. Information on all adverse events will be 
cumulated and reported to the NIDA IRB with each continuing review application. 
Unexpected or serious adverse events (defined in accordance with NIH and NIDA IRP 
policy) will be promptly reported to the NIDA Clinical Director and IRB in accordance 
with NIH and NIDA IRP policy. 

PI Name: Yihong Yang, Ph.D. 
 
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Seizure monitoring procedures: Participants will be monitored throughout each iTBS 
session for signs of seizures such as involuntary muscle movements or loss of 
consciousness. In the event of a seizure, staff will have immediate access to life support 
equipment and anti-seizure drugs. In the event of a seizure, the procedure outlined 
below129 will be followed:   
1. Protect patient’s head and limbs from injury. 
2. Ensure an adequate airway. 
3. Call 911 to have the patient transferred to Johns Hopkins emergency room. 
4. Observe Patient for: 
a. Initial movements/ sensations. 
b. Progression of movements. 
i. 
Change in respiratory status 
ii. 
Skin color 
iii. 
Incontinence 
iv. 
Level of consciousness 
v. 
Ability to communicate 
vi. 
Level of orientation 
vii. 
Duration of seizure activity  
If after two minutes, the seizure has not resolved, administer: 
midazolam IM, 10 mg that is contained in a lock box in the TMS suite. 
5. Provide supportive care after the seizure resolves.  
6. Orient patient to time and place.                     
Session video recording: If a potential adverse event occurs during iTBS stimulation, 
video footage of the session can help determine the nature of the incident. Thus, video 
will be recorded during threshold determination and during iTBS, barring any technical 
difficulties with recording instrumentation. If the session progresses without incident, this 
footage will be deleted within a week. Otherwise, during sessions with abnormal events, 
the video will be retained in accordance with NIH Records Management policy 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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(https://oma.od.nih.gov/DMS/Documents/Records/NIH_Intramural_Research_Recor
ds_Schedule.pdf) for 7 years after the completion of the study or when no longer 
needed for scientific reference, whichever is longer. This footage may be used by the 
MAI and any experts the MAI wishes to consult to determine the nature of the event. 
Participants will not be given the option to opt out of the video recordings. If they do not 
wish to be recorded, the alternative is to not participate in the study. 
 
 
Risks 
The side effects associated with TMS treatment in large clinical trials have been 
published130. Published consensus safety guidelines for TMS have resulted in reduced 
frequency of adverse events131. The following clinical data associated with depression 
treatments are provided to emphasize the extensive medical experience with TMS and 
its safety.  
Unlike electroconvulsive therapy (ECT), TMS does not involve general anesthetic or 
inducing a seizure. Numerous sham-controlled trials and several meta-analyses support 
its efficacy in treating depression94, 132-134. The largest TMS sham-controlled trial to date 
involving 301 pharmacotherapy refractory depressed participants reported positive 
results70. Sessions of rTMS were conducted for 4 to 6 weeks five times per week. 
Stimulation was set at 120% RMT with 10 pulses per second for a total of 3000 pulses 
per session. Active rTMS was well tolerated, with low dropout rate for adverse events 
(4.5%) that were generally mild and limited to transient scalp discomfort or pain. In the 
current proposed study, iTBS will be used, which is similar to rTMS but with higher 
participant compliance and a lower level of stimulation (100% of RMT compared to 
120% of RMT for rTMS). 
 
 EXPANDED FEASIBILITY STUDY 
This phase of the study began after IRB and FDA approval, and completion of the 
FDA review of Pilot data. 
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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A. Study Objectives 
The Expanded Feasibility Study of this protocol is designed to implement the iTBS 
administration parameters established from the Pilot with a large sample of treatment 
seeking CD participants. HC participants will be recruited as a comparison group and 
participate in two days of iTBS (1 active day and 1 sham day of iTBS). Regardless of 
group, each day of iTBS will include 3 iTBS sessions with at least a 60-minute interval 
between administrations.  
Note that a 3-minute iTBS application is referred to as a SESSION and 3 iTBS 
sessions is referred to as a DAY of treatment. Therefore, each DAY of iTBS 
treatment includes 3 iTBS SESSIONS and 10 DAYS of iTBS treatment includes a 
total of 30 iTBS SESSIONS.  
All participants will complete the same battery of characterization instruments. 
Participants who successfully complete the iTBS orientation phase (receiving either 
active or sham iTBS as randomly assigned) will be eligible to participate in iTBS 
treatment days. CD participants will be scheduled for 10 DAYS of iTBS treatment and 
receive either active or sham iTBS (assigned randomly prior to orientation). HC 
participants will be scheduled for 2 DAYS of iTBS and receive 1 DAY of active iTBS (3 
active sessions with at least 60 minutes between sessions) and 1 DAY of sham iTBS (3 
sham sessions with at least 60 minutes between sessions) with at least 1 week between 
days. The order of these days will be counterbalanced. Note that 3 sessions of iTBS is 
well under the minimum number needed to assess efficacy clinically for a treatment 
effect in depression71 and has been previously safely carried out in healthy controls 99, 
100, 135. These 3 published studies administer iTBS more aggressively than 
proposed here.in healthy controls without adverse events. One study 
administered 2 iTBS sessions back-to-back in healthy controls without adverse 
events135. Two studies administered 3 iTBS sessions with 15 minutes between 
sessions in healthy controls without adverse events99, 100.    
 
B. Goals 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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The primary goal is to characterize neurobiological processing of and behavioral 
responding in cue reactivity, reward processing, executive control, and intrinsic network 
connectivity differences between HC and CD participants at baseline, during and 
following iTBS intervention. The Expanded Feasibility Study is powered to assess 
neuroplastic changes between completers in the CD group who receives active iTBS (N 
= 30), the CD group who receives sham iTBS (N = 30), and the HC group who receives 
a within-participant active/sham iTBS manipulation (N = 40). Specifically, we will test for 
potential neural plasticity over time in the CD cohort and relate any changes to 
treatment group ongoing substance use (i.e., reductions or maintenance of use). Each 
CD participant is expected to complete a total of 8 MRI scan sessions across 5 days 
over a 14-week period 1. Multiple MRI scan sessions will allow for direct comparisons of 
neural plasticity within participants over time.  
 
C. Aims 
1. To characterize neural differences between CD and HC participants at baseline. 
2. To determine if iTBS alters networks related to cognitive/affective function by: 
a. Identifying networks and cognitive/affective functions that change with 
acute treatment in both HC and CD. 
b. Identifying networks and cognitive/affective functions that show sustained 
change (2 weeks after end of treatment) with chronic treatment in CD. 
3. To determine if imaging measures can reliably predict which individuals will 
respond to treatment, either at baseline or after completion of treatment.  
4. To determine the trajectory of neural plasticity related to chronic iTBS and 
cocaine abstinence.  
5. To monitor safety of iTBS applied in cocaine dependent individuals. 
 
D. Hypotheses 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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1. Functional imaging correlates of cue reactivity, reward processing, executive 
control, and intrinsic network connectivity will differentiate CD and HC 
participants at baseline. 
2. Within the CD group, measures of cue reactivity, reward processing, executive 
control, and intrinsic network connectivity will be predictive of treatment success 
and reduction in drug use. 
3. Acute iTBS will alter cue reactivity, reward processing, executive control, and 
intrinsic network connectivity in both CD and HC.  
4. Within the CD group, chronic Active iTBS, relative to Sham, will modulate cue 
reactivity, reward processing, executive control, and intrinsic network 
connectivity, which will relate to changes in drug use after the 2-week treatment. 
5. Within the CD group, chronic Active iTBS, relative to Sham, will modulate cue 
reactivity, reward processing, executive control, and intrinsic network connectivity 
such that neuronal processing in CD participants following iTBS will approximate 
that in HC (i.e. normalize processes). 
 
E. Experimental Design 
Two groups of participants will be recruited: 1) treatment seeking cocaine dependent 
individuals (CD; n = 90; 45 Active-iTBS and 45 Sham-iTBS); 2) matched community 
healthy controls (HC; n = 45; within-subject crossover iTBS manipulation). Fifty CD 
participants in each group will be recruited to obtain the necessary number of 
participants (n = 30) to complete treatment (see power analysis calculated to ensure 
necessary power for MRI measures). CD participants may stay in the on-campus 
inpatient facility approved by the NIDA Clinical Director’s office while they participate in 
this iTBS protocol. The inpatient unit will be available to every CD participant to increase 
compliance with protocol scheduling. In general, participants will arrive at the inpatient 
facility the day before their iTBS session. CD participants will be escorted by study staff 
to and from the inpatient unit on treatment days, which may include automotive pick-up 
service (e.g., shuttle, taxi). We will implement a within-subject crossover Active- 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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and Sham-iTBS method with the HC participants to provide for the necessary 
sham control.  
All participants will receive a post-iTBS nursing assessment and cognitive 
assessment prior to discharge. An approximate timeline is described below but may 
vary to account for participant, staff, and facility availability. All participants, 
regardless of group, will be scheduled to complete baseline data collection 
(Characterization; Figures 1 & 2: Visit 1). An initial scan (Scan 1) will be performed to 
acquire MRI localization to be used in the iTBS protocol as well as cognitive and 
affective characterization imaging tasks (week 1); Visit 2) clinical characterization 
instruments (per protocol 10-DA-N457) and MRI scan (Scan 2; week 1) [participants 
may be scheduled to complete these characterizations over more than one day, if 
needed to ensure completion prior to the first iTBS day];  
HC participants will be scheduled to participate in 2 days of iTBS (Figure 1): 
Visits 3-4) Each day, HC participants will receive either Active or Sham-iTBS in a 
randomized and counterbalanced schedule. Each day will include 2 MRI scan sessions 
(Scans 3a/4a & 3b/4b), 1 before and 1 after the iTBS intervention. These 2 visits will be 
identical except for the within-subject manipulation of Active- vs Sham-iTBS 
administration. At least 1 week will pass between HC visits 3 (Scans 3a & 4a) and 4 
(Scans 3b & 4b).  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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After visits 1 and 2 (described above), CD participants will be scheduled to 
participate in the following visits (Figure 2): Visit 3: the first iTBS treatment day, 
which also includes two, pre/post-acute iTBS MRI scan sessions (Scans 3 & 4; week 2). 
Visits 4-12: iTBS treatments in CD (weeks 2-3); Visits 13-40: urine samples will be 
acquired from participants to assess cocaine use and is the start of CM (week 4); Visit 
19: Two scan sessions (Scans 5 & 6; week 6) will be completed; Visit 40: two scan 
sessions (Scans 7 & 8; week 14) will be completed; Additional monthly follow-up visits 
(Visits 41-43; weeks 18, 22, & 26, respectively) with weekly phone contact in between 
(9 calls; weeks 15-26) will be attempted to assess post-treatment drug use patterns. 
 
 
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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The MRI scans (1 & 2) will assess differences between groups prior to the iTBS 
intervention. The MRI scans from scan 4 will be compared to scan 3 to assess neuronal 
modulations related to acute iTBS administration. Scans 5-8 will be compared to scans 
1-3 to assess neural plasticity post-treatment modulated by chronic Active-iTBS (vs. 
Sham) administration. All scan sessions will be approximately 2 hours in duration.  
Contingency Management (CM): Drug use will be monitored following the iTBS 
treatment period with urine samples collected each week as outlined in table 1. Urine 
samples will be used for the TAU CM. Clinical trials research supports CM as an 
efficacious approach to cocaine use reduction136-142. With this evidence, CM was 
selected as the TAU. The qualitative urine analysis will be used to assess positive or 
negative urine samples for cocaine use. When a positive sample is recorded, that 
sample will be sent for quantitative ‘additional use’ analysis to the NIDA IRP’s 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Translational Analytical Core facility. If the positive sample immediately follows another 
positive sample, the quantitative results, are often available within 7-10 days, will be 
used to determine eligibility for CM payment. At the next participant visit, after the 
results are known, the participant will be notified of the test results and if that analysis 
suggests no additional use for the participant, CM payments will be paid accordingly. If 
the positive qualitative result follows a negative qualitative result, CM payment will be 
withheld and the amount rewarded the next negative (or no new-use) urine reset to $5, 
per Table 1. The quantitative result from the positive urine will be used as baseline for 
the next CM urine to determine if there has been new use. Follow-up of CD participants 
will continue without CM for up to 3 months post scans 7 and 8. Drug use will be 
monitored with a once-a-week phone contact and monthly in-person visits.  
In the present study, participants have the possibility of earning $1075 during the 
CM program. Incentives for negative urine tests will escalate to $80 in the later portions 
of the program. A considerable amount of controlled clinical trials research supports CM 
as a promising and innovative approach to cocaine use reduction136 even as a stand-
alone intervention promoting abstinence137-142. However, most participants will not likely 
be abstinent throughout the CM period, which affects the amount of the total possible 
earned (e.g., an estimate of 45% of the total possible amount will be earned, reducing 
effective possible amount to ~$484. As is standard usage, we will implement an 
escalating schedule of incentive amounts with a reset penalty for detection of drug use 
(Table 1). A reset penalty is implemented if a cocaine positive urine sample is detected. 
Avoidance of the reset serves as a motivator for continued abstinence. Earned money 
will be distributed immediately after each negative urine test, generally by cash, check, 
or e-payment (e.g., PayPal) per NIDA IRP remuneration guidelines. Doing so provides 
immediate acknowledgement and reinforcement for the negative test. After money is 
earned, it belongs to the participant and is never taken back irrespective of subsequent 
drug use or other adverse behaviors. It is expected, based on previous experience with 
these types of interventions, that exposure to this incentive program will produce 
reduced overall amounts of cocaine use in the majority of participants with long periods 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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of sustained abstinence in some participants. Continuing CM through the last scan 
increases the possibility of obtaining scan data with similar amounts of drug use in both 
groups of participants. During the follow-up period after CM, we expect the groups to 
diverge in use patterns. Differences in the scan data will therefore, likely reflect 
differences between sham and real iTBS treatment uncontaminated in differences in 
drug use between the groups. We anticipate that the compensation for routine data 
collection visits plus the completion bonus at the end of the three-month follow-up will 
maintain participant engagement in this protocol. 
 
Table 1. Contingency Management Schedule of Reinforcement 
CM week 
Study Week 
Urine Sample 
Award Amount ($) 
for Negative Urine 
Test 
Running Total 
Amount ($) 
 
1 
None 
None 
None 
 
2 
None 
None 
None 
 
2 
None 
None 
None 
 
2 
None 
None 
None 
 
3 
None 
None 
None 
 
3 
None 
None 
None 
 
3 
None 
None 
None 
1 
4 
1 
5 
5 
1 
4 
2 
10 
15 
1 
4 
3 
10 
25 
2 
5 
4 
20 
45 
2 
5 
5 
20 
65 
2 
5 
6 
20 
85 
3 
6 
7 
20 
105 
3 
6 
8 
20 
125 
3 
6 
9 
20 
145 
4 
7 
10 
30 
175 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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4 
7 
11 
30 
205 
4 
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235 
5 
8 
13 
40 
275 
5 
8 
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315 
5 
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355 
6 
9 
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395 
6 
9 
17 
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435 
6 
9 
18 
40 
475 
7 
10 
19 
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515 
7 
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555 
8 
11 
21 
40 
595 
8 
11 
22 
60 
655 
9 
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60 
715 
9 
12 
24 
60 
775 
10 
13 
25 
60 
835 
10 
13 
26 
80 
915 
11 
14 
27 
80 
995 
11 
14 
28 
80 
1,075.00 
 
 
Introduction to Treatment: Before initiation of iTBS, a session will take place to 
assess and attempt to enhance individual motivation and preparation to reduce or 
eliminate cocaine use. During this session, participants may repeat some assessments, 
such as the BCCMA. This session is designed to inform the participant of the treatment 
trajectory, introduce the concept of CM, introduce techniques to manage cue-induced 
craving, and assess and enhance their motivation to quit using cocaine. This will be 
conducted by the MAI, study therapist, or designee. 
 
F. Inclusion and Exclusion  
 
Description of the Study Population 
We will enroll 45 (within-subject crossover active- vs sham-iTBS manipulation) HC 
and 90  treatment seeking CD (45 active-iTBS and 45 sham-iTBS) individuals who meet 
the inclusion and exclusion criteria. Fifty CD participants in each group will be recruited 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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to obtain the necessary number of (n = 30) treatment completers (see power analysis; 
calculated to ensure necessary power for MRI measures). Screening will be conducted 
under the approved NIDA IRP general screening protocol to determine eligibility 
(Expanded Feasibility Study Eligibility Checklist; Appendix 31). Participants will also be 
required to enroll in the NIDA protocol 10-DA-N457 to gather characterization data not 
otherwise collected in this protocol but which will be used in the planned analyses. 
Generally, CD participants will be current cocaine users and HC participants will be non-
users matched on measures including age, sex, ethnicity, race, etc.  
 
