MDE enantomer effects and toxicity

[Sturnam]

I recently came across a study listed on MAPS about MDE. It was about the subjective effects of the R and S enantomers, as well how the fMRI imaging of each.

As far as subjective effects, they found that:

Taken together, the (S)-enantiomer produced the entactogenic subjective effects of increased talkativeness, openness, and elevated mood whereas the (R)-enantiomer mainly caused dysphoria and somatic complaints.

Anyways, the point of their study was that the S enantomer was mainly responsible for the empathogenic effects, and R was responsible for the neurotoxic effects.

With respect to the neurotoxic effects of substituted
amphetamines, our data favour the (R)-enantiomer as a
possible candidate for the following reasons. This
enantiomer acts upon visual cortical areas into which the
5-HT system preferentially projects. This is in line with a
previous single-photon emission computed tomography
study demonstrating 5-HT related effects to be promi-
nent in the visual cortex of abstinent MDMA users
(Chang et al., 2000). In addition, the (R)-enantiomer
affects cortical areas relevant for carrying out those cog-
nitive functions that have been found to be impaired after
excessive abuse of MDMA, possibly by causing 5-HT
depletion after increased activity of these regions.
Finally, the approximately three-fold plasma concen-
trations of (R)-MDE alone would render this enantiomer
as the likely candidate for any neurotoxic effects.
Together with the differential psychological effects of
the agent, this suggests that any future medical appli-
cations of MDE within the framework of psychothera-
peutic interventions should make use of the (S)-enanti-
omer only.

Does anyone know of any other studies of this nature, maybe on MDMA? I'm also interested in how the S enantomer of MDMA differs subjectively from the racemate. There are only a few reports in PiHKAL, and the only other thing I could find with some brief searching was Shulgin saying that neither isomer produced the magic.

Is it possible that the R-MDxx preferentially turns into toxic metabolites, or creates ROS?

Oh, and here's the source for that article:
Spitzer M, Franke B, Walter H, Buechler J, Wunderlich AP, Schwab M, Kovar K, Hermle L, Gron G (2001) Enantio-selective cognitive and brain activation effects of N-ethyl-3,4-methylenedioxyamphetamine in humans. Neuropharmacology 41: 263-71.

edit::
Found a study dealing with the different isomers of both MDA and MDMA. Unfortunately they use detro/levo to describe their results, and I'm not completely sure how to translate D/L into R/S, so if someone knows which is which, it would be a big help in interpreting these studies. However, they say that D-MDA is more stimulative, which leads to believe that it's the same as S-MDA. Can anyone confirm this?

Anyways, on to results:
- D-MDA has more of an effect on neurotransmitters than L-MDA, but this is lost at high doses
- D-MDMA has more of an effect on neurotransmitters, but only at high doses
- L-MDMA is more potent than D-MDMA at decreasing neostriatal 5-HT concentrations 3h after a single dose
- they hypothesize that both D-MDA and D-MDMA induce greater changes associated with neurotoxic properties

M Johnson, AA Letter, K Merchant, GR Hanson, and JW Gibb (1998). Effects of 3,4-methylenedioxyamphetamine and 3,4- methylenedioxymethamphetamine isomers on central serotonergic, dopaminergic and nigral neurotensin systems of the rat
J Pharmacol Exp. Ther. 244: 977-982.

 

[pofacedhoe]

the effects of the s and r are farrrrrrrrrrrr more different for mda than mdma. one is a chatechloamine releaser the other a 5ht1a tippy effect. anyone who can clarify my messy point (i'm experiencing mania so my head is a confused errection vivisection!)go for it!!!!!!!!!!!!!!!!!!!!!!!!!!!!11

 

[tryp2fun]

Pharmacol Biochem Behav. 2008 Jan;88:318-31. Epub 2007 Sep 14.
MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice.
Young R, Glennon RA.

Department of Medicinal Chemistry, School of Pharmacy, Box 980540, Virginia Commonwealth University, Richmond, VA 23298, USA.

Racemic MDMA (0.3-30 mg/kg), S(+)-MDMA (0.3-30 mg/kg), R(-)-MDMA (0.3-50 mg/kg) and saline vehicle (10 ml/kg) were comprehensively evaluated in fully automated and computer-integrated activity chambers, which were designed for mice, and provided a detailed analysis of the frequency, location, and/or duration of 18 different activities. The results indicated that MDMA and its isomers produced stimulation of motor actions, with S(+)-MDMA and (+/-)-MDMA usually being more potent than R(-)-MDMA in measures such as movement (time, distance, velocity), margin distance, rotation (clockwise and counterclockwise), and retraced activities. Interestingly, racemic MDMA appeared to exert a greater than expected potency and/or an enhanced effect on measures such as movement episodes, center actions (entries and distance), clockwise rotations, and jumps; actions that might be explained by additive or synergistic (i.e. potentiation) effects of the stereoisomers. In other measures, the enantiomers displayed different effects: S(+)-MDMA produced a preference to induce counterclockwise (versus clockwise) rotations, and each isomer exerted a different profile of effect on vertical activities and jumps. Furthermore, each isomer of MDMA appeared to attenuate the effect of its opposite enantiomer on some behaviors; antagonism effects that were surmised from a lack of expected activities by racemic MDMA. S(+)-MDMA (but not R(-)-MDMA), for example, produced an increase in vertical entries (rearing) and a preference to increase counterclockwise (versus clockwise) rotations; (+/-)-MDMA also should have induced such effects but did not. Apparently, R(-)-MDMA, when combined with S(+)-MDMA to form (+/-)-MDMA, prevented the appearance of those increases (from control) in activities. Similarly, R(-)-MDMA (but not S(+)-MDMA) produced increases in episodes (i.e. jumps) and vertical distance that racemic MDMA also should have, but were not, exhibited. Evidently, the presence of S(+)-MDMA in the racemic mixture inhibited the appearance of those increases (from control) in behavior. Taken together, the various and complex effects of MDMA and its stereoisomers are noted and a strategy is suggested for future studies that stresses the importance of steric effects and interplay, probable interaction(s) with various neurotransmitters, and interaction(s) with the particular behavioral or biological event (or action) being measured.

The situtation is complicated, as the paper from Glennon above shows. The activity of the racemate of MDMA clearly is not the sum of the activities of the separated enantiomers. As Shulgin says in Pihkal, the most active enantiomer of MDMA is the S, while for psychedelics like DOM it is the R.

 

[Rectify]

That's great and everything, but the question is about (S) and (R) N-ethyl-MDA [Eve].

 

[Sturnam]

^ I asked about the other MDxx's at the end too. Looking through articles, it seemed as if the consensus was that S(+) was actually more neurotoxic for MDMA, which was sorta let-down. It also made me wonder if MDE is actually different, or if they didn't get an accurate measure of neurotoxicity.

I also saw something interesting about how when racemic MDMA breaks down, there are measurable levels of the S(+)-MDA metabolite, but only trace amounts of R(-)-MDA. This S(+)-MDA metabolite is obviously neurotoxic, where they hypothesized that R(-)-MDA metabolized quickly into some other nontoxic compounds. So it seems as if stereoselective metabolism might be responsible for part of the neurotoxic effects, and so MD analogues without this chiral center may be overall less neurotoxic.

Oh, and does anyone know which MDxx analogues don't have a chiral center? I'm still not very good with my organic chemistry.

 

[hugo24]

"Oh, and does anyone know which MDxx analogues don't have a chiral center? I'm still not very good with my organic chemistry."

The only compound (besides the phentermine analogs) coming to my mind is MDAI because its symmetric.