CB1 receptor-enriched functional connectivity analysis revealed target-specific modulation by cannabidiol in early psychosis.

Background: Cannabidiol (CBD) has emerged as a potential antipsychotic treatment, acting as a negative allosteric modulator of cannabinoid type-1 (CB1) receptors within the endocannabinoid system. Although previous neuroimaging studies have shown that CBD induces changes in aberrant brain activity and functional connectivity (FC) in psychosis, they have not directly integrated information about the spatial distribution of the molecular targets through which CBD may act.

Aim: In this study, we aimed to investigate whether a single dose of CBD may acutely modulate CB1 receptor-enriched FC in patients with early psychosis and to compare these effects with healthy controls (HC).

Methods: Thirteen patients with early psychosis (PSY) and 14 age- and sex-matched HC underwent resting-state functional magnetic resonance imaging (fMRI). Patients participated in a randomised, double-blind, placebo-controlled crossover study receiving 600 mg CBD (PSY-CBD) or matched placebo (PSY-PLB). CB1 receptor-enriched FC was computed using Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), integrating Positron Emission Tomography (PET)-derived CB1 receptor maps with fMRI data.

Results: Three main findings emerged: (i) PSY-PLB showed increased CB1 receptor-enriched FC across multiple regions compared to HC; (ii) a single dose of CBD significantly reduced CB1 receptor-enriched FC of the right insular cortex relative to PLB; (iii) no differences were observed when CB1 receptor-enriched FC maps of PSY-CBD were compared with those of HC.

Conclusion: Our findings support the potential of CBD to regulate CB1 receptor-enriched FC in early psychosis, providing mechanistic insight into its antipsychotic effects and highlighting REACT as a valuable tool for integrating molecular and functional imaging in psychiatric research.