Cannabis, Schizophrenia and Reward: Self-Medication and Agonist Treatment?

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2014 by Dartmouth-Hitchcock Medical Center
Sponsor:
Collaborators:
Columbia University
Harvard Medical School
Massachusetts Institute of Technology
Massachusetts General Hospital
Nathan Kline Institute for Psychiatric Research
University of Vermont
Information provided by (Responsible Party):
Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier:
NCT01964404
First received: October 15, 2013
Last updated: April 30, 2014
Last verified: April 2014
  Purpose

Substance use disorders are strikingly common in patients with schizophrenia and contribute to its morbidity and cost to society. We have proposed a neurobiological formulation suggesting that cannabis and other substance use in these patients may ameliorate a dysfunction in the brain reward circuit(thus serving a "self-medication" function), while also worsening the symptoms and course of schizophrenia.

In this translational research proposal, based on our formulation, we seek to confirm and expand upon data obtained in our pilot study suggesting that cannabis and the cannabinoid agonist dronabinol, given in low dose to patients with schizophrenia and co-occurring cannabis use disorder, will in fact ameliorate the brain reward circuit dysregulation in these patients and, thereby, provide evidence in support of the role of cannabis as a "self-medication" agent for them. Also, by also testing the full range of effects produced by dronabinol (effects on brain reward circuitry assessed with task-based function MRI and resting state connectivity), as well as on reward responsiveness, mood, craving, cognition, psychiatric and extrapyramidal symptoms), we will provide clues as to whether dronabinol should be tried in low doses as an adjunctive agent (with an antipsychotic medication) to limit cannabis use in patients with schizophrenia.

Substance use disorders are strikingly common in patients with schizophrenia and contribute to its morbidity and cost to society. We have proposed a neurobiological formulation suggesting that cannabis and other substance use in these patients may ameliorate a dysfunction in the brain reward circuit(thus serving a "self-medication" function), while also worsening the symptoms and course of schizophrenia.

In this translational research proposal, based on our formulation, we seek to confirm and expand upon our pilot data suggesting that cannabis and the cannabinoid agonist dronabinol, given in low dose to patients with schizophrenia and co-occurring cannabis use disorder, will in fact ameliorate the brain reward circuit dysregulation in these patients and, thereby, provide evidence in support of the role of cannabis as a "self-medication" agent for them. Also, by also testing the effects produced by dronabinol (effects on brain reward circuitry assessed with task-based function MRI and resting state connectivity), as well as on reward responsiveness, mood, craving, cognition, psychiatric and extrapyramidal symptoms), we will provide clues as to whether dronabinol should be tried in low doses as an adjunctive agent (with an antipsychotic medication) to limit cannabis use in patients with schizophrenia.

This study will involve 8 groups of 25 participants each. Groups 1-3 will have diagnoses of schizophrenia and cannabis use disorder; Group 4 will have schizophrenia only, Groups 5-7 will have cannabis use disorder only and Group 8 will be healthy control participants. Following screening and baseline neuropsychiatric testing, participants will have two tests days (T1 and T2) that will include task-based functional MRI, including assessment of resting state connectivity, and measuring a number of other parameters including reward responsiveness, mood, craving, symptoms and cognition. The assessments at T1 will be virtually the same for all groups. At T2 Groups 1-3, and Groups 5-7 will be randomly assigned to one of the following conditions prior to the assessments: receiving 15mg of dronabinol and smoking a placebo marijuana cigarette, receiving a placebo pill and smoking a real marijuana cigarette, or receiving a placebo pill and smoking a placebo marijuana cigarette. Group 4 and Group 8 will receive no drug or placebo at T2. Participants receiving drug will have safety assessments before the drug is administered, after the drug is administered but before leaving the research clinic for the day, and again a week later.


Condition Intervention Phase
Schizophrenia
Dual Diagnosis
Psychotic Disorder
Cannabis Use Disorder
Drug: Marijuana
Drug: Dronabinol
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Cannabis, Schizophrenia and Reward: Self-Medication and Agonist Treatment?

Resource links provided by NLM:


Further study details as provided by Dartmouth-Hitchcock Medical Center:

Primary Outcome Measures:
  • Brain Reward Circuit Activation [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
    Activation of the Brain Reward Circuit (particularly the nucleus accumbens) in anticipation of monetary reward.