 
Inclusion Criteria 
1. Be able to give valid informed consent. 
2. Agree to also participate in study 10DAN457, where characterization 
information is gathered and shared with this protocol. 
3. Be 22 – 60 years of age.  
a. Justification: Many neural processes change with age, and these 
changes could introduce unwanted variability in both behavioral and 
MRI signals. 
b. Screening tool: Self-report.  
4. Right-handed. 
a. Justification: Differences in hemispheric dominance could confound 
iTBS administration and MRI measurements. 
b. Screening tool: Edinburgh Handedness Inventory. 
5. Be in good health.  
a. Justification: Many illnesses may alter neural functioning as well as 
fMRI signals. 
b. Screening tools: Medical Assessment, Medical History and Physical 
Examination. Medical assessments include: Vital Signs, EKG, oral HIV 
test, height/weight measurements, urinalysis, and blood sample. Tests 
on the blood sample include CBC, complete metabolic profile, TSH, 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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ESR, syphilis test, and HIV (if needed to confirm a positive salivary test 
for HIV). The following individual laboratory results will independently 
disqualify individuals: Hemoglobin < 10 g/dl, WBC < 2400/µl, LFTs > 3 
X upper normal limit, HCG positive, Casual serum glucose > 200 
mg/dl, Urine protein > 1+, HIV positive. (less extreme serum glucose 
elevations will be evaluated for diabetes as clinically indicated.) Liver 
function will be evaluated with aspartate aminotransferase (AST) and 
alanine transaminase (ALT). A greater than 3 x upper normal limit for 
AST or ALT will disqualify individuals. MAI reserves the right to exclude 
at less extreme lab values if clinical judgment warrants exclusion. 
6. Absence of a specific learning disability, ADHD or cognitive impairment 
a. Justification: Participants must be able to perform a cognitively 
challenging task to a high standard.  
b. Screening tool:  SCID-research version, computerized Shipley-2 (cut-
off of < 70 to be excluded), History of placement in special education 
classes for a learning problem. 
7. CD Participants, and not HC 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 and currently seeking treatment. They will be 
using at least once a week in the month prior to enrollment.  
a. Justification: cocaine use disorder, in regular users, is the focus of this 
protocol. 
b. Screening tool: Potential diagnoses will be evaluated by a counselor 
using any one or more of the following: Drug Use Survey, SCID-
research version and Brief Cocaine Cessation Motivation Assessment. 
The MAI may be consulted in this determination. 
8. Treatment seeking CD participants  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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a. Justification: The population of interest is CD dependent individuals 
motivated to reduce or eliminate their cocaine use. 
b. Screening tools: Brief Cocaine Cessation Motivation Assessment. 
9. MRI compatible 
a. Justification: MRI is the primary data gathering tool 
b. Screening tools: current clinical procedures in use at the NIDA IRP 
 
 
Exclusion Criteria 
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. 
a. Justification: Stroke, vascular lesions or head trauma can lower the 
seizure threshold and are therefore contra-indications for iTBS. 
Fainting episodes or syncope of unknown cause could indicate an 
undiagnosed condition associated with seizures. 
b. Screening tool: TMS safety Screen and Medical History. 
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 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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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. 
a. Justification: While use of multiple substances is the norm and some 
use will be allowed, the focus of the current protocol is on cocaine. 
However, participants with tolerance or withdrawal symptoms to a 
sedative/hypnotic/ anxiolytic will be at increased risk of a seizure from 
iTBS and will therefore be excluded. Alcohol withdrawal will be 
assessed on ITBS days and rescheduled if in withdrawal. Individuals 
receiving maintenance treatment for OUD and struggling with cocaine 
use are an ecologically valid population in the greater Baltimore area 
and do not increase risk of seizure. 
b. Screening tool: Drug Use Survey and SCID-research version. 
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. 
a. Justification: The population of interest is a healthy control population 
with no substance use disorder. Current use of illicit substances or 
alcohol could impact on seizure threshold and is therefore contra-
indicated for iTBS. 
b. Screening tools: SCID-research version. Potential diagnoses will be 
further evaluated by a counsellor, Drug Use Survey (DUS), Substance 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Use Disorder Evaluation, Medical Assessments: urine qualitative drug 
screen is performed for cocaine, THC, benzo, morphine/opiates, 
MDMA, amphetamine /methamphetamine, methadone, buprenorphine, 
PCP, and oxycodone. 
4. First-degree family history of any form of epilepsy with a potentially hereditary 
basis .  
a. Justification: First-degree family history of epilepsy with a hereditary 
component increases the risk of the participant having an undiagnosed 
condition that is associated with lowered seizure threshold. 
b. Screening tool: TMS safety screening, Medical History. 
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. 
a. Justification: Certain metal in the body is a contra-indication for iTBS 
administration, as this method involves exposure to a relatively strong 
static magnetic field that can move magnetic material not securely 
bound and rapidly alternating magnetic fields that can generate heat 
and current in metal contained in the body.  
b. Screening tool: Medical History, TMS safety screen. 
6. Noise-induced hearing loss or tinnitus.  
a. Justification: individuals with noise-induced hearing problems may be 
particularly vulnerable to the acoustic noise generated by iTBS 
equipment.  
b. Screening tools: TMS safety screening. 
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 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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psychotropic (e.g., benzodiazepines), anti or pro-convulsive action, or anti-
coagulants. This will be determined at the discretion of the MAI. 
a. Justification: The use of certain medications or drugs can lower seizure 
threshold during use or withdrawal and is therefore contra-indicated for 
iTBS. Such medications may also alter neural functioning independent 
of the individual’s drug use or the effects of the iTBS and thus add 
more variability to our data. 
b. Screening tools: Medical history, Medical Assessments: Urine 
toxicology analysis for presence of a broad range of prescription and 
nonprescription drugs.  
8. Lifetime history of schizophrenia, bipolar disorder, mania, or hypomania. 
a. Justification: The population of interest here is a healthy population 
with no psychiatric disorders other than substance use disorders. In 
participants with bipolar disorder, mania or hypomania, there is a small 
chance that iTBS can trigger (hypo)manic symptoms. As some degree 
of depressive symptoms is common in cocaine dependence and may 
result from the drug use, mild unipolar depression will not be 
exclusionary. 
b. Screening tools: SCID-research version or M.I.N.I. .  
 
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). 
a. Justification: it is unknown whether iTBS poses a risk to fetuses.  
b. Screening tool: Urine and/or serum pregnancy tests, and clinical 
interview.  
10. Participation in any NIBS session less than two weeks prior to admission.  No 
NIBS exposure for treatment purposes in the last 6 months.  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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a. Justification: in order to avoid possible carry-over effects from previous 
exposure to NIBS prior to participation in the proposed intervention, we 
will not enroll participants who have received any NIBS in the two 
weeks preceding enrollment or treatment with NIBS modality with the 
last 6 months preceding enrollment.  
b. Screening tool: TMS safety screening questionnaire. 
11. Non-English speaking.  
a. Justification: To include non-English speakers, we would have to 
translate the consent and other study documents and hire and train 
bilingual staff, which would require resources that we do not have and 
could not justify given the small sample size for each experiment. 
Additionally, the data integrity of some of the cognitive tasks and 
standardized questionnaires used in this study would be compromised 
as they have only been validated in English. Most importantly, ongoing 
communication regarding safety procedures is necessary when 
participants are undergoing study procedures. The inability to 
effectively communicate safety procedures in a language other than 
English could compromise the safety of non-English speaking 
participants.  
b. Screening tool(s): self-report. 
 
 
G. Clinical and Laboratory Methods  
 
Study Procedures 
Participants will be scheduled for multiple clinical assessment and data collection 
sessions to complete the protocol. Similar to the Pilot study, a 10 day iTBS treatment 
protocol will be implemented. Based on the Pilot, a schedule of 3 daily iTBS sessions 
with at least a 60-minute interval between administrations is outlined below. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Protocol completers are defined as CD participants who complete 10 iTBS days of 
treatment within 3 weeks and visit 19 (first post-treatment scan day). CD participants 
who complete at least 5 iTBS treatment days in 3 weeks are eligible to begin with CM 
and follow-up visits. All study visits, including those with MRI scans, will be offered to 
these individuals as if they had completed all 10 iTBS treatment days. An HC participant 
is considered a protocol completer after completing all scheduled visits (baseline 
characterization visits and 2 iTBS treatment days with MRI scans). 
Overall, CD participants will complete about 43 visits and HC participants 5 visits, 
with 8 and 6 MRI scans collected for CD and HC participants, respectively. Most of the 
visits for CD participants will be to collect urine samples and implement CM. The order 
of procedures completed during each visit may vary slightly, depending on availability of 
staff and other resources (mock scanner, MRI, study rooms, etc.). 
Each study visit day will start with a brief nursing assessment that includes a urine 
sample for drugs of abuse, a breathalyzer, and vital signs. A urine pregnancy test for 
females will occur weekly during the iTBS treatment and any visit that includes an MRI 
scan thereafter. If breathalyzer is positive for alcohol participants may be rescheduled. 
In the event of a positive drug test, an interview to assess last drug use and a 
neuromotor assessment to test for acute intoxication will be performed. If participants 
test positive for drugs other than marijuana, based on MAI judgment, they may be 
rescheduled. If urine is positive for other illicit drugs, and if there are no known TMS 
contraindications, the participants may be allowed to participate at the discretion of the 
MAI. Otherwise, participants will be rescheduled. The CD group is expected to be 
current users and will likely test positive for illicit drugs. These procedures are designed 
to identify if CD participants are currently impaired and if HC participants have recently 
used illicit or licit drugs. Participants who smoke will be allowed breaks to smoke to 
preclude acute nicotine withdrawal. If a participant runs out of cigarettes, we will provide 
them on an as-needed basis to avoid withdrawal, which requires us to reschedule the 
visit. All study visits will take place at National Institute on Drug Abuse Intramural 
Research Program (NIDA-IRP). 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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 Screening 
Candidate participants will be screened based on the Inclusion and Exclusion criteria 
listed above under the aegis of the approved NIDA IRP general screening protocol. 
During in-person screening, potential participants will be given some initial information 
regarding the study (see attached “Fact Sheets” and “TBS Information Sheet”) to 
determine if they are interested in possible participation. The following assessments will 
be administered during screening: 
Brief Cocaine Cessation Motivation Assessment (BCCMA)(Appendix 28): a semi-
structured interview to assess the stage of change and motivation level for cocaine 
dependent participants. Completion time: 10-15 minutes.  
Contact Information Form: This form requests multiple methods of contact for a 
participant, as well as the preferred contact method, preferred contact time, and 
emergency contact information. Completion time: < 5 minutes. 
Drug Use Survey (DUS): An interviewer-administered questionnaire designed to 
collect information regarding lifetime history of substance use. Completion time: < 40 
minutes. 
Edinburgh Handedness Inventory103: This 12-item questionnaire assists in 
determining the dominant hand (or handedness) of a particular participant by inquiring 
which hand the participant uses for various tasks. Completion time: ~ 5 minutes. 
Medical Assessments: Vital Signs, height/weight measurements, urinalysis, EKG, 
oral HIV test, blood draw for CBC, chemistries, thyroid and liver function, erythrocyte 
sedimentation rate, urine qualitative drug screen for cocaine, THC, benzo, 
morphine/opiates, MDMA, amphetamine /methamphetamine, methadone, 
buprenorphine, PCP, and oxycodone, urine toxicology which analyzes for presence of a 
broad range of prescription and nonprescription drugs, as well as urine and/or serum 
pregnancy testing for menstruating females. Breathalyzer for alcohol will be taken at this 
time as well. Completion time: 30-40 minutes. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Medical History and Physical Examination: This is a standard physical and detailed 
medical history and physical examination designed to capture the inclusion and 
exclusion criteria for NIDA-IRP protocols. It is administered by a Physician’s Assistant or 
other credentialed medical staff. The estimated time to complete is variable. Completion 
time: 45 to 90 minutes. 
Mini International Neuropsychiatric Interview (M.I.N.I)104: a brief structured interview 
for the major psychiatric disorders in DSM-5 and ICD-10. Follow up questions may 
ensue. Completion time: ~20 minutes. (Participants will complete either the MINI or the 
SCID). 
Participant Safety – MRI Screening Form: A questionnaire that aids in determining 
appropriateness of MRI scan. Completion time: < 5 minutes. 
SCID-Research Version Structured Clinical Interview for DSM-5™ (SCID), used in 
assisting with diagnosis of DSM-5 Axis I disorders. (Participants will complete either the 
MINI or the SCID). 
TBS Information Sheet: A general information sheet on TBS administration with 
common questions and answers is given to participants as an informational item only. 
Participants are given time to read the handout and to ask questions about it while in 
the clinic. Completion time: ~ 20 minutes. 
TMS Safety Screen:  A questionnaire that aids in determining appropriateness of 
administering TBS. Completion time: < 5 minutes. 
Shipley-2, computerized version  Completion time: ~ 45 minutes.  
Brain Imaging Information Handout: A general information sheet on brain imaging 
research with common questions and answers is given to participants as an 
informational item only. Participants are given time to read the handout and to ask 
questions about it while in the clinic. Completion time: ~ 20 minutes. 
Mock Scanner: Participants are taken to a mock MRI scanner during their screening 
visit. The scanner environment is explained to the participant and they are asked to lie 
in the scanner to make sure there are no problems with body fit or comfort. This gives 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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participants the opportunity to opt out of scanning experiments if they are not 
comfortable with the scanner environment. Completion time: < 10 minutes.  
 
