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    D-methamphetamine/L-methamphetamine effects 
    #1
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    I thought any methamphetamine based substance all did the following; raise blood pressure, alertness,causes the heart to beat rapidly...
    But i recently read
    that only D-methamphetamine (the most pure, crystal)makes the brain more alert but **has little effect on the heart and blood pressure**
    and L-methamphetamine raises blood pressure and causes the heart to beat rapidly, but does not increase alertness very much.
    Is this accurate? Why does d-meth have little to do with physical effects?
    -
    Last edited by Strawberry Cub Muffin; 23-03-2005 at 14:14.
     

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    #2
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    Yeah, this is accurate in a rough sense. Although this shouldn't be taken to mean that the physical effects of l-meth are necessarily stronger than the physical effects of d-meth. Basically, d-meth has both significant physical and mental effects while l-meth has practically insignificant mental effects. This sort of thing is typically caused by the differences in interactions of the drug molecules with some recptor protein as a result of the different three dimensional structures of the isomers. So in general, you would expect the stereoisomers of a drug to have differing effects; it just happens that meth produces the results it does.
    I'm not sure if they know precisely why this difference exists for meth. The difference is large enough that l-meth is actually available over the counter as the primary ingredient in Vicks Inhalers (sometimes listed as "levmetamfetamine" or "l-desoxyephedrine").
    One odd thing about this whole thing is that mentally the effects of a mixture of l- and d-meth are different from the effects of d-meth alone. This also holds true for amphetamine, and this is why, for instance, Dexedrine (d-amphetamine) does not just feel like a stronger version of Adderall (a mixture of l- and d-amphetamine) on a mg for mg basis.
    Incidentally, meth sold on the street as "pure" doesn't necessarily mean pure d-meth. There are various ways of synthesizing meth, and some of them produce pure d-meth while others produce a 50:50 mixture. The typical purification procedures will not remove l-meth from the product. Actually separating the two is a pretty tedious process and would probably be a waste of time and money for a clandestine chemist. The most common synths used these days (i.e. starting from pseudoephedrine) does only produce the d-form though.
     

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    #3
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    the 50:50 mixture (a 'racemic mixture' or sometimes just 'racemate') is produced by a synthesis from starting materials that were once widely available, but are now highly controlled. btw, the L-isomer and D-isomer are "enantiomers", meaning a stereochemical or optical difference exists between them.
    the difference occurs because receptors in the body are almost always specific to a certain enantiomer (because they are proteins, constructed entirely from L-amino acids). D-methamphetamine affects primarily affects receptors in the dopamine system, which is in the brain and related to pleasure. L-methamphetamine is not active in the brain, because it can't bind to those receptors, but it *can* bind to receptors in the body, primarily the adrenergic system. the adrenergic system (the sympathetic autonomous nervous system, the one dependent on adrenaline) is responsible for all the effects of an adrenaline rush: increased heart rate, dilated pupils, dry mouth, and so on.
    it would seem that D-meth would be twice as strong as DL-meth, therefore twice as 'good', but apparently the tweakers who've done both usually prefer DL-meth. they may have had to do more, but it's actually logical if you think about it; L-meth would produce a strong body buzz in addition to the subtler mental effects of D-meth.
    there is really no need to resolve the enantiomers, since neither is harmful. it is not a particularly difficult process. in fact, the classic example of resolution of enantiomers involves amphetamine (with tartaric acid). which means i sat through a lecture on how to do it. the professor insinuated that illegal drug manufacturers may want to resolve enantiomers for a better product, but i suspect the resolution of amphetamine was primarily used to isolate dextroamphetamine (a useful stimulant) from levoamphetamine (which mainly just increases heart rate). this would have been useful since the synthetic pathway to racemic amphetamine (Benzedrine) is much easier than a direct pathway to dextroamphetamine (Dexedrine).
    names
    there are tons of naming systems for optical isomerism:
    D- = (+)- = dextro-
    L- = (-)- = levo-
    DL- = ()- (racemic mixture)
    the symbols are preferred the letters because there are also d/l- and small capital D-/L- systems which are totally different. a small capital D- compound might be capital L- or (-)-. and then there's R/S-, which is the modern system based on structure.
     

