Insular Cortical Thinning and Altered Structural Connectivity in Chronic Cannabis Users: A High-Resolution Morphometry and Diffusion Tractography Study

Abstract Background The insula, a central hub of the salience network, is implicated in craving and loss of control in addiction. Despite its relevance, the structural morphometric and white matter connectivity correlates of chronic cannabis use remain inconsistent across studies.

Methods: Twenty-six all-male participants (13 chronic cannabis users, 13 controls) underwent a 3.0 Tesla MRI. Cortical thickness and volume were quantified using the Yale Brain Atlas (YBA-696) parcellation. Subcortical volumes were extracted via FreeSurfer. Insula-targeted probabilistic tractography (MRtrix3/iFOD2) was used to assess white matter microstructure through fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Group differences were tested with general linear models and Benjamini–Hochberg FDR correction.

Results: Cannabis users showed bilateral insular cortical thinning at whole-insula and parcel levels (eight parcels surviving FDR correction), without volumetric loss. Additional structural differences included reduced total gray matter volume and lower volumes in the brainstem, left amygdala, right thalamus, left cerebellar cortex, and right orbitofrontal gyrus. Tractography revealed reduced diffusivity in left insula–amygdala pathways, lower FA in right insula–hippocampus and right insula–precentral gyrus connections, and reduced FA in left insula–occipital pathways.

Conclusion: Chronic cannabis use is associated with focal insular thinning and selective microstructural alterations in insula–limbic and insula–cortical pathways. These findings support an endocannabinoid-linked vulnerability model in which circuits subserving salience, interoception, and affective valuation are preferentially disrupted, potentially contributing to the transition toward compulsive use.