At the end of last year the media was full of articles about Professor David Nutt’s proposal to develop a drug that mimics the effect of alcohol without creating a hangover. Not surprisingly, this caused major discussions. Besides the legal concerns of replacing alcohol with another psychoactive drug, his suggestion came attached to a call for funding which was seen as a cheeky lobbying attempt by some.
Nutt, professor of neuropsychopharmacology at Imperial College London, is certainly right when he claims that western society has a problem with alcohol consumption. Alcohol is one of the oldest but also most harmful drugs, responsible for ~2.5 million deaths each year, according to the WHO. But because it is so immersed in our culture and has been around forever, people tend to turn a blind eye. As Prof Nutt says: “If alcohol was discovered today it could never be sold as it is far too toxic to be allowed under current food regulations”.
We’re still happy to put up with its after-effects if that means we can enjoy a night of excitement, uninhibited pleasure and jauntiness. But would we still drink alcohol if we could experience most of the positive effects without next day’s hangover? What exactly is it that alcohol, or more accurately ethanol, does to our brains?
Because of its molecular structure ethanol is highly cell membrane-permeable and will quickly reach all the tissues in the body, including the brain where it affects human consciousness (psychoactive). It is mostly a central nervous system depressant.
On a molecular level, ethanol binds to the receptor for gamma aminobutyric acid (GABA-A) which is a neurotransmitter system in the brain that helps to keep it calm (1). In addition, it inhibits NMDA receptors, which are important for memory functions, learning and a target of the main activating neurotransmitter glutamate in the brain (1). When ethanol, at low or moderate doses, mimics the GABA function the result is an overall sedative effect: it delays reactions, impairs memory (you forget your trouble but might also have difficulties remembering your night of drinking afterwards), judgement and comprehension, disrupts your balance and vision (2). It therefore temporarily reduces your brain functions. And as we all know ignorance is bliss.
The main “wished-for” effects, an overall improvement of mood, loss of inhibition which boosts self-confidence and sociability, decreased anxiety and a shortened attention span, are also caused by ethanol’s activity at the GABA-A receptor (2). In that it is similar to other sedative drugs such as benzodiazepines (Valium), barbiturates and even anaesthetics (e.g. Propofol) which are also binding the receptor and can all have relaxing, anti-anxiety effects.
It is well-known that all these effects are dose-dependent. Because ethanol affects the brain so profoundly, high doses (blood alcohol content over 1 g/L or 1 permille) can disrupt its functions severely: this ranges from impaired speech, sensory & motor function, confusion, vomiting to unconsciousness, decreased heart-rate, coma and death by acute alcohol poisoning (3).
Prolonged heavy consumption of alcohol causes permanent damage to the brain and other organs. It also has lasting effects on the cell surface receptors ethanol binds to (1), which is why abrupt abstinence can result in hallucinations, seizures, tremor and delirium tremens, similar to drug withdrawal symptoms (4). Because ethanol is highly neurotoxic, long-term drinking causes neuronal damage, contributing to lasting neurological disorders, including dementia, depression, mania and paranoia, and an overall decline of mental abilities (4). These effects are irreversible because ethanol also reduces the brain’s ability to produce new neurons (5). Besides, it has been reported to induce DNA damage in cells (6), which increases the risk to develop cancer – depending on a person’s genetic profile (7). And it is teratogenic (8), which means it will cause neurological and physical defects in a fetus if consumed during pregnancy (again: it easily passes through the placenta and is taken up by the fetus).
But this is not the only reason why drinking – and not only heavy drinking – comes with a higher risk for certain diseases. Acetaldehyde, which is one of the substances ethanol gets metabolised into when it is processed in the liver, is highly carcinogenic (classified by the IARC as Group 1 carcinogen). Ethanol also disrupts the fat metabolism in the liver, leading to accumulation of lipids in the liver cells (“fatty liver”) which eventually causes cell death, inflammation, cirrhosis and – if untreated – might result in liver cancer (7). The risk for diabetes mellitus type 2 is higher because ethanol taps into glucose metabolism and causes insulin resistance (9). This effect has only been observed in heavy drinkers, though, and light-to-moderate drinking might actually improve insulin sensitivity. Occasional alcohol consumption is in fact associated with a lower incidence rate of type 2 diabetes (9). This touches on another controversy in studies about the effects of alcohol: moderate drinking seems to reduce the risk of coronary disease and stroke, but only if less than 12 g ethanol (less than 1 beer) per day are consumed. More than 60 g per day increases the risk again (9).
