All the pleasure of drinking, without the pain
New Scientist, 15 July 2006
Why is it
that when you step into a bar for a glass or two of cheer, you so often
leave with five drinks' worth of impending doom? All you wanted was to
loosen up, have some fun, unleash the gregarious you stuck somewhere in
sobriety. Yet it is all too likely that this feel-good glow will be
followed by a hard-luck chaser. Several drinks later, you stumble home,
clumsy, belching and battling to stay awake. Your judgement's shot: you
urinate in a doorway, stuff down two kebabs and narrowly escape getting
killed on the road. At home, your partner declares you disgusting and,
though you rant defiantly, you know it's true.
You toss and turn
all night and in the morning wake tired, with a throbbing head and an
uncanny certainty that you made an ass of yourself last night, though
you can't remember the details. As you trudge off to work, a few brain
cells lighter and with a slightly more withered heart and liver, you
swear you won't do it again.
But you probably will. The simple
fact is that alcohol makes people feel good. There are obvious
downsides, but it also relaxes you, makes you happy, chatty and
What if you could have all that is good about alcohol,
with none of the bad? What if you could enjoy a night of frivolous fun,
then simply pop a pill for instant revival? Your sobriety restored,
home you'd ride - or even drive - to a good night's sleep (or better)
with no risk of a hangover. Or what if, before imbibing, you could
swallow a tablet that would block the negative effects, such as memory
loss? Better yet, imagine there was a substitute that could deliver
relaxation and merriment without the nausea, disorientation or
aggression. In fact, what if one day this dream drink could be so
well-tailored that even a lifetime of indulgence would leave the liver,
brain and heart unharmed?
It may sound too good to be true, but
that day may not be as far off as you think. There's already a drug
that can sober up a drunken rat in 2 minutes flat, and researchers are
busy searching for compounds to do the same in humans. The memory
preservative is not fantasy either, nor is the notion that with a
little tinkering, pharmacologists could come up with a faux alcohol
able to mimic the charms of booze with less of the sordidness.
is one of the last great technological throwbacks. It is made today
pretty much the way it was 4000 years ago. And it's crude stuff. Which
makes you wonder: if we can take the calories out of food, the
pregnancy out of sex and even the sex out of pregnancy, why not take
the harm out of alcohol? "We know what alcohol does," says David Nutt,
a psychopharmacologist and advocate of safer alcohol at the University
of Bristol, UK. "Why not just make better drugs?"
problem with alcohol is that it kills people (see Diagram). And while
there's an obvious way to stop this happening - drink less or not at
all - for some reason, humans find this advice nigh on impossible to
follow. According to the US Centers for Disease Control, 19,928
Americans died in 2002 from the direct effects of alcohol, including
poisoning and alcohol-induced liver and heart disease. According to the
UK Office for National Statistics, the comparable number for England
and Wales in 2003 was 6580, and it's rising. Many more deaths are
caused indirectly by alcohol: accidents, homicides and suicides, to
name just three. If this harm could be mitigated by drugs, or if
alcohol could somehow be replaced by safer substitutes, argues Nutt,
many lives could be saved.
Lovely as that sounds, the history of
alcohol harm-reduction efforts is not encouraging. Full-blown
prohibition, as seen in the US in between 1920 and 1933 (and a handful
of other places worldwide), did not lead to less drinking or
alcohol-related problems. Attempts to divert drinkers to slightly less
toxic vices - everything from cola to marijuana and the Fijian herb
kava - have also proven tricky, largely because none of them turn
people off alcohol. Rather they seem either to mix very agreeably with
it, or combine dangerously (see "In place of liquor"). Perhaps
unsurprisingly, low-alcohol and alcohol-free beers and wines have not
Nonetheless, harm reduction has a decent track
record with other dangerous drugs, notably heroin and nicotine, and
Nutt is optimistic that the same can be done for alcohol. He believes
that sophisticated pharmacology holds the key.
alcohol-brain interaction is not completely understood, it is widely
believed that ethanol, booze's active ingredient, is a general
inhibitor of brain activity. It does this both by damping down
excitatory circuits and firing up inhibitory ones. Most researchers
agree that a big part of alcohol's effect - most importantly, the
feel-good factor - is probably mediated through the latter mechanism,
via brain receptors for the neurotransmitter GABA (gamma-aminobutyric
acid), the brain's universal inhibitory signalling molecule.
are many different flavours of GABA receptor, found in various
combinations throughout the brain. Crucially, different types seem to
be associated with different alcohol effects. For instance, the 1
subtype seems to be responsible for that woozy, sedated feeling, while
the 2s calm us down; 5s, meanwhile, may be behind a number of negative
effects, including memory loss, motor impairment and "reinforcement" -
that hankering to follow your first drink with another, and then
another. Alcohol researchers still don't have the complete picture but
they expect to find many more specific links between receptor type and
Nutt and others believe this means it will be
possible to develop drugs that selectively block alcohol's undesirable
effects while leaving the desirable ones alone. For instance, a
molecule that prevents alcohol from binding to 5 subunits might just
stop us from getting clumsy and drowsy, and may even make it easier to
know when to call it a night. In fact, neuropsychopharmacologist Harry
June at the University of Maryland School of Medicine in Baltimore has
already tested just such a compound in rats. He's also working on
compounds that extinguish some of the euphoric effects of alcohol,
which he says might some day be useful in helping alcoholics stay
sober. Nutt, meanwhile, is testing 5 blockers as memory preservers,
with promising results. Using a drug originally developed to enhance
memory in older people, he was able to preserve memory in drunken human
volunteers. Apply that logic elsewhere - to the GABA subunits that are
presumably linked with aggression, loss of judgement or addiction, for
example - and we would be well on our way to a safer tipple.
