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Synthetic Spirits

By David Nutt Synthetic Spirits Can we use science to reduce the harms of alcohol? © Ljupco / Istockphoto.com Alcohol 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 Kingdo

By | January 1, 2011

Synthetic Spirits

Can we use science to reduce the harms of alcohol?

© Ljupco / Istockphoto.com

Alcohol 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 first question appears to be partly due to the fact that many people (and governments) take an ostrich-like view of the health hazards of alcohol. This attitude is compounded by the argument (probably false) that, at low doses and in some populations, alcohol may, in fact, have certain health benefits. Both attitudes belie the facts. If alcohol were invented today and subjected to current safety-of-use assessments, it would fail badly. Ethanol, the active ingredient, is toxic itself, which is why it is used to protect food from microbial infections and to sterilize skin. An amount only three times higher than a common intoxicating dose leads to death in naive users. And there is no antidote. Moreover, ethanol is converted to acetaldehyde as part of its elimination process. This is a highly toxic substance that in effect pickles the liver and other organs of regular drinkers.

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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Comments

Avatar of: Henry James

Henry James

Posts: 2

January 4, 2011

The article failed to mention the WHO project to reduce alcohol harm. It was signed on to by 128 of 168 countries (not the U.S., Canada, or other alcohol producers.) The damage done to individuals, families and communities by alcohol pales all that done by all other illegal and legal drugs put together. Only (legal) tobacco beats it in actual deaths/user. \n\nBut America focuses it's power and money on much less dangerous drugs and leaves the real problems with insufficient funds. How come? Alcohol Lobby? Alcohol Taxes? Alcohol at Congress/Senate/Administration parties? \n\nNature has provided cannabis, an alternative that works for many and is much safer than alcohol (or tobacco,) by any measures. But we're spending all our big money on the War On Drugs and cannabis control eats up 3/4 of that, leaving little to spend on the real tragic problems. \n\nToo bad. I don't think we need spend any more on designer drugs to replace alcohol until we use up the good natural ones we already have. Who has ever found a real reason to prohibit cannabis in favor of alcohol, other than for political or cash-flow reasons? I know cannabis is a big threat to alcohol producers because users drink less, and the subsequent loss of taxes threatens politicians. And the prison industry needs inmates.\n\nSo, this seems crazy to me - we prohibit a relatively safe alternative to a dangerous drug while trying to invent a synthetic, "better" one with unknown effects. I hope scientific rationality takes over and we deal better with humans' ability to alter internal states without trying to invent some insane non-drug recreational drug.\n\n
Avatar of: ROBERT HURST

ROBERT HURST

Posts: 31

January 10, 2011

The thought behind the article assumes that the main reason for drinking alcohol is to activate GABA receptors. It's much more complicated than that! When one pours a snifter of a fine cognac, much more than GABA receptors are activated. A smoky Islay scotch is truly one of life's experiences when savored on a winter evening before a warm fire. Simply taking a pill to feel buzzed is in no way comparable!\n\nAnd, I would point out, several very large epidemiological studies have shown the beneficial effects of moderate alcohol consumption.
Avatar of: Tarakad Raman

Tarakad Raman

Posts: 31

January 11, 2011

The author says, "... death rate from liver disease has risen 500% over the past 40 years." Is this a real increase, or is it due to better diagnosis? In any case, I wonder whether the alleged increase in liver disease or deaths due to it can be attributed mainly or exclusively to alcohol consumption.
Avatar of: Andrew Ostrom

Andrew Ostrom

Posts: 1

January 11, 2011

I think the author's intentions are good, but I don't think he's thought through all aspects of his suggestion. I fear that in this case, the cure may be worse than the disease... If his proposal is adopted, what would we have? In many cases, instead of having intoxicated people too sleepy and uncoordinated to cause trouble, we'd have a lot of "wide awake drunks". Back when I was preparing to take the EMT exam we were warned never to feed coffee to a drunk because, "it doesn't sober them up; it just creates a wide awake drunk, and NOTHING is worse than a wide awake drunk." \n\nFor example, I can imagine huge carnage on the highways if we create a large population of intoxicated people who think they're coordinated and awake enough to drive while under the influence. At least the medical impact of alcohol consumption is self-inflicted; what about all those innocents killed by the users of these new designer drugs?\n\nI'm certainly not advocating the long-term abuse of alcohol, but sometimes we're actually better off with the Devil we know. In this case I think we need to be really careful that the unintended side-effects don't make things worse rather than better.

