Pilot Study of Repetitive Transcranial Magnetic Stimulation in Cocaine Craving

Primary objective: Repetitive transcranial magnetic stimulation (rTMS) provides a
non-invasive means of altering brain neural activity. This pilot study will test whether 5
days of rTMS reduces cue-induced cocaine craving and cocaine use in cocaine users.

Hypothesis: We predict that active rTMS will significantly lower craving for cocaine
compared with sham rTMS.

Study population: Thirty healthy adult cocaine users (for at least 2 years, currently
averaging at least 3 times weekly) with no other major psychiatric disorders except nicotine
dependence (DSM IV criteria) will be recruited from the community.

Design: Following a baseline phase to evaluate subject characteristics, subjects will be
randomly assigned to receive 5 days of active or sham rTMS treatment. rTMS at 1 Hz and
strength 120% of the motor threshold will be applied to the dorsolateral prefrontal cortex
(DLPFC) using an H-coil (HADD version) contained in a helmet, beginning 1 second before
presentation of a cocaine-associated visual cue and lasting for 30 seconds. Brain site
localization will use a computerized navigation system based on structural MRI scans
obtained before the first session. Each treatment session (lasting around 31 minutes) will
consist of 54 trials (cue presentations): 36 with cocaine-associated cues and 9 each with
non-drug-associated positive or neutral cues. No rTMS will be administered with the
non-cocaine-associated cues. Subjects return for follow-up assessments one and two weeks
after the final rTMS session.

Outcome measures: The primary outcome measure will be cocaine craving assessed by 100-mm
visual analog scales before and after every TMS treatment and at one- and two week
follow-up. Secondary outcome measures will be the 14-item Cocaine Craving Questionnaire,
self-reported cocaine use, and urine drug testing at each rTMS session and follow-up visit,
and changes in regional brain responses to cocaine-associated visual cues assessed by fMRI
done before and after the 5 rTMS sessions.

Benefits: There is no direct benefit to individual subjects. The future benefit to society
may be development of better methods for treatment of cocaine addiction.

Risks: The primary risks from rTMS are transient headache, scalp discomfort, decreased
spatial recognition memory, and hearing loss (minimized by wearing ear plugs). Seizures are
very rare when rTMS is administered within accepted safety guidelines and individuals at
increased risk of seizures are excluded. The risk of inducing a manic episode is minimized
by excluding individuals with a history of non-drug-induced mania/hypomania.

-INCLUSION CRITERIA:

i) Eighteen to sixty-five years of age

ii) Cocaine user for at least 2 years, currently averaging at least 3 times weekly, with
period of continuous abstinence no longer than one month within the past year

iii) Reading level of at least 6th grade, based on the Wide Range Achievement Test (WRAT)

iv) Ability to give valid informed consent

v) Right-handed

vi) If the subject is female and of childbearing potential, she agrees to use a medically
acceptable form of contraception, and not become pregnant for the duration of the study. A
woman is considered of childbearing potential unless post-menopausal or surgically
sterilized. Female patients of childbearing potential must use either: (1) contraceptive
pill or IUD or depot hormonal preparation (ring, injection, implant); and/or (2) a barrier
method of contraception such as diaphragm, sponge with spermicide, or condom.

Contraceptive measures will be reviewed with female subjects at each visit prior to the
rTMS treatment.

vii) Self-report experiencing cocaine craving when exposed to cocaine-associated cues

EXCLUSION CRITERIA:

i) Personal or first-degree family history of any clinically defined neurological
disorder, including organic brain disease, epilepsy, stroke, brain lesions, or multiple
sclerosis; or personal history of previous neurosurgery or head trauma that resulted in
loss of consciousness.

ii) 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 within or near the head that cannot be safely
removed.

iii) Metal shrapnel or bullet in the head or body, including metal shavings.

iv) Current use of any investigational drug or of any medications with anti- or
proconvulsive action, such as tricyclic antidepressants or neuroleptics (which lower
seizure threshold).

v) Increased intracranial pressure (lowers seizure threshold)

vi) Lifetime history of major depressive disorder, schizophrenia, bipolar disorder, mania,
or hypomania

vii) History of myocardial infarction, angina, congestive heart failure, cardiomyopathy,
stroke or transient ischemic attack, or any heart condition currently under medical care.

viii) Pregnant or nursing women or women with reproductive potential not using an
acceptable form of contraception.

ix) Any history of seizure

x) Current dependence (DSM-IV criteria) on substances other than cocaine and/or nicotine.

xi) Claustrophobia making them unable to tolerate lying in the MRI scanner.

xii) History of HIV infection or positive HIV antibody test.