 Nursing Assessments and Task Preparation 
Nursing Assessment. After completing the consent interview and prior to study 
sessions, participants will undergo a nursing assessment, which may include measuring 
vital signs, a breathalyzer test for expired ethanol, an observed urine test for common 
abused drugs, a metal/MRI safety screening (scan sessions only), a TMS safety 
questionnaire (iTBS sessions only) and if female, a urine pregnancy test. Participants 
will also be asked when they last had NIBS and whether this was at NIDA or elsewhere.  
Participants with a positive breathalyzer will be rescheduled. In the event of a positive 
drug test, an interview to assess last drug use and a neuromotor assessment to test for 
acute intoxication will be performed. If participants test positive for drugs other than 
THC (current clinical practice by C. A. Hanlon and J. Downar is to not exclude THC 
positive participants [personal communication, July 19, 2018]), or cocaine for the CD 
group, based on the MAI’s judgment, they may be rescheduled. However, if they test 
positive on a second occasion they may be excluded from the study. This will be made 
clear to the participant in the consent process. In addition, participants will be asked to 
report changes in medical history, recent over-the-counter, prescription, or other 
substance intake, time of last meal, hours slept the previous night, and, if female, last 
menstrual period and whether or not they are currently taking a contraceptive pill. After 
all TMS sessions, participants will have their heart rate and blood pressure taken. 
Participants will be asked to abstain from caffeine consumption for 12 hours prior to 
scan sessions, as well as alcohol and other drugs for 24 hours prior to TMS and scan 
sessions. Participants who use alcohol will be assessed for withdrawal smptoms with 
the CIWA-Ar and rescheculed if they show signs of withdrawal (>=8).  
CD participants who opt to stay at the CRU will be searched upon intake (Appendix 
29) and will have vital signs assessed in accordance with the standards of the inpatient 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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unit. Upon intake, participants will complete a breathalyzer and urine drug screen. 
Completion time: ~30 minutes. 
Orientation. Prior to the commencement of iTBS treatment sessions, participants will 
complete a training session where they will be oriented to iTBS. Orientation may take up 
to 1 hour where the motor hotspot and resting motor threshold (RMT) will be recorded. 
RMT will be identified each iTBS treatment day. Each DAY, after the first, will use the 
motor hotspot from the previous day as a guide. Localization of left dorsolateral 
prefrontal cortex (dlPFC) stimulation site will be defined within-subject using MRI 
coordinates (see below). After motor hotspot, RMT and left dlPFC are identified, the 
participant will be oriented to iTBS (either active or sham as assigned). Participants who 
fail to tolerate iTBS at 100% of RMT during this orientation session will be discharged 
from the study, however their characterization assessments and scans will be retained 
to compare with CD. 
Before commencing the visit 1 scanning sessions, participants will complete a 
training session where they will be oriented to the scanner environment and instructed 
on and practice the experimental tasks inside a mock scanner. Participants will 
complete baseline characterization measures at this time. Characterization measures 
may be completed on multiple visits if it is more convenient to the participant’s schedule.  
Mock Scanner. Individuals will receive training or refreshers, either verbally, on the 
bench, or in a mock scanner, during subsequent visits. Completion time: between 10 
minutes and 1.5 hours. 
Baseline and characterization questionnaires. A series of questionnaires related to 
cocaine use and dependence, withdrawal symptoms, psychological state, motivation to 
quit, and mood inventories as well as several characterization measures will be 
administered during the orientation visit or later sessions. Some characterization and 
state measures listed under this protocol may be completed under protocol 10-DA-
N457, and vice versa. These data will be linked across protocols so that participants do 
not have to complete them more often than necessary.  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Participants will complete the following questionnaires; only the CD group will 
complete the assessments marked with an *: 
Attitudes Towards Risk Questionnaire (Appendix 7): A 34-item self-report with 5-
point Likert scales that assess attitudes towards physical and psychological risk. 
Completion time: < 10 min.  
*Addiction Severity Index (ASI, Appendix 44):  A semi-structured interview designed 
to provide information in 6 areas related to drug abuse and drug abuse treatment: 
medical, employment/support, alcohol and drug use, legal, family/social and psychiatric. 
Completion time: 45-60 minutes. 
Brief Externalizing Inventory108 (Appendix 9): A 159-item self-report adapted from 
the full Externalizing inventory109 used to assess a range of behavioral and personality 
characteristics that have been attributed to a broad psychological construct termed 
externalizing. These characteristics include: physical/relational destructive-aggression, 
boredom proneness, irresponsibility, problematic impulsivity, drug and alcohol use or 
problems, theft, fraud, rebelliousness, alienation, and blame externalizing. Completion 
time: ~ 15 min.  
The Revised Social Anhedonia Scale (Appendix 42): A 40-item true-false self-report 
questionnaire intended to measure decreased pleasure derived from interpersonal 
sources.  Completion time: ~10 minutes. 
The Physical Anhedonia Scale (Appendix 43): A 61-item true-false self-report that 
taps a range of presumably pleasurable experiences involving eating, touching, feeling, 
sex, movement, smell, and sound. Completion time: ~15 minutes.  
*Cocaine craving likert scales (Appendix 11): “How much are you craving right 
now?” and “On average, how much of a problem has craving been for you over the past 
week?”  
*Cocaine use, Pattern, and Withdrawal Questionnaire (Appendix 12): This is an 
interview-guided questionnaire, designed by Dr. B. J. Salmeron, and has been 
successfully employed in previous studies. Completion time: ~ 10 minutes.  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Montgomery-Asberg Depression Rating Scale (MADRS112; Appendix 13): A clinical 
assessment to identify symptoms of depression. This assessment is especially useful in 
identifying changes in depression symptoms over time. If a participant reports suicidal 
thoughts, the CDW Critical Item Alert System will be initiated following the NIDA SOP to 
address such responses. Completion time: < 10 minutes.  
*Modified Positive and Negative Affect Scale (Modified version of the PANAS; 
Appendix 14): Participants are asked to fill in a questionnaire about possible side-effects 
since the last iTBS session (the NIBS monitoring questionnaire), and a questionnaire 
about their affect (a modified version of the PANAS). The sole purpose for the modified 
version of the PANAS is to assess the answer to one single question (“Right now I feel 
… detached: rate from “not at all” to “extremely”). This is not in the original, validated 
PANAS-SF. Instead, the modified questionnaire is used as a device to ask this one 
single question, without calling unwanted attention to it by asking it as a single item. A 
self-report scale to assess state-level affect. Completion time: < 5 Minutes.  
Profile of Mood States (POMS; Appendix 15): A questionnaire designed to measure 
present mood state by a list of adjectives on a 5-point Likert scale and measures six 
dimensions of affect, including tension-anxiety, depression-dejection, anger-hostility, 
vigor-activity, fatigue-inertia, and confusion-bewilderment. The measure has been 
shown to produce reliable and valid profiles of mood state113, 114. Completion time: ~ 5 
minutes.  
*Scale for the Assessment of Positive Symptoms for Cocaine-Induced Psychosis 
(SAPS-CIP115, Appendix 32): The SAPS-CIP is a modification of the Scale for 
Assessment of Positive Symptoms designed to focus on psychotic symptoms related to 
cocaine use. We will use the hallucinations and delusions sections which have been 
shown to be particularly useful in assessing cocaine-induced psychosis. If endorsed, the 
MAI (or staff clinician) will assess current psychosis and need for further evaluation 
and/or treatment. Completion time: < 30 minutes.  
*Cocaine-Induced Psychosis: Screener (CIP: Screener, Appendix 33): The CIP: 
Screener is designed for efficient assessment of cocaine-induced psychosis and will be 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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used to assess changes, relative to baseline, throughout the protocol. Any worsening 
from baseline in cocaine-induced psychosis measured throughout the protocol will be 
evaluated by the MAI (or staff clinician). Completion time: < 5 minutes. 
Sensation Seeking Scale V (SSS-V, 116; Appendix 67): A 40-item self-report 
questionnaire that assesses individual differences in sensation seeking. The scale 
consists of four subscales (Boredom Susceptibility [BS], Thrill and adventure seeking 
[TAS], Experience seeking [ES], and Disinhibition [Dis]) composed of 10-items each. 
Completion time: < 10 minutes.  
Snaith-Hamilton Pleasure Scale (SHAPS, 117; Appendix 17): A 14-item self-report 
scale designed to measure hedonic-tone/anhedonia. Completion time: ~ 5 minutes.  
Temperament and Character Inventory118 (Appendix 18): A widely used test that 
assesses dimensions of personality (e.g., harm avoidance, novelty seeking, reward 
dependence, and persistence) that are considered to be related to monoaminergic 
function. Completion time: ~ 25 minutes.  
The Multidimensional Social Contact Circle119 (Appendix 19): A self-report scale 
designed to measure social ties between the participants and their friend, family, co-
workers, etc. Completion time: ~ 15 minutes.  
Time-line follow back (TLFB; Appendix 20). The TLFB will be used to assess 
substance use behavior. This assessment will be either self-administered or 
administered by one of the investigators. Participants will read the instructions and/or 
will be guided by the therapist or investigator in filling out the calendar. A lifetime TLFB 
will be administered at the start of the protocol. An interim version with be administered 
at each visit to assess substance use between administrations. Completion time: 15 
minutes to 2 hours.  
*Risk Assessment Battery (RAB) (Appendix 21): Self-administered questionnaire 
assessing HIV risk behaviors including drug use, needle use, sexual practices and HIV 
testing behavior. Completion time: < 10 minutes.  
 

PI Name: Yihong Yang, Ph.D. 
 
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Debriefing. At the end of each visit, there will be a debriefing period for discussion of 
questions/issues related to the day’s tasks, scheduling/reminder of subsequent visits. 
They will also schedule a time for their next session. 
Urine Benzoylecgonine Test. Urine samples will be collected from all CD participants 
and will be used in the implementation of CM. These samples will be collected under 
observation of a same-sex observer to confirm its validity. The urine toxicology analysis 
will be used to assess a broad range of prescription and nonprescription drugs by 
metabolite quantitation using a dip card, which is a one-step urinalysis 
immunochromatography drug rapid test (5 minutes), to assess recent use of drugs of 
abuse. It is designed for qualitative screening of cocaine metabolite in human urine 
specimens and provides a preliminary analytical test result for on-site testing.   
Additionally, the urine sample, when positive for cocaine, will be sent for quantitative 
‘additional use’ analysis in the NIDA-IRP Translational Analytical Core (TAC), for 
implementation of CM. Missing samples will be considered positive. Completion time: 
~10 minutes. 
 
 MRI Scan Sessions 
On all days with an MRI scan, participants are expected to complete several clinical 
assessments as well as experimental tasks (see Figures 1 and 2 for graphical 
summary). However, availability of staff, facilities and participant schedule may require 
some flexibility in timing and measures performed in the outline below. CD participants 
will be scheduled to complete all 8 scans described below and HC participants will be 
scheduled to complete up to scan 4. Because HC participants will have a within 
participant active vs sham manipulation (described below), they will complete scans 3 
and 4 twice; once with active and once with sham iTBS (see Figures 1 and 2). 
Pre-scan Assessment. Participants will complete a nursing assessment (as 
described above) upon arrival for each scan session. nursing assessments that occur 
on scan days will include an MRI safety screening.  

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Pre-scan task practice. Prior to each scan, participants will be reacquainted with the 
task instructions and will complete brief training runs. Completion time: ~30 minutes.  
Self-report measures. At each scan session, participants will be administered 
several brief measures to assess current arousal (modified version of the PANAS), 
mood (POMS) and other withdrawal symptoms (CD participants only; Cocaine Craving 
Likert Scales, Cocaine use, Pattern, and Withdrawal Questionnaire). These measures 
will be administered on a computer in a private area. Completion time: ~30-40 minutes. 
Drug Use. A urine sample will be collected from CD participants which will be used 
to implement CM. 
Scan 1. Completed on visit 1: Localizer (~ 1 min); Structural scan (~ 5 mins); MID (~ 
30 mins); Flanker (~25 mins); N-Back Task (~ 10 mins); SSRT (~ 15 mins); 
Approximately 2 hours. 
Scan 2. Completed on visit 2: Localizer (~ 1 min); DTI (~ 10 mins); Resting (~ 10 
mins); Amygdala task (~7 mins); ASL (~10 mins); Approximately 1.5 hours. 
Scan 3. Completed on visit 3 (preceding the first iTBS treatment on the first 
treatment day): Localizer (~ 1 min); ASL (~ 10 mins); Resting (~ 10 mins); SSRT (~ 15 
mins); Amygdala (~7 mins); Cue Reactivity (~ 15 mins): Approximately 1 hour.  
Scan 4. Completed on visit 3 (following the last iTBS treatment on the first treatment 
day): Localizer (~ 1 min); ASL (~ 10 mins); Resting (~10 mins); SSRT (~ 15 mins); 
Amygdala (~7 mins); Cue Reactivity (~ 15 mins); ASL (~ 10 mins). ASL at the beginning 
and end of this scan session will measure trajectory of change of blood flow/neuronal 
activity over time after the TMS session. Approximately 1.5 hours. 
Scans 5 & 7. Completed on visits 19 and 36: Localizer (~ 1 min); ASL (~ 10 mins); 
Resting (~10 mins); Amygdala (~7 mins); Cue Reactivity (~15 mins); Flanker (~25 
mins); N-Back (~10 mins); Approximately 2 hours. 
Scans 6 & 8. Completed on visits 19 and 36: Localizer (~ 1 min); Structural (~5 
mins); DTI (~10 mins); SSRT (~15 mins); MID (~30 mins). Approximately 2 hours. 

PI Name: Yihong Yang, Ph.D. 
 
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Debriefing. At the end of the scanning session there will be a debriefing period for 
discussion of questions and issues related to the day’s tasks. They will also schedule a 
time for their next session. 
 
 iTBS Sessions 
HC participants will be scheduled for 2 days of iTBS - 1 DAY of active iTBS and 1 
DAY of sham iTBS, with at least a 60-minute interval between sessions and at least 1 
week between DAY. The order of these days will be counterbalanced.   
 
CD participants will be scheduled for 10 days of iTBS treatment and randomly 
assigned to receive either active or sham iTBS. Participants will initially be scheduled to 
complete all treatment DAYS in 2-weeks whenever possible, however, they will have up 
to 3 weeks to complete the 10 DAYS of treatment.  
 
On iTBS days, participants will complete several questionnaires in addition to the 
iTBS treatments. During iTBS, participants will view cocaine cues (i.e., pictures; 
Appendix 25) in an attempt to control affective state across participants while also 
potentially eliciting activation in networks specifically related to cocaine use and 
substance abuse in general.  
Pre-iTBS. Participants will complete a questionnaire about possible side-effects 
since the last iTBS session (the NIBS monitoring questionnaire) and a questionnaire 
about their affect (the modified version of the PANAS; see Appendix 1 & 15). 
Participants will also complete Trails A and B (Appendix 22) prior to and following iTBS 
administration each day.  These assessments will also be collected at baseline prior to 
any TMS or iTBS administration to assess a true baseline measure for each participant. 
Also, measures of mania (Young Mania Rating Scale [YMRS]; Appendix 23), suicidality 
(Columbia-Suicide Severity Rating Scale: Baseline [C-SSRS]; Appendix 24) and 
depression (MADRS112; Appendix 14)  will be collected prior to the first iTBS session in 
CD. 

PI Name: Yihong Yang, Ph.D. 
 
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iTBS Session. Resting motor threshold will be determined daily, as described below. 
Recruitment curves will be measured during orientation (HC and CD), and in the CD 
group, before the first iTBS administration on iTBS day 1, after the last iTBS 
administration on iTBS day 10, and each of the follow-up visits with an MRI scan. 
Approximately 1 hour. 
Post-iTBS. At the end of the visit, participants are asked to fill in a questionnaire 
about possible side-effects (the NIBS monitoring questionnaire), a questionnaire about 
their affect (the modified version of the PANAS; see Appendix 1 & 15), questionnaires 
assessing the blind will be administered (Appendix 46), and an assessment of pain will 
be administered (Appendix 46). The iTBS administrator will also fill out an assessment 
of the blind (Appendix 47). Questions about blinding and pain levels will be asked of the 
participant after the last iTBS session. Questions about blinding will be asked of the 
TMS operator after the last iTBS session. Participants will also complete Trails A and B 
(Appendix 22) after the final iTBS administration each day, prior to discharge. After the 
final iTBS session (i.e., on Day 10, prior to discharge), measures of mania (Young 
Mania Rating Scale [YMRS]; Appendix 23), suicidality (Columbia-Suicide Severity 
Rating Scale: Baseline [C-SSRS]; Appendix 24) and depression (MADRS112; Appendix 
14)  will be collected.Contact attempts will be made by phone 1-3 days after the last 
iTBS session to assess any acute behavioral or health related changes from treatment 
(Appendix 1). 
 
 Post-Treatment Follow-Up 
Ongoing follow-up will be attempted for 24-weeks post-treatment and will include 
urine samples for implementation of CM, as outlined in Table 1, and assessments of 
substance use (participants may repeat some or all characterization measures and 
assessments of drug use). MRI scans will be performed about one month and three 
months after the start of iTBS treatments (on approximately visits 19 and 36) to assess 
neural plasticity related to abstinence, reduction, or continuation of drug use post-
treatment. The ASI will be scheduled to be completed within 1-week of all follow-up 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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visits that include an MRI scan, along with the three mood measures (YMRS, MADRS 
and C-SSRS). ASI will also be completed at the final vist of the study. The first 12-
weeks post-treatment follow-up appointments will be in-person. The next 12-weeks will 
consist of once-a-week phone contact attempts and once-a-month in-person visits to 
assess drug use post-treatment. Additional attempts will be performed only through 
means approved by the participant. These may include such alternative methods as text 
and e-mail if phone contact is not successful. 
Questionnaires/Behavioral measures: Some or all assessments and/or tasks may be 
completed remotely via a secure platform approved by NIDA-IRP’s ISSO, or via a 
secure web link set up by the NIDA-IRP BIS team. For this option, participants must 
have use of a private space with secure internet connection. Participants will be 
instructed how to complete the assessments/tasks via phone or encrypted video chat 
program approved by NIDA IRP’s ISSO. 
SARS-CoV-2 antibody testing: COVID-19 has been reported to be capable of 
producing long-lasting neurological effects that might include subtle cognitive deficits 
(Ritchie et al 2020). The prevalence of such deficits, if they exist, is unknown. 
Therefore, we will assess SARS-CoV-2 antibodies in order to assess for possible 
effects. How this data will be used will depend on the number of antibody-positive 
participants in the final cohort as well as future publications on the impact of antibody 
status on the data being gathered. We will not use antibody testing for diagnosis or 
treatment of participants, and participants will not be informed of the results, as they 
have no clear clinical significance and could be misinterpreted. We may collect about 1 
mL of blood or up to 2mL of saliva for antibody testing. We may collect this sample at 
the first visit that includes an MRI scan and at other visits including an MRI scan if the 
participant has not been recently tested for COVID-19, and/or if subsequent scan(s) are 
more than a few weeks apart. If a participant has a documented history of positive 
COVID-19 diagnostic or antibody test, the MAI will determine whether antibody testing 
under this protocol is necessary. 
 

PI Name: Yihong Yang, Ph.D. 
 
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Experimental Measures 
 Imaging Measures 
MRI Scanner Sessions. The total time that participants will be inside the scanner 
each session is approximately 2 hours (note: all times approximate and order of scans 
generally fixed but may be switched in the event of instrument problems or participant 
compliance). 
The study may use the 3T MRI with custom pulse sequences and image 
reconstruction and analysis software (via CRADA with Siemens using sequences 
developed at various universities). All sequences are within FDA approved specific 
absorption radiation (SAR) limits. We believe this study is a non-significant risk (NSR) 
device study subject to the abbreviated IDE requirements of 21 CFR 812.2(b). The 
devices (custom pulse sequences and image reconstruction and analysis software), as 
used in this study, do not meet the definition of a significant risk (SR) device per 21 CFR 
812.3(m) because: 
1.       It is not intended as an implant and presenting a potential for serious risk to 
the health, safety, or welfare of a subject because the MRI is not an implant. 
2.       It will not be used in supporting or sustaining human life and does not present 
a potential for serious risk to the health, safety, or welfare of a subject because MRI will 
not be used in supporting or sustaining human life.  
3.       It will not be for a use of substantial importance in diagnosing, curing, 
mitigating, or treating disease, or otherwise preventing impairment of human health and 
presenting a potential for serious risk to the health, safety, or welfare of a subject 
because the MRI results will not be used to provide clinically relevant information for 
participants.  
4.       It does not otherwise present a potential for serious risk to the health, safety, 
or welfare of a subject because the pulse sequences and image reconstruction and 
analysis software are used within the FDA approved SAR limits. 
 

PI Name: Yihong Yang, Ph.D. 
 
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Per regulations, abbreviated IDEs (NSR device studies) do not require an 
application to the FDA as the IRB acts as FDA’s surrogate for review, approval, and 
continuing review of these type of device studies. 
 