To sum it all up
Ethanol is a toxic chemical which anyone with a healthy consideration for his or her body would hesitate to touch if it was presented with a patient information leaflet and a list of side-effects. Some people freak out when they read the information on the back of their aspirin package. But the same bunch heads cheerfully into the next bar and orders rounds and rounds of shots (by the way: ethanol is a painkiller, too (10) – it induces analgesia via the activation of potassium channels; but considering the after-effects and the necessary dose it’s really quite inefficient).
The ancient societal role as (legal) collective pleasure inducer – in combination with peer pressure, of course – is hard to argue with. Even while I’m writing this article I know that my next week will probably include several after-work beers and some casual weekend drinking. It’s a habit and it’s hard to break – especially if the negative consequences are not (yet) noticeable and outweighed by seemingly many reasons to go for it.
But aren’t they really? What about all those countless weekend-morning hangovers? The headaches or, worse, vomiting and memory loss (OK, the days when I was getting that drunk are mostly over). Isn’t that my body yelling “stop poisoning me!” with quite some vehemence? Provided I want to keep drinking (casually) – does it really have to be like this?
Can we reverse the effects?
Not only scientists are thinking about this issue for quite some time now. The question probably already came up during the neolithic period, when the first fermented beverages were produced. Generally, two main ideas have been suggested which are intended to take care of the hangover once and for all:
Imagine you’re out on a Friday night, it’s late and you’ve had a few. Actually way more than a few, you realise as you walk outside and notice that your motor skills are a thing of the past and your stomach feels like its ready to jump straight through your throat. Wouldn’t it be nice to just pop a pill now and within half an hour revert back to a normal human being?
In a recent nature nanotechnology paper (11), a group from UCLA reports the successful construction of nanocapsules which contain enzymes that can metabolise ethanol and decompose of toxic by-products, while circulating in the blood and stomach. The researchers tested the capsules on mice and reported a quick reduction in blood alcohol content of treated animals as opposed to controls. They propose that their invention could be used as a prophylactic and as an antidote which prevents alcohol intoxication even after you’ve already had a few drinks. Sounds too good to be true?
So far, the authors have used nanocomplexes containing two enzymes, alcohol oxidase and catalase, combined to reduce blood alcohol level. This only takes care of the initial metabolising step and does not remove acetaldehyde, the toxic by-product which is generated in a later step by different enzymes. A look at the statistics also shows that the blood alcohol reduction is not massive but noticeable: oral administration of alcohol and nanocapsules at the same time results in a reduction of blood alcohol concentration by 31.8% after 90 minutes (compared to drunk mice which get drug-free capsules and obviously also showed reduced blood alcohol levels, but less so).
If already intoxicated mice are injected with the capsules, the reduction is lower but still quite noticeable (26.1%), indicating that the drug also works as an antidote. Unfortunately, the nanocapsules are washed out from the blood stream after a while and will reach the kidney after about 40 minutes, which means that they lose their function.
Studies in humans have not been conducted and so far there is little known about physiological effects of the nanocapsules. But the idea is certainly worth a try – a patent has already been filed.
The availability of a drug which helps your body to metabolise ethanol faster after you’ve had too much would certainly be a useful thing. I’m still skeptic about the use of it as a prophylactic. In theory that would mean that you pop the pill before you head out with your colleagues for some after-work drinks, you have your beers and won’t feel hardly any effects – at least as long as your capsules are present in your blood and stomach. But why then drink at all? In any case, you will only drink more and spend more money to get yourself relaxed. So unless you want to embark on a drinking competition with a group of dedicated alcoholics a prophylactic pill would probably be of little use.
If ethanol is toxic why don’t we just use something with a similar, but less powerful effect on the brain that comes without side-effects?
This idea is not entirely new. When researchers tried to delineate the mechanisms of opioid addiction, for instance, they found that it is caused when the drug binds to specific opioid receptors in the brain, which can also be activated by endorphins and other endogenous proteins in the body. Opioid drugs such as morphine and its derivative heroin bind to the μ-opioid receptor which is responsible for the main drug effects and side-effects: analgesia, sedation, euphoria, constricted pupils, constipation, respiratory problems etc. Recent studies suggest that this receptor, at least in part, is also to blame for the addictive potential of these drugs by inducing tolerance and a rewarding feeling after use (12). This is further supported by the δ-opioid receptor which interacts with the μ-receptor upon drug binding (12).
But as always there is a third opiod receptor, κ, which seems to antagonise the other two. Opioid drugs that bind there even produce an aversive effect in mice (12). It has therefore been suggested that unwanted effects of opioids, such as tolerance and psychological dependence, could be prevented by activation of the κ receptor, while the analgetic and sedative effects would remain. This would make common opioid-based analgesics safer for patients, but it could also be used to treat drug addicts and help them reduce withdrawal symptoms and stop their drug use.
