Why do our bodies build up a tolerance to some medications but not others?

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Why do our bodies build up a tolerance to some medications but not others?

In: Biology

It’s kinda hard without specifics, but it has to do with upregulation of receptors a lot of the time.

Imagine you’re delivering goods to a factory. The first delivery, they send two guys to unload a whole truck, and it ends up taking hours. The factory learns their lesson and sends two extra guys the next time, so it takes half the time. You keep making the deliveries until the factory sends out so many guys that a few of them are just standing around while everyone else grabs one box each.

The factory is your cell (basic building block of you) and the workers are receptors (the bits on the cell that uptake/respond to meds).

Some drugs target cells in a way that doesn’t cause them to send out more receptors, while others can reach saturation/oversaturation quickly so your cell doesn’t respond as strongly/for as long.

Edit: this model might be a little backwards for the drugs people are picturing. The opposite version of this is if the boxes are heavy and the workers start slacking off (downregulation) and don’t engage as much. After revising a few things, the model I suggested originally is one of up-regulation and doesn’t quite fit the question. Hopefully it helps some of you understand/visualise cell receptors a little better, and also hammer home that this is a complex subject.

Medications that mess with receptors (mood, pain, etc) are similar to a younger sibling running around shutting every door in the house, flicking every light, making a ton of noise. Your brain eventually tunes it out by ignoring the drug (whether its effects are good or bad, it sees it as an imbalance). It does this by learning to open the doors, turning the lights off, and ignoring the noise just as fast as the medication. Eventually it cancels out the medication as the brain becomes balanced again. This is usually the point where your dose would be raised and the cycle would repeat.

Now while we’re here, to understand withdrawals, imagine the sibling was suddenly removed from the household. Now your brain is going around opening already open doors, turning off lights that are already off, and trying to tune out noise that isn’t there. This is what produces the unpleasant feelings of withdraw.

**Simpler version that doesn’t try to setup for a withdraw example:** You take a medicine to turn down how loud your pain signals are. The brain wonders why it can’t hear the pain very well, and as a result it eventually starts to listen harder. Soon enough it’s like you aren’t taking it at all.

Some medications build tolerance like a seesaw (essentially fighting it to try to create balance), causing unpleasant effects when you stop them and the brain levels out again. Others build tolerance and just stop working.

A few people have explained what tolerance is pretty well but haven’t really answered the question.

The reason some medications build up a tolerance and others don’t is because, there really isn’t any medication that doesn’t build up a tolerance.

The main factor is how long it takes to build one up and some meds happen really quickly, within days to weeks, and others can take several years but eventually, the body will try to normalize itself and a tolerance will be built.

The factors that dictate how long it may take are many and specific to the type of medication you’re taking as well as your own physiology. It has to do with your metabolism, the enzymes your body produces to break them down, the amount you take as well as the frequency, and a ton of other variables, but eventually, you’ll become tolerant.

Here’s an actual ELI5

Say you’re deficient in X. Or, say you have too much of Y. So, you take the medication. When you take medication for X, hopefully it increases your production of X. When this happens, your body’s mechanisms it used to produce (subpar) amounts of X will switch off. So, you will need more of it to feel the effects at the beginning. Combine this with the fact that it’s akin to taking a pebble out of your shoe (the immediate difference is always the most pleasurable).

One way some drugs work is by either blocking or boosting a signal in your brain or other part of your body. Much of your body works by cells releasing a chemical and another cell receiving that chemical and reacting to it (maybe a nerve sending a pain signal or your stomach creating acid) and then a third cell reabsorbs that chemical to stop the process. Drugs can “pretend” to be that chemical – so the those receiving cells start reacting, the drugs can block the cells that absorb the chemical making your natural chemicals last longer, or the drug can block the cell that’s receiving the chemical – stopping the reaction.

If a drug blocks the receiving cell from “sensing” the chemical, your body might continue to create the chemical. Alcohol does this. Your body will adopt to chronic use of the drug by creating more of the chemicals to compensate. your body can actual overdose on it’s naturally occurring chemicals if you remove the blocking drug suddenly.

