Effectiveness Study of Dronabinol and BRENDA for the Treatment of Cannabis Withdrawal
Condition: Marijuana Dependence
MeSH terms: Marijuana Abuse
Study type: Interventional
Phase: Phase 2

Summary: 
      This treatment study is targeted specifically for those who want to stop using marijuana. We
      want to find out if patients who are dependent on marijuana and want to stop using are helped
      by a combination of the drug dronabinol and six sessions of individual therapy (BRENDA).
      Dronabinol is a pill form of the active ingredient in marijuana (THC). Currently, dronabinol
      is approved for the treatment of nausea in people receiving cancer chemotherapy and as an
      appetite stimulant in people with AIDS.

      In some studies, dronabinol reduced the amount of psychological and physical discomfort
      experienced when people stopped using marijuana. One purpose of our study is to see if people
      who are on dronabinol have fewer problems with psychological and physical discomfort than
      those who are on a placebo.

      In addition to treatment, this research trial will also be measuring the reactions of
      subjects to drug-related cues, and also to computer-presented tasks unrelated to drug use. We
      may examine whether the response to these cues/tasks either predicts treatment outcome, or is
      affected by your treatment. This information may also help us to understand the ways in which
      chronic drug use causes changes in our subjects' mental functioning and how those changes
      respond to treatment.

      In addition to participation in the treatment research trial, some subjects may be asked to
      undergo a brain scan in an MRI. The purpose of the brain scan research project is to measure
      brain reactions with a non-invasive, non-radioactive imaging technique known as fMRI
      (functional magnetic resonance imaging) in marijuana subjects before and after treatment with
      the medication dronabinol or with an inactive substance (placebo).
    

Detailed description: 
      1. Background: Cannabis is the most widely used illicit drug in the U.S. According to the
      2004 U.S. The 2004 NSDUH estimates there are 3.2 million daily or almost daily marijuana
      smokers in the United States. Recent reports have estimated that 1.5% of the US population
      meets DSM-IV diagnostic criteria for cannabis abuse or dependence, with the sharpest
      increases among young black men and women and young Hispanic men (2). Cannabis users commonly
      endorse adverse psychosocial and medical effects from their cannabis use, which include
      dysphoria, loss of control over use, cognitive impairment, and strained social relationships.

      In humans, the cannabis withdrawal syndrome is a constellation of affective and behavioral
      symptoms that occur within 24 to 48 hours after abrupt cessation of marijuana use with a
      gradual return to baseline after 1-2 weeks. A recent review of the literature on cannabis
      withdrawal identified consistent reports of anxiety, irritability, physical discomfort,
      insomnia, and appetite suppression to be associated with abrupt cessation of cannabis use in
      heavy users across controlled inpatient and outpatient trials.

      The agonist dronabinol (Marinol) has shown promise in the prevention of cannabis withdrawal
      in human lab studies and its reported amelioration of anxiety, misery, insomnia, drug craving
      and appetite suppression from abrupt cannabis cessation provides the rationale for its use as
      an agent to prevent cannabis withdrawal in an outpatient, treatment seeking population(9).
      Dronabinol has also been used as a brief "maintenance" treatment in a cannabis
      self-administration study in humans. Currently, dronabinol is indicated for treatment of
      AIDS-related anorexia and nausea associated with cancer chemotherapy. Two principle aims of
      our proposal are therefore to gain familiarity with cannabis withdrawal in a naturalistic
      outpatient treatment setting and compare an agonist therapy to placebo to attenuate cannabis
      withdrawal and enhance treatment outcome.

      The general pattern of low rates of total abstinence and lack of significant differences
      between high intensity psychotherapy treatment vs. low intensity and voucher-based treatment
      holds across all psychosocial treatment studies. In keeping with prior evidence supporting
      the relative efficacy of brief interventions for cannabis dependence, the current proposal
      will apply a well-established brief medicalized psychotherapy known as B.R.E.N.D.A. for the
      treatment of cannabis dependence.

