769. Can the genetic of liver enzyme involved in THC metabolism tell us who are the cannabis users at greater risk of psychosis?
Marta Di Forti, Isabelle Austin-Zimmerman, Edoardo Spinazzola, Uri Bright, Daniel F. Levey, Joel Gelernter, D D'Souza, S Haussler, Z Li, Giulia Trotta, Robin Murray, Evangelos Vassos
International Journal of Neuropsychopharmacology September 9, 2026 DOI: 10.1093/ijnp/pyag040.402 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Genetic association study Peer reviewed |
|---|---|
| Population | Cannabis users in two independent samples |
| Topics | Cannabis |
| Key points | Variation in a genetic risk score for CYP3A4 expression was associated with differences in paranoia scores and overall likelihood of reporting psychotic-like experiences among cannabis users in two independent samples. The authors suggest higher genetic liability to produce CYP3A4 may lead to faster THC metabolism and reduced psychotomimetic effects. |
Abstract
Abstract Background Epidemiological data have consistently shown an association between heavy cannabis use and increased risk of psychotic disorders. Nevertheless, not all cannabis users develop the illness. Evidence from other substance of abuse such as Alcohol suggest how genetic differences in enzymes involved in its metabolism influence individual response to the drug. No studies to data have explored if liver enzymes involved in the metabolism of THC might explain differences in psychosis liability among cannabis users. Aims & Objectives 1. Explore if differences in genetic risk score (GRS) for the liver enzyme involved in the metabolism of THC, influenced individual proness to psychosis in two independent samples of cannabis users.
Method: We used available GWAS data to build a risk score (GRS) including genes regulating the expression of the liver enzyme CYP3A4. We tested if the enzyme GRS influenced individual proness to psychosis in two independent samples of cannabis users.
Results: Variation in CYP3A4 expression GRS were associated with differences in paranoia scores and overall likelihood of reporting psychotic like experiences among cannabis users from both samples. This suggests that higher genetic liability to produce CYP3A4 may be associated with a faster metabolism of THC and the consequential inhibition of its psychomimetic effects. Discussion & Conclusions Genetic liability to the metabolism of cannabis active compound THC might affect users behaviour and their proness to experience adverse effects such as psychosis. Identifying this individual might increase cannabis base product safe prescribing as well as offering a screening tool for identifying recreational user at greater risk of harm.