Oxytocin and Cognitive Behavioral Therapy in Drug Dependence

Objective The therapeutic alliance (TA), a working relationship between therapist and
patient, may contribute to favorable outcomes in all types of psychotherapy, including
cognitive-behavioral therapy (CBT) for drug dependence. Enhancement of the TA may be
possible through intranasal administration of the hormone and neurotransmitter oxytocin,
which is associated with social bonding and trust. The objective of this study is to
determine whether addition of intranasal oxytocin to a course of CBT for drug dependence
enhances TA and treatment retention and reduces drug use post-treatment. The study will
assess changes in performance on tasks that probe decision-making, emotional processing, and
drug-cue reactivity. We will employ fMRI on a subset of participants to study the neural
correlates of these processes.

Study population. The treatment portion of the study will be conducted in three parallel
arms, not intended to be statistically compared to each other: (1) Outpatient Methadone arm
(physically dependent heroin users, n = 80 evaluable); (2) Outpatient Cocaine arm
(cocaine-dependent individuals, non-opiate-dependent, n = 80 evaluable); 3) Inpatient
Cocaine arm (cocaine-dependent individuals, non-opiate-dependent, n = 80 evaluable). There
will also be two groups of non-treatment-seeking controls (20 cocaine-using, 20
non-drug-using) to rule out practice effects on tasks; controls will not receive oxytocin or
CBT.

Experimental design and methods. Primary outcome measures will be TA in all arms and drug
use for methadone and cocaine outpatient arms. (1) Methadone arm: after a 5-week baseline
for stabilization on methadone, participants will undergo 12 weeks of CBT, with random
assignment to oxytocin (24 IU, administered before each session) or placebo. (2 and 3)
Cocaine arms, inpatient and outpatient: after a 1-week baseline for assessment of drug use,
participants will undergo 6 and 12 weeks respectively of CBT, with random assignment to
oxytocin (24 IU, administered before each session) or placebo.

Outcome measures: Principle outcome measures for the outpatient arms will be TA measured at
several points during CBT, treatment retention, and attendance at CBT sessions. Secondary
outcome measures are drug use during treatment and at follow-up, drug craving during
treatment and at follow-up, stress reduction during treatment and at follow-up, HIV risk
behaviors during treatment and at follow-up, behavioral performance on various tasks, and
neural response to these tasks for the imaging subgroup. The outcome measures for the
inpatient arm will be the same as for the outpatient arms with the exception of drug use
during treatment.

- INCLUSION CRITERIA:

All participants must:

1. Be between age 18 and 65.

2. Methadone arm only: opiate dependence for the past year determined by clinical exam,
opiate-positive urine during screening and diagnosis confirmed by SCID.

3. Cocaine outpatient arm: cocaine dependence determined by clinical exam,
cocaine-positive urine during screening and diagnosis confirmed by SCID.

4. Cocaine inpatient arm: Cocaine dependence determined by clinical exam during
screening and diagnosis confirmed by SCID.

5. Control participants: cocaine dependent and non-drug using, will be recruited to
provide appropriate matches for subjects in the two treatment arms with respect to
the following characteristics: age, gender, IQ, socioeconomic factors, and years of
education.

6. Be free of dependence on other substances except nicotine, heroin (for the methadone
arm only), or cocaine at the time of participation. Justification: Dependence on
other substance may result in unique CNS deficits that would confound our results.
Nicotine dependence will be allowed because nicotine use is not associated with a
drug high in normal usage and the prevalence of nicotine dependence in cocaine users
may make it impractical to exclude nicotine users. While it might be preferable to
exclude individuals whose use of other substances reaches the threshold of abuse,
inclusion of such individuals will not necessarily contaminate the data. Inpatient
cocaine arm subjects who meet DSM-IV TR criteria for the course specifier In a
Controlled Environment may have a history of dependence on substances other than
cocaine before their admission to the inpatient treatment program. Assessment
tool(s): SCID with confirmation by negative urine drug screen.

For participation in the scanning portion of the study, participants must also:

7. Be between the ages of 18-55. Justification: Many of the cognitive processes under
study change with age. In addition, the risk of difficult-to-detect medical
abnormalities such as silent cerebral infarcts increases with age. Individuals over
55 will therefore be excluded. Assessment tool(s): driver s license, birth
certificate, or other government-issued form of identification.

8. Be in good health. Justification: Many illnesses can alter fMRI signal and alter
cognition. Assessment tool(s): Participants will provide a brief health history
during phone screening, and undergo a history and physical examination with a
qualified IRP clinician (exam details discussed below in reference to specific
exclusion criteria).

9. Be right-handed. Justification: Many of the brain functions to be assessed in this
protocol have shown some evidence of being lateralized in the brain. In order to
reduce variability in the data, participants must be right-handed. Assessment
tool(s): Edinburgh Handedness Inventory.

EXCLUSION CRITERIA:

Participants will be excluded if they have evidence of:

1. Schizophrenia or any other DSM-IV psychotic disorder; history of bipolar disorder;
current major depressive disorder.

2. Current dependence on alcohol or sedative-hypnotic, e.g. benzodiazepine (by DSM-IV
criteria), except for inpatient cocaine arm.

