Primer on the workings of cognition-affecting chemicals
May 27, 2012 9:33 AM   Subscribe

Neuropharmacologyfilter. Brief me on the practical basics (and the theoretical rudiments) of what it means to have a chemical in one's "system."

In particular here I'm interested in cognition-affecting chemicals, rather than more bodily drugs like, say, poisons or painkillers. (I understand, at least reductively, how a chemical could affect non-brain functions -- dilates the blood vessel, accumulates in the liver, causes a muscle to fire, etc. Much more mysterious to me are the workings of chemicals that interact with the mind.)

- What is one's "system"? First, when we speak of "having a (cognition-affecting) drug in your system", what are we referring to? Just your bloodstream (plus the brain and the various filtration organs that abut it)?
.......> Does every chemical that affects one's cognition/mood/psychology do so by interacting directly with neurons?

- Duration. Suppose that if I ingest n amount of a chemical, it will take exactly 4 hours before I am again functioning as though I had never taken any. What happens if I ingest 2n amount of the same chemical?
.......> Will it take 8 hours before I am functioning normally? 4 hours? Somewhere in between? Why?
.......> Does it depend on the chemical? If so, what if the chemical is caffeine?

- Intensity. Are there practical "ceilings" on the intensity with which a given chemical can affect a person at a given time?
.......> The mechanism I imagine for this would be: if you take n amount of cocaine then 33% of your receptors will bind with it; if you take 2n amount then 67% of your receptors will bind with it; if you take 3n amount then 100% of your receptors will bind with it; but if you take 4n amount then still only 100% of your receptors can bind with it. Is this a correct understanding?
.......> If so, what happens to the extraneous n amount? Does it get filtered out of one's "system" and go to waste, or does it linger until receptors are again available, effectively prolonging the high?
.......> In what ways, and for what reasons, do the answers to these questions depend on the chemical?

- Latency. Why do some drugs (e.g., recreational drugs) produce an instantaneous but relatively short-lived effect, while others have no immediate impact but affect cognition for days (e.g., SSRI's)?

- Why does a high end? If your mind is affected because molecules of the drug are chemically binding with the receptor cells in your brain -- why don't the molecules just continue to stick to those receptors forever (or at least until some even more receptive chemical comes along to stick to them instead)? Are the molecules of the drug somehow being metabolized or broken-down by the receptors? Are the receptors themselves being replaced or recycled?
posted by foursentences to Science & Nature (5 answers total) 7 users marked this as a favorite
Very basically: chemicals tend to hit various receptor sites in the body in order to replicate or enhance the body's natural production of chemicals. If you are, for example, super excited to see someone, your body produces adrenelin and dopamine and serotonin that hit other sites in order to make you feel excited and good about that. Drugs like caffeine and amphetamine join in the party of naturally produced chemicals and hit those same receptors harder than they would naturally be hit.

Just as an example:

Does it depend on the chemical? If so, what if the chemical is caffeine?

When a drug enters your system, it immediately begins being metabolized, or broken down by the body's defenses against chemical intruders. That usually happens at a certain rate- there are only so many sites where the liver can break something down, or the kidney can filter out, or the brain can oxidize. This is usually expressed in half lives, because as the chemical is diffused throughout the blood, only some of the blood gets near enough to those places where the breakdown can occur. So like musical chairs, each time the blood passes, some of the molecules get grabbed, and some don't. The half life is the time it takes your body to clean out half of the drug.

At the same time, the drug is running around having its intended effect.

Now, with caffeine, at the peak effect, we get used to the feeling. It starts to drop off because there is no more caffeine being introduced but it is still being filtered out. As it drops off, all those good feelings that we had stop happening and we generally want them to continue. So even though there is lots of caffeine wandering around, we feel like we are tired because the accelerating up feeling actually felt more like baseline, and dropping off the baseline is a sign that we need to do something. Normally, without caffeine, this means sleep.

In other words, for a lot of our cognitive processes, our brains tend to notice the ups and downs a lot more than where the baseline is actually at.

- Why does a high end? If your mind is affected because molecules of the drug are chemically binding with the receptor cells in your brain -- why don't the molecules just continue to stick to those receptors forever (or at least until some even more receptive chemical comes along to stick to them instead)? Are the molecules of the drug somehow being metabolized or broken-down by the receptors? Are the receptors themselves being replaced or recycled?

