Cannabis and Schizophrenia: Self-Medication and Agonist Treatment

This study has been completed.
Sponsor:
Collaborators:
Indiana University
Columbia University
University of Vermont
University of Massachusetts, Worcester
Information provided by (Responsible Party):
Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier:
NCT00946348
First received: July 24, 2009
Last updated: April 25, 2013
Last verified: April 2013
  Purpose

The first aim of this study is to determine whether a brain reward center (BRC) deficiency in patients with schizophrenia (SCZ) and cannabis use disorder (CUD) will be normalized when patients are given cannabis or dronabinol. The second aim will serve to further assess the effects of dronabinol on symptoms and medication side effects in this population.


Condition Intervention Phase
Schizophrenia
Dual Diagnosis
Schizoaffective Disorder
Psychotic Disorder
Cannabis Use Disorder
Drug: Dronabinol
Drug: Cannabis
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 and Schizophrenia: Self-Medication and Agonist Treatment

Resource links provided by NLM:


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

Primary Outcome Measures:
  • fMRI activation of regions of interest (ROI) within the brain reward circuitry (BRC). [ Time Frame: 1 hour ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To assess the effects of dronabinol in this population to determine whether measures of craving, mood and negative symptoms will improve using the PANSS; and to determine whether measures of psychotic symptoms and cognitive deficits will increase. [ Time Frame: Over 8 hours ] [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: December 2009
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dronabinol
Dronabinol 10mg or 15 mg
Drug: Dronabinol
Dronabinol 10 mg or 15 mg
Other Name: Marinol
Active Comparator: Cannabis
Cannabis cigarette
Drug: Cannabis
Cannabis cigarette
Other Name: Marijuana

Detailed Description:

Cannabis use disorder (CUD) is up to ten times more common in schizophrenia (SCZ) than in the general population, and substantially worsens the course of this severe psychiatric disorder. Since SCZ occurs in 1% of the population, the comorbidity of CUD in 13% to 42% of people with this disorder presents society with an important public health problem. At present, treatments available for these "dual diagnosis" patients are inadequate. New treatments to limit cannabis use in patients with schizophrenia are sorely needed.

While the basis of substance use in patients with SCZ is not clear, some have suggested that use of substances may "self-medicate" negative symptoms or the side effects they experience from antipsychotic treatment. We have proposed an alternative formulation of this "self-medication hypothesis" -- a neurobiological formulation suggesting that a dysregulated mesocorticolimbic "brain reward circuit" (BRC) in patients with SCZ underpins their substance use, and that cannabis or other substance use ameliorates this dysregulated circuitry.

Our formulation is based on literature suggesting that the reinforcing effects of substances of abuse, including cannabis, may be related to their stimulation of dopamine (DA) neurons in the prefrontal cortex (PFC) and the mesolimbic system, key components of the BRC. Thus, according to this formulation, cannabis use "medicates" the dysregulated brain reward circuitry in patients with SCZ and allows them to have more normal responses to naturally rewarding events. Using a monetary probe linked to fMRI, we have demonstrated that patients with SCZ and co-occurring CUD (in agreement with preliminary studies from other investigators of non substance abusing patients) do indeed have a deficit within their BRC (reduced activation of the nucleus accumbens) as compared to normal subjects. This proposal will allow us to directly test the effects of cannabis on the BRC in patients with SCZ and CUD and thus to confirm our hypothesis regarding its effects in these patients. In addition, the proposal seeks to assess whether the cannabinoid agonist dronabinol, when given to patients with SCZ and CUD, will also ameliorate this BRC deficit, and, thus, whether dronabinol could be considered as a potential adjunctive treatment (given with an antipsychotic medication) to decrease their cannabis use.

