The Causes of Hangovers

If you want to make two dull but reliable predictions,  one would be that the sun will still be there for us in 2017. Our star will continue to offer stability for another 5 billion years, a number as hard to imagine as the fact that France produces 4.3 billion litres of wine annually. Another sure-to-materialize prediction is that a fair number of people will overindulge in drinking alcohol on New Year’s Eve and wake up with a hangover.

from GQ magazine

Is alcohol the only cause of the hangover? It is its main cause,  but the severity of a hangover is correlated with a higher concentration of congeners. Congeners are minor compounds that appear in alcoholic drinks as a result of both fermentation and distillation. These include amyl alcohols, methanol, acetone, furfural and tannins.


Before examining congeners, let’s look at ethanol itself, the main active ingredient in alcoholic drinks. The common explanation as to why alcohol causes hangovers is based on the compound’s ability to cause dehydration. But the biochemistry involved seems to be more complicated than that. The best hypothesis out there is based on cytokine levels. Excessive drinking raises levels of pro-inflammatory cytokine. In general cytokines are small proteins that play important roles in cell signalling. There are receptors for cytokines in the brain, especially in the hippocampus, a structure important in forming memories, so the memory-impairment from heavy drinking could very well be linked to cytokines. In a study where cytokines’ concentration was raised by injecting patients with 0.8 nanograms of S abortus equi endotoxin per kilogram of body weight, a “global decrease of memory function was observed” .

There is also evidence that a pair of cerebral cytokines (IL-1β and IL-6) and tumour necrosis factor (TNF-α) lead to malaise similar to hangover. For example in animals, elevated levels of cytokine cause weakness, inability to concentrate, decreased appetite, reduced activity, sleepiness, and loss of interest in everyday activities such as calculus. As recently as last year , research continued to provide evidence that cytokine levels are high during hangover.


So do congeners accentuate that mechanism? It’s not known yet. But bourban, brandy and red wine have the highest concentrations of congeners ( about 30 to 55 mg per liter) and produce more severe hangovers than vodka, which is low in congeners.

I have had only one hangover in my life, over 35 years ago, and I have not been drunk since. Once we start drinking our judgement is impaired, leading us to drink more, and I don’t like to yield my control to a single type of molecule.  I’m also lucky to have had a life so far in which I want to remember more than what I want to forget, so alcohol is of little use to me. Except for a few good-tasting wines and beers, most alcoholic drinks also taste like poison.

Although no one in 2017 will find a general cure for all the different diseases labelled as cancer, I hope that more people will take prevention seriously. It’s not common knowledge that alcohol is a very dose-dependent class 1 carcinogen. For example, if women refrain from doubling the recommended maximum intake of 14 units of alcohol per week(equivalent of 1.6 bottles of 12% wine), about 30 more women per 1000 will avoid breast cancer. Men are not as sensitive to alcohol from a cancer-perspective, but they are not immune to it either. The National Cancer Institute site does a good job outlining which cancers are associated with alcohol and the amounts of drinking involved. Why alcohol is carcinogenic is probably related to

(1) the genotoxic effects of its metabolite, acetaldehyde;

(2)to its ability to raise estrogen levels ( hence its breast cancer-causing role)

(3) to the reactive nitrogen and oxygen species it produces

(4) and to its ability to act as a solvent for other carcinogens, especially those in tobacco smoke.

So avoid a hangover and reduce your chances of cancer by toasting the New Year with only a test tube’s worth of champagne!

Other Sources:

Carfentanil has killed hostages and even moose!

Source: Vancouver, Royal Canadian Mounted Police

Carfentanil is a potent opioid, one of many molecules from the Pandora’s box of organic chemistry labs.  Derived from fentanyl, another synthetic morphine-like compound,  carfentanil has been deliberately introduced into samples of  heroin. Frontline emergency responders have been advised to wear masks and gloves to avoid ingesting minute amounts of the drug. It’s also been described as a substance designed to knock out elephants.

I will describe a couple of related stories from the research literature that have not been mentioned in the news recently, and of course since unlike newspapers, I don’t mind losing readers by dwelling on chemistry,  I will also take a closer look at the molecule. 🙂

hostageOn October 23, 2002, more than 800 people attending a stage show in Moscow were taken hostage by about 50 Chechen rebels. After the latter threatened to blow up everyone in there if their political demands were not met, 3 days later, the Russian military stormed the theatre. To subdue the rebels, an unidentified “gas” was introduced through the ventilation system about 15 minutes before the soldiers moved in.  Things however did not go according to plan. After the “rescue”, the hostages had to be taken to the hospital. Due to wrong assumptions about the nature of the “gas”, many patients were given ineffective treatments and died. But a couple of doctors noticed that the patients showed classic signs of opioid intoxication: pinpoint pupils, unconsciousness and depressed breathing. The opioid hypothesis was supported by the fact that naloxone was able to save those who received the same drug that’s typically used in opioid-related emergencies. Later, the Russian health minister tried to assure the public that the  mixture used during the military intervention was not lethal. They admitted that the aerosol included an opioid, specifically a fentanyl-derivative (likely carfentanil). But convinced of the opioid’s harmlessness, they tried to pin the blame for all of the 127 deaths on the conditions experienced by hostages during the 3 days of captivity.

What else was in the opioid mixture? German chemists found it contained halothane, an anaesthetic, but that wasn’t the fatal ingredient. According to a report of three medical toxicologists from the Good Samaritan Regional Medical Center, the problem was rooted in the Russians’ underestimation of carfentanil’s potency. They had extrapolated rat models that did not apply to humans.  In addition, the Russians didn’t take into account that a ventilation system will not evenly distribute an aerosol.