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    #4
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    yah that comment about resolution was probably misleading. I was thinking back to my own experience with this last semester when I tried to separate the enantiomers of racemic alpha-phenylethylamine. The process relies on the small difference in solubilities of the diastereomeric tartrate salts in some chosen solvent. So it was a pain in the butt and my results were disheartening.
    Anyway, Roches, since you seem to understand the pharmacology of amps to some extent, maybe you can answer a question i've been thinking about. I have some experience with amphetamine (racemic) taken orally, nasally and iv, and i've noticed something weird. Going along with the two types of effects discussed above, I've found that the mental effects are strongest orally and weakest iv, and the physical effects follow the reverse order. Any idea why this happens? Maybe it's just me, i dunno.
     

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    #5
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    no, it's definitely true.
    i'm not entirely sure why. even D-meth probably does have some effect on the adrenaline system as well as the dopamine system since the two are closely related. i'll assume that meth causes the release of adrenaline, in the same way that ephedrine does, and (if i remember correctly) prevents the uptake of dopamine.
    if that's true, then shooting it or smoking it would probably concentrate the adrenergic effects in the early part of the trip, because absorption is so much faster. in other words, your adrenergic system would quickly be flooded with meth and you'd have a massive adrenaline release. but adrenaline can be metabolized fairly rapidly, so with oral D-meth the effects on the adrenaline system might be stretched out over a long time so as to be hardly noticable.
    the mental effects may follow along the same lines, but it may also be that the physical effects are just outweighing the mental effects, but still there. even so, since smoking/shooting meth is apparently to be highly euphoric, i'd say the mental effects are still quite pronounced.
    that's all hypothetical though.
     

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    #6
    Bluelighter fairnymph's Avatar
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    I know this isn't really the right forum for this question, but it relates to the topic of enantiomers.
    Which enatiomer is the one commonly called MDMA, and what is the effect of the other enantiomer? How do the effects of the two enantiomers differ?
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    I suspect that the overwhelming majority of MDMA available on the street is the racemic mixture of l-MDMA and d-MDMA.
    I think I remember reading somewhere that the synthesis procedures are non-stereospecific.
    Interesting question though...I wonder what the mental/physical differences would be if one were to take JUST l-MDMA as opposed to JUST d-MDMA?
    - Citrus
     

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    #8
    Bluelighter fairnymph's Avatar
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    yeah Citrus...ever since I learned about enantiomers and isomers in chemistry last month, I've been DYING to know whether the l and d forms of MDMA differ, and how.
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    #9
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    the substance commonly called MDMA is a racemic mixture of d-MDMA and l-MDMA. (probably all syntheses will result in an entantiomeric product.)
    d-MDMA and d-methamphetamine are actually the S- enantiomers. they rotate polarized light to the right, but if you assign their structural isomerism (this is somewhat complicated) they're "left-handed", in a way (actually more like "counterclockwise"). weird, but it happens; d/l- and R/S- aren't related. anyway they are both called MDMA; *sometimes* enantiomers have different names (like ephedrine and pseudoephedrine) but it's not common.
    effects: with meth, the relationship is fairly clear-cut, but MDMA gets interesting. the S isomer (d-MDMA) is more potent, but the R isomer (l-MDMA) still does something, and tihkal even says that d-MDMA 'lacks the fire of the racemate'.
    that's all here: http://www.erowid.org/library/books_...ihkal109.shtml
     

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    #10
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    An organic chemist once told me that one of the MDMA isomers is speedier, and the other is more psychedelic. I'm not sure which one's which, though.
     

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    #11
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    shulgin doesn't comment on the psychological effects of the optically pure isomers, just the racemate. the R isomer (l-MDMA) he says does almost nothing. the S isomer caused various effects, including all of the amphetamine-like ones like teeth clenching and raised blood pressure.
    what you said is true of methamphetamine, but MDMA works on the serotonergic system, not dopamine, and you can't really expect the same effects, although there are both somatic and cerebral serotonin systems.
     

