Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis

Robin Wilson, Matthijs G Bossong, Elizabeth Appiah-Kusi, Natalia Petros, Michael Brammer, Jesus Perez, Paul Allen, Philip McGuire, Sagnik Bhattacharyya, Robin Wilson, Matthijs G Bossong, Elizabeth Appiah-Kusi, Natalia Petros, Michael Brammer, Jesus Perez, Paul Allen, Philip McGuire, Sagnik Bhattacharyya

Abstract

Accumulating evidence points towards the antipsychotic potential of cannabidiol. However, the neurocognitive mechanisms underlying the antipsychotic effect of cannabidiol remain unclear. We investigated this in a double-blind, placebo-controlled, parallel-arm study. We investigated 33 antipsychotic-naïve subjects at clinical high risk for psychosis (CHR) randomised to 600 mg oral cannabidiol or placebo and compared them with 19 healthy controls. We used the monetary incentive delay task while participants underwent fMRI to study reward processing, known to be abnormal in psychosis. Reward and loss anticipation phases were combined to examine a motivational salience condition and compared with neutral condition. We observed abnormal activation in the left insula/parietal operculum in CHR participants given placebo compared to healthy controls associated with premature action initiation. Insular activation correlated with both positive psychotic symptoms and salience perception, as indexed by difference in reaction time between salient and neutral stimuli conditions. CBD attenuated the increased activation in the left insula/parietal operculum and was associated with overall slowing of reaction time, suggesting a possible mechanism for its putative antipsychotic effect by normalising motivational salience and moderating motor response.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Mean reaction time by condition by group
Fig. 2. Salience network region-of-interest analysis of…
Fig. 2. Salience network region-of-interest analysis of salience>neutral contrast (small-volume corrected, p < 0.05 FWE-corrected at voxel level, k ≥ 3 voxels).
a Pairwise comparison CHR-PLB>HC with clusters in bilateral frontal operculae and left insula/parietal operculum. b Pairwise comparison CHR-PLB>CHR-CBD with cluster in left insula/claustrum. c Three-way ANOVA CHR-PLB>CHR-CBD>HC with clusters in left frontal operculum and left insula/parietal operculum. d Mean b-value parameter estimates extracted from the two clusters generated by ANOVA for each group (CHR-PLB, CHR-CBD, and HC) showing increased activation in CHR-PLB relative to HC with CHR-CBD intermediate in the left frontal operculum and left insula/parietal operculum. e Negative correlation between mean b-value from ANOVA-derived cluster of left insula/parietal operculum and mean reaction time for salience condition in HC. f Positive correlation between mean b-value from ANOVA-derived cluster of left insula/parietal operculum and CAARMS positive subscale in CHR-PLB. g Negative correlation between mean b-value from ANOVA-derived cluster of left insula/parietal operculum and difference in mean reaction time between neutral and salience condition in CHR-PLB

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