© LJUPCO / ISTOCKPHOTO.COMAlcohol is the oldest of all recreational drugs. While its psychological complications have long been known, only in the past century have its medical complications, such as liver cirrhosis, cardiovascular disease, and cancers, become recognized. In many Western countries these medical problems have increased at an alarming rate. In the United Kingdom, for example, the death rate from liver disease has risen 500% over the past 40 years. It is predicted that, within a decade, liver disease will overtake cardiovascular disease as the leading cause of death in the UK. For these reasons, a recent systematic assessment of drug-related health hazards in the UK scored alcohol as the worst drug overall (Nutt et al., Lancet, 376:1558-66, 2010).

These facts raise two questions: why is alcohol so widely available if it is so toxic and what can we do about it? The answer to the...

So what can we do about it? I think it is time to use the now-considerable knowledge of the neuropsychopharmacology of alcohol to develop safer, alternative intoxicants whose effects can be reversed by antidotes. A prime target of alcohol in the brain is the GABA-A receptor. Alcohol enhances the actions of the endogenous neurotransmitter GABA, which regulates the major inhibitory system in the brain. Since GABA-A receptors are found on most neurons, alcohol has a wide range of effects. Other drugs that enhance GABA at this receptor mimic the relaxing, antianxiety effects of alcohol. The best examples are the benzodiazepines, which enhance GABA action. Drinkers report that agonists at benzodiazepine receptors behave just like alcohol (Psychopharmacology, 166:181-87, 2003), and there exist potent and effective antagonist/antidotes, which are currently clinically available.

In addition, we now know that the GABA-A receptor comes in many subtypes. These have quite specific localizations in the brain and it seems that different subtypes mediate different effects of alcohol. For example the a5 subtype has been shown to be involved in the memory-impairing actions of alcohol in humans, as these impairments can be fully reversed by a drug that reduces GABA function only at this receptor subtype (Neuropharmacology, 53:810-20, 2007). It is suggested that the relaxation and pleasure-mediating effects of alcohol may be mediated by the a2 and a3 subtypes, whereas a1 stimulation leads to sedation and unsteadiness. This raises the possibility that agonists targeting these receptor subtypes might provide alcohol alternatives with more subtle actions, such as relaxation and intoxication, without accompanying unsteadiness or amnesia. Although the benzodiazepines are very safe drugs, even greater safety margins could be provided by the development of partial, rather than full, agonists, several of which have already been made available (bretazenil and pagoclone).

Given this knowledge base, why do we not use science to reduce the harms of alcohol? Maybe it is because the opportunity has not, until now, been viable. More likely is the implicit assumption by the public and legislators alike that alcohol is a foodstuff/commodity rather than a drug. Current regulations mean that replacing alcohol with a real “drug” would be challenging; it might have to pass the same safety hurdles as medicines, rather than the much lower hurdles for foods. If governments gave a signal that they wanted a safe alternative to alcohol, I am sure the skills of the pharmaceutical industry, coupled with the knowledge of academia, could rapidly produce viable candidate molecules. With 1.5 million people dying of alcohol-related diseases every year, surely it is now time for scientists to open up the debate?

David Nutt is the Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London and chair of the Independent Scientific Committee on Drugs. He is a practicing psychiatrist whose main research interest is the brain imaging and translational medicine of addictions. Nutt has been an F1000 section head (Psychiatry: Substance Abuse) for the last five years.

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