Sure, one can hardly compare the effects of heroin to those of alcohol but the pharmacological principles behind receptor binding and drug effects remain the same.
So could we replace ethanol with a drug that gives us the inebriation without the damage and hangover?
We know that ethanol targets the GABA-A receptor and we also know that a range of GABA subsystems can be targeted by other, selective drugs. The entire GABA-A system is extremely complex and so far 19 different subunits of the receptor have been identified (13), resulting in a remarkably diverse spectrum of receptor subtypes throughout the brain. And all these receptors come with different functional roles which are also dependent on the drug they bind. So in theory we could identify substances that only activate the systems which cause sedation and relaxation, and remove the unwanted effects, such as aggression and addiction. Prof Nutt claims he has identified five feasible compounds and is in the process of testing them to see if people find the effects comparable to alcohol.
It is difficult to believe, though, that a drug like this would come completely without side effects. It would still need to be membrane-permeable to be delivered in a drink – and it would need to be psychoactive to have the sedating or euphoric effect on the brain. As mentioned earlier in the example of opioid substitution the addiction is something that could probably be selected against. But heavy drinking would likely remain as deleterious as it is now, because anything that affects the brain will disrupt the careful balance in the neurotransmitter systems that keep our mind healthy. It doesn’t even have to be neurotoxic for this – but chances are that it would be, because as it permeates the membrane it destabilises the organisation of the lipid components and attached proteins, impairing receptor functionality. With this, the cell loses its ability to communicate with surrounding cells.
But at least an alcohol surrogate would come without the nasty company of acetaldehyde and that, for sure, would decrease toxicity, overall damage and cancer risk.
The challenge is to overcome all the legal hurdles of introducing a new, psychoactive drug. There is a difference between releasing a pharmacologically tested, FDA-approved substance onto the market for medical purposes – and selling it as (a component?) of a drink. Prof Nutt speaks of an enormous health potential of a safer alternative to alcohol. But he has also realised that alcohol, as it is, would never be legalised nowadays – because of its harmful effects. And they do not only include toxicity and hangovers, most of all they lead people to act carelessly, endanger themselves and others, lose control and their common sense.
As long as people are getting drunk, one way or another, this will be bound to happen. We will have many more serious discussions ahead of us, should Prof Nutt ever find a feasible candidate drug he wants to put on the market.
Things you can do
While you’re waiting for a human version of the sober-up pill and the legalisation of Prof Nutt’s GABA wonder-drug, here is a list of common sense principles that will help you deal with your hangovers. You’ll find it’s all the usual stuff that sometimes works – and sometimes doesn’t. I’m afraid I have to end this article with the rather bleak confession that there still isn’t any real cure for hangovers out there. Most of the strategies mentioned in the link above are simply myths. Except for the water, food and sleep advice – and, of course, the best recommendation of all: if you want to avoid a hangover, don’t drink too much.
And if there are any questions left, please don’t hesitate to mention them in the comment sheet below. I’ll make sure to update this article as soon as the wonder-drug has been announced 🙂
Want the scientific details? Here are the references:
- Sanna et al, 2006. Chronic Ethanol Intoxication Induces Differential Effects on GABA-A and NMDA Receptor Function in the Rat Brain.
- GABA Receptor Physiology and Pharmacology. Richard W Olsen and Timothy M DeLorey. 1999.
- Alcohol poisoning: http://www.nhs.uk/conditions/alcohol-poisoning/Pages/Introduction.aspx
- Ethanol and Cognition: Indirect Effects, Neurotoxicity and Neuroprotection: A Review. Brust, 2010.
- Alcohol inhibition of neurogenesis: a mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model. Morris et al, 2010.
- Acute exposure of cultured neurones to ethanol results in reversible DNA single-strand breaks; whereas chronic exposure causes loss of cell viability. Lamarche et al, 2003.
- Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus. Hassan et al, 2002.
- Fetal alcohol. Teratogenic causes of developmental disabilities. Streissguth et al, 1987.
- Diabetes mellitus and alcohol. van de Wiel A., 2004; Ethanol-induced Alterations of Glucose Tolerance, Postglucose Hypoglycemia, and Insulin Secretion in Normal, Obese, and Diabetic Subjects, Nikkilä EA, Taskinen MR., 1975; Ethanol causes acute inhibition of carbohydrate, fat, and protein oxidation and insulin resistance. Shelmet et al, 1988.
- Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? Ikeda et al, 2002.
- Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication. Liu et al, 2012.
- Narita et al, 2001. Regulations of opioid dependence by opioid receptor types; Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. E E Abdelhamid et al, 1991.
- GABA-A receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Keith A Wafford. 2005.