 MRI Measures 
Arterial Spin Labeling (ASL) Scan. We will acquire ASL images to quantitatively 
assess potential changes in regional blood flow and thus neuronal activity resulting from 
iTBS. Completion time: ~ 10 minutes. 
Diffusion Tensor Imaging (DTI) Scan. A DTI scan will be performed allowing for the 
assessment of white matter microstructure and tracks in both HC and CD. Completion 
time: ~ 10 minutes. 
Structural Images. A set of high resolution structural MR images will be collected. 
The images will be acquired using a T1-weighed three-dimensional MPRAGE. 
Completion time: ~ 5 minutes. 
 
 fMRI Measures 
Amygdala Reactivity Task: Participants will complete a simple perceptual task 
previously shown to produce robust bilateral amygdala activity61, 143, 144, as well as top-
down prefrontal regulation of amygdala reactivity143, 144. This is a blocked fMRI paradigm 
where participants are asked to either match faces or geometric shapes145. Completion 
time: ~ 7 minutes.   
Cue reactivity: Participants passively view two kinds of stimuli, cocaine-related 
picture cues and neutral pictures (c.f., 55), in a block design. The MAI or other NRB 
clinical personnel will intervene to mitigate craving before discharge in the event of 
clinically significant craving. A response of 6 or 7 on the CCQ Likert scale for questions 
3, 4, 16, 33, or 34 or a response of 1 or 2 question 28 would constitute clinically 
significant craving. Similarly, a response of 9 or 10 on the CCS Likert scale for question 
1 would constitute clinically significant craving. The MAI or other NRB clinical personnel 
will intervene to mitigate craving before discharge if the participant’s self-report of 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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craving level arouses concern (in the participant or staff) in the context of conversation. 
Completion time: ~ 15 minutes. 
Flanker: Participants will complete a modified Flanker task designed to yield 
sufficient error rates to study the signatures of error processing146. Participants respond 
to the central letter (e.g., H or S) of a congruent (HHHHH or SSSSS) or incongruent 
(HHSHH or SSHSS) stimulus array. To elicit comparable error rates, a participant 
specific, adjustable response time deadline will be calculated and implemented for each 
participant. Completion time: ~ 25 minutes. 
Monetary Incentive Delay (MID) Task. The MID task was designed to identify brain 
circuitry involved with anticipation and receipt of monetary gains and losses62, 147-149. 
Participants respond within a time-window optimized to the participant’s behavior  
during win, loss, or neutral trials with the aim to maximize overall winnings. A 
performance-based payment is payed equal to 10% of the theoretical total that they 
score on the task, with a maximum bonus payment of $53. Completion time: ~ 30 
minutes. 
N-Back. The n-back visual working memory task150 will be administered to assess 
working-memory performance. During the n-back task, participants are presented with a 
series of single letters in a pseudorandom order and are required to decide whether the 
current stimulus matches that which appeared n items previously150. Completion time: ~ 
10 minutes. 
Resting Scan. An eyes open EPI scan to assess resting-state fluctuations will be 
conducted to provide information relating to trait and perhaps state connectivity between 
regions of interest. Completion time: ~ 10 minutes. 
Stop Signal Reaction Time Task (SSRT). The task requires participants to execute a 
motor response (Go trials) on most trials and to withhold their response on some trials 
(Stop trials). On each trial, a target stimulus is displayed. On Go trials (e.g. ~75% of 
trials), participants respond as quickly as possible with a key press. For the Stop trials 
(~ 25% of trials), participants are instructed to stop their response when they receive a 
Stop signal (a visual cue) presented at a particular delay [stop-signal delay (SSD)] 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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subsequent to the target stimulus. The SSD value for the Stop trial is adaptively 
determined to ensure that participants inhibit their response successfully on 50% of 
trials151. Completion time: ~ 15 minutes. 
 
 Behavioral Measures 
Two experimental tasks will be collected outside the scanner. The Stroop task will be 
administered as a baseline characterization instrument for both HC and CD and 
repeated in order to assess the effects of iTBS on prefrontal cortex function within one 
week of scans 5/6 and scans 7/8 in CD.. The Risk/Reward task will be collected once 
within the baseline characterization phase for both HC and CD and weekly after that 
throughout the protocol (when possible) for CD. A performance-based payment is 
payed equal to 10% of the theoretical total that they score on the task, with a maximum 
bonus payment of $6.60.Tasks administered on a iTBS day will be done prior to iTBS 
treatment. 
Stroop/Drug Stroop:  This is combined task that includes stimuli of both the Stroop 
task and the Drug Stroop task. During the Stroop task56, participants are presented with 
color words (e.g., RED) in either congruent (e.g. red) or incongruent (e.g., blue) font 
colors. Participants are to report the font color for each stimulus. Due to the automaticity 
of reading the word, incongruent trials are more difficult than congruent trials leading to 
delayed responding and more errors than congruent trials. The Drug Stroop is similar to 
the Stroop task, participants are presented drug-related words or pictures (e.g., pipe, 
smack, and lighter) that have elicit behavioral and neural differences between users and 
non-users57, 153, 154. Completion time: ~ 15 minutes. 
Risk/Reward Task152: In this task, participants make decisions about risks and 
rewards. Two parameters of interest are collected: Risk tolerance and ambiguity 
tolerance.  These parameters measure known and unknown risks and have been linked 
to predicting relapse. This task will be collected once within the first 3 visits and weekly 
after that throughout the protocol (when possible). A performance-based payment is 

PI Name: Yihong Yang, Ph.D. 
 
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payed equal to 10% of the theoretical total that they score on the task, with a maximum 
bonus payment of $6.60. Completion time: ~20 minutes.  
 
 
iTBS Administration 
 
 Apparatus and tests 
To administer the iTBS treatment, a MagVenture MagPro 100 with MagOption 
(MagVenture Inc, Alpharetta, GA) stimulator equipped with a figure-8 coil will be used. 
Two separate coils will be utilized that are all similar in weight, appearance, and 
acoustic properties. One active coil will be unblinded and used to determine RMT and 
deliver pulses for the recruitment curves; the other will be blinded (one side active, one 
side sham). All personnel interacting with the participant will be blind to coil assignment. 
The Sham stimulation and preservation of the blind is described below. 
 
 Localization of Dorsolateral Prefrontal Cortex 
iTBS stimulation will be targeted using specific coordinates (MNI coordinates: -50, 
30, 36). The network connectivity with this coordinate has recently been shown to be 
most predictive of relapse to cocaine use (recently submitted internal lab data) and thus 
a promising target for iTBS stimulation. In this work, other dlPFC TMS target 
coordinates were tested and found to be not predictive of relapse to cocaine use.  
 
 Motor Threshold Determination 
In determining motor threshold, first the scalp position closest to the motor 
representation (the “motor hot spot”) is sought. Then the RMT at this location is 
determined. The hotspot is located during the initial session and verified at subsequent 
sessions, whereas the RMT will be measured every treatment day. In accordance with 
the manufacturer’s instructions and accepted standards, hand motor cortex will be 
stimulated to obtain RMT123, 124. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Participants will be seated in a recliner in a comfortable resting position and fitted 
with earplugs. The TMS figure-8 coil will be placed over the hand-associated primary 
motor cortex. The coil will be held tangentially on the head with the handle pointing 
backward and 45° laterally from the midline. Using repeated single pulse, 
suprathreshold stimuli, the coil will be moved to determine the optimal scalp position for 
producing visible contralateral hand twitches. Pulses over this motor cortex location will 
be administered to identify the resting motor threshold using PEST125 software. 
Responses will be either visually detectible motor twitches or motor evoked potentials of 
the muscles that move the contralateral hand. Recruitment curves will be measured as 
a proxy for the ratio between gamma amino butyric acid (GABA) and glutamate126-128. 
The recruitment curve will be measured at orientation in both HC and CD, and before 
the first iTBS administration on iTBS day 1, after the last iTBS administration on iTBS 
day 10, and each of the follow-up visits with an MRI scan.in CD  
This entire procedure (hotspot and threshold determination) can take 30-90 minutes. 
If no motor hotspot can be determined within 1 hour or if the motor threshold exceeds 
83% of maximal stimulator output, the participant may be discontinued from the study at 
the discretion of the LAI and/or MAI. Because the initial motor hotspot determination will 
be catalogued, subsequent determinations on treatment days are expected to take very 
little time. 
 
 Stimulation Procedure 
A pre-selected protocol is programmed into the iTBS stimulator73. Three pulses will 
be given at 50 Hz repeated every 200 ms for a 2 second duration followed by 8 seconds 
of no stimulation. This sequence repeats for a total of 190 seconds and 600 pulses. 
Magnetic field intensity will be set at a medium intensity and gradually increased to the 
goal of 100% of that participant’s measured daily RMT, accounting for cortical distance 
as measured with a structural MRI, depending on participant tolerability. Cortical 
distance has been shown to be greater over dlPFC than motor cortex155. Also, group 
differences have been identified between CD and HC participants156. Therefore, these 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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differences will be adjusted within participant to ensure similar cortical excitation is 
achieved over the dlPFC as motor areas. 
 
 Sham Stimulation  
The double-blind will be preserved by allowing research staff not present during the 
iTBS session to be responsible for randomizing the active and sham coil. Therefore, 
research staff present during the iTBS session may be responsible for clinical ratings. 
The sham coil setting is designed to mimic the auditory artifact and scalp sensations 
evoked by the real coil without stimulating the brain. The blinded coil has two sides that 
can be placed on the participant’s head; one side active and one side sham. These 
sides look identical to the researcher and the participant but TMS/iTBS pulses are 
delivered from only the active side. Which side is facing the participant is determined by 
the TMS machine or by self-application. The TMS operator will use the coil as set up by 
the research staff not present ensuring that both the operator and the participant will not 
know the orientation (active or sham) of the coil. However, in experienced participants, 
the difference between real and sham iTBS, as well as the difference between different 
intensities of iTBS is likely to be noticeable. The TMS operator is responsible for 
verifying the correct iTBS sequence is loaded into the TMS stimulator prior to 
administering an iTBS session. If a CD participant is randomized to the sham-iTBS 
group, all iTBS sessions will be sham. Each HC participant will be randomly assigned to 
either sham- or active-iTBS for visit 3 then crossed over to the other iTBS administration 
for visit 4. Measurement of motor evoked potentials will be identical between active- and 
sham-iTBS groups. In an attempt to avoid placebo effects, it is emphasized to the 
participant that the sensation is related to the stimulation of scalp nerves and muscles, 
and brain stimulation itself cannot be felt. While our sham stimulation does produce a 
sensation that is comparably uncomfortable in at least some participants and can 
produce muscle twitches, it is not qualitatively identical to the active iTBS. Therefore, 
while efforts are taken to preserve the double-blind, it is possible that the participant 
and/or the experimenter will become unblinded to the treatment condition. Because of 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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this, a questionnaire assessing the blind will be administered to the participant 
(Appendix 46) and the iTBS administrator (Appendix 47). Also, an assessment of pain 
will be administered to the participant (Appendix 46). 
 
6. Discharge Procedures  
If a participant experiences somatic or psychological symptoms that interfere with 
his/her ability to participate then he/she will be discharged from the study. The most 
frequent symptom is pain over the area of stimulation which could interfere with 
participation in the study. DLPFC stimulation has rarely been associated with mania. 
The investigators will monitor participants for changes in mood and may discharge a 
participant at any time if they believe that it is in the best interest of the participant. 
Participants who fail to tolerate iTBS at 100% of RMT during their toleration session will 
be discharged from the study. Those with RMT over 83% of MSO will be discharged as 
the recruitment curves require administering pulses up to 120% RMT, which is only 
possible if RMT is 83% or less. 
 
 
7. Participant Monitoring 
The NIBS monitoring questionnaire (Appendix 1), Trails A and B (Appendix 22), and 
staff observation and interactions with participants will be assessed daily. A NIDA-IRP 
physician or Physician’s Assistant knowledgeable about iTBS will be immediately 
available in the building whenever iTBS is administered and will be available by 
telephone or pager 24 hours a day for consultation or in the event of a medical 
emergency. If immediate medical intervention is required, the participant will be referred 
to an appropriate medical facility. Information on all adverse events will be cumulated 
and reported to the NIH IRB with each continuing review application. Unexpected or 
serious adverse events (defined in accordance with NIH and NIDA IRP policy) will be 
promptly reported to the NIDA Clinical Director and IRB in accordance with NIH and 
NIDA IRP policy (see DSMP below). 

PI Name: Yihong Yang, Ph.D. 
 
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Seizure monitoring procedures: Participants will be monitored throughout each iTBS 
session for signs of seizures such as involuntary muscle movements or loss of 
consciousness. In the event of a seizure, staff will have immediate access to life support 
equipment and anti-seizure drugs. In the event of a seizure, the procedure outlined 
below129 will be followed:   
1. Protect patient’s head and limbs from injury. 
2. Ensure an adequate airway. 
3. Call 911 to have the patient transferred to Johns Hopkins emergency room, if the 
seizure requires medication intervention to resolve or is otherwise clinically 
indicated. 
4. Observe Patient for: 
a. Initial movements/ sensations. 
b. Progression of movements. 
1. Change in respiratory status 
2. Skin color 
3. Incontinence 
4. Level of consciousness 
5. Ability to communicate 
6. Level of orientation 
7. Duration of seizure activity  
If after two minutes, the seizure has not resolved, administer: 
midazolam IM, 10 mg that is contained in a lock box in the TMS suite. 
5. Provide supportive care after the seizure resolves.  
6. Orient patient to time and place.                     
Session video recording: If a potential adverse event occurs during iTBS stimulation, 
video footage of the session can help determine the nature of the incident. Thus, video 
will be recorded during threshold determination and during iTBS, barring any technical 
difficulties with recording instrumentation. If the session progresses without incident, this 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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footage will be deleted within a week. Otherwise, during sessions with abnormal events, 
the video will be retained in accordance with NIH Records Management policy 
(https://oma.od.nih.gov/DMS/Documents/Records/NIH_Intramural_Research_Recor
ds_Schedule.pdf) for 7 years after the completion of the study or when no longer 
needed for scientific reference, whichever is longer. This footage may be used by the 
MAI and any experts the MAI wishes to consult to determine the nature of the event. 
Participants will not be given the option to opt out of the video recordings. If they do not 
wish to be recorded, the alternative is to not participate in the study. 
 
 
Risks 
The side effects associated with TMS treatment in large clinical trials have been 
published130. Published consensus safety guidelines for TMS have resulted in reduced 
frequency of adverse events131. The following clinical data associated with depression 
treatments are provided to emphasize the extensive medical experience with TMS and 
its safety.  
Numerous sham-controlled trials and several meta-analyses support its efficacy in 
treating depression94, 132-134. The largest TMS sham-controlled trial to date involving 301 
pharmacotherapy refractory depressed participants reported positive results70. Sessions 
of rTMS were conducted for 4 to 6 weeks five times per week. Stimulation was set at 
120% RMT with 10 pulses per second for a total of 3000 pulses per session. Active 
rTMS was well tolerated, with low dropout rate for adverse events (4.5%) that were 
generally mild and limited to transient scalp discomfort or pain. In the current proposed 
study, iTBS will be used, which is similar to rTMS but a lower level of stimulation (100% 
of RMT compared to 120% of RMT for rTMS). 
There are no published reports of iTBS related seizures. Dr. Eric Wasserman, a 
TMS expert and pioneer at NINDS, summarized the occurrence of seizures in Table 2 
from largely unpublished reports. As shown, his survey reported a single iTBS seizure  
in a stroke patient who was at high risk for seizure. Also, his survey has determined that 
there is a 0.002% chance of a seizure in healthy participants. Several published reports 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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are available in which healthy control participants receive multiple iTBS sessions within 
a day without serious adverse events99, 100, 135. 
 
Table 2: Seizures by mode of stimulation 
Total 
No elevated risk 
Mode 
Seizures 
Session
s 
Risk 
Seizur
es 
Sessions 
R
isk 
Single/Paired-pulse  
13 
112897 
.12 
3 
100696 
.
030 
Low-frequency (≤1 Hz)  
3 
90631 
.03 
0 
54373 
- 
High-frequency (>1 Hz) 
4 
82588 
.05 
1 
76181 
.
01 
Intermittent Theta Burst   
1 
16952 
.06 
0 
2729 
Continuous Theta Burst  
0 
8568 
. 
0 
4994 
H-Coil high-frequency 
3 
6924 
.43 
1 
3094 
.
32 
Totals 
23 
318560 
.07 
5 
242067 
.
02 
Note: Number of sessions and seizures for different modes of NIBS. Seizure risk is per 1000 
sessions. There is 1 unpublished seizure related to iTBS but that occurred in a stroke patient (i.e., at high 
risk for seizure). The overall risk for NIBS-related seizure in healthy participants is 0.002% which is well 
below (500x) the prevalence of epilepsy (1%). 
 
 
Additional Considerations 
 Reproducibility of Task Paradigms   
One potential concern related to the present design pertains to the stability of the 
imaging and behavioral outcomes across repeated assessments. Most of the task 
paradigms were chosen based on literature suggesting they are relatively resistant to 
practice effects. For example, in interference tasks such as the Flanker or Stroop, 
hundreds-to-thousands of trials (or several hours of training) are generally needed 
before practice effects in behavioral measures can be observed157-159. If we assume that 
behavioral measures remain stable across repeated assessments, particularly error 
rates, it is also reasonable to assume that neurophysiological correlates of error 
processing are likely to be unaffected as well. Furthermore, our group has two ongoing 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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or completed protocols where task reproducibility was not compromised in several of 
the tasks we will implement here (i.e., Flanker, Stroop, the decision making task, MID, 
or SSRT). In addition, it should also be noted that participants will receive extensive and 
repeated training on all tasks throughout the protocol. This training, taking place on 
multiple days, is expected to help mitigate the impact of in-scanner practice effects on 
the measures of interest. The presence of a group receiving CM and sham-ITBS will 
also help control for any practice effects. Nonetheless, potential confound of practice 
effects will be examined and if observed, may be a potential limitation of the study.  
 
 Relationship to Other Protocols 
All participants in this protocol will first enter the approved NIDA-IRP general 
screening protocol. Data from the screening protocol will be used to determine eligibility. 
Every participant in the Expanded Feasibility Study will also be enrolled in protocol 10-
DA-N457 to obtain characterization information. Data obtained under the screening 
protocol and 10-DA-N457 may be shared with this and potentially other protocols.  
 
