Hormesis - The science behind drug response & tolerance

[DarkGhost101]

It is well known that consuming any psychoactive drug for a long time will lead to the development of dependence and tolerance to the effects of the drug.

But have you ever wondered how exactly tolerance works? Even if you understand this concept well, keep reading, because you might be surprised.

First of all, let's start with a general rule: All psychoactive drugs are seen by the brain as toxic agents that have to be destroyed, and the type of drug doesn't matter here.

Let's take for example a Dopamine D2 agonist. A continued exposure to this specific agonist will lead to a downregulation of Dopamine D2 receptors, and as a result a decrease in the effect of the agonist (tolerance).
Stopping the use of this agonist will eventually lead to upregulation of the D2 receptors (normal state, like there was before the use of this agonist).

But this is where it gets interesting...

Did you know that small doses of the D2 agonist will cause a quick upregulation of these receptors?

That's true - low doses of this D2 agonist will result in upregulation of the Dopamine D2 receptors, which is the exact opposite of moderate-high doses that cause downregulation.
This mechanism is called Hormesis (an opposite response to low doses of a toxin than a moderate-high dose of the same toxin).

Here's an example graph for this model (taken from Wikipedia):

This graph shows the response to the toxin according to the dose.
So in terms of psychoactive drugs, this graph means:

Stimulation = upregulation (decrease of tolerance and dependence)
Inhibition = downregulation (increase of tolerance and dependence)

As you can see, very small doses of a drug cause upregulation, whereas higher doses cause more and more downregulation.

There exact mechanisms behind Hormesis aren't exactly known, but it's medically accepted that low doses of a toxin activate the repair mechanisms of the body (positive effect), unlike high doses of toxins that overwhelm the body and suppress repair mechanisms (negative effect). Since all drugs are toxins, this mechanism should work here too.

There is only one study about Hormesis in relation to psychoactive drugs, and it's about MDMA. This study claims that low doses of MDMA (1mg/kg) upregulate Serotonin receptors, while high doses (2mg/kg) downregulate Serotonin receptors. Of course, low doses of MDMA that cause upregulation will result in a decrease of MDMA tolerance.

There are no more studies about this mechanism in other drugs, but it's safe to assume that it works the same way with all drugs (since the brain sees all of them as toxins).

What do you think? Can this mechanism be effectively used with other psychoactive drugs? If yes, it can be a huge benefit for medicine. Tolerance to medication which is taken for a chronic disease is a big problem with chronic medications, and if this works with all psychoactive drugs/medications, it can help to eliminate this difficulty in chronic treatment. And that's just one example...

Sources:

Hormesis - General Information: http://en.wikipedia.org/wiki/Hormesis
Hormesis - General Information: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1299203/
Hormesis - General Information: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248601/
Low doses of MDMA cause Serotonin receptor upregulation: http://naturalsolutionsradio.com/bl.../ecstasy-manifesto-can-mdma-use-be-made-safer

 

[Bagseed]

interesting, thanks for sharing. unfortunately I cannot really add to the topic because of my very limited knowledge of pharmacology.

 

[Black]

i've read about that and wanted to try it out last summer. i took a few low doses of mdma (way below 1mg/kg, rather like 0.05mg/kg) leading up to a nice rolling opportunity, but had a sunstroke on the day when i planned the large dose, so i didn't follow though on it...

 

[Solipsis]

Small doses of MDMA administered before a larger dose a little later also prevents part of the toxicity, right? Is that mediated by hormesis, or something else?

Also, can you decrease your say opioid tolerance by taking very low doses (probably hard to say how low you'd have to go exactly)? And is lowering of opioid tolerance by taking NMDA antagonists indirectly mediated by hormesis because the NMDA antagonist causes mild inhibition and upregulation in its signal cascade?

By the way, very interesting but I don't think that it is meaningful to say that "the brain sees psychoactives as toxins". I think psychoactives are usually structurally related to neurotransmitters, there are mechanisms in place to get rid of excess neurotransmitter, and the psychoactives are usually picked up by those mechanisms. Paths like that have developed evolutionary and by some logic, but not intention.

 

[Black]

Small doses of MDMA administered before a larger dose a little later also prevents part of the toxicity, right? Is that mediated by hormesis, or something else?

serotonin depletion or tolerance probably. their "low doses" were around 3mg/kg.

