Pregnenolone and Marijuana Dependence
Condition: Marijuana Dependence
MeSH terms: Marijuana Abuse
Study type: Interventional
Phase: Phase 2

Summary: 
      The cannabinoid delta 9-tetrahydrocannabinol (THC) is the primary psychoactive component of
      marijuana. THC is believed to be a significant factor in the addictive potential associated
      with marijuana use. In addition, attenuated levels of endogenous endocannabinoids have been
      found in alcohol-dependent individuals as compared to social drinkers, suggesting that
      changes in the sensitivity of the endogenous endocannabinoid system play a role in the
      transition from recreational drug use to substance use disorders. Thus, pharmacotherapies
      that target the cannabinoid system may be effective strategies for reducing marijuana use and
      dependence. Recent preclinical data demonstrate that the neurosteroid pregnenolone (PREG)
      inhibits THC activation of cannabinoid receptors and decreases symptoms of marijuana
      intoxication. In addition, other studies show that PREG inhibits drug-seeking behavior. This
      pilot study will provide important preliminary data on the effect of an acute dose of PREG on
      cue-related craving in individuals with cannabis use disorder.
    

Detailed description: 
      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.
    

Intervention name(s): Pregnenolone; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Pregnenolone is a steroid that occurs naturally in the body, and early studies have shown that pregnenolone may block the effects of marijuana intoxication; Inactive comparator
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment