How does methamphetamine work?

[Kandy K]

I was under the impression that meth actually increases the flow of dopamine to your brain, but some bluelighter told me that the meth particles are actually what is going to your dopamine receptors, thus damaging them, because it is not the dopamine chemical. True or not?

 

[mitogen]

Kandy K:

not true in a classical sense. primarily because methamphetamine agonism at dopamine receptors (*note, lots and lots of different DA receptor subtypes and complexes which all do different things and themselves form a complex) doesn't really matter

-not referenced.

 

[BilZ0r]

Meth doesn't bind at all to dopamine receptors at the concentrations reached during recreational usage. Meth doesn't work by increasing the flow of dopamine into your brain either.

Methamphetamine works by causing dopamine, noradrenaline and serotonin reuptake transporters (the proteins that pull those neurotransmitters out of the extracellular fluid, and into the cell) to work in reverse, pumping the neurotransmitters back out of the cell, increasing the amount of dopamine/noradrenaline/serotonin which can bind to their respective receptors.

 

[qwe]

how does damage to the dopaminergic system occur? is the damage confined specifically to the dopamine system?

 

[BilZ0r]

No one knows. Probably through some mechanism involving hyperthemia limiting endogenous anti-oxidants as well as oxidative dopamine metabolism.

 

[Kandy K]

OK seriously WTF I failed biology for a reason

 

[Reuptake]

^^^Bilz0r stated it as simply as possible.

 

[Slaughterhousefive42]

So meth only works by reversing cleanup? I would have thought that the massive allosteric similarity bt DA and meth ensured meth would hit DA receptors directly.

 

[DexterMeth]

http://www.bluelight.ru/vb/showthread.php?s=&threadid=189518&highlight=meth
The immune system reckognizes meth, and boosts tolerance to the drug through a vaccine-liky system.

 

[TheDEA.org]

Small differences in structure can make rather large differences in pharmacology; consider the order-of-magnitude increase in potency between AMT and 5-methoxy-AMT, or the single oxygen atom that separates ephedrine from meth. In the case of MDMA, extending the N-methyl group converts from a strongly noradrenergic (and serotonergic and to a lesser extent dopaminergic) drug to a pretty much purely serotonergic drug (MDEA).

Still, the mechanism of meth/amphetamine is rather surprising; somehow it screws with the dopamine transport mechanism, allowing neurotransmitters to be released more easily. Usually it is a safe bet to assume a psychoactive drug works largely or wholly by hitting receptors.

Neurotoxicity seems to be the result of oxidation produced as a side effect of breaking down the drug or a metabolite of it (or perhaps something else entirely.) I suppose the analogy would be taking out your garbage to burn it, throwing gas on it, and catching your clothes on fire; a normal process running a little too 'hot' to be contained. With meth, the damage (in lab animals) seems to be limited to dopamine neurons. As with the MDMA debacle, it doesn't seem that the average user is actually suffering this sort of damage (although there are plenty of very real health concerns with meth.)

Meth doesn't bind at all to dopamine receptors at the concentrations reached during recreational usage.

There will be some binding at any concentration; binding values and whatnot are a reflection of how tenaciously the molecule binds to the protein, which when coupled with the concentration will affect how often a molecule of the drug will be occupying a protein. A low-affinity drug will only briefly occupy the protein; if it's concentration is also low, the protein will rarely be occupied by the drug.

 

[BilZ0r]

^ Yes, but if one was going to put things like that, the it would be safe to say that all chemicals bound to all receptors.

So meth only works by reversing cleanup? I would have thought that the massive allosteric similarity bt DA and meth ensured meth would hit DA receptors directly.

Nope, and are you sure 'allosteric' is the word you're looking for?

 

[TheDEA.org]

My point being that if a molecule is capable of 'binding' to a protein (regardless of what you consider an appropriate affinity to call binding), then binding will occur at all concentrations of the molecule. Increasing concentration merely increases the likelihood that the protein will be occupied by the molecule at a given moment in time; it has no affect on the ability of the individual molecule to bind to the protein.

Ergo, to say that meth does not bind to receptors at a given concentration is incorrect; either it can bind at any concentration or it can't bind at any concentration.

 

[leungkachong]

TheDEA.org: Actually, what BilZ0r i believe is trying to say (accurately), is that you need to consider the phrase "able to bind to the receptor" as implying that it's k values (equil. constants for affinity to and strength [ability to agonize] the receptor are high enough w/ the concentrations to have physiological significance. What your mistaken in thinking is that:

"either it can bind at any concentration or it can't bind at any concentration.".

The binding and strength exist in equilibrias, and no matter what there will be some small incidence of occupying the receptor. This can be very insignificant, but it is still how it works. Think of it as analagous to the fact that there is no such thing as "insoluble". Instead, Merck just makes cut-offs for what is considered "insoluble" by their dissociation equilibria constants. It's small, but in reality oil does mix w/ water . (Actually.. off-topic, if you are able to freeze out gasses dissolved in an oil water mixture, they will form a spontaneous emulsion and a function of reducing long-range hydrophobic force...)

And BilZ0r: I think by allosteric he meant the similarity in how DA and meth probably cause change to the G-protein coupled receptors conformationally as a result of their electronic geometry?

