use of the more potent isomer to reduce toxic effects

[kidamnesiac]

Say one was going to ingest MDA. Normal doses is 100mg. Shulgin and others estimate the R- isomer to be "several" times more potent than the S- isomer. So in theory one could take ~30-50mg of the R- isomer to get the same effects.
Would this result in a lesser "fatigue'' (for lack of a full knowledge as to the permanent/precise effects of the MDX compounds) than if one took the racemic mixture?
Put another way, are the toxic effects related to the molecule and it's metabolites in the brain, or something further downstream that is mitigated by agonist/RUI/etc actions and the receptor cascades?
If the downstream scenario is the case, are the downstream effects dependent on the ratio isomers present?
If the molecules/metabolites are responsible, it would obviously better to be taking the more potent isomer, so that would be good for the 'ole noodle.

 

[nuke]

hmmm.

Effect of alpha-methyl epinine in neurotoxicity
Alpha-methyl epinine is one of the major microsomal metabolites of MDMA. Steele , et al. 1991 investigated the possible involvement of this compound in the serotonergic neurotoxicity attributed to MDMA. Brain microsomal fractions from mice and rats both produced similar amounts of the metabolite on incubation with MDMA. Rat liver microsomes produced a significantly greater amount of alpha-methyl epinine than did mouse liver microsomes. There was no evidence of stereoselectivity for the reaction, in contrast to the neurotoxicity, which is attributable primarily to the S(+) isomer of MDMA. Intracerebroventricular injection of alpha-methyl epinine resulted in no significant decline in biogenic amines or their metabolites one week later, indicating that this metabolite alone is not responsible for neurotoxicity.

http://www.erowid.org/chemicals/mdma/mdma_health1.shtml

Differential release of 5-HT/DA - correlation with neurotoxicity
McKenna, et al. 1991 investigated the effects of MDMA and a number of it structural congeners on the differential release of [3H]5-HT and [3H]DA from synaptosomal preparations. They reported that the release of [3H]5-HT induced by MDMA is partially blocked by 10-6 M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both [3H]5-HT and [3H]DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of [3H]5-HT than of [3H]DA. The hallucinogen DOM does not cause significant release of either [3H]monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using [3H]paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls.

http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=780

Fantegrossi WE, Woolverton WL, Kilbourn M, Sherman P, Yuan J, Hatzidimitriou G, Ricaurte GA, Woods JH, Winger G
Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys.
Neuropsychopharmacology. 2004 Jul;29(7):1270-81.
The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose-effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(-)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S+-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=PubMed&dopt=Abstract&list_uids=15039771

So the answer is possibly (not that MDMA is entirely comparable because the enantiomers are reversed and because it seemed to be more stereoselective as to pharmacological effect). I'm not entirely sure as to why this is at the moment. Kinda funny that the toxicity is specific to the s-isomers of both compounds, though in monkeys the r-isomer of MDMA produces greater desensitization.

 

[MattPsy]

That's because the (R) isomer is the better 5-HT2A agonist, and the (S) isomer is the one with most of the monoamine release + reuptake inhibition activity.

So yeah you could just take the (R) isomer of MDA, but you'll be getting mostly psychedelic effects, and little empathogenesis - which is consistent with a lower neurotoxicity, as we expect from mostly removing the empathogenic component

 

[nuke]

Maybe that's the reason the monkeys would be less likely to self-administer the R isomer after a while, if it were to be more psychedelic and less monoamine releasing. Does that hold true for MDMA, too?

S-methamphetamine is the more active enantiomer as well. Maybe someone should start working on a monoamine releasing SAR, what with all the stuff here about 5HT2A/C agonizing compound SARs.

 

[Adrenochrome]

I've heard that the best MDMA is the racemate

 

[MattPsy]

nuke: Nah, the relationship with MDMA is reversed - the (S) isomer is the more psychedelic one and and the (R) isomer is the more empathogenic one. But the differences between them are less pronounced than with MDA.
So yeah I would expect we would see a more pronounced decrease in self administration with the (S) isomer of MDMA, like what we see with (R)-MDA.

And yeah, I too have heard racemic MDMA is the best. Indeed, even Sasha said so. Even so, I would quite like to taste both isomers in isolation, just to see .

 

[Jamshyd]

To my knowledge, the "magic" of MDMA (or MDA if you think thats worth anything) is due to the synergy between the two isomers. If you wanted to take just one of them, then you might as well just take 2C-x or Amphetamine.

 

[nuke]

nuke: Nah, the relationship with MDMA is reversed - the (S) isomer is the more psychedelic one and and the (R) isomer is the more empathogenic one. But the differences between them are less pronounced than with MDA.
So yeah I would expect we would see a more pronounced decrease in self administration with the (S) isomer of MDMA, like what we see with (R)-MDA.

And yeah, I too have heard racemic MDMA is the best. Indeed, even Sasha said so. Even so, I would quite like to taste both isomers in isolation, just to see .

The difference in potency of the enantiomers of MDA vs. MDMA is greater in MDMA; I recall seeing this stated in one study on toxicity (I think, kinda trashed at the moment), and you can see in PiHKAL that r-MDMA has little effect even at 200mg (+1) while 160mg of s-MDA is rather potent and 120mg is a +1 (giving MDA's less potent enantiomer a little less than twice the potency of MDMA's).