If a drug mimics a chemical in your system, your body may respond by not bothering to make it’s own version of the chemical. Since you don’t have the naturally occurring chemical, you will need more to get the same effect. The same is true with blocking the reuptake of the chemical.

Your body can’t always make more of these chemicals. If that is the case, you won’t develop a tolerance or a dependency (generally) since your body doesn’t adjust.

There are other factors as well. Some of your organs (like your liver) can actually grow to filter more.

First off it has to do with your body always trying to stay in a state of balance. Most drugs involve binding to different receptors and your body has counters to the effects of binding to these receptors. It’s able to learn how to regulate them differently and control how “sensitive” they are with different hormones and other chems lime adrenaline. This is why some drugs have hangovers, because once the drug itself has worn out, the body’s chemicals and mechanisms it released to try and balance you out into homeostasis still exist. For instance, an alcoholic after a binder will have the shakes because the body was releasing adrenaline to counter the depressant alcohol. And since they person was drinking for so long, not only is the body exhausted from tons of adrenaline but it’s still pumping out, causing shakes and in extreme cases, delusions.

But with other drugs like say DMT, the body doesn’t have a counter chemical for this. It can’t pump another drug into your body to level you out. But it does have a defense mechanism specifically for just this drug since the body already produces it in low doses. So while it can’t counter it with another drug it does have a hormone which catches and kills DMT in the brain, which is why it only lasts 15 minutes but also doesn’t have a hangover because there wasn’t any adrenal or neuron fatigue.

But then you gave drugs like datura which can last literally days because the body has absolutely no defense mechanism against this. Not a counter hormone nor a cleanup hormone. Nothing. So it just has to get cleared by the liver and kidneys and you will never build a tolerance.

That being said you will eventually still build a pseudo tolerance against anything that impacts you. Eventually your brain will adapt to the changed state of reality and start rewiring itself to adapt to the differences. So eventually a person will still be super high but they’ll just have had their brain learn how to handle the intensity because the brain has rewired itself to navigate it.

But that too comes with a problem. This is why if someone gets off something like long term chronic use of things like LSD it can take sometimes months to years to get back mentally normal again. Because once they stop using, their brain has to again rewire itself to being a normal brain again. In some extreme and rare cases of extreme chronic abuse of lsd of really really long periods of time, like years, they can’t possibly come back. The brain has been so heavily rewired that it can’t undo itself.

We don’t really know, for the most part. We’ve observed which receptors downregulate in response to stimulation and which don’t, to some extent, but the reasons why are *usually* not known, and when we have an idea at all it’s specific to that receptor or even to the way that particular drug binds to that receptor.

Long story short, because tolerance is not some emergent property of biological systems, but rather a complex behavior that had to specifically evolve.

Some medications target systems that have negative feedback loops built into them, and those negative feedback loops are the reason for the tolerance.

And some medications target systems that do not have negative feedback loops built into them.

So to go with some analogies, a building with a thermostat that drives an HVAC system has a negative feedback loop for temperature.

If you put a space heater in that building you will see a rise in temperature for a bit, but within some operational range the thermostat will just turn up the air conditioners and the temperature will come back down. This is like the building has developed a “tolerance” for the space heaters.

If you want to permanently elevate the temperature inside that building you’d have to keep upping the number of space heaters to stay ahead of the thermostat system.

But let’s say instead of temperature we pick noise levels. You can put a radio in the building as while that radio plays music the noise level inside the building will he higher. Because the building doesn’t have any kind of negative feedback noise dampening system, it’s got no way of responding to lower the noise, so the building doesn’t develop “tolerance” for those radios.

Other buildings might actually have some feedback mechanisms in place. Maybe there is some of that sound absorbing foam and if noise levels are high the building pushes that foam out of little holes in the wall to lower the noise levels.