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    #12
    Thumbs up
    This is why OD forum is shits better than those other hug and snuggle forums. Thumbs ups on educating yourself and us on such indepth matters
     

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    #13
    Bluelighter fairnymph's Avatar
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    So, Roches, you would imagine that pure d-MDMA would be stronger than l-MDMA? Or would pure d-MDMA be TOO speedy/strong?
    Also, if Shulgin says that l-MDMA does almost nothing...then why wouldn't he have been curious to try to isolate pure d-MDMA? It seems very strange to me that NO ONE has tried to isolate each enantiomer and study the effects.
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    #14
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    Resolving enantiomers is important for morethan one reason. However from the point of phychedelics it is probably more balanced just to have an R,S mixture. If one sucessfully brews their own ephedrine though only d-meth will be the product because of the specificity of enzymes (they are very fussy).
     

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    #15
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    fairnymph, at the link i posted he actually describes the effects at different doses of the racemate and both the d- and l- isomers (he refers to them by their "S" and "R" labels, respectively; remember they're reversed)
    look above.. he says that d-MDMA "lacks the fire of the racemate"... pure d-MDMA would definitely be better than pure l-MDMA, but evidently the racemate is the best way to go. there's probably some perfect blend; no idea what it would be.
    since you always end up with a racemate, if you separate the d- isomer because it's 'more potent', all you end up doing is throwing the l- isomer away, even though it *does something*. i mean, look at his descriptions... even at very low doses, with the racemate he's always amazed, blown away, classical MDMA experiences. with the pure enantiomers he's more like "Some jaw clenching, no nystagmus." that's from 120 mg of the d- isomer; if you assume, incorrectly, that the l- isomer does nothing, that would be equivalent to 240 mg of racemic mdma, and he doesn't even *try* that much (he's not a raver, yknow).
    it's quite possible that the receptor binding profiles of the enantiomers are very different, and somehow the full experience only occurs if both isomers are present (like two drugs in one...). there are many 5HT receptor types, and shulgin points out that the fact that MDMA and MDA are not cross-tolerant suggests THEY work at different receptors, so why not the enantiomers too?
    ronald: i'm not sure about clandestine LSD, but wasn't sandoz's Delysid enantiomerically pure d-lysergic acid diethylamide tartrate? when they made acid illegal, everyone apparently said that delysid was way better or at least subtly different because it was 'natural'... maybe it was the stereochemistry?
    as for your last part... the stereospecificity of enzymes almost makes me surprised that the whole concept of a drug is even possible. but it's not the enzyme that *makes* it d-meth... you're still working with a compound that's already '2S-N-methylamino'. the two starting materials are chiral at their 1-carbon too. the product is not. the synthesis eliminates a chiral center and produces d-meth in all cases.
     

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    #16
    Bluelighter fairnymph's Avatar
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    Roches - I didn't realize there was more about the isomers in the link you provided. I went and read it, and it pretty much answered my questions (although I'm still quite curious about the exact effects and mechanism of l-MDMA/the R isomer). Thanks so much!
    ------------------
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    [This message has been edited by fairnymph (edited 21 May 2001).]
     

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    #17
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    so i looked it up=)
    these are some of the things i found. with references, in case you feel like looking them up (heh... *i* don't, but i had to do it to look all hardcore.)
    there is nothing at all here about any kind of behavioral study in humans; the search didn't cover it. it *did* cover chemical abstracts and medline over the entire history of interest in MDMA.
    note:
    d-MDMA = S(+)-MDMA
    l-MDMA = R(-)-MDMA
    - racemic and d-MDMA inhibit A10 dopamine neurons, but l-MDMA does not (Gifford et al., Synapse 23(1) (1996))
    - d-MDMA is eliminated from rats faster than l-MDMA (Fitzgerald et al., Chirality (1990))
    - MDMA undergoes N-demethylation to form MDA in rats; this may be an active metabolite. levels of MDA formed were 3 times higher for d-MDMA than l-MDMA. [this means that the d-isomer has greater affinity for the enzyme that demethylates it, as well as the 5ht receptor] (Cho et al., Drug. Metab. Dispos. (1990))
    - d-MDMA inhibits serotonin nerve firing 2 to 3 times better than l-MDMA (Sprouse et al, Eur. J. Pharmacol. (1989) 167(3))
    one about MDA:
    - R(-)-MDA (l-MDA) is MORE potent than S(+)-MDA (d-MDA). however, l-MDA and l-MDMA both have *higher* affinity for 5HT1 and 5HT2 serotonin receptors than d-MDA and d-MDMA. this means that, since we know that d-MDMA *is* more potent in a living system, d-MDMA does not work directly on serotonin receptors (and later research seems to have supported this) (Lyon et al, Psychopharmacology (1986) 84))
    one more thing i found:
    MDMA (irreversibly) and meth (reversibly) both inhibit tryptophan hydroxylase, the enzyme that catalyzes the rate-limiting step in the synthesis of serotonin:
    Trp ('TP') --Trp hydroxylase--> 5-HTP --> 5-HT (serotonin)
    it's the same 5-htp. so yeah, if someone in here doesn't think 5-htp works...
     

