Pregnenolone and Marijuana Dependence

Overview Thirty participants between the ages of 18 and 65 who meet DSM-V criteria for
current for cannabis use disorder will complete a study visit. Participants will be
randomized to receive either PREG (400 mg) (n=15) or placebo (PBO) (n=15). Two-hours after
medication administration, the participants will complete a cue reactivity session. Blood
samples will be collected prior to medication, post-medication and after the cue-reactivity
session. The blood samples will be assayed for endogenous PREG and endocannabinoid levels.
Subjective craving and mood data will also be collected.

Subjects Participants will be 30 men or women between the ages of 18 and 65 years who meet
DSM-V criteria for cannabis use disorder. Additional inclusion criteria include use of
acceptable methods of birth control if female and of childbearing potential, positive urine
drug screen for cannabinoids at screening, consent to random assignment, and ability to read
and provide informed consent. Exclusion criteria include women who are pregnant, nursing, or
plan to become pregnant during the course of the study; having a history of or current
psychotic disorder, bipolar disorder, or eating disorder; posing a current suicidal or
homicidal risk; having evidence or history of serious medical disease; requiring concomitant
therapy with psychotropic medication; being currently dependent on other substances, with the
exception of nicotine; and patients who, in the investigator's opinion, would be unable to
comply with study procedures or assessments.

Procedures

1. Recruitment. Subjects will be primarily recruited through media advertisements. The
investigators have an active recruitment network in place, and have been able to
consistently surpass recruitment goals even with concomitantly recruiting studies in
this population, averaging enrollment of 11 participants per month. As such, the
investigators do not anticipate any issues with successfully recruiting for this study
in the proposed timeframe.

2. Screening/Assessment. Individuals will be initially screened for eligibility over the
telephone by a trained research assistant. Major inclusion/exclusion criteria will be
assessed during the phone interview, and if an individual seems potentially eligible,
(s)he will be invited for an in-person interview with a member of the research team.
Prior to any study procedures being performed, the individual will sign an IRB-approved
informed consent form. A battery of standardized assessments will then be delivered
(described below). A general medical history and physical exam will also be performed to
ensure that the subject is eligible to participate. In the event that a patient is found
to be ineligible to participate in this research protocol, he or she will be given an
appropriate referral for further medical care or to an appropriate treatment program.

3. Session Preparation. The test session will be conducted at the MUSC Research NEXUS.
Prior to leaving the assessment visit, participants will be instructed to avoid caffeine
and marijuana on the day of the study visit. Participants will also be instructed to
abstain from other drug (including alcohol) use for the three days prior to the study
visit.

4. Study Visit. Participants will present to the Addiction Sciences Division at 12:00 on
the day of the study visit. Female participants will complete a urine pregnancy test. If
the results are negative, or if the participant is male, the subject will be
breathalyzed and will provide a urine sample, which will be tested for the presence of
cocaine, opiates, benzodiazepines, THC, and stimulants. If either test is positive for
alcohol or any drug with the exception of marijuana, the study visit will be
rescheduled. A saliva sample to test for drugs of abuse will also be collected. Nicotine
patches will be provided to cigarette smokers to avoid nicotine withdrawal. Participants
will be escorted to the MUSC Research NEXUS by study personnel. At 12:30, a blood sample
will be collected from each participant. Each participant will also be asked to rate
their craving and mood (described below). Medication will be administered to the
participants by NEXUS personnel. Each participant will remain in a private room for two
hours. At 2:30 a second blood sample will be collected from each participant and
subjective ratings will be obtained. After the blood draw, study personnel will provide
the participant with standardized cue-exposure instructions, stating that two sets of
items will be presented and audio will be played through headphones. Control cues will
be presented to each participant. Examples of these cues include a note pad, pencil,
marker, cotton swabs and teabags.Wood chips will be presented as an olfactory cue and an
auditory script will be played in which each participant will be asked to imagine a day
at the beach. A third blood sample will be drawn and the participant will be asked to
rate their craving and mood. Afterwards each participant will be presented with the
marijuana cues. Examples of these cues include, blunt wrap, rolling papers, pipes, a
pipe cleaner, small bag containing fake marijuana, an ashtray, a water bong and a fake
joint. A marijuana stick cigarette and/or marijuana scented oil will be burned presented
as an olfactory cue and each participant will listen to a script prompting recall of a
recent pleasant experience with marijuana. Dr. McRae-Clark has a Schedule I DEA license,
and has obtained marijuana for clinical trial use from NIDA. The investigators'
laboratory and others have used these procedures to evoke craving in marijuana-dependent
individuals [11, 12]. Blood samples and subjective ratings will be collected
immediately, 15 minutes, 30 minutes and 60 minutes after the start of the marijuana cue
session. After the final assessment each participant will be debriefed and compensated.
In the event that a participant's craving remains elevated, he or she will be asked to
remain in the NEXUS until their craving has subsided.

General Inclusion / Exclusion Criteria Inclusion Criteria

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

2. Subjects must meet DSM-5 criteria for current cannabis use disorder (within the past
three months). While individuals may endorse use of other substances, they must
identify marijuana as their primary substance of abuse and must not meet criteria for
any other substance use disorder (except nicotine) within the last 60 days. Due to the
high comorbidity of marijuana and alcohol use disorder, subjects who meet criteria for
mild alcohol use disorder will be included.

3. Subjects must consent to remain abstinent from alcohol for 24 hours and other drugs of
abuse (except nicotine and marijuana) for three days immediately prior to the study
visit. Subjects must abstain from marijuana for 24 hours prior to the study visit. By
restricting marijuana use as proposed, subjects should not be under the acute effects
of marijuana.

4. Subjects must consent to random assignment.

Exclusion Criteria

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

2. Individuals taking exogenous gonadal steroids including estrogens, progestins and
testosterone. This includes hormonal contraception and replacement therapy.

3. Subjects with evidence of or a history of significant hematological, endocrine,
cardiovascular, pulmonary, renal, gastrointestinal, neurological disease including
diabetes or cancer, as these conditions may affect study outcomes.

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

5. Subjects taking any psychotropic medications, including SRI's or other
antidepressants, opiates or opiate antagonists because these may affect test response.
Individuals who take stimulants for treatment of ADHD will be allowed to participate.

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

7. Subjects who are unwilling or unable to maintain abstinence from alcohol and marijuana
for 24 hours and other drugs of abuse (except nicotine) for three days prior to the
study visit.

8. Subjects meeting DSM-5 criteria for a substance use disorder (other than nicotine,
marijuana, or alcohol) within the past 60 days.