 
Statistical Analysis  
Behavioral performance measures (e.g., response time, error rate, and hit rate) on 
each of the cognitive tasks as well as questionnaire data from each of the experimental 
conditions will be compared both within and between experimental groups using mixed, 
repeated-measures ANOVA, and linear mixed models. When assessing the statistical 
results from the behavioral and questionnaire data, a standard α-level of 0.05 will be 
used. Alpha-levels for multiple comparison follow-up tests will be corrected using an 
appropriate method (e.g., Bonferroni, Tukey, Scheffe).  
Without knowing the final breakdown of completers and non-completers, we cannot 
definitively outline the planned analyses, but several options are possible. For example, 
if a substantial number of participants fail to complete 10 iTBS treatment days, this 
group could be included as a separate group for comparison. Further analyses with this 
group would depend on the characteristics of the group vis a vis the 10 iTBS treatment 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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day completers. On the other hand, if most participants fail to complete 10 iTBS 
treatment days, all participants who complete five days of treatment would be 
considered in the final analysis and the number of iTBS treatment days would be 
included as a covariate. In the end, the protocol allows for data collection to be 
maximally flexible while allowing the measurement of iTBS efficacy in treating cocaine 
use disorder. 
An outline of proposed imaging analysis steps is presented below. Current 
techniques are outlined with the understanding that while these data are collected, new 
analysis techniques may be developed. These new techniques may be better suited to 
answer our questions with the data collected. Therefore, the specific analyses carried 
out at the end of this protocol are subject to change to reflect the most advanced and 
appropriate analysis techniques available.  
The imaging data will be pre-processed and analyzed with Analysis of Functional 
Neuro-Images (AFNI160). All functional images will be directly registered upon high 
resolution MPRAGE anatomical scans obtained during the same imaging session. 
Location and intensity of activations from individual and/or grouped data will be 
translated into 3D stereotaxic coordinates161. Functional images of activation-induced 
BOLD signal changes will be determined using cross correlation or multiple regression 
analyses162, 163. The specific statistical analyses to be performed on the fMRI 3-D 
datasets will be dictated by the nature of the factors involved and the specific scientific 
question addressed. For example, ANOVA models (3dANOVA, 3dANOVA2, 
3dANOVA3) can be used to test for differences between participant groups or iTBS 
condition. Differences in structural and functional measures between CD and HC 
participants will be assessed using between group comparisons (e.g., independent 
samples t-tests). Differences within the CD group across sessions will be assessed 
using within group comparisons (e.g., dependent samples t-tests). Correlation and 
multiple regression approaches will be used to test for an association between clinical 
assessment measures and task-specific neural measures (e.g., correlation between 
cocaine craving scores and neural activation in the striatum).  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Each of the cognitive task paradigms was chosen to tap into specific psychological 
constructs and neural substrates that have been shown to be associated with cocaine 
dependence. Across each paradigm there are multiple dependent variables (i.e., RT, 
error rates, and neural signal) that will be examined to assess for effects with CD 
participants and contrast with HC participants. The initial independent variable of 
interest is the group variable, used to assess for differences between CD and HC 
participants. A simple independent samples t-test can be used to detect differences. 
Paired samples t-tests will be used to determine differences between active and sham 
iTBS conditions, as well as between longitudinal MRI measures. Ultimately, more 
advanced factorial designs will be used to explore differences between groups and 
sessions. The selected paradigms have overlapping neural circuitries. Although the 
primary analyses are conceived of as separate studies, the secondary analyses will 
integrate the results from each of the paradigms. These secondary analyses will be 
used to gain a more complete understanding of the neural circuitries involved in goal 
directed behavior and decision making in control populations as well as factors leading 
to addiction, drug seeking behavior, continued abstinence, and possible relapse in drug-
addicted populations.  
For MRI analyses, the AlphaSim program (within AFNI) will be implemented to 
correct for multiple comparisons. AlphaSim is a Monte Carlo simulation technique that 
provides a method for multiple comparison correction while persevering statistical 
power. Using random image generation, Gaussian filtering (to simulate voxel 
correlations), thresholding, and tabulation of cluster size frequencies, the program 
generates an estimate of the overall significance level achieved for various 
combinations of probability and cluster size thresholds assuming spatially uncorrelated 
voxels. Overall, simulations using this program indicate that by accepting a minimum 
cluster size it is possible to obtain an order-of-magnitude improvement in probability 
threshold over the value of probability threshold required if cluster size thresholding is 
not used. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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General fMRI power. Since fMRI is the main outcome measurement utilized in the 
present protocol, the key power analysis pertains to the fMRI data. However, 
prospective power analyses for fMRI data are complicated for several reasons. First, 
fMRI data are analyzed in a hierarchal manner such that both the intra-participant 
variance from the time-course data and the inter-participant variance across individuals 
could affect statistical power. A large number of time points tend to mitigate effects of 
intra-participant variance, but temporal autocorrelation and scanner limitations limit the 
number of independent measurements per unit time and thus the number of 
independent time points that are collected. In addition, effect sizes and both types of 
variance will vary spatially. Because of this, a given study may have sufficient power to 
detect differences in some brain regions, but lack sufficient power in other regions 
where the null hypothesis is false. Finally, fMRI analysis consists of a very large number 
of non-independent multiple comparisons, greater than 1.5 million at the group level, 
necessitating correction methods less severe than a Bonferroni correction, as discussed 
above. Thus, a proper power analysis on fMRI data requires simulating all of these 
effects. Desmond and Glover164 have performed such a simulation. They show for a 
relatively modest signal change of 0.5% during a cognitive task and with an intra-
participant standard deviation of 0.75% and an inter-participant standard deviation of 
0.5%, that 11 participants are required for a power of 0.8 using p < 0.05. Using a false 
positive rate of p < 0.002, a level more consistent with a cluster size threshold to correct 
for multiple comparisons165, and with the variances kept the same, approximately 21 
participants are needed for an expected signal change of 0.5% and 11 participants for a 
signal change of 0.75%. For more than ~100 independent time points, power (and 
hence the intra-participant variance) is relatively independent of the number of time 
points164. All current analyses should fall within this range.  
There are no published reports of the effects of chronic application of iTBS in 
cocaine users with functional connectivity measures on which to base a power analysis 
and the acute effects of iTBS on functional connectivity alterations are not relevant to 
our study as we seek to understand neural changes after chronic application of iTBS. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Nonetheless, there is a single published report in a sample of participants with major 
depression where functional connectivity was measured pre- and post-rTMS treatment 
166. In this report, the mean functional connectivity pre-TMS (0.38 z-scored connectivity) 
was greater than post-TMS (0.22 z-scored connectivity) with an average standard 
deviation of 0.17 z-scored connectivity. We calculated the effect size to be 0.91. This 
effect size is likely unrealistically high due to ‘double-dipping’ in their analyses167, a 
small sample size, and publication bias toward significant effects, all of which affect the 
effect size calculation and generalizability.  
To better assess a more realistic effect size based on these findings, we simulated 
an effect size (N =10,000) based on the published means and standard deviations. The 
effect size that falls 1 standard deviation below the mean was 0.64. This effect is 
remarkably close to a published report comparing functional connectivity between 
healthy controls and cocaine users44 without a TMS intervention (calculated effect size 
of 0.67).  
Together, when assessing functional connectivity differences post-iTBS treatment 
between active and sham groups, we conservatively select an effect size 0.65 to 
capture a reliable effect while reducing the likelihood of committing a Type II error and a 
power level (1-β) of 0.8 to achieve an appropriate balance between the ability to detect 
significant differences and the number of participants needed. Therefore, for power 
analysis calculations (i.e., Statistical Analysis Plan), we anticipate a mean functional 
connectivity measure post-iTBS for the sham group to be 0.210 z-scored connectivity 
and active group to be 0.405 z-scored connectivity with a standard deviation of 0.299 z-
scored connectivity, which produces an effect size of 0.65 and an estimated sample 
size needed per group to be 30 with a one-tailed t-test assuming a p-value of .05. We 
anticipate approximately 60% retention rate by visit 19, based on previous NIDA 
protocols. Therefore, 100 CD participants will be recruited at baseline, 45 active and 45 
sham iTBS, to acquire the necessary 30 participants in each group for analysis.  
 
 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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 COLLECTION AND STORAGE OF HUMAN SPECIMENS OR DATA  
Paper copies of research records such as ‘Run Sheets’ (i.e., procedural checklists) 
will be kept in study-specific binders kept in a locked cabinet, in a limited access locked 
room. Binders remain in this room at all times, apart from when required for study 
sessions. At the completion of each session paper records will be returned to the locked 
cabinet by the investigator or research associate responsible for the experimental 
session. Electronic research records and/or data (e.g., physiological, imaging, 
behavioral) obtained during experimental sessions is stored on password protected, 
network drives, or other secure application (e.g., CDW, RedCap, Qualtrics) in line with 
NIH policies, which have limited access. Data stored on these drives is identified by 
study number, participant ARC and/or task. No personal identifiers are stored with the 
data. Data will be stored indefinitely. Urine samples acquired for measurements of 
pregnancy and drug usage will be destroyed once valid assays have been obtained. 
 
A. Genomic Data Sharing (GDS) 
This protocol does not meet criteria to require a GDS plan. 
 
B. Human Data Sharing (HDS) 
The proposed research will include data from approximately 170 participants being 
screened for substance use disorders in the Baltimore, Maryland area. The final dataset 
will include self-reported demographic, behavioral, and imaging data and laboratory data 
from urine specimens provided. Because of the longitudinal nature of this protocol, we 
will be collecting identifying information. Even though the final dataset will be stripped of 
identifiers prior to release for sharing, we believe that there remains the possibility of 
deductive disclosure of subjects with unusual characteristics. Thus, we will make the data 
and associated documentation available to users only under a specific data-sharing 
agreement that provides for: (1) a commitment to using the data only for research 
purposes and not to identify any individual participant, (2) a commitment to securing the 
data using appropriate computer technology, and (3) a commitment to destroying or 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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returning the data after analyses are completed. Sharing will be limited to NRB protocols 
(current, future, and those in the repository) and restricted access to personnel with 
access to CDW and NRB network. No data with leave NIH without first obtaining a transfer 
agreement and IRB approval or OHSRP exemption. No additional funds are needed for 
this plan. 
 
C. Participant Safety Monitoring 
The NIBS monitoring questionnaire (Appendix 1), Trails A and B (Appendix 22), and 
staff observation and interactions with participants will be assessed daily. A NIDA-IRP 
physician or Physician’s Assistant knowledgeable about iTBS will be immediately 
available in the building whenever iTBS is administered and will be available by 
telephone or pager 24 hours a day for consultation or in the event of a medical 
emergency. If immediate medical intervention is required, the participant will be referred 
to an appropriate medical facility. Information on all adverse events will be cumulated 
and reported to the NIH IRB with each continuing review application. Unexpected or 
serious adverse events (defined in accordance with NIH and NIDA IRP policy) will be 
promptly reported to the NIDA Clinical Director and IRB in accordance with NIH and 
NIDA IRP policy. 
Seizure monitoring procedures: Participants will be monitored throughout each iTBS 
session for signs of seizures such as involuntary muscle movements or loss of 
consciousness. In the event of a seizure, staff will have immediate access to life support 
equipment and anti-seizure drugs. In the event of a seizure, the procedure outlined 
below129 will be followed:   
1. Protect patient’s head and limbs from injury. 
2. Ensure an adequate airway. 
3. Call 911 to have the patient transferred to Johns Hopkins emergency room, if the 
seizure requires medication intervention to resolve or is otherwise clinically 
indicated. 
4. Observe Patient for: 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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a. Initial movements/ sensations. 
b. Progression of movements. 
c. Change in respiratory status 
d. Skin color 
e. Incontinence 
f. Level of consciousness 
g. Ability to communicate 
h. Level of orientation 
i. Duration of seizure activity 
 
If after two minutes, the seizure has not resolved, administer: midazolam 
IM, 10 mg that is contained in a lock box in the TMS suite. 
5. Provide supportive care after the seizure resolves.  
6. Orient patient to time and place.            
          
Session video recording: If a potential adverse event occurs during iTBS stimulation, 
video footage of the session can help determine the nature of the incident. Thus, video 
will be recorded during threshold determination and during iTBS, barring any technical 
difficulties with recording instrumentation. If the session progresses without incident, this 
footage will be deleted within a week. Otherwise, during sessions with abnormal events, 
the video will be retained in accordance with NIH Records Management policy 
(https://oma.od.nih.gov/DMS/Documents/Records/NIH_Intramural_Research_Recor
ds_Schedule.pdf) for 7 years after the completion of the study or when no longer 
needed for scientific reference, whichever is longer. This footage may be used by the 
MAI and any experts the MAI wishes to consult to determine the nature of the event. 
Participants will not be given the option to opt out of the video recordings. If they do not 
wish to be recorded, the alternative is to not participate in the study. 
MRI: At screening and on each study day involving an MRI scan, participants will fill 
out an MRI safety form to ensure that there is no change in the participant’s suitability 
for MRI scanning. They will also have a urine drug screen and pregnancy test (females). 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
Protocol Number/ Title: 17-DA-N002/ Neuroplasticity Following Theta-Burst Stimulation in Cocaine Use Disorder 
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If urine drug screen is positive for drugs other than cocaine and THC, they will be 
rescheduled; if pregnant, females will be notified, referred if necessary for care, and 
discontinued from participation in the study. At all times during MRI scanning study, a 
scan operator will be present in the control room and participants will be able to 
communicate via an intercom. Participants will also have a device they can squeeze to 
alert the operator in case of an urgent issue. 
Acute clinical needs: ‘Red flags’ observed during clinical assessments will be used 
to identify acute clinical needs. The first-level evaluation is participant interaction with a 
nurse at intake. NIDA nurses are well trained to identify abnormal behavior that may 
need immediate clinical attention. When such behavior is identified, a flag will be 
generated and the MAI will be contacted. A second flag level is programmed into the 
CDW system to be triggered if a participant endorses a specific state. The LAI will 
routinely review CDW files for such flags while the participant is at NIDA-IRP. A failsafe 
mechanism is in place such that remuneration cannot be disbursed with an 
unaddressed red flag. Therefore, participants who endorse specific states during a visit 
will be identified and assessed by clinical staff prior to discharge for the day. 
Endorsing suicidality on the MADRS is an example of a red flag. If a participant 
endorses this state while the MADRS is administered, a flag is generated, and usually 
addressed immediately by the clinician administering the MADRS. If a participant 
reports suicidal thoughts, the CDW Critical Item Alert System will be initiated following 
the NIDA SOP. Participants may also endorse acute states of depression or mania 
while participating in this study. Sleep patterns will be tracked to assess potential sleep 
deprivation. Significant sleep deprivation, or lack of sleep, may have a clinical impact on 
participants. If this occurs, the LAI will initiate the intervention protocol. This intervention 
may include referral and/or discharge from the study if clinically significant. 
 
 
Primary Saftey Endpoints and Associated Stop Rules  
Three outcomes will be monitored throughout the study as safety endpoints 
associated with a stop rule. As described below, we will track iTBS-induced seizures, 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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neurocognitive function, and clinically significant adverse events requiring outside 
evaluation. Chi-square tests will be calculated to test frequency differences between 
groups (active iTBS vs sham iTBS) for each of these endpoint measures. Each stop 
rule is described in detail below.  
1. Number of iTBS-induced seizures: more than 1 iTBS-induced seizure 
resulting in hospitalization within any 10 consecutive participants who receive 
iTBS will result in a protocol hold until further evaluation by the PI, FDA, and 
DSMB. The Blind will be broken for any participant with an iTBS-induced 
seizure. We will also consult Dr. Alexander Rotenberg, M.D., Ph.D., Director, 
Neuromodulation Program within the Division of Epilepsy and Clinical 
Neurophysiology, Department of Neurology, Boston’s Children’s Hospital and 
Associate Professor of Neurology at Harvard Medical School. Dr. Rotenberg 
is a member of our DSMB and possesses the necessary clinical expertise to 
evaluate the proposed safety endpoints. No new iTBS sessions will be 
administered to any participant once this stop rule is enacted until evaluation 
of the events is concluded and it is deemed appropriate to proceed. However, 
participants who have completed their iTBS treatments may be scheduled for 
Contingency Management (CM), MRI scan, or follow-up visits. 
2. Cognitive performance on Trails B:  Neurocognitive function will be 
assessed with Trails A and B before and after each iTBS day. Although Trails 
A and B are usually administered in sequence, only Trails B will be 
evaluated in relation to this stop rule. A completion time for Trails B greater 
than 90 seconds169 is considered abnormally long. Therefore, if a participant 
requires more than 90 seconds to complete Trails B after iTBS, the 
following steps will be taken: 
a. The participant will rest and be observed for 60 minutes after 
completion of post-iTBS Trails B. 
b. Trails A and B will be administered again after the 60 minute timeout 
period. 

