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  • Genetic Variations in THC Metabolism: Implications for Cannabis Use Disorder Risk

    In a recent study published in Addictive Behaviors, a team led by Rachel Tomko, Ph.D., from the Medical University of South Carolina, alongside former psychology intern Christal Davis, Ph.D., now a postdoctoral fellow at the University of Pennsylvania, delved into the intricacies of THC metabolism among young adults and its potential link to cannabis use disorder (CUD). The research, conducted in collaboration with colleagues from the University of Florida and the University of Colorado, casts light on how genetic variations in THC-metabolizing enzymes might influence an individual's reaction to cannabis and their risk of developing CUD.

    CUD, characterized by withdrawal symptoms, cravings, and an increased tolerance to cannabis, affects approximately 20% of cannabis users. The study focuses on a particular age group, 18-25 years old, which is notably more susceptible to CUD. The selection of this demographic is strategic, given the ongoing brain development during this period, emphasizing the critical need for early intervention.

    Genetic Variations and Their Impact on THC Breakdown
    Participants, including 38 individuals with CUD and 16 with non-CUD substance use disorders, were genetically screened to identify variants in enzymes responsible for THC metabolism. This biochemical process is crucial for breaking down THC into psychoactive and inactive compounds. Approximately 25% of the population carries a gene variant that leads to less efficient THC breakdown, potentially intensifying and prolonging cannabis's effects.

    The research methodology involved collecting blood samples for genetic analysis and administering questionnaires to assess the participants' subjective experiences with cannabis. This approach allowed the researchers to classify individuals as either normal or slow THC metabolizers and correlate these categories with reported effects.

    Sex-Specific Findings in THC Metabolism Rates
    One of the more surprising findings emerged from the sex-specific data analysis. Female participants with CUD were more frequently identified as slow metabolizers compared to their counterparts with other substance use disorders. This suggests that slower THC metabolism in females could heighten the risk of developing CUD. In contrast, young adult males with a predisposition to slower THC metabolism reported more adverse effects during their initial cannabis use.

    The implications of these findings extend beyond young adults, as many individuals with CUD begin cannabis use in their teenage years. The evolving social landscape, which increasingly normalizes cannabis use, might obscure potential risks, particularly for teens unaware of how individual differences in THC metabolism could influence their experiences and susceptibility to CUD.

    Despite the tendency to associate negative drug effects with cessation, the study observed that the presence of rewarding experiences might encourage continued use, even in the face of adverse consequences. This paradox underscores the complexity of CUD and the need for targeted educational interventions.

    Implications and Future Directions
    The research team advocates for educational initiatives, such as the Just Say “Know” program, to enlighten adolescents about the neuroscience of drug addiction and the factors that could predispose them to CUD. By improving understanding among teens, the aim is to mitigate the risk factors associated with cannabis use.

    Looking forward, the study paves the way for exploring novel treatment avenues, such as pharmacological interventions that could modify THC metabolism. This direction is particularly relevant in light of the
    increasing potency of cannabis products, which could amplify the effects observed in slow metabolizers.


    Original Publication:
    ​Davis, C. N., Markowitz, J. S., Squeglia, L. M., Ellingson, J. M., McRae-Clark, A. L., Gray, K. M., ... Tomko, R. L. (2024). Evidence for sex differences in the impact of cytochrome P450 genotypes on early subjective effects of cannabis. Addictive Behaviors, 153, 107996. https://doi.org/10.1016/j.addbeh.2024.107996

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