Imaging the neurocognitive and neurochemical effects of cannabinoids on the human brain

Student thesis: Doctoral ThesisDoctor of Philosophy


There is longstanding evidence that cannabis use represents an environmental risk factor for psychosis and may impair cognitive functioning. The detrimental effects of cannabis use appear to be mainly driven by its key psychoactive ingredient delta-9-tetrahydrocannabinol (Δ9-THC). Also, individuals may respond differently to Δ9-THC as a function of their previous exposure to cannabis, possibly due to the development of tolerance. The use of Δ9-THC as a drug model for psychosis is well documented in the literature and experimental investigations employing Δ9-THC challenge have proven to be effective in investigating the neural underpinnings of emerging psychotomimetic and anxiety symptoms. In this thesis I aimed to contribute to a better understanding of the neurobiological mechanisms underlying the association between cannabis use and psychosis, by employing pharmacological magnetic resonance imaging (phMRI) with oral or intravenous Δ9-THC challenge to assess changes in neurophysiology (functional MRI, fMRI) and neurochemistry (proton magnetic resonance spectroscopy, 1H-MRS). Two independent samples of healthy individuals differing in the extent of their previous cannabis exposure and abstinent from cannabis for at least 3 months underwent 2 testing sessions with at least 2-week inter-scan interval employing a double-blind, placebo-controlled, within-subjects design. In the first study sample (N=36), I investigated the effects of previous cannabis exposure, acute Δ9-THC administration, and their interaction on brain activity and related behavior while performing different cognitive tasks, including verbal memory, response inhibition, attentional salience, and emotional processing. In the second study sample (N=16), I investigated the effect of acute Δ9-THC administration on psychotomimetic symptom manifestation as well as glutamate levels in the striatum, hippocampus, and anterior cingulate, and their association. Acute administration of Δ9-THC induced anxiety and psychotomimetic symptoms, the latter being more pronounced in individuals who had never used cannabis. Similarly, Δ9-THC challenge induced neurophysiological dysfunction and associated poorer cognitive functioning that were more marked in non-users. Indeed, among the non-users those experiencing the most severe psychotomimetic symptoms and cognitive impairments had the greatest neurophysiological dysfunction under the effect of Δ9-THC. Also, Δ9-THC challenge appeared to transiently reverse some of the neurocognitive impairments observed in cannabis users. Results from this thesis support an effect of acute Δ9-THC administration on glutamate signaling, specifically an increase in the total glutamatergic pool available for synaptic/ metabolic activity in the form of glutamate or glutamine in the striatum. As exploratory analyses revealed no effect of Δ9-THC on glutamate signaling neither in the anterior cingulate nor in the hippocampus, this disruptive effect of Δ9-THC on striatal glutamate levels appeared to be region-specific. Also, the Δ9-THC-induced increase in striatal glutamate seemed to modulate the manifestation of psychotomimetic symptoms, such that the Δ9-THC-induced Glutamate + Glutamine increase was more marked in those experiencing psychotomimetic symptoms following the acute challenge. Moreover, those exposed to cannabis the most often had the highest increase in glutamate-derived metabolites under the effect of Δ9-THC. These findings suggest that cannabis use may induce psychosis-like symptoms by disrupting glutamate signaling in the striatum. Also, they indicate that cannabis use may affect brain function in order to induce acute neurocognitive effects. Further studies are needed to track longitudinally the long-term changes in striatal glutamate and brain function in the context of cannabis use as pathophysiological mechanisms that may underlie the development of psychosis and cognitive impairments.
Date of Award1 Nov 2018
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorSagnik Bhattacharyya (Supervisor) & Philip McGuire (Supervisor)

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