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c. A score to complete Trails B a second time greater than 90 seconds 
will call for the MAI (or covering clinician) to evaluate the participant. 
d. If the MAI (or covering clinician) deems outside evaluation or treatment 
is necessary, the participant will be discharged from the study and 
appropriate steps will be taken to seek an outside 
evaluation/intervention (e.g., an ER visit). The Blind will be broken for 
this participant at this time.  
If more than 1 neurocognitive event identified with Trails B is seen within any 
10 consecutive participants, the protocol will be put on hold until further 
evaluation by the PI, FDA, and DSMB. As above, Dr. Rotenberg will be 
consulted for his evaluation of the stop rule; CM, MRI scan, and follow up 
visits, may continue but iTBS will not be administered until the hold is 
resolved. 
3. Clinically significant adverse events (i.e. adverse events that require 
referral for further evaluation) likely related to iTBS. For example, a mild 
headache after iTBS that resolves spontaneously or with over-the-counter 
medication will not be considered clinically significant. A severe headache 
that starts during or shortly after iTBS and fails to resolve with time and/or 
OTC intervention would prompt referral to an Emergency Department and will 
be considered clinically significant.  
a. If more than 1 clinically significant adverse event related to iTBS 
administration and having similar clinical features is seen within any 10 
consecutive participants, the protocol will be put on hold until further 
evaluation by the PI, FDA, and DSMB. As above, Dr. Rotenberg will be 
consulted for his evaluation of the stop rule; CM, MRI scan, and follow 
up visits, may continue but iTBS will not be administered until the hold 
is resolved. 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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Clinical Efficacy Cocaine Use Endpoint 
1. Clinically significant worsening of cocaine use behavior will be 
evaluated and monitored as follows: Although neuroplastic changes in 
brain activity assessed with fMRI is our primary outcome variable of interest, 
we will measure cocaine use behavior (Appendices 13: Cocaine use, Pattern, 
and Withdrawal Questionnaire, & 21 Time-Line Follow back) at baseline and 
longitudinally throughout the protocol. Among the cocaine use behaviors 
assessed is maximum dollar amount spent during the longest lifetime binge. 
Chi-square tests will be calculated to test frequency differences between 
groups (active iTBS vs sham iTBS) for this endpoint measure. If a participant 
reports a binge amount in dollars that exceeds 3 X the greatest binge dollar 
amount, the following steps will be taken: 
a. The iTBS treatment for this participant will be paused  
b. The participant will be scheduled to return the next day for further 
evaluation, which will include reassessment of cocaine use behavior  
i. If the participant reports continued excessive cocaine binge 
behavior, the participant will be referred for alternative 
treatment. The Blind will be broken for this participant at this 
time.  
ii. If the participant reports a return to their normal cocaine use 
pattern, they will be scheduled for further evaluation in about 1 
week.  
c. After about 1 week, cocaine use behavior will be re-assessed.   
i. If the participant reports further episodes of excessive cocaine 
binge behavior, the participant will be referred for alternative 
treatment. The Blind will be broken for this participant at this 
time.  

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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ii. If the participant reports a return to their normal cocaine use 
pattern, they will be allowed to continue in the study. Their 
treatment schedule will be resumed at this point.  
As soon as the increase is noted and at each follow-up visit, the MAI (or 
covering clinician) will assess precipitants to the change in cocaine use 
behavior to ascertain whether a significant life-event (e.g., death of a family 
member) could be related to a spike in cocaine use behavior (vs. the iTBS 
itself). Detailed evaluation of the situation is necessary to understand the 
clinical ramifications of continuing, or discontinuing, the iTBS administrations. 
If, at any point, the MAI (or covering clinician) concludes that iTBS was likely 
responsible for the change in cocaine use, the participant will not resume 
iTBS treatments.  
If the participant has a second episode of excessive use in excess of 3 X 
their previous greatest binge dollar amount after resuming iTBS treatments, 
they will be discharged and referred for alternative treatment. 
Participants who are to be discharged and referred for alternative 
treatment will be followed as clinically indicated for up to one month to track 
their clinical course and facilitate transfer to alternative treatment. The 
participant will be discharged at this point. 
If more than 1 clinically significant worsening of cocaine use behavior is 
seen within any 10 consecutive participants, the protocol will be put on hold 
until further evaluation by the PI, FDA, and DSMB. As above, CM, MRI scan, 
and follow up visits may continue but iTBS will not be administered until the 
hold is resolved. 
 
All research staff who administers iTBS to participants must meet the following 
training requirements: 
1. Bachelor’s degree (or higher) in psychology or a biological or social science, with 
at least 6 months experience working in clinical research. 

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2. Certification in basic adult life support. 
3. Working knowledge of the principles and practices of iTBS and the iTBS device 
being used in the study, including common side-effects and how to recognize 
them. Knowledge will be based on completing assigned readings given by the 
investigators and tutorial sessions with the investigators. Adequate level of 
knowledge will be assessed by passing (80% correct) a written examination 
constructed by the investigators. 
4. Knowledge of the location of the emergency equipment and medication and how 
to engage the emergency response system. Only staff with the appropriate 
education, training, licensure, and certification will provide medical care or 
supervision to participants. 
5. Practical demonstration of ability to perform 5 determinations of the RMT, under 
the supervision of a doctoral-level investigator or iTBS consultant before 
performing any iTBS procedures, 
6. Performing the first 2 iTBS study sessions under the supervision of a doctoral-
level investigator experienced in iTBS or the iTBS consultant identified above. 
 
D. Consent Process 
 
Informed consent will be obtained from each participant at entry into the study. The 
consent document will include details regarding all study procedures (e.g. iTBS and 
fMRI). The participant will be provided with the study consent form and instructed to 
review it prior to the consent session. An investigator authorized to obtain consent then 
meets with the participant in a private area to review the consent and confirms the 
participant understands the consent and answers any questions. Alternatively, the 
investigator may conduct the verbal review of the consent form via an encrypted video 
chat type program approved by NIDA’s ISSO. The method of consent review will be 
determined at the discretion of the designated study investigator and with the 
agreement of the participant. Whether in person or remote, the privacy of the subject 

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will be maintained. When consent is conducted remotely, the participant will be informed 
of the private nature of the discussion and will be encouraged to relocate to a more 
private setting if needed. 
Once the participant verbally demonstrates understanding to the investigator and 
agrees to the process, a consent quiz is administered. they are asked to sign and date 
the consent form. The investigator co-signs the consent form. The signatures may be 
hand written or obtained on an electronic consent form with a finger, stylus, mouse  or 
the like. The signed consent and quiz will be a part of the participant’s medical record 
and the participant will be given a copy of the consent form for his/her own records. 
Once the signed consent has been obtained, the investigator will note the participant’s 
enrollment in the study in the CDW database. Only after this last step has been 
completed will study procedures begin.  
 
Four consent documents, containing all required elements, are submitted with this 
protocol: Pilot: inpatient volunteers (Consent 1, 2: archived); 3) Expanded Feasibility 
Study: CD volunteers;  4) Expanded Feasibility Study: HC volunteers. 
The informed consent document will be provided as a physical or electronic 
document to the participant as applicable for review prior to consenting. A designated 
study investigator will carefully explain the procedures and tests involved in this study, 
and the associated risks, discomfort and benefits. In order to minimize potential 
coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors as 
applicable, and to ask questions of any designated study investigator. 
The initial consent process as well as re-consent, when required, may take place in 
person or remotely (e.g., via telephone or other NIH approved remote platforms used in 
compliance with policy, including HRPP Policy 303) per the discretion of the designated 
study investigator and with the agreement of the participant. Whether in person or 
remote, the privacy of the subject will be maintained. Consenting investigators (and 
participant, when in person) will be located in a private area (e.g., study room). When 

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consent is conducted remotely, the participant will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed. 
Whether the consent process is in-person or remote, participants and investigators may 
view individual copies of the approved consent document or the same copy (e.g., the 
investigator may share their screen with the participant onsite or remotely). 
Once the subject verbally demonstrates understanding to the investigator and 
agrees to the process, a consent quiz is administered. Participants will be required to 
correctly answer questions #5 and #7 of the quiz in order to be in the study (#5 states “I 
cannot be in this study if I have certain types of metal in your body (T/F)” and #7 states 
“I cannot withdraw from the study once I sign the consent form (T/F).” If the score on the 
consent quiz is less than 80% correct or the questions #5 and 7 are answered 
incorrectly, the investigator will review the incorrect answers with the participant and re-
administer the consent quiz. Provided the participant scores at least 80% correct, the 
participant is invited to be consented. If the score on the quiz is less than 80% correct, 
the investigator will review the quiz results and clarify incorrect answers, then re-
administer the consent quiz. Failure to obtain 80% correct with questions #5 and 7 also 
answered correctly on the second administration of the quiz excludes the participant 
from participating in the study. If the participant does score  80% on the consent quiz 
and questions #5 and 7 are also correct, they will be invited to sign the consent.  
 
A signed informed consent document will be obtained prior to any research activities 
taking place. Consent will be documented with required signatures on the physical 
document (which includes the printout of an electronic document sent to the participant) 
or on the electronic document. Electronic signatures (i.e., the “signature” is digitally 
generated) will not be used. When a hand signature with a finger, stylus, mouse, or the 
like on an electronic document is used for the documentation of consent, this study will 
use one of the following electronic platforms to obtain the required signatures: 
• Adobe Acrobat platform (which is not compliant with 21 CFR Part 11); 
• Foxit (which is not compliant 21 CFR Part 11); 

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• DocuSign (which is not compliant 21 CFR Part 11);  
 
The participant is provided a copy of the signed consent form for his/her own records. 
Enrollment is documented in the participant’s electronic research record. 
 
E. Rational for Participant selection 
Participant selection will be based strictly on the inclusion and exclusion criteria. No 
preferences in participant recruitment will be made on the bases of gender, race, or 
ethnic background. Participants will be recruited from the local community.  A sample 
comprised largely of Black or African American males is anticipated based on previous 
IRP studies recruiting cocaine dependent participants from the Baltimore area. 
However, all interested, eligible participants may be recruited and enrolled. The ethnic 
and racial summary reported below is based on the Treatment Episode Data Set170 
statistics of cocaine use in Maryland.  
 
 

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REQUESTED – PILOT STUDY POPULATION (Completed) 
 
TOTAL ENROLLMENT REQUESTED 
# COMPLETERS REQUIRED 
 
FEMAL
E 
MALE 
TOTAL 
FEMALE 
MALE 
TOTAL 
 
CEILING 
9 
11 
20 
4 
6 
10 
 
PILOT NIH TARGETED/PLANNED ENROLLMENT 
 
ETHNIC CATEGORY 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0** 
Not Hispanic or Latino 
9 
11 
20 
Ethnic Category: Total of All 
Participants* 
 
 
20* 
RACIAL CATEGORIES 
 
 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
5 
7 
12 
White 
4 
4 
8 
Racial Categories: Total of All 
Participants* 
9 
11 
20* 
*The “Ethnic Category: Total of All Participants” must be equal to the “Racial Categories: total of All Participants.” 
 EXPANDED FEASIBILITY STUDY POPULATION 
 
TOTAL ENROLLMENT REQUESTED 
# COMPLETERS REQUIRED 
 
FEMALE 
MALE 
TOTAL 
FEMALE 
MALE 
TOTAL 
 
CEILING 
45 
90 
135 
33 
67 
100 
 

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EXPANDED FEASIBILITY  NIH TARGETED/PLANNED 
ENROLLMENT 
 
ETHNIC CATEGORY 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3** 
Not Hispanic or Latino 
44 
8 
132 
Ethnic Category: Total of All Participants* 
 
 
135* 
RACIAL CATEGORIES 
 
 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
27 
54 
81 
White 
18 
36 
54 
Racial Categories: Total of All 
Participants* 
45 
90 
135* 
*The “Ethnic Category: Total of All Participants” must be equal to the “Racial Categories: total of All Participants.” 
 
 
 
 
Justification for excluding individuals older than 60 years of age: Many cognitive 
processes change with age. In addition, the risk of difficult-to-detect medical 
abnormalities such as silent cerebral infarcts increases with age. 
Justification for excluding Left-handed individuals: Some of the neural processes 
assessed in this protocol may be lateralized in the brain. In order to reduce potential 
variance, participants will be required to be right-handed. 
Justification for exclusion of children: Children will not be included in the present 
study. This study focuses on cocaine dependence which generally necessitates 
participants have years of experience with cocaine and are over the age of 22. 
Therefore, children under the age of 22 will not be recruited.  

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Justification for exclusion of vulnerable population: There will be no inclusion of 
vulnerable populations in the current study. The study focuses on the effects of iTBS as 
an intervention to reduce cocaine use in CD participants using a diverse range of 
affective, cognitive, behavioral and neurobiological indices. To control for variance in 
these domains we need to exclude individuals suffering from mental illness, intellectual 
impairment or any other condition that may affect neurological functioning (e.g. HIV). 
Pregnant women are also explicitly excluded due to the unknown risks that iTBS and 
MRI poses to the unborn fetus. 
Safeguards for vulnerable populations: Measures of intellectual functioning, mental 
health and HIV screening will be conducted under the approved NIDA IRP general 
screening protocol and used in the current protocol to identify and exclude individuals in 
vulnerable populations. Urine and/or blood serum pregnancy testing will also be 
employed in the current protocol to screen for pregnancy.  
 
 EVALUATION OF RISKS/DISCOMFORTS AND BENEFITS 
     
 
A. Anticipated Benefit 
CM is designed to help CD participants reduce their drug use throughout treatment. 
The iTBS administration is an experimental manipulation in this study and could yield 
generalizable knowledge about its potential therapeutic application as a treatment in 
drug abuse.  
 
 
B. Risks and discomforts 
 
Experimental Tasks 
Participants may find the tasks that they are asked to perform during, before, and 
after scanning sessions boring, difficult, and/or frustrating.  

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Risk Minimization. In order to reduce discomforts associated with performing 
the experimental tasks, scanning sessions, and task sessions outside of the 
scanner are organized in such a way that participants will not perform tasks for 
extended periods of time and will be given a chance to rest between tasks. In 
addition, the tasks are designed to make performance neither too difficult nor too 
easy. Ideally, individual adjustments of task difficulty enable participants to 
remain actively engaged in the task.  
 
 
iTBS  
iTBS is similar to rTMS which has has been considered “non-significant risk” by the 
FDA  when applied at similar intensities, durations, and frequencies to those outlined in 
this protocol. Therefore, previous adverse events from rTMS are reviewed as potential 
risks for implementing iTBS. 
 
 Magnetic stimulation 
iTBS uses magnetic pulses, and could therefore interfere with the function of 
pacemakers, implanted pumps or stimulators. Moreover, the use of magnetic pulses 
over the head could affect metallic objects inside the eye or skull. The effects of 
magnetic stimulation on fetal development are unknown.  
Risk minimization: Participants will undergo TMS safety screening and will be 
excluded from participation if they have pacemakers, implanted pumps or 
stimulators, and metal objects inside the eye or skull. If they have a question 
about any metal objects being present in their body, they will be prompted to 
inform the physician. In addition, all magnetic objects (for example, watches, 
coins, jewelry, and credit cards) must be removed. Women of childbearing 
potential will have a weekly pregnancy test during iTBS treatment and each day 
of an MRI scan and pregnant women will be excluded. 
 
 Seizure   

PI Name: Yihong Yang, Ph.D. 
 
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The greatest concern with iTBS treatment is the possibility of inducing a seizure. The 
Pilot was successfully completed without seizures. The tolerability parameters 
implemented in the study are well within recommended applications of iTBS, a form of 
TMS which has substantial published guidelines. The 1996 and 2008 International 
Consensus Safety Guidelines describe the maximum safe duration of an rTMS train 
based on intensity and frequency of the stimulation131. Since the issuance of these 
guidelines, the incidence of TMS-induced seizures worldwide is very low, estimated as 
“rare” 131. There have been no reports of any participant developing epilepsy or 
repeated spontaneous seizures after rTMS. All rTMS-induced seizures to date have 
been transient and self-limiting, without long-term sequela131, 132. Concurrent medication 
has been implicated as a risk factor in some of the seizures reported with rTMS. Some 
have suggested that certain medications (e.g. tricyclic antidepressants and 
neuroleptics), should be contra-indicated in those receiving rTMS131.  
Risk Minimization: There is a small risk of seizures from iTBS; nonetheless, 
participants will be thoroughly monitored first in the Pilot (completed) then in the 
Expanded Feasibility Study to guard against potential negative effects of iTBS. 
Participants will undergo screening which will exclude those with a family history 
of epilepsy, participants who take medication that can affect the seizure 
threshold, and participants with recurring fainting spells. Psychotropic 
medications and use of illicit drugs (other than cocaine) associated with a 
reduction in the seizure threshold will also be exclusionary in this study. All staff 
administering iTBS will be trained in BLS. A physician or physician assistant will 
be available in the building while iTBS sessions are in progress and will be called 
in the event of any medical issue.  
 
 Vasovagal Syncope  
A small number of vasovagal syncopes have been reported following rTMS 
stimulation. In a number of the reports on rTMS-induced seizures, it is unclear whether 
the event was a seizure or syncope131.  

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Risk minimization: Participants undergo screening and are not admitted to the 
protocol if they have a history of fainting from an unknown cause. All staff 
administering iTBS will be trained in BLS. A physician or physician’s assistant will 
be available in the building while iTBS sessions are in progress and will be called 
in the event of any medical issue. Throughout each study day containing a 
TMS/iTBS session, staff will regularly check with the participant for well-being 
and encourage them to report possible symptoms such as feeling faint. 
 