Secondary Outcome Measures:
  • Resting State Connectivity [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
    Resting state connectivity within the brain reward circuit


Estimated Enrollment: 240
Study Start Date: June 2014
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Marijuana cigarette and placebo capsule
3-5% tetrahydrocannabinol cannabis cigarette smoked immediately prior to the second functional MRI and a placebo capsule (for dronabinol) by mouth taken approximately 2.75 hours prior to the second functional MRI.
Drug: Marijuana
Other Name: Cannabis
Experimental: Dronabinol and placebo cigarette
Dronabinol 15mg 3-5% by mouth taken approximately 2.75 hours prior to the second functional MRI and a placebo cigarette (for marijuana) smoked immediately prior to the second functional MRI.
Drug: Dronabinol
Other Name: Marinol
Placebo Comparator: Placebo cigarette and placebo capsule
Placebo cigarette (for marijuana) smoked immediately prior to the second functional MRI and a placebo capsule (for dronabinol) by mouth taken approximately 2.75 hours prior to the second functional MRI.
Drug: Placebo

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Groups 1-3 Participants with schizophrenia and a cannabis use disorder

  1. Ages 18 - 50 years
  2. Diagnosis of schizophrenia
  3. Diagnosis of cannabis abuse or dependence
  4. Use of cannabis within the month prior to screening
  5. Willing to remain abstinent for the 14 days before the baseline assessments and throughout the two scans.
  6. Psychiatrically stable
  7. Treated with a stable dose of an antipsychotic medication (except clozapine) for the past month
  8. Not seeking treatment for their cannabis use disorder.

Group 4 - Control participants with schizophrenia

  1. Ages 18 - 50 years
  2. Diagnosis of schizophrenia
  3. Willing to remain abstinent as described above
  4. Psychiatrically stable
  5. Treated with a stable dose of an antipsychotic medication (except clozapine) for the past month

Groups 5-7 - Control participants with cannabis use disorder

  1. Ages 18 - 50 years
  2. Diagnosis of cannabis abuse or dependence
  3. Use of cannabis within the month prior to screening
  4. Willing to remain abstinent as described above
  5. Not seeking treatment for their cannabis use disorder.

Group 8 - Healthy control participants

  1. Ages 18 - 50 years
  2. Willing to remain abstinent as described above

Exclusion criteria:

Groups 1-3 with schizophrenia and a cannabis use disorder

  1. Positive symptoms of psychosis (> 4 [moderate]) on any item of the Positive and Negative Syndrome Scale psychosis subscale (once abstinent)
  2. Cocaine/stimulant use disorder
  3. Pharmacological treatment for addiction
  4. Mental retardation
  5. History of head injury
  6. Metal objects within the body that would contraindicate and MRI
  7. Pregnancy or currently nursing
  8. Uncontrolled medical condition
  9. Taking clozapine
  10. Any condition that would contraindicate use of cannabis or dronabinol.
  11. History of a seizure disorder

Group 4 - Control participants with schizophrenia

  1. Positive symptoms of psychosis (> 4 [moderate]) on any item of the Positive and Negative Syndrome Scale psychosis subscale (once abstinent)
  2. Any history of a substance use disorder other than nicotine
  3. Pharmacological treatment for addiction
  4. Mental retardation
  5. History of head injury
  6. Metal objects within the body that would contraindicate and MRI
  7. Pregnancy or currently nursing
  8. Uncontrolled medical condition
  9. Taking clozapine

Groups 5-7 - Control participants with cannabis use disorder

  1. Axis I psychiatric diagnosis other than a cannabis use disorder
  2. Taking any psychotropic medication
  3. Pharmacological treatment for addiction
  4. Mental retardation
  5. History of head injury
  6. Metal objects within the body that would contraindicate and MRI
  7. Pregnancy or currently nursing
  8. Uncontrolled medical condition
  9. History of a seizure disorder

Group 8 - Healthy control participants

  1. Any Axis I psychiatric diagnosis
  2. Taking any psychotropic medication
  3. Pharmacological treatment for addiction
  4. Mental retardation
  5. History of head injury
  6. Metal objects within the body that would contraindicate and MRI
  7. Pregnancy or currently nursing
  8. Uncontrolled medical condition
  9. Current tobacco smokers
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01964404

Contacts
Contact: Christopher OKeefe, MA 603-271-5287 christopher.okeefe@dartmouth.edu

Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Columbia University
Harvard Medical School
Massachusetts Institute of Technology
Massachusetts General Hospital
Nathan Kline Institute for Psychiatric Research
University of Vermont
Investigators
Principal Investigator: Alan I Green, MD Geisel School of Medicine at Dartmouth
  More Information

No publications provided

Responsible Party: Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT01964404     History of Changes
Other Study ID Numbers: 1R01DA034699-01A1
Study First Received: October 15, 2013
Last Updated: April 30, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dartmouth-Hitchcock Medical Center:
Dronabinol
Schizophrenia
Dual Diagnosis
Substance Abuse
Cannabis Use Disorder

Additional relevant MeSH terms:
Marijuana Abuse
Psychotic Disorders
Mental Disorders
Schizophrenia
Substance-Related Disorders
Chemically-Induced Disorders
Schizophrenia and Disorders with Psychotic Features
Dronabinol
Hallucinogens
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Cannabinoid Receptor Agonists
Cannabinoid Receptor Modulators
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 14, 2014