Newscientist Article

[jamman]

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 sociable.

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.

Alcohol 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?"

The big 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 proved popular.

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.

Although the 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.

There 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 alcohol's effects.

“It should be possible to design drugs that block alcohol's undesirable effects”

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.

Blocking 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 Nutt.

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 itself.

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.

June's 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.

Tasty tipples

Having 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 against it.

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.

Three 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.

But 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.

“People are always trying to get drunk without consequences. It's a misguided illusion”

"People 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 misguided illusion."

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 the counter?

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 pill

Roche 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.

Even with 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.

Add 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 bar-room speculation.

From issue 2560 of New Scientist magazine, 15 July 2006, page 30

In place of liquor

Coca-Cola

Coca-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.

Marijuana

In 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.

Kava

Kava 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.

GHB

Gamma-hydroxybutryrate, 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 alcohol substitute.

Lower-alcohol beers

Let's 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.