Usually its due to downstream pharmacokinetic effects that involve downregulation/upregulation of whatever responds to what the substance is as an attempt to establish homeostasis.
This usually happens in two ways, the first is downregulation of receptors. Whatever the substance is providing (dopamine, serotonin, norepinephrine, etc) it has to bind with a receptor which acts as a signal to your body to produce whatever effect that substance is supposed to. Overtime, the expression, tonality, or even quantity of receptors reduce (downregulation) because your body has way more of whatever that substance is delivering than it needs or knows what to do with.
The second way tolerance can build is upregulation of transporters. Whatever is in the synaptic cleft, it gets moved away by transporters (e.g. DAT/NET). If you consistently flood your synapse with exogenous source of something, your body may start to produce & release more transporters than normal (upregulation) because it has more of that substance than it needs. You can think of these transporters as little vacuums that clean up the cleft.
So net, you have reduced receptors so the potency of the substance is lower and increased transporters so the durability of the substance is lower. Those two combined are the primary mechanisms that create tolerance.
Imagine you’re in a room that kind of stinks. After you live there for a while it stops stinking even though the smell is still there because your nose has gotten used to it. If you leave for a few weeks and come back it will smell again. If you introduce the same smell but much much stronger inside the room you will also notice it again until you get used to that as well. It’s kind of like that except your nose is the receptor for the chemical in question.
In the case of caffeine, for example, which is an adenosine blocker (the stuff that makes you sleepy), the more you take it, the more adenosine receptors your brain creates. So to achieve the same level of adenosine receptor saturation, you progressively need more and more caffeine
When you are tired, one bit of your brain releases a chemical message that says “I am tired”. It has to reach a receptor in another bit of your brain, for the brain to understand that you are tired. The more chemical message reaches the receptors, the more tired you feel. Caffeine is a drug used by many people to stay awake by reducing the feeling of tiredness. Caffeine works by sticking to the same receptors that detect the tiredness chemical, preventing the tiredness chemical from reaching the receptors, so you don’t feel tired, even though you are.
After a while your brain notices that something isn’t working right. It’s sending all the tiredness chemicals, but you aren’t receiving them or doing anything about them. So it actually builds MORE receptors, to make sure that you receive the tiredness chemicals. Now, the same amount of caffeine isn’t enough to stick to all the receptors, and some of the tiredness chemical messages actually get to the receptors. You feel tired despite the caffeine, because of the extra receptors. You drink the same amount of caffeine, but you start to feel tired still. So you drink more caffeine, and can stay awake without feeling tired again, because the extra caffeine is now enough to stick to all the new receptors.
But then your body gets wise to what you are doing, and creates more receptors, so you drink more caffeine and it creates more receptors. The cycle continues slowly, and to you, it feels like the same amount of caffeine is no longer effective.
In some cases, your body physiologically adapts and subtly changes how it reacts to a substance due to consistent or extreme exposure.
In other cases your body may not change how it reacts to the substance but instead your brain adapts by changing the lived experience of the substance.
Consider the case of being in a room with a distinct smell. After a while you won’t smell it anymore. That effect is both psychological and physiological. Receptors in your nose become less responsive to an oder when continuously exposed and your brain filters out information it determines is unimportant to conserve energy.
Your body is always trying to reach homeostasis (baseline state). When you take a drug, it triggers an A process (the high), and your body fights back with a B process (the counter‑reaction) to pull you back to a homeostatic baseline.
For every A process exerted by a drug, there will always be at least an equal and opposing B process exerted by the brain and body.
At first the A process is bigger than the B process, so you feel that rush. Over time the A process shrinks while the B process grows and speeds up. This is tolerance and withdrawal.
Eventually you need the drug just to fend off the growing B process instead of chasing the A process.
Comments
[removed]
Usually its due to downstream pharmacokinetic effects that involve downregulation/upregulation of whatever responds to what the substance is as an attempt to establish homeostasis.
This usually happens in two ways, the first is downregulation of receptors. Whatever the substance is providing (dopamine, serotonin, norepinephrine, etc) it has to bind with a receptor which acts as a signal to your body to produce whatever effect that substance is supposed to. Overtime, the expression, tonality, or even quantity of receptors reduce (downregulation) because your body has way more of whatever that substance is delivering than it needs or knows what to do with.
The second way tolerance can build is upregulation of transporters. Whatever is in the synaptic cleft, it gets moved away by transporters (e.g. DAT/NET). If you consistently flood your synapse with exogenous source of something, your body may start to produce & release more transporters than normal (upregulation) because it has more of that substance than it needs. You can think of these transporters as little vacuums that clean up the cleft.
So net, you have reduced receptors so the potency of the substance is lower and increased transporters so the durability of the substance is lower. Those two combined are the primary mechanisms that create tolerance.
Imagine you’re in a room that kind of stinks. After you live there for a while it stops stinking even though the smell is still there because your nose has gotten used to it. If you leave for a few weeks and come back it will smell again. If you introduce the same smell but much much stronger inside the room you will also notice it again until you get used to that as well. It’s kind of like that except your nose is the receptor for the chemical in question.
In the case of caffeine, for example, which is an adenosine blocker (the stuff that makes you sleepy), the more you take it, the more adenosine receptors your brain creates. So to achieve the same level of adenosine receptor saturation, you progressively need more and more caffeine
A real example.
When you are tired, one bit of your brain releases a chemical message that says “I am tired”. It has to reach a receptor in another bit of your brain, for the brain to understand that you are tired. The more chemical message reaches the receptors, the more tired you feel. Caffeine is a drug used by many people to stay awake by reducing the feeling of tiredness. Caffeine works by sticking to the same receptors that detect the tiredness chemical, preventing the tiredness chemical from reaching the receptors, so you don’t feel tired, even though you are.
After a while your brain notices that something isn’t working right. It’s sending all the tiredness chemicals, but you aren’t receiving them or doing anything about them. So it actually builds MORE receptors, to make sure that you receive the tiredness chemicals. Now, the same amount of caffeine isn’t enough to stick to all the receptors, and some of the tiredness chemical messages actually get to the receptors. You feel tired despite the caffeine, because of the extra receptors. You drink the same amount of caffeine, but you start to feel tired still. So you drink more caffeine, and can stay awake without feeling tired again, because the extra caffeine is now enough to stick to all the new receptors.
But then your body gets wise to what you are doing, and creates more receptors, so you drink more caffeine and it creates more receptors. The cycle continues slowly, and to you, it feels like the same amount of caffeine is no longer effective.
In some cases, your body physiologically adapts and subtly changes how it reacts to a substance due to consistent or extreme exposure.
In other cases your body may not change how it reacts to the substance but instead your brain adapts by changing the lived experience of the substance.
Consider the case of being in a room with a distinct smell. After a while you won’t smell it anymore. That effect is both psychological and physiological. Receptors in your nose become less responsive to an oder when continuously exposed and your brain filters out information it determines is unimportant to conserve energy.
Your body is always trying to reach homeostasis (baseline state). When you take a drug, it triggers an A process (the high), and your body fights back with a B process (the counter‑reaction) to pull you back to a homeostatic baseline.
For every A process exerted by a drug, there will always be at least an equal and opposing B process exerted by the brain and body.
At first the A process is bigger than the B process, so you feel that rush. Over time the A process shrinks while the B process grows and speeds up. This is tolerance and withdrawal.
Eventually you need the drug just to fend off the growing B process instead of chasing the A process.
https://imgur.com/gallery/Y7MENWx