January 13, 2011

Interesting idea. Skipping ahead to the marketing .... would be "low calorie" compared to alcohol.
Avatar of: Thomas Lucero

Thomas Lucero

Posts: 1

January 14, 2011

In the U.S., heavy drinkers have an average lifespan of 64 years, non-drinkers have a lifespan of 72 years, while moderate drinkers (defined as 1-2 drinks per day) have an average lifespan of 80 years. \n\nDrinking is a net minus before age 30 in the U.S. (accidents and violence), a net plus age 30-75, and if you live past age 90, a net minus. The large decrease in cardiovascular mortality (50-60%) easily offsets accidents and cirrhosis until age 85-90, where those who live that long die more from causes other than cardiovascular (cancer, infections, complications after fractures, etc.) Alcohol also protects less against stroke than heart attack.\n\nPeople who drink often do it because of the social interaction, and a pill will not substitute for that. A different approach would be to add vitamins and antioxidants to alcoholic beverages. However, that has been a felony in the US for decades.
Avatar of: IGOR GONDA

IGOR GONDA

Posts: 1

January 26, 2011

We admire the ambitions of Dr. David Nutt to find a safe replacement for ?alcohol? (i.e., ethanol)(ref.1) . Finding synthetic molecules that emulate the beneficial effects of natural substances - but without the side effects they cause - has been a very risky, costly and lengthy process dotted with many more failures than successes ? decades of R&D and billions of dollars per each success are the norm. \n\nAlcohol dependence is one of several dependence syndromes with devastating effects on global public health but it is far from the worst drug overall. That prize is won hands down by tobacco smoking: The World Health Organization?s (WHO) recent report states that tobacco smoking is the single most preventable cause of death in the world today. Already tobacco smoking kills more than five million people per year ? more than tuberculosis, HIV/AIDS and malaria combined. WHO warns that by 2030, the death toll could exceed eight million a year. Unless urgent action is taken, smoking tobacco could kill one billion people by the end of this century (ref.2). According to the National Institute on Drug Abuse (USA), ?Economically, more than $75 billion of total U.S. healthcare costs each year is attributable directly to smoking. However, this cost is well below the total cost to society because it does not include burn care from smoking-related fires, perinatal care for low birth-weight infants of mothers who smoke, and medical care costs associated with disease caused by secondhand smoke. In addition to healthcare costs, the costs of lost productivity due to smoking effects are estimated at $82 billion per year, bringing a conservative estimate of the economic burden of smoking to more than $150 billion per year.?(ref.3) \n\nIn contrast to alcohol, nicotine is relatively safe; it is its ?delivery system?, i.e., the cigarette, that generates the toxic components of tobacco smoke responsible for the devastating health impact of smoking. A product that was able to deliver ?harmless? nicotine to smokers with the same satisfying effect as the cigarette, but without the toxic components of tobacco smoke, would be a groundbreaking development. The perceived satisfaction from administering nicotine (and thus the reduction of craving for cigarettes) appears to correlate with the speed of entry of the substance into the brain - the fastest resulting from the absorption of nicotine from the lung (vs. nicotine patches, lozenges or nasal drops). It is now possible to deliver pure nicotine into the deep lung which might turn out to be the most effective method to wean people of cigarettes and the deadly toxins delivered through them.(refs.4,5) Exploration of lung delivery of inhaled nicotine for smoking cessation in controlled human clinical trials is urgently needed to explore this promising method of addressing the arguably most serious preventable health care problem in the world.\n\n1. D. Nutt, ?Synthetic Spirits: can we use science to reduce the harms of alcohol?, The Scientist, 25:23, January 2011.\n\n2. WHO report on the global tobacco epidemic, 2008 (2008). The MPOWER Package, World Health Organization, Geneva, Switzerland, http://www.who.int/tobacco/mpower/en/ \n\n3. National Institute on Drug Abuse (2006). Research Report on Tobacco Addiction. http://www.nida.nih.gov/PDF/RRTobacco.pdf\n \n4. I. Gonda, P. Bruinenberg, S. Mudumba and D. Cipolla, ?Smoking Cessation Approach via Deep Lung Delivery of ?Clean? Nicotine?, Respiratory Drug Delivery Europe 2009 (Eds. P.R. Byron et al.), Davis Healthcare International Publishing, River Grove, IL, USA, pp.57-62 (2009), http://www.rddonline.com/publications/articles/article.php?ArticleID=1352\n\n5. B.A. Otulana, R.J. Morishige, P. Bruinenberg and J. K.Marjason, ?Nicotine Delivery Using a Novel Inhaler?, National Conference on Tobacco or Health, Minneapolis, MN, USA, 2007, http://ncth.confex.com/ncth/2007/techprogram/P15442.HTM\n\nIgor Gonda, Aradigm Corporation, Hayward, CA, USA, gondai@aradigm.com\n\nElena Ratschen, University of Nottingham, Division of Epidemiology and Public Health\nUK Centre for Tobacco Control Studies, Nottingham, UK\nElena.Ratschen@nottingham.ac.uk\n

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