Spitzer M, Franke B, Walter H, Buechler J, Wunderlich AP, Schwab M, Kovar KA, Hermle L, Gron G. (2001) Enantio-selective cognitive and brain activation effects of N-ethyl-3,4-methylenedioxyamphetamine in humans. Neuropharmacology 41:263-271.

The effects of MDE enantiomers on regional blood flow, information processing, executive function and subjective experience were compared in five healthy male physicians free of major mental illness or drug abuse. All subjects received placebo, 70 mg R-(-)-MDE (59 mg base), and 70 mg S-(+)-MDE (59 mg base) in a randomized, double-blind study. Brain imaging was done with functional magnetic resonance imaging (fMRI), while participants performed several tasks. These included visual "pop out" search for one differently oriented line among a group of lines, indicating the similarity (directly related, indirectly related, unrelated) of word pairs or arrays of colored objects, and a simplified version of the Wisconsin Card Sort Test (WCST), a measure of executive function. Subjective effects were measured via the von Zerssen Depression Scale (DS), the Actual Subjective Mental State scale, consisting of 28 semantic differential (paired opposite words) items, the Altered States of Consciousness (ASC) and the List of Somatic Complaints (BL). Serum concentrations of each enantiomer were measured immediately after drug administration, and at 20, 30, 60, 90 minutes and at 2, 4, 6, 10, 12, 14, 24, 30 and 34 hours after drug administration. R-(-)-MDE produced activation of the right visual and left frontal areas during the word and object pair association task, while S-(+)-MDE produced right frontal and bilateral temporoparietal activation during the pair association task. R-(-)-MDE was associated with a slightly longer time for correctly identifying indirectly associated pairs, and S-(+)-MDE was associated with more rapid response to indirectly associated pairs, potentially suggesting activation of a more remote association network after the S enantiomer. Participants had shorter visual search times after R-(-)-MDE than at pre-drug or after S-(+)-MDE, and participants took significantly longer to switch sorting when appropriate ("switch costs") with the WCST after S-(+)-MDE than at pre-drug or . People reported elevated mood after S-(+)-MDE, decreased self-reported depression and elevated ASC "oceanic boundlessness" (positive altered state) scores compared to placebo. Participants reported increased depression after R-(-)-MDE, and they had a greater number of somatic complaints than after S-(+)-MDE, as well as lower ASC "oceanic boundlessness" scores. Participants were more talkative, open and exhibited elevated mood after S-(+)-MDE. Though R-(-)-MDE and S-(+)-MDE had relatively similar peak activity times (measured in serum), of 2.61 +/- 0.58 for S-(+)-MDE and 2.76 +/- 0.94 for R-(-)-MDE, the two had somewhat different half-lives (4.18 +/- 1.44 for S-(+)-MDE and 7.45 +/- 2.38 for R-(-)-MDE, and markedly different levels of clearance, with R-(-)-MDE having a larger area under curve (AUC) and more R-(-)-MDE in plasma over time (S-(+)-MDE AUC = 535.41 +/- 262.51 versus R-(-)-MDE AUC of 1706.81 +/- 340.16. Study findings suggest that the two enantiomers of MDE affect brain activity and task performance differently, and that R-(-)-MDE is not just a less active form of the substance, but produces different effects. R-(-)-MDE is also apparently metabolized less rapidly than S-(+)-MDE, though both share similar peak times in plasma.

Though at least two pharmacokinetic studies of MDMA enantiomers exist (e.g. Fallon et al. 1999; Hensley and Cody 1999), there are no formal investigations that compare subjective effects, brain activity, physiological effects or cognitive task performance across the two enantiomers. Hence this study using MDE is the closest approximation we have to a behavioral study of MDMA enantiomers. Previous informal reports (Anderson and Shulgin 1978) have suggested that there is a synergistic effect between R-(-)-MDMA and S-(+)-MDMA when administered together as a racemate. However, this study does not provide comparisons with a racemic mixture of MDE. MDMA is nearly always taken as a racemic mixture, both in non-medical and in medical settings.

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