 Scalp Pain, Headache, and Other Minor Symptoms  
Mild headache responding readily to non-opioid analgesics is the most common 
side-effect of iTBS reported in depression treatment trials. It may result from direct 
stimulation of superficial facial muscles or nerves and cause an uncomfortable facial 
twitch132. However, discomfort levels are quickly habituated to and painful sensations 
over the scalp decrease over sessions70, 72. In rTMS sham-controlled studies that 
reported rates of side-effects, about 28% of participants experienced headache and 
39% experienced pain or discomfort during stimulation, compared with rates of 16% and 
15%, respectively, after sham rTMS132. In a single case report, a 57-year-old women 
being treated for major depressive disorder reported a pulsating, localized dental twinge 
in the region of the upper left jaw associated with the rTMS treatment173. The pain 
disappeared during the inter-train interval but emerged again during the next train of 
stimuli. The pain was dependent on the stimulus intensity and remained despite 
repositioning of the coil. The cause of the pain is unclear, but may be due to stimulation 
of the trigeminal nerve by the rTMS magnetic field. An event will be reported as an 
adverse event when its severity either requires interruption of the normal flow of 
experimental procedures or requires a medication intervention. 
Risk Minimization: Participants generally find iTBS more tolerable than rTMS 
which is widely used. In this expanded feasibility study, we are retaining the 
parameters that were used in the pilot study. This includes extensive monitoring 
and safeguards will be in place to assess any transient or long-term 

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uncomfortable side-effects of iTBS. Headaches and scalp pain usually go away 
promptly with nonprescription medication, such as acetaminophen. Coil heating 
will be avoided in the present study by using a cooled coil and by allowing the 
coil to cool off between treatment sessions. If a participant reports dental pain, 
iTBS will be stopped. Acetaminophen or other medications may be provided for 
treatment of pain, if necessary. 
 
 Acoustic Noise  
Rapid excitation of the stimulation coil produces clicks that have resulted in transient 
increase in the auditory threshold of human participants. This should not occur if 
earplugs are used. Others have measured auditory thresholds with rTMS which we will 
use for our iTBS administration. Auditory thresholds were measured before and after 30 
sessions of rTMS have been assessed given over 6 weeks in a depression treatment 
trial174. All participants wore earplugs during stimulation. No significant mean changes in 
hearing threshold were detected. Two participants showed small bilateral increases in 
threshold at mid to high frequencies, which returned to previous levels when retested 1 
month later. FDA guidelines require testing of auditory threshold only if participants 
receive rTMS at a frequency higher than 1 Hz for four or more weeks. Auditory 
threshold will not be monitored in the current proposed study. 
Risk Minimization: Participants will be fitted with earplugs to wear during the 
study to protect their hearing from the noise of the magnet. Participants with 
known hearing loss will be excluded. Investigators will ask each participant to 
report immediately any loosening or detachment of the earplugs during 
application of iTBS. If a participant reports or if an investigator observes that the 
earplugs have loosened or fallen out, investigators will immediately stop applying 
iTBS. 
 
 Other Complications  

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rTMS over dorsolateral prefrontal cortex has induced manic and hypomanic 
symptoms in a very small number of healthy and depressed participants. Three female 
participants reported hypomanic symptoms after single session of rTMS without a prior 
history of mood disorder175. Stimulation parameters were comparable to those used in 
depression treatment studies and studies of mood changes in healthy participants. Mild 
hypomania was reported in a patient with refractory recurrent unipolar depression77. 
This female patient had responded well to previous shorter courses of rTMS, but 
became hypomanic after nine treatment sessions in the third course. The hypomanic 
symptoms resolved when rTMS was reduced to treatment every second day. A 55-yr-
old depressed male became hypomanic for the first time after 3 weeks of twice daily 
rTMS to the left dorsolateral prefrontal cortex and concomitant citalopram176. Over the 
following week, medication was stopped, but rTMS continued. His symptoms 
deteriorated into mania and rTMS was also stopped. The patient gradually became 
depressed again and five months later, a second course of 2 weeks of twice-daily rTMS 
also resulted in hypomania. Treatment intensity was decreased to once-a-day TMS 
treatment, and the patient returned to a normothymic state. rTMS may also have a 
therapeutic effect in mania, with high-frequency application to the right prefrontal 
cortex177. 
We are aware of six reports of mania induced by rTMS in patients with bipolar 
disorder176, 178-181, in some cases while taking mood-stabilizing medications. In a trial of 
right prefrontal rTMS for post-traumatic stress disorder, two patients developed a manic 
episode after the third session182. One patient was randomized to 1 Hz rTMS and one to 
10 Hz. Another participant in this trial developed a ‘mild rage attack, probably related to 
the stimulation’. Apart from manic symptoms, there is a single case report of high-
frequency left prefrontal rTMS inducing transient persecutory delusions in a depressed, 
non-psychotic participant183. 
In all the above cases, the psychiatric side-effects induced by rTMS were transient, 
resolving with the cessation of rTMS or rapidly responding to pharmacological 
treatment.  

PI Name: Yihong Yang, Ph.D. 
 
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Risk Minimization: Reports of manic symptoms occurred exclusively after 
unilateral or bilateral DLPFC stimulation but the risk for psychiatric complications 
appears to exist predominantly in participants with pre-existing psychiatric 
morbidity (all except one report), and in patients who are on antidepressants or 
antipsychotics. An important means of minimizing risk in the current proposed 
study is therefore to exclude this population. Participants will be informed of the 
small risk of transient mania or hypomania, informed of early symptoms to look 
out for, and instructed to contact the study physician if they believe they are 
experiencing any such symptoms. 
 
 
MRI scanning 
 Magnetic Field 
When used on appropriately qualified individuals, MRI presents virtually no risk as 
long as technical scan parameters remain within FDA guidelines. There is no exposure 
to x-rays or radioactivity. The radio waves used have produced burns (most of these 
minor) in about one in a million exams. The field of the 3T scanner is higher than that of 
most clinical magnets and there is a remote chance of other risks associated with the 
stronger magnetic field that might include temporary dizziness with nausea and 
flickering light sensations. The magnet may move metal implants in the body, the 
motion of which could be painful and harmful. Metal implants may also cause burns 
from the radio frequency energy used. While inside the magnet, participants may 
experience an acute panic attack due to claustrophobia. Participants may also 
experience mild, remittable discomfort from lying in the scanner. 
Risk Minimization. To ensure adherence to FDA guidelines for MRI, a trained 
MRI operator who has been instructed in these guidelines performs all machine 
manipulations. Other preventative measures include assuring that all equipment 
to be used during imaging sessions is MR compatible, that participants are 
familiar with the MRI environment (using the mock scanner), and that participants 
are aware of how to signal the MR operator if they need to do so during the 

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session. Furthermore, participants are screened prior to each MRI session for 
any MR contraindications, including metal implants, pregnancy, fear of small, 
enclosed spaces, and inability to lie still for prolonged periods of time.  
 
 Acoustic Noise   
The sound generated by an MR system usually consists of a series of repetitive 
pulses. Acoustic noise is a result of the mechanical vibration produced by the 
gradient coils when the large currents are applied to them to create time varying 
imaging gradient fields. Some participants may experience temporary, reversible 
shifts in hearing threshold after MRI. 
Risk Minimization: MRI compatible headphones and earplugs will be used for 
hearing protection. The use of these two devices in combination reduces the 
noise level to levels much lower than those required by the Occupational Safety 
and Health Administration (OSHA) regulations (Occupational Noise Exposure – 
1910.95, www.osha.gov) regulations for lifetime exposure, and provides effective 
hearing protection for the participants. Nevertheless, some participants may 
experience temporary, reversible shifts in hearing threshold after MRI. 
 
 
Mock Scanner 
Potential side effects associated with the mock scanner include mild backache from 
having to lie still for a prolonged period of time, temporary difficulty hearing soft sounds 
after the exam, and being uncomfortable being in a small enclosed space.  
Risk Minimization. Pre-study screening for history of back problems or 
claustrophobia will minimize the likelihood of side effect from mock scanning. In 
addition, participants will be given adequate hearing protection to minimize 
hearing difficulties resulting from Classification of risk (for the study as a whole). 
 

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Research Involving NIH Employees as Participants  
Potential risks should be considered for NIH staff when participating in an NIH 
protocol because NIH staff may be a vulnerable class of participants. NIH staff will not 
be allowed to participate in this protocol.  
 
 
 PROTECTION OF PARTICIPANTS’ PRIVACY AND CONFIDENTIALITY  
Great care is taken to protect participants’ privacy and strict participant 
confidentiality will be maintained throughout. Participants will be consented in a private 
setting. Participants will be assigned a code number without personally-identifying 
information following their first contact in the protocol. This number will be used 
throughout the experiment and will be on specimen samples, behavioral, physiological 
archival, fMRI/MRI, and iTBS data. The identity of participants will not be revealed at 
scientific meetings, in publications or other vehicles of public communication. The PI 
and co-investigators will use an ID code (e.g., ARC#), which is generated in a secure 
database on a closed network (Human Research Information System [HuRIS], aka 
CDW). Access to records in CDW is protected by a system of password-protected 
accounts and monitored by the Clinical Director (CD). Data downloaded for analysis will 
be identified only by participant number. A Certificate of Confidentiality is in place for the 
NIDA IRP and covers this protocol. 
 
A. Medical Records  
All medical history information is stored in the CDW database, which is password 
protected and has limited access. Any paper records are kept in a locked cabinet and 
access to these files is limited to study personnel, including study investigators, nursing 
staff and clinicians.  
 
B. Research Records/Data  

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Paper copies of research records such as ‘Run Sheets’ (procedural checklists) used 
by investigators will be kept in study-specific binders. These binders are kept in a locked 
cabinet, in a locked room, which has limited access. Binders remain in this room at all 
times, apart from when required for study sessions. At the completion of each session 
paper records will be returned to the locked cabinet by the investigator or research 
associate responsible for the experimental session. Electronic research records and/or 
data (physiological, imaging, behavioral) obtained during experimental sessions is 
stored on password protected, network drives, or other secure application (e.g., CDW, 
RedCap, Qualtrics) in line with NIH policies, which have limited access. Data stored on 
these drives is identified by study number, participant ARC# and/or task. No personal 
identifiers are stored with the data outside of the participant’s clinical research record 
(CDW).  
 
C. Stored Samples  
 No biological samples will be stored for future use. 
 
 STUDY AGENTS/INTERVENTIONS  
This protocol uses iTBS as an add-on treatment intervention. We will use the 
MagVenture MagPro 100 with MagOption (MagVenture Inc, Alpharetta, GA) machine 
equipped with a figure-8 coil. This protocol is intended to determine efficacy of iTBS in 
reducing cocaine use and is participant to CRF Title 21, part 812. An IDE is necessary 
for this protocol and will be applied for after reviews from SRC and IRB.  
The MRI is used as a data collection tool and all sequences and scans conducted 
are within FDA approved parameters and the scans are not conducted to assess safety 
or efficacy of the scans themselves. 
 
 PLAN FOR REPORTING UNANTICIPATED PROBLEMS AND ADVERSE EVENTS  
NIH OHSRP Policies 801 and 802 (effective July 1, 2019; supersedes SOP 16) will 
be followed for reportable events and non-compliance. 

PI Name: Yihong Yang, Ph.D. 
 
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Please note that the PI is the sponsor for the IDE in this protocol until the 
sponsorship changes over to the NIDA-IRP’s Clinical Director, effective October 1, 
2019. The Sponsor will report to the FDA as required. 
 
 DATA SAFETY MONITORING PLAN 
A. Selection of a Data and Safety Monitoring Mechanism  
1. Daily Study Monitoring: Data and safety for this protocol will be monitored by the 
Principal Investigator and MAI.  
2. The FDA has approved an IDE for a “staged study” and reviewed a supplement 
to the IDE application that contained pilot data (See letter from the FDA). IRB 
approval of the Expanded Feasibility Study is contingent on the approval from the 
FDA after review of the pilot data (i.e., up to 20 enrollees to yield 10 participants 
who complete the two-week iTBS intervention).  [Approved by the FDA 
December 12, 2018]. 
3. Overall Study Monitoring: Data and safety will be monitored by the NIDA-IRP 
Data and Safety Monitoring Board (DSMB). 
 
B. Frequency of the Monitoring 
The DSMB will review after: 
1. Five participants complete the Pilot inpatient protocol. 
2. Five participants complete the Pilot outpatient protocol. Barring any unforeseen 
adverse events in the Pilot, recruitment for the Expanded Feasibility Study will 
commence while the DSMB reviews data collected during the Pilot. 
3. Every year, after the first participant receives iTBS treatment in the Expanded 
Feasibility Study, unless there has not been any iTBS administration in the one 
year reporting period. However, if that is the case, the DSMB will be notified of 
the lack of progress with explanation. The DSMB review will be requested one 
year following the next iTBS administration. 
4. If either the primary or secondary stop rules are triggered (described below). 

PI Name: Yihong Yang, Ph.D. 
 
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C. Stop or Change Rules 
 
Primary Safety Endpoints and Associated Stop Rules 
Three outcomes will be monitored throughout the study as safety endpoints 
associated with a stop rule. As described below, we will track iTBS-induced seizures, 
neurocognitive function, and clinically significant adverse events requiring outside 
evaluation. Chi-square tests will be calculated to test frequency differences between 
groups (active iTBS vs sham iTBS) for each of these endpoint measures. Each stop 
rule is described in detail below.  
1. Number of iTBS-induced seizures: more than 1 iTBS-induced seizure 
resulting in hospitalization within any 10 consecutive participants who receive 
iTBS will result in a protocol hold until further evaluation by the PI, FDA, and 
DSMB. The Blind will be broken for any participant with an iTBS-induced 
seizure. We will also consult Dr. Alexander Rotenberg, M.D., Ph.D., Director, 
Neuromodulation Program within the Division of Epilepsy and Clinical 
Neurophysiology, Department of Neurology, Boston’s Children’s Hospital and 
Associate Professor of Neurology at Harvard Medical School. Dr. Rotenberg 
is a member of our DSMB and possesses the necessary clinical expertise to 
evaluate the proposed safety endpoints. No new iTBS sessions will be 
administered to any participant once this stop rule is enacted until evaluation 
of the events is concluded and it is deemed appropriate to proceed. However, 
participants who have completed their iTBS treatments may be scheduled for 
Contingency Management (CM), MRI scan, or follow-up visits. 
2. Cognitive performance on Trails B:  Neurocognitive function will be 
assessed with Trails A and B before and after each iTBS day. Although Trails 
A and B are usually administered in sequence, only Trails B will be 
evaluated in relation to this stop rule. A completion time for Trails B greater 
than 90 seconds169 is considered abnormally long. Therefore, if a participant 

PI Name: Yihong Yang, Ph.D. 
 
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requires more than 90 seconds to complete Trails B after iTBS, the 
following steps will be taken: 
1. The participant will rest and be observed for 60 minutes after completion of post-
iTBS Trails B. 
2. Trails A and B will be administered again after the 60 minute timeout period. 
3. A score to complete Trails B a second time greater than 90 seconds will call for 
the MAI (or covering clinician) to evaluate the participant. 
4. If the MAI (or covering clinician) deems outside evaluation or treatment is 
necessary, the participant will be discharged from the study and appropriate 
steps will be taken to seek an outside evaluation/intervention (e.g., an ER visit). 
The Blind will be broken for this participant at this time. 
If more than 1 neurocognitive event identified with Trails B is seen within any 
10 consecutive participants, the protocol will be put on hold until further 
evaluation by the PI, FDA, and DSMB. As above, Dr. Rotenberg will be 
consulted for his evaluation of the stop rule; CM, MRI scan, and follow up 
visits, may continue but iTBS will not be administered until the hold is 
resolved. 
3. Clinically significant adverse events (i.e. adverse events that require 
referral for further evaluation) likely related to iTBS. For example, a mild 
headache after iTBS that resolves spontaneously or with over-the-counter 
medication will not be considered clinically significant. A severe headache 
that starts during or shortly after iTBS and fails to resolve with time and/or 
OTC intervention would prompt referral to an Emergency Department and will 
be considered clinically significant.  
a. If more than 1 clinically significant adverse event related to iTBS 
administration and having similar clinical features is seen within any 10 
consecutive participants, the protocol will be put on hold until further 
evaluation by the PI, FDA, and DSMB. As above, Dr. Rotenberg will be 
consulted for his evaluation of the stop rule; CM, MRI scan, and follow 

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up visits, may continue but iTBS will not be administered until the hold 
is resolved. 
 
Clinical Efficacy Cocaine Use Endpoint 
1. Clinically significant worsening of cocaine use behavior will be 
evaluated and monitored as follows: Although neuroplastic changes in 
brain activity assessed with fMRI is our primary outcome variable of interest, 
we will measure cocaine use behavior (Appendices 13: Cocaine use, Pattern, 
and Withdrawal Questionnaire, & 21 Time-Line Follow back) at baseline and 
longitudinally throughout the protocol. Among the cocaine use behaviors 
assessed is maximum dollar amount spent during the longest lifetime binge. 
Chi-square tests will be calculated to test frequency differences between 
groups (active iTBS vs sham iTBS) for this endpoint measure. If a participant 
reports a binge amount in dollars that exceeds 3 X the greatest binge dollar 
amount, the following steps will be taken: 
a. The iTBS treatment for this participant will be paused  
b. The participant will be scheduled to return the next day for further 
evaluation, which will include reassessment of cocaine use behavior  
i. If the participant reports continued excessive cocaine 
binge behavior, the participant will be referred for 
alternative treatment. The Blind will be broken for this 
participant at this time.  
ii. If the participant reports a return to their normal cocaine 
use pattern, they will be scheduled for further evaluation 
in about 1 week.  
c. After about 1 week, cocaine use behavior will be re-assessed.   
i. If the participant reports further episodes of excessive 
cocaine binge behavior, the participant will be referred for 
alternative treatment. The Blind will be broken for this 
participant at this time.  

PI Name: Yihong Yang, Ph.D. 
 