3. Cognitive impairment severe enough to preclude informed consent or valid responses on
questionnaires.

4. Renal insufficiency with serum creatinine greater than 1.7.

5. Medical illness that in the view of the investigators would compromise participation
in research such as: a history of syncope, family history of sudden death,
electrolyte imbalance, bradycardia, arrhythmias, marked sustained high BP with SBP >
160 and or DBP > 100 on more than two readings without 3rd reading being below these
parameters and not stabilized on antihypertension medications before the starting the
study, congestive heart failure, history or finding on screening EKG of significant
abnormality such as prolonged QTc (> 450ms) , or AIDS or HIV positive with T cell
count less than or equal to 200.

6. Urologic conditions that would inhibit urine collection.

7. Untreated Endocrine disorders.

8. Pregnancy, planning to become pregnant, or breastfeeding. In addition, women of
child-bearing age who are sexually active are required to use an effective form of
birth control for the duration of the study. Effective forms of birth control
include:

1. hormonal contraceptives (birth control pills, injectable hormones, vaginal ring
hormones),

2. surgical sterility (tubal ligation or hysterectomy)

3. IUD

4. Diaphragm with spermicide

5. Condom with spermicide

9. For the methadone arm, use of any drugs that would interact with methadone to produce
adverse effects such as Class I or Class III antiarrhythmics, TCA s, MAOI s, calcium
channel blockers, neuroleptics or frequent use of sedative hypnotic drugs.
Justification: Avoidance of adverse interaction with methadone. Assessment tool(s):
Clinical interview and tox screen.

10. Use of any drugs (prostaglandins, vasoconstricting agents or anesthetic medications,
for example) that may interact with oxytocin. Justification: Avoidance of adverse
interaction with oxytocin. Assessment tool(s): Clinical interview and tox screen

11. History of hypersensitivity to oxytocin or vehicle, i.e. propylparahydroxybenzioate,
methylparahydroxybenziate, chlorbutanol hemihydrate. Assessment tool: clinical
interview

12. Presence of or history of clinically significant allergic rhinitis as assessed by MRP
or PI. Justification: Inflammation of nasal mucosa could interfere with mucosal
absorption of intranasally administered OT.

In addition, participants will be excluded from fMRI scanning if they:

13. Are not suitable for fMRI due to pregnancy, implanted metallic devices (cardiac
pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or
other implanted metal parts), body morphology, or claustrophobia. Justification: MR
scanning is the primary measurement tool used in this portion of the protocol.
Assessment tool(s): Prospective participants will fill out an MRI screening
questionnaire and undergo an interview with an MR technologist. Pregnancy tests will
be performed on all female participants of childbearing age before each experimental
session. Questions concerning suitability for scanning will be referred to the MR
Medical Safety Officer. Prospective participants will be questioned about symptoms of
claustrophobia and placed in the mock scanner during their screening visit to assess
for possible difficulty tolerating the confinement of the scanner and for ability to
physically fit into the scanner.

14. Have coagulopathies, history of or current superficial or deep vein thrombosis, or
musculoskeletal abnormalities restricting ability to lie flat for extended periods.
Justification: MR scanning sessions require participants to lie flat on their backs
and remain perfectly still for approximately two hours. Therefore, conditions that
would make that difficult (e.g. chronic back pain, significant scoliosis) or
dangerous (e.g. familial hypercoagulability syndrome, history of thrombosis) will be
exclusionary. Assessment tool(s): History and physical examination by a qualified IRP
clinician, supplemented with a trial of lying in the mock scanner to assess comfort
issues.

15. Have HIV or syphilis. Justification: HIV and syphilis can both have CNS sequelae,
thus introducing unnecessary variability into the data. Assessment tool(s): HIV blood
test, syphilis serology (positive FTA).

16. Have any neurological illnesses. This includes, but is not limited to, seizure
disorders, migraine, multiple sclerosis, movement disorders, or history of head
trauma, CVA, or CNS tumor. Justification: CNS diseases alter CNS function and,
possibly, the neuronal-vascular coupling that forms the basis of the BOLD fMRI signal
to be used in this study. Assessment tool(s): History and physical examination by a
qualified IRP clinician, urine drug screening for anticonvulsants not disclosed by
history. History of head trauma with loss of consciousness of more than 5 minutes or
with postconcussive sequelae lasting more than two days, regardless of loss of
consciousness, will be exclusionary.

17. Regularly use any prescription, over-the-counter, or herbal medication that may alter
CNS function, cardiovascular function, or neuronal-vascular coupling. Justification:
Compounds that alter BOLD signal will alter the primary measure used in the study.
Assessment tool(s): History and comprehensive urine drug screening to detect use of
antidepressants, benzodiazepines, antipsychotics, anticonvulsants, barbiturates, and
other common medications and drugs of abuse.

All participants who are fullfill criteria for fMRI scanning will be asked to undergo
scanning; we anticipate that approximately 50 percent of enrolled participants will be
scanned.