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    #18
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    - racemic and d-MDMA inhibit A10 dopamine neurons, but l-MDMA does not (Gifford et al.,
    Synapse 23(1) (1996))
    This means that d-MDMA causes a dopamine rush and l-MDMA doesn't?
    - d-MDMA is eliminated from rats faster than l-MDMA (Fitzgerald et al., Chirality (1990))
    So if one took pure d-MDMA, would the high be shorter than with a racemic mixture?
    - MDMA undergoes N-demethylation to form MDA in rats; this may be an active metabolite.
    levels of MDA formed were 3 times higher for d-MDMA than l-MDMA. [this means that the
    d-isomer has greater affinity for the enzyme that demethylates it, as well as the 5ht receptor](Cho et al., Drug. Metab. Dispos. (1990))
    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?
    - d-MDMA inhibits serotonin nerve firing 2 to 3 times better than l-MDMA (Sprouse et al, Eur. J.Pharmacol. (1989) 167(3))
    What does this mean? That there is less or more serotonin??
    one about MDA:- R(-)-MDA (l-MDA) is MORE potent than S(+)-MDA (d-MDA). however, l-MDA and l-MDMA both have *higher* affinity for 5HT1 and 5HT2 serotonin receptors than d-MDA and d-MDMA. this means that, since we know that d-MDMA *is* more potent in a living system, d-MDMA does not work directly on serotonin receptors (and later research seems to have supported this)(Lyon et al, Psychopharmacology (1986) 84))
    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)? And if d-MDMA doesn't work directly on serotonin receptors, how and to what degree does it work on them?
    one more thing i found: MDMA (irreversibly) and meth (reversibly) both inhibit tryptophan hydroxylase, the enzyme that catalyzes the rate-limiting step in the synthesis of serotonin:
    Trp ('TP') --Trp hydroxylase--> 5-HTP --> 5-HT (serotonin)
    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)? Does this mean permanently? And if Trp h. catalyzes a "rate-limiting step", does that mean the reaction goes FASTER or SLOWER in the absence of Trp h. ?
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    Bluelighter fairnymph's Avatar
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    Back again.
    Thanks Roches for digging up that information for me. I'm sorry if I have so many questions - I have a decent understanding of neurochemistry and organic chemistry but I haven't come across some of the terminology. These topics interest me immensely and thus I'm extremely curious to find out more.
    Another question/thought:
    It seems to me from what you've explained above that d-MDMA is the isomer which accounts for most of the meth-like effects of racemic MDMA. I also get the impression that the l- isomer produces most of the "lovey" effect of racemic MDMA. MDMA is primarily neurotoxic because of dopamine release, and thus is less neurotoxic than MDA or meth, which cause more dopamine release. 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 reason I wonder about this is there could be possible therapeutic applications of l-MDMA if the above is true. Could l-MDMA act as an antidepressant of sorts, without substantial side effects? Has anyone ever looked into this before?
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    bump?
     

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    #21
    Talking
    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..
     

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    #22
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    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).]
     

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    #23
    Bluelighter fairnymph's Avatar
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    Thanks Roches! I really appreciate all the clarification, it all makes sense now. Thanks again.
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    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.
     

  25. Collapse Details
     
    #25
    Post
    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.
     

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