Analysis of six CYP450 genetic variants regarding the response to Cannabidiol combined with anticonvulsant medication in Mexican patients with drug-resistant epilepsy

Iris Angelica Feria-Romero¹Luisa Lilia Rocha²Araceli Reyes-Cuayahuitl³Iris E. Martínez-Juárez⁴DANIEL SAN-JUAN⁴CONSUELO ESCAMILLA-NUÑEZ⁵Sandra Orozco-Suárez^1*

• ¹Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, “Dr. Bernardo Sepúlveda”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
• ²CENTER FOR RESEARCH AND ADVANCED STUDIES, MEXICO CITY, Mexico
• ³Servicio de Neurología Pediátrica, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
• ⁴NATIONAL INSTITUTE OF NEUROLOGY AND NEUROSURGERY, MEXICO CITY, Mexico
• ⁵NATIONAL INSTITUTE FOR PUBLIC HEALTH, CUERNAVACA, Mexico

Background: Cannabidiol (CBD) reduces the frequency of seizures in individuals with specific epileptic syndromes, but its effectiveness for other types of drug-resistant epilepsy (DRE) is unclear. CYP450 enzymes primarily metabolize CBD. The aim of this study was to identify CYP450 genotypes regarding the response of CBD treatment concomitant with anti-seizure drugs in patients with DRE. Methods: This observational, retrospective, comparative study examined patients with DRE who incorporated CBD into their treatment. Genomic DNA was extracted from the patients’ blood. Patients were divided into two groups: CBD responders and CBD non-responders. Six genetic variants of CYP450 genes were analyzed using real-time polymerase chain reaction (PCR). Statistical significance was determined using Fisher’s exact, chi-squared, and Mann–Whitney U tests. The analysis of polymorphisms involved a statistical test for proportion differences of more than 10% between the comparison groups. Results: This study examined 47 patients with DRE, of which 68% showed a positive response to CBD treatment in combination with their current medications. Among the patients who did not respond to adjuvant treatment with CBD, the CYP3A4 *1/rs2242480 genotype was present in 50%. These patients exhibited focal seizures along with various lesions in imaging studies. In contrast, the CYP2B6 *1/*2 and *2/*2 genotypes were identified in 42% of patients with drug-resistant epilepsy who did respond to CBD treatment. These patients had unknown causes of their epilepsy and showed expected results in imaging studies. Conclusion: Treatment with CBD reduced seizures in most patients (68%), which was independent of etiology and seizure type. The genotype CYP3A4 *1/rs2242480 may be associated with low response to CBD.