Author's note: The compound ethanol can sometimes be referred to as alcohol. In this article, "alcohol" refers to alcoholic drinks.
“Pick your poison” the saying goes… wine, beer, or spirits. While their taste and method of preparation may differ, the one thing they all have in common is ethanol.
Ethanol is an organic compound with the chemical formula C2H5OH. It is the active ingredient in recreational alcoholic drinks and produces the psychoactive and physiological effects that some of us have experienced. Here, we will explore some of these effects at the molecular level, and understand how long-term alcohol consumption can affect the body.
How is alcohol metabolised?
Alcohol is a foreign substance to the body, and so is primarily metabolised by the liver. The liver cells secrete an enzyme called alcohol dehydrogenase (ADH), which breaks down alcohol into acetaldehyde. Acetaldehyde is also toxic and needs to be broken down further in the mitochondria by aldehyde dehydrogenase (ALDH), producing non-toxic acetic acid. These reactions require the presence of nicotinamide dinucleotide (NAD), which is a coenzyme in many metabolic reactions. Coenzymes are molecules that ‘help’ enzymes catalyse biochemical reactions, for example by donating or receiving an electron. Finally, acetic acid can be converted into acetyl-CoA, a critical coenzyme in the Krebs cycle, required to produce energy in cells.
Figure 1: Reduction of ethanol by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH).
Interestingly, some people have defects in their ALDH enzyme, which causes a build-up of acetaldehyde in the body. This build-up causes the cheeks to flush, and can also cause nausea and a more pronounced, rapid heartbeat.
Alcohol is metabolised at the rate of approximately 10 mL of pure ethanol per hour, or 15 mg per 100 mL of blood per hour. Thus, alcoholic drinks are usually measured in ‘units’, where one unit refers to the amount of alcohol that can be broken down in one hour by an average adult. Since different drinks have different amounts of pure ethanol, the amount of time required to process the alcohol differs between beverages. Hence, different drinks of the same volume will have a different number of units. For example, spirits usually contain 40% pure ethanol, thus 25 mL will equate to one unit; while for wine, which is around 12% ethanol, 83 mL will equate to one unit.
Bearing this in mind, if you consume more than one unit per hour, the liver is unable to bear the load, consequently, the level of alcohol in the blood begins to rise. The un-metabolised alcohol travels through the blood to other organs, where it may cause a myriad of physiological and psychological effects. The next section will explore these effects in more detail:
How does alcohol affect the body?
Physiological and psychological effects of alcohol
Different blood alcohol concentrations (BAC) have different associated behaviours, with the effects becoming more dangerous as the concentration increases.
As mentioned earlier, alcohol is metabolised by the liver at a rate of 15 mg per 100 mL of blood per hour. If the BAC is below this, the liver will process all the alcohol and there will not be enough left in the blood to cause any side effects. At a concentration of 0.001%, there is 1 mg of ethanol per 100 mL of blood. There is not much change in behaviour or any notable physiological symptoms as this BAC is below the metabolic rate for alcohol. If a person consumes only one unit per hour, their BAC is likely to remain around this level as the liver has enough time to metabolise all the alcohol.
However, when one begins to consume alcohol faster than the liver can metabolise it, behavioural changes begin to appear.
At 0.03%, where there is 30 mg of ethanol per 100 mL of blood, the symptoms associated with social drinking begin to appear. These symptoms include slight euphoria, increased talkativeness, and relaxation. As the BAC increases to 0.06%, one can experience symptoms such as increased pain tolerance, lack of inhibition, impulsivity, speaking at a louder volume, and blurry vision.
At 0.1%, more pronounced and potentially dangerous symptoms begin to appear. These include increased risk-taking, loss of motor coordination, nausea, impaired reflexes, slurring of speech, and possible vomiting. At concentrations higher than 0.2-0.3%, a person may experience memory loss, serious motor impairment, loss of consciousness, and cardiorespiratory impairments such as a lowered heart rate and breathing rate. If the BAC goes above 0.4%, there is a risk of coma or death.
Figure 2: Spectrum of blood alcohol concentrations (BAC) and some associated symptoms. These noticeable symptoms begin to appear as the BAC exceeds the metabolic rate of alcohol.
Effects of ethanol at a molecular level
Ethanol, being the active ingredient in alcoholic drinks, causes these symptoms at a molecular level. Ethanol has the ability to bind to ion channels and neurotransmitter receptors in the brain and hence modulate their normal function. Ion channels allow ions to pass in and out of cells down a concentration gradient, while neurotransmitter receptors convey downstream signals in the neuron when a neurotransmitter molecule binds to them.
One such receptor which ethanol affects is the GABA_A receptor. Studies have shown that ethanol binds and activates GABA_A receptors in neurons, causing sedative and muscle-relaxing effects. At the molecular level, this happens due to the opening of the GABA_A ion channel, which allows the movement of negative ions in and out of the neuron. The movement of ions disrupts the formation of an action potential (an electric signal crucial to the communication between neurons), preventing the neuron from firing. Overall, the activity of the affected neurons is reduced. Hence, alcohol can be described as a depressant (as opposed to a stimulant such as caffeine), as it dampens overall neuronal activity.
Ethanol is also known to activate other receptors, such as nicotinic acetylcholine receptors, which respond to acetylcholine as well as nicotine. Activation of these receptors leads to the release of dopamine in the brain, responsible for feelings of euphoria and happiness.
