Cannabis and Schizophrenia: Self-Medication and Agonist Treatment

• Sponsor: Dartmouth-Hitchcock Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00946348
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH), Indiana University (Other), Columbia University (Other), University of Vermont (Other), University of Massachusetts, Worcester (Other)
• Enrollment: 12
• Location: 1
• Arms: 2
• Duration (Months): 34
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

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

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Cannabis and Schizophrenia: Self-Medication and Agonist Treatment
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dronabinol Dronabinol 10mg or 15 mg	Drug: Dronabinol; Dronabinol 10 mg or 15 mg; Other Names: Marinol
Active Comparator: Cannabis Cannabis cigarette	Drug: Cannabis; Cannabis cigarette; Other Names: Marijuana

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts 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

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

Locations

	Site	City	State	Country	Postal Code
1	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756

Sponsors and Collaborators

• Dartmouth-Hitchcock Medical Center
• National Institute on Drug Abuse (NIDA)
• Indiana University
• Columbia University
• University of Vermont
• University of Massachusetts, Worcester

Investigators

• Principal Investigator: Alan I Green, MD, Dartmouth-Hitchcock Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT00946348
• Other Study ID Numbers: R01DA013196; 1R01DA026799-01; R01DA013196; R01DA026799-01; DPMC
• First Posted: Jul 27, 2009
• Last Update Posted: Jul 12, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by 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

Participant Flow

Recruitment Details	Recruitment was conducted through Dartmouth Hitchcock Medical Center, and local community mental health centers.
Pre-assignment Detail	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.

Arm/Group Title	Dronabinol	Cannabis
Arm/Group Description	Dronabinol 15 mg	Cannabis cigarette (3.6% THC)
Period Title: Overall Study
STARTED	6	6
COMPLETED	6	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Dronabinol	Cannabis	Total
Arm/Group Description	Dronabinol 15 mg	Cannabis cigarette (3.6% THC)	Total of all reporting groups
Overall Participants	6	6	12
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	6 100%	12 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.17 (8.32)	36.2 (9.6)	34.2 (10.6)
Sex: Female, Male (Count of Participants)
Female	2 33.3%	1 16.7%	3 25%
Male	4 66.7%	5 83.3%	9 75%
Region of Enrollment (participants) [Number]
United States	6 100%	6 100%	12 100%

Outcome Measures

1. Primary Outcome

Title	fMRI Connectivity of Regions of Interest (ROI) Within the Brain Reward Circuitry (BRC).
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dronabinol	Cannabis
Arm/Group Description	Dronabinol 15 mg	Cannabis cigarette (3.6% THC)
Measure Participants	6	6
Mean (Standard Deviation) [Z score]	.40 (.85)	.33 (.38)

2. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were recorded from the date of consent through the final telephone contact with the patient after the second scan. Though the time differed based on scheduling of patients, it was typically 4-5 weeks.
Arm/Group Title	Dronabinol		Cannabis
Arm/Group Description	Dronabinol 15 mg		Cannabis cigarette (3.6% THC)
All Cause Mortality
	Dronabinol		Cannabis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Dronabinol		Cannabis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Dronabinol		Cannabis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		3/6 (50%)
Gastrointestinal disorders
Less Appetite	1/6 (16.7%)	1	0/6 (0%)	0
Psychiatric disorders
Cannabis Withdrawal	2/6 (33.3%)	5	3/6 (50%)	11
Anxiety	1/6 (16.7%)	1	1/6 (16.7%)	1
Increased Psychiatric Symptoms	0/6 (0%)	0	1/6 (16.7%)	1
Decreased Sleep	1/6 (16.7%)	1	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.