Humans have been consuming alcohol and tobacco since a long time. But interestingly, their consumptions are co-related. Nicotine increases alcohol craving, and alcohol use can enhance nicotine craving. Data from recent years shows that people are consuming both of them together more than in previous times, perhaps because of peer pressure and stress. Consuming them together is alarming because they increase chances of many diseases, some even fatal. This dual addiction heightens the risk of cancer and cardiovascular damage. It also magnifies mental health issues and creates a multiplicative effect that poses significant challenges for personal as well as public health.
There are medicines such as varenicline and naltrexone that are used to treat addictions of nicotine and alcohol respectively. There are receptors in neuronal cells in the brain to which nicotine and alcohol go and bind. Varenicline go and bind to the same receptor, thus not allowing space for nicotine to bind to the neurons. Naltrexone binds and inhibits receptor which activate brain’s reward function, thus blocking pleasure sensation of alcohol and reducing craving. However, the same medicines are not as effective in treating co-abuse of nicotine and alcohol. This means a simple combination therapy of these medicines does not solve the problem of co-addiction of nicotine and alcohol. Hence, it is important to understand what happens in a brain co-addicted to nicotine and alcohol, which seems to be more than just sum of the two individual addictions. Unravelling these complexities could lead to more effective interventions.
Why brain seeks alcohol and nicotine together
A major understanding lies in how neuronal cells in brain communicate with each other and the effect of nicotine and alcohol on this process. Neurons exist as networks and they talk to each other using chemicals called neurotransmitters. Simplistically put, a neuron releases a neurotransmitter, and its adjoining neurons, physically connected to it, have specific receptors to receive the neurotransmitter. But neurotransmitters are of many kinds, and their release and reception by neurons elicit a range of sensations, including pleasure, euphoria, and relaxation.
Any addiction is most widely understood from the context of release of one neurotransmitter – dopamine. Its release creates a feeling of pleasure – an outcome of activating a set of neurons involved in what is called the reward circuitry. The feeling of pleasure, in turn, forces the person to take more of the substance recreating this sensation. Food, sex and social interactions activate this circuitry. Such a response to these stimuli offers a clear survival value. But the same circuitry gets activated by most addictive substances, including nicotine and alcohol and other drugs of abuse, with far more potency. And, when some of them are taken together, like alcohol and nicotine, they increase dopamine even more.
Rising number of neuroscience research tells us that there is more to the story of addiction than just dopamine. Our brains are much more than just the reward circuitry. And, glutamate is the largest excitatory neurotransmitter whereas gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the overall brain. Glutamate and GABA, together with dopamine, play a role in co-dependence of alcohol and nicotine.
Alcohol alone, initially acts as a stimulant through increasing dopamine release in the reward circuitry, causing pleasure and euphoria. These feelings last until alcohol concentration is rising in blood. Acetaldehyde, product of ethanol metabolism, also contributes to this feeling. Acetaldehyde in low concentration in the brain brings pleasure and at high concentration sedation. Also, at low concentrations ethanol causes dopamine release in the brain reward areas. In the other areas of the brain, alcohol increases GABA, and simultaneously decreases glutamate. These slow the physical actions of the body. Together, these create a calming effect.
With time, acetaldehyde as well as alcohol concentration decreases. As a result, the dopamine levels go down in the reward areas. In the overall brain, GABA and glutamate also tend to come back to their normal levels. But in doing so, they rebound such that the glutamate levels are higher and GABA is lower than when one has not consumed alcohol. This causes irritability to the drinker. To subside the feeling, one is lured to another round of alcohol consumption.
This problem exacerbates with time. For those consuming alcohol regularly, over time, the same amount of alcohol doesn’t give the same pleasure. This happens because the brain tries to offset the behavioral effects of alcohol by secreting less dopamine over time. The brain does this by reducing dopamine and GABA receptors, and increasing glutamate receptors. This helps the brain return to its earlier balanced state of neuronal firing and the release of various neurotransmitters. An increase in the metabolism rate of alcohol over time also contributes to this. The liver increases the production and activity of alcohol-metabolizing enzymes (specifically the CYP2E1 enzyme), which helps to break down alcohol to its byproducts and get cleared from the bloodstream more quickly. That results in reduced alcohol levels in the brain than earlier for the same intake. Thus, further contributing to diminished feelings of pleasure. Hence, to recreate the same degree of pleasure, one needs to consume higher quantities of alcohol.
More the amount of alcohol consumption, higher is the rebound effect of GABA and glutamate, and thus, higher irritability. To alleviate this feeling, one tends to consume even more alcohol. More alcohol results in stronger sedation. Smoking brings in nicotine which counteracts alcohol’s sedation and allows for more alcohol intake. It adds a new way to pump up dopamine and glutamate with better arousal and alertness.
Repeated consumption of alcohol and nicotine together ties them in the brain’s learning circuits, leading to paired cue association. That means a cue for alcohol creates an urge to take nicotine, and vice versa. A common example of this occurs in a social setting, such as a bar. A person who habitually smokes while drinking feels a strong desire to light a cigarette the moment they hold a glass of wine or even just see a bar.
Glutamate is key for cue association, and intake of alcohol and nicotine increases glutamate. Researchers found that simultaneous withdrawal from alcohol and nicotine worsens the severity and duration of withdrawal symptoms. This leads to more craving and stronger urges to consume both the substances, leading to their heavy use. Hence, new medications have to target nicotine and alcohol craving together. Otherwise, by blocking one, the urge for the other substance increases, ultimately leading to relapse.
Design of new medicines
Many current deaddiction medicines increase dopamine. Such medications themselves have a risk of abuse. Hence, medications like acamprosate, which don’t increase dopamine and CGP44532, which increases inhibition by GABA in nicotine addiction, are being tested for de-addiction treatments. Acamprosate targets glutamate and GABA imbalance to stay alcohol free after deaddiction, whereas CGP44532 helps to reduce cue-induced nicotine taking and overall nicotine consumption.
Similarly, medications like clonidine are used to manage withdrawal symptoms, including craving of individual alcohol or nicotine addiction. Norepinephrine is the neurotransmitter also responsible for withdrawal, and clonidine inhibits norepinephrine release as well as binds to its receptors.
New research is enabling targeting neuronal pathways and neurotransmitters in different ways. But there are also missing links that should be kept in mind for co-addiction treatments. Scientists do not yet know many details of neurotransmitters involved in co-addiction of alcohol and nicotine. And, with rising incidences of co-addiction, it is important to look at this more urgently.
