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D-methamphetamine/L-methamphetamine effects

gawd you people blow my mind! what thorough answers and info to my inquiry...i still can't fathom it though, because i don't understand and am not that familiar with the terminology you use.
i'll definitely try researching the keywords to catch up with you..this is an exciting and veeeery useful subject to add to one's ken..
 
This means that d-MDMA causes a dopamine rush and l-MDMA doesn't?
d-MDMA inhibits *uptake* of dopamine, which would lead to more dopamine being available in the synapses. this is consistent with the other articles.
[see below for another possibility]
So if one took pure d-MDMA, would the high be shorter than with a racemic mixture?
Possibly. Unlike the article on N-demethylation this refers to the total amount of MDMA eliminated, so it doesn't matter by what pathway. Since the high from the d-isomer seems to resemble the racemate quite closely ('lacks the fire' doesn't seem to imply it has *that* much of a decreased effect) the difference would probably be more in the late stages; you'd have a longer plateau after peaking, but that's about it.
I've never heard of anything like this! Does this imply that much of what is really in our brains when we use MDMA is MDA? About what percentage of MDMA is converted to MDA?
It surprised me too, and certainly N-demethylation is not the most likely means of breaking down MDMA, since the N-CH3 bond would be much more stable than the ether linkages in the 3,4-methylenedioxy group. If it did occur, it would certainly happen in the liver and not the brain, so any MDA would have to be reabsorbed to have an effect. The effect is probably minor and certainly is not be the primary mode of action, because if it was the two drugs would be more similar in effect and MDMA would probably take longer to kick in. (does anyone know how long it takes to come up on MDA relative to MDMA?). I don't think the actual percentage was given in the abstract.
What does this mean? That there is less or more serotonin??
More; I think again they mean inhibits uptake, see above.
For both of these, where it says "inhibits nerve firing", there's a second possibility. It's possible that when MDMA binds to a 5-HT receptor, it may NOT actually cause the neuron to fire (it may be a ligand, but not an agonist, hence an inhibitor). In that case, it may just mean d-MDMA has more affinity. HOWEVER: These experiments are in vitro in a dilute medium. In the actual brain, the mode of action may be different (release of serotonin from storage vesicles; see below). Since the synapse is a very limited space compared to a culture flask, any serotonin release from the neuron induced by MDMA would be lost to the surroundings. In the brain, that serotonin would activate the neuron.
d-MDMA is more potent and doesn't work directly on serotonin receptors?? I'm really confused by this. It makes sense that l-MDMA would act momre on serotonin receptors, but why does this imply that d-MDMA is more potent (what do they mean by the term potent here)?
"Potent"-- as in, it fucks you up more. it has more overall psychoactivity. we know this from prior observation, not from the experiment. what this means then is that some other aspect of the drug must be responsible for making the d-isomer more potent. it could be several things:
- maybe d-MDMA has affinity for a serotonin receptor other than the ones they tested for
- maybe the overall potency of MDMA is more related to dopamine than serotonin (doubtful)
- or it's also possible that MDMA causes serotonin release in another way, possibly *primarily* in another way. one current hypothesis is that it may cause the serotonin transporter pump to release serotonin from the neuron. this is not the same thing as triggering the receptor directly. (this is the explanation i most favor, though i don't know exactly how the experiment was done because i can only read the abstracts)
And if d-MDMA doesn't work directly on serotonin receptors, how and to what degree does it work on them?
elaborating on this... MDMA seems to have affinity for a number of proteins and enzymes, which makes sense since it closely resembles a neurotransmitter. binding directly to a 5-HT receptor would cause that neuron to transmit its signal, doing whatever that does. but there are other ways of activating the neuron. one favored hypothesis is that MDMA binds to the serotonin reuptake transporter, which normally removes serotonin from the synapses for storage. it then causes the neuron to actively transport serotonin out of its storage vesicles and *into* the synapse. the resultant increased 5-HT levels would result in more 5-HT binding to receptors and causing the neuron to transmit. since this would affect all serotonin receptors rather than the ones MDMA selectively binds to, it would have a more generalized effect. in reality the effect is probably the sum of increased serotonin levels with some degree of direct activation of 5-HT receptors.
I'm confused again. What is meant by the fact that MDMA "irreversibly", and meth "reversibly" inhibits Trp hydroxylase (I don't understand the usage of these terms)?
Normally, an enzyme-substrate reaction is an reversible, equilibrium process:
E + S <--> ES
There are several types of inhibition. Reversible inhibition is either competitive or non-competitive. Competitive means the substrate and the inhibitor "compete" for the same binding site, while in non-competitive inhibition the inhibitor binds at a separate site. At any rate, when the inhibitor is bound, the enzyme cannot catalyze a reaction.
"Reversible" means that after a period of time the inhibitor will break away from the enzyme and allow it to work again. This happens because the enzyme-inhibitor bonds are relatively weak (hydrogen bonds), and random motion due to thermal energy will eventually cause those bonds to break.
Irreversible inhibition means the inhibitor does *not* detach from the enzyme. The inhibition is permanent, and the enzyme will have no effect. Eventually, it will be broken down and replaced, but it takes time (about 2 weeks in this case). Irreversible inhibition generally occurs when the enzyme-inhibitor bonds are covalent.
Does this mean permanently?
Yes; the enzyme must be broken down and replaced with a newly synthesized enzyme.
And if Trp h. catalyzes a "rate-limiting step", does that mean the reaction goes FASTER or SLOWER in the absence of Trp h. ?
Faster. Trp hydroxylase catalyzes a reaction that would never be expected to occur randomly; if you mixed tryptophan and NaOH you would never expect to get 5-HTP. The "rate-limiting step" is the slowest reaction in the pathway. In other words, the second step occurs relatively fast, so the limiting factor in the synthesis of serotonin is how much 5-HTP is available. If Trp hydroxylase has been inhibited, very little 5-HTP will be present and very little serotonin will be produced. (unless there's 5-HTP from an outside source.)
[This message has been edited by Roches (edited 22 May 2001).]
 
Thanks Roches! I really appreciate all the clarification, it all makes sense now. Thanks again.
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"I could not/Speak, and my eyes failed, I was neither/Living nor dead, and I knew nothing" - T.S. Eliot, The Wasteland
 
fairnymph:
d-MDMA is the isomer which accounts for most of the meth-like effects of racemic MDMA.
I'd agree, especially since it has higher affinity for dopamine receptors.
I also get the impression that the l- isomer produces most of the "lovey" effect of racemic MDMA.
Depends on what 'love' is =).. it's partly serotonin, partly dopamine. Now d-MDMA has a higher affinity for both of those... The only thing I can see making l-MDMA *more* lovey than the d-isomer is the greater affinity of the l-isomer for 5-HT1 and 5-HT2. But like I've said, that's not necessarily the actual mechanism in the brain.
It follows from what has been said above that d-MDMA probably releases most if not all of the dopamine released by racemic MDMA. Would l-MDMA then have little or no neurotoxicity?
The neurotoxicity is probably not caused by the release of dopamine itself (which is good, it would suck to get brain damage for being *really happy* for a few hours); most evidence suggests it's actually a metabolite.
The title of this article says it pretty well:
Shankaran, M. et al, Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT. Synapse (2001), 40(1), 55-64.
I actually could get this one (not just the abstract). Essentially it found that treating rats with vitamin C before giving them a neurotoxic regimen of MDMA causes no significant difference in serotonin levels relative to a control (meaning no damage), and MDMA alone reduces 5-HT by almost half. That should be enough; the article discusses how MDMA forms hydroxyl radicals and has potentially toxic metabolites. If vitamin C, an antioxidant, eliminates the damage, then it cannot be serotonin release itself that causes the damage to occur.
Since we know from those other articles that l-MDMA is metabolized more slowly, it follows that it would be less toxic, but it still *will* be toxic. All the metabolites will still be produced, just more slowly, and unless more vitamin C or E is introduced it will probably continue to do damage until it's excreted.
So for using MDMA as an anti-depressant, I doubt it. Clearly d-MDMA is not acceptable, and it's only about 3 times more neurotoxic than l-MDMA; over an extended period it would certainly cause damage. Another *major* problem with using MDMA as an antidepressant is that it is literally a pro-depressant: y'know the Trp hydroxylase inhibitor thing? Since it interferes directly with the synthesis of serotonin, not only could you not use MDMA as an antidepressant (except by a single life-changing experience), you could use it to *cause* depression in normal subjects.
I don't hear about pre- and post- loading much anymore; I think that goes along with a general decline in ravers' ages and intelligence. But there are studies suggesting neuroprotective effects of everything from vitamin C to ketamine... and because it's a *metabolite* that causes the damage, neuroprotection doesn't even necessarily mean that you don't get as high.
 
