Cannabis Use Disorder, Dual Diagnosis, Psychotic Disorder, Schizoaffective Disorder, Schizophrenia
Conditions
Keywords
Dronabinol, Schizophrenia, Dual Diagnosis, Substance Abuse, Cannabis Use Disorder
Brief summary
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.
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.
Interventions
DRUGDronabinol
Dronabinol 10 mg or 15 mg
DRUGCannabis
Cannabis cigarette
Sponsors
National Institute on Drug Abuse (NIDA)
Indiana University
Columbia University
University of Vermont
University of Massachusetts, Worcester
Dartmouth-Hitchcock Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| fMRI Connectivity of Regions of Interest (ROI) Within the Brain Reward Circuitry (BRC). | Measures were acquired at peak THC level for each of the two drugs up to 4 hours. | Average Z scores for the region-of-interest functional connectivity at the second scan (when subjects received either a cannabis cigarette or 15mg of dronabinol) between the bilateral nucleus accumbens (NAc) and ventral anterior cingulate cortex (vACC) for patients with schizophrenia and co-occurring cannabis use disorder. |
Secondary
| Measure | Time frame |
|---|---|
| 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. | Over 8 hours |
Countries
United States
Participant flow
Recruitment details
Recruitment was conducted through Dartmouth Hitchcock Medical Center, and local community mental health centers.
Pre-assignment details
Of the 52 people who consented to participate in the study, 12 met eligibility criteria for the main study and were randomized. Because persons who met entry criteria received study treatment on only one day, all randomized participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Dronabinol Dronabinol 15 mg | 6 |
| Cannabis Cannabis cigarette (3.6% THC) | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Cannabis | Dronabinol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Continuous | 36.2 years STANDARD_DEVIATION 9.6 | 32.17 years STANDARD_DEVIATION 8.32 | 34.2 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 6 | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
fMRI Connectivity of Regions of Interest (ROI) Within the Brain Reward Circuitry (BRC).
Average Z scores for the region-of-interest functional connectivity at the second scan (when subjects received either a cannabis cigarette or 15mg of dronabinol) between the bilateral nucleus accumbens (NAc) and ventral anterior cingulate cortex (vACC) for patients with schizophrenia and co-occurring cannabis use disorder.
Time frame: Measures were acquired at peak THC level for each of the two drugs up to 4 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dronabinol | fMRI Connectivity of Regions of Interest (ROI) Within the Brain Reward Circuitry (BRC). | .40 Z score | Standard Deviation 0.85 |
| Cannabis | fMRI Connectivity of Regions of Interest (ROI) Within the Brain Reward Circuitry (BRC). | .33 Z score | Standard Deviation 0.38 |
Secondary
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