There’s no fundamental difference between heat and sound; it’s just that in our current state of engineering we tend to have buildings that *do* have negative feedback systems for temperature, but *don’t* have negative feedback systems for sound. And that, in turn, is driven by the fact that the environment we’re engineering for tends to have big changes in temperature and not really big changes in noise.

Well, let’s take this analogy back to the human body. There are certain systems that are “designed” by evolution to modulate in response to variations in environment. Like dopamine. Dopamine levels determine how likely you are to act on some idea that passes into your head. The higher your dopamine, the more responsive you are to things in general.

We have a really wide range of possible dopamine response because there are many pathways to dopamine release, and it has to keep us properly motivated – not too much and not too little – across a range of environments with different levels of stimulation. So there was an evolutionary advantage to developing internal dopamine regulation, i.e. to have some negative feedback to amp it up or dampen it down based on whether our environment or whatever other mechanism was bringing it up or down.

Once again, it’s not just an emergent property of the way dopamine works. Evolution had to sort of “go out of its way” to create that complex
mechanism of negative feedback. It’s a feature.

So you take a dopamine releaser like amphetamine or a reuptake inhibitor like cocaine, and this starts to trigger that feedback mechanism which decides there’s too much dopamine signaling going on and it lowers the responsiveness.

But then you take another neurotransmitter like glutamate. Well that’s been around for much longer. It’s older, evolutionarily speaking. It’s from the days when environments were less complex and you could get away with a simpler feedback mechanism.

Maybe glutamate receptors have some particular density, and then any time an organism encounters stress levels beyond some threshold, the glutamate activity just goes up permanently. It’s like instead of some “current level” of danger, the nervous system is just designed to remember the maximum level it’s ever encountered. The question is just “what’s the most dangerous situation I’ve ever been in?” and then glutamate activity goes up to match that.

So a glutamate antagonist like L-theanine doesn’t develop tolerance, because there’s no
mechanism that’s “watching” the level of glutamate activation to decide whether to upregulate or downregulate receptor density.

TL;DR: lack of tolerance is the default, and we have tolerance where there are specific feedback loops for specific homeostatic variables

So first we need to talk about a negative feedback loop. A house thermostat is my go-to example. The furnace makes heat *until* the thermostat senses too much heat and turns it off. That’s simple negative feedback. Now a thermostat that can control the AC and heat at the same time can do two directions of negative feedback and can modulate toward a “center” setting. Many parts of the body use a similar system to control things like heart rate, blood presure, body temp, stomach acid, bone growth, and so many more…

Now most of the drugs that create tolerances will be messing with one of these systems. Now a drug doing its job may be a bit like a space heater. You and your doctor think the room needs to be warmer, so you take your space heater drug. But now your body is kicking on the AC and fighting your space heater drugs, so you need more of them (and then the body fights more and the cycle gets worse), and that’s the crux of where tolerance build-up comes from.

Drugs that **don’t** create tolerance over time often affect body systems indirectly, are absorbed in unusual ways, or are specifically meant to not affect body systems at all. A good example of the last category is any antibiotic, antifungal, or antiparasite medication. The intent when creating one of those is to find a substance that is toxic to the invader you want to kill and doesn’t do anything to the human cells at all. So *you* will never build a tolerance to penicillin because penicillin doesn’t normally interact with your cells. (The bacteria-tolerance is another story) Most of these drugs are imperfect and can cause some side effects. You may actually be able to develop tolerance to those side effects if your body has a regulatory system related to them.

Some medications don’t get absorbed into you at all. Digestive meds are a common one. Simethicone and Pepto don’t need to get into your cells or blood to do their work, and there’s no system that can build a tolerance to their effects. I hope that’s helpful.

You build a tolerance to anything despite what anyone here says. You can have withdrawals from changing your diet too fast. Even supplements and antidepressants can cause extreme withdrawals that last years. Your central nervous system will do the opposite of whatever you throw at it to get back in balance. Every new drug claims it isn’t addicting and corporations spend fortunes telling doctors and patients this but it’s simply not true. It’s a law of nature. YOU CAN AND WILL BUILD A TOLERANCE TO ANYTHING.