Effect of Oxytocin on Stress in Marijuana Users

Stress is commonly associated with drug craving and relapse in substance-dependent
individuals. Several studies indicate that hypothalamic neuropeptides may mediate behavioral
response to stress. For example, preclinical and clinical investigations have indicated that
the neuropeptide oxytocin exerts anxiolytic effects in stress paradigms. Several studies
have indicated that oxytocin promotes trust, social bonding, and calmness; however, little
is known about the potential anxiolytic affects of oxytocin in marijuana-dependent
individuals. A preclinical study investigating the effects and mechanism of lithium on
cannabinoid withdrawal in rats had positive findings, with increasing oxytocin levels
hypothesized to moderate this effect (Cui et al, 2001). Given the anxiolytic nature of
oxytocin, it may have a therapeutic role in ameliorating the negative affect commonly
observed prior to relapse in marijuana-dependent individuals, as well as the anxiety
associated with marijuana withdrawal. This pilot protocol will provide important preliminary
data on the effect of oxytocin on stress in marijuana-dependent individuals.

Inclusion Criteria:

- Subjects must be able to provide informed consent and function at an intellectual
level sufficient to allow accurate completion of all assessment instruments.

- Subjects must meet DSM-IV criteria for current marijuana dependence (within the past
three months). While individuals may also meet criteria for abuse of other
substances, they must identify marijuana as their primary substance of abuse and must
not meet criteria for dependence on any other substance (except nicotine) within the
last 60 days.

- Subjects must consent to remain abstinent from all drugs of abuse (except nicotine
and marijuana) for a three-day period immediately prior to the CTRC admission.
Subjects must abstain from marijuana for 24 hours prior to testing. By restricting
marijuana use as proposed, subjects should not be under the acute effects of
marijuana, and also may be experiencing mild withdrawal symptoms, the measurement of
which is one of the outcome variables being tested.

- Subjects must consent to random assignment.

Exclusion Criteria:

- Women who are pregnant, nursing or of childbearing potential and not practicing an
effective means of birth control.

- Subjects with evidence of or a history of significant hematological, endocrine,
cardiovascular, pulmonary, renal, gastrointestinal, or neurological disease including
diabetes, as these conditions may affect physiological/subjective responses.

- Subjects with Addison's disease, Cushing's disease or other diseases of the adrenal
cortex likely to affect hormonal/neuroendocrine status.

- Subjects with a history of or current psychotic disorder or bipolar affective
disorder as these may interfere with subjective measurements.

- Subjects with current major depressive disorder or post-traumatic stress disorder as
these disorders are associated with characteristic changes in stress response.

- Subjects receiving synthetic glucocorticoid therapy, any exogenous steroid therapy,
or treatment with other agents that interfere with hormonal measurements within one
month of test session.

- Subjects taking any psychotropic medications, including SRI's or other
antidepressants, opiates or opiate antagonists because these may affect test
response.

- Subjects with any acute illness or fever. Individuals who otherwise meet study
criteria will be rescheduled for evaluation for participation.

- Subjects who are obese (³ 20% over ideal weight) as this may interfere with hormonal
status.

- Subjects who are unwilling or unable to maintain abstinence from alcohol and other
drugs of abuse (except nicotine) for three days prior to the stress task procedure.

- Subjects meeting DSM-IV criteria for substance dependence (other than nicotine or
marijuana) within the past 60 days.