"A short explanation on comedowns, tolerance & compensatory responses

All of the information below is based on the following paper:

Aspects of the Relationship Between Drug Dose and Drug Effect (2009).

Comedowns refer to the effects felt when the drug wears off. Comedowns might be unpleasant.

The reason for comedowns is a compensatory response of your brain. Comedowns are closely related to tolerance.

Compensatory response is a mechanism that causes the opposite effects to the drug being taken in order to protect the brain - that is the main contributor to tolerance AND to comedowns.

For example, if you have Amphetamine tolerance, whenever you take an Amphetamine dose, the brain will detect the drug and immediately reduce dopamine concentrations globally in the brain, to counteract the dopamine increasing actions of Amphetamine.

Now, the compensatory response usually lasts longer than the drug itself. That means that even after the drug has mostly left the brain, the compensatory response will keep lowering dopamine concentrations, hence the comedown.

The homeostatic model theory of tolerance and withdrawal (receptor regulation and enzymatic modifications) is insufficient to explain the mechanisms standing behind these principles. It is concluded, then, that compensatory responses and environmental cues are more closely related to tolerance and withdrawal, respectively (withdrawal is dependent on the appearance of environmental cues related to it). Tolerance to receptor agonists is not primarily because of receptor downregulation, but because of a compensatory response consisting receptor antagonists or a reduction in release of the endogenous ligand to that receptor.

It is known, though, that very low doses of the drug which tolerance has been developed to have interesting effects on the compensatory response.

For example, if someone with Amphetamine tolerance takes a very low dose of Amphetamine, the compensatory response will be disproportional to the dose and reduce dopamine concentrations more than it needed to (because the compensatory response develops to drug dose, not to the drug itself). The result is a mathematically negative drug effect, induced by a too powerful compensatory response.

So, after a single very low dose of Amphetamine, the compensatory response will be very strong and reduce dopamine concentrations too much, but afterwards, it'll adjust itself to be NEGATIVE - that means, after a very low dose of Amphetamine, subsequent Amphetamine doses will be stronger, since the compensatory response will increase Amphetamine's effects instead of decreasing it (this is because the compensatory response will adjust itself to the very low dose, reversing itself and therefore increasing the effects of high doses).

So, in essence that means, that very low doses can change the compensatory response so it makes drugs even stronger than what they are supposed to be (the response will amplify the effect).

To sum up:

Tolerance and comedown are more closely related to compensatory responses than to receptor regulation itself.

Withdrawal symptoms mainly occur because of environmental cues that are related to the drug.

Low doses can reverse the compensatory effect, making it increase the drug effect instead of countering it, causing the drug effect to be stronger."