The danger of alcohol addiction
Although it is generally safe and socially acceptable to drink alcohol, heavy and prolonged consumption puts people at risk of developing addictions to alcohol, also known as alcoholism.
This addiction occurs due to ethanol’s effects on the reward pathways in the brain, specifically the mesolimbic pathway. This pathway connects the ventral tegmental area of the midbrain, containing dopamine neurons, to the nucleus accumbens, the part of the brain responsible for processing reward, motivation, and reinforcement.
When alcohol is consumed, the neurons in the ventral tegmental area release dopamine, which activates D1 receptors in the nucleus accumbens. Activation of these receptors causes a cell signalling cascade inside the neuron, leading to an increased expression of the protein ΔFosB, which is responsible for inducing reward-seeking behaviours. With prolonged alcohol consumption, ΔFosB is consistently overexpressed and accumulates in the nucleus accumbens. This accumulation of ΔFosB leads to reinforcement of the behaviour - in this case, alcohol consumption. As this continues, the neurons become sensitized to the alcohol and release more dopamine the more one drinks. This leads to an association between drinking and increased dopamine release, resulting in addiction.
Figure 3: Signalling pathway in the brain leading to addiction. VTA: Ventral tegmental area. NA: Nucleus accumbens.
In addition to the main ΔFosB-associated pathways, there are several other factors that contribute to the development and persistence of addiction. These could include environmental stimuli associated with drinking, as well as other signalling pathways in the brain.
Thankfully, there are many rehabilitation strategies for alcoholism, and the persistent activation of these addiction-associated pathways is reversible. The main methods are group counselling, cognitive behavioural therapy, abstinence or moderation, and anti-alcohol drugs. In particular, anti-alcohol drugs are mainly used to prevent a relapse into heavy drinking. Finally, a combination of different strategies can often lead to successful alcohol independence.
Unfortunately, if left untreated, alcohol addiction can lead to other illnesses, particularly relating to the liver and brain, as we will explore in the following section:
Alcohol-related illnesses
Liver-related conditions
As mentioned earlier, ethanol is broken down into acetaldehyde and then acetic acid. These two reactions require the presence of nicotinamide dinucleotide (NAD+), a coenzyme involved in a myriad of other metabolic processes. During the reduction of alcohol, NAD+ is converted to its reduced form, NADH.
In the case of heavy drinking, the presence of ethanol in the liver will change the normal NAD+/NADH ratio, as more NADH will be produced. This disrupts the normal metabolic processes in the liver, specifically that of fat metabolism. NADH promotes the formation of fatty acids, while NAD+ promotes their breakdown. As the NADH level rises, so does the abundance of fatty acids in the liver cells. This leads to a condition known as fatty liver. If a person stops drinking, fatty liver disease can usually recover by itself.
However, if one continues to drink heavily and regularly, the liver cells become overloaded with fat and begin to die. This leads to fibrosis (i.e. the formation of scar tissue) on the liver, making those cells non-functional.
The final stages of alcohol-related liver damage culminate in a condition known as cirrhosis, where a large portion of liver tissue is scarred and unable to function properly. Although the liver is a very resilient organ and is able to carry out many of its functions despite the damage; the serious damage in cirrhosis is irreversible. Liver function can be improved by abstaining from alcohol and other medical support. However, a transplant is needed in some severe cases.
Neurological conditions
Excessive amounts of alcohol can lead to cell death in the brain, and cause the brain to shrink. This has further consequences, such as faulty decision making patterns, impaired cognition and memory loss.
Prolonged exposure of neurons to alcohol can change the receptor profile and activity of the neurons to the point where they do not function normally, especially in the sudden absence of alcohol. This is because the brain’s physiology has adapted to the high alcohol intake, when there is a sudden lack of alcohol, withdrawal symptoms occur due to faulty signalling in the brain. Specifically, the GABA receptors have adapted to the high levels of alcohol, and have become less sensitive, thus require more stimulation to feel ‘normal’. When alcohol is suddenly absent, GABA signalling is highly reduced, causing withdrawal symptoms.
Another common manifestation of alcohol-related brain damage is Wernicke-Korsakoff syndrome, which is characterised by a severe deficiency in vitamin B1 (thiamine). The deficiency occurs because ethanol disrupts the uptake of thiamine in the digestive tract, as well as thiamine storage in the liver. This is a very dangerous illness and usually manifests with symptoms of dementia such as confusion, memory loss, and lack of muscle coordination. Furthermore, it is difficult to reverse these symptoms, but abstaining from alcohol can stop symptoms from getting worse.
Concluding remarks
As explored in this article, alcoholic drinks are metabolised by well-controlled enzymes in the liver. Moreover, both the downstream metabolites of ethanol and unmetabolised ethanol affect the body through many interesting pathways. At a molecular level, ethanol is known to bind to GABAA receptors in the brain, causing nervous system depression and reduced neuronal signalling. It also causes a release of dopamine in the brain, leading to feelings of euphoria.
However, despite the allure of its sedative effects, alcohol has the potential to become addictive if consumed regularly and in large amounts. Thankfully, most alcohol-related illnesses can be improved and cured by reducing or cutting out alcohol completely.
Regardless, remember to always drink responsibly!
Author
Devyani Saini
MRes Molecular and Cellular Biosciences
Imperial College London