Neurocognitive and genetic basis of the effects of cannabis
Lead Research Organisation:
King's College London
Department Name: Institute of Psychiatry
Abstract
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Technical Summary
BACKGROUND: Although multiple lines of evidence suggest a link between cannabis use and psychotic symptoms, there is a marked variability in the effects of the drug across individuals, and most people who use cannabis do not develop schizophrenia. This variability in the effects of cannabis may reflect differences in genetic factors, particulary in genotypes that confer vulnerability to schizophrenia.
OBJECTIVES: I will investigate this by studying three groups of individuals who vary in their vulnerability to develop psychosis. I will examine the effect of the experimental adminstration of tetrahydrocannabinol (THC; the main active ingredient of cannabis) on their mental state, cognitive function and brain activation.
DESIGN & METHODOLOGY: Subjects: 35 first-degree relatives of patients with schizophrenia, 35 healthy volunteers with high levels of schizotypal features and 35 healthy volunteers with no family history of schizophrenia and low levels of schizotypal features. All subjects will have used cannabis at least once but less than 25 times in their lifetime. They will be given a small safe oral dose of either THC or placebo on 2 separate occasions. The symptomatic effects will be assessed using psychopathological rating scales, and subjects will perform 5 cognitive tasks that engage processes implicated in psychosis and are known to be affected by cannabis use. In a subset of each group 3 of the cognitive tasks will be performed while the subjects are undergoing functional MRI. All subjects will be genotyped for the main genes implicated in schizophrenia (Dysbindin, DISC-I, Neuregulin 1, G72, COMT and D-AminoAcid Oxidase). Pilot work has established the feasibility, power and safety of the methods. At the doses used, when THC does have psychological effects these are relatively mild and do not lasted more than a few hours. As further precautions, only subjects who have used cannabis before with no adverse effects can participate, and the relatives will be beyond the age of risk for schizophrenia. Hypothesis: The effects of THC on symptoms, cognitive performance and brain activation will depend on the individual‘s genetic vulnerability to schizophrenia.
SCIENTIFIC & MEDICAL OPPORTUNITIES: This study should clarify how cannabis acts on the brain to produce its effects, and establish if the variability in the sensitivity to its effects is genetically determined.
OBJECTIVES: I will investigate this by studying three groups of individuals who vary in their vulnerability to develop psychosis. I will examine the effect of the experimental adminstration of tetrahydrocannabinol (THC; the main active ingredient of cannabis) on their mental state, cognitive function and brain activation.
DESIGN & METHODOLOGY: Subjects: 35 first-degree relatives of patients with schizophrenia, 35 healthy volunteers with high levels of schizotypal features and 35 healthy volunteers with no family history of schizophrenia and low levels of schizotypal features. All subjects will have used cannabis at least once but less than 25 times in their lifetime. They will be given a small safe oral dose of either THC or placebo on 2 separate occasions. The symptomatic effects will be assessed using psychopathological rating scales, and subjects will perform 5 cognitive tasks that engage processes implicated in psychosis and are known to be affected by cannabis use. In a subset of each group 3 of the cognitive tasks will be performed while the subjects are undergoing functional MRI. All subjects will be genotyped for the main genes implicated in schizophrenia (Dysbindin, DISC-I, Neuregulin 1, G72, COMT and D-AminoAcid Oxidase). Pilot work has established the feasibility, power and safety of the methods. At the doses used, when THC does have psychological effects these are relatively mild and do not lasted more than a few hours. As further precautions, only subjects who have used cannabis before with no adverse effects can participate, and the relatives will be beyond the age of risk for schizophrenia. Hypothesis: The effects of THC on symptoms, cognitive performance and brain activation will depend on the individual‘s genetic vulnerability to schizophrenia.
SCIENTIFIC & MEDICAL OPPORTUNITIES: This study should clarify how cannabis acts on the brain to produce its effects, and establish if the variability in the sensitivity to its effects is genetically determined.