But maybe I'm missing the point and you're saying 5HT2 agonism vs monoamine releasing ability of both enantiomers of MDMA vs MDA.

Are there any studies on this specifically?

edit:

This study investigates the effects of methylenedioxymethamphetamine (MDMA) and amphetamine on monoamine release from rat superfused brain slices in both the presence and absence of vesicular stores of transmitter. MDMA caused the release of radioactivity from slices incubated with [3H]5-hydroxytryptamine, [3H]noradrenaline or [3H]dopamine with EC50 values of 1.9 mol/l (95% confidence limits 1.5–2.3 mol/l), 4.5 mol/l (2.3–8.7 mol/l), and greater than 30 mol/l, respectively. In contrast, amphetamine (0.1–300 mol/l) was more effective in releasing radioactivity from slices incubated with [3H]dopamine than [3H]noradrenaline or [3H]5-hydroxytryptamine. When Ca2+ was excluded from the superfusion fluid, the MDMA induced release of radioactivity from slices incubated with [3H]dopamine was unaltered, but that from slices incubated with [3H]noradrenaline or [3H]5-hydroxytryptamine was enhanced. MDMA (10 mol/l) facilitated the stimulation-induced (5 Hz, 1 min) outflow of radioactivity from slices incubated with [3H]noradrenaline or [3H]5-hydroxytryptamine to 7.5-fold and 2.1-fold of control values, respectively, but had no effect on that from slices incubated with [3H]dopamine. Amphetamine (1 mol/l) increased the stimulation-induced outflow from slices incubated with [3H]noradrenaline, but not that from slices incubated with [3H]5-hydroxytryptamine or [3H]dopamine.

http://www.springerlink.com/content/m277237m6732484v/

There are some values for racemic MDMA's releasing ability... Interesting that the ratio of effect on 5HT:NE:DA release is about 1:3:15 for MDMA. Maybe the effect on NE release in the psychopharmaceutical effect of MDMA has been overlooked? (or maybe it's nothing) I'm very curious as to how this differs between different enantiomers of MDMA and MDA, and just the effect of racemic MDA itself if anyone has a source.

Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors.

Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA
Department of Psychiatry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-5000.

The effect of the R(-) and S(+) isomers of 3,4-methylenedioxyamphetamine (MDA) and its N-methyl analog 3,4-methylenedioxymethamphetamine (MDMA) on [3H]inositol monophosphate accumulation was studied in cells expressing either 5-HT2A or 5-HT2C receptors. The isomers of MDA produced a concentration dependent increase in phosphatidyl inositol (PI) hydrolysis at the 5-HT2A receptors, with the R(-) isomer of MDA being more potent than the S(+) at the 5-HT2A receptor. The R(-) and S(+) isomers of MDMA were significantly less efficacious at the 5-HT2A receptor as compared to MDA; S(+)MDMA had no effect. At the 5-HT2C receptor, both R(-) and S(+)MDA were equipotent at stimulating PI hydrolysis, with the S(+) isomer of MDMA being more efficacious at the 5-HT2C receptor compared with the R(-) isomer. In all cases at both the 5-HT2A and 5-HT2C receptors, the affinities of the isomers of MDMA and MDA were at least 2-3 orders of magnitude less than 5-HT. Despite the weak effect of these compounds at the 5-HT2A and 5-HT2C receptors, these substituted amphetamines do possess intrinsic activity which may contribute to their neurotoxic effects when administered at high doses.

http://www.ihop-net.org/UniPub/iHOP/pm/8211858.html?nr=2&pmid=7824160

This casts a pretty interesting picture of 5HT2 stimulation:

Inositol monophosphate accumulation at 5HT2 receptor subtypes
------------5HT2A---5HT2C
R-MDA----- ++ -------+
S-MDA----- + ---------+
R-MDMA---- - --------- -
S-MDMA----NE-------- +

++ = More effective
+ = Effective
- = Less Effective
NA = Not Effective

From Bilz0r a while ago:

According to Nash et al., Neurosci Letters 177:111-115, the EC50 of the amphetamines for 5-HT2a mediated inositol turnover is (in uM):

(-)MDMA: 3.1
(+)MDMA 10.3
(-)MDA 5.6
(+)MDA 18.2

But that is very misleading, because they stopped assaying at concentrations over 1mM. You see, the Vmax (effacacy) for the MDMA(-/+) isomers were 21 and 9% respectively, while the effacacy for the MDA(-/+) isomers were 95 and 89% respectively.

Still, that probably means that the effect at these receptors is negligable, because the EC50 (or affinity) for the SERT and DAT is in the nanomolar range.

The fact is that racemic MDA has an EC50 for 5-HT2a activation (assuming species homology) some 1000x lower than its EC50 for 5-HT release.

I don't know whether it is particularly more hallucinogenic, Speedy, yes, hallucinogenic is news to me, not that I'm disagreeing. My point isn't that it isn't more hallucinogenic, just that if it is, it can't be attributed to direct 5-HT2a agonism.

5HT release at 5HT2 receptors could cause hallucinogenic effects in and of itself, but I don't know?

 

[Morninggloryseed]

As a subjective aside, I've tried S-MDMA many times and it is no where near as 'magical' as the racemate. As mentioned above...the magic is from a combination of the two. I would not doubt the same is said of MDA.