Old Nutt’s new fangled Ale

Deck the hall with boughs of holly
Fa la la la la la la la la
‘Tis the season to be jolly
Fa la la la la la la la la

Christmas may still be several weeks away but there’s no shortage of people urging us to be jolly. Our local baker has been selling mince pies since early November and one of his fastest selling new lines is a mini Christmas pudding cake decorated with marzipan holly leaves. Our weekly vegetable box arrives stuffed like a Christmas turkey with leaflets encouraging us to buy festive meat, cheese, chocolate and wine. Despite all these signs, I was surprised to see a large advertisement in the Guardian (November 15th) for cheap booze from Tesco. The ad was decorated with Christmas ribbon and offered, for a few days, 40 cans of Fosters Lager or Strongbow Cider for £22. The small print told me that this offer was not available in Scotland; this is because in Scotland these cheap multi-buy offers are banned in an attempt to cut back on problem drinking. But Tesco are responsible people and the ad included a referral to drinkaware.co.uk “for the facts”.

We have big problems with alcohol misuse in the UK. There are as many as a million alcohol-related hospital admissions each year; alcohol fuels crime and civil disorder and is estimated to cost the economy up to £20 billion a year. The health effects of alcohol abuse were illustrated starkly to me by a recent account of a 35-year old woman from Middlesbrough with cirrhosis of the liver so serious that her only hope is a transplant. Her liver damage arose from just two years of heavy drinking (up to 3 bottles of wine a day) superimposed on low-level regular drinking. She is not unique and clinicians in the North East have noted an increase in the number of under 30 year olds being admitted to hospital for alcohol related liver disease: 23 were admitted in 2003 compared to 115 in 2012.

Someone who speaks out about the problems of alcohol abuse is David Nutt, also well known for his strident views on the drug laws. Following his 2010 study on the harms of different drugs he bravely labelled alcohol as being even more damaging than heroin or crack cocaine. He was recently awarded the John Maddox Prize for Standing up for Science. He has been speaking up again and in a Comment piece for the Guardian he proposed replacing alcohol with synthetic alternatives in order to reduce harms. I want to look at his proposal in detail.

First, a bit of background. David Nutt’s target for his alcohol substitutes is a brain protein called the GABAA receptor. This receptor is the normal physiological site of action of a brain chemical (GABA) which tends to damp down brain activity. It is also an important, but by no means exclusive, site of action of alcohol in achieving its relaxant/sociability effects. The GABAA receptor is also the site of action of drugs such as Valium (diazepam), used to calm anxiety. Diazepam is a member of a large family of drugs called benzodiazepines and diazepam itself binds to the receptor at a site separate from the natural chemical GABA and increases its effects. In this way, diazepam damps down brain activity reducing anxiety, but also causing sedation and sleepiness; tolerance can also develop and is a serious problem.

Benzodiazepines are abused by some people who take them to achieve a “high” which includes feeling energetic, relaxed, drunken, talkative and euphoric. This sounds rather like the effects of alcohol and shows that, in principle, a drug related to diazepam might take the place of alcohol. The tendency for diazepam to cause tolerance and dependence means that in designing any alcohol substitute, substantial molecular tinkering would be needed to remove the potential for addiction.

The pharmaceutical industry has been very busy over recent years making all sorts of benzodiazepine derivatives as potential drugs. One group of compounds exhibits partial or selective activation of GABAA receptors when compared to diazepam. The partial/selective activators were developed in the hope that they would calm anxiety but produce less sedation, although none has been marketed.

Another class of compound binds to the benzodiazepine site but does not alter the activity of GABA. In principle, these should interfere with the effects of the other benzodiazepines. The proper pharmacological term for these is antagonists.

These two kinds of compound are, I believe, the drugs that David Nutt has in his sights. He proposes to develop alcohol replacements based on the partial/selective activators. They would probably produce some of the desirable aspects of alcohol such as relaxation/sociability/ inebriation without the unwanted effects such as liver and brain damage because these effects occur via mechanisms not associated with the GABAA receptor. They may lack the tolerance/dependence/overdose problems. They would be available in drinks at bars or possibly in pill form at pharmacies.

He also proposes to include the antagonist compounds in his cocktail cabinet. The antagonists should, in principle, terminate the actions of the partial activators. So, in Old Nutt’s Tavern, when we are ready to go home we take the antagonist drug and sober up directly.

Although this proposal has attracted considerable interest, it is not a new one. Nutt first proposed it seven years ago in a Critique in the Journal of Psychopharmacology. The current flurry of activity is a kite flying exercise to try to drum up financial interest and, I suspect, also to stir up some general discussion about alcohol. Nutt says he has five compounds ready to test in humans but it is important to be clear: no drug is currently available that would substitute for alcohol and we should not underestimate the time it would take to develop and test these new compounds. It would also be a major legal and social departure to develop lifestyle drugs as opposed to medicines.

I have several other queries about the approach. Will the effects of the compounds be acceptable to those who currently use alcohol? We have no idea but it seems unlikely that the GABAA receptor is the sole mediator of the positive effects of alcohol so that the proposed alcohol substitutes may lack something. Nutt says he has taken one of the proposed substitutes and he felt “quite relaxed and sleepily inebriated for an hour or so”. He then reversed the sensation by taking an antagonist, and successfully delivered a lecture. Will feeling “relaxed and sleepily inebriated” really be what people want? It all sounds a bit tame.

But let’s assume that the psychological/physical effects will be sufficient. I can then see that for people who consume mixed drinks such as cocktails and alcopops the approach might work. For those who currently “pre-load” with cheap alcohol before going out, a pill might be acceptable. I can’t, however, see this satisfying the wine buffs and real ale fanatics.

I also find it quite difficult to imagine someone in a bar, inebriated on one of these alcohol substitutes, meekly making the decision to go home and taking the antagonist to sober up. Would they really hop in to their car and drive home? Would we want them to?

How would the manufacturers of alcoholic drinks view this idea? I suspect that profit will be the driver. While society finds alcoholic drinks and their consequences acceptable, the drinks manufacturers will either ignore or oppose development of alcohol substitutes. Should society change its view and should acceptable alternatives become available then I would expect the drinks manufacturers to embrace the new technology.

If all of these questions can be addressed and, if a safe, efficacious and acceptable alcohol substitute were to be developed, then this would substantially reduce alcohol-related disease – that would be a great step forward. However, we are not going to see this in the near future so we should be looking at other ways to reduce harms and here reduced alcohol consumption must surely be the goal. The coalition government recognised the problems that alcohol was causing and in 2012 published its Alcohol Strategy. One of the key proposals was minimum unit pricing to curb binge drinking. The strategy document contains a strongly worded introduction from David Cameron supporting the approach. Despite this, the idea of minimum pricing was subsequently dropped, most likely because of pressure from the drinks manufacturers. This U-turn has been heavily criticised by many and some local councils believe so strongly that minimum pricing will control problem drinking that they have imposed the idea. Most notably, Scotland has passed legislation with a minimum 50p unit price for alcohol, although this has not yet begun.

The government’s Alcohol Strategy emphasised the relation between alcohol price and alcohol consumption. That is why it initially supported the idea of minimum pricing to curb consumption. It’s disappointing to see Tesco, one of the major UK supermarkets, advertising in the Guardian and offering promotions which equate to a cost per unit of alcohol of 31p for the Fosters lager and 25p for the Strongbow cider.

Drunken Noah (Michelangelo)