      To date, studies evaluating cannabis patients have primarily focused on identifying
      neurotoxic drug effects such as impaired learning, memory, attention and executive function.
      We propose to more fully examine the behaviors with relevance to addiction vulnerability and
      relapse. Such behaviors include but are not limited to poor inhibition, high risk-taking,
      positive affective bias toward drug stimuli, poor affect regulation, and poor
      decision-making. We plan to utilize standardized tasks and questionnaires to objectively
      characterize dimensions of these addiction relevant behaviors in cannabis patients and to
      examine the effect of cannabis withdrawal and dronabinol treatment on these behavioral
      measures. We will also correlate brain differences (structural and functional) with
      behavioral measures in cannabis dependent patients before and after treatment with dronabinol
      as compared to placebo.

      The search for effective treatment of addictive disorders is limited by our incomplete
      knowledge about the brain substrates critical for addiction and for addiction recovery. The
      recent use of PET and fMRI has allowed researchers to examine connections between brain
      activity and vulnerability to addiction and relapse. In marijuana users, PET and fMRI
      techniques have been used to study regional brain volumes, blood flow, metabolism. However,
      understanding cue induced craving is more immediately relevant to treatment and relapse
      prevention in cannabis addiction since cannabis users have a high rate of relapse compared to
      those found for other drugs of abuse. In addiction, cues that have been consistently
      associated with drug reward can trigger craving for the drug. Clinically, the craving for the
      drug is sufficiently compelling in many cases to precipitate a relapse despite significant
      effort on the patient's part to maintain abstinence and despite significant negative
      consequences. Although PET and fMRI techniques have been successfully used to study cue
      induced craving in other drugs of abuse (e.g. cocaine) leading to greater understanding of
      the mechanism of relapse (limbic activation in response to drug cues), these techniques have
      not been utilized in cannabis patients. Several preliminary studies used patient self-report
      to demonstrate cue induced craving in cannabis patients. We propose to utilize physiological
      measures and functional neuroimaging to objectively demonstrate cue-induced craving in
      cannabis dependent subjects and to identify the brain substrates that mediate this craving.
      Similarly, dronabinol reduced self-reported drug craving in one recent human laboratory
      study. We propose to examine whether dronabinol will change physiological measures and brain
      activation in response to drug cues.

      2. Study objectives:

        1. To evaluate the cannabis withdrawal syndrome in a naturalistic outpatient setting as one
           possible cause for the low rates of total abstinence seen in our trial and all other
           clinical trials of adult cannabis dependence.

             1. Primary Hypothesis: Subjective ratings of cannabis withdrawal can be assessed
                reliably in an outpatient treatment setting.

             2. Secondary Hypothesis: Subjects with high subjective ratings of cannabis withdrawal
                will have lower rates of abstinence regardless of treatment group (dronabinol vs.
                placebo).

        2. To determine the feasibility and efficacy of a three-week trial of a cannabinoid agonist
           medication under double blind placebo controlled conditions to treat cannabis
           withdrawal.

             1. Primary Hypothesis: Dronabinol can be used safely at a dosage of 10mg qid (four
                times per day) as an outpatient treatment for cannabis withdrawal

             2. Secondary Hypothesis: Dronabinol will perform better than placebo in attenuating
                the symptoms of cannabis withdrawal.

        3. To determine the feasibility and efficacy of providing brief psychotherapy (BRENDA) to
           patients seeking treatment for cannabis dependence.

             1. Primary Hypothesis: Six sessions of BRENDA therapy can be applied to the treatment
                of cannabis dependence.

             2. Secondary Hypothesis: Six-sessions of BRENDA therapy for cannabis dependence is an
                adequate "dose" of individual therapy for subjects motivated to stop smoking
                marijuana.