some of the actions of alcohol is one approach, but what about building
a replacement drug from the ground up? It so happens that many of the
GABA receptors where alcohol works its magic are the same ones engaged
by a class of drugs called benzodiazepines. These are sold as
anti-anxiety drugs, but share many of the psychoactive properties of
alcohol, most notably relaxation. "It's an alcohol-like effect," says
He is principally interested in coming up with an alcohol
substitute that does not cause chronic damage to the heart, liver and
brain. To engineer just such a safe proxy, he proposes using the
benzodiazepine molecule as a starting point. It has been around for 40
years, he points out, and vast numbers of people have used it for long
stretches of time with scant signs of organ damage. What's more, the
effects can be instantly reversed with existing antidotes, such as
flumazenil. Benzodiazepines, though, have an insurmountable drawback as
an alcohol substitute: they are dangerous when combined with alcohol
Nutt, however, thinks it will be possible to "engineer"
these problems away. He has his eye on a new class of benzodiazepines
called partial agonists (PAs). These don't bind as strongly to GABA
receptors as do full agonists such as diazepam (Valium), and produce
less of a physiological effect. And this, says Nutt, gives them certain
advantages as alcohol substitutes. PAs show little or no interaction
with alcohol, little sedation even in overdose, and few signs of
creating dependence or causing serious withdrawal effects.
team is already at work on that. They have found and patented two
compounds that seem to be able to mimic some of the desirable effects
of alcohol, such as euphoria and relaxation, in rats and baboons. A
team led by Richard Olsen at the University of California, Los Angeles,
is also hot on the trail of alcohol-mimicking compounds.
a substitute drug is one thing; delivering it is something else. It's
unlikely that someone who fancies a sociable drink after work would opt
to swallow a pill instead. Clearly, the best way to deliver an alcohol
substitute would be in drinks similar to existing alcoholic beverages,
but that raises another significant problem: taste. Many drinkers
report a strong liking for the taste of alcohol and would be unlikely
to switch to a safer alternative.
Nutt believes this is
solvable. He says that drinkers learn to like the taste of alcohol
because they associate it with pleasure, so they could gradually
re-educate their palates to appreciate substitutes too. Another
possibility is to get food scientists to replicate the taste of alcohol
and add it to the substitute, though no one knows whether that is
doable. Anyone who has tasted alcohol-free beer would probably bet
There is, however, another possibility. Our growing
understanding of how alcohol interacts with the brain is leading some
researchers to suggest that we could develop a magical sobering-up pill.
years ago a team led by Olsen showed that the effects of low doses of
alcohol - the equivalent of two or three drinks - were largely mediated
through another GABA receptor subunit called . Then, in May this year,
the group published two papers about these subunits and how they
interact with an existing experimental drug, Ro15-4513. This potent
antidote to alcohol intoxication can get a drunk animal up and running
in mere minutes.
It wasn't entirely clear how Ro15-4513 achieved
this, but Olsen and his colleagues have now explained the mystery: the
drug dislodges ethanol from sites (Proceedings of the National Academy
of Sciences, vol 103, p 8540). What's more, by working out what the
ethanol molecule and the antidote drug have in common, the researchers
believe they have pinpointed which part interacts with the receptor.
This raises the possibility of designing other alcohol antidotes.
Ro15-4513 has some unsavoury side effects including seizures, and only
lasts about 30 minutes. Understanding that common chemical structure
also makes it more likely that a good alcohol substitute can be found.
it's not that simple, says Ian Ragan, a pharmaceutical company
researcher turned consultant. It's one thing to know which receptors
alcohol affects, he points out, but quite another to tease out exactly
which combination produces what effect. "You have to know what's
responsible for the 'feel-good'," he says, "and that's hard to
demonstrate in animals." Besides, everyone agrees that GABA receptors
are not the only targets for alcohol in the brain. Receptors for other
neurotransmitters including glutamate, opioids, dopamine and serotonin
are all thought to be involved in some way too.
are always trying to find a way to get drunk without the consequences,"
adds Ames Sweet of the US National Council on Alcohol and Drug
Dependence, a not-for-profit organisation based in New York. "It's a
The reality is, though, that the biggest
hurdles to safer alcohol may not be technical ones. Even if someone
developed good alcohol blockers, booze substitutes or sobering-up
pills, chances are they would end up gathering dust. Consider the
sobering-up drug Ro15-4513. You may be surprised to hear that it was
developed more than 20 years ago by pharmaceutical company Roche. Why
have you never heard of it? Why can't you buy something similar over
When Roche researchers discovered that the compound
could undo the behavioural effects of drunkenness, they were surprised
and delighted. However, they later found out the drug has no effect on
blood alcohol levels and consequently does nothing to prevent acute
alcohol poisoning, which is probably caused by alcohol's effect on cell
membranes throughout the body.