fairnymph:
d-MDMA is the isomer which accounts for most of the meth-like effects of racemic MDMA.
I'd agree, especially since it has higher affinity for dopamine receptors.
I also get the impression that the l- isomer produces most of the "lovey" effect of racemic MDMA.
Depends on what 'love' is =).. it's partly serotonin, partly dopamine. Now d-MDMA has a higher affinity for both of those... The only thing I can see making l-MDMA *more* lovey than the d-isomer is the greater affinity of the l-isomer for 5-HT1 and 5-HT2. But like I've said, that's not necessarily the actual mechanism in the brain.
It follows from what has been said above that d-MDMA probably releases most if not all of the dopamine released by racemic MDMA. Would l-MDMA then have little or no neurotoxicity?
The neurotoxicity is probably not caused by the release of dopamine itself (which is good, it would suck to get brain damage for being *really happy* for a few hours); most evidence suggests it's actually a metabolite.
The title of this article says it pretty well:
Shankaran, M. et al, Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT. Synapse (2001), 40(1), 55-64.
I actually could get this one (not just the abstract). Essentially it found that treating rats with vitamin C before giving them a neurotoxic regimen of MDMA causes no significant difference in serotonin levels relative to a control (meaning no damage), and MDMA alone reduces 5-HT by almost half. That should be enough; the article discusses how MDMA forms hydroxyl radicals and has potentially toxic metabolites. If vitamin C, an antioxidant, eliminates the damage, then it cannot be serotonin release itself that causes the damage to occur.
Since we know from those other articles that l-MDMA is metabolized more slowly, it follows that it would be less toxic, but it still *will* be toxic. All the metabolites will still be produced, just more slowly, and unless more vitamin C or E is introduced it will probably continue to do damage until it's excreted.
So for using MDMA as an anti-depressant, I doubt it. Clearly d-MDMA is not acceptable, and it's only about 3 times more neurotoxic than l-MDMA; over an extended period it would certainly cause damage. Another *major* problem with using MDMA as an antidepressant is that it is literally a pro-depressant: y'know the Trp hydroxylase inhibitor thing? Since it interferes directly with the synthesis of serotonin, not only could you not use MDMA as an antidepressant (except by a single life-changing experience), you could use it to *cause* depression in normal subjects.
I don't hear about pre- and post- loading much anymore; I think that goes along with a general decline in ravers' ages and intelligence. But there are studies suggesting neuroprotective effects of everything from vitamin C to ketamine... and because it's a *metabolite* that causes the damage, neuroprotection doesn't even necessarily mean that you don't get as high.
CuriousCub:
I could define some terms you need, if you want... most aren't that difficult, nowhere near as difficult as a textbook is gonna make it look, anyway.
 
What would I know about clandestine LSD manufacture? The last I heard that shit was illegal! I would find out for you cept I don't really care. I know meth & MDMA etc do not have a chiral centre so it is not logical tosay they are enantiomorphic. However I believe that is what the topic heading implies. Is meths mirror image somehow nonsuperimposable. And stop pratting about!
 
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