The study will consist of two phases - a Pilot Study and the Main Study. The Pilot Study, completed in 10 "dual diagnosis" patients prior to the initiation of the Main Study, will establish the dose of oral dronabinol and the THC concentration of the cannabis cigarette to be used in the subsequent Main Study. The Main Study will involve 3 groups of subjects: two groups of dual diagnosis patients (with SCZ and co-occurring CUD), randomly assigned to one of the groups, and a group of healthy control patients. All subjects will be studied at baseline (T1) and 4 days later (T2) with a monetary probe linked to fMRI to evaluate their brain reward circuitry. At T1 all subjects will be tested without any intervention. At T2, patients in Groups 1 and 2 will receive both a dronabinol (or placebo) pill and a cannabis (or placebo cannabis) cigarette in a blinded fashion before testing. Group 1 patients will receive an active cannabis cigarette and a placebo pill; Group 2 patients will receive an active dronabinol pill and a placebo cannabis cigarette. Multiple measures will be taken to insure the safety of these patients during the use of cannabis and dronabinol. Group 3 (healthy controls) will not receive pill or cannabis cigarette and will serve as a control for repeated testing. Analyses will assess whether baseline BRC activation is different between patients and the control group, and whether use of cannabis and of dronabinol at T2 normalizes activation of BRC relative to T1 and relative to controls at T2.

  Eligibility

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

Inclusion Criteria:

Inclusion criteria for study subjects (dual diagnosis patients):

  • Age 18-50;
  • Diagnosis of schizophrenia or schizoaffective disorder (by SCID)
  • Diagnosis of current cannabis abuse or dependence (by SCID);
  • Recent use of cannabis (within the past month on Timeline Follow-Back);
  • Stability on antipsychotic medication for past 1 month);
  • Outpatient status for past 3 months;
  • Willing and able to participate as demonstrated by a signed informed consent document.

Inclusion criteria for normal control subjects:

  • Age 18-50;
  • Willing to participate as demonstrated by a signed informed consent document

Exclusion Criteria:

Exclusion criteria for study subjects (dual diagnosis patients):

  • PANSS subscale for positive symptoms of psychosis item > 3 [moderate] on Day 15 (once they are abstinent from cannabis);
  • Cocaine/stimulant use disorder;
  • Pharmacological treatment for addiction (e.g., disulfiram, naltrexone, acamprosate, topiramate); Mental retardation;
  • Pregnancy or currently nursing;
  • Uncontrolled serious medical condition;
  • Seizure disorder
  • Seeking treatment to limit their cannabis use
  • Taking clozapine

Additional Exclusion criteria for Main Study patients only:

  • Claustrophobia prohibiting scanning
  • History of head injury with period of unconsciousness;
  • Metal objects within the body;
  • Taking antipsychotic other than risperidone or first generation antipsychotic as main treatment
  • Previous participation in the Pilot Dose Finding Study

Exclusion criteria for normal control subjects:

  • Axis I or Axis II psychiatric diagnosis (including substance use disorder) based on SCID
  • Mental retardation;
  • History of head injury with period of unconsciousness;
  • Metal objects within the body;
  • Pregnancy or currently nursing;
  • Uncontrolled serious medical condition;
  • Current tobacco smokers. Note: We exclude current tobacco smoking (but not a history of smoking) in the normal control subjects since the fact of cigarette smoking could select subjects with a dysregulated BRC as a basis for their continued cigarette smoking in the face of social conventions toward non-smoking.
  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: NCT00946348

Locations
United States, New Hampshire
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Indiana University
Columbia University
University of Vermont
University of Massachusetts, Worcester
Investigators
Principal Investigator: Alan I Green, MD Dartmouth-Hitchcock Medical Center
  More Information

No publications provided

Responsible Party: Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT00946348     History of Changes
Other Study ID Numbers: R01 DA013196, 1R01DA026799-01, R01DA013196, R01DA026799-01, DPMC
Study First Received: July 24, 2009
Last Updated: April 25, 2013
Health Authority: United States: Federal Government

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
Schizophrenia and Disorders with Psychotic Features
Tetrahydrocannabinol
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

ClinicalTrials.gov processed this record on July 22, 2014