Abstracts

Rationale: Cannabidiol (CBD) is efficacious in improving seizure control in people with treatment-resistant epilepsy (TRE), but its effects on brain structure are poorly understood. Chronic cannabis use results in long-lasting changes in brain morphology; documented effects include cortical thinning and grey matter volume (GMV) reductions in the hippocampus, amygdala, and other subcortical structures. However, whether such effects are present in patients with TRE exposed to highly-purified, pharmaceutical-grade cannabidiol oral solution (CBD; Epidiolex; Greenwich Biosciences, Inc.) has not been investigated to date. The objective of this study was to investigate whether daily CBD administration produced any changes in cerebral macrostructure; and whether improvements in seizure frequency and severity were related to the structural brain changes, if present. We hypothesized that there would be no changes in cerebral structure following 10-24 weeks of CBD administration. Methods: Twenty-seven patients with TRE were recruited from a larger study of 169 participants in the University of Alabama at Birmingham Cannabidiol Program. CBD was initiated at a daily dose of 5-mg/kg with bi-weekly titration up to a stable dosage of 15-25 mg/kg administered twice daily in equal doses. At baseline and at >=10 weeks following CBD initiation, participants provided seizure diaries, completed the Chalfont Seizure Severity Scale and Adverse Events Profile inventory. Participants underwent magnetic resonance imaging at 3-Tesla at baseline and at >=10 weeks following CBD initiation. T1-weighted 3D high-resolution anatomical scans were acquired using a magnetization-prepared rapid acquisition with gradient echo sequence. T1-weighted scans were analyzed by voxel-based morphometry (VBM) to investigate changes in GMV before and after CBD initiation for 18 participants. Cortical thickness analyses were conducted by surface-based morphometry. Images were preprocessed using the fully automated Computational Anatomy Toolbox (CAT12) in Statistical Parametric Mapping (SPM12) running in MatLab R2017b. An omnibus F-test and voxel-level paired-samples t-tests for directional contrasts were performed to compare GMV and cortical thickness at baseline and on-CBD. Between-group differences were assessed with an exploratory whole-brain approach (p<0.001, uncorrected) followed by p<0.05 corrected for multiple comparisons. Covariates included: 1) total intracranial volume (to correct for different brain sizes), and 2) seizure frequency (to determine if GMV changes corresponded to changes in seizure control).  Results: Voxel-level paired samples t-tests did not identify significant changes in GMV or cortical thickness between the baseline and on-CBD conditions. Paired-samples t-tests confirmed reductions in seizure frequency [t(17) = 3.08, p=0.0069], seizure severity [t(17) = 5.77, p<0.001], and adverse events [t(17) = 3.04, p=0.0074]. Mean seizure frequency (per 28-day period) at baseline was 29.3 with a standard deviation (SD) of 39.4. The maximum seizure frequency score at baseline was 168, while the minimum score was 4. Five participants experienced a 100% decrease; others experienced more moderate decreases (e.g. 14.3% reduction).  Conclusions: As hypothesized, the present study did not find significant GMV or cortical thickness changes in participants following 10-24 weeks of daily CBD administration. Despite CBD's positive action at molecular targets to reduce seizure frequency and severity, the lack of structural change in the brain indicates CBD's safety and efficacy in a limited sample of patients. Further longitudinal assessments are critical to ascertain that chronic CBD administration will not change GMV or cortical thickness.  Funding: The State of Alabama General Funds supported this work.