Treatment for Cannabis Withdrawal and Dependence

This study will be a Phase II, single-site, 8-week, randomized, double-blind,
placebo-controlled, parallel group comparison of aprepitant (125 mg/d) or placebo. Subjects
will be 100 outpatients seeking treatment for current cannabis dependence with no clinically
significant medical or psychiatric disorders (including substance use disorders or a
positive drug screen for substances other than cannabis or nicotine). All subjects will
receive weekly manual-guided abstinence-oriented counseling to facilitate showing a drug
effect above and beyond available therapies (Weeks 0-8). Research assessments of marijuana
use and withdrawal and drug safety and tolerability will occur weekly through the treatment
phase of the 8-week study. Post treatment follow-up assessments will occur at Weeks 9 and
12. Neuropsychological testing will occur at Weeks 0 and 4 and 8.

Specific Aim 1: To evaluate the relative efficacy of aprepitant 125 mg/d vs. placebo for
reducing cannabis withdrawal symptoms in cannabis dependent outpatients, including anxiety,
mood, craving and sleep symptoms.

Specific Aim 2: To evaluate the relative efficacy of aprepitant 125 mg/d vs. placebo for
reducing marijuana use in cannabis dependent outpatients.

Specific Aim 3: To evaluate the relative efficacy of aprepitant 125 mg/d vs. placebo for
reducing cannabis related impairments in executive functioning in cannabis dependent
outpatients.

Inclusion Criteria:

- Males or females from 18-70 years of age

- Meets DSM IV criteria for current cannabis dependence

- Seeking research-based outpatient treatment for cannabis dependence that involves
daily oral medication

- Smoked MJ daily at least 25 days per month during the 90 days prior to randomization

- Current cannabis use verified by a positive urine test > 50 ng/ml

- At least a 2-year history of regular MJ use

- Willing and able to give informed consent

Exclusion Criteria:

- Abstinent from cannabis more than 2 days at the time of randomization

- Currently meets DSM IV criteria for dependence on substances, or has urine drug
screen positive for substances, other than cannabis or nicotine

- Meets DSM IV criteria for a major AXIS I disorder other than cannabis and nicotine
dependence,

- Active suicidal ideation

- Significant medical disorders that will increase potential risk or interfere with
study participation,

- Females who are pregnant, nursing or who are sexually active with child-bearing
potential and refuse to use a double-barrier method of birth control during the study
and for up to 4 weeks after study termination

- Ongoing treatment with medications that may affect study outcomes,

- Use of CYP3A4 strong inhibitors (e.g., ketoconazole, itraconazole, nefazodone,
troleandomycin, clarithromycin, ritonavir, nelfinavir) and CYP3A4 moderate inhibitors
(e.g., diltiazem) within the 2 week period prior the study drug administration or
within 5 half-lives of the respective medication, whichever is longer, until study
conclusion.

- Consumption of grapefruit or grapefruit products from at least 2 weeks prior to study
drug administration until study conclusion.

- Ongoing treatment with medications that are primarily metabolized by CYP3A4 and may
have increased plasma concentrations when co-administered with aprepitant, such as
pimozide, terfenadine, astemizole or cisapride or corticosteroids, as well as
benzodiazepines including midazolam, alprazolam, and triazolam.

- Ongoing treatment with medications that are primarily metabolized by CYP2C9 (e.g.,
warfarin, tolbutamide).

- Use of drugs (e.g., rifampin, carbamazepine, phenytoin) or herbal supplements (e.g.,
St John's wort) that induce CYP3A4 activity and may result in reduced plasma
concentrations of aprepitant and decreased efficacy of aprepitant.

- Inability to understand and/or comply with the provisions of the protocol and consent
form.