Genetic variation at AKT1 rs1130233 and DNA methylation at a nearby site independently influenced how THC altered brain activation during fear processing, with methylation partially mediating the genetic effect.
Genetics researchers, people interested in individual differences in cannabis response, those concerned about cannabis and psychosis risk
Both genetic and epigenetic factors independently predicted THC brain effects
What the researchers found
The number of A alleles at AKT1 rs1130233 and methylation percentage at the CpG11-12 site independently predicted greater THC effects on parahippocampal/amygdala activation during fear processing. The genetic effect was partially mediated by methylation in sections of the left parahippocampal gyrus and hippocampus.
Why it matters
This demonstrates that both inherited genetic variation and modifiable epigenetic factors shape individual responses to THC, helping explain why some people are more vulnerable to cannabis-related anxiety and psychotic symptoms.
The numbers in context
36 healthy males (34 with complete data); 2-session crossover design; THC increased anxiety and psychotomimetic symptoms; AKT1 gene is part of the dopamine signaling cascade
How the study worked
Double-blind, cross-over, randomized placebo-controlled THC administration study in 36 healthy males, with functional MRI during a fear processing task. Genetic (AKT1 rs1130233) and epigenetic (DNA methylation) data were analyzed.
What this study cannot tell us
Small sample of only males, limiting generalizability. Single acute THC dose may not reflect chronic use effects. Epigenetic measurements from blood may not perfectly reflect brain methylation patterns.
How to read the evidence
Small randomized controlled trial with rigorous crossover design but limited to 36 male participants
When this study was published
Published in 2021. Pharmacogenomic research on cannabis response is still in early stages.
The bigger picture
Understanding the genetic and epigenetic factors that modify THC sensitivity could eventually enable personalized risk assessment for cannabis use, identifying individuals who may be particularly vulnerable to adverse psychological effects.
Questions still open
- Do these genetic and epigenetic factors predict real-world vulnerability to cannabis-related psychosis? Could epigenetic screening be used clinically to assess cannabis risk? Do females show the same patterns?
Common questions
Do genes affect how THC impacts the brain?
What role does epigenetics play in THC response?
Read the original research
Epigenetic Mediation of AKT1 rs1130233's Effect on Delta-9-Tetrahydrocannabinol-Induced Medial Temporal Function during Fear Processing.
Brain sciences, 11(9)
Citation
Blest-Hopley, Grace; Colizzi, Marco; Prata, Diana; Giampietro, Vincent; Brammer, Michael; McGuire, Philip; Bhattacharyya, Sagnik. (2021). Epigenetic Mediation of AKT1 rs1130233's Effect on Delta-9-Tetrahydrocannabinol-Induced Medial Temporal Function during Fear Processing.. Brain sciences, 11(9). https://doi.org/10.3390/brainsci11091240
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