Alcohol: Tale of a Toxin. Is It Good for Us?

Alcohol consumption is part of many cultures and wildly so in American culture. Mortality from alcohol-related disease was up 40% from 1999-2017, and in 2020 alcohol intake increased by over 30% by some reports, creating a pandemic of its own.

From an evolutionary standpoint intake of alcohol containing fermented liquids and foods may have had an advantage for us. In the primitive world, the fermentation process may have had a preservative role and controlled the pathogen load we might have ingested. Fermentation may have allowed safe hydration in times of clean water scarcity and allowed for some food preservation to bridge times of food scarcity.

Alcohol was never a foreign substance to us, as some bacteria in our intestines that we evolved with use fermentation for metabolism and produce alcohol at low levels every day. Therefore, we evolved with enzymes, most notably alcohol dehydrogenase, that metabolize alcohol and convert it into a usable energy source for us, as well. Another evolutionary advantage.

However, the concentration of alcohol in fermented liquids and foods was very low compared to the concentrations we see today from the more complex brewing and distilling processes of the modern world.

The concentration of alcohol produced or consumed by us in our prehistoric lives was easily metabolized prior to any significant toxic effects. The alcoholic drinks and the patterns of alcohol consumption we see today can overload our system's ability to metabolize the alcohol, resulting in intoxication and toxicity.

A recent University of Oxford study concluded that no amount of alcohol is good for you. Moderate alcohol consumption was associated with lower total brain volumes, lower brain grey matter volumes, negative white matter changes, higher blood pressure, and higher body mass index. Binge drinking made the picture even worse.

We have been taught for generations that moderate alcohol consumption may in fact be good for us. The thought has been that the relaxation effect was therapeutic. This rational lead to the common theory that alcohol exerts its effects primarily through our bodies’ neurotransmitter network.

Alcohol has been reported to enhance GABA (gamma amino butyric acid, an inhibitory neurotransmitter) release and act directly at GABA receptors as mechanisms by which alcohol causes relaxation.

Alcohol has also been reported to decrease glutamate (an excitatory neurotransmitter) receptor activity, thus furthering a relaxation response.

These combined effects would result in increased inhibition and decreased excitation and would produce a state of overall calm and relaxation, if not sleepiness. However, people who consume alcohol aren’t always relaxed and subdued: Sometimes they are euphoric, excited, hyperactive, impulsive, disinhibited, and aggressive. There is some explaining to do.

So, the story goes that alcohol also causes the release of dopamine, an activating, feel good, re-enforcing neurotransmitter that stimulates sympathetic nervous system activity, movement, and approach behavior.

Which is it? Relaxed? Activated?

To make things more complicated, there has been some further thought that serotonin release may be increased as well; yet, in general, alcohol is considered a depressant, which seems inconsistent with this thought.

Acetylcholine is frequently left out of this conversation. Acetylcholine is the major neurotransmitter in our parasympathetic nervous system, the breed, feed, digest and rest system, and would be a likely candidate for precipitating a relaxation response. However, acetylcholine seems to be down-regulated by alcohol. Hmm.

In addition, there has been the thought that alcohol may also stimulate the endogenous opioid system to provide a further sense of relaxation, reward, and pleasure.

There is an incoherence to this story, in that fundamentally we are first taught alcohol relaxes us (+GABA, feel good) but also stimulates us (+dopamine), feel good, then that it acts as a depressant (-dopamine/-norepinephrine/-serotonin, feel bad).

So what is it: up or down? Feel good or feel bad?

Can this incoherence be pulled together into a story with coherence?

In fact, it can, and the story that evolves can not only further our understanding of alcohol's effects on our physiology but shed some light on how we can stay well and healthy overall—unfortunately, not with the use of alcohol.

What if alcohol is simply a toxin? A physical threat to us?

Not to discount the findings outlined above, in fact to include and explain most of them, we should look at alcohol as a toxin under the lens of Threat versus Safety and the associated physiologies of threat to see how the story may play out.

We humans are not constant even in threat. We are ever-changing in our physiology depending on our environment (extracorporeal and intracorporeal, and extracellular and intracellular). We lack distinct set points, and homeostasis is more of a myth than a reality, but there are patterns of physiologic change that are similar whether we are under a physical attack by a virus, a bear, a toxin, or even another person—whether it be a physical attack or a psychological one. Even social and cultural attacks such as disenfranchisement, discrimination, and injustice present with similar physiologic changes.

The patterns can be viewed as programmed biological survival mechanisms that involve resource conservation and allocation when we are under attack. With all that in mind, let's set aside the neurotransmitters for the moment and view alcohol as just a toxin not a ligand, neither an agonist nor an antagonist.

Consider the brain’s dissociation or dissolution process when under the threat of alcohol.

