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All the pleasures of alcohol, with no downsides

CASUAL drinkers are unlikely to have raised their glass to the news last month that most people who suffer severe alcohol-induced liver disease are social drinkers not alcoholics. Nor to the finding that moderate drinking might not, after all, help prevent heart disease.

There may, however, just be a solution to our drinking woes - one that will allow us to go to a bar and drink as much as we want; get merry, not legless; wake without a hangover; and never have to worry that one of our favourite pastimes may be killing us. It's a cocktail of drugs that mimics the pleasurable effects of alcohol without the downsides. The idea is only on the drawing board, but there is no scientific reason why it could not be made right now, says psychopharmacologist David Nutt of the University of Bristol in the UK.

Alcohol exerts its effects on the brain mainly by latching onto signalling molecules called GABA-A receptors. There are dozens of subtypes of these, some of which are associated with specific effects of alcohol. Memory loss, for example, seems to occur because alcohol binds to a subtype in the hippocampus called alpha-5. Nutt says it would be possible to design molecules that bind strongly to the good subtypes but more weakly to the bad ones.

In fact such "partial agonists" of GABA-A receptors already exist in the form of bretazenil and pagoclone, which were developed as anti-anxiety drugs but never commercialised. These molecules also have the advantage of being instantly reversible by the drug flumazenil, which is used as an antidote to overdoses of tranquillisers such as Valium. Alcohol also inhibits NMDA receptors, which are p sad.gif art of a general excitatory signalling circuit, so a second ingredient of the alcohol substitute would be an NMDA antagonist such as dizoclipine, originally developed as a drug for stroke.

The trick pharmacologists need to pull off is to make a mixture of molecules that deliver alcohol's pleasurable effects, notably relaxation and sociability, without the aggression, nausea, loss of coordination and amnesia that can cause drinkers and those around them so much grief. Long-term problems such as cirrhosis of the liver could also be eliminated, says Nutt, who publishes the idea next month in the Journal of Psychopharmacology, (vol 20, p 318).

There would be obstacles of course. The pharmaceutical industry may be unwilling to develop and test such a complex and expensive formulation, while there would be political and moral difficulties in creating a new lifestyle drug. And drinkers might need some persuading to give up fine wine or their favourite beer. Still, it's an idea worth toasting.
From issue 2547 of New Scientist magazine, 11 April 2006, page 18
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