Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial

Sagnik Bhattacharyva, Robin Wilson, Elizabeth Appiah-Kusi, Michael J. Brammer, Jesus Perez, Robin Murray, Matthijs G. Bossong, Paul Allen, Philip K. McGuire, Aisling O'Neill

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Importance: Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brainremains unclear.Objective: To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in66 psychosis.Design: Parallel-group, double-blind, randomized, placebo-controlled design in people at clinical high risk(CHR) for psychosis. Healthy control (HC) participants were studied under identical conditions without anydrug treatment.Setting: Academic Health Science Centre, UKParticipants: Thirty-three medication-naïve CHR and 19 HC participants.Intervention: CHRs received a single oral dose of either 600mg of CBD (CHR-CBD) or a placebo (CHR-PLB). HCs were not given any drug. All participants were then studied using functional magnetic resonanceimaging (fMRI) whilst performing a verbal learning task.Main Outcomes and Measures: Brain activation during verbal encoding and recall, indexed using the blood- oxygen level-dependent haemodynamic response (BOLD) fMRI signal.Results: Seventeen CHR-PLB [mean (SD) age= 25.35 (5.24) years; 10 females] and 16 CHR-CBD [mean (SD) age= 22.43 (4.95) years; 6 females] were compared with 19 HC [mean (SD) age= 23.89 (4.14) years; 8 females] participants. Brain activation (indexed using median sum of squares ratio of the BOLD effects model component to residual sum of squares) was analyzed from 16 CHR-PLB, 15 CHR-CBD and 19 HC. CHR-PLB had reduced activation relative to HC in the right caudate during encoding (CHR-PLB: median=-0.027, IQR= -0.041, -0.016; HC: median=0.020, IQR= -0.022, 0.056; p<0.001), and in the parahippocampal gyrus and midbrain during recall (CHR-PLB: median=0.002, IQR= -0.016, 0.010; HC:median=0.035, IQR= 0.015, 0.039; p=0.000096). Within these three regions, activation in the CHR-CBD was greater than in CHR-PLB, but lower than in HCs (parahippocampal gyrus/ midbrain- CHR-PLB: median=- 0.007, IQR= -0.019, 0.008; CHR-CBD: median= -0.013, IQR= -0.027, 0.002; HC: median=0.034, IQR= 0.005, 0.059; p<0.005): the level of activation was thus intermediate to that in the other two groups. There were nosignificant group differences in task performance.© 2018, American Medical Association. The attached document (embargoed until 30/11/2019) is an author produced version of a paper published in JAMA PSYCHIATRY uploaded in accordance with the publisher’s self-archiving policy. The final published version (version of record) is available online at the link below. Some minor differences between this version and the final published version may remain. We suggest you refer to the final published version should you wish to cite from it.
Original languageEnglish
Pages (from-to)1107-1117
Issue number11
Early online date29 Aug 2018
Publication statusPublished - 30 Nov 2018

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