The neurocognitive and neurochemical effects of cannabidiol in psychosis

Student thesis: Doctoral ThesisDoctor of Philosophy


Traditionally, antipsychotic drugs have targeted the dopaminergic and glutamatergic neurotransmitter systems, with varying efficacy. While dopaminergic antipsychotics are effective at treating positive symptoms, they are less effective for negative symptoms and cognitive impairments, glutamatergic antipsychotics have had inconsistent results at the clinical trial level; and both have poor side effect profiles. Recently, interest has grown in the antipsychotic potential of cannabidiol (CBD), a non-intoxicating extract of cannabis. This has stemmed from cannabis research linking the endogenous cannabinoid (eCB) system to psychosis, with clinical studies of CBD showing relative success in patients with psychosis. Considered a multimodal drug, which may directly or indirectly affect multiple distinct modes of neural signalling (including the eCB system, and also the dopaminergic and glutamatergic systems); CBD displays none of the side-effects of traditional antipsychotics, has high tolerability, and may also display neuroprotective properties. However, what effect a challenge of the eCB system with acute CBD would have on the neurophysiological and neurochemical substrates implicated in psychosis is currently unknown. Therefore, the aims of the current thesis were to provide novel mechanistic insight into these neurophysiological and neurochemical processes potentially underlying the antipsychotic effects of CBD, in psychosis. To do this, I conducted four experiments within the same group of psychosis patients, employing functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H-MRS), with a CBD challenge. Patients were administered a single dose of oral CBD (600mg) compared to a matched placebo, on separate days, at least one week apart, using a double-blind, randomized, placebo-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug, participants were scanned using i) a block design fMRI paradigm, while performing a verbal paired associate learning task; ii) a resting-state 1H-MRS paradigm; and iii) a resting-state fMRI paradigm. 15 psychosis patients completed both study days. All patients were within 5 years of illness onset, and receiving standard antipsychotic treatment. 19 healthy controls were also scanned using the same task fMRI and 1H-MRS paradigms under identical conditions, and 14 separate healthy controls were scanned using the same resting-state fMRI paradigm under identical conditions. The healthy controls were not administered any drug. In the four experiments, I investigated the effects of a single dose of CBD in psychosis patients in relation to: i) brain function in regions implicated in psychosis during a verbal memory task; ii) the context-dependent functional connectivity between brain regions implicated in psychosis; iii) hippocampal glutamate, and the relationship between hippocampal glutamate and memory related functional activation; and iv) resting-state functional connectivity of the hippocampus, and of the three large-scale functional networks. In the first three experiments, CBD partially normalised abnormal memory related functional activation, functional connectivity, and the associations between hippocampal glutamate and memory related functional activation, in the psychosis patients. Acute CBD resulted in a non-significant increase in hippocampal glutamate in the psychosis patients, which was positively associated with task performance. Additionally, CBD resulted in trend-level reductions in symptoms, and in anandamide and palmitoylethanolamine (components of the eCB system), within the psychosis patients. These reductions did not correlate with any neurophysiological changes. No CBD related differences were observed in the resting-state fMRI experiment. Collectively, these findings provide novel insight into the neurophysiological and neurochemical mechanisms potentially underlying the antipsychotic effect of CBD in psychosis, and emphasise the importance of investigation of these effects with sustained treatment, and at different doses. Furthermore, these findings support a link between the potential antipsychotic effect of CBD and glutamatergic signalling pathways, which could have implications for psychosis patients who do not respond to traditional dopaminergic antipsychotic drugs.
Date of Award1 Apr 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorSagnik Bhattacharyya (Supervisor) & Andrea Mechelli (Supervisor)

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