Cannabis and Schizophrenia: Self-Medication and Agonist Treatment

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.

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.