It depends on the chemical. Some DO stick to the receptor forever, or kill the receptor. Those things are generally poisons. Take carbon monoxide- it will attach to the oxygen receptors in your blood cells more readily than oxygen. If you are in a room with nothing but oxygen and enough carbon monoxide to bind to all your blood cells, you will die. Why? Because every time a blood cell hits the lungs and looks for something to bind to, it will grab the CO before it grabs the O.

Receptors (generally) have refractory periods. They can only do so much until they get worn out and have to be regenerated or otherwise restored. It has been theorized this is why we need to sleep. When we are awake, we are using all these receptors pretty heavily and the get worn out. Which is why we tend to go wonky when we don't sleep.

SSRIs, for example, take biological effect more or less immediately, but because depression isn't just chemical switches being turned on and off, it takes a while for someone's conscious and subconscious thought patterns to readjust to the new reality of life not seeming awful.
posted by gjc at 10:50 AM on May 27, 2012 [2 favorites]

You might want to take a look at this book chapter to get an idea of the basics of how drugs "enter your system". This reference will answer your question about latency and how fast it can clear your system.

In terms of intensity of the effect, it depends on the binding kinetics of the drug and its receptor. See: pharmacodynamics.

Regarding how these drugs can affect the brain, they mainly act through affecting the chemical synapse (also: Neurons, Brain Chemistry, and Neurotransmission).
posted by scalespace at 11:45 AM on May 27, 2012

Does every chemical that affects one's cognition/mood/psychology do so by interacting directly with neurons?

No. An example might be the MAOI antidepressants, which inhibit an enzyme in the blood (monoamine oxidase). I've read that this enzyme helps break down some neurotransmitters. Inhibiting it allows the neurotransmitters to hang around longer.

while others have no immediate impact but affect cognition for days (e.g., SSRI's)?

One current thought on that is that SSRIs encourage neurogenesis in parts of the brain and this new growth takes weeks to begin to make a difference.
posted by DarkForest at 12:21 PM on May 27, 2012

Your question is simple but the answer is extremely complex. There is an enormous variety of ways in which various drugs operate. And there are a lot of drugs whose operation isn't well understood. In some cases they aren't understood at all; everything about them was determined empirically.

The basic overall pattern begins with the drug being introduced into your body (by being eaten, by applying it to your skin, by being placed under the tongue, by injection into a muscle, by injection just under the skin, ingested through lungs or nasal linines, among other ways). Eventually you get some level of the drug into your blood stream.

As soon as this happens, your liver begins taking it back out again. The rate at which is does so varies from drug to drug, and also varies depending on the current blood level. The more drug there is, then usually the better the liver is at getting rid of it. As a result, the rate of this is usually referred to as a "half-life", the time it takes for the liver to dispose of half the blood load.

This is further complicated by the fact that some ways of introducing the drug into your system are very rapid and some are quite slow. In the latter case, even as the liver is beginning to work on destroying the drug, more is being introduced. So the blood load curve can be quite complicated.

So what do they do? Well, that at least is all over the map. In some cases what they do is stimulate existing receptors.

Receptors are special orifices on the surfaces of particular kinds of cells, which respond when certain specific chemicals touch the receptor. Adrenaline I'm sure you're familiar with; there are adrenaline receptors in all kinds of cells in your body, and when your adrenal glands release adrenaline into your blood, it stimulates various behaviors in all the cells which have receptors for it.

Adrenaline is interesting because the blood half-life is only a couple of minutes.

Why doesn't it stick forever? Well, it doesn't really stick at all, in fact. What's happening is that it brushes up against the receptor and triggers it. The more adrenaline there is in the blood, the higher the rate at which this takes place.

There are things which outright bind to receptors, but it's not absolutely permanent. There's a chance that it'll fall off. If the blood level of that drug is high, another molecule will probably grab that receptor soon. If not, then as the liver reduces the blood level, eventually most or all of them will fall off, travel to the liver, and be destroyed.

A different internal chemical like that is a class of proteins known as "endorphins" which can be released by the pituitary. It turns out that morphine and the other opiates work by stimulating endorphin receptors.

