Abstracts

Rationale: The effects of individual cannabinoids on white matter integrity are unclear. Human studies have shown white matter maturation alterations in regular recreational cannabis users, having varying effects in different age groups. Given greater than 100 phytocannabinoids found in the cannabis plant, studies have yet to determine which cannabinoids are most responsible for these white matter changes. In the current study, we analyzed the effects of pharmaceutical grade cannabidiol oral solution (CBD; Epidiolex®) on white matter integrity using diffusion MRI in patients with treatment resistant epilepsy. Our hypothesis was that CBD has no effects on white matter integrity metrics. Methods: The UAB CBD Program recruited and enrolled 169 patients who met inclusion criteria (www.uab.edu/cbd). Of those patients, 15 underwent 3T diffusion MRI (5 on Siemens Allegra, 10 on Siemens Prisma) prior to receiving CBD and then again while on stable doses for at least two weeks. Those patients included 12F/3M, mean age = 36.6 years (SD=17.4), with mean duration of epilepsy 15.8 years (SD=14.2), and mean age of epilepsy onset 20.8 years (SD=17.5). Each subject underwent pre-CBD and then repeat diffusion MRI after being on stable doses (7 at 25 mg/kg/day, 4 at 20 mg/kg/day, and 4 at 15 mg/kg/day; mean time between beginning CBD administration and the second scan = 13.8 weeks (SD=4.9)). Seizure frequency was documented at each visit, and percent of seizure improvement was determined. Diffusion data were analyzed using both DSI Studio (http://dsi-studio.labsolver.org) and FSL's tract based spatial statistics (TBSS) to determine the diffusion tensor imaging (DTI) metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Results: The 15 patients included in this imaging portion of the UAB CBD program showed a mean reduction in monthly seizures from 27.9 to 9.4 with 5 patients achieving seizure freedom. Mean percentage of seizure reduction was determined to be 60.4%. Concerning diffusion imaging, DTI analysis using DSI Studio showed the following significant results using a paired t-test: increased fractional anisotropy (FA) in the right medial lemniscus (p=0.03), right superior cerebellar peduncle (p=0.03) and the pontine crossing tract (p=0.04); decreased mean diffusivity (MD) in the left uncinate fasciculus (p=0.02) and the middle cerebellar peduncle (p=0.04); decreased axial diffusivity (AD) in the left superior cerebellar peduncle (p=0.05), right anterior limb of the internal capsule (p=0.03), and right posterior limb of the internal capsule (p=0.02); and lastly, decreased radial diffusivity (RD) in the middle cerebellar peduncle (p=0.03) and left uncinate fasiculus (p=0.01). However, a subsequent paired t-test using TBSS and controlling for CBD dosage, age, gender, seizure frequency, and scanner type showed no significant differences in white matter metrics between subjects. Conclusions: Regular recreational cannabis use in humans has been associated with abnormal white matter maturation. The significant results in the univariate DTI analyses, not controlling for the epilepsy-related variables, suggests minor changes in white matter connectivity in the cerebellar peduncles, internal capsule, pons, and uncinate fasciculus in patients being administered pharmaceutical grade CBD. However, one limitation of this study is the use of two distinct MRI scanners which could have contributed to the diffusion related changes seen among these 15 patients. Additionally, after controlling for the epilepsy-related variables and differing scanners, our subsequent TBSS analysis indicates that administration of pharmaceutical grade CBD in patients with treatment resistant epilepsy does not result in significant white matter changes. Repeat analyses using a larger cohort of patients and utilizing identical MRI scanners may help further clarify these findings. Funding: No funding