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

Phase 1CompletedNCT01964404

Dartmouth-Hitchcock Medical Center263 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Brain Reward Circuit Activation on fMRI Scan

Activation of the Brain Reward Circuit (particularly the nucleus accumbens) in anticipation of monetary reward. The 'Measure' is a mean of the Fisher-Z transform of the inter-regional correlation measured for each participant between the nucleus accumbens and anterior cingulate cortex. The Fisher-transformation creates a normally distributed correlation value for statistical analyses assessing between group differences. A Fisher-Z transform of '0' represents a value of '0' for the estimated correlation, which represents no correlation in the activity time series between the regions. The values reflect strengths of functional connectivity between brain regions that can be compared between groups (e.g. Healthy controls and SCZ-CUD groups who received different study drugs). Means and standard deviations similar to healthy controls would be considered a good outcome.

Time frame: 3 hours

Resting State Connectivity Within the Brain Reward Circuitry

Resting state connectivity within brain reward circuitry as measured with the Fisher-transformed r value of the connectivity maps between the nucleus accumbans and other brain areas. The Fisher-transformation creates a normally distributed correlation value for statistical analyses assessing between group differences (smoked THC vs placebo; oral dronabinol vs placebo)

Time frame: 1 hour after smoking study drug, 3 hours after oral dronabinol

Secondary Outcomes

PANSS Positive Symptoms

Positive and Negative Symptom Scale (PANSS) Positive Symptom Mean Subscale Score at 2nd Assessment Day, range 7-49, higher = more symptoms. The outcome measure was recorded at single time of measurement. The time frame includes 3 hours after oral THC/placebo and 1 hour after smoked THC/placebo (the three-hour window is inclusive of the one-hour post smoke). Each individual smoked THC or placebo AND took oral THC or placebo.

Time frame: 3 hours after oral THC/placebo

PANSS Negative Symptoms

Positive and Negative Symptom Scale Negative Symptom Mean Subscale Score at 2nd Assessment Day, range 7-49, higher = more symptoms. The time frame includes 3 hours after oral THC/placebo and 1 hour after smoked THC/placebo (the three-hour window is inclusive of the one-hour post smoke). Each individual smoked THC or placebo AND took oral THC or placebo.

Time frame: 3 hours after oral THC/placebo

Cognitive Functioning, Verbal Learning

Cognitive functioning, verbal learning Hopkins Verbal Learning Test (HVLT-R) total raw score. Possible range of scores is 0-35, higher is better functioning. The time frame includes 4 hours after oral THC/placebo and 2 hour after smoked THC/placebo (the three-hour window is inclusive of the one-hour post smoke). Each individual smoked THC or placebo AND took oral THC or placebo.

Time frame: 4 hours after oral drug

Drug Experience, Anxiety

Drug experience ratings of mood and desirability, anxiety rating on a scale of 0-100, higher means more anxiety. The time frame includes 3 hours after oral THC/placebo and 1 hour after smoked THC/placebo (the three-hour window is inclusive of the one-hour post smoke). Each individual smoked THC or placebo AND took oral THC or placebo.

Time frame: 3 hours after taking oral drug

Drug Experience Ratings of Drug Liking

Drug experience ratings of liking rating on a scale of 0-100, higher number = more liking The time frame includes 3 hours after oral THC/placebo and 1 hour after smoked THC/placebo (the three-hour window is inclusive of the one-hour post smoke). Each individual smoked THC or placebo AND took oral THC or placebo.

Time frame: 3 hours after taking oral drug

Cognitive Function, CPT-IP 2 Digit

Cognitive function, CPT-IP 2 digit measure of Attention. The Continuous Performance Test-Identical Pairs version (CPT-IP)80 assessed attention with range of 1-5, hirer scores indicating better function The outcome measure was recorded at single time of measurement. The time frame includes 4 hours after oral THC/placebo and 2 hour after smoked THC/placebo (the three-hour window is inclusive of the one-hour post smoke). Each individual smoked THC or placebo AND took oral THC or placebo.