Abstract High doses of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, have been shown to have anxiogenic effects. Also, THC effects have been shown to be modulated by genotype, including the single nucleotide polymorphism (SNP) rs1130233 at the protein kinase AKT1 gene, a key component of the dopamine signaling cascade. As such, it is likely that epigenetic methylation around this SNP may affect AKT gene expression, which may in turn impact on the acute effects of THC on brain function. We investigated the genetic (AKT1 rs1130233) and epigenetic modulation of brain function during fear processing in a 2-session, double-blind, cross-over, randomized placebo-controlled THC administration, in 36 healthy males. Fear processing was assessed using an emotion (fear processing) paradigm, under functional magnetic resonance imaging (fMRI). Complete genetic and fMRI data was available for 34 participants. THC caused an increase in anxiety and transient psychotomimetic symptoms and para-hippocampal gyrus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methylation at the CpG 11-12 site, were independently associated with a greater effect of THC on activation in a network of brain regions including left and right parahippocampal gyri, respectively. AKT1 rs1130233 moderation of the THC effect on left parahippocampal activation persisted after covarying for methylation percentage, and was partially mediated in sections of the left parahippocampal gyrus/ hippocampus by methylation percentage. These results may offer an example of how genetic and epigenetic variations influence the psychotomimetic and neurofunctional effects of THC.

Epigenetic mediation of AKT1 rs1130233’s effect on delta-9-tetrahydrocannabinol-induced medial temporal function during fear processing