What comes first, the drinking or the anxiety?

It happens to many of us – we choose to turn to alcohol to numb the anxiety felt at a socially awkward occasion. It works as a temporary fix. The next day, although free of that social context, you continue to feel anxious. The “hangxiety” has settled in. For many people it stops there. However, alcohol abuse kills millions of people around the world each year and can account for up to 8% of all male deaths. 

Alcohol helps relieve short-term anxiety because it is a depressant drug. This makes “people feel calm physically and mentally as it depresses the central nervous system,” according to a spokesperson for Aquarius, a UK charity that supports people affected by alcohol. Upon leaving the body, alcohol “agitates the central nervous system and can lead to increased physical and psychological effects of anxiety”. You drink to relieve anxiety, yet you feel anxious because you drink – a “vicious circle” is created, resulting in an increased tolerance. People then “drink more alcohol in order to get the same calming effect over time”. This can lead to an alcohol use disorder partnered with anxiety.

But there is one big question that remains unanswered: does anxiety lead to increased alcohol intake, or does alcohol induce anxiety? Or could there be a common mechanism driving both anxiety and alcohol intake?

A genetic link in males

New research in mice has identified the first genetic link between alcohol abuse and anxiety in men that could help answer this question.

Scientists at the University of Aberdeen and the University of Edinburgh have identified a “DNA switch” called GAL5.1 which, when turned off, reduces both alcoholism and anxiety in male mice. The switch controls a gene called Gal that is expressed in the hypothalamus and amygdala of the brain – two regions that are associated with mood and alcohol use disorder. The team deleted this switch from mouse DNA using gene editing techniques to see its effect on behaviour. When given the choice between water or alcohol, ordinary mice drunk mostly alcohol, but the mice without the switch largely avoided the alcohol.

Interestingly, the mice that avoided alcohol also showed fewer signs of anxiety than the ordinary mice. This may only be in male mice. A section of the gene called the promoter responds to oestrogens, so there could be sex-associated hormonal influences on the gene.

These results “mirrored what we saw in humans”, which was “very surprising”, says Alasdair MacKenzie, lead author of the study. The research marks the first time a “DNA switch” has been identified that could have such large implications on human health. “The switch comes in two forms in the human population … one is associated with anxiety and alcohol intake in males, the other is protective.” Understanding the protective version, found in 15-20% of the population, could help understand the genetic link between alcohol use disorder and anxiety.

Understanding a toxic relationship

With alcohol abuse, it is “very common” to also have chronic anxiety says Josh Smith, Clinical Director at the Center for Drug and Alcohol Programs at the Medical University of South Carolina. Concerns over these two associated conditions continue to grow during the Covid-19 pandemic; Aquarius has seen that many people are experiencing increased anxiety, which for a significant number of people is leading to increased drinking.

The most commonly associated anxiety conditions include “panic disorder, agoraphobia and social anxiety disorder,” which can make someone feel “panicky sensations or make the mind feel frantic,” says Smith. Once the anxiety and alcohol disorder co-exist, they “drive a mutual maintenance”, and both the alcohol and anxiety need to be treated independently.

The discovery is a “step in the right direction” to understanding the “genetic architecture” of alcoholism and anxiety says MacKenzie. “No individual gene is responsible for why people drink or are more anxious … you are talking about hundreds of different changes and each one gives a small contribution … and whether you get the condition or not depends on the lottery of your genetic makeup.”

Despite this finding, the question of what came first – the alcohol use disorder or the anxiety – remains unclear, as the activity of the Gal gene is increased when alcohol is consumed. “It may contribute to the idea that alcohol induces anxiety,” says MacKenzie. Although understanding the development of disease is key, for Smith “the more important factor is once they are together, how do we treat both.”

“The next step is how to translate this to the clinic,” says MacKenzie. Research teams have found a number of different molecular targets that allow the beginnings of personalised therapeutics based on sex and genetics. But for now, Aquarius advises that any person struggling with alcohol and anxiety issues should reach out and “seek support”.

Alana Cullen is studying for an MSc in Science Communication at Imperial College London.