What kind of a job does carfentanil do on large mammals? The Quebec Environment Ministry did a 10-year study in the late 1980s to 1990s involving carfentanil and free- ranging moose. A dose of 3 mg of carfentanil was mixed with xylazine and injected into 69 different animals. The xylazine was included to smooth out induction and recovery.  Although 3 mg represents only only 7.1 parts per billion for moose with an average mass of 422 kg, most animals slowed down in only 6 minutes and were immobilized in half an hour. Four moose however died. So if in reading the news you became under the impression that for large mammals carfentanil is innocuous, well the reality is that it could be lethal for them too even in small doses, albeit in a smaller percentage of cases compared to humans. As a result of the study, carfentanil is no longer used on moose, but is still mixed with xylazine on some animals who are less sensitive to minute amounts of the opioid.

Opioids can act on several opiate receptors in the central nervous system. To date there are three known varieties of such receptors known as μ , κ and σ. Carfentanil is a strong agonist specific to a pair of μ type receptors known as μ1 and μ2, leading to, among other things, intense euphoria. Interacting with μ1 also leads to analgesic effects, whereas bonding to μ2 leads to respiratory depression, which is the cause of death when the drug kills.

The morphine rule consists of structural criteria for a molecule to have morphine-like effects. The rule applies to natural opiates but no longer to all opioids.

Carfentanil is more potent than fentanyl, which is in turn is far stronger than morphine. Fentanyl was first synthesized from demerol(pethidine)-analogues in the 1960s. Until that point pharmacologists were under the false impression that to act like morphine a drug had to have a quaternary carbon linked to an aromatic ring and to have that quaternary carbon linked to a tertiary amine via a pair of CH2 groups. But fentanyl has only a tertiary carbon, and it is not directly bonded to an aromatic group. It became the first drug to violate the so-called morphine rule, and yet ironically it was stronger than most of the opioids that stuck to the rule.

A comparison of the structures of the two opioids. Carfentanil has an ester group on a carbon that is quaternary and not tertiary. (See green, circled carbon in each case.) Like all opiates both have a carbon linked to tertiary amine (asterisk) separated by a pair of Ch2 groups(green dots). Carfentanil violates the morphine rule by not having its quaternary carbon directly linked to an aromatic ring.

In contrast, carfentanil is like the traditional opiates in that it has a quaternary carbon, one created by the addition of a methyl ester group on that carbon—the only difference in structure between the two molecules. But like fentanyl, it still violates the morphine rule because the carbon is not directly linked to an aromatic ring.


Unexpected “gas” casualties in Moscow: A medical toxicology perspective  Annals of emergency medicine May 2003Volume 41, Issue 5, Pages 700–705

Unintentional opioid overdose deaths in New York City, 2005–2010: A place-based approach to reduce risk Original International Journal of Drug Policy 25 (2014) 569–574 reveals that carfentanil was a factor in unintentional drug overdose-deaths in a study involving such cases in 2010 to 2014.

Restraint and Handling of Wild and Domestic Animals 2008 By Murray E. Fowler

Not Yawning at Pure Science

The world would be a different place if people valued science, even as a hobby. In the same way that cities invest heavily in building indoor pools and artificial turf for amateur swimmers and soccer players, respectively, a society that relishes science for curiosity’s sake would alternately build centers for amateur research. The thought was inspired by a doctor’s answer to a radio listener’s question about yawning:

Unfortunately there’s not much research into finding out why people yawn. It would need a lot more work in the areas of psychology and group behavior, but there is not much interest in it. A lot of the granting agencies would probably consider the field a big yawn 1.

YawnWhy should we be enslaved to doing research only for what tickles the fancy (or serves the interests) of sponsors and agencies? And why should practicing science only be for those who get paid for it? I find yawning a great subject and the modest knowledge we’ve gained about the topic was enough to awake me this morning. But as interested as I was in the topic, due to the mysterious contagious nature of yawning, while I read less than 500 words, I yawned no less than four times.

Ultrasounds reveal yawn-like behavior during the first 3 months of development in the womb, suggesting that it goes far back in our evolution. The notion that it was a warning to predators is a pure guess and probably a wrong one. Something that triggers more questions and which is more substantial is the fact that two different neurotransmitters, dopamine and serotonin, increase the frequency of yawning. The experiments were done on rats, and since dopamine does not cross the blood brain barrier, a researcher either has to use a dopamine precursor such as L-dopa or an agonist—a compound that triggers the same receptors. From what I could gather, they used apomorphine, an agonist for two of the 5 known receptors of dopamine.

The above structures reveal the similarities between the two molecules. Apomorphine is synthetically derived from the biologically produced morphine by treating the opium- product with phosphoric acid. Morphine’s protruding OH group gets dehydrated by the acid, which rearranges the structure to that of apomorphine.


Compounds that fail to do likewise include CO2 and O2. Increasing either gas in the air we breathe has no effect on how often we yawn, which puts a major dent in the hypothesis that yawning is induced by a change in the composition of air.

Physiologically, a  morning yawn differs from a yawn in the evening. The former spreads beyond the face, as if to help awaken us. A night- yawn is more localized, and maybe its role is simply to prepare us for sleep. I’m guessing that if members of a social group share the same shelter it may be advantageous if a behavior helps others reach a state of alertness in the morning and a period of needed rest at night. That could explain the contagiousness of yawning.

Five hours after I’ve awakened, just writing about yawning has induced two more yawns on my part. How many on yours?

1 Irvin Mayers, Catching the Common Yawn, The Quirks and Quarks Question Book. 2002. CBC

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