Chronic cannabis use is associated with alterations in resting-state cerebellar-cortical connectivity

Rationale: Cannabis is one of the most widely used psychoactive drugs in the United States, yet its long-term effects on brain function remain poorly understood. Prior resting-state functional connectivity (rsFC) studies have yielded inconsistent findings, likely due to variability in cannabis use thresholds, a predominant focus on younger populations, and region-of-interest (ROI)-based approaches limited to a small number of a priori brain regions. Objectives: We aimed to address these limitations by examining rsFC across the entire brain using an atlas-based, whole-brain, ROI-to-ROI approach in a middle-aged sample (mean age = 41.64 years) of individuals with chronic cannabis use (CCU) and a demographically matched group of controls who did not use cannabis or other illicit substances. Based on the known neuroanatomical distribution of type 1 cannabinoid receptors (CB1Rs), we hypothesized that regions with high CB1R density would be the most affected. However, given our whole-brain approach, we were also sensitive to other regions that may exhibit altered connectivity. Methods: Using the Automated Anatomical Labeling (AAL) atlas, we computed rsFC matrices across 116 brain regions in 22 adults with CCU and 23 demographically matched controls. Results: The CCU group showed decreased rsFC (p_FDR<.05) between the right cerebellar Crus II and the left pars triangularis, bilateral pars orbitalis, left superior frontal gyrus, left middle temporal gyrus, and left inferior temporal gyrus compared with the control group. The CCU group also had lower rsFC (p_FDR <.05) between the right cerebellar Crus I and the left pars triangularis compared with controls. Conclusions: Our findings revealed disrupted rsFC between cerebellar and prefrontal-temporal regions in the CCU group. This study advances the literature by using an atlas-based, whole-brain, ROI-to-ROI approach in a middle-aged sample with sustained cannabis use. Future studies should integrate neuropsychological assessments and task-based paradigms to understand how such alterations in rsFC affect behavioral outcomes.