Cannabis and Schizophrenia: Self-Medication and Agonist Treatment
Condition: Schizophrenia; Dual Diagnosis; Schizoaffective Disorder; Psychotic Disorder; Cannabis Use Disorder
MeSH terms: Marijuana Abuse; Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Dronabinol; Cannabis
Intervention type(s): Drug; Drug
Intervention description(s): Dronabinol 10 mg or 15 mg; Cannabis cigarette
Other intervention name(s): Marinol; Marijuana
Intervention MeSH terms: Dronabinol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Dronabinol; Schizophrenia; Dual Diagnosis; Substance Abuse; Cannabis Use Disorder