Sobriety pillRoche was not
keen on pursuing a simple sobriety tablet. It feared that, in the long
run, such a pill might encourage drinking, rather than make it safer.
Worse, they could envisage what might happen if someone used the drug,
then caused an accident while driving home. They may have taken a
sobering-up pill, but their blood alcohol level would still prove
drunkenness. Roche's lawyers saw it as a legal nightmare, and the
company dropped it.
There is another paradox. Psychoactive and
addictive though it is, alcohol is regulated not as a drug but as a
foodstuff. Any new substance purporting to counteract alcohol or
replace it, on the other hand, would be regulated as a pharmaceutical.
This creates potential barriers. For one thing, it might make alcohol
blockers or substitutes harder to obtain than alcohol itself. It's hard
to imagine ever getting to the point where such a drug or additive was
being sold casually over the bar alongside beer, says Robin Room,
director of alcohol policy research at Turning Point, an alcohol and
drug research centre in Melbourne, Australia. What's more, he says,
it's unlikely that anyone would want memory preservers badly enough to
go and get a prescription.
Nutt suspects that only an
intervention by government - announcing that it supports the making of
safer alcohol, that they will tax it preferentially, or regulate it
differently - is likely to make the difference. There are reasons for
optimism on this front. New Scientist has learned that the UK
government has asked the Academy of Medical Sciences to look at the
case for safer alcohol and make recommendations.
government backing, drug companies will be cautious. "The
pharmaceutical industry does not position itself to be going into the
recreational market," says Ragan. There are always risks when you take
a drug, he points out. When you're treating a life-threatening disease
such as alcohol addiction, they may be risks you are willing to take.
But those risks are harder to justify in the merely sozzled.
to that the moral indignation that attaches to any suggestion that
boozers should be allowed to drink more safely, and it looks like an
uphill battle for safer alcohol. Many people in the alcohol addiction
recovery field believe fervently that the only solution is outright
abstention, and any drug of the type Nutt suggests would meet with
stiff opposition. As an example, Room points to a drug called
propylthiouracil. Normally prescribed for an overactive thyroid, it has
also been shown to protect against cirrhosis of the liver in
alcoholics, but is not widely used for that purpose. "My theory of why
[it] has not become better established as a medication for reducing the
harm to an alcoholic's liver," he says, "is the fear that it will allow
the alcoholic to continue drinking."
But things change. Ragan
recalls working in the pharmaceutical industry in the 1980s, when the
idea of drugs to fight obesity was raised. "There was almost a riot,"
he says. Obesity, his colleagues felt, was a lifestyle problem. "So
that's how far we've moved." Safer alcohol may not be coming to a pub
near you just yet, but it's surely too good an idea to dismiss as idle
In place of liquorCoca-Cola
was originally formulated as an invigorating drink "without the vices
of alcohol". From its introduction in 1886 until 1903, it contained
about 60 milligrams of cocaine per serving. By 1906 the cocaine was all
but gone and Coca-Cola was touting itself as "The Great National
Temperance Beverage". But as you would expect with something that mixes
so delightfully with rum, its potential as an alcohol substitute turned
out to be limited.
the 1960s and early 1970s, cannabis was talked about as a possible safe
alternative to alcohol. It never caught on in that context. If
anything, pot went the way of Coca-Cola: it made a nice drinking
companion. It is still being tested, however, as an alternative for
alcoholics trying to dry out.
is an ancient western Pacific crop, usually consumed as a tea in Fiji,
but sometimes chewed. Advocates claim it calms you, clears your head,
relaxes your muscles and creates a sense of euphoria. It was introduced
into some of Australia's indigenous communities as a safer alternative
to alcohol, but whereas in Fiji it is used slowly and communally, in
Australia people binged on the stuff, and faced some serious side
effects. Kava is another nice alcohol mixer.
to give it its formal name, is used as an anaesthetic, a sleep aid and
a recreational drug. In Italy GHB is also employed as an alcohol
substitute for alcoholics trying to abstain; it has been used there
since 1991, and several studies have concluded that it is safe if
administered in the right way. Unfortunately, it is all too easy to get
it wrong: GHB is addictive, lethal in very high doses and interacts
dangerously with alcohol. Italy is the only country to use GHB as an
face it, they don't taste as good as the real thing, but they seem to
help curb people's excesses. An experiment during the Euro 2000
football tournament suggested that the concentration of alcohol can
make all the difference. The mayor of Eindhoven in the Netherlands
allowed only beer of 2.5 per cent alcohol or less to be sold during the
tournament, and there was little trouble from English football fans
when their team played a match there. The next week, imbibing
full-strength beer, drunken English fans participated in large-scale
riots in Charleroi, Belgium.