Background: Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown.

Methods: Using a double-blind, parallel-group design, 33 CHR patients were randomised to a single oral 600mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labelling. We examined differences relating to CHR status (controls vs placebo), effects of CBD in CHR (placebo vs CBD) and linear between-group relationships, such that placebo>CBD>controls or controls>CBD>placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses.

Results: Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<.01) compared to healthy controls. There were no suprathreshold effects in the CBD vs placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE=.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo.

Conclusions: These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalised by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.