Fear and Loathing

With Grace Blest-Hopley, Research Director at Heroic Hearts Project and Postdoctoral Researcher at King’s College London, UK

What was your starting point for the study?

We knew that the coding variation of SNP rs1130233 had been linked to differential expression of the AKT protein – and that the AKT protein modulates the acute effects of THC from our previous studies – (2, 3). We decided to build on these previous findings and explore how symptoms and activation under the influence of THC was affected by genetic and epigenetic variation. 

Is there a difference between fear-related brain activity and associated anxiety-like behavior? 

Fear and anxiety are related emotional states though there are some differences between them. For example, it has been suggested that fear is related to a known external threat, while anxiety may be related to an unknown threat, uncertainty, or some sort of mental conflict. However, there is clearly an overlap of the brain substrates involved in fear and anxiety. As such, effects of THC on brain substrates involved in fear processing have been shown to correlate with anxiety symptoms measured under its influence under experimental conditions. 

How do these findings build on what we already know about the influence of genetic variation on the effect of THC?

As cannabis and cannabinoid use is entering a new era, the need to understand why people respond differently to them is becoming increasingly apparent. Our study begins to suggest a further level of complexity in our understanding of what may underlie differences between individuals in response to cannabis. Our environment and behaviors can cause epigenetic alterations. These epigenetic alterations can in turn influence the way our genes work by turning them “on” or “off.” In essence, our present study suggests that epigenetic alterations that are linked to previous experiences or behaviors may also influence the effects of THC.

You suggest the THC-induced increase in brain activation may represent a genetically-mediated lack of efficiency in processing emotion. Could you tell us more about this?

To be clear, we have stated this is just one of the possible explanations for the results that we have reported, rather than an empirical observation. Future work is needed to investigate this further...

Were there any limitations to the study?

Our main limitation was the size of the sample; we would most certainly want to find funding for a further study in a much larger population. Other limitations are outlined in the paper but another one to note here was the use of only male subjects, which limits the application of our findings. That said, focusing on a single sex allowed us to detect an effect – even with such a modest sample size. 

If you were to repeat the research with men and women, would you expect to see methylation manifest differently across genders?

We have seen evidence that the effects of cannabis and THC do appear to be different between the sexes. Therefore, it would be important to examine whether methylation is one of the drivers behind this. It’s too early to predict anything at this point, but, as with many other aspects of cannabis’ effects, knowing what might underlie differences between sexes is vital if we are to apply our findings to the wider population.