 

[BilZ0r]

Exactly... all compounds can bind to all receptors. But a compound with a Kd of 1M (and I appriciate the stupidity/immpracticality in that quantification) can be considered functionally inactive. Meths Kd at D1 and D2 like receptors well over 10mM, in fact, no appriciable binding can be noticed at that concetration, so it's Kd is going to be at least 0.1M which is just stupid.

It's a question of signal to noise. At a physiologically/pharmacologically relavent range of concentrations do you get any effect which can produce a physiological or pharmacological effect. And at those concetrations, I'm sure basal G-protein activation by dopamine receptors is orders of magnitude higher than any induced by methamphetamine directly.

 

[TheDEA.org]

you need to consider the phrase "able to bind to the receptor" as implying that it's k values (equil. constants for affinity to and strength [ability to agonize] the receptor are high enough w/ the concentrations to have physiological significance.

Considered and rejected. While I agree that he probably meant to say that at recreational doses receptor binding is not a pharmacologically important contributor to the drug's effects, the actual statement:

Meth doesn't bind at all to dopamine receptors at the concentrations reached during recreational usage.

...is illogical. The capacity of an individual molecule to stick to a protein isn't a dose-dependent effect. To say "meth doesn't significantly bind at x concentration" would be correct; "doesn't bind at all because of low concentration" is not correct. (And no amount of eye-rolling about 'if you call such a low affinity binding' is going to save it.)

Granted this is an academic distinction, with no real bearing on pharmacological effects...but I think it's still important to make that distinction in the name of understanding the mechanisms and not just the net effects.

 

[leungkachong]

The capacity of an individual molecule to stick to a protein isn't a dose-dependent effect.

I don't think anyone was trying to say that it was. The capacity of a compound to stick is simply dependant on it's equil. constants. The actual amount of binding that occurs howevera dose-dependant (well.. concentration-dependant). But in your saying that there is such thing as a compound that doesn't bind, this still stands as incorrect.

 

[BilZ0r]

This isn't even an academic distiniction. It is one that gets in the road of understanding.

The capacity of an individual molecule to stick to a protein isn't a dose-dependent effect.

Sure, but the capacity of a molecular to stick to a protein SPECIFICALLY is dose dependent. At very very high concentrations non-specific binding ~= specific binding, but at very very low concentrations (relative to Kd) the law of mass action gives out... You get ligand depletion because of non-specific binding.

You can keep holding onto your point, which we both know, in some abstract context, is correct, but it serves no purpose to anyone.

 

[Smyth]

Methamphetamine certainly does play around with the NET/DAT receptors/neurotransmitters (although im just a chemist here [so dont expect a detailed pharmacological profile]). Other drugs that do this include phenyltropane (which I have not tried yet) and also ritalin. However none of these drugs strongly engage in SERT receptor activity very much.

Drugs that do bind to the SERT receptor include cocaine, MDX, Effexor and lastly Tramadol (to a limited extent although this does not get a great amount of attention).

So I think it is necessary to draw a distinction between psychomotor stimulants and so-called 'happy drugs' but such a distinction is not really there since obviously there will be drugs displaying characteristics in between (different shades of grey).

However methamphetamine definately appears to lie on the psychomotor end of the spectrum and does not muck around with serotonin in anyway.

 

[5-HT2]

Methamphetamine certainly does play around with the NET/DAT receptors/neurotransmitters (although im just a chemist here [so dont expect a detailed pharmacological profile]). Other drugs that do this include phenyltropane (which I have not tried yet) and also ritalin. However none of these drugs strongly engage in SERT receptor activity very much.

Drugs that do bind to the SERT receptor include cocaine, MDX, Effexor and lastly Tramadol (to a limited extent although this does not get a great amount of attention).

So I think it is necessary to draw a distinction between psychomotor stimulants and so-called 'happy drugs' but such a distinction is not really there since obviously there will be drugs displaying characteristics in between (different shades of grey).

However methamphetamine definately appears to lie on the psychomotor end of the spectrum and does not muck around with serotonin in anyway.

I think it's safe to say that methamphetamine action at the SERT is behaviorally and psychopharmacologically significant. This is why, after all, meth feels different from dexedrine, or adderall. As you said, there are different shades of grey, and meth is definitely in this gray area. If I had to put monoamine transporter-targeting drugs along a line with "pure SERT" and "pure DAT" at the ends, this is how I would rank them (this is open to debate):

DAT

• amphetamine
• methylphenidate (not sure about how strong the serotonergic effects of this one are)
• methamphetamine/cocaine
• MDA (this may not all be due to direct action at the DAT, since DA neurons express the 5-HT2A receptor and thus MDA probably stimualtes DA release in this manner as well)
• MDMA
• MDEA/MBDB

Ideally you would want a triangle with one monoamine transporter on each corner for purposes of drug effect classification. But that task requires more research than I am willing to put in right now.

 

[Smyth]

Methylphenidate does not act on serotonin receptors what-so-ever.

Neither does nicotine or epibatidine, clearly showing that hard-cut stimulants dont need to display activity towards the SERT receptor.

Whilst I believe that there may be some sort of 'butterfly effect' whereby stimulants such as ephedrine can activate SERT receptors as a secondary effect, I dont forsee that this lies in the primary domain of its activity.