        4. To characterize the neurocognitive aspects (e.g. attention, working memory, impulsivity,
           decision making, risk-taking, affective bias/drug preference, reward and punishment
           sensitivity, affect regulation) of cannabis dependence, cannabis withdrawal and
           dronabinol effects by utilizing a battery of tasks, questionnaires and interviews.

             1. Primary Hypothesis: Poor performance on neurocognitive tasks and questionnaires
                will be correlated with duration and amount of cannabis use.

             2. Secondary Hypothesis: Cannabis withdrawal will be correlated with impaired
                performance on neurocognitive tasks and questionnaires. Dronabinol treatment will
                reduce this impairment on tasks of affect regulation and affective bias/drug
                preference compared to placebo.

        5. To objectively demonstrate cue-induced craving in cannabis dependent patients and to
           determine whether baseline measures of our cannabis patients' brain vulnerabilities (of
           structure, and of function; e.g., resting perfusion) can predict both brain and
           behavioral outcomes.

             1. Primary Hypothesis: Cue-induced craving will be positively correlated with changes
                in physiological measures and increased amygdalar activation and negatively
                correlated with prefrontal activation in cannabis dependent patients during
                cannabis discontinuation, and dronabinol treatment will reduce the intensity of
                cue- induced physiological changes and brain activation compared to placebo.

             2. Secondary Hypotheses: Measures of prefrontal cortex gray matter and resting
                perfusion in prefrontal cortex, cingulate cortex and amygdala will be positively
                correlated with performance on neurocognitive tasks and questionnaires as well as
                treatment outcome.

      3. Location: This is a single site study. All patient recruitment and data collection will
      occur at the Treatment Research Center at the University of Pennsylvania, 3900 Chestnut
      Street, Philadelphia, PA 19104, except for the Neuroimaging which will take place at the HUP6
      fMRI in the basement of the Hospital of the University of Pennsylvania, 34th and Spruce
      Streets, Philadelphia, PA 19104.

      STUDY DESIGN

      4. Research design & methodology: This is a Phase 2 double blind placebo controlled trial. We
      will recruit 60 cannabis dependent subjects and treat them with the combination of dronabinol
      10mg QID (four times per day) and BRENDA or placebo qid (four times per day) and BRENDA to
      reduce their consumption of cannabis. Subjects will be 60 men and women with current DSM-IV
      diagnosis of cannabis dependence. All patients will receive six sessions of BRENDA at visits
      1, 3, 6, 9, 11, and 12. The study length for each patient will be one week for screening and
      baseline self-report and neurocognitive battery measures. Patients who qualify will be
      offered an opportunity to participate in the fMRI portion of the study with baseline fMRI
      obtained in the first week prior to starting medications and second fMRI obtained during week
      two of medications. This is followed by 3 weeks of medication and, after completing
      medications, three additional weekly visits (two for BRENDA and one for final assessment).

      5. Duration: Each subject will participate in a 7 week treatment trial with the following
      schedule of visits: STUDY VISITS

      Week 1 (Baseline Measures):

      Week 2 - 4 (Medication Treatment):

      Weeks 5-6 (Medication Washout)

      Week 7 (Final Visit):

      We anticipate that we will require two years to complete data collection with 60 subjects and
      will require one year for data analysis. Thus, the proposed study will be completed in
      approximately three years.

      SUBJECT SELECTION & WITHDRAWAL
    

Intervention name(s): Dronabinol; BRENDA therapy; Placebo
Intervention type(s): Drug; Behavioral; Drug
Intervention description(s): 10mg capsules taken 4 times daily for 2 weeks and then tapered over 1 week; weekly therapy sessions for 6 weeks; 4 capsules daily for 2 weeks followed by a 1 week taper
Other intervention name(s): Marinol
Intervention MeSH terms: Dronabinol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Marijuana; Addiction; Substance Withdrawal Syndrome; Clinical Trial; Dronabinol; Behavioral Therapy; Adults; Neuroimaging; Neuropsychological Testing; Neurocognitive Testing; Behavioral Probes