Blue mice and pink elephants: Why alcohol is among the worst drugs for dependence and withdrawal

Most of us have been there. The next morning after a night of alcohol consumption is usually met with headaches, nausea, sleep deprivation, dizziness, dry mouth and excessive thirst. The reason for some of these symptoms can be attributed to the bodies fast response to the presence, and excretion of excessive alcohol. Drinking large amounts of alcohol over the course of an evening allows for the body and the brain to briefly adjust its homeostasis to adapt to increased levels of alcohol, operating at a “new normal”. When you abruptly stop drinking, your body and brain chemistry must now normalize on its own, and this leads to the symptoms mentioned above. But what happens when you drink excessively over long periods of time (i.e. months), forcing a homeostatic shift to the point where your body and brain become reliant and tolerant to alcohol? In this article, I will be explaining why alcohol may be one of the worst drugs to come off of.

Alcohol is considered a depressant, which refers to a class of drugs that inhibit or depress the central nervous system (CNS). Neurotransmission of gamma-Aminobutyric acid (GABA) — a neurotransmitter that works to inhibit neuronal excitability in the CNS — is increased during the consumption of alcohol. By increasing the availability of GABA, behaviors such as decreased attention, relaxation, alternation in memory, dizziness (alcohol reduces the viscosity of your inner ear fluid, messing with your balance) and drowsiness become apparent during a night of heavy drinking [1].

But unlike most other drugs, alcohol also suppresses the neurotransmission of an excitatory neurotransmitter known as glutamate. Glutamate is the major excitatory neurotransmitter in the brain and it is responsible for many important cognitive functions. If inhibited, it can also cause sedative effects [2]. Together, these dual processes decrease the flow of calcium, which is central for control of cell excitability and neurotransmitter release [3, 4]. So, to summarize, alcohol acts as a depressant through two main pathways. It increases the availability and activity of GABA (an inhibitory neurotransmitter), and it decreases the activity of glutamate (an excitatory neurotransmitter) [4]. This leads to an overall mass depression of the CNS.

Figure 1. Alcohol dependence and withdrawal. The behavioral symptoms above are brought on by alterations in inhibitory and excitatory systems in the central nervous system [4,5].

Over long periods of significant alcohol consumption, your brain tries to restore its equilibrium (homeostasis) by fine-tuning the receptor functions for GABA and glutamate. This results in a decreased sensitivity for alcohol, which means you now need more alcohol to achieve the same effect on the body and brain as before. This is known as pharmacodynamic tolerance. As a result, your CNS compensates for the increased GABA by reducing GABA reception functions and up-regulates glutamate receptors due to a lack of glutamate [2,4]. When alcohol is abruptly reduced or discontinued, that’s when things go from bad to worse.

The moment your CNS is devoid of alcohol, mass hyper-excitability of neuronal firing occurs (known as sympathetic overdrive or autonomic hyperactivity). GABA receptors, which were previously down-regulated to reduce neurotransmission can no longer inhibit cellular function properly anymore. Additionally, glutamate receptors are now unregulated, which leads to a much higher flow of Ca2+ and this can be highly toxic for cellular functioning [4]. As a result, you will now start feeling symptoms opposite of sedative effects you felt before. This is known as the “rebound effect” and can be visualized in the figure below.

Figure 2. Relationship between drug tolerance and withdrawal. The same adaptive neurophysiological changes that develop in response to drug exposure and produce drug tolerance manifest themselves as withdrawal effects once the drug is removed. As these changes develop, tolerance increases; as they subside, the severity of the withdrawal effects decreases [6].

An individual coming off of long term alcohol abuse may experience severe symptoms such as paranoia, altered sensations, delusions and worst of all, Delirium Tremens (DT). DT is a set of symptoms that include seizures, tremors, psychosis, vivid hallucinations (often terrifying), and even death [7,8]. Seeing “pink elephants” and “blue mice” serve as euphemisms for the severe hallucinations one may experience when withdrawing from alcohol.

To conclude, the rebound effects of alcohol are dangerous because of its parallel effects on GABA and glutamate neurotransmitters and their receptors. Upon consumption, alcohol initially enhances inhibitory receptor function (GABA increases) and decreases excitatory function in the brain (glutmate decreases). Sedation, relaxation, decreased attention, and memory loss are a result of initial alcohol consumption. This leads to the development of neural changes to offset the drug effect in the CNS (trying to achieve balance of these systems). When the drug is no longer available, GABA receptors are greatly diminished (GABA decreases) and glutamate receptors (glutamate increases) are amplified, leading to an overactive CNS. This results in symptoms such as tremors, anxiety, psychosis, seizures, convulsions and DT. Unlike some other drugs, alcohol simultaneously disrupts both inhibitory and excitatory receptor functions in such a way that when alcohol use ceases, these unregulated mechanisms result in mass hyperactivity [8].

References

  1. Role of Acetaldehyde in Mediating the Pharmacological and Behavioral Effects of Alcohol. doi: https://doi.org/10.1016/j.pharmthera.2006.02.001
  2. What Alcohol Really Does to Your Brain. https://www.forbes.com/sites/daviddisalvo/2012/10/16/what-alcohol-really-does-to-your-brain/#4e06effc664e
  3. Calcium influx during an action potential. doi: https://doi.org/10.1016/S0076-6879(98)93023-3
  4. Alcohol and neurotransmitter interaction. https://pubs.niaaa.nih.gov/publications/arh21-2/144.pdf
  5. Alcohol dependence and withdrawal. https://www.youtube.com/watch?v=1RxATXURxQM
  6. Biopsychology, 9th edition, Chapter 15: Drug addiction and the Brain’s Reward Circuits.
  7. Recognition and management of withdrawal delirium (delirium tremens). doi:10.1056/NEJMra1407298
  8. Alcohol, benzos and opiates — Withdrawal that might kill you. https://www.psychologytoday.com/ca/blog/all-about-addiction/201001/alcohol-benzos-and-opiates-withdrawal-might-kill-you

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One thought on “Blue mice and pink elephants: Why alcohol is among the worst drugs for dependence and withdrawal

  1. So would treating withdrawal focus more on the brain activity or focus on reducing the symptoms or a mix of both?

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