In this randomized, double-blind study (n=5) the MDMA like drug (S)-MDE and (R)-MDE were tested for their effect on mood, cognition and brain activity.

Abstract

“In a randomised double-blind trial the subjective, neuropsychological and brain activation effects of the two enantiomers of the MDMA (ecstasy-) like drug N-ethyl-3,4-methylenedioxyamphetamine (MDE) were studied in five normal subjects using functional magnetic resonance imaging (fMRI). (S)-MDE produced elevated mood, impairments in conceptually driven cognition and marked right frontal activation. In contrast, (R)-MDE produced increased depression, enhanced visual feature processing, and activation of visual cortical and left frontal areas. Plasma concentrations were higher for the (R)-enantiomer. The so-called entactogenic effects of MDE are likely to be caused by the (S)-enantiomer, whereas (R)-MDE appears to be responsible for neurotoxic effects.”

Authors: Manfred Spitzer, Beate Franke, Henrik Walter, Jochen Buechler, Arthur P. Wunderlich, Matthias Schwab, Karl-Artur Kovar, Leo Hermle & Georg Grön

Summary

The subjective, neuropsychological and brain activation effects of the two enantiomers of the MDMA (ecstasy-) like drug N-ethyl-3,4-methylenedioxyamphetamine were studied in five normal subjects using functional magnetic resonance imaging.

MDMA is neurotoxic.

Substituted amphetamine derivatives induce subjective effects that are different from classic hallucinogens such as lysergic acid diethylamide (LSD) and stimulants such as amphetamine. These effects can be studied in unprecedented detail in human subjects using cognitive neuroscience and functional brain imaging.

MDMA and MDE share a similar acute psychoactive profile, but MDE is less neurotoxic than MDMA and has been shown to have enantiomer-specific effects in mice. We used functional magnetic resonance imaging (fMRI) during a language and a perceptual task, in addition to neuropsychological tests and subjective rating scales, to study these effects.

The mood-elevating effects of (S)-MDE may be caused by dopaminergic projections to the frontal cortex, while (R)-MDE may cause visual hallucinogenic effects. We used standard neuropsychological paradigms and adapted semantic and perceptual paradigms for use in the MR scanner.

To assess early and automatic visual processes, controlled conceptual thought processes, and perceptual effects of MDE enantiomers on higher cognition, a visual popout search task, a Wisconsin Card Sorting Test, and a colour and a semantic discrimination task were used.

The study was carried out on five healthy young male physicians, all of which were right-handed. They gave written informed consent prior to the study.

A fixed dose of 70 mg MDE hydrochloride (59 mg base) was given to each subject in a randomised double-blind design. Blood samples were collected 10 min, 20 min, 30 min, 60 min, 90 min, 2 h, 4 h, 6 h, 10 h, 12 h, 14 h, 24 h, 30 h, and 34 h after drug intake.

The priming tasks consisted of four conditions: directly associated, indirectly associated, non-associated words and pseudo-words. Reaction times were measured by a PC, and differences in reaction times between pre- and post-drug measurements were calculated for the non-pseudo word conditions.

Four self-rating psychopathometric scales were used: the Depression Scale (DS), the Actual Subjective Mental State Scale (BfS), the list of Somatic Complaints (BL) and the Altered States of Consciousness (OAV). The difference scores between the (R)- and (S)-enantiomer were computed by Wilcoxon tests for paired samples.

Data were acquired using a 1.5 Tesla Magnetom VISION whole-body MRI system equipped with a head volume coil. T2*-weighted functional MR images were obtained using echo-planar imaging in axial orientation (TE=50 ms), and T2-weighted structural MRI images were coregistered to the mean image of the realigned volumes. The fMRI protocol was a block design, with each activation epoch lasting 21 s. Images were globally scaled to 100 and low frequency drifts were removed via a high pass filter.

The task consisted of making decisions on the similarity of 120 word pairs and 120 pairs of asterisks, with 40 trials for each of the three categories. The test was split into two half forms with an equal number of conditions, trials and task difficulty. The subjects controlled the presentation of stimuli, and the intertrial interval was set to 150 ms. The stimulation protocol was realised by means of Experimental Run Time System (ERTS) on a standard personal computer, and responses were given by button press.

Functional MRI data showed that (R)-MDE caused significant activation of right visual and left frontal areas, whereas (S)-MDE caused activation of right frontal and bilateral temporoparietal areas.

The (R)-enantiomer of MDE activates visual areas, thereby facilitating bottom-up driven information processing, as indicated by facilitating parallel visual search. This is consistent with the fact that people in bad mood prefer systematic strategies, whereas people in good mood prefer heuristic problem-solving strategies.

Although the hallucinogenic activity of MDE may be caused by its (R)-enantiomer, our subjects did not report prominent positive visual non-object bound phenomena. This is consistent with the view that higher doses of (R)-MDE may cause hallucinatory effects in humans.

The (S)-enantiomer has an emotional effect and a negative effect on cognition. It increases right frontal areas, which are responsible for remote associations, and decreases ability to consider contextual cues.

The data clearly demonstrate that the (R)-enantiomer of (MDE) has different neuropsychological effects from the (S)-enantiomer, and repetition effects can be ruled out because the sequence of drug application was balanced over sessions.

The (R)-enantiomer of substituted amphetamines is the likely candidate for any neurotoxic effects, because it affects visual cortical areas into which the 5-HT system preferentially projects, and because it causes 5-HT depletion after increased activity of these regions.

In conclusion, this study links the pharmacological study of psychoactive agents and neuromodulatory systems with the neuropsychology of specific cognitive functions and with brain activation by cognitively defined paradigms.