Sep 11 2023

How Substance Abuse Affects the Brain

I will acknowledge up front that I never drink, ever. The concept of deliberately consuming a known poison to impair the functioning of your brain never appealed to me. Also, I am a bit of a supertaster, and the taste of alcohol to me is horrible – it overwhelms any other potential flavors in the drink. But I am also not judgmental. I understand that most people who consume alcohol do so in moderation without demonstrable ill effects. I also know I am in the minority when it comes to taste.

But we do need to recognize that alcohol, like many other substances of abuse like cocaine, has the ability to be addictive, and can result in alcohol use disorder. Excessive alcohol use costs the US economy $249 billion per year from health care costs, lost productivity, traffic accidents, and criminal justice system costs. It dwarfs all other addictive substances combined. It is also well established that long term, excessive alcohol use reduces cognitive function.

Recent research has explored the question of exactly what the effects of addictive substances are on the brain with chronic use. One of the primary effects appears to be on cognitive flexibility. In general terms this neurological function is exactly what it sounds like – flexibility in thinking and behavior. But researchers always need a way to operationalize such concepts – how do we measure it? There are two basic ways to operationalize cognitive flexibility – set shifting and task switching. Set shifting involves change the rules of how to accomplish a task, while task switching involves changes to a different task altogether.

For example, a task switching test might involve sorting objects that are of different shapes, colors, textures, and sizes. First subjects may be told to sort by colors, but also they are to respond to a specific cue (such as a light going on) by switching to sorting by shape. The test is – how quickly and effectively can a subject switch tasks like this? How many sorting mistakes will they make after switching tasks? Set shifting, on the other hand, changes the rules rather than the task – push the button every time the red light comes on, vs the green light.

These laboratory tests do correlate with more general behaviors that reflect cognitive flexibility. Interestingly, chronic alcohol use is associated with reduced cognitive flexibility, and the arrow of causation may go both ways. Addiction itself can be seen as the inability to change behaviors, even when one knows the behavior is self-destructive. There is evidence that baseline low cognitive flexibility predisposes to substance addiction, which makes sense. But substance abuse, especially alcohol, may also further reduce cognitive flexibility, exacerbating the addiction itself. This is why overuse of alcohol can be no pernicious – alcohol overuse can change the brain to make it more difficult to stop overusing alcohol.

Recent research has further looked into the actual mechanisms by which alcohol and potentially other substances change the brain to impair cognitive flexibility. Teasing apart or reverse engineering brain circuits, especially for such a complex cognitive phenomenon as flexibility, is extremely difficult. But we do have a reasonable schematic of what’s going on, and new research can add further details and complexity. Cognitive flexibility is largely a function of frontal lobe executive function circuits. Some researchers think it is an emergent property of sufficient executive function, which is the ability to plan and to focus attention. This makes sense from the perceptive that shifting focus may underlie both shifting tasks and shifting attention.

But these frontal lobe circuits also connect with deeper brain structures, and several in particular have emerged as likely very important. Cognitive flexibility seems to be stimulated by excitatory activity from the striatal cholinergic interneurons (CINs). CINs, in turn, are activated by inputs from the thalamus (thalamostriatal circuits). A 2022 study found that chronic alcohol use was associated with decreased thalamostriatal excitatory activity.

A recently published study, however, also found that increased activity in the striatal direct-pathway medium spiny neurons (dMSNs) inhibits CIN activity (this is inhibitory input). Essentially what the neuroscientists are finding is that CIN activity is critical to cognitive flexibility, and alcohol use both increases inhibitory input and decreases excitatory input to this brain region. The result is reduced cognitive flexibility, which reinforces the substance use itself, making it more difficult to stop. Interestingly, these same circuits are implicated in disease states that also are associated with reduced cognitive flexibility, such as Parkinson’s disease.

The brain changes are long term. That doesn’t mean they can’t improve with time, or even mostly reverse. This likely depends on a host of other factors, such as age, and duration and intensity of alcohol use. Those with substance use disorder also have a long list of other health effects that go along for the ride, such as chronically poor nutrition.

All of this is extremely interesting but not surprising. The basic health concept of “everything in moderation” is generally good advice. This is related to another important concept – the dose makes the poison. Pretty much everything we consume has the potential to cause toxicity or harm given a high enough dose. As long as we don’t have a habit of consuming the same thing in large amounts on a regular basis, we probably don’t have to worry about this background noise of toxicity. We do need to avoid substances which have toxicity even at low dose. Alcohol is interesting, because the typical use and the toxicity range overlap. But also, it’s an addictive substance – it causes changes to the brain which impair our ability to use it in moderation, creating a potentially destructive feedback loop. This is another feature of things we consume that we need to watch out for.


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