With low levels of threat (consider 1-3 drinks) our system tends towards a mobilization response—something is wrong, so do something. We turn down the brain functions that won’t help us in an attack, notably the prefrontal cortex (PFC). With the loss of PFC functions, we can become kinetic, reactive, impulsive, and sometimes aggressive.

More specifically, whether a bear attack or a toxin attack, the dorsal lateral prefrontal cortex (DLPFC), the part of the brain that helps us to plan and reason and to be contemplative and creative, is not of value and is turned down. It isn’t time to negotiate a settlement nor invent the wheel when being attacked by a bear, and a toxin attack follows suit.

Whether a bear attack or a toxin attack, we also turn down the ventral medial prefrontal cortex (VMPFC), the part of the brain that allows us to have empathy for others and to connect and bond with others. Neither toxins nor angry bears respond well to these functions.

Maybe, most important to this discussion is our turning down the medial prefrontal cortex (MPFC) when under attack. This part of the brain is involved in emotional regulation and social calculations, norms, constructs, and constraints. This is the part of the brain involved with our sense of “shoulds”, “musts”, “need to's” and “have to's”—the governance of our behavior. In a bear or toxin attack survival is key; who cares what the bear or toxin thinks of us!

Resource conservation and allocation rule in an attack. Survival is key.

Why is the MPFC so important?

The MPFC can directly inhibit the nucleus accumbens (NAc), the tip-top of a part of our brain that integrates our emotions with our cortex and our awareness. This nucleus is connected all the way down to the midbrain’s ventral tegmentum, and when eMOTIONS arise they create impulses to move and express, seek pleasure and pursue rewards, or just be pissed off and angry and fight, or triggered and kinetic and flee.

It is our MPFC that inhibits these eMOTIONs and says “no, don’t to that”, “you should do this”, “you must do that”, “you need to do this”, or “you have to do that”, thus stifling the eMOTIONs' impulse or desire for movement, for action. But the eMOTIONs don’t easily go away. They may continue to poke and prod to get out, thus keeping the MPFC and the NAc in a constant tug of war—conflict. Or our thoughts and eMOTIONS may be suppressed and repressed below awareness where they continue to push our threat and stress buttons. Neither scenario is particularly good for our physiology.

With alcohol consumption, the cortical dissociation or dissolution that occurs turns down the MPFC and its control over the NAc, thus releasing the eMOTIONAL network to express itself in a flush of euphoria and excitement. We feel free from the chains of the MPFC. This release feels really good.

Perhaps this is why moderate drinkers could possibly live longer—a brief reprieve from the burdens of life, mediated by a toxic retreat of the cortical brain. It is also most certain that this effect, and the brief pleasure associated with it, is a major driver of alcohol addiction.

However, in the background of this initial pleasurable response is the progression of the threat response and toxicity.

As the alcohol concentration increases, the threat load increases (consider 3-6 drinks); we see further cortical dissociation in the PFC and the dissociation descends below the PFC into older cortical structures such as the cingulate and insular cortex. With this we not only see the loss of executive functions (IQ) and deterioration in emotional regulation and social integration (EQ) but a more generalized fogging and numbing progression into a stuporous state.

Consistent with a progressive threat response we can see the transition from a mobilization response to an immobilization response (threat1 to threat2 phenotype). What we initially saw as disinhibition of our eMOTIONAL system can, with a progressive concentration of alcohol, flip to dissociation or dissolution of both our eMOTIONAL and movement systems. This progression can run through the entirety of the striatum all the way down into the midbrain, as well as, involving the cerebellar structures.

At this point we are progressively stuporous—cognitions, emotions, sensations and coordinated movements are all shutting down. Eventually, it becomes difficult to remain upright and coherent. At this point we can have a desire to lie down or we may simply pass out.

More worrisome is when the dissociation or dissolution progresses into the medullary structures of the brain. Vestibular dysfunction with vertigo is common. The toxin trigger zone for nausea and vomiting will sense too much alcohol and initiate purging.

Most worrisome is the down-regulation of the autonomic nervous system's control of our heart and respiratory rates and rhythms. As brainstem functions slip away due to severe alcohol intoxication, coma is induced and death can follow.

In this model one can visualize with increasing alcohol intake and intoxication the progressive dissociation or dissolution of the brain from the tip of the prefrontal cortex to the deeper cortical structures to subcortical structures to the very basal brainstem structures. Intoxication is the progressive shutting down of the brain (and body) from a toxin that follows the pattern of all progressive threat responses.

The elation of the initial MPFC dissociation or dissolution can be followed by a whole lot of hurt.

The neurotransmitter model is probably not the right way to look at alcohol intoxication, but as the neurotransmitters are a part of THE SYSTEM and a coordinated threat response, they are involved, just not primary mediators of the response.

