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.
Highlights
The aberrant salience hypothesis of psychosis[1] postulates that hyperdopaminergia in the mesostriatal pathway leads to aberrant assignment of salience to everyday experiences and stimuli, which in turn result in psychotic symptoms
There were no significant differences between clinical high risk for psychosis (CHR)-PLB and CHR-CBD in either positive or negative symptom subscale of the Comprehensive Assessment of At-Risk Mental States interview (CAARMS) or in terms of current tobacco smoking and cannabis use
Accuracy: There was a significant likelihood of increased accuracy in the salience condition compared to neutral in both healthy control (HC)-vs-CHR-PLB (p < 0.001) and CHRPLB-vs-CHR-CBD (p < 0.001)
Summary
The aberrant salience hypothesis of psychosis[1] postulates that hyperdopaminergia in the mesostriatal pathway leads to aberrant assignment of salience to everyday experiences and stimuli, which in turn result in psychotic symptoms. It has been suggested that mesostriatal dopaminergic overactivity may be driven by glutamatergic dysfunction in the medial temporal lobe (MTL)[6], and both increased hippocampal blood flow[7] and metabolism[8] have been reported in CHR subjects and established psychosis. CHR subjects have been found to have hypoactivation in the ventral striatum (VS) and midbrain[11] and right inferior parietal lobule[12], with VS activity to ‘aberrant’ or non-salient stimuli correlating with severity of positive psychotic symptoms[13]. Meta-analysis suggests hypoactivation of the VS16, and individual studies have reported reduced activation in the cingulate and ventral tegmentum in unmedicated patients[12,17], and in the right insula in medicated patients[12] while processing motivational salience
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