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.