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In patients with treatment‐resistant epilepsy (TRE), cannabidiol (CBD) produces variable improvement in seizure control. Patients in the University of Alabama at Birmingham CBD Expanded Access Program (EAP) were enrolled in the genomic study and genotyped using the Affymetrix Drug Metabolizing Enzymes and Transporters plus array. Associations between variants and CBD response (≥50% seizure reduction) and tolerability (diarrhea, sedation, and abnormal liver function) was evaluated under dominant and recessive models. Expression quantitative trait loci (eQTL) influencing potential CBD targets was evaluated in the UK Brain Expression Consortium data set (Braineac), and genetic co‐expression examined. Of 169 EAP patients, 112 (54.5% pediatric and 50.0% female) were included in the genetic analyses. Patients with  AOX1  rs6729738 CC (aldehyde oxidase; odds ratio (OR) 6.69, 95% confidence interval (CI) 2.19–20.41,  P  = 0.001) or  ABP1  rs12539 (diamine oxidase; OR 3.96, 95% CI 1.62–9.73,  P  = 0.002) were more likely to respond. Conversely, patients with  SLC15A1  rs1339067 TT had lower odds of response (OR 0.06, 95% CI 0.01–0.56,  P  = 0.001).  ABCC5  rs3749442 was associated with lower likelihood of response and abnormal liver function tests, and higher likelihood of sedation. The eQTL revealed that rs1339067 decreased  GPR18  expression (endocannabinoid receptor) in white matter ( P  = 5.6 × 10 −3 ), and rs3749442 decreased hippocampal  HTR3E  expression (serotonin 5‐HT 3E ;  P  = 8.5 × 10 −5 ). Furthermore, 75% of genes associated with lower likelihood of response were co‐expressed. Pharmacogenetic variation is associated with CBD response and influences expression of CBD targets in TRE. Implicated pathways, including cholesterol metabolism and glutathione conjugation, demonstrate potential interactions between CBD and common medications (e.g., statins and acetaminophen) that may require closer monitoring. These results highlight the role of pharmacogenes in fundamental biologic processes and potential genetic underpinnings of treatment‐resistance.

Pharmacogenetic Predictors of Cannabidiol Response and Tolerability in Treatment‐Resistant Epilepsy