Theta-Burst Stimulation as a Treatment for Reducing Cocaine Use

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 a NIBS, delivered to left dorsolateral prefrontal cortex (dlPFC) is implemented to
modulate substance abuse related circuit dysregulations and assess effectiveness of iTBS in
promoting abstinence.

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. For the
Clinical Trial, 50 healthy adults (HC) and 100 CD individuals will be recruited. All of the
HC group will receive both active- and sham-iTBS in a within-subject crossover design. Half
of the CD group will receive active-iTBS and half will receive sham-iTBS. The Clinical Trial
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 clinical
trial). Throughout the Pilot, clinical measures will be collected and participants closely
monitored. The general outline for the Clinical Trial is to characterize the treatment cohort
(vs. HC) and assess effectiveness of iTBS over the left dlPFC in reducing cocaine use. The
iTBS intervention consists of 30 sessions over a 2-week (10 treatment days) period as an
add-on to a treatment-as-usual, contingency management. 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 changes with treatment. Contingency management will
continue for 13 weeks and a 3-month follow-up will be scheduled. The Clinical Trial includes
39 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 cocaine use. Overall, the current protocol
is designed to test whether iTBS to left dlPFC is efficacious in reducing cocaine use.

- INCLUSION CRITERIA - TOLERABILITY PILOT:

1. Be able to give valid informed consent.

2. Be 18 - 60 years of age.

1. Justification: Many neural processes change with age, and these changes
could introduce unwanted variability in both behavioral and MRI signals.

2. Screening tool: Self-report. Government-issued forms of identification (e.g.
driver s license, birth certificate)

3 .Right-handed.

1. Justification: Differences in hemispheric dominance could confound iTBS
administration and MRI measurements.

2. Screening tool: Edinburgh Handedness Inventory.

4. Be in good health.

1. Justification: Many illnesses may alter neural functioning as well as fMRI
signals.

2. 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/microliter, 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.

5. Absence of a specific learning disability, ADHD or cognitive impairment

1. Justification: Participants must be able to perform a cognitively challenging
task to a high standard.

2. 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.

6. Participants will meet DSM-5 criteria for current moderate to severe substance
(i.e., cocaine) use disorder, without a period of continuous abstinence lasting a
one-month period over the last year, other than in a controlled environment.

1. Justification: cocaine use disorder, in regular users, is the focus of this
protocol.

2. 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 - TOLERABILITY PILOT:

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.

1. 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.

2. Screening tool: TMS safety Screen, Medical History and clinical MRI/MRA scan.

2. Current DSM-5 moderate-severe substance use disorder on a substance other than
cocaine, nicotine, marijuana, or opiates (provided they are currently stable on
Suboxone) or meeting withdrawal criteria for alcohol or a
sedative/hypnotic/anxiolytic, or tolerance criteria in an individual using 3 or more
days/week, regardless of diagnosis. Individuals will be considered stable on

Suboxone if they have been on a stable dose for at least 2-weeks prior to consenting
to 17-DA-N002 and have provided at least 3 urine specimens negative for illicit
opioids over the same 2-week period (10 business days) with at least one test
collected within two business days of the start of the period, one collected within
three business days of the end of the period and one collected at

least two days from either of the other two specimens. Urine results may be gathered
at NIDA as part of screening or be provided by the Suboxone prescriber. Communication
between the Suboxone provider and the MAI (or covering Staff Clinician) will be
ongoing to establish continued illicit opioid abstinence between participant clearance
and consent to 17-DA-N002. Individuals must be receiving their Suboxone as take-home
doses from an external (i.e., non-NIDA-IRP) provider.

1. 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 Suboxone and struggling with
cocaine use are an ecologically valid population in the greater Baltimore area
and do not increase risk of seizure.

2. 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.

1. ustification: 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.

2. Screening tool: TMS safety screening, Medical History.

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.

1. 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.

2. Screening tool: Medical History, TMS safety screen.

5. Noise-induced hearing loss or tinnitus.

1. Justification: individuals with noise-induced hearing problems may be
particularly vulnerable to the acoustic noise generated by iTBS equipment.

2. 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.

1. 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.

2. Screening tools: MRI safety screening questionnaire, Medical history, Medical
Assessments: Urine toxicology analyzes for presence of a broad range of
prescription and nonprescription drugs.

7. Lifetime history of schizophrenia, bipolar disorder, mania, or hypomania.

1. 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.

2. 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.

1. Justifications: the risk of iTBS for individuals with a heart condition is
unknown.

2. 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).

1. Justification: it is unknown whether iTBS poses a risk to fetuses.

2. 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.

1. 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.

2. Screening tool: TMS safety screen.

INCLUSION AND EXCLUSION - CLINICAL TRIAL (PHASE II):

The same inclusion and exclusion criteria will be used as in the Pilot with the exception
of:

1. CD participants, and not HC participants, will meet current DSM-5 criteria for current
moderate to severe substance (i.e., cocaine) use disorder and currently seeking
treatment.

2. Justification: cocaine use disorder is the focus of this protocol.

3. 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 by a counselor.

4. Treatment seeking CD participants will be recruited.

5. Justification: The population of interest is CD dependent individuals motivated to
reduce or eliminate their cocaine use.

6. Screening tools: Addiction Severity Index and Brief Cocaine Cessation Motivation
Assessment.

7. 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.

8. 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.

9. Screening tools: SCID Screen Patient Questionnaire (or similar tool for assessment of
psychiatric disorders). The interviewer will supplement SCID with questions to assess
for DSM-5 substance use disorders. Potential diagnoses will be further evaluated by a
counsellor, Drug Use Survey (DUS), Substance 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.

10. Participation in any NIBS session less than two weeks prior to admission (inclusing
Pilot participants of this protocol who completed fewer than 5 iTBS treatment days but
excluding ongoing participation in the Clinical Trial of the current protocol). No
NIBS exposure for treatment purposes in the last 6 months.

11. 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.

12. Screening tool: TMS safety screening questionnaire.

13. 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
and MRI scanning.

14. Justification: Certain metal in the body is a contra-indication for iTBS
administration and MRI scanning, 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.

15. Screening tool: MRI and TMS Safety screening questionnaires.

INCLUSION CRITERIA - TMS:

Participants must:

1. Be able to give valid inform...