Medical Marijuana and Treatment Personalization: The Role of Genetics and Epigenetics in Response to THC and CBD

Personalizing therapy using medical marijuana (MM) is based on understanding the pharmacogenomics (PGx) and drug-drug interactions (DDIs) involved, as well as identifying potential epigenetic risk markers. In this work, the evidence regarding the role of variants in phase I (<i>CYP2C9</i>, <i>CYP2C19</i>, <i>CYP3A4/5</i>) and II (<i>UGT1A9</i>/<i>UGT2B7</i>) genes, transporters (<i>ABCB1</i>), and selected neurobiological factors (<i>AKT1</i>/<i>COMT</i>) in differentiating responses to Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been reviewed. Data indicating enzyme inhibition by CBD and the possibility of phenoconversion were also considered, which highlights the importance of a dynamic interpretation of PGx in the context of current pharmacotherapy. Simultaneously, the results of epigenetic studies (DNA methylation, histone modifications, and ncRNA) in various tissues and developmental windows were summarized, including the reversibility of some signatures in sperm after a period of abstinence and the persistence of imprints in blood. Based on this, practical frameworks for personalization are proposed: the integration of PGx testing, DDI monitoring, and phenotype correction into clinical decision support systems (CDS), supplemented by cautious dose titration and safety monitoring. The culmination is a proposal of tables and diagrams that organize the most important PGx-DDI-epigenetics relationships and facilitate the elimination of content repetition in the text. The paper identifies areas of implementation maturity (e.g., <i>CYP2C9</i>/THC, CBD-<i>CYP2C19</i>/clobazam, <i>AKT1,</i> and acute psychotomimetic effects) and those requiring replication (e.g., multigenic analgesic signals), indicating directions for future research.