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ii. If the participant reports a return to their normal cocaine 
use pattern, they will be allowed to continue in the study. 
Their treatment schedule will be resumed at this point.  
As soon as the increase is noted and at each follow-up visit, the MAI (or 
covering clinician) will assess precipitants to the change in cocaine use 
behavior to ascertain whether a significant life-event (e.g., death of a family 
member) could be related to a spike in cocaine use behavior (vs. the iTBS 
itself). Detailed evaluation of the situation is necessary to understand the 
clinical ramifications of continuing, or discontinuing, the iTBS administrations. 
If, at any point, the MAI (or covering clinician) concludes that iTBS was likely 
responsible for the change in cocaine use, the participant will not resume 
iTBS treatments.  
If the participant has a second episode of excessive use in excess of 3 X 
their previous greatest binge dollar amount after resuming iTBS treatments, 
they will be discharged and referred for alternative treatment. 
Participants who are to be discharged and referred for alternative 
treatment will be followed as clinically indicated for up to one month to track 
their clinical course and facilitate transfer to alternative treatment. The 
participant will be discharged at this point. 
If more than 1 clinically significant worsening of cocaine use behavior is 
seen within any 10 consecutive participants, the protocol will be put on hold 
until further evaluation by the PI, FDA, and DSMB. As above, CM, MRI scan, 
and follow up visits may continue but iTBS will not be administered until the 
hold is resolved. 
 
D. Advanced Plans for Any Interim Analyses and/or Futility Analyses 
There are no current plans for interim analyses and/or futility analyses.  
 
E. Information to be Monitored 

PI Name: Yihong Yang, Ph.D. 
 
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1. Progress of the study, including assessment of participant recruitment and 
accrual and adverse events will be reviewed to determine whether there is any 
change to the risk/benefit ratio of the study. This information will be reported to 
the IRB at the time of continuing review. 
2. Participants will be monitored for adverse events by study staff. Significant as 
well as mild adverse effects of iTBS stimulation will be monitored through 
questionnaires (see Appendix 1 & 15; NIBS monitoring questionnaire) before and 
after each iTBS session. At the start of each session, an events checklist will be 
asked for (i.e. how often do you experience these symptoms per week, per 
month?). Moreover, participants will be contacted, as described in the follow-up 
procedures, and will again be asked the questions from the NIBS monitoring 
questionnaire. The MAI will confirm that AE’s have been appropriately reported 
and determine whether the risk to benefit ratio has changed.  
3. The DSMB will periodically review the study to ensure appropriate safety 
monitoring measures are followed and to detect unforeseen patterns of adverse 
events that may indicate the study is riskier than originally assessed. 
4. There are no external factors (e.g., developments in the literature, results of 
related studies, etc.) that may have an impact on the safety of participants or on 
the ethics of the research study. 
 
F. Communication  
1. The DSMB will receive access to information on any adverse events that have 
occurred as well vital signs from study visits and the results of follow-up 
assessments to assess post-participation changes in participants’ drug use, 
particularly with regard to cocaine use.  
2. The PI will report all adverse events according to established NIH IRB guidelines. 
The study does not involve any invasive procedures.  
3. The PI and/or the CD will report DSMB findings and recommendations to the 
IRB. A written report will be provided by the DSMB to the CD and PI confirming 

PI Name: Yihong Yang, Ph.D. 
 
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their review of the data and summarizing any recommendations. Furthermore, 
the DSMB will be required to report on any significant trends in the data that are 
indicative of negative or adverse events to the PI and the office of the CD.  
 
G. Criteria for Study Withdrawal 
A participant will be withdrawn from the study if he or she: 
1. so requests, or withdraws consent. 
2. is an HC participant whom requires study visits to be rescheduled more than 
twice for positive urine triage.  
3. develops an exclusionary medical condition or medical problem, for which, in the 
MAI’s judgment, it is in the participant’s best interest to be withdrawn from the 
study. 
4. becomes or is found to be pregnant. 
5. Participants withdrawn from the study for any medical concerns will be referred 
for appropriate medical follow-up. 
 
 DATA/RECORDS MANAGEMENT 
Medical and questionnaire data will be gathered in the CDW, a secure database on 
a closed network. Access to records in the CDW is protected by a system of password-
protected accounts and monitored by the Clinical Director (CD).  
Data (physiological, behavioral) obtained during experimental sessions is stored on 
password protected, network drives, which have limited access. Data stored on these 
drives are identified by study number, participant code number, and/or task. Some files 
may also include age, race and gender. No personal identifiers are stored with the data. 
Imaging data is stored on a password-protected LINUX computer with limited access. 
Data on this server is identified by participant number only with no other identifying 
information. These data are backed up nightly to a second secure server. 
 

PI Name: Yihong Yang, Ph.D. 
 
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 COMPENSATION  
All participants:  
Participants will be compensated for their participation following the NIDA-IRP 
remuneration guidelines. Participants will be compensated for those parts of the study 
completed. Remuneration rates are summarized in table 3. In addition to the hourly rate 
($20/hr for the first hour and $10/hr for subsequent hours each visit), participants will 
receive the following remuneration: Participants will be given their choice to have 
transportation provided or to have travel expenses (e.g., shuttle, taxi) reimbursed for 
each visit; Participants will be paid $50 per MRI scan (Controls – 6 scans - $300/ CD 
participants 8scans - $400). Participants are also paid for task performance, which has 
a maximum amount of $53 (max of $53 for the MID task) possible at each of three 
separate scan days. Task performance for the Risk/Reward task will also be paid with a 
maximum amount of $6.60 weekly (up to 3 for HC and 26 for CD participants) 
throughout the protocol.  $10 will be given for each observed urine sample; $10 for the 
venipuncture for the COVID-19 antibody test. A stand-by incentive may be used to 
ensure a study slot is filled. That is, if a participant cancels at the last minute or is a no-
show, a second participant may be called to fill that slot. The second participant will be 
called that day regardless and a $25 stand-by incentive will be payed if the participant 
answers their phone and are available for the study. The amounts summarized in table 
3 may vary depending upon participant compliance and supplementary procedures that 
may be deemed necessary, such as repeat testing. 
 
Cocaine-dependent Participants: 
Contingency management cash payouts will be given for clean urine samples on the 
schedule outlined in table 1 Following NIH remuneration guidelines related to providing 
treatment, no hourly compensation will be offered for visits scheduled for only CM. On 
those days, participants will be compensated for urine samples and CM payments 
earned. Because the longitudinal measures are crucial to the aims of this protocol, 
additional completion incentives will be offered to participants.  

PI Name: Yihong Yang, Ph.D. 
 
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Pilot (completed): A $50 incentive will be offered to participants during the pilot at the 
completion of each week of the iTBS administration.  
Main Phase: A completion incentive will be given to CD participants during the 
Expanded Feasibility Study after completing completing the study (visit 43) ($200).  
Alternatively, these participants may receive the total amount due in gift certificates, 
or payments can be made directly towards rent, mortgage, food, utilities, medical care, 
travel, insurance, clothing, etc. Inpatient participants may request payments prior to 
discharge. Payment types, as listed above, may be dispensed to a third party (e.g., 
spouse) via a staff member. This procedure is designed as a precaution to ensure no 
illicit substances will be introduced from an outside individual during the inpatient stay. 
To dispense payments prior to discharge, the participant must agree to this procedure. 
Outpatient participants may postpone payments or request smaller payments to reduce 
the potential trigger to use cocaine from cash-in-hand post-iTBS treatment. These 
participants may postpone or receive some or all their remuneration in the approved 
methods listed above. Participants will have up to 1-year after completing the study to 
receive full remuneration. 
 
Healthy Controls: 
HC participants will be offered a $25 completion incentive after completing all study 
procedures.  
Travel: Based on current NIDA IRP Remuneration guidelines, travel will either be: 1) 
provided for directly, 2) reimbursed or 3) they may receive a $15 flat rate per roundtrip 
to NIDA. Meals or snacks will be provided during study visits. Travel is arranged via a 
contract in place for the IRP Clinical Program. If participants come to NIDA as part of 
another study, they will receive travel compensation through only one protocol.  
Method of Payment: The NIDA IRP has a contractor in place for remuneration and 
payments will be made in accordance with NIDA IRP Remuneration guidelines and may 
include cash, check, gift card or electronic payment (e.g., PayPal). Remuneration will 
generally be in cash payments. However, NIDA IRP has limited cash disbursement so 

PI Name: Yihong Yang, Ph.D. 
 
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participants may choose multiple payment methods if owed more than the daily limit. 
Participants may also choose to put payments towards rent, mortgage, food, utilities, 
and/or medical care. If participation runs into the evening or occurs on weekends, the 
amount due to the participant will be estimated on the low end, and the participant may 
return to NIDA another business day to pick up their balance, may receive balance due 
either at their next session, or receive their balance via a check in the mail or electronic 
payment (e.g., PayPal) (whichever they prefer). Compensation may also be given in the 
form of gift cards to local area stores. Participants who complete an MRI scan will also 
be offered a T-shirt with an ironed-on picture of their brain as part of their compensation. 
 
Table 3a. Remuneration rates: Pilot – Inpatient (Complete) 
  
Rate 
Time/frequency 
Hourly rate (first hour) 
$20/hour 
1 hour per visit 
Hourly rate (subsequent 
hours) 
$10/hour 
1-7 hours per visit 
 
 
 
Compensation in addition to hourly rate: 
 
 
 
Urine Test 
$10/test 
Up to 14 
Compliance Incentive 
$50 
Twice 
Inpatient Compensation 
$40/night 
Up to 10 days 
Total (max) per visit  
$180 
Total (min) per visit  
$70 
Total (max) overall 
$1,640 
 
Table 3b. Remuneration rates: Pilot – Outpatient (Complete) 
  
Rate 
Time/frequency 
Hourly rate (first hour) 
$20/hour 
1 hour per visit 
Hourly rate (subsequent 
hours) 
$10/hour 
1-7 hours per visit 
 
 
 
Compensation in addition to hourly rate: 
 
 
 
Urine Test 
$10/test 
Up to 14 

PI Name: Yihong Yang, Ph.D. 
 
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Compliance Incentive 
$50 
Twice 
Total (max) per visit  
$140  
Total (min) per visit  
$70 
Total (max) overall 
$1,230 
 
Table 3c. Remuneration rates: Expanded Feasibility Study – CD 
  
Rate 
Time/frequency 
Max 
Hourly rate (first hour) 
$20/hour 
1 hour per visit 
Varies 
Hourly rate (subsequent 
hours) 
$10/hour 
1-11 hours per visit 
varies 
 
 
 
 
Compensation in addition to hourly rate: 
 
MRI scan 
$50/scan 
Up to 8 scans 
$400 
Task Performance (MID) 
$53 
Up to 3 scan sessions 
$159 
Task Performance 
(Risk/Reward) 
$6.60 
Up to 26 sessions 
$171.60 
Urine Test 
$10/test 
Up to 43 
$430 
Contingency Management 
Variable 
Up to 28 visits 
$1075  
Venipuncture for COVID-19   
antibody test 
$10 
Up to 4 
$40 
Follow-up Phone contacts 
$5 
Up to 9 contacts 
$40 
Completion Incentive 
$200 
Visit 43 
$200 
Total (max) per visit  
$299.6  
 
  
(12 hour visit, 2 scans, 
urine test, task 
performance but not 
completion incentive) 
 
N/A 
Total (min) per visit  
$10 
N/A 
Total (max) overall 
$3975.60          (includes $1075 CM at           
                          100% abstinence) 
  
 
 
 
The max overall payment is based on the following: 
The total of the non-hourly rate earnings (See Table 3c above: $2,715.60) plus the 
estimated hourly pay based on 2 Baseline vists x 10hrs ($220), 9 iTBS visits without 
scan x 6hrs ($630), one iTBS/scan day x 12hrs ($130); 10 longitudinal data visits 
(weeks 3-5 and  7-13) x 1 hour each ($200) and 2 longitudinal follow-up scan visits x 
10hrs ($220) and 3 post-CM follow-up visits at 1hour ($60). The CM only visits don’t get 
hourly compensation. 

PI Name: Yihong Yang, Ph.D. 
 
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Table 3d. Remuneration rates: Expanded Feasibility Study – HC 
  
Rate 
Time/frequency 
Max 
Hourly rate (first hour) 
$20/hour 
1 hour per visit 
varies 
Hourly rate (subsequent 
hours) 
$10/hour 
1-11 hours per visit 
varies 
 
 
 
 
Compensation in addition to hourly rate: 
 
Urine Test 
$10/test 
Per visit (~4 visits) 
$40 
MRI Scan 
$50/scan 
Up to 6 scans 
$300 
Task Performance (MID) 
$53 
One 2 scan    
sessions 
$53 
Task Performance  
(Risk/Reward) 
$6.60 
Up to 3 sessions 
$19.80 
Compliance Incentive 
$25 
At final visit 
$25 
Venipuncture for COVID-19 
antibody test 
$10 
Up to 2 
$20 
Total (max) per visit  
$160  
N/A 
Total (min) per visit  
$40 
N/A 
Total (max) overall 
$937.80  (depending on total number of  
               visits) 
N/A 
 
 
 
 
The max overall payment is based on the following (assuming 4 visits): 
The total of the non-hourly rate earnings (See Table 3d above: $457.80) plus the 
estimated hourly pay based on 2 Baseline vists x 10hrs ($220), two iTBS/scan day x 
12hrs ($260) is $937.80 
 
 
 QUALITY ASSURANCE  
A. Quality Assurance Monitor 
The PI, LAI, and MAI will be monitoring data collection and the study on an ongoing 
basis. Quality assurance will be monitored by the NIDA Quality-Assurance Team on a 
schedule to be determined by the Clinical Director. 
 

PI Name: Yihong Yang, Ph.D. 
 
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B. Quality Assurance Plan  
We will use the quality-assurance plan that is in place under the aegis of the NIDA-
IRP Clinical Director. 
 
 ALTERNATIVES TO PARTICIPATION OR ALTERNATIVE THERAPIES 
Individuals who are not eligible to participate in this protocol or who no longer want to 
participate in this protocol may be able to receive substance abuse treatment outside of 
the study, under the care of their own physician. They will be given referrals, when 
appropriate, for substance abuse treatment programs in the community. 
 
 CONFLICT OF INTEREST 
There are no conflicts of interests to report. 
 
 DISTRIBUTION OF NIH GUIDELINES 
NIH guidelines on conflict of interest have been distributed to all investigators. There 
are no conflicts of interest to report.  
 
 ROLE OF A COMMERCIAL COMPANY OR SPONSOR  
This study is investigator-initiated and Institute-sponsored.  
 
IDE Sponsor:  National Institute on Drug Abuse, Intramural Research Program (NIDA   
                           IRP)  
BRC Building Room 04A511,  
251 Bayview Blvd, Baltimore, MD 21224,  
Phone:   
443-740-2801 
Email:  
 
Lorenzo.leggio@nih.gov  
 
 
 
 
Sponsor Authorized Representative  
Name:  
 
Lisa C. Goldfeder, RAC, CCRP 

PI Name: Yihong Yang, Ph.D. 
 
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Section Head, Regulatory Support Section 
Office of Research Support and Compliance 
Clinical Center, NIH 
Phone: 
 
301-655-4369 
Email Address: lisa.goldfeder@nih.gov  and REGSupportORSC@cc.nih.gov  
 
 
 TECHNOLOGY TRANSFER 
There are no tech transfer agreements or confidential disclosure agreements 
necessary for this protocol. 
 
 
 

PI Name: Yihong Yang, Ph.D. 
 
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 REFERENCES  
 
 
1. 
Volkow, N.D., Koob, G.F. & McLellan, A.T. Neurobiologic Advances from the 
Brain Disease Model of Addiction. The New England Journal of Medicine 374, 363-371 
(2016). 
2. 
NDIC. National Drug Threat Assessment. (ed. US DEP’T OF JUSTICE NAT’L 
DRUG INTELLIGENCE CTR.) (2010). 
3. 
Grant, B.F., et al. Epidemiology of DSM-5 Drug Use Disorder: Results From the 
National Epidemiologic Survey on Alcohol and Related Conditions-III. JAMA psychiatry 
73, 39-47 (2016). 
4. 
Hubbard, R.L., Craddock, S.G. & Anderson, J. Overview of 5-year followup 
outcomes in the drug abuse treatment outcome studies (DATOS). Journal of Substance 
Abuse Treatment 25, 125-134 (2003). 
5. 
Artigiani, E.E. & Wish, E.D. Patterns and Trends of Drug Abuse in the 
Baltimore/Maryland/Washington, DC, Metropolitan Area—Epidemiology and Trends: 
2002–2013 (University of Maryland, College Park, Center for Substance Abuse 
Research, 2014). 
6. 
Jovanovski, D., Erb, S. & Zakzanis, K.K. Neurocognitive deficits in cocaine users: 
A quantitative review of the evidence. J Clin Exp Neuropsychol 27, 189-204 (2005). 
7. 
Spronk, D.B., van Wel, J.H., Ramaekers, J.G. & Verkes, R.J. Characterizing the 
cognitive effects of cocaine: a comprehensive review. Neurosci Biobehav Rev 37, 1838-
1859 (2013). 
8. 
Koob, G.F. & Volkow, N.D. Neurocircuitry of addiction. 
Neuropsychopharmacology 35, 217-238 (2010). 
9. 
Goldstein, R.Z. & Volkow, N.D. Dysfunction of the prefrontal cortex in addiction: 
Neuroimaging findings and clinical implications. Nature Reviews Neuroscience 12, 652-
669 (2011). 

PI Name: Yihong Yang, Ph.D. 
 
Version Date: December 6, 2023 
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