Analyzing the DNA methylation alterations induced by cannabis use has provided a wealth of evidence of potential harms, with recent studies focusing on neurodevelopmental problems after prenatal exposure, increased risk of adverse health outcomes, and accelerated epigenetic aging. Now, a study reports the first epigenome-wide association study (EWAS) exploring the interplay between cannabis use, DNA methylation, and critical mental health-associated biological pathways.
In a recent publication, researchers from the lab of Emma L. Dempster (University of Exeter) generated DNA methylation profiles from blood-derived DNA samples of individuals from two independent first-episode psychosis cohorts (188 cannabis users and 494 never users) via the Illumina 450 K and EPIC arrays. Their findings now underscore how epigenetic mechanisms function at the interplay between risk factors and mental health, further our appreciation of the epigenetic impact of cannabis use, and highlight molecular pathways affected by cannabis exposure that impact mental health.
Let’s hear more on the interplay between cannabis use, mental health, and epigenetics from Dempster and Colleagues:
- Analysis of differentially methylated positions (DMPs) and regions (DMR) associated with cannabis use reveals links to the hypomethylation of genes involved in mitochondrial function
- DMPs associated with CAVIN1/PTRF (mitochondrial bioenergetics) and MCU (mitochondrial calcium uniporter) display significant hypomethylation with cannabis use and high-potency cannabis use, respectively, with values remaining independent of the tobacco-related epigenetic signature
- A DMR upstream of TOP1MT (mitochondrial genome regulator) associates with cannabis use
- Pathway and regional analyses identify cannabis-related epigenetic variation near genes linked to immune and mitochondrial function, which are both known to be influenced by cannabinoids
- A DNA methylation/cannabis use model with an interaction term between cannabis use and first-episode psychosis status identifies significant main effects/nominally significant interaction terms for DMPs at ME1 (cytosolic cell metabolism) and NEK6 (cell cycle progression) with cannabis use and high-potency cannabis use, respectively
- Multiple DMPs in SH3BP4 (endocytic function) and ECHDC3 (predicated mitochondrial gene) also display significant effects
- Importantly, first-episode psychosis status moderates how cannabis use affects DNA methylation
Overall, this EWAS identifies a DNA methylation blood-based signature of cannabis use/potency, suggests a moderating role of first-episode psychosis status on DNA methylation, and highlights cannabis-related regulatory changes in genes related to biological processes that may impact mental health outcomes.
“With the increasing prevalence of cannabis use and more availability of high potency cannabis, there is a pressing need to better understand its biological impact, particularly on mental health. Our study is the first to show high potency cannabis leaves a unique signature on DNA related to mechanisms around the immune system and energy production. Future research needs to explore if the DNA signature for current cannabis use, and in particular the one of high potency types, can help identify those users most at risk to develop psychosis, both in recreational and medicinal use settings,” said senior author Marta Di Forti.
For more on how EWAS can reveal how cannabis use impacts DNA methylation and mental health, see Molecular Psychiatry, October 2024.