Does cannabis use modulate brain glutamate levels in early psychotic illness?

Schizophrenia is a devastating psychotic disorder, accounting for over 1% of the worldwide burden of disability. Use of cannabis makes both developing and relapsing into psychotic illness more likely.

We do not quite know why this is. Psychosis is normally associated with abnormal levels of a brain chemical called dopamine. However cannabis does not appear to cause substantial changes in the dopamine system that fully explain this. Another explanation could be related to a brain chemical called glutamate. This study will therefore investigate brain glutamate in a group of patients with psychosis who use cannabis and compare them to patients who do not and another group of healthy volunteers. We will undertake a brain scan known as magnetic resonance spectroscopy for this. We will also compare groups to see if their brains function differently while they perform a memory task inside the scanner. This is because cannabis use is known to affect memory and the function of brain regions involved in memory.

This may guide us in future as to what type of treatments might work in patients with psychosis who continue to use cannabis. This is particularly important as the current treatments do not work well in this group.

Schizophrenia is a devastating disease with around 30-40% of patients using cannabis at presentation. Why cannabis-using patients have worse outcomes is unclear. Dysfunction of glutamatergic pathway may explain this, with demonstrable abnormalities detected on proton magnetic resonance spectroscopy (1H-MRS) in both psychotic patients and cannabis-users. However, no study to date has compared glutamatergic abnormalities in cannabis-using and non- using patients with psychosis. This is important as establishing an alternative biochemical abnormality in cannabis-using patients may suggest alternative pharmacological treatment for this group. Furthermore memory has consistently been noted to be impaired in both cannabis use and psychosis. Yet whether functioning of the critical neural substrate for memory, in particular the medial temporal cortex is altered in cannabis-using patients with psychosis compared to non-users, has never been tested.

This study will therefore examine whether differences exist in brain glutamatergic levels and verbal learning between cannabis-using and non-using patients with psychosis. I will study the following three cohorts: cannabis users (n=30); non-cannabis users (n=30); alongside healthy controls (n=20). Participants will be interviewed using SCID to confirm diagnoses, the Cannabis Experiences Questionnaire (CEQ), Severity of Dependence Scale (SDS), and other measures; and interviewed to ascertain duration of illness, history of relapse/ hospitalisation, dose and duration of antipsychotic and other psychotropic drug exposure and severity of psychopathology. Participants will be studied using a combination of 1H-MRS and functional MRI (fMRI). Region of Interest analysis will be undertaken in the left Hippocampus and left Anterior Cingulate Cortex, key regions implicated in psychotic illness.

This research looks to determine biological difference between two groups of patients with psychosis. Psychosis can be a highly debilitating condition and several groups will benefit from the results of this research in different ways:

(i) Scientists and Academic Researchers who will learn about how cannabis may affect the brain. They will also have to undertake further research to confirm the results and determine how to explain the changes. Finding these differences may help us determine targets to treat patients with psychotic illness who use cannabis and therefore this research may have longer term implications for patients.

(ii) Clinical staff such as psychiatrists, psychologists and those working across mental health teams who will be able to add this knowledge to the advice they give to their patients

(iii) Patients with schizophrenia and their carers. They may find out that cannabis is associated with changes in the brain between using and non-using patients. In the longer term this research could help inform us of possible treatment strategies.

(iv) The general public who may be able to make a more informed choice about the use of cannabis

(v) Policy Makers who will be in a more informed position to draw up preventative strategies for patients with psychotic illness.