A specific gene variant determined who lost motor control after THC | Research

The takeaway

Carriers of a specific AKT1 gene variant showed significantly impaired psychomotor control after THC, while those with a different variant were unaffected, explaining some of the variability in how people respond to cannabis.

Read this if you want to understand why some people are more impaired by cannabis than others, and the genetics behind it.

AKT1 gene variant determined whether THC impaired motor control (P = 0.008)

What the researchers found

In a double-blind study, healthy occasional cannabis users received either THC or placebo and performed a response inhibition task during brain imaging. Carriers of the A allele of the AKT1 rs1130233 gene variant showed significantly increased errors after THC (P = 0.008), while G allele homozygotes showed no impairment.

Brain imaging revealed that A allele carriers showed reduced activation in the left inferior frontal gyrus (a region critical for motor control) after THC, while G homozygotes showed modest enhancement. There was a direct correlation between the behavioral impairment and the brain activation change in this region.

The AKT1 gene influences dopamine signaling, and the inferior frontal cortex is rich in dopaminergic innervation, providing a mechanistic pathway linking genetics to THC-induced behavioral impairment.

Why it matters

People respond very differently to cannabis, and understanding why has been a persistent question. This study identified a specific genetic mechanism: a variant in a dopamine-related gene that determines whether THC impairs the brain region responsible for stopping inappropriate actions.

The numbers in context

A allele carriers showed significantly increased inhibition errors (P = 0.008). G homozygotes showed no impairment. Behavioral-brain activation correlation: r = -0.327 (P = 0.045). AKT1 genotype modulated THC effects specifically in the inferior frontal gyrus.

How the study worked

Double-blind, repeated-measures design in healthy occasional cannabis users. Participants received acute oral THC or placebo and performed a Go/No-Go response inhibition task during functional MRI. Participants were genotyped for the AKT1 rs1130233 single nucleotide polymorphism.

What this study cannot tell us

The sample consisted of healthy occasional users and may not represent heavy or dependent users. The authors noted these results require independent replication. Oral THC administration differs from smoking in pharmacokinetics. Only one genetic variant was tested.

How to read the evidence

Well-designed double-blind pharmacogenetic study with brain imaging, providing mechanistic evidence for gene-drug interaction.

When this study was published

Published in 2014. The authors noted results require independent replication.

The bigger picture

This is one of the clearest demonstrations of gene-drug interaction for cannabis. It has implications for understanding who is most vulnerable to cannabis-impaired driving, impulsive behavior, and other psychomotor control issues. The dopaminergic mechanism also connects to broader cannabis-psychosis genetics research.

Questions still open

Has this AKT1 finding been replicated in independent samples? Does the same genetic vulnerability apply to other cannabis-related impairments? Could genetic testing inform personalized risk assessment for cannabis use?

Common questions

Why do some people get more impaired by cannabis than others?

This study found that a specific variant in the AKT1 gene (which affects dopamine signaling) determined whether THC impaired psychomotor control. Carriers of the A allele showed significant impairment, while G homozygotes did not.

What does the AKT1 gene do?

AKT1 encodes a protein involved in dopamine signaling. The gene variant studied here modulated how THC affected the inferior frontal cortex, a brain region rich in dopamine neurons that is critical for stopping inappropriate motor responses.

Read the original research

Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control.

Psychological medicine, 44(15), 3315-28

View on PubMed ↗Publisher’s paper ↗

Citation

Bhattacharyya, S; Iyegbe, C; Atakan, Z; Martin-Santos, R; Crippa, J A; Xu, X; Williams, S; Brammer, M; Rubia, K; Prata, D; Collier, D A; McGuire, P K. (2014). Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control.. Psychological medicine, 44(15), 3315-28. https://doi.org/10.1017/S0033291714000920