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

• Sponsor: Dartmouth-Hitchcock Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01964404
• Collaborator: Columbia University (Other), Harvard Medical School (HMS and HSDM) (Other), Massachusetts Institute of Technology (Other), Massachusetts General Hospital (Other), Nathan Kline Institute for Psychiatric Research (Other), University of Vermont (Other), National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 261
• Locations: 2
• Arms: 3
• Duration (Months): 86.6
• Patients Per Site: 130.5
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Dual Diagnosis; Psychotic Disorder; Cannabis Use Disorder	Drug: Marijuana; Drug: Dronabinol; Drug: Placebo	Phase 1

Detailed Description

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.

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 261 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Cannabis, Schizophrenia and Reward: Self-Medication and Agonist Treatment?
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Sep 18, 2021
• Actual Study Completion Date: Sep 18, 2021

Arms and Interventions

Arm	Intervention/Treatment
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; Smoked plant with THC; Other Names: 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; Capsule with THC; Other Names: 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; Capsule with no active ingredient

Outcome Measures

Primary Outcome Measures

1. Brain Reward Circuit Activation [3 hours]

   Activation of the Brain Reward Circuit (particularly the nucleus accumbens) in anticipation of monetary reward.

Secondary Outcome Measures

1. Resting State Connectivity [3 hours]

   Resting state connectivity within the brain reward circuit

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

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

1. Ages 18 - 55 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 - 55 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 - 55 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 - 55 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) except for the hallucination item. We will exclude for a rating > 5 for this item.

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) except for the hallucination item. We will exclude for a rating > 5 for this item.

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

Locations

	Site	City	State	Country	Postal Code
1	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
2	University of Vermont	Burlington	Vermont	United States	05401

Sponsors and Collaborators

• Dartmouth-Hitchcock Medical Center
• Columbia University
• Harvard Medical School (HMS and HSDM)
• Massachusetts Institute of Technology
• Massachusetts General Hospital
• Nathan Kline Institute for Psychiatric Research
• University of Vermont
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Mary F Brunette, MD, Dartmouth College

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mary F. Brunette, MD, Principal Investigator, Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT01964404
• Other Study ID Numbers: D14061; 1R01DA034699-01A1
• First Posted: Oct 17, 2013
• Last Update Posted: Oct 13, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mary F. Brunette, MD, Principal Investigator, Dartmouth-Hitchcock Medical Center: Dronabinol; Schizophrenia; Dual Diagnosis; Substance Abuse; Cannabis Use Disorder
• Additional relevant MeSH terms: Disease; Marijuana Abuse; Schizophrenia; Mental Disorders; Psychotic Disorders; Dronabinol

Study Results

No Results Posted as of Oct 13, 2021