The Brain Endocannabinoid System is Differentially Regulated in Male and Female Patients with First-Episode Psychosis

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Male patients with first-episode psychosis show significantly lower brain CB1R availability compared with male healthy controls.
Female patients with first-episode psychosis do not differ from female healthy controls in brain CB1R availability.
Sex-specific ECS alterations in early psychosis suggest developing tailored treatments targeting CB1R and related pathways for male and female patients.

Schizophr Bull. 2026 Apr 10;52(3):sbag038. doi: 10.1093/schbul/sbag038.

ABSTRACT

BACKGROUND AND HYPOTHESIS: A sex difference in the clinical presentation of schizophrenia is well known. Males have on average an earlier symptom onset, worse functional capacity, and more negative symptoms. Studies on the neurobiological correlates of psychosis show that brain endocannabinoid system (ECS) is dysregulated in male patients with first-episode psychosis (FEP). We now evaluated whether the brain ECS is also altered in female patients with FEP.

STUDY DESIGN: In this cross-sectional case-control study, brain CB1R availability was measured in 39 participants, including groups of male and female patients with FEP, and healthy control participants (HC) of similar age and sex (n = 8-11/group). Brain CB1R availability was measured with the selective CB1R radiotracer [18F]FMPEP-d2 and positron emission tomography. Arterial input derived distribution volumes (VT) were extracted from regions of interest (ROI) representing the anterior cingulate cortex, hippocampus, thalamus, and putamen.

STUDY RESULTS: Within-subjects analyses showed a regionally differential effect of ROI*sex*group (ε = 0.77; F(2.31,80.85) = 4.31, P = .013). Simple effect analyses indicates that male FEP had significantly lower overall CB1R VT when compared to male HC (F(1,17) = 15.64, pFWER = 0.018), while female FEP VT did not differ from female HC (F(1,18) = 0.12, pFWER = 1). A regionally specific difference of VT between males and females with FEP (F(3,48) = 3.43, P = .024) did not survive the correction for multiple comparisons (pFWER = 0.14).

CONCLUSIONS: The availability of brain CB1R is differentially altered in males and females with early psychosis. Sex-related neurobiological patterns including the ECS may offer new treatment strategies for alleviating the core symptoms of psychotic disorders in male and female patients.

PMID:42084438 | DOI:10.1093/schbul/sbag038

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