Role of the endocannabinoid system in brain functions relevant for schizophrenia: An overview of human challenge studies with cannabis or Δ9-tetrahydrocannabinol (THC) Matthijs G. Bossong a, ⁎, J. Martijn Jansma b , Sagnik Bhattacharyya a , Nick F. Ramsey b a Institute of Psychiatry, Department of Psychosis Studies, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom b Rudolf Magnus Institute of Neuroscience, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands abstract article info Article history: Received 16 June 2013 Received in revised form 16 October 2013 Accepted 25 November 2013 Available online xxxx Keywords: Δ9-Tetrahydrocannabinol (THC) Cannabis Cognition Endocannabinoid system Neuroimaging Schizophrenia Accumulating evidence suggests involvement of the endocannabinoid system in the pathophysiology of schizo- phrenia, which signifies a potential application for this system in the treatment of this disorder. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of schizophrenia. Here we review human studies that investigated acute effects of cannabis or Δ9-tetrahydrocannabinol (THC) on brain functions that are implicated in schizophrenia. Results suggest that the impact of THC administration depends on the difficulty of the task per- formed. Impaired performance of cognitive paradigms is reported on more challenging tasks, which is associated with both activity deficits in temporal and prefrontal areas and a failure to deactivate regions of the default mode network. Comparable reductions in prefrontal activity and impairments in deactivation of the default mode net- work are seen in patients during performance of cognitive paradigms. Normal performance levels after THC ad- ministration demonstrated for less demanding tasks are shown to be related to either increased neural effort in task-specific regions (‘neurophysiological inefficiency’), or recruitment of alternative brain areas, which suggests a change in strategy to meet cognitive demands. Particularly a pattern of performance and brain activity corre- sponding with an inefficient working memory system is consistently demonstrated in patients. These similarities in brain function between intoxicated healthy volunteers and schizophrenia patients provide an argument for a role of the endocannabinoid system in symptoms of schizophrenia, and further emphasize this system as a poten- tial novel target for treatment of these symptoms. © 2013 Published by Elsevier Inc. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2. Striatal dopamine function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1. Striatal dopamine function and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.2. Neuroimaging studies on acute effects of THC on striatal dopamine function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3. Encoding and recall processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.1. Encoding and recall processes and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.2. Neuropsychological studies on acute effects of THC on encoding and recall processes . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.3. Neuroimaging studies on acute effects of THC on encoding and recall processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4. Working memory function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.1. Working memory function and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.2. Neuropsychological studies on acute effects of THC on working memory function . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.3. Neuroimaging studies on acute effects of THC on working memory function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2014) xxx–xxx Abbreviations: 2-AG, 2-Arachidonylglycerol; CB, cannabinoid; CBD, cannabidiol; CPT, continuous performance task; fMRI, functional magnetic resonance imaging; PET, positron emis- sion tomography; SIRP, Sternberg item-recognition paradigm; SPECT, single-photon emission computed tomography; THC, Δ9-tetrahydrocannabinol. ⁎ Corresponding author at: Institute of Psychiatry, Department of Psychosis Studies (PO67), King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom. Tel.: +44 207 848 0897; fax: +44 207 848 0976. E-mail address: matthijs.bossong@kcl.ac.uk (M.G. Bossong). PNP-08531; No of Pages 17 0278-5846/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.pnpbp.2013.11.017 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp Please cite this article as: Bossong MG, et al, Role of the endocannabinoid system in brain functions relevant for schizophrenia: An overview of human challenge studies with cann..., Prog Neuro-Psychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpbp.2013.11.017