That's one way drugs can work. Another way is by interfering with enzymes. As mentioned above, MAOI's work by interfering with an enzyme called "monoamine oxydase" which is involved in breaking down the monoamine neurotransmitters in nerve synapses. As a result, this increases the background level of serotonin, norepinephrine, and dopamine, which makes it so that those synapses can fire more easily.

Turns out that monoamine oxydase is involved in a lot of other things, particularly in digestion. People who take MAO inhibitors have to be careful about their diets to avoid things like red wine, hard cheese, and avocado because while taking the drug they are no longer capable of fully digesting them. Intermediate breakdown products can build up and cause strange (and potentially fatal) symptoms.

Tricyclic antidepressants don't have that particular side effect. It's been determined clinically that they increase the levels of serotonin and/or norepinephrine, but no one knows how.

Even stranger, no one knows why this matters. Many of those drugs take weeks to result in clinical effects, and they don't work for everyone. Everyone who takes one gets an almost immediate rise in serotonin and/or norepinephrine levels, but that doesn't seem to have any immediate clinical effect.

I heard of a study that suggested that long term exposure resulted in an increase in the number of synapses using those neurotransmitters, but it was very preliminary. And even if that is confirmed, there's no explanation of why that makes any difference.

Most current antidepressants work by messing with the levels of the monoamine neurotransmitters. In some cases it's been determined how they affect the levels. But no one knows why doing that helps -- when it does, because it doesn't help everyone.

Something like LSD is a complete enigma. It affects all kinds of receptors in the brain, in different ways. That, at least, has been determined. But why does it make the user have hallucinations? No one has the slightest idea.

So in answer to some of your specific questions, "What is one's system?" It's the whole body, but in particular it's the brain, the blood, and the liver. (Also the kidneys; some drugs are eliminated in your urine instead of being broken down by the liver.)

Duration: Usually it's an inverse exponential curve. Because of that, doubling the dose doesn't double the duration. If it increases the duration at all, the increase is usually pretty small.

Intensity: Doubling the blood level doesn't necessarily result in a linear increase in perceived effect. There are exponential effects involved there, too. Is there a ceiling? well, if it kills you, then that's a ceiling. If it causes permanent damage (and some drugs do, or can) then that's something of a ceiling, too.

Latency: that's complicated, and in fact in some cases no one knows the answer. For the fast-acting drugs, it's pretty straight forward: it's the rate of ingestion in competition with the rate of breakdown. Someone just announced an inhaler containing ethanol. Using it, you get a huge spike of alcohol that only lasts a few seconds. That's because it's very fast for the alcohol to hit your blood stream, but there isn't very much of it, and so it doesn't last long. (Also there are plumbing issues involved. The alcohol lasts until the blood hits the liver, where it's all gotten rid of. But because of where the lungs are in the blood system, the blood absorbing alcohol from your lungs takes one trip around your entire body before reaching the liver.)

Why does a high end? Because the blood level of the drug has dropped far enough so that it no longer causes much effect, either because most of the drug has been broken down in the liver, or because most of it has been eliminated in urine by the kidneys.

By the way, I'm not a doctor but I am fascinated with this stuff and have done a lot of reading.
posted by Chocolate Pickle at 5:03 PM on May 27, 2012

Yeah, if those questions had one answer for all drugs, there wouldn't really *be* much of a field of psychopharmacology. It varies by drug, by receptor, by route of administration, by formulation of the drug, by set (the person's mood/pre-existing ideas about what the drug should be like), by setting (environment), by how many times the person has taken the drug before, by what other drugs they've taken with it, by what they've eaten and drank if it's taken orally, by the timing and pattern of the doses, by the other people they are with and their moods and expectations and by a huge other amount of individual genetic factors (not only in the brain: there's a complex system of enzymes in the liver that metabolize drugs and some drugs make these work faster and others slower and grapefruit can have a huge effect on some of them) and I'm sure I've left a ton of factors out.

People think a drug has X effect: actually the same drug can have the opposite effect on the same person in different conditions and on different people. This is why we get this absurd arguments about whether antidepressants are placebo, whether they cause suicide or homicide or whether they are miracle cures. They're all three, for different people at different times and obviously, with different drugs.
posted by Maias at 7:02 PM on May 27, 2012

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