<http://www.newscientist.com/article/mg19025474.100-all-the-pleasures-of-alcohol-with-no-downsides.html>
All the pleasures of alcohol, with no downsides

11 April 2006, Graham Lawton

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 part 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.