The Pharmaco-genetic and Brain Mechanisms Associated With Cannabis- Induced Psychosis

Study Overview
=================
Brief Summary
-----------------
There is growing evidence of high rates of substance use disorders among individuals with psychotic disorders especially in young people with predisposition for psychosis. There is some genetic evidence that carriers of the valine158 allele of the catechol-O-methyltransferase (COMT) gene had increased risk to exhibit psychotic symptoms and to develop schizophrenia if they used cannabis by the age of 18. It was also shown that carriers of the COMT val/val genotype were most sensitive to THC-induced psychotic experiences but this was conditional on pre-existing susceptibility to psychosis. The investigators propose to use brain-imaging and molecular genetics to investigate whether genetic factors may contribute to the THC-induced dopamine release and possibly to cannabis- induced psychosis.

Detailed Description
-----------------
Genetic association study will be performed in 100 young cannabis users (age 18-26 years) for genes that are related to the neurotransmitters dopamine (D2, DAT, COMT), GABA, glutamate and the cannabinoid receptor CB1. Out of this cohort, 24 male subjects without history of cannabis or drug-induced psychosis will undergo brain imaging procedure in order to measure THC-induced dopamine release using [11C] Raclopride in PET imaging. Carriers of high activity COMT158Val allele are expected to show higher meso-limbic DA release than carriers of low activity COMT 158Met homozygotes and after smoking a cigarette with THC which in turn are thought to underlie the risk for THC-induced psychotic symptoms. The aim of the present study is to evaluate the relationship between the COMT genotype and cannabis-induced meso-limbic dopamine release as measured by D2 occupancy. In addition, the association between predisposition to psychosis, age of onset of cannabis dependence, and genotype of COMT and other neurotransmitters-related genes will be evaluated. Such finding could provide novel pharmaco-genetic explanation for the psychogenic effects of cannabis in vulnerable individuals.

Official Title
-----------------
The Pharmaco-genetic and Brain Mechanisms Associated With Cannabis- Induced Psychosis

Conditions
-----------------
Cannabis Dependence, Psychosis

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age 18-26 meeting DSM-IV-TR (American Psychiatric Association, 1994) diagnosis of THC dependence will be recruited from the general population by advertisement in the newspapers. Exclusion Criteria: dependence on other substances or alcoholism a history of CNS disease a history of infection that might affect CNS (HIV, syphilis, cytomegalovirus, herpes) a history of head injury with loss of consciousness and pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 26 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| High activity COMT<br>Carriers of high activity COMT158Val allele who are expected to show higher THC-induced meso-limbic DA release | |
| Low activity COMT<br>Carriers of low activity COMT 158Met homozygotes are expected to release low amount of dopamine after smoking a cigarette with THC | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genetic variations of Dopamine, GABA, glutamate, cannabis CB1 receptor | DNA will be extracted from saliva of participants. Genetic variations of DA, GABA, glutamate and cannabis receptor CB1 will be coded. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measures of dopamine D2 receptor occupancy before and after smoking a cigarette containing THC. | Participants will be studied in a brain imaging study using [C 11] raclopride radioligand in Positron Emission Tomography (PET). Measures of D2 receptor occupancy will be taken at baseline and after smoking a cigarette containing 15 mg THC. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cannabis, THC, COMT, psychosis, D2