 

[chaos_destroy]

serotonin depletion or tolerance probably. their "low doses" were around 3mg/kg.

It is a shame that this is true though at least it highlights the fact that even people with big tolerance to MDMA that hence dose higher still don't get to the dosage required in studies to induce neurotoxicity because of the protection from their existing tolerance. Also suggests that the neurotoxicity of MDMA is likely directly caused by the pharmacological action of MDMA and not some side action or the MDMA molecular or metabolite itself. Otherwise tolerance should have no effect. Not that neurotoxicity is really relevant to recreational dosage anyway.

 

[Jonneh]

Hormesis is a powerful and elegant idea, and this is an interesting attempt to implicate it in an important process.

I would echo Solipsis' point about psychoactives as neurotransmitter analogues rather than toxins. 'Recognition' of such simple molecules consists in large part of the ability of degradative enzymes to access them. Any endogenous molecule with similar proerties will be similarly vulnerable. DMT is a case in point. Since hormesis pertains to a response to toxins or other stressors, I'm not sure this is the right concept to explain the process of drug tolerance.

Empirical evidence stands alone though (although there doesn't seem to be too much of it yet) and if the curve you say has been described for MDMA is true for other drugs, then it's still a very interesting phenomenon. There could be other ways to explain it, of course. For instance, it could be a gain control response of neurons to concentrations of an effector that are above noise level, but sub-threshold in terms of their ability to elicit a response. The small but significant concentration of the drug looks meaningful, so the responsiveness of its targets is increased. The prediction with this model would be that the same low dose of the drug would have less and less of an upregulatory effect as the system is more confident of suitable calibration (meta-tolerance, if you will).

 

[Zeds(NCO2CH2CH3)2]

Your forefront idea has meaning but you are missing that acute increased receptor activity(upregulation) can mean a variety of things, and that this doesnt correlate COMPLETELY at all with inhibition of tolerance. There is research that point to receptor density dependent and receptor density independent mechanism for tolerance in mu opiate receptors for example.
One major theory is the endocytotic mechanism of tolerance. Tolerance appears to be mediated by increased stimulation of the receptor in question- but the receptor cannot undergo endocytosis(the normal process for repair/resynthesis) so in turn the protein receptor, responds thermodynamically by internalizing itself by "hiding" a few angstroms this is a massive effect you must realize! But it is still being stimulated somewhat and the second aspect prevents complete endocytosis.
The enzymes responsible for degrading the receptor are also inhibited by prolonged effects as internally the major energy carriers(kinases and the phosphate groups they carry!) are all phosphorylated lets say "near indefinitely" because of prolonged stimulation, the normal cascade is affected greatly and the body makes up for this change by upgregulating everything(transcriptional control) but still- due to receptor internalization etc and varied enzyme counts euphoria markedly diminishes because the activity is reduced and despite the bodies efforts to return to a homeostatic balance- it cant- we try to make up for this by taking more drugs (flooding effect) and this can help, this can do things, but it leads to further complications of the cycle.

I hope that explanation was kind of helpful- its a hard topic- but upregulation is not upregulating euphoria but upregulating affected proteins in the area-

Check out these articles (Please read them)

[h=1]Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. (Note that we discussed that drugs i.e morphine inhibit endocytosis-or the recycling)[/h]http://www.ncbi.nlm.nih.gov/pubmed/11738029

Protein kinase A and mu opiate receptor

http://www.jneurosci.org/content/21/9/2967.full.pdf (FREE PDF)

hope this helps(see picture too)

zedsdead

 

[Black]

It is a shame that this is true though at least it highlights the fact that even people with big tolerance to MDMA that hence dose higher still don't get to the dosage required in studies to induce neurotoxicity because of the protection from their existing tolerance. Also suggests that the neurotoxicity of MDMA is likely directly caused by the pharmacological action of MDMA and not some side action or the MDMA molecular or metabolite itself. Otherwise tolerance should have no effect. Not that neurotoxicity is really relevant to recreational dosage anyway.

interesting point, but iirc injcting high doses mdma directly into brains has never led to any neurotoxicity at all. so the reason for the protective might rather be upregulation of glutathione or something rather than tolerance...
but that's going pretty much offtopic now.