The MPFC dissociation or dissolution and release of the NAc restraint will result in a dopamine surge and, less so, a serotonin surge, flowing from the ventral tegmentum and raphe nucleus up the striatum into the cortex. This surge can explain the euphoric, energized, reinforcing and disinhibited state of early intoxication. Note that this state has more to do with alcohol/toxin-induced prefrontal senescence than direct alcohol-induced agonist or antagonist neurotransmission itself.

Beyond the initial dopamine and serotonin surge from the dissociation of the PFC, dopamine and serotonin production and signaling are waning with progressive alcohol use and associated toxicity. Norepinephrine will eventually follow suit. Also, acetylcholine and GABA production and signaling are reduced.

Viewing this progression through the neurotransmitters one can see “the relaxation response” is progressive brain dissociation more than neurotransmission, as the relaxation neurotransmitters are being down-regulated.

The outlier neurotransmitter is glutamate, which rises quickly in threat.

Glutamate is our most abundant and most primitive neurotransmitter and a primary danger signaler. Glutamate is more persistent than norepinephrine and epinephrine in progressive threat states. Common to threat responses is the activation of glutaminergic signaling. While most neurotransmitters are being down-regulated under progressive threat, glutamate signaling irises for a much longer period of time; its production from glucose, alpha-ketoglutarate and glutamine increases. Breakdown of glutamate is decreased, through inhibition of glutamine synthesis. Too, conversion of glutamate to GABA is blocked. Enzymes, such as the transaminases, are required in this process, and ammonia is a byproduct of glutamate production.

In general glutamate is an excitatory neurotransmitter but at times glutamate can have an inhibitory effect. Because of this multiplicity, glutamate can influence different brain structures differently.

Glutamate can strengthen certain structures while weakening other structures. In threat, glutamate is initially selectively more excitatory to the more primitive limbic structures of the brain, while having deleterious effects to newer cortical structures. This model holds up for both acute and chronic alcohol use and helps explain both the acute and chronic physiologic changes, if not disease and illness, associated with alcohol use.

The model of progressive threat explains the neurophysiologic changes, including the neurotransmitter changes, seen with alcohol use. It also explains the increase in endogenous opioids (remember that endogenous opioids are less a part of the pleasure/reward network and very much a part of the threat response). Therefore, as alcohol-induced threat escalates, one would expect endogenous opioids to rise.

It is also notable that the classic neurotransmitters—dopamine, norepinephrine, serotonin, acetycholine, GABA, and glutamate—are contextual and can have roles in both threat and safety physiology. In exploring threat signaling, clarity demands that we leave the neurotransmitters behind and dive into molecular, intracellular, and intercellular networks and signaling..

It is at this deeper level where we can really see the toxic effects of alcohol and its stimulation of a danger response. At this level there are changes in genetic transcription, increases in intercellular signaling by threat cytokines, alterations in mitochondrial structures and metabolism to favor glycolysis and inflammation, all of which can progress to overall cellular alterations and eventual cellular shut down that extends well beyond the brain.

The response to alcohol is one of systemic intoxication and toxicity that comes to our awareness in our brains but has not spared our bodies. Alcohol consumption is associated with obesity, diabetes, cardiovascular disease including arrhythmias, gastrointestinal disease including liver and pancreas diseases, psoriasis, gout, anxiety, depression, dementia, and cancer, just to name a few comorbidities. It all comes from the same soup and is dictated by total threat load, to which the toxin alcohol can be a substantial contributor.

Within this model also consider:

Hangovers are less alcohol metabolite- (aldehyde) induced and more threat cytokine-induced.

Craving is reverse dissociation or dissolution into a low dopamine, serotonin, acetylcholine, and GABA state (no rush or relief), and a high threat cytokine, glutamate, and norepinephrine state.

Withdrawal is craving in the extreme—high threat cytokines, glutamate, norepinephrine—characterized by headache, body ache, goose flesh, sweating, nausea, vomiting, loss of appetite, fast heart rate, high blood pressure, tremor, anxiety, irritability, disorientation, hallucinations and seizures.

In fact, all of these symptoms, illnesses and diseases can be explained through a threat response and the threat cytokine pathways.

In summary it is well worth considering:

• Alcohol is a toxin and little more than a toxin.
• Alcohol is a threat and creates a threat response.
• No amount of alcohol is actually good for us even if it makes us feel good.
• Alcohol intoxication is progressive dissociation or dissolution of the brain.
• Alcohol has many deleterious effects throughout the body.
• Cultural constructs and constraints play major roles in the drive for alcohol use.
• If we decrease the conflict between the medial prefrontal cortex and the nucleus accumbens by other healthy means, we won’t want or “need